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Using non-steroidal anti-inflammatory drugs in the treatment of depression. Incidence of sexual side effects in refractory depression during treatment with citalopram or paroxetine. Randomized double-blind comparison of serotonergic (Citalopram) versus noradrenergic (Reboxetine) reuptake inhibitors in outpatients with somatoform, DSM-IV-TR pain disorder. Efficacy of intravenous citalopram compared with oral citalopram for severe depression. Safety and efficacy data from a double-blind, double-dummy trial. Does comorbid substance use disorder impair recovery from major depression with SSRI treatment? An analysis of the STAR*D level one treatment outcomes. 5-HTTLPR modulates antidepressant efficacy in depressed women Comparison of moclobemide with selective serotonin reuptake inhibitors (SSRIs) on sexual function in depressed adults Notes on the use of fluvoxamine as treatment of depression in HIV-1-infected subjects. 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World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders – First Revision Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition. Treatment of Post-Myocardial Infarction Depressive Disorder: A Randomized, Placebo-Controlled Trial With Mirtazapine Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. The Alpha 2A-Adrenergic Receptor Gene Polymorphism Modifies Antidepressant Responses to Milnacipran Clinical and Neurobiological Effects of Tianeptine and Paroxetine in Major Depression [Evaluation of analgesic action of fluvoxamine compared with efficacy of imipramine and tramadol for treatment of sciatica--open trial]. Fluoxetine, but not Tricyclic Antidepressants, Potentiates the 5-Hydroxytryptophan-Mediated Increase in Plasma Cortisol and Prolactin Secretion in Subjects with Major Depression or with Obsessive Compulsive Disorder Serotonin transporter gene polymorphism and antidepressant response Start of a selective serotonin reuptake inhibitor (SSRI) and increase of antiparkinsonian drug treatment in patients on levodopa. Compliance with antidepressant medication in the treatment of major depressive disorder in primary care: a randomized comparison of fluoxetine and a tricyclic antidepressant. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Efficacy of venlafaxine in major depression resistant to selective serotonin reuptake inhibitors Safety and Tolerability of Dexmecamylamine (TC-5214) Adjunct to Ongoing Antidepressant Therapy in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy: Results of a Long-Term Study Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. II. Psychotherapy alone or in combination with antidepressant medication. Costs and outcomes of use of amitriptyline, citalopram and fluoxetine in major depression: exploratory study. Different gender response to serotonergic and noradrenergic antidepressants. A comparative study of the efficacy of citalopram and reboxetine. The diagnosis and treatment of generalized anxiety disorder. Paroxetine versus nortriptyline in the continuation and maintenance treatment of depression in the elderly. Factors contributing to the increasing placebo response in antidepressant trials. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Differential actions of antidepressant treatments on cardiac autonomic alterations in depression: A prospective comparison. 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A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. Nine-month predictors and outcomes of SSRI antidepressant continuation in primary care. Effectiveness and acceptability of sertraline and citalopram in major depressive disorder: pragmatic randomized open-label comparison. Trajectories of depression severity in clinical trials of duloxetine: insights into antidepressant and placebo responses. Escitalopram maintenance treatment for prevention of recurrent depression: a randomized, placebo-controlled trial. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Effects of Zinc Supplementation in Patients with Major Depression: A Randomized Clinical Trial TREAD: TReatment with Exercise Augmentation for Depression: study rationale and design Patterns and predictors of remission, response and recovery in major depression treated with fluoxetine or nortriptyline. Selecting among second-step antidepressant medication monotherapies: predictive value of clinical, demographic, or first-step treatment features. Serotonergic and Noradrenergic Modulation of Emotion Processing by Single Dose Antidepressants A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. Danish University Antidepressant Group. Venlafaxine extended release versus citalopram in patients with depression unresponsive to a selective serotonin reuptake inhibitor Antidepressant Class, Age, and the Risk of Deliberate Self-Harm: A Propensity Score Matched Cohort Study of SSRI and SNRI Users in the USA Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants. Treatment of depression in patients with breast cancer: a comparison between paroxetine and amitriptyline Further evidence of a combined effect of SERTPR and TPH on SSRIs response in mood disorders Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. Venlafaxine extended release versus conventional antidepressants in the remission of depressive disorders after previous antidepressant failure: ARGOS study. Onset and Early Behavioral Effects of Pharmacologically Different Antidepressants and Placebo in Depression Male Sexual Side Effects Associated with Antidepressants: A Descriptive Clinical Study of 32 Patients A double-blind comparison of sertraline and fluoxetine in depressed elderly outpatients. Citalopram treatment of paroxetine-intolerant depressed patients. Diminished Neural Processing of Aversive and Rewarding Stimuli During Selective Serotonin Reuptake Inhibitor Treatment Pharmacokinetically and clinician-determined adherence to an antidepressant regimen and clinical outcome in the TORDIA trial. Effect of a single dose of citalopram on amygdala response to emotional faces Suicide and self-harm following prescription of SSRIs and other antidepressants: confounding by indication. Paroxetine versus placebo: a double-blind comparison in depressed patients. Direct Cost of Depression: Analysis of Treatment Costs of Paroxetine versus Imipramine in Canada Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study A cluster randomized trial comparing two interventions to improve treatment of major depression in primary care. A controlled trial of antidepressants in patients with Parkinson disease and depression Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial. Remission with venlafaxine extended release or selective serotonin reuptake inhibitors in depressed patients: a randomized, open-label study. Does fetal exposure to SSRIs or maternal depression impact infant growth? Gender differences in the efficacy of fluoxetine and maprotiline in depressed patients: a double-blind trial of antidepressants with serotonergic or norepinephrinergic reuptake inhibition profile Evaluation of the Prophylactic Efficacy of Amitriptyline and Citalopram, Alone or in Combination, in Patients with Comorbidity of Depression, Migraine, and Tension-Type Headache Effect of nortriptyline and paroxetine on extrapyramidal signs and symptoms: A prospective double-blind study in depressed elderly patients. Differential effects of trimipramine and fluoxetine on sleep in geriatric depression. A critical examination of the sensitivity of unidimensional subscales derived from the Hamilton Depression Rating Scale to antidepressant drug effects. 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Depression is one of the most common psychiatric disturbances in Parkinson 's disease ( PD ) . Recent review s have highlighted the lack of controlled trials and the ensuing difficulty in formulating recommendations for antidepressant use in PD . We sought to establish whether antidepressants provide real benefits and whether tricyclic and selective serotonin reuptake inhibitor ( SSRI ) antidepressants differ in their short-term efficacy , because the time to onset of therapeutic benefit remains an important criterion in depression . The short-term efficacy ( after 14 and 30 days ) of two antidepressants ( desipramine , a predominantly noradrenergic reuptake inhibitor tricyclic and citalopram , a SSRI ) was assessed in a double-blind , r and omized , placebo- controlled study of 48 nondemented PD patients suffering from major depression . After 14 days , desipramine prompted an improvement in the Montgomery Asberg Depression Rating Scale ( MADRS ) score , compared with citalopram and placebo . Both antidepressants produced significant improvements in the MADRS score after 30 days . Mild adverse events were twice as frequent in the desipramine group as in the other groups . A predominantly noradrenergic tricyclic antidepressant induced a more intense short-term effect on parkinsonian depression than did an SSRI . However , desipramine 's lower tolerability may outweigh its slight short-term clinical advantage The objective of this study was to compare efficacy and tolerability of the selective noradrenalin reuptake inhibitor reboxetine with the selective serotonin reuptake inhibitor citalopram , in the treatment of major depressive disorder ( MDD ) . In total , 357 out patients with MDD were r and omized to treatment with reboxetine 8 - 10 mg or citalopram 20 - 40 mg per day during 24 weeks . Primary end-point was change from baseline in the Hamilton Depression Rating Scale ( HAM-D , 21 items ) . Sexual function/dysfunction was measured by the Sexual Function scale ( SF ) . Observed case analysis showed that both treatments yielded a gradual reduction of HAM-D scores : reboxetine with -21.4 and citalopram with -22.1 points ( NS ) . LOCF analysis showed a greater reduction of the HAM-D scores with citalopram compared with reboxetine ( -19.6 vs. -17.8 ; P = 0.034 ) . The response rate was 90.3 % for reboxetine and 92.7 % for citalopram ( NS ) . The most common side effect in the reboxetine group was dry mouth , and in the citalopram group sexual dysfunction . At week 24 , anorgasmia was reported by 5.9 % of the sexually active women in the reboxetine group vs 39 % in the citalopram group . The  dropout number  was 91 in the  reboxetine group , and 54 in the citalopram group . To summarize , both treatments gave a satisfactory antidepressant effect . The side effect profile differed between the groups , with a notably high prevalence of sexual dysfunctions in the citalopram group . The high number of dropouts in the reboxetine group , is considered as a result of the non-titration starting dose of 8 mg reboxetine per day , which gave a high incidence of early side-effects .  Depressive disorders including major depression ( MDD ) is very common , with a lifetime prevalence of at least 15 % in men and 25 % in women.1,2 Depression can be treated effectively by a range of antidepressant agents . Recent review s have suggested that the selective serotonin reuptake inhibitors ( SSRIs ) offer equal efficacy to the older antidepressant agents , such as tricyclic antidepressants , with the advantage of greater tolerability.3 - 5 Other review ers have reported that non-SSRI antidepressants , such as clomipramine , have been found to be significantly more effective than fluoxetine for the treatment of patients with severe depression.6  Reboxetine ( reboxetine mesylate , Edronax ; Pfizer , New York ) is a highly selective noradrenaline reuptake inhibitor , and the efficacy of reboxetine has been independently demonstrated in multiple r and omized , double-blind , placebo-controlled studies .7 - 9 In addition to improvements in depressive symptoms , treatment-associated improvements in social behavior ( measured using the Social Adaptation Self-evaluation Scale [SASS]),10 were noticed in one of these studies .8 In this study , reboxetine was statistically and clinical ly superior to both placebo and fluoxetine in improving social functioning . The primary objective of the current study was to assess efficacy and tolerability of reboxetine  in comparison with those of citalopram ( Cipramil ; H. Lundbeck , Copenhagen , Denmark ) in patients with MDD .  Citalopram is a highly SSRI . The antidepressant mechanism is presumed to be a result of stimulation of serotonergic neurotransmission in the central nervous system as a consequence of higher serotonin levels result ing from inhibition of the serotonin transporter . The therapeutic efficacy of citalopram in patients with MDD has been investigated in several placebo-controlled studies and in long-term and extension studies .11 The underlying rationale for this comparison was to study 2 different drug profiles , 1 drug being pure " adrenergic " and the other pure " serotonergic . " A secondary objective was to analyze the correlation between the types of depression ( ie , degree of melancholia and the efficacy of the 2 drugs ) Abstract Objectives . Evidence in favour of switching between selective serotonin reuptake inhibitor ( SSRI ) and tricyclic ( TCA ) antidepressants in treatment resistant depression has been tested in a few studies only , consequently a prospect i ve study was undertaken to evaluate the impact of switching strategies . Methods . One hundred eighty-nine patients who failed to respond to a previous antidepressant were r and omised to four arms : firstly they received citalopram or desipramine for a 4-week period ; secondly , those who failed to respond were treated for a further 4-week period with the same antidepressant ( citalopram-citalopram and desipramine-desipramine arms ) or switched to the alternate one ( citalopram-desipramine and desipramine-citalopram arms ) . Results . There was no difference in the first 4-week phase between patients receiving citalopram versus desipramine in Hamilton Rating Scale for Depression ( HRSD ) , Montgomery – Asberg Depression Rating Scale ( MADRS ) , and Clinical Global Impression ( CGI ) scores . In the second 4-week phase remitter rates were higher among non-switched patients ( P = 0.04 ) . Moreover , considering HRSD and MADRS , switched patients reported significantly higher scores ( P ≤ 0.02 for both scales at each time-point ) . Conclusions . This study supports the thesis that switching from an SSRI to a TCA ( and vice versa ) in non-responders to a 4-week trial of an SSRI/TCA is not associated with improved response . The result goes in the opposite direction to that predicted by current guidelines OBJECTIVES Depression in older patients contributes to personal suffering and family disruption and increases disability , medical morbidity , mortality , suicide risk , and healthcare utilization . The majority of clinical trials of antidepressant treatments are conducted in younger patients . For this reason , clinicians often have to extrapolate from studies in population s that do not present the same problems as older patients . For example , older patients often have serious coexisting medical conditions that may contribute to the depression and complicate the choice of treatment . Older patients as a rule need to be on many medications , some of which may contribute to depression and /or interact with antidepressants . Finally , older adults metabolize medications slowly and are more sensitive to side effects than younger patients . Because of these complexities , we conducted a consensus survey of expert opinion on the pharmacotherapy of depressive disorders in older patients to address clinical questions not definitively answered in the research literature . METHOD After review ing the literature and convening a work group of experts , we prepared a written survey with 64 questions that asked about 857 options . 618 of the options were scored using a modified version of the R AND 9-point scale for rating appropriateness of medical decisions . For the other options , the experts were asked to write in answers ( e.g. , average doses ) or to check a box to indicate their preferred answer . We sent the survey to 50 national experts on geriatric depression , all of whom completed it . Consensus on each option was defined as a nonr and om distribution of scores by chi-square " goodness-of-fit " test . We assigned a categorical rank ( first line/preferred choice , second line/alternate choice , third line/usually inappropriate ) to each option based on the 95 % confidence interval around the mean rating . Guideline tables indicating preferred treatment strategies were then developed for key clinical situations . RESULTS The expert panel reached consensus on 89 % of the options rated on the 9-point scale . The experts stress the importance of identifying coexisting medical conditions that may be contributing to the depression or complicate treatment . For unipolar nonpsychotic major depression , the preferred strategy is an antidepressant ( selective serotonin reuptake inhibitor [ SSRI ] or venlafaxine XR preferred ) plus psychotherapy . For unipolar psychotic major depression , the treatment of choice is an antidepressant ( SSRI or venlafaxine XR ) plus one of the newer atypical antipsychotics . Electroconvulsive therapy is also first line . For dysthymic disorder or persistent milder depression , the experts recommend combining an antidepressant ( SSRIs preferred ) and psychotherapy . If the patient has a comorbid medical condition ( e.g. , hypothyroidism ) that is contributing to the depression , the experts recommend treating both the depression and the medical condition from the outset . The SSRIs were the top-rated antidepressants for all types of depression . Among them , the experts gave the highest ratings for efficacy and tolerability to citalopram and sertraline . Paroxetine was another first-line option , and fluoxetine was rated high second line . The preferred psychotherapy techniques for treating depression in older patients are cognitive-behavioral therapy , supportive psychotherapy , problem-solving psychotherapy , and interpersonal psychotherapy . The experts also give strong support to including appropriate psychosocial interventions ( e.g. , psychoeducation , family counseling , visiting nurse services ) in the treatment program . The majority of experts would continue treatment with antidepressant medication for at least 1 year if a patient has had a single episode of severe unipolar major depression , for 1 - 3 years for a patient who has had 2 such episodes , and for longer than 3 years if there is a history of 3 or more episodes . CONCLUSIONS The experts reached a high level of consensus on the appropriateness of including both antidepressant medication , specifically SSRIs , and nonpharmacological modalities in treatment plans for severe depression . Within the limits of expert opinion and with the expectation that future research data will take precedence , these guidelines provide direction for addressing common clinical dilemmas in older individuals . They can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions . Nonetheless , the guidelines can not address the complexities involved in the care of each individual patient and can be most helpful in the h and s of experienced clinicians BACKGROUND Previous comparative studies of the selective serotonin reuptake inhibitors ( SSRIs ) have rarely included a placebo control group and have rarely demonstrated significant between-group differences . The study reported on here was a placebo-controlled comparison of the antidepressant effects of two SSRIs , citalopram and sertraline . METHODS Three hundred twenty-three patients with DSM-IV-defined major depressive disorder were r and omized to 24 weeks of double-blind treatment with citalopram ( 20 - 60 mg/day ) , sertraline ( 50 - 150 mg/day ) , or a placebo . The primary efficacy measure was the Hamilton Depression Rating Scale ( HAMD ) and the primary statistical analysis was an analysis of variance comparing the change from baseline to the last observation carried forward in each treatment group . RESULTS Both citalopram and sertraline produced significantly greater improvement than placebo on the HAMD , the Montgomery-Asberg Depression Rating Scale , and the Clinical Global Impression Scale . Significant improvement was observed at earlier timepoints in the citalopram group than the sertraline group ; however , sertraline treatment was associated with increased gastrointestinal side effects and a tendency toward early discontinuation , and analyses that excluded early dropouts revealed similar acute efficacy for the two active treatments . The Hamilton Anxiety Scale demonstrated a significant anxiolytic effect of citalopram , but not sertraline , relative to placebo . CONCLUSIONS This study confirms the antidepressant efficacy of two SSRIs , citalopram and sertraline . It is hypothesized that the more consistent evidence of antidepressant activity that was observed early in treatment in the citalopram group was related to more pronounced antianxiety effects and better tolerability upon initiation of therapy The enhanced sensitivity of the elderly to the side effects produced by tricyclic antidepressants ( TCAs ) , and the frequency and type of adverse events , have made the treatment of depression in this group difficult . The selective serotonin reuptake inhibitors ( SSRIs ) have been reported to produce significantly fewer undesirable side effects and display better tolerance than TCAs . We compared the therapeutic actions and side effects produced by citalopram , the most selective SSRI available , with amitriptyline in a group of elderly patients ( aged 65 and older ) diagnosed with major depression . In a double-blind , double-dummy , parallel-group , multicenter comparison of citalopram ( 20 or 40 mg/day ) and amitriptyline ( 50 or 100 mg/day ) , patients who did not respond to placebo during a 1-week single-blind phase were r and omly assigned to receive citalopram or amitriptyline for 8 weeks . Efficacy measures included the Montgomery-Asberg Depression Rating Scale ( MADRS ) , the Hamilton Depression Scale ( HAMD ) , and Clinical Global Impressions . Both drug treatments produced equivalent time-related declines in severity of depression , so that by 8 weeks slightly more than 50 % of the patients in each group experienced marked recovery , defined as MADRS scores < or = 12 . Amitriptyline produced a greater overall incidence of adverse events , including a significantly higher ( P < 0.001 ) percentage of patients reporting dry mouth ( 34 % vs. 7 % ) , as well as a significantly higher ( P < 0.02 ) incidence of somnolence . Constipation and fatigue also occurred more frequently in the amitriptyline than in the citalopram group . For only one event ( nausea ) did the citalopram group report a significantly greater ( P = 0.012 ) incidence ( 12.8 % vs. 4.8 % ) . On the basis of these results , it was concluded that citalopram is as effective an antidepressant as amitriptyline in the treatment of the depressed elderly . Because of its low incidence and low magnitude of side effects , citalopram seems especially useful in private practice Rationale and objective Depression is a significant complication of stroke . The effectiveness of antidepressant drugs in the management of post-stroke depression ( PSD ) has been widely investigated . However , the choice of antidepressant drug is critically influenced by its safety and tolerability and by its effect on concurrent pathologies . Here we investigate the efficacy and safety of a selective serotonin reuptake inhibitor ( SSRI ) , citalopram , and a noradrenaline reuptake inhibitor ( NARI ) , reboxetine , in post-stroke patients affected by anxious depression or retarded depression . Methods This was a r and omized double-blind study . Seventy-four post-stroke depressed patients were diagnosed as affected by anxious or retarded depression by using a synoptic table . R and omisation was planned so that 50 % of the patients in each subgroup were assigned for 16 weeks to treatment with citalopram and the remaining 50 % were assigned to treatment with reboxetine . The Beck Depression Inventory ( BDI ) , the Hamilton Depression Rating Scale ( HDRS ) and a synoptic table were used to score depressive symptoms . Results Both citalopram and reboxetine showed good safety and tolerability . Citalopram exhibited greater efficacy in anxious depressed patients , while reboxetine was more effective in retarded depressed patients . Conclusions Citalopram or other SSRIs and reboxetine may be of first choice treatment in PSD because of their good efficacy and lack of severe side effects . In addition , PSD patients should be classified according to their clinical profile ( similarly to patients affected by primary depression ) for the selection of SSRIs or reboxetine as drugs of choice in particular subgroups of patients BACKGROUND Antidepressants exhibit a variety of pharmacological actions including inhibition of the serotonin and noradrenaline transporters . We wished to investigate whether genetic variation could be used to target or personalise treatment , in a comparison of selective serotonin reuptake inhibitors ( SSRIs ) with noradrenaline reuptake inhibitors ( NARIs ) . AIMS To test the hypothesis that patients homozygous for the long ( insertion ) polymorphism of the serotonin transporter ( 5-HTTLPR ) have an increased response to SSRI antidepressants but not to NARI antidepressants . METHOD In an individually r and omised , parallel-group controlled trial , people meeting criteria for a depressive episode who were referred by their general practitioner were r and omised to receive either citalopram ( an SSRI ) or reboxetine ( an NARI ) . R and omisation was by means of a remote automated system accessed by telephone . The main outcome was depressive symptoms , measured by Beck Depression Inventory ( BDI ) total score 6 weeks after r and omisation . The trial was registered with the International St and ard R and omised Controlled Trials Number registry ( IS RCT N31345163 ) . RESULTS Altogether 298 participants were r and omised to receive citalopram and 303 were r and omised to reboxetine . At 6 weeks follow-up , complete data were available for 258 participants taking citalopram and 262 taking reboxetine . We found no evidence to support an influence of 5-HTTLPR on outcome following antidepressant treatment . The interaction term for BDI score at 6 weeks was 0.50 ( 95 % CI -2.04 to 3.03 , P = 0.70 ) , which indicated that responses to the SSRI and NARI were similar irrespective of 5-HTTLPR genotype . CONCLUSIONS It is unlikely that the 5-HTTLPR polymorphism alone will be clinical ly useful in predicting response to antidepressants in people with depression BACKGROUND clinicians have long noticed a correlation between physiological markers of inflammation and depression . The best-known example is the activation of the hypothalamus-pituitary-adrenal axis and cortisol secretion ; however more recent studies have demonstrated increased salivary prostagl and ins and plasma acute phase proteins in depressed patients . To date four r and omised controlled trials have used celecoxib or rofecoxib as adjuncts to serotonin selective reuptake inhibitors in the treatment of depression . These suggested a statistically significant decrease in depressive symptoms in the patients taking NSAIDs and SSRIs , compared to patients taking SSRIs alone . Interpretation of these results is limited by the small sample size and short duration of these preliminary studies . The research only considers depressed patients receiving treatment in secondary care ; no study has examined the effectiveness of NSAIDs as an adjunct in primary care , even though most cases of depression in the UK are managed in the community by general practitioners . PROPOSAL we propose a multi-centre double-blinded r and omised controlled trial with two objectives : to determine whether citalopram plus celecoxib dual therapy achieves a greater reduction in depressive symptoms ( quantified using the Hamilton Depression Rating Scale ( HDRS ) ) within four weeks , compared to citalopram monotherapy ; and to determine whether citalopram plus celecoxib dual therapy is more likely to achieve remission ( HDRS score ? 7 ) of moderate to severe depression within six months , compared with citalopram monotherapy . The endpoints will be the reduction in HDRS score after 4 weeks of treatment , and the HDRS score after 26 weeks of treatment . The study will enrol 452 participants from general practice s who have a moderate or severe , current or recurrent major depressive episode when medication with an SSRI is considered . The study population will be stratified according to age , sex , HDRS score , age of onset of first episode , number of previous depressive episodes and duration of current episode . The population will then be r and omised into two groups . Subjects will be interviewed to determine HDRS score , measure blood pressure , count pills and discuss side-effects . This will occur weekly for the first four weeks , and every four weeks thereafter OBJECTIVE The incidence of  sexual dysfunction  due to antidepressant drugs reported in pre-marketing clinical efficacy trials is often several times lower than in subsequent clinical experiences and independent reports . Although it is commonly believed that the reason for this discrepancy is that the nonleading questions employed in conventional clinical trials underestimate sexual dysfunction while the direct question ing used in independent trials provides more accurate data , few studies have actually compared these 2 methods . METHOD In this study , 119 patients with a DSM-IV-defined major depressive episode ( 82 women and 37 men ) who had been treated with but not responded to a selective serotonin reuptake inhibitor ( SSRI ; either citalopram or paroxetine )  were assessed regarding sexual functioning by means of open-ended questions and direct question ing at baseline ( after SSRI treatment only ) and after 4 weeks of SSRI treatment plus buspirone or placebo . RESULTS More patients reported sexual dysfunction in response to direct question ing ( 41 % ) as compared with spontaneous report ( 6 % ) ( p < .001 ) . Sexual dysfunction correlated with the duration of the depressive episode , but not with age , dose of SSRI , plasma level of SSRI , duration of SSRI treatment , or any measurement of depression . No statistically significant differences regarding the incidence of sexual dysfunction were found between the citalopram and the paroxetine groups . CONCLUSION Open-ended questions are an insufficient tool to estimate sexual dysfunction , and premarketing clinical trials should therefore include basic explicit assessment s. The failure to find a correlation between treatment duration and sexual dysfunction adds to the notion that sexual side effects due to SSRIs do not abate over time OBJECTIVES Whether the effect of tricyclic antidepressants on Pain Disorder arises from their noradrenergic or serotonergic actions or both remains unclear . We compared the selective serotonin reuptake inhibitor ( SSRI ) citalopram and the noradrenergic reuptake inhibitor ( NARI ) reboxetine in out patients with Pain Disorder . We also distinguished the drugs ' analgesic and antidepressant effects . METHODS In this 8-week , r and omized double-blind study , 35 patients with a DSM-IV-TR diagnosis of Pain Disorder were r and omly assigned to receive either citalopram 40 mg/day ( N=17 patients ) or reboxetine 8 mg/day ( N=18 ) . The  Present Pain Intensity ( PPI ) scale and the Total Pain Rating Index ( tPRI ) of the McGill Pain Question naire were used to measure the effect on pain symptoms . Changes in the Zung Self-Rating Depression Scale ( Zung-D ) scores were evaluated to monitor a possible antidepressant effect . For all patients who had at least one assessment , an intent-to-treat analysis was performed . RESULTS No significant differences were found in the demographic variables or clinical characteristics of the two treatment groups . In the citalopram group , PPI and tPRI scores measured at baseline decreased after treatment ( tPRI : 41.9 vs. 30.0 , p=.004 ; PPI : 3.5 vs. 2.8 , p=.045 ) whereas in the reboxetine group differences were not statistically significant ( tPRI : 35.2 vs. 31.5 ; PPI : 3.7 vs. 3.1 ) . The Zung-D showed no significant changes between baseline and endpoint assessment in either group . CONCLUSIONS Our study suggests that the SSRI citalopram may have a moderate analgesic effect in patients with Pain Disorder , and that this analgesic activity appears to be not correlated to changes in depressive scores . If confirmed in a larger sample , this evidence suggests that patients who are intolerant or resistant to tricyclic antidepressants , may be treated with SSRIs BACKGROUND Intravenous administration is often beneficial in the treatment of severely depressed patients . It is mainly the tri- and tetracyclic antidepressant drugs that can be administered intravenously . However , these drugs have a less favourable safety profile than newer antidepressants , such as the selective serotonin reuptake inhibitors ( SSRIs ) . Citalopram is the only SSRI that is available in a formulation for infusion . This double-blind , r and omised , multicentre trial was design ed to compare the efficacy and tolerability of citalopram infusion ( 40 mg per day ) and citalopram tablet ( 40 mg per day ) . METHODS Patients were r and omised to receive either placebo tablet plus citalopram infusion ( the infusion group ; n=135 ) or citalopram tablet plus placebo infusion ( the tablet group ; n=119 ) . After receiving r and omised treatment for eight days , all patients entered an open treatment phase , during which they received oral citalopram 40 mg per day for five weeks . RESULTS Although there was no difference in Montgomery-Asberg Depression Rating Scale ( MADRS ) scores at the end of the r and omised treatment period , by the end of the open treatment phase the reduction in MADRS scores was significantly greater in the infusion group than in the tablet group ( p=0.015 ) . The infusion group also showed superior efficacy in Clinical Global Impressions assessment s. Citalopram was equally well tolerated in both treatment groups . CONCLUSIONS This trial confirmed the efficacy of citalopram 40 mg per day , and clearly supports the use of citalopram infusion in the treatment of severely depressed , hospitalised patients Many patients with major depressive disorder ( MDD ) present with concurrent substance use disorders ( SUDs ) , which has been thought to impair their response to antidepressants . Clinicians often delay antidepressant treatment until sustained sobriety has been established . Unfortunately , these comorbid subjects are typically excluded from depression treatment trials , leaving a gap in underst and ing the treatment outcomes . In the Sequenced Treatment Alternatives to Relieve Depression ( STAR*D ) study , 2876 adult out patients diagnosed with nonpsychotic MDD were prospect ively treated with the selective serotonin-reuptake inhibitor ( SSRI ) , citalopram , and returned for at least one post-baseline visit .  Participants with SUD ( 29 % ) and without SUD ( 71 % ) were compared in regard to baseline clinical and sociodemographic features and treatment response . The group with MDD and SUD was further subdivided into those with alcohol only , drug only , and both alcohol and drug use . Despite clear sociodemographic and clinical differences , there were no significant differences between groups in the time to achieve response or rates of response to citalopram ;  however , those who endorsed both alcohol and drug use had significantly reduced rates of remission and significantly increased times to reach remission compared to the MDD group without SUD . In addition , subjects with MDD and SUD had higher risk of psychiatric serious adverse events ( 3.3 % vs. 1.5 % ) and hospitalization ( 2.8 % vs. 1.2 % ) . The results indicate that first-line treatment with citalopram in depressed patients with alcohol or drug use respond as well as those without SUD . More intensive treatment is most likely needed for MDD patients with both drug and alcohol use disorders Background As compared with the long variant ( L ) , the short variant ( S ) of the functional polymorphic region of the serotonin transporter gene ( 5-HTTLPR ) has been associated with a lower antidepressant efficacy in major depression , but some replication studies have evidence d contradictory results . Sex differences may explain these contradictory results . Methods One hundred and three in patients ( 74 women and 29 men ) with a major depressive episode were assessed prospect ively for antidepressant efficacy after 4 weeks of treatment with selective serotonin reuptake inhibitors ( SSRI ) and non-SSRI drugs . Results As compared with LL/LS , the SS genotype of the 5-HTTLPR was associated with a lower antidepressant efficacy in depressed women ( 79 vs. 50 % responders , P = 0.035 ) . This result was shown with both SSRI and non-SSRI antidepressants . The logistic regression performed in women showed that response to treatment was related to genotype ( odds ratio=0.15 ; 95 % confidence interval=0.03–0.85 ; P = 0.03 ) and not to other variables . No effect of 5-HTTLPR was found in depressed men . Conclusion Despite a low power , this study suggests a significant effect of 5-HTTLPR genotype on antidepressant efficacy in depressed women but not in men , with both SSRI and non-SSRI drugs . Further research is needed to confirm this result and investigate its underlying mechanisms OBJECTIVE To compare the emergent sexual effects of moclobemide and selective serotonin reuptake inhibitors ( SSRIs ) during acute and maintenance therapy in routine practice . METHOD 268 patients were evaluated for sexual function  at baseline , 6 weeks , 3 and 6 months of treatment using physician ratings and self-rating question naires . Patients received moclobemide , an reversible monoamine oxidase A inhibitor ( RIMA ) , or a SSRI ( fluoxetine , fluvoxamine , paroxetine , sertraline ) . RESULTS Baseline values were similar in all groups . Incidences of impairments of sexual functioning with treatment , whether clinical ly relevant or not , were 24.3 % with moclobemide and 61.5 % with SSRIs ( physician ratings ) , with no significant tolerance to these effects . There was a suggestion of differences between the SSRIs in their specific dysfunctions they cause . SSRIs ( 21.6 % of patients ) had about ten times the moclobemide rate ( 1.9 % ) of sexual dysfunction reported as adverse events . Antidepressant efficacy was comparable between treatments . CONCLUSION In patients for whom sexual function  is important or sexual dysfunction  is present , moclobemide should be considered a first line antidepressant Fluvoxamine belongs to the class of selective serotonin reuptake inhibitors ( SSRIs ) which have recently gained large popularity as antidepressant agents essentially because they lack the most troublesome adverse effects of older antidepressants ( i.e. tricyclic antidepressants ) such as anticholinergic effects and cardiotoxicity . Recent studies in the literature suggest that HIV-1 infected subjects are affected by depressive episodes with a relatively high frequency , often requiring an antidepressant treatment . Due to its favorable adverse effects profile , we used fluvoxamine as first line treatment for sixteen depressed HIV-1 infected subjects . They were administered the drug at a daily dosage of 100 mg in the evening . Fluvoxamine provided a good clinical efficacy for six of these patients , whereas the other ten had to discontinue the drug because of the presence of severe adverse effects such as acute total insomnia , gastro-intestinal disturbances together with anorexia , aggressive and impulsive behavior and excessive sedation . The observed fluvoxamine side-effects are not typical or specific for this particular patient group since they are also described in seronegative subjects taking fluvoxamine ; however , our findings seem to indicate that they become more frequent and more severe when the drug is administered to HIV-1 infected patients OBJECTIVE To determine the relative cost-effectiveness of three classes of antidepressants : tricyclic antidepressants ( TCAs ) , selective serotonin reuptake inhibitors ( SSRIs ) , and the modified TCA lofepramine , as first choice treatments for depression in primary care . DESIGN Open , pragmatic , controlled trial with three r and omised arms and one preference arm . Patients were followed up for 12 months . SETTING UK primary care : 73 practice s in urban and rural areas in Engl and . PARTICIPANTS Patients with a new episode of depressive illness according to GP diagnosis . INTERVENTIONS Patients were r and omised to receive a TCA ( amitriptyline , dothiepin or imipramine ) , an SSRI ( fluoxetine , sertraline or paroxetine ) or lofepramine . Patients or GPs were able to choose an alternative treatment if preferred . MAIN OUTCOME MEASURES At baseline the Clinical Interview Schedule , Revised ( CIS-R PROQSY computerised version ) was administered to establish symptom profiles . Outcome measures over the 12-month follow-up included the Hospital Anxiety and Depression Scale self-rating of depression ( HAD-D ) , CIS-R , EuroQol ( EQ-5D ) for quality of life , Short Form ( SF-36 ) for generic health status , and patient and practice records of use of health and social services . The primary effectiveness outcome was the number of depression-free weeks ( HAD-D less than 8 , with interpolation of intervening values ) and the primary cost outcome total direct NHS costs . Quality -adjusted life-years ( QALYs ) were used as the outcome measure in a secondary analysis . Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were computed . Estimates were bootstrapped with 5000 replications . RESULTS In total , 327 patients were r and omised . Follow-up rates were 68 % at 3 months and 52 % at 1 year . Linear regression analysis revealed no significant differences between groups in number of depression-free weeks when adjusted for baseline HAD-D. A higher proportion of patients r and omised to TCAs entered the preference arm than those allocated to the other choices . Switching to another class of antidepressant in the first few weeks of treatment occurred significantly more often in the lofepramine arm and less in the preference arm . There were no significant differences between arms in mean cost per depression-free week . For values placed on an additional QALY of over 5000 pounds , treatment with SSRIs was likely to be the most cost-effective strategy .  TCAs were the least likely to be cost-effective as first choice of antidepressant for most values of a depression-free week or QALY respectively , but these differences were relatively modest . CONCLUSIONS When comparing the different treatment options , no significant differences were found in outcomes or costs within the sample , but when outcomes and costs were analysed together , the result ing cost-effectiveness acceptability curves suggested that SSRIs were likely to be the most cost-effective option , although the probability of this did not rise above 0.6 . Choosing lofepramine is likely to lead to a greater proportion of patients switching treatment in the first few weeks . Further research is still needed on the management of depressive illness in primary care . This should address areas such as the optimum severity threshold at which medication should be used ; the feasibility and effectiveness of adopting structured depression management programmes in the UK context ; the importance of factors such as physical co-morbidity and recent life events in GPs ' prescribing decisions ; alternative ways of collecting data ; and the factors that give rise to many patients being reluctant to accept medication and discontinue treatment early BACKGROUND The cost-effectiveness of tricyclic antidepressants ( TCAs ) and selective serotonin reuptake inhibitors ( SSRIs ) has not been compared in a prospect i ve study in primary care . AIMS To determine the relative cost-effectiveness of TCAs , SSRIs and lofepramine in UK primary care . METHOD An open-label , three-arm r and omised trial with a preference arm . Practitioners referred 327 patients with incident depression . RESULTS No significant differences were found in effectiveness or cost-effectiveness . The numbers of depression-free weeks over 12 months ( on the Hospital Anxiety and Depression Scale ) were 25.3 ( 95 % CI 21.3 - 29.0 ) for TCAs , 28.3 ( 95 % CI 24.3 - 32.2 ) for SSRIs and 24.6 ( 95 % CI 20.6 - 28.9 ) for lofepramine .  Mean health service costs per patient were pound 762 ( 95 % CI 553 - 1059 ) for TCAs , pound 875 ( 95 % CI 675 - 1355 ) for SSRIs and pound 867 ( 95 % CI 634 - 1521 ) for lofepramine .  Cost-effectiveness acceptability curves suggested SSRIs were most cost-effective ( with a probability of up to 0.6 ) . CONCLUSIONS The findings support a policy of recommending SSRIs as first-choice antidepressants in primary care BACKGROUND Antidepressant prescribing is widespread . Nonetheless , response to antidepressants is variable . If it was possible to predict response to medication and thus tailor treatment accordingly , this would not only improve patient outcomes but may also have economic benefits . AIMS To test the hypothesis that individuals with more severe depression would benefit more from noradrenaline reuptake inhibitors ( NARIs ) than selective serotonin reuptake inhibitors ( SSRIs ) compared with individuals with less severe depression . METHOD Individuals recruited from UK primary care who met ICD-10 criteria for a depressive episode and scored 15 or more on the Beck Depression Inventory ( BDI ) were r and  omised to either an SSRI ( citalopram 20 mg daily ) or a NARI ( reboxetine 4 mg twice daily ) . R and omisation was by means of a remote automated telephone system . The main outcome was depressive symptoms measured by the BDI total score 6 weeks after r and omisation . ( TRIAL REGISTRATION IS RCT N31345163 . ) RESULTS In total , 601 participants were r and omised  ( citalopram : n = 298 , reboxetine : n = 303 ) . Ninety-one per cent were followed up at 6 weeks ( citalopram : n = 274 , reboxetine : n = 272 ) . There was little evidence to support an interaction between treatment and severity of depression ( interaction term : 0.02 , 95 % CI -0.59 to 0.62 , P = 0.96 ) . Adjustment for potential confounders ( age , gender , employment status , history of depression , number of life events and social support ) did not affect the findings ( interaction term : 0.06 , 95 % CI -0.54 to 0.66 , P = 0.85 ) . CONCLUSIONS Treatment with NARIs does not confer any advantage over SSRI treatment for outcome in those with more severe depressive illness presenting in primary care Background The most effective pharmacological treatments for depression inhibit the transporters that reuptake serotonin ( Selective Serotonin Reuptake Inhibitors – SSRIs ) and noradrenaline ( Noradrenaline Reuptake Inhibitors – NaRIs ) into the presynaptic terminal . There is evidence to suggest that noradrenaline and serotonin enhancing drugs work through separate mechanisms to produce their clinical antidepressant action . Although most of the current evidence suggests there is little difference in overall efficacy between SSRIs and NaRIs , there are patients who respond to one class of compounds and not another . This suggests that treatment response could be predicted by genetic and /or clinical characteristics . Firstly , this study aims to investigate the influence of a polymorphism ( SLC6A4 ) in the 5HT transporter in altering response to SSRI medication . Secondly , the study will investigate whether those with more severe depression have a better response to NaRIs than SSRIs . Methods / design The GenPod trial is a multi-centre r and omised controlled trial . GPs referred patients aged between 18–74 years presenting with a new episode of depression , who did not have any medical contraindications to antidepressant medication and who had no history of psychosis or alcohol/substance abuse . Patients were interviewed to ascertain their suitability for the study . Eligible participants ( with a primary diagnosis of depression according to ICD10 criteria and a Beck Depression Inventory ( BDI ) score > 14 ) were r and omised to receive one of two antidepressant treatments , either the SSRI Citalopram or the NaRI Reboxetine , stratified according to severity . The final number r and omised to the trial was 601 . Follow-up assessment s took place at 2 , 6 and 12 weeks following r and omisation . Primary outcome was measured at 6 weeks by the BDI . Outcomes will be analysed on an intention-to-treat basis and will use multiple regression models to compare treatments . Discussion The results of the trial will provide information about targeting antidepressant treatment for individual patients ; in turn this may increase prescribing efficacy , thereby speeding recovery and reducing the cost to the NHS . It will also help to underst and the different roles that noradrenaline and serotonin might play in the biology of depression . The trial is expected to report in the autumn of 2008.Trial Registration IS RCT N Several previous studies , including a meta- analysis , reported no significant differences between various selective serotonin reuptake inhibitors ( SSRIs ) in the treatment of major depressive disorder . However , because of the different chemical structure of SSRIs and the difference in the frequency of serotonin transporter polymorphisms between ethnic groups , a head-to-head comparative study between SSRIs in different population s may be enlightening . We compared the efficacy and adverse effect profiles of citalopram and sertraline in a double-blinded r and omized clinical trial in a Chinese population of drug-naïve patients with first-episode major depressive disorder . Fifty-one patients were r and omly assigned to citalopram or sertraline treatment . The Montgomery-Åsberg Depression Rating Scale ( MADRS ) was used as the primary outcome . Efficacy and adverse effects were analyzed in an intent-to-treat population . Efficacy was analyzed using a last-observation-carried-forward method for early terminators . There were no significant differences in demographic characteristics at baseline . No significant differences were found in MADRS scores between citalopram and sertraline at baseline ( 36.6 ± 5.5 vs 38.2 ± 4.9 ; P = 0.322 ) or at the end of treatment ( week 6 ; 10.8 ± 10.0 vs 16.7 ± 11.3 ; P = 0.082 ) . However , MADRS scores in the citalopram group were significantly lower at week 1 ( 25.2 ± 8.5 vs 30.4 ± 6.1 ; P = 0.029 ) and week 3 ( 15.9 ± 10.0 vs 22.1 ± 8.7 ; P = 0.037 ) . Overall , treatment-emergent adverse effects were reported by 14.3 % and 28.6 % of patients in the citalopram and sertraline groups , respectively . In conclusion ,  citalopram  and sertraline were both efficacious and well tolerated . However , citalopram exhibited a significantly faster onset than sertraline during the early weeks of treatment and tended to have a better efficacy in overall treatment , although the statistic was not significant BACKGROUND We evaluated the efficacy of a second serotonin selective reuptake inhibitor ( SSRI ) in patients who had failed to respond to the first SSRI used . METHOD Fifty-five patients with major depression who had failed one of the SSRIs for their current depressive episode were included . After failing a trial of one SSRI , they received a second SSRI in an open clinical trial . RESULTS On the basis of the Clinical Global Impression-Improvement scale , 28 of 55 patients had a marked or complete antidepressant response . CONCLUSION These data provide preliminary clinical evidence that substituting a second SRI may be a useful clinical alternative in depressed patients who fail to respond to an adequate trial of an SSRI BACKGROUND An estimated 30 % to 40 % of patients with depression do not sufficiently respond to treatment with selective serotonin reuptake inhibitors ( SSRIs ) and the period in which treatment efficacy can be assessed is relatively long . Therefore , a test to identify potential nonresponders could be useful in the treatment of depression . Serotonin transporter gene ( SLC6A4 ) variations have been reported to account for differences in the way individuals respond to SSRI treatment . OBJECTIVE A decision-analytic model was used to assess whether pretreatment genetic testing for 5-HTTLPR , a polymorphism of the SLC6A4 genotype , could be an efficient tool in the treatment of depression . METHODS A theoretical clinical decision-analytic model was constructed to compare the current treatment strategy in The Netherl and s with an alternative strategy for the treatment of depression . Under treatment guidelines in The Netherl and s , all patients with depression receive SSRI treatment ( nontesting strategy ) . Under the alternative strategy , genetic testing would be performed to identify which class of antidepressant would be the best choice for initiation of treatment ( genetic testing strategy ) . Probabilities ( predicted results ) for this model were based on data from previous studies and the opinions of experts in the field of psychopharmacology . To test the robustness of the model , 6- and 12-week remission rates for patients treated with SSRIs were varied in a sensitivity analysis using a predetermined range that was established based on expert opinion . Threshold analyses were performed on the parameters of serotonin transporter genotype frequency and response and nonresponse rates for patients receiving SSRIs , serotonin-norepinephrine reuptake inhibitors ( SNRIs ) , and tricyclic antidepressants ( TCAs ) to determine the value for a variable at which it could be concluded that a change in treatment strategy would be preferred . RESULTS When genetic testing was performed before an antidepressant was prescribed , 64.6 % of patients were predicted to be in remission after 6 weeks of treatment compared with 60.0 % of patients who did not receive genetic testing . After 12 weeks , 79.5 % of patients in the testing group who received an SNRI as initial treatment and 83.2 % of those who received a TCA initially were predicted to be in remission compared with 76.7 % of patients in the nontesting group . Sensitivity analyses indicated that the model was robust to variation of probability estimates within their plausible ranges . However , these findings were based on a theoretic model and did not include cost assessment . Pretreatment genetic testing must be evaluated further in r and omized clinical trials and costs must be assessed before implementing this strategy in routine psychiatric practice can be recommended . CONCLUSIONS The findings of this study suggest that performing genetic testing before prescribing antidepressant treatment may lead to greater numbers of patients experiencing remission early in treatment This paper reports the results of two studies of depressed patients , evaluating the efficacy and toleration of the selective serotonin reuptake inhibitor  ( SSRI ) sertraline  in a general practice setting in the UK . In the first of these studies , 308 patients , with a DSM-III-R diagnosis of major depressive episode , were treated for 6 weeks with either sertraline 50–100 mg/day or the tricyclic antidepressant dothiepin 75–150 mg/day , or placebo . Seventy-six per cent of sertraline-treated patients were maintained on the lower dose ( 50 mg/day ) , whereas 81 % of dothiepin-treated patients required the higher dose ( 150 mg/day ) . Sertraline-treated patients demonstrated a significant improvement in the Montgomery-Asberg Depression Rating Scale ( MADRS ) and the Clinical Global Impression ( CGI ) severity scores compared with placebo-treated patients , while dothiepin-treated patients did not show significant improvement compared with placebo . The active drugs were well tolerated , and there were no significant differences in adverse events between the groups . The second study , “ Sertraline in General Practice , A Multicenter Assessment ” , or SIGMA , was a large , multicentre trial with a cohort of 3396 patients recruited to receive 6 weeks of treatment . Patients started on sertraline 50 mg/day , and for 59 % of patients this was the final dose ; less than 10 % of patients reached final doses of more than 100 mg/day . A 50 % or greater reduction in MADRS scores was seen in 69 % of patients across a wide range of severity of symptoms at baseline , and 87 % of patients demonstrated excellent or good toleration of the drug . A review of the relevant literature and the results of these studies show that sertraline is well suited to treatment of depression in the general practice setting & NA ; The abrupt discontinuation of antidepressants can result in a syndrome of adverse events , including somatic , mood and psychomotor reactions . This study examined the effects of discontinuing and resuming antidepressant treatment with four selective serotonin reuptake inhibitors ( SSRIs ) on cognitive and psychomotor function . Eighty‐seven patients receiving maintenance therapy with fluoxetine , sertraline , paroxetine or citalopram had their treatment interrupted for 4‐7 days using double‐blind placebo . Assessment s of aspects of cognitive and psychomotor performance , mood and symptoms were carried out at each visit . Following interruption of treatment , significant differences between the groups emerged . Paroxetine treated patients experienced significantly more cognitive failures ( P = 0.007 ) , poorer quality of sleep ( P = 0.016 ) , and an increase in depressive symptoms , as rated both subjectively , using the Zung scale ( P = 0.006 ) and by the clinician , using the Montgomery‐Asberg Depression Rating Scale ( P = 0.0003 ) and Clinical Global Impression ( P = 0.0003 ) , compared to some or all of the other drugs . All changes were reversed on reinstatement of treatment . Abrupt discontinuation of treatment with paroxetine leads to deterioration in various aspects of health and functioning , which may be related to the antidepressant discontinuation syndrome . These effects are not evident in patients receiving fluoxetine , sertraline and citalopram , suggesting they are not an SSRI class phenomenon . Int Clin Psychopharmacol 15:305‐318 © 2000 Lippincott Williams & Major Depressive Disorder ( MDD ) is a common illness that affects > 40 million people worldwide , and antidepressants are one of the top 5 leading classes of pharmaceuticals with annual sales in excess of $ 20 billion ( 1,2 ) . The current st and ard of care focuses on serotonin−norepinephrine reuptake inhibitors ( SNRI ) and selective serotonin reuptake inhibitors ( SSRI ) ; however , patients often respond poorly . In fact , the National Institute of Mental Health conducted a large-scale STAR*D study and found that 63 % of patients did not achieve remission with the SSRI Citalopram ( 1,3−5 ) . Citalopram was originally developed in Lundbeck in the late 1980s and sold as a racemate . Lundbeck , in collaboration with Forest Laboratories , has recently released an up date d version called Escitalopram ( also known as Lexapro ) , which is the single (S)-enantiomer of the racemic Citalopram , which provided new patent life . In 2009 , Lexapro garnered ∼$2.7 billion in sales in the US ( Figure ​(Figure1)1 ) ( 2 ) . Figure 1 Structures of Citalopram , Escitalopram , and TC-5214 . An alternative hypothesis for depression emerged over 30 years ago and suggests that a cholinergic imbalance ( hypercholinergic tone ) is a major factor in depression , and both clinical and pre clinical studies have implicated neuronal nicotinic cholinergic receptors ( NNRs ) rather than muscarinic receptors ( 5 ) . On the basis of these data , AstraZeneca and Targacept have explored the role of NNR antagonism in depressive disorders and recently announced the initiation of a phase III trial of TC-5214 , (S)-(+)-mecamylamine , as an adjunct therapy with Citalopram . TC-5214 is a low molecular weight ( 167.3 as free base , 203.8 as the HCl salt ) , basic ( pKa = 11.5 ) compound , freely soluble in water . While TC-5214 displays modest selectivity among the NNRs , its antidepressive properties are presumed to be the result of inhibition of the α4β2 NNRs . Pre clinical ly , TC-5214 demonstrated robust efficacy in rodent models of depression ( forced swim and behavioral despair ) and anxiety ( social interaction and light/dark chamber ) . The (S)-enantiomer showed a superior preclincial safety profile compared to that of either the racemic compound or the (R)-enantiomer . Furthermore , TC-5214 was well tolerated in both acute and chronic toxicity tests , displayed no mutagenic potential , and possessed pharmacokinetic properties suitable for development ( 3−5 ) . In 2009 , Targacept conducted a double blind , placebo controlled phase IIb trial in MMD patients with TC-5214  , as an adjunct treatment with Citalopram demonstrated superiority to placebo in both primary and secondary outcome measures ( 3−5 ) . This positive outcome led to a license agreement in December of 2009 with AstraZeneca for the global development and commercialization of TC-5214 . On June 23 , 2010 , AstraZeneca and Targacept announced the enrollment of the first patients in the phase III trial of TC-4214 . Coined the Renaissance Program , the trial will include two fixed dose and two flexible dose phase III studies of TC-5214 as an adjunct treatment for patients with poor response to st and ard SSRI or SNRI therapy . Each fixed dose and flexible dose phase III study will employ an initial open label phase wherein patients diagnosed with MDD receive one of seven marketed SSRIs or SNRIs for eight weeks to assess therapeutic response . Patients that respond poorly will then be r and omized into a double blind , placebo controlled second phase to receive a fixed or a flexible dose of TC-5214 or placebo , twice daily , while continuing the SSRI or SNRI therapy . A change from double blind baseline for TC-5214 on the Montgomery−Asberg Depression Rating Scale ( MADRS ) as compared to placebo is the primary outcome measure . The program will also include a double blind , placebo controlled study for long-term safety . The companies plan completion of the trial in time to file an IND with the FDA in late 2012 ( 3−5 ) . MMD is the leading cause of disability in the US for people 15−44 , and the burden for MDD in the US in 2000 was in excess of $ 83 billion ( 6 ) . When broken down , the workplace burden for lost time is ∼62 % , treatment costs account for ∼31 % , and suicide related costs average 7 % ( 6 ) . For those suffering from MDD with poor response to SSRIs and SNRIs , the phase III data is anxiously awaited Abstract Patients with chronic tension- type headache ( CTTH ) are the most difficult to treat . Tricyclic antidepressants are the first-line therapeutic agents , but their anticholinergic side effects limit their usage . Selective serotonin reuptake inhibitors ( SSRI ) with fewer side effects than tricyclic antidepressants have also been used in treatment of CTTH , but the results are conflicting . In this study , prophylactic action of sertraline in treatment of nondepressed patients with CTTH was investigated and compared with amitriptyline in a prospect i ve , r and omized , open label , parallel-group study . A 4-week baseline period was followed by a 12-week treatment period with either 50 mg sertraline  ( n=41 patients ) or 25 mg amitriptyline  ( n=44 patients ) . Efficacies of treatments were determined by using a headache diary , in which patients recorded the occurrence , number , intensity and duration of headaches in days , analgesic drug consumption and any adverse events . Both drugs reduced headache symptoms and analgesic drug consumption at the first , second and third months of treatment compared to baseline values . There was significant superiority of amitriptyline in the headache symptoms and drug consumption reductions versus sertraline at the second and third months of treatment . Side effects were more favorable in the sertraline-treated patients , but dropouts were similar in both groups . These results suggest that both drugs were effective in the treatment of non-depressed patients with CTTH , but in comparison between groups , amitriptyline was more effective than sertraline Depression is the most common psychiatric disorder among the elderly and in old age may interact with emotional and cognitive functioning . Depression in old age has been shown to be associated with degenerative changes in the brain . It is , therefore , important that in this patient population antidepressants with a favourable tolerability profile , such as the selective serotonin reuptake inhibitors ( SSRIs ) , are examined for both antidepressant efficacy and effect on cognitive function and emotional impairment . This r and omised , double-blind study compared the efficacy and tolerability of citalopram and mianserin in 336 elderly , depressed patients with or without dementia . Patients received either citalopram 20 - 40 mg/day or mianserin 30 - 60 mg/day for 12 weeks . The treatments were equivalent with respect to change in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score ; patients in both treatment groups responded well . Patients with dementia showed a smaller decrease in total MADRS score than patients without dementia . Both treatments were well tolerated with a relatively low incidence of adverse events . Fatigue and somnolence were more frequent with mianserin , while insomnia was more frequent with citalopram . Overall , this study showed that the two treatments were equivalent in efficacy , and that citalopram is an effective , well-tolerated and non-sedative treatment for elderly depressed patients with or without dementia BACKGROUND Up to 30 % of patients with major depression fail to respond to an antidepressant trial , with most taking a selective serotonin reuptake inhibitor ( SSRI ) as initial treatment . While the tricyclic antidepressants might be effective for SSRI nonresponders , they have been relegated to third- and fourth-line treatment . This study assesses the efficacy of nortriptyline for patients with treatment-resistant major depression . METHOD 92 patients with treatment-resistant DSM-III-R major depression , with resistance defined by at least 1 , but no more than 5 , well-documented adequate trials of antidepressants during the current episode , were treated openly with nortriptyline for 6 weeks . Patients were titrated up to full target doses of nortriptyline within 1 week , with target blood levels of 100 ng/mL. Response was defined as a 50 % or greater decrease of baseline 17-item Hamilton Rating Scale for Depression score . We performed an intent-to-treat analysis with the last observation carried forward . RESULTS Approximately 40 % of patients were responders ( N = 39 ) and 12 % were remitters ( N = 11 ) after 6 weeks of nortriptyline . Over a third of patients were unable to complete the trial . CONCLUSION Nortriptyline was effective for over a third of patients with treatment-resistant depression , and nortriptyline should be considered as potential treatment if patients fail to respond to other antidepressants To evaluate the possible influence of buspirone on sexual dysfunction in depressed patients treated with a selective serotonin reuptake inhibitor ( SSRI )  , we analyzed data from a placebo-controlled trial design ed to explore the efficacy of buspirone as add-on treatment for patients not responding to an SSRI alone . At baseline , all patients met the criteria for a major depressive episode according to DSM-IV and had received citalopram or paroxetine during a minimum of 4 weeks without responding to the treatment .  Buspirone ( flexible dosage , 20 - 60 mg/day ) or placebo was added to the SSRI for 4 weeks ; the mean daily dose of buspirone at endpoint was 48.5 mg ( SD = 1.0 ) . Sexual dysfunction was evaluated using a structured interview . Before starting medication with buspirone or placebo , 40 % ( 47 of 117 ) reported at least one kind of sexual dysfunction ( decreased libido , ejaculatory dysfunction , orgasmic dysfunction ) . During the 4 weeks of treatment , approximately 58 % of subjects treated with buspirone reported an improvement with respect to sexual function ; in the placebo group , the response rate was 30 % . The difference between placebo and active drug treatment was more pronounced in women than in men . The response was obvious during the first week , with no further improvement during the course of the study . It is suggested that the effect of buspirone on sexual dysfunction is a result of a reversal of SSRI-induced sexual side effects rather than of an antidepressant effect of the drug OBJECTIVES : Although the tricyclic antidepressant amitriptyline is extensively used in the prophylactic treatment of chronic tension-type headache , only few studies have investigated the efficacy of this treatment and the results are contradictory . In addition , the new selective serotonin reuptake inhibiting antidepressants , which are widely used in depression and of potential value in pain management , have never been investigated in a placebo controlled study of tension-type headache . The aim was to evaluate the efficacy of amitriptyline and of the selective serotonin reuptake inhibitor citalopram in chronic tension-type headache . METHODS : Forty non-depressed patients with chronic tension type headache were included in a 32 week , double blind , placebo controlled , three-way crossover study . RESULTS : Thirty four patients completed the trial .  Amitriptyline reduced area under the headache curve by 30 % compared with placebo ( P = 0.002 ) , whereas citalopram had no significant effect ( P = 0.68 ) . Explanatory analyses showed that amitriptyline significantly reduced the duration of headache ( P = 0.01 ) , headache frequency ( P = 0.01 ) , and intake of analgesics ( P = 0.02 ) but not headache intensity ( P = 0.12 ) . CONCLUSION : Although amitriptyline did not eliminate the headache , it provided a clinical ly important reduction of headache in the majority of otherwise treatment resistant patients . The differential effect of amitriptyline and citalopram indicates that mechanisms other than inhibition of serotonin reuptake are involved in the analgesic effect of the tricyclic antidepressants . Amitriptyline , but not citalopram , is valuable in the prophylactic treatment of chronic tension type headache This paper examines the relationship between plasma concentration of antidepressant and both clinical response and adverse effects in treatment-resistant depressed adolescents . Adolescents ( n = 334 ) with major depression who had not responded to a selective serotonin reuptake inhibitor ( SSRI )  were r and omized to 1 of 4 treatments : switch to another SSRI ( fluoxetine , citalopram , or paroxetine ) , switch to venlafaxine , switch to SSRI plus cognitive behavior therapy , or switch to venlafaxine plus cognitive behavior therapy . Adolescents who did not improve by 6 weeks had their dose increased . Plasma concentrations of medication and metabolites were measured at 6 weeks in 244 participants and at 12 weeks in 204 participants . Adolescents treated with citalopram whose plasma concentration was equal to or greater than the geometric mean ( GM ) showed a higher response rate compared to those with less than the GM , with parallel but nonsignificant findings for fluoxetine . A dose increase of citalopram or fluoxetine at week 6 was most likely to result in response when it led to a change in concentration from less than the GM at 6 weeks to the GM or greater at week 12 . Plasma levels of paroxetine , venlafaxine , or O-desmethylvenlafaxine were not related to clinical response . Exposure was associated with more cardiovascular and dermatologic side effects in those receiving venlafaxine . Antidepressant concentration may be useful in optimizing treatment for depressed adolescents receiving fluoxetine or citalopram Depressive disorders are a major health care issue and one of the foremost causes of disability in adults around the world , result ing in significant costs to society and health care systems ( 1 ) . The estimated economic burden associated with depression was $ 83.1 billion in 2000 and is probably higher today ( 2 ) . Depressive disorders include major depressive disorder ( MDD ) ; dysthymia ; and subsyndromal depression , including minor depression . Major depressive disorder is the most prevalent depressive disorder , with an estimated lifetime prevalence of 16 % in the United States ( 3 ) . An average of 8 million ambulatory care visits per year result in a primary diagnosis of MDD ( 4 ) . The American Psychiatric Association ( 5 ) defines MDD as depressed mood or loss of pleasure or interest along with other symptoms , including significant change in weight or appetite , insomnia or hypersomnia , psychomotor agitation or retardation nearly every day , fatigue or loss of energy , feelings of worthlessness or excessive or inappropriate guilt , indecisiveness or decreased ability to concentrate , and recurrent thoughts of death or suicide , that last for at least 2 weeks and affect normal functioning . Dysthymia is less severe , but symptoms last for 2 or more years . In contrast , subsyndromal depression is associated with less severe symptoms of depression that do not qualify for MDD or dysthymia diagnoses . The treatment of depression can be characterized by 3 phases ( Figure 1 ) : acute ( 6 to 12 weeks ) , continuation ( 4 to 9 months ) , and maintenance ( 1 year ) ( 7 ) . Relapse is defined as the return of depressive symptoms during the acute or continuation phases and is therefore considered part of the same depressive episode , whereas recurrence is defined as the return of depressive symptoms during the maintenance phase and is considered a new , distinct episode . Response to treatment ( typically defined as 50 % reduction in measured severity ) can be quantified using various tools , such as the Patient Health Question naire-9 ( PHQ-9 ) ( 7 ) or the Hamilton Depression Rating Scale ( HAM-D ) ( 8) . Figure 1 . Phases of treatment of major depression . Adapted from reference 6 . TX = treatment . Various treatment approaches can be used to manage MDD , such as psychotherapy , complementary and alternative medicine ( CAM ) , exercise , and pharmacotherapy . The psychological interventions used to treat depression include acceptance and commitment therapy , cognitive therapy , cognitive behavioral therapy ( CBT ) , interpersonal therapy , and psychodynamic therapies ( Table 1 ) . The CAM treatments include acupuncture , meditation , -3 fatty acids , S-adenosyl-l-methionine ( SAMe ) , St. John 's wort , and yoga . Exercise includes a broad range of activities that can be done for varying duration s , in classes , individually , or in informal groups . For pharmacologic therapy , the scope of this guideline is limited to second-generation antidepressants ( SGAs ) ( selective serotonin reuptake inhibitors , serotonin norepinephrine reuptake inhibitors , and selective serotonin norepinephrine reuptake inhibitors ) . First-generation antidepressants ( tricyclic antidepressants and monoamine oxidase inhibitors ) are very rarely used because SGAs have lower toxicity in overdose than first-generation antidepressants and similar efficacy . Table 1 . Common Psychological Interventions to Treat Depression Guideline Focus and Target Population The purpose of this guideline from the American College of Physicians ( ACP ) is to summarize and grade the evidence on the comparative effectiveness and safety of nonpharmacologic treatments and SGAs ( including serotonin reuptake inhibitors , serotonin norepinephrine reuptake inhibitors , bupropion , mirtazapine , nefazodone , and trazodone ) , alone or in combination , for MDD . The target audience for this guideline includes all clinicians , and the target patient population includes all adults with MDD . These recommendations are based on a background evidence article ( 9 ) and a systematic evidence review sponsored by the Agency for Healthcare Research and Quality ( AHRQ ) ( 6 ) . Methods Systematic Review of the Evidence The systematic evidence review was conducted by the AHRQ 's RTI InternationalUniversity of North Carolina at Chapel Hill Evidence -based Practice Center ( 6 ) . Additional method ological details can be found in the Appendix ) , accompanying background evidence article ( 9 ) , and full report ( 6 ) . Review ers search ed several data bases for studies published in English , German , or Italian from 1 January 1990 through September 2015 . Studies on efficacy were limited to r and omized , controlled trials and systematic review s and meta-analyses , although evidence on harms included observational studies . Review ers combined data when possible using meta- analysis and assessed the risk of bias and quality of studies according to established methods . The study population included adult out patients ( aged 18 years ) with MDD during either an initial or a second treatment attempt who did not remit after an initial adequate trial with an SGA . The review evaluated the following classes of interventions : depression-focused psychotherapy , CAM , exercise , and SGAs . Outcomes assessed included benefits in response ( often defined as 50 % improvement in HAM-D scores ) , remission ( often defined as a HAM-D score 7 ) , speed of response , speed of remission , relapse , quality of life , functional capacity ( as assessed by various scales ) , reduction of suicidality , or reduction of hospitalization . Harms assessed included overall adverse events , withdrawals because of adverse events , serious adverse events , and specific adverse events . Quality of life , functional status , suicidality , and hospitalizations were rarely reported . Grading the Evidence and Developing Recommendations This guideline was developed by the ACP Clinical Guidelines Committee according to the ACP guideline development process , which has been described ( 10 ) . The Clinical Guidelines Committee used the evidence tables in the accompanying systematic review and full report ( 9 ) when reporting the evidence and grade d the recommendations using ACP 's guideline grading system ( Table 2 ) . Table 2 . The American College of Physicians ' Guideline Grading System * Peer Review The AHRQ evidence review was sent to invited peer review ers and posted on the AHRQ Web site for public comments . The guideline was peer- review ed through the journal and was posted online for comments from ACP Governors and Regents . Comparative Benefits of Pharmacologic Versus Nonpharmacologic Treatment Options for Initial Management Refer to Appendix Table 1 and the accompanying systematic review ( 9 ) for additional details of the evidence . Appendix Table 1 . First-Line Treatment for MDD : SGAs Versus Nonpharmacologic Therapies * SGA Versus Psychological Interventions SGA Versus CBT Monotherapy . Moderate- quality evidence from 5 trials ( 1115 ) showed no difference in response when comparing SGAs ( fluoxetine , fluvoxamine , paroxetine , or sertraline ) with CBT in patients with MDD after 8 to 52 weeks of treatment . Low- quality evidence from 3 trials ( 11 , 14 , 15 ) showed no difference between remission rates ( fluoxetine , fluvoxamine , and paroxetine ) and functional capacity ( 14 ) ( fluvoxamine and paroxetine ) for SGAs compared with CBT . Combination Therapy . Low- quality evidence from 2 trials ( 14 , 16 ) showed no difference in response or remission when comparing monotherapy using SGAs ( escitalopram , fluvoxamine , or paroxetine ) with combination therapy using SGAs plus CBT ( problem-solving therapy or telephone-based CBT ) in patients with MDD after 12 to 52 weeks of treatment . Low- quality evidence from 2 trials ( 14 , 16 ) assessed function , and 1 trial showed that patients who received the combination therapy reported more improvement on 3 of 5 work-functioning measures than those who received SGA monotherapy , although clinical ly important differences on these measures are uncertain . SGA Versus Interpersonal Therapy Monotherapy . Low- quality evidence showed no difference in response ( 1 trial ; escitalopram ) ( 17 ) or remission ( 2 trials ; citalopram , escitalopram , or sertraline ) ( 17 , 18 ) for SGAs compared with interpersonal therapy for patients with MDD after 12 weeks of treatment . Combination Therapy . Low- quality evidence from 1 trial ( 19 ) showed increased remission for SGA monotherapy compared with SGA combined with interpersonal therapy ( with nefazodone ) in patients with MDD after 12 weeks of treatment . SGA Versus Psychodynamic Therapies Monotherapy . Low- quality evidence from 1 trial ( 20 ) showed no difference in remission for fluoxetine compared with psychodynamic monotherapy in patients with MDD after 16 weeks of treatment . Low- quality evidence from 2 trials ( 20 , 21 ) showed few differences in functional capacity between the treatments . Combination Therapy . Low- quality evidence from 1 trial ( 21 ) showed no difference in functional capacity for SGA monotherapy compared with SGA plus psychodynamic combination therapy . SGA Versus CAM Interventions SGA Versus Acupuncture Monotherapy . Low- quality evidence from 2 trials ( 22 , 23 ) showed no difference in treatment response when comparing fluoxetine with acupuncture monotherapy for patients with MDD after 6 weeks of treatment . Combination Therapy . Low- quality evidence from 2 trials ( 24 , 25 ) showed that combination therapy of SGAs with acupuncture improved treatment response compared with monotherapy with SGAs ( fluoxetine or paroxetine ) in patients with MDD after 6 weeks of treatment . However , low- quality evidence from 1 trial ( 24 ) showed no difference in remission when comparing paroxetine monotherapy with paroxetine plus acupuncture combination therapy . SGA Versus -3 Fatty Acids Monotherapy . Low- quality evidence from network meta- analysis showed that SGAs ( fluoxetine ) were associated with a greater response than -3 fatty acids in patients with MDD .  SGA Versus SAMe Monotherapy . Low- quality evidence from network meta- analysis showed no difference in response between treatment with escitalopram OBJECTIVE The authors examined gender differences in treatment response to sertraline , a selective serotonin reuptake inhibitor ( SSRI ) , and to imipramine , a tricyclic antidepressant , in chronic depression . METHOD A total of 235 male and 400 female out patients with DSM-III-R chronic major depression or double depression ( i.e. , major depression superimposed on dysthymia ) were r and omly assigned to 12 weeks of double-blind treatment with sertraline or with imipramine after placebo washout . RESULTS Women were significantly more likely to show a favorable response to sertraline than to imipramine , and men were significantly more likely to show a favorable response to imipramine than to sertraline . Gender and type of medication were also significantly related to dropout rates ; women who were taking imipramine and men who were taking sertraline were more likely to withdraw from the study . Gender differences in time to response were seen with imipramine , with women responding significantly more slowly than men . Comparison of treatment response rates by menopausal status showed that premenopausal women responded significantly better to sertraline than to imipramine and that postmenopausal women had similar rates of response to the two medications . CONCLUSIONS Men and women with chronic depression show differential responsivity to and tolerability of SSRIs and tricyclic antidepressants .  The differing response rates between the drug classes in women was observed primarily in premenopausal women . Thus , female sex hormones may enhance response to SSRIs or inhibit response to tricyclics . Both gender and menopausal status should be considered when choosing an appropriate antidepressant for a depressed patient Enhancement of serotonin neurotransmission plays an important role in the antidepressant response to agents presently available to treat depression . This response forms the major evidence for the role of serotonin in affective and social behaviour in humans . The present study investigated the effects of acute administration of the selective serotonin reuptake inhibitor ( SSR1 ) , citalopram ( 10 mg , i.v . ) upon a measure of emotional processing in healthy female volunteers . Subjects completed a facial expression recognition task following infusion of citalopram or saline ( between-subjects design , double-blind ) . Facial expressions associated with five basic emotions — happiness , sadness , fearfulness , anger and disgust — were displayed . Each face had been ‘ morphed ’ between neutral ( 0 % ) and each emotional st and ard ( 100 % ) in 10 % steps , leading to a range of emotional intensities . Mood and subjective experience were also monitored throughout the testing session . Volunteers receiving citalopram detected a higher number of facial expressions of fear and happiness , with reduced response times , relative to those given the placebo . By contrast , changes in the recognition of other basic emotions were not observed following citalopram . Notable differences in mood were also not apparent in these volunteers . These results suggest that acute administration of antidepressant drugs may affect neural processes involved in the processing of social information . This effect may represent an early acute effect of SSRIs on social and emotional processing that is relevant to their therapeutic actions BACKGROUND Inositol has been reported to be an effective treatment in depression , and we hypothesized that inositol addition might enhance or speed up response to  serotonin selective reuptake inhibitors ( SSRI ) . METHODS Twenty-seven depressed patients completed a double-blind controlled 4-week trial of SSRI plus placebo or SSRI plus inositol .  Hamilton Depression Rating Scale was used as an assessment tool at baseline , and 1 , 2 , 3 , and 4 weeks . RESULTS No significant difference was found between the two treatment groups . CONCLUSIONS Previous studies combining different effective antidepressant therapies similarly found no evidence for additive effects [ e.g. , monoamine oxidase inhibitors ( MAOI ) plus tricyclic antidepressants ( TCA ) , TCA plus lithium ] . By contrast , augmentation by lithium or MAOI after a failed course of antidepressant treatment is effective and should be studied with inositol BACKGROUND Selective serotonin reuptake inhibitors are effective in approximately 70 % of patients with a major depressive episode , but therapeutic changes usually require 2 weeks of administration to become clinical ly relevant . Adjunct light therapy has been proposed to hasten the effects of drug treatment . The purpose of the present study was to evaluate the effect of morning light therapy or placebo combined with citalopram in the treatment of patients affected by a major depressive episode without psychotic features . METHOD Thirty in patients ( DSM-IV major depressive disorder [ N = 21 ] and bipolar disorder [ N = 9 ] ) were treated with citalopram , 40 mg , and r and omized in a 3:2 manner to receive 30 minutes of 400 lux green light treatment in the morning or placebo ( exposure to a deactivated negative ion generator ) during the first 2 weeks of drug treatment . Timing of light therapy was individually defined to obtain a 2-hour phase advance to morning light . Outcome was measured with the Hamilton Rating Scale for Depression and the Zung Self-Rating Depression Scale every week , and with a Visual Analogue Scale 3 times a day during the first week . RESULTS All outcome measures showed significantly ( p < .05 ) better mood improvement in light-treated patients , result ing in faster responses to antidepressant treatment . CONCLUSION The combination of citalopram and light treatment was more effective than citalopram and placebo in the treatment of major depression . With an optimized timing of administration , low-intensity light treatment significantly hastened and potentiated the effect of citalopram , thus providing the clinical psychiatrists with an augmenting strategy that was found effective and devoid of side effects Both noradrenergic and serotonergic systems have been implicated in the pathophysiology of panic disorder . The advent of selective serotonin ( 5-HT ) reuptake inhibitors ( SSRIs ) ( e.g. citalopram ) and , more recently , selective noradrenergic ( NA ) reuptake inhibitors ( NRIs ) ( e.g. reboxetine ) has provided potentially important avenues of treatment for the disorder . To date , the comparative efficacy of selective NA and 5-HT reuptake inhibitors for panic disorder remains unresolved . Nineteen patients with panic disorder were r and omized in a single-blind , cross-over design to either citalopram or reboxetine for 8 weeks and after a 2-week washout were switched to the other study drug . At week 18 , seven of 13 patients ( 54 % ) in the intent-to-treat sample responded to reboxetine and nine of 11 patients responded to citalopram ( 82 % ) . Both citalopram and reboxetine led to significant improvements in panic attack severity with no apparent between-drug differences in efficacy . However , citalopram demonstrated superior efficacy in treating depressive symptoms . One non-responder to citalopram responded to reboxetine and three non-responders to reboxetine responded to citalopram . Although SSRIs are viewed as a first-line treatment for panic disorder , these results suggest that a NA agent such as reboxetine may also have a role . These data also suggest an advantage for citalopram in treating comorbid depressive symptoms , although some patients may respond preferentially to an SSRI and other patients to an NRI Objective : Recognition that depression is associated with increased morbidity and mortality in coronary artery disease ( CAD ) patients has augmented the need for evidence -based treatment guidelines . This article presents the design of a multisite , Canadian trial of the efficacy , safety , and tolerability of interpersonal psychotherapy ( IPT ) , an empirically supported , depression-focused therapy , and the selective serotonin reuptake inhibitor citalopram , alone or in combination , in the treatment of major depression in CAD patients . Methods : Two hundred eighty stable CAD patients with a current major depressive episode of at least 4 weeks ’ duration , based on the Structured Clinical Interview for Depression ( SCID ) , and who have a baseline score > 19 on a central ized , telephone-administered , 24-item Hamilton Depression Rating Scale ( HAM-D ) will be r and omly assigned to receive 12 weekly IPT sessions or 12 weekly sessions of st and ardized clinical management ( CM ) . Patients are also r and omly assigned to receive 20 to 40 mg per day of citalopram or pill-placebo . This results in a 2-by-2 factorial design with four groups : IPT plus pill-placebo , IPT plus citalopram , CM plus pill-placebo , and CM plus citalopram . This permits the evaluation of both IPT and citalopram . Blinded , central ized , 24-item , HAM-D telephone ratings constitute the primary outcome variable . The self-report Beck Depression Inventory-II is the secondary outcome . Analyses will involve the intent-to-treat principle with last observation carried forward for incomplete assessment s. Results : Not applicable . Conclusions : The results of this trial will contribute to the development of evidence -based clinical guidelines for managing depression in the context of CAD . CREATE = Canadian Cardiac R and omized Evaluation of Antidepressant and Psychotherapy Efficacy ; IPT = interpersonal psychotherapy ; CAD = coronary artery disease ; SCID = Structured Clinical Interview for Depression ; HAM-D = Hamilton Depression Rating Scale ; CM = clinical management ; SADHART = Sertraline Antidepressant Heart Attack R and omized Trial ; ENRICHD = Enhancing Recovery in Coronary Heart Disease ; SSRI = selective serotonin reuptake inhibitor ; ECG = electrocardiogram ; NIMH = National Institute of Mental Health ; TDCRP = Treatment of Depression Collaborative Research Program ; MMSE = Mini-mental Status Exam ; STAR*D = Sequenced Treatment Alternatives to Relieve Depression ; IDS = Inventory for Depressive Symptomatology ; BDI-II = Beck Depression Inventory-II ; IPRI = Interpersonal Relationship Inventory ; FPI = Functional Performance Inventory ; SAE = serious adverse event ; LOCF = last observation carried forward ; DSMB = data safety monitoring board INTRODUCTION Sexual dysfunction is common with serotonergic antidepressants , including selective serotonin reuptake inhibitors ( SSRIs ) and serotonin-norepinephrine reuptake inhibitors ( SNRIs ) , and does not resolve in most patients . Vortioxetine , an antidepressant with a multimodal mechanism of action , has shown low rates of sexual dysfunction in previous major depressive disorder ( MDD ) trials . AIM This study compared the effects of vortioxetine and escitalopram on sexual functioning in adults with well-treated MDD experiencing treatment-emergent sexual dysfunction ( TESD ) . METHODS Participants treated with , and responding to , citalopram , paroxetine , or sertraline were r and omized to switch to either vortioxetine ( 10/20 mg ; n = 225 ) or escitalopram ( 10/20 mg ; n = 222 ) for 8 weeks . Sexual function was assessed using the Changes in Sexual Functioning Question naire Short Form ( CSFQ-14 ) , and antidepressant efficacy was assessed using the Montgomery-Åsberg Depression Rating Scale ( MADRS ) , Clinical Global Impressions ( CGI ) scale , and Profile of Mood States brief form ( POMS-brief ) . Safety and tolerability were also assessed . MAIN OUTCOME MEASURES The primary endpoint was change from baseline in the CSFQ-14 total score after 8 weeks of treatment . The MADRS , CGI , and POMS-brief were used to assess antidepressant efficacy . Safety was assessed via adverse events , vital signs , electrocardiograms , laboratory values , weight , and physical examination findings . RESULTS Vortioxetine showed significantly greater improvements in CSFQ-14 total score ( 8.8 ± 0.64 , mean ± st and ard error ) vs. escitalopram ( 6.6 ± 0.64 ; P = 0.013 ) . Benefits vs. escitalopram were significant on four of five dimensions and all three phases of sexual functioning assessed by the CSFQ-14 ( P < 0.05 ) . Antidepressant efficacy continued in both groups , with similar , but slight , improvements in MADRS and CGI scores . Vortioxetine and escitalopram had similar clinical efficacy profiles in this study , with safety profiles similar to previous trials . Nausea ( n = 9 , 4.0 % ) was the most common treatment-emergent adverse event leading to discontinuation of vortioxetine . CONCLUSION Switching antidepressant therapy to vortioxetine may be beneficial for patients experiencing sexual dysfunction during antidepressant therapy with SSRIs INTRODUCTION : Reboxetine is the first available selective noradrenaline re-uptake inhibitor ( selective NRI ) . This paper gives an overview of its antidepressant efficacy and tolerability in eight r and omized double-blind , multicentre clinical trials . The clinical profile of reboxetine is also compared with that of the tricyclic antidepressants ( TCAs ) desipramine and imipramine and the selective serotonin re-uptake inhibitor ( SSRI ) fluoxetine . METHODS : Pooled data were analysed from seven short-term ( 4 - 8 weeks ) and one long-term ( up to 1 year ) trials comparing reboxetine with placebo , imipramine , desipramine or fluoxetine . The tolerability of reboxetine was evaluated in 2613 patients with major depression or dysthymia . Data from 1959 patients with major depressive disorder were included to assess drug efficacy . Efficacy was principally assessed using the Hamilton Depression Rating Scale ( HAM-D ) . RESULTS : Reboxetine was more effective than placebo in three of four short-term trials , and it was as effective as fluoxetine , imipramine and desipramine . In long-term treatment , reboxetine was more effective than placebo in preventing relapse ( S 50 % increase in HAM-D ) and recurrence ( HAM-D total score h 10 ) . In a subset of severely depressed patients , reboxetine was as effective as imipramine and significantly more effective than fluoxetine . Reboxetine was as effective as imipramine in the elderly , but better tolerated . The most common adverse events among the 1503 patients ( adults and elderly ) who received reboxetine were dry mouth ( 22 % ) , constipation ( 15 % ) , sweating ( 12 % ) and insomnia ( 11 % ) . Overall , reboxetine was well tolerated , as well as the SSRI fluoxetine and better than the TCAs imipramine and desipramine . CONCLUSIONS : Reboxetine is effective and well tolerated in the short and long-term treatment of depression . It is as well tolerated as fluoxetine and better than imipramine and desipramine . ( Int J Psych Clin Pract 2000 ; 4 : 201 - 208 BACKGROUND Whether the Brain Derived Neurotrophic Factor ( BDNF ) Val66Met polymorphism can predict antidepressant drug efficacy in depressed patients remains unclear , suggesting that it may depend on antidepressant classes . We assessed the impact of Val66Met polymorphism on antidepressant response and remission depending on antidepressant classes . METHODS In a 6-month prospect i ve , real-world setting , treatment study , 345 Caucasian depressed patients requiring a new or different drug treatment with a selective serotonin reuptake inhibitor ( SSRI ) , a serotonin and noradrenalin reuptake inhibitor ( SNRI ) or a tricyclic antidepressant ( TCA )  , were genotyped and assessed for response and remission . RESULTS 231 ( 67 % ) patients were homozygous for the Val66 allele ( Val/Val ) and 114 ( 33 % ) were carriers of Met allele ( Met ) . 152 ( 44.1 % ) patients were treated with SSRI , the others with SNRI/TCA . Both response and remission were explained by interactions between the Val66Met polymorphism and antidepressant drug classes ( multivariate models adjusted for propensity-scores : p=0.02 and p=0.03 respectively ) . With SSRI , Val/Val patients had a higher response rate 3 months post-treatment than Met patients ( 68.1 % versus 44 % ; adjusted-OR : 3.04 , IC95 % [ 1.05 ; 9.37 ] , p=0.04 ) . With SNRI/TCA , Val/Val patients had a lower remission rate 6 months post-treatment than Met patients ( 33.3 % versus 60.9 % , adjusted-OR : 0.27 , IC95 % [ 0.09 ; 0.76 ] , p=0.02 ) . LIMITATIONS Limited sample size . CONCLUSIONS This study argues for a personalized prescription of antidepressants in Caucasian patients with major depressive disorder , based on the BDNF Val66Met polymorphism : SSRI should be preferred for Val/Val patients and SNRI/TCA for Met patients . Further studies are required to confirm these data OBJECTIVE Predictors of treatment response to serotonergic versus nonserotonergic , e.g. , noradrenergic , antidepressants are of considerable clinical relevance as they could help to reduce the occurrence of patients ' receiving weeks or even months of unsuccessful treatment . Several studies show that the response to selective serotonin reuptake inhibitors can be successfully predicted by using the loudness dependence of auditory evoked potentials ( LDAEP ) , which denotes change in the amplitudes in response to different stimulus intensities and is to date one of the best vali date d indicators of the central serotonergic system . The aim of the current r and omized prospect i ve study was to investigate whether or not LDAEP also allows the differential prediction of treatment response to serotonergic versus noradrenergic antidepressants . METHOD Electrophysiologic recordings were performed on 48 subjects between 1999 and 2001 . After exclusions due to artifacts , the study sample consisted of 35 unmedicated in patients with a DSM-IV or ICD-10 diagnosis of major depressive disorder ( mean + /- SD age = 42.5 + /- 10.8 years ; 13 male , 22 female ; mean + /- SD score of 28.9 + /- 5.7 on the Hamilton Rating Scale for Depression [ HAM-D ] , the primary measure for psychopathology ) . The patients were then treated for 4 weeks with either the selective serotonin reuptake inhibitor citalopram or the noradrenaline reuptake inhibitor reboxetine . RESULTS Analysis of variance ( F = 5.05 , df = 1,31 ; p = .03 ) revealed that responders ( 50 % improvement in HAM-D score ) to the citalopram treatment were characterized by a strong LDAEP at baseline , and responders to reboxetine were characterized by a weak LDAEP at baseline . Non-responders to citalopram or reboxetine showed the inverse LDAEP characteristics , respectively . CONCLUSION This study is one of the first to demonstrate differential prediction of response to different classes of antidepressants . Patients at the beginning of an antidepressant treatment who show an initially strong LDAEP have a greater probability of responding to a serotonin-agonist antidepressant , whereas patients with a weak LDAEP will probably benefit more from a nonserotonergic , e.g. , noradrenergic , antidepressant . If these results were replicated in a larger sample , this simple electroencephalographic method could be more broadly used in clinical practice to support clinicians in replacing the trial and error method with a more targeted and individualized approach to antidepressant treatment The antidepressant selective serotonin transporter inhibitors ( SSRIs ) are clinical ly active after a delay of several weeks . Indeed , the rapid increase of serotonin ( 5-HT ) caused by SSRIs , stimulates the 5-HT(1A ) autoreceptors , which exert a negative feedback on the 5-HT neurotransmission . Only when autoreceptors are desensitized , can SSRIs exert their therapeutic activity . The 5-HT(1A ) receptor antagonist pindolol has been used to accelerate the clinical effects of antidepressant by preventing the negative feedback . Using the alpha-[(11)C]methyl-L-tryptophan/positron emission tomography ( PET ) , the goal of the present double-blind , r and omized study was to compare the changes in alpha-[(11)C]methyl-L-tryptophan trapping , an index of serotonin synthesis , in patients suffering from unipolar depression treated with the SSRI citalopram ( 20 mg/day ) plus placebo versus patients treated with citalopram plus pindol ( 7.5 mg/day ) .  PET and Hamilton depression rating scale ( HDRS-17 ) were performed at baseline , and after 10 and 24 days of antidepressant treatment . Results show that the combination citalopram plus pindol , compared to citalopram alone shows a more rapid and greater increase of an index of 5-HT synthesis in prefrontal cortex ( BA 9 ) . This research is the first human PET study demonstrating that , after 24 days , the combination SSRIs plus pindolol produces a greater increase of the metabolism of serotonin in the prefrontal cortex , an area associated to depressive symptoms Objective : The presence of co-morbid depressive symptoms may have a negative impact on the management of diabetes mellitus . Moreover , some antidepressants may adversely affect glycemic control . Selective serotonin reuptake inhibitors ( SSRIs ) may improve glycemic control and may be beneficial for patients with co-morbid depression and diabetes . We examined the safety and efficacy of s-citalopram therapy in patients with co-morbid depression and diabetes , and its ability to improve glycemic control . Research Design and Methods : 17 patients were enrolled into the trial and 14 patients received open-label s-citalopram therapy for up to 16 weeks . Clinical outcome measures included the 17-item Hamilton depression rating ( HAM-D 17 ) and the clinical global impressions severity ( CGI/S ) and change ( CGI/C ) ratings . In addition , fasting glucose , fructosamine , and glycosylated hemoglobin-A1C measures were obtained before and during s-citalopram therapy . Results : We observed a significant reduction in mean HAM-D 17 ( p < 0.001 ) , CGI/S ( p = 0.001 ) and CGI/C ( p = 0.001 ) ratings during s-citalopram therapy . We also observed a modest , non-significant reduction in fasting glucose , fructosamine , and glycosylated hemoglobin-A1C levels during s-citalopram therapy . Limitation : Limitations of this study include a modest patient sample size and a 16-week treatment duration which may have been insufficient to demonstrate the full effect of SSRI therapy on glycemic control . Conclusion : We observed a significant reduction in depressive symptoms and modest , non-significant reductions in fasting glucose , fructosamine , and glycosylated hemoglobin-A1C levels during SSRI therapy of co-morbid depression and diabetes OBJECTIVE Psychomotor disturbances can frequently be found in depressed patients and may have an important influence on the ability to drive . Additionally , effects of sedation , as seen with some antidepressants , probably impair driving performance . The present study was design ed to evaluate the effects of antidepressant monotherapy on psychomotor functions related to car-driving skills in depressive patients in a routine clinical setting . METHOD In patients ( N = 100 ) who met the ICD-10 and DSM-IV criteria for major depressive disorder were tested under steady-state plasma level conditions prior to being discharged to out-patient treatment . The study ran from January 2004 through March 2005 . All patients participated voluntarily and gave informed consent . According to the German guidelines for road and traffic safety , data were collected with the computerized Act & React Testsystem ART-90 and the Wiener Testsystem , measuring visual perception , reaction time , selective attention , vigilance , and stress tolerance . Psychopathologic symptoms were rated with the Hamilton Rating Scale for Depression . RESULTS Before discharge to outpatient treatment , 24 % of the patients tested were without clinical ly relevant psychomotor disturbances . In 60 % of the cases , mild to moderate impairments could be seen , and about 16 % of the patients were considered as severely impaired in psychomotor functions related to car-driving abilities . Data show that patients treated with selective serotonin reuptake inhibitors ( SSRIs ) or the noradrenergic and specific serotonergic antidepressant ( NaSSA ) mirtazapine had an altogether better test performance in comparison with patients receiving tricyclic antidepressants ( TCAs ) . Differences were most pronounced in measures of reactivity , stress tolerance , and selective attention . Statistically significant differences between patients treated with TCAs or the serotonin-norepinephrine reuptake inhibitor ( SNRI ) venlafaxine could not be found . Among the newer antidepressants there is an advantage for patients treated with mirtazapine , especially in tasks with high multi-channel perception and output dem and s. CONCLUSION About 16 % of depressive patients discharged from hospital to outpatient treatment must be considered unfit to drive . In 60 % of the cases , patients performed at a question able level of fitness for driving , and it seems justified to counsel patients individually , taking into account compensational factors . Data point to an advantage for patients treated with SSRIs or mirtazapine when compared with TCAs or venlafaxine . However , causal relationships can not be drawn from our data BACKGROUND The amygdala is believed to play a key role in processing emotionally salient , threat-relevant , events that require further online processing by cortical regions . Emotional disorders such as depression and anxiety have been associated with hyperactivity of the amygdala , but it is unknown whether antidepressant treatment directly affects amygdala responses to emotionally significant information . METHODS The current study assessed the effects of 7 days administration of the selective serotonin reuptake inhibitor ( SSRI ) , citalopram , on amygdala responses to masked presentations of fearful and happy facial expressions in never-depressed volunteers using blood oxygenation level-dependent ( BOLD ) functional magnetic resonance imaging . A double-blind , between-groups design was used with volunteers r and omized to 20 mg/day citalopram versus placebo . RESULTS Volunteers receiving citalopram showed decreased amygdala responses to masked presentations of threat compared with those receiving placebo . Citalopram also reduced responses within the hippocampus and medial prefrontal cortex ( mPFC ) specifically during the fear-relevant stimuli . These neural differences were accompanied by decreased recognition of fearful facial expressions assessed after the scan . By contrast , there was no effect of citalopram on the neural or behavioral response to the happy facial expressions . CONCLUSIONS These results suggest a direct effect of serotonin potentiation on amygdala response to threat-relevant stimuli in humans . Such effects may be important in the therapeutic actions of antidepressants in depression and anxiety BACKGROUND Citalopram , the most selective serotonin reuptake inhibitor ( SSRI ) , is a bicyclic phthalane derivative with a chemical structure that is unrelated to that of other SSRIs and available antidepressants . The drug is approved for use in 69 countries . This 6-week , fixed-dose , placebo-controlled , parallel-arm , multicenter trial was performed to confirm its efficacy and safety in treatment of out patients with major depression in the United States . METHOD Six hundred and fifty adult out patients with moderate-to-severe major depression ( DSM-III-R ) were r and omly assigned to receive citalopram at doses of 10 mg ( N = 131 ) , 20 mg ( N = 130 ) , 40 mg ( N = 131 ) , or 60 mg ( N = 129 ) or placebo ( N = 129 ) once daily . Outcome assessment s were the 21-item Hamilton Rating Scale for Depression ( HAM-D ) , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , and the Clinical Global Impressions scale . RESULTS Between-group comparisons of the change from baseline to endpoint revealed significantly greater improvement in the citalopram patients relative to the placebo patients on all 3 efficacy measures . Patients r and omly assigned to 40 mg/day and 60 mg/day of citalopram showed significantly greater improvement than placebo on all efficacy measures , as well as on the HAM-D symptom clusters measuring depressed mood , melancholia , cognitive disturbance , and psychomotor retardation . Patients who received 10 mg/day and 20 mg/day of citalopram also showed consistent improvement relative to placebo on all efficacy ratings , with statistical significance demonstrated in the MADRS response rate , the HAM-D depressed mood item , and the HAM-D melancholia subscale . Citalopram was well tolerated , with only 15 % of patients discontinuing for adverse events . The side effects most commonly associated with citalopram treatment were nausea , dry mouth , somnolence , insomnia , and increased sweating . CONCLUSION Citalopram was significantly more effective than placebo in the treatment of moderate-to-severe major depression , especially symptoms of depressed mood and melancholia , with particularly robust effects shown at doses of 40 and 60 mg/day . Citalopram was well tolerated in spite of forced upward titration to fixed-dose levels , with a low incidence of anxiety , agitation , and nervousness BACKGROUND After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor ( SSRI ) , it is not known whether switching to one antidepressant is more effective than switching to another . METHODS We r and omly assigned 727 adult out patients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram  to receive one of the following drugs for up to 14 weeks : sustained-release bupropion ( 239 patients ) at a maximal daily dose of 400 mg , sertraline ( 238 patients ) at a maximal daily dose of 200 mg , or extended-release venlafaxine ( 250 patients ) at a maximal daily dose of 375 mg . The study was conducted in 18 primary and 23 psychiatric care setting s. The primary outcome was symptom remission , defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) at the end of the study . Scores on the Quick Inventory of Depressive Symptomatology - Self Report ( QIDS-SR-16 ) , obtained at treatment visits , determined secondary outcomes , including remission ( a score of 5 or less at exit ) and response ( a reduction of 50 percent or more on baseline scores ) . RESULTS Remission rates as assessed by the HRSD-17 and the QIDS-SR-16 , respectively , were 21.3 percent and 25.5 percent for sustained-release bupropion , 17.6 percent and 26.6 percent for sertraline , and 24.8 percent and 25.0 percent for extended-release venlafaxine . QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion , 26.7 percent for sertraline , and 28.2 percent for extended-release venlafaxine . These treatments did not differ significantly with respect to outcomes , tolerability , or adverse events . CONCLUSIONS After unsuccessful treatment with an SSRI , approximately one in four patients had a remission of symptoms after switching to another antidepressant . Any one of the medications in the study provided a reasonable second-step choice for patients with depression . ( Clinical Trials.gov number , NCT00021528 . ) Accumulating evidence suggests that noradrenergic and serotonergic drugs are equally effective in ameliorating the depressive symptoms of major depression . Major depression is associated also with memory impairments , but the comparative effects of the antidepressant drugs on memory are not clear . We previously found that serotonergic neurotransmission is of particular importance for some aspects of episodic memory . We set out to test whether treatment with the selective serotonergic drug Fluoxetine ( Prozac ) would be advantageous in this respect over treatment with the selective noradrenergic tricyclic antidepressant drug Desipramine ( Deprexan ) .  Seventeen patients with major depressive episode , r and omly assigned for treatment with either Fluoxetine ( n = 8) or Desipramine ( n = 9 ) , were assessed for their clinical situation and for memory performance at the beginning of treatment , after 3 weeks , and after 6 weeks of pharmacological treatment . We found that although clinical ly both drugs were equally effective , the improvement of memory performance in the Fluoxetine-treated patients was significantly greater compared with that of the Desipramine-treated patients . The results support the role of serotonin in memory . More studies in larger sample s of patients are required , but it may be that in cases where memory impairment is a major symptom , it would be beneficial to consider serotonergic antidepressant drugs for treatment . Furthermore , in cases where , for various reasons , the treatment of choice is noradrenergic , it may be worthwhile to consider a supplementary serotonergic drug to improve memory deficits INTRODUCTION The serotonin-1A ( 5-HT1A ) receptor subtypes are considered as targets of a variety of antidepressant drugs . Previous studies have suggested different adaptive changes in pre- and post-synaptic 5-HT receptors in the brain after treatment with non-selective tricyclic antidepressants ( TCA ) and selective 5-HT re-uptake inhibitors ( SSRIs ) . The present study aim ed to investigate the adaptive effect of the TCA imipramine on the post-synaptic 5-HT1A receptor function in the hypothalamus . METHODS A longitudinal design was used in 14 patients with major depressive disorder ( DSM-IV ) with endogenous features ( Newcastle Scale ) in order to assess the functional status of post-synaptic 5-HT1A receptors before and after successful antidepressant treatment with imipramine . The effect of the 5-HT1A receptor agonist , buspirone , on ACTH , cortisol , and prolactine ( PRL ) plasma levels was used to assess the functional status of hypothalamic 5-HT1A receptors . A group of 15 concurrent normal subjects were used as control . RESULTS Endogenous depressed patients in remission and currently receiving treatment with imipramine ( mean length of treatment 145 days , SD=27 ) presented significantly lower buspirone responses to ACTH and cortisol than in the pre-treatment condition ( Deltamax p < or = .05 ; AUC p<.001 ) and to ACTH in comparison with healthy controls ( Deltamax p<.01 ; AUC p<.05 ) . No significant differences were found between the post-treatment and pre-treatment PRL responses , or between patients in both conditions and controls ; nevertheless , the PRL response in patients in remission and receiving treatment almost reached the values seen in controls . CONCLUSIONS This study extends previous findings from our group using the SSRI citalopram as an antidepressant . Imipramine and citalopram induce similar changes in the endocrine response to buspirone in depressed patients . As the direction of change in ACTH-cortisol and PRL responses after treatment is the opposite , we can not substantiate increases or decreases in the sensitivity of post-synaptic 5-HT1A receptors in the hypothalamus by long-term imipramine treatment and /or resolution of illness . Therefore , the hormonal changes may result from different or multiples unknown mechanisms Objectives : Although antidepressant medications are effective , they have a delayed onset of effect . Mirtazapine , an atypical antidepressant is an important option for add-on therapy in major depression . There is insufficient data on mirtazapine in Indian population ; hence this study was design ed to study the add-on effect of low-dose mirtazapine with selective serotonin reuptake inhibitors ( SSRIs ) in major depressive disorder ( MDD ) in Indian population . Material s and Methods : In an open , r and omized study , 60 patients were divided into two groups . In Group A ( n=30 ) patients received conventional SSRIs for 6 weeks . In Group B ( n=30 ) patients received conventional SSRIs with low-dose mirtazapine for 6 weeks . Patients were evaluated at baseline and then at 1 , 2 , 3 , 4 , 5 , and 6 weeks . Results : There was significant improvement in Hamilton Depression Rating Scale ( HDRS ) , Montgomery and Asberg depression rating scale ( MADRS ) scores ( P<0.05 ) in both groups . Mirtazapine in low dose as add on therapy showed improvement in scores , had earlier onset of action , and more number of responders and remitters as compared to conventional treatment ( P<0.05 ) . No serious adverse event was reported in either of the groups . Conclusion : Low-dose mirtazapine as add-on therapy has shown better efficacy , earlier onset of action and more number of responders and remitters as compared to conventional treatment in MDD in Indian patients Background Early rehabilitation after stroke is essential to help reduce disability . Purpose To summarize evidence on the benefits and harms of nonpharmacologic and pharmacologic treatments for motor deficits and mood disorders in adults who have had stroke . Data Sources English- language search es of multiple electronic data bases from April 2009 through July 2018 ; targeted search es to December 2018 for studies of selective serotonin reuptake inhibitors ( SSRIs ) or serotonin-norepinephrine reuptake inhibitors . Study Selection 19 systematic review s and 37 r and omized controlled trials addressing therapies for motor deficits or mood disorders in adults with stroke . Data Extraction One investigator abstract ed the data , and quality and GRADE assessment were checked by a second investigator . Data Synthesis Most interventions ( for example , SSRIs , mental practice , mirror therapy ) did not improve motor function . High- quality evidence did not support use of fluoxetine to improve motor function . Moderate- quality evidence supported use of cardiorespiratory training to improve maximum walking speed and repetitive task training or transcranial direct current stimulation to improve activities of daily living ( ADLs ) . Low- quality evidence supported use of robotic arm training to improve ADLs . Low- quality evidence indicated that antidepressants may reduce depression , whereas the frequency and severity of antidepressant-related adverse effects was unclear . Low- quality evidence suggested that cognitive behavioral therapy and exercise , including mind-body exercise , may reduce symptoms of depression and anxiety . Limitation Studies were of poor quality , interventions and comparators were heterogeneous , and evidence on harms was scarce . Conclusion Cardiorespiratory training , repetitive task training , and transcranial direct current stimulation may improve ADLs in adults with stroke .  Cognitive behavioral therapy , exercise , and SSRIs may reduce symptoms of poststroke depression , but use of SSRIs to prevent depression or improve motor function was not supported . Primary Funding Source U.S. Department of Veterans Affairs , Veterans Health Administration Previous research demonstrated that depression is associated with hyperactivity of the hypothalamus-pituitary-adrenocortical ( HPA ) system after stimulation . There is also strong evidence that the modulation of corticosteroids in the brain induces memory dysfunction which represents core features of depression . Antidepressant treatment with serotonin reuptake inhibitors ( SSRIs ) alleviates both dysfunctions . Thus , these previous observations propose a correlation between treatment induced changes of the endocrinological response of the HPA system to challenge with dexamethasone and CRH and changes of memory functions during antidepressant treatment . This study explores the relationship between depression , memory functions and the responsiveness of the HPA system as assessed by the combined DEX/CRH test during antidepressant treatment in n = 64 patients with major depression during a four weeks treatment with citalopram .  We found that treatment induced changes of the cortisol response pattern in the DEX/CRH test were correlated with improvement of working memory but not so with episodic memory , sustained attention or global severity of depression . We suggest that improvement of working memory is more sensitive to the changes of hormones of the HPA system ( e.g. cortisol ) than other cognitive functions and the global severity of depression Major depression disorder is most commonly treated with antidepressants . However , due to their side effects clinicians seek non-pharmacologic options , and one of these is exercise . The literature on the benefits of exercise for depression is extensive . Nevertheless , two recent review s focusing on antidepressants vs. other therapies as a basis for clinical practice guidelines recommended mainly antidepressants , excluding exercise as a viable choice for treatment of depression . The aim of this perspective is to analyze the literature exploring the reasons for this discrepancy . Two categories of publications were examined : r and omized controlled trials ( RCTs ) and meta-analyses or systematic review s. Based on this re assessment , RCTs comparing exercise to antidepressants reported that exercise and antidepressants were equally effective . RCTs comparing exercise combined with antidepressants to antidepressants only reported a significant improvement in depression following exercise as an adjunctive treatment . Almost all the review s examining exercise vs. other treatments of depression , including antidepressants , support the use of exercise in the treatment of depression , at least as an adjunctive therapy . The two review s examining pharmacologic vs. non-pharmacologic therapies as a basis for clinical practice guidelines examined limited evidence on exercise vs. antidepressants . In addition , it is possible that academics and health care practitioners are skeptical of viewing exercise as medicine . Maybe , there is a reluctance to accept that changes in lifestyle as opposed to pharmacological treatment can alter biological mechanisms . Longitudinal studies are needed for assessing the effectiveness of exercise in real clinical setting s , as well as studies exploring dose-response relationship between exercise and depression The Treatment of SSRI-Resistant Depression in Adolescents study ( TORDIA ) was design ed to inform clinicians as to the best next step in the treatment after a depressed adolescent has not responded to an adequate trial with a selective  serotonin re-uptake inhibitor (SSRI).[1 ] In this six-site study , conducted from 2000 to 2006 , 334 treatment-resistant adolescents with major depressive disorder ( MDD ) were r and omized to one of the four treatment strategies in a two-by-two balanced factorial design : ( a ) switch to another SSRI ; ( b ) switch to venlafaxine ; ( c ) switch to another SSRI and add cognitive behavioral therapy ( CBT ) ; or ( d ) switch to venlafaxine and add CBT . The SSRI switch options were fluoxetine , and for the first half of the trial ( n = 181 ) , paroxetine . Because of the concerns about the safety and efficacy of paroxetine , citalopram was used instead during the second half of the trial ( n = 153 ) . All enrolled youth had not responded to an “ adequate trial ” with an SSRI , defined as treatment for at least 8 weeks , with the last 4 weeks at a dosage that was the equivalent of 40 mg of fluoxetine . This communication focuses on acute treatment , which was 12 weeks in duration In this report , which is an up date of a guideline published in 2002 ( B and elow et al. 2002 , World J Biol Psychiatry 3:171 ) , recommendations for the pharmacological treatment of anxiety disorder , obsessive-compulsive disorder ( OCD ) and post-traumatic stress disorder ( PTSD ) are presented . Since the publication of the first version of this guideline , a substantial number of new r and omized controlled studies of anxiolytics have been published . In particular , more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs . The recommendations , developed by the World Federation of Societies of Biological Psychiatry ( WFSBP ) Task Force for the Pharmacological Treatment of Anxiety , Obsessive-Compulsive and Post-traumatic Stress Disorders , a consensus panel of 30 international experts , are now based on 510 published r and omized , placebo- or comparator-controlled clinical studies ( RCTs ) and 130 open studies and case reports . First-line treatments for these disorders are selective serotonin reuptake inhibitors ( SSRIs ) , serotonin-noradrenaline reuptake inhibitors ( SNRIs ) and the calcium channel modulator pregabalin . Tricyclic antidepressants ( TCAs ) are equally effective for some disorders , but many are less well tolerated than the SSRIs/SNRIs . In treatment-resistant cases , benzodiazepines may be used when the patient does not have a history of substance abuse disorders . Potential treatment options for patients unresponsive to st and ard treatments are described in this overview . Although these guidelines focus on medications , non-pharmacological were also considered . Cognitive behavioural therapy ( CBT ) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders , OCD , and PTSD to support them being recommended either alone or in combination with the above medicines OBJECTIVE Antidepressants that inhibit the reuptake of serotonin ( SSRIs ) or norepinephrine ( SNRIs ) are effective in the treatment of disorders such as depression and anxiety . Cognitive psychological theories emphasize the importance of correcting negative biases of information processing in the nonpharmacological treatment of these disorders , but it is not known whether antidepressant drugs can directly modulate the neural processing of affective information . The present study therefore assessed the actions of repeated antidepressant administration on perception and memory for positive and negative emotional information in healthy volunteers . METHOD Forty-two male and female volunteers were r and omly assigned to 7 days of double-blind intervention with the SSRI citalopram ( 20 mg/day ) , the SNRI reboxetine ( 8 mg/day ) , or placebo . On the final day , facial expression recognition , emotion-potentiated startle response , and memory for affect-laden words were assessed . Question naires monitoring mood , hostility , and anxiety were given before and after treatment . RESULTS In the facial expression recognition task , citalopram and reboxetine reduced the identification of the negative facial expressions of anger and fear . Citalopram also abolished the increased startle response found in the context of negative affective images . Both antidepressants increased the relative recall of positive ( versus negative ) emotional material . These changes in emotional processing occurred in the absence of significant differences in ratings of mood and anxiety . However , reboxetine decreased subjective ratings of hostility and elevated energy . CONCLUSIONS Short-term administration of two different antidepressant types had similar effects on emotion-related tasks in healthy volunteers , reducing the processing of negative relative to positive emotional material . Such effects of antidepressants may ameliorate the negative biases in information processing that characterize mood and anxiety disorders . They also suggest a mechanism of action potentially compatible with cognitive theories of anxiety and depression Objective : To examine the antidepressant efficacy of a dual-acting antidepressant ( mirtazapine ) in patients with post-myocardial infa rct ion ( MI ) depressive disorder . Antidepressants used in post MI trials with a r and omized , double-blind , placebo-controlled design have been restricted to selective serotonin reuptake inhibitors ( SSRIs ) . Antidepressant effects have been limited . Methods : In a prospect i ve multicenter study , 2177 patients with MI were evaluated for depressive disorder during the first year post MI . Ninety-one patients who met the Diagnostic and Statistical Manual of Mental Disorders , 4th Edition ( DSM-IV ) criteria for major or minor depressive disorder were r and omized to a 24-week , double-blind , placebo-controlled trial . Antidepressant efficacy was tested using last-observation-carried-forward procedure and repeated measurements analysis using the SPPS mixed models approach , with as primary outcome reduction in depressive symptomatology on the 17-item Hamilton-Depression Rating Scale ( Ham-D ) , and secondary outcomes the Beck Depression Inventory ( BDI ) and depression subscale of the Symptom Check List 90 items ( dSCL-90 ) as well as the Clinical Global Impression ( CGI ) scale . Results : Using the “ last observation carried forward ” ( LOCF ) method , mirtazapine did not show to be superior to placebo on the Ham-D , but did on the BDI , dSCL-90 , and CGI scale over the acute treatment phase of 8 weeks ( n = 91 ) . Using mixed models analysis over the entire 24 weeks of treatment ( n = 40 ) , we did find a significant difference favoring mirtazapine to placebo on the Ham-D , BDI , and CGI , but on the dSCL-90 , this difference was not significant . Conclusions : This trial shows efficacy of mirtazapine on primary and secondary depression measures . Mirtazapine seems to be safe in the treatment of post-MI depression . MI = myocardial infa rct ion ; RCT = r and omized controlled trial ; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders ; CAD = coronary artery disease ; SSRI = selective serotonin reuptake inhibitors ; TCA = tricyclic antidepressant ; Ham-D = Hamilton-Depression Rating Scale ; BDI = Beck Depression Inventory ; CGI = Clinical Global Impression ; dSCL-90 = Symptom Check List 90 items , depression subscale ; SES = st and ardized effect size BACKGROUND Escitalopram is the single isomer responsible for the serotonin reuptake inhibition produced by the racemic antidepressant citalopram . The present r and omized , double-blind , placebo-controlled , fixed-dose multicenter trial was design ed to evaluate the efficacy and tolerability of escitalopram in the treatment of major depressive disorder . METHOD Out patients with an ongoing DSM-IV major depressive episode ( N = 491 ) were r and omly assigned to placebo , escitalopram , 10 mg/day , escitalopram , 20 mg/day , or citalopram , 40 mg/day , and entered an 8-week double-blind treatment period following a 1-week single-blind placebo lead-in . Clinical response was evaluated by the Montgomery-Asberg Depression Rating Scale ( MADRS ) , the 24-item Hamilton Rating Scale for Depression ( HAM-D ) , the Clinical Global Impressions ( CGI ) scales , the Hamilton Rating Scale for Anxiety ( HAM-A ) , and patient-rated quality -of-life scales . RESULTS Escitalopram , at both doses , produced significant improvement at study endpoint relative to placebo on all measures of depression ; significant separation of escitalopram from placebo was observed within I week of double-blind treatment . Citalopram treatment also significantly improved depressive symptomatology compared with placebo ; however , escitalopram , 10 mg/day , was at least as effective as citalopram , 40 mg/day , at endpoint . Anxiety symptoms and quality of life were also significantly improved by escitalopram compared with placebo . The incidence of discontinuations due to adverse events for the escitalopram 10 mg/day group was not different from the placebo group ( 4.2 % vs. 2.5 % ; p = .50 ) , and not different for the escitalopram 20 mg/day group and the citalopram 40 mg/day group ( 10.4 % vs. 8.8 % ; p = .83 ) . CONCLUSION Escitalopram , a single isomer SSRI , is well-tolerated and has demonstrated antidepressant efficacy at a dose of 10 mg/day STAR*D is a multisite , prospect i ve , r and omized , multistep clinical trial of out patients with nonpsychotic major depressive disorder . The study compares various treatment options for those who do not attain a satisfactory response with citalopram , a selective serotonin reuptake inhibitor antidepressant . The study enrolls 4000 adults ( ages 18 - 75 ) from both primary and specialty care practice s who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode . After receiving citalopram ( level 1 ) , participants without sufficient symptomatic benefit are eligible for r and omization to level 2 treatments , which entail four switch options ( sertraline , bupropion , venlafaxine , cognitive therapy ) and three citalopram augment options ( bupropion , buspirone , cognitive therapy ) . Those who receive cognitive therapy ( switch or augment options ) at level 2 without sufficient improvement are eligible for r and omization to one of two level 2A switch options ( venlafaxine or bupropion ) . Level 2 and 2A participants are eligible for r and om assignment to two switch options ( mirtazapine or nortriptyline ) and to two augment options ( lithium or thyroid hormone ) added to the primary antidepressant ( citalopram , bupropion , sertraline , or venlafaxine ) ( level 3 ) . Those without sufficient improvement at level 3 are eligible for level 4 r and om assignment to one of two switch options ( tranylcypromine or the combination of mirtazapine and venlafaxine ) . The primary outcome is the clinician-rated , 17-item Hamilton Rating Scale for Depression , administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments . Secondary outcomes include self-reported depressive symptoms , physical and mental function , side-effect burden , client satisfaction , and health care utilization and cost . Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessment Objective : The alpha 2A-adrenergic receptor ( ADRA2A ) plays a central role in the regulation of systemic sympathetic activity . Recently , the functional defect of ADRA2A has been implicated as a cause of depression , attention deficit hyperactivity disorder , and Tourette syndrome . In this study , the effect of genetic variants of the ADRA2A gene on the response to selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors ( SNRIs ) was examined in depressed patients . Method : Ninety-three Japanese depressed patients were recruited in the present study , assigned r and omly to paroxetine or milnacipran , and assessed by the Hamilton Rating Scale for Depression ( HAM-D ) scoring every 2 weeks before and after drug administration . The ADRA2A C-1297 G polymorphism was considered in the association analysis with the efficacy of antidepressants . Results : There were significant differences in the HAM-D percent score change over time ( P = 0.019 ) among C/C , C/G , and G/G of the ADRA2A C-1297 G polymorphism in the total subjects . The C allele carriers of the ADRA2A C-1297 G polymorphism showed a significantly better improvement than G/G subjects at weeks 2 , 4 , and over time ( P = 0.037 ) in the milnacipran group . Discussion : Our findings suggest that ADRA2A plays an important role in depression therapy . The level of ADRA2A expression could be associated with the efficacy of SSRIs/SNRIs , especially milnacipran , although the functional change brought about by C-1297 G polymorphism has not yet been fully identified in vivo and in vitro . Conclusions : The ADRA2A polymorphism could be a reasonable c and i date to predict the response to milnacipran . Our results are still preliminary , and a large sample size will be required to confirm our findings . However , to the best of our knowledge , this study is the first to suggest a possible association of ADRA2A variants with the SNRI response Selective serotonin reuptake inhibitors ( SSRIs ) are widely used as effective pharmacological agents to treat depressive disorders . In contrast to the SSRIs , which block the presynaptic serotonin ( 5-HT ) transporter and by this route increase the concentration of serotonin in the synaptic cleft , the antidepressant tianeptine enhances the presynaptic neuronal reuptake of 5-HT and thus decreases serotonergic neurotransmission . Both SSRIs and tianeptine are clinical ly effective ; however , their opposite modes of action challenge the prevailing concepts on the need of enhancement of serotonergic neurotransmission . To better underst and the differences between these two opposite pharmacological modes of action , we compared the changes induced by tianeptine and paroxetine on psychopathology , the hypothalamic-pituitary-adrenocortical ( HPA ) system , and cognitive functions in a double-blind , r and omized , controlled trial including 44 depressed in patients over a period of 42 days .  Depressive symptomatology significantly improved in all efficacy measures , with no significant differences between tianeptine and paroxetine . There was a trend toward better response to the SSRI among women . Assessment of the HPA system showed marked hyperactivity before the beginning of treatment , which then normalized in most of the patients , without significant differences between the two antidepressants . Cognitive assessment s showed no significant differences between the two drugs investigated . The results of the current study suggest that the initial effect , i.e. , enhancement or decrease of 5-HT release , is only indirectly responsible for antidepressant efficacy , and they support the notion that downstream adaptations within and between nerve cells are crucial . The normalization of the HPA system as a common mode of action of different antidepressants seems to be of special interest UNLABELLED At present time tricyclic antidepressants ( TA ) are important tools in therapy of chronic pain . However administration of TA produce a number of side effects . Antidepressants of new generation , selective serotonin reuptake inhibitors ( SSRI ) induce less side effects in patients than TA . The aim of the study was to estimate an analgetic effect of antidepressant of new generation -- fluvoksamine ( Fevarin ) in treatment of ischialgia and comparison with an analgetic effect of impramine and tramadol -- opoid receptors antagonist .  70 patients with sociatic neuralgia were included to the research . They were at r and om divided into three groups . First one was treated with tramadol consisted of 22 persons ( 18 men and 4 women , average age--42.9 y. ) , second one treated with impramine consisted of 24 persons ( 18 men and 6 women , average age--43.2 y. ) and third one treated with  fluvoksamine  consisted of 24 persons ( 15 men and 9 women , average age--42.3 y. ) . Observation time was 19 days . Pain intensity was evaluated in four degree descriptive scale . Before and after treatment clinical symptoms of depression were estimated in groups of patients treated with impramine or fluvoksamine by Zung 's Depression Scale . There were no statistically significant differences in analgetic effect after treatment with fluvoksamine or impiramine . There was meaningly few number of side effects in the group treated with fluvoksamine . CONCLUSION Fluvoksamine and impramine have similar effectiveness in treatment of ischialgia , that is why fluvoksamine should be considered as medication when TA are contraindicated It has been suggested that the clinical efficacy of chronic treatment with selective serotonin reuptake inhibitors ( SSRIs ) such as fluoxetine and perhaps all antidepressants is due to their ability to enhance serotonergic activity . The effects of chronic treatment with fluoxetine or tricyclic antidepressants on the L-5-hydroxytryptophan ( 200 mg , L-5-HTP ; PO)–induced increases in plasma cortisol and prolactin ( PRL ) concentrations were studied in patients with major depression or obsessive compulsive disorder ( OCD ) . Administration of L-5-HTP increased plasma cortisol and PRL levels in medicated and unmedicated patients with major depression or OCD . The  L-5-HTP – induced cortisol and PRL responses were significantly higher in fluoxetine-treated than in tricyclic-treated or unmedicated major depressed patients . The latter two groups did not differ significantly in their cortisol or PRL responses to L-5-HTP . The L-5-HTP – induced increases in cortisol and PRL in fluoxetine-treated patients with major depression or OCD were not significantly different . The results suggest that fluoxetine , but not tricyclic antidepressants , potentiates 5-HT receptor – mediated stimulation of cortisol and PRL secretion in humans , consistent with available evidence that fluoxetine treatment , but not tricyclic antidepressants , increases central serotonergic activity in patients with MD or OCD by a presynaptic mechanism We examined allelic polymorphisms of the serotonin transporter ( 5-HTT ) gene and antidepressant response to 6 weeks ' treatment with the selective serotonin reuptake inhibitor ( SSRI ) drugs fluoxetine or paroxetine . We genotyped 120 patients and 252 normal controls , using polymerase chain reaction of genomic DNA with primers flanking the second intron and promoter regions of the 5-HTT gene . Diagnosis of depression was not associated with 5-HTT polymorphisms . Patients homozygous I/I in intron2 or homozygous s/s in the promoter region showed better responses than all others ( p < 0.0001 , p = 0.0074 , respectively ) . Lack of the I/I allele form in intron 2 most powerfully predicted non-response ( 83.3 % ) . Response to SSRI drugs  is related to allelic variation in the 5-HTT gene in depressed Korean patients AIMS We determined whether the start of selective serotonin reuptake inhibitors ( SSRI ) in levodopa users was followed by a faster increase of antiparkinsonian drug treatment . METHODS Selected were all levodopa users of 55 years and older from the PHARMO prescription data base . The rate of increase of  antiparkinsonian drug treatment  was compared using Cox 's proportional hazard model for starters of SSRI ( n = 15 ) with starters of tricyclic antidepressants ( TCA ) ( n = 31 ) and with patients not using antidepressants ( n = 304 ) , and was adjusted for age , gender , and duration of levodopa use . RESULTS The hazard ratio for the SSRI group compared with the TCA group was 4.2 ( 95 % confidence interval 1.4 , 12.6 ) and compared with the second control group was 2.7 ( 1.2 , 5.2 ) . CONCLUSIONS The start of SSRI therapy in levodopa users is followed by a faster increase of antiparkinsonian drug treatment OBJECTIVE Many cl aims have been made for superior compliance with selective serotonin reuptake inhibitors ( SSRIs ) compared with tricyclic antidepressants , but to date meta-analyses have not confirmed reduced dropouts in r and omized controlled trials . The authors used a r and omized study design to evaluate differential compliance with antidepressant medications in a primary care setting . METHOD A total of 152 patients treated in 10 primary care practice s in the United Kingdom were included in a r and omized , open-label , parallel-group study of fluoxetine and dothiepin at therapeutic doses for 12 weeks . Compliance was assessed by using pill count , patient question naires , and the Medication Event Monitoring System . RESULTS The level of compliance with fluoxetine was numerically higher than the level of compliance with dothiepin on all three primary outcome measures , although the differences were not significant . In a secondary analysis using data from the Medication Event Monitoring System , both a survival analysis for length of time without a gap in medicine taking and a derived compliance index showed a significant advantage to fluoxetine . Patients in the fluoxetine group reported superior response on the health transition scale of the 36-item Short-Form Health Survey Question naire and numerically greater improvement on the Hamilton Depression Rating Scale . In both treatment arms patients with a superior compliance index were more likely to have improved in Hamilton depression scale scores by the last study visit . CONCLUSIONS This study supports recent meta-analyses of SSRIs versus tricyclic antidepressants in finding no significant differences in crude indices of compliance between fluoxetine and dothiepin , despite marked differences in side effect profile and dose regimen . However , both a survival analysis and a new measure that takes account of prolonged periods of noncompliance distinguished between the treatments and was associated with improvement in both groups OBJECTIVE Selective serotonin reuptake inhibitors ( SSRIs ) are widely used to treat depression , but the rates , timing , and baseline predictors of remission in " real world " patients are not established . The authors ' primary objectives in this study were to evaluate the effectiveness of citalopram , an SSRI , using measurement-based care in actual practice , and to identify predictors of symptom remission in out patients with major depressive disorder . METHOD This clinical study included out patients with major depressive disorder who were treated in 23 psychiatric and 18 primary care " real world " setting s. The patients received flexible doses of citalopram prescribed by clinicians for up to 14 weeks . The clinicians were assisted by a clinical research coordinator in the application of measurement-based care , which included the routine measurement of symptoms and side effects at each treatment visit and the use of a treatment manual that described when and how to modify medication doses based on these measures . Remission was defined as an exit score of < or=7 on the 17-item Hamilton Depression Rating Scale ( HAM-D ) ( primary outcome ) or a score of < or=5 on the 16-item Quick Inventory of Depressive Symptomatology , Self-Report ( QIDS-SR ) ( secondary outcome ) . Response was defined as a reduction of > or=50 % in baseline QIDS-SR score . RESULTS Nearly 80 % of the 2,876 out patients in the analyzed sample had chronic or recurrent major depression ; most also had a number of comorbid general medical and psychiatric conditions . The mean exit citalopram dose was 41.8 mg/day . Remission rates were 28 % ( HAM-D ) and 33 % ( QIDS-SR ) . The response rate was 47 % ( QIDS-SR ) . Patients in primary and psychiatric care setting s did not differ in remission or response rates . A substantial portion of participants who achieved either response or remission at study exit did so at or after 8 weeks of treatment . Participants who were Caucasian , female , employed , or had higher levels of education or income had higher HAM-D remission rates ; longer index episodes , more concurrent psychiatric disorders ( especially anxiety disorders or drug abuse ) , more general medical disorders , and lower baseline function and quality of life were associated with lower HAM-D remission rates . CONCLUSIONS The response and remission rates in this highly generalizable sample with substantial axis I and axis III comorbidity closely resemble those seen in 8-week efficacy trials . The systematic use of easily implemented measurement-based care procedures may have assisted in achieving these results INTRODUCTION Some studies suggest that venlafaxine , due to its pharmacodynamic characteristics , could be an effective drug in depression , resistant to other antidepressive agents . This investigation explores the efficacy and tolerability of venlafaxine in major depression , resistant to a selective serotonin reuptake inhibitor ( SSRI ) . METHODS A multicenter naturalistic study was performed during 6 months and included those patients diagnosed of major depression according to the criteria of DSM-IV who had a minimum score of 18 on the Hamilton Depression Rating Scale ( HAM-D ) and who had not responded to previous treatment with a SSRI at therapeutic doses for a minimum of 4 weeks . The assessment of efficacy was performed with the HAM-D scale , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , the Hamilton Anxiety Rating Scale ( HAM-A ) and the Global Clinical Impression ( GCI ) . Tolerability was evaluated by recording the adverse reactions and with the GCI score on overall drug tolerability . RESULTS A total of 69 patients , of which 59 were evaluable for efficacy ( they had fulfilled at least 4 weeks of treatment ) , were included . About 81 % of all of them obtained a reduction of at least 50 % in the HAM-D , 74 % were considered as " quite improved " or " very improved " in the GCI and 69 % met both criteria . The mean dose of venlafaxine used was 170.4 ( S.D.=43.8 ) mg . Of the 21 patients who did not complete the 6 months of treatment , 3 were due to lack of efficacy , 6 due to adverse effects and 12 for other reasons . About 89.2 % of side effects were considered as mild or moderate . CONCLUSION The results of our study support the efficacy and tolerability of venlafaxine in patients suffering from depression who have not responded to SSRI treatment Abstract Safety and tolerability are important considerations when selecting patients ’ treatment for major depressive disorder . We report the long-term safety and tolerability of the nicotinic channel modulator dexmecamylamine ( TC-5214 ) , adjunct to selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors ( SNRIs ) in patients with major depressive disorder and who had an inadequate response to antidepressants . This 52-week , double-blind , placebo-controlled study explored the long-term safety and tolerability of dexmecamylamine .  Patients were r and omized 3:1 to receive flexibly dosed dexmecamylamine 1 to 4 mg adjunct to SSRI/SNRI or placebo plus SSRI/SNRI . The patient population comprised inadequate responders from 2 Phase III acute  dexmecamylamine  studies ( NCT01157078 [ study 002 ] , NCT01153347 [ study 004 ] ) and de novo patients who responded inadequately during a 6-week open-label antidepressant treatment period preceding r and omization .  Safety and tolerability were assessed by monitoring adverse events , vital signs , and physical and laboratory parameters . Descriptive statistical analyses were performed on most efficacy-related end points . Sustained efficacy was analyzed using logistic regression . Overall , 813 patients were r and omized ( 610 received dexmecamylamine , 203 received placebo ) . In total , 82.4 % and 84.6 % of patients , respectively , experienced an adverse event . Adverse events occurring more frequently with dexmecamylamine vs placebo were constipation ( 19.6 % vs 6.0 % ) , dizziness ( 12.0 % vs 7.0 % ) , and dry mouth ( 9.7 % vs 5.0 % ) . Back pain ( 2.8 % vs 8.5 % ) , weight increase ( 4.4 % vs 7.0 % ) , and fatigue ( 5.6 % vs 7.5 % ) occurred more frequently in placebo-treated patients . No notable differences were observed between dexmecamylamine and placebo for any secondary end point . In this long-term study , safety and tolerability of dexmecamylamine were consistent with that reported in acute Phase III studies of dexmecamylamine BACKGROUND In 2001 , the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments ( CANMAT ) partnered to produce evidence -based clinical guidelines for the treatment of depressive disorders .  A revision of these guidelines was undertaken by CANMAT in 2008 - 2009 to reflect advances in the field . This article , one of five in the series , review s new studies of psychotherapy in the acute and maintenance phase of MDD , including computer-based and telephone-delivered psychotherapy . METHODS The CANMAT guidelines are based on a question -answer format to enhance accessibility to clinicians . Evidence -based responses are based on up date d systematic review s of the literature and recommendations are grade d according to the Level of Evidence , using pre-defined criteria . Lines of Treatment are identified based on criteria that included evidence and expert clinical support . RESULTS Cognitive-Behavioural Therapy ( CBT ) and Interpersonal Therapy ( IPT ) continue to have the most evidence for efficacy , both in acute and maintenance phases of MDD , and have been studied in combination with antidepressants . CBT is well studied in conjunction with computer-delivered methods and bibliotherapy . Behavioural Activation and Cognitive-Behavioural Analysis System of Psychotherapy have significant evidence , but need replication . Newer psychotherapies including Acceptance and Commitment Therapy , Motivational Interviewing , and Mindfulness-Based Cognitive Therapy do not yet have significant evidence as acute treatments ; nor does psychodynamic therapy . LIMITATIONS Although many forms of psychotherapy have been studied , relatively few types have been evaluated for MDD in r and omized controlled trials . Evidence about the combination of different types of psychotherapy and antidepressant medication is also limited despite widespread use of these therapies concomitantly . CONCLUSIONS CBT and IPT are the only first-line treatment recommendations for acute MDD and remain highly recommended for maintenance . Both computer-based and telephone-delivered psychotherapy -- primarily studied with CBT and IPT -- are useful second-line recommendations . Where feasible , combined antidepressant and CBT or IPT are recommended as first-line treatments for acute MDD BACKGROUND The increasing cost of pharmaceuticals in the Czech Republic has led to the restriction on prescriptions of expensive new antidepressants . The aim of the study was to compare the costs and outcomes of using amitriptyline , citalopram and fluoxetine in the treatment of major depression . METHODS Ninety patients ( 69 women ) with a mean age of 44.5 years ( S.D. = 14.3 ) suffering from major depression were treated with amitriptyline ( N = 31 ) , citalopram ( N = 29 ) and fluoxetine ( N = 30 ) . Direct medical costs and effectiveness ( indicated by the number of hospitalization-free days ) were assessed in a prospect i ve , open , intent-to-treat study . RESULTS Neither cost nor effectiveness were significantly different among the treatment groups . CONCLUSION Amitriptyline treatment is not less expensive nor more effective than citalopram or fluoxetine therapies . There is no advantage in restricting patients from treatment with SSRIs , which have fewer adverse effects and a decreased risk of a lethal overdosage in comparison with tricyclic antidepressants BACKGROUND It is well established that depressive disorders are more prevalent in women ; however gender differences in the pharmacological response to antidepressants are not a consistent finding in all reports . It is considered that this discrepancy can be explained by the fact that in most clinical trials drug use for comparative purpose s is not completely different . In this study gender differences in antidepressant response with citalopram ( CTP ) , a selective serotonin reuptake inhibitor and reboxetine ( RBX ) , a selective noradrenaline reuptake inhibitor were evaluated in a group of young men and premenopausal women . METHOD Eighty-six depressed patients 18 to 40 years old participated in an 8-week double-blind clinical trial . Subjects were divided in four groups according to sex and treatment assignation : females treated with CTP ( n = 25 ) or RBX ( n = 23 ) , and males treated with CTP ( n = 19 ) or RBX ( n = 19 ) . Response was determined using HDRS and BDI . RESULTS ANOVA analysis considering change in HDRS scores from baseline to last evaluation found a significant interaction between gender and type of treatment . Females treated with CTP showed a significantly greater response than females treated with RBX , while in men no differences were observed for both drugs . LIMITATIONS Replication using larger sample size and longer treatment periods is required . CONCLUSIONS These results support previous findings which show that premenopausal women respond better than men to serotonergic antidepressants . They also support that a plausible interaction between gonadal hormones and serotonin may explain gender differences in antidepressant response BACKGROUND Generalized anxiety disorder  ( GAD ) is a common and serious disease with a lifetime prevalence of 4.3 % to 5.9 % . It is underdiagnosed in primary care . METHODS Recommendations on the treatment of GAD are given on the basis of all available findings from pertinent r and omized trials , retrieved by a selective search of the literature . RESULTS Among psychotherapeutic techniques , various kinds of cognitive behavioral therapy ( CBT ) have been found useful in controlled trials . The drugs of first choice include selective serotonin reuptake inhibitors ( SSRIs ) , serotonin-norepinephine reuptake inhibitors ( SNRIs ) , and the calcium-channel modulator pregabalin . Tricyclic antidepressants are also effective but have more adverse effects than SSRIs . Although benzodiazepines are effective anxiolytic agents for short-term use , they should not be given over the long term because of the danger of addiction . Buspirone , an azapirone , was found to be effective in a small number of trials , but the findings across trials are inconsistent . The response rate of GAD to CBT in published studies lies between 47 % and 75 % , while its response rate to drug treatment lies between 44 % and 81 % . CONCLUSION The treatment of GAD with CBT and drugs is evidence -based and has a good chance of improving the manifestations of the disorder Elderly depressed patients are vulnerable to recurrence of depression and benefit from long-term antidepressant therapy . Physicians increasingly use selective serotonin re-uptake inhibitors ( SSRIs ) as maintenance therapy , although in the absence of data showing that SSRIs are as efficacious as tricyclic antidepressants ( TCAs ) in the prevention of depression relapse and recurrence . Our objective was to evaluate , in an open trial , the efficacy of paroxetine versus nortriptyline for preventing recurrence of depression in the elderly . Elderly patients with major depression were r and omly assigned in a double-blinded fashion to receive either paroxetine or nortriptyline for the acute treatment of depression . Patients who did not respond or tolerate their assigned medications were crossed over openly to the comparator agent . Patients whose depression remitted continued antidepressant medication ( paroxetine n = 38 ;  nortriptyline  n = 21 ) during an open 18-month follow-up study . We examined the rates of and times to relapse and to termination of treatment for any reason . Paroxetine  ( PX ) and nortriptyline ( NT ) patients had similar rates of relapse ( 16 % vs. 10 % , respectively ) and time to relapse ( 60.3 weeks vs. 58.8 weeks , respectively ) over 18 months . A lower burden of residual depressive symptoms and side effects during continuation and maintenance treatment was evident in nortriptyline-treated patients . Paroxetine and nortriptyline demonstrated similar efficacy in relapse and recurrence prevention in elderly depressed patients over an 18-month period In their interesting paper , Khan and Brown ( 1 ) sought to summarize the factors contributing to the trend of continuously decreasing drug-placebo differences in antidepressant r and omized controlled trials ( RCTs ) ( 2 ) . This trend conveys the impression that the newer marketed antidepressants are less efficacious than the older ones , or even that the older and well-established antidepressants have lost efficacy over time . Thus , recognizing the method ological reasons for the decline in antidepressant-placebo separation within RCTs is highly relevant in order to appraise the clinical value of an antidepressant for psychiatric routine care . This is especially meaningful with regard to newly developed and newly introduced antidepressants . In our opinion , the constant increase in placebo response over the last decades is the main factor accounting for the mitigation of the drug-placebo differences in antidepressant RCTs . Due to the larger symptom improvement of study participants r and omized to placebo , it is much more difficult for an antidepressant to outperform placebo at a statistically significant level . This could be the beginning of an ominous cascade . The diminishing drug-placebo contrast leads to a higher probability of so-called inconclusive or even negative trials . As a consequence , the risk for a newly developed compound to fail the market approval because of negative phase III studies increases . As such late failure is associated with enormous costs for the pharmaceutical industry , this could result in a slowdown of research efforts for new antidepressant agents . An often cited reason for the continuously increasing placebo response is the fact that placebo administration represents in itself a non-specific treatment ( 3 ) . Study participants in the placebo groups of RCTs receive enormous clinical attention . Indeed , parallel to the raising placebo response in RCTs , the requirements concerning the accomplishment of RCTs have become more stringent , for instance through the need of an increasingly closer monitoring of participants ( 4 ) . The intensive contact with the clinical staff can produce positive effects in terms of symptom improvement , particularly in not severely ill participants , who are nowadays increasingly included in RCTs , because the enrollment of more severely ill patients is often not possible due to ethical concerns ( a phenomenon called “ baseline inflation ” ) . Another element contributing to the magnitude of placebo response in RCTs is the hope of participants in the placebo groups to receive an active , efficacious treatment ( a phenomenon called “ hope induction ” or “ expectation bias ” ) . A number of systematic evaluations corroborate this assumption : the more study arms an RCT comprised ( i.e. , the lower the probability to receive placebo ) , the higher was the placebo response . On the other h and , the highest antidepressant response was found in direct drug comparisons ( head-to-head trials ) , where participants were certain to receive active drug treatment ( 5 ) . Furthermore , in many antidepressant RCTs , the enrolled subjects are not representative of clinical practice , in which a number of depressive patients suffer from severe comorbidities or suicidal ideation . Exactly those severely ill patients who are excluded from RCTs might particularly benefit from antidepressant pharmacotherapy . However , it must be noted that , in some analyses , a higher symptom severity at baseline was associated with a higher placebo response ( 6 ) , a phenomenon which is not fully understood as yet . There is a large body of evidence suggesting that clinical studies carried out in the U.S. are characterized by a larger placebo response compared to non-U.S. trials . This phenomenon could be observed , to provide a recent example , in RCTs of vortioxetine ( 7 ) . The inclusion of so-called professional research participants in U.S. studies may account for this finding . These subjects are mainly recruited by advertisements , and their motivation is often the prospect for free medication or other financial compensation . Therefore , they often aim to please the investigators in order to be invited again for participation in a clinical study . It appears meaningful to emphasize that the drug-placebo contrast in long-term , relapse-prevention studies is usually higher compared to acute-phase trials ( 8) . Interestingly , in a double-blind , long-term citalopram RCT , responders to acute-phase treatment were r and omized to either placebo or continuing citalopram , while placebo responders of the acute phase continued the placebo administration under double-blind conditions . Both placebo responders and citalopram responders receiving placebo in the long-term study exhibited a higher relapse rate compared to the participants in the citalopram continuation arm ( 9 ) , suggesting that the underlying biological abnormality is not sensitive to placebo . In summary , the reasons contributing to the raising placebo response over time and the subsequent decreasing drug-placebo separation should be critically considered in the interpretation of antidepressant clinical trial results . Expectation bias and increased clinical attention are often called “ unspecific effects ” of placebo administration , and these effects are not present in routine clinical care ( 10 ) . Therefore , it can be assumed that the effectiveness of an antidepressant in the routine care is higher than the antidepressant-placebo difference of RCTs indicates . The increase over time of  placebo response should also be considered in meta-analyses ( 11 ) , in which data are pooled from trials carried out in different periods CONTEXT Only about 60 % of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor ( SSRI ) . There are no data to guide clinicians on subsequent treatment strategy . OBJECTIVE To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI .  DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI , conducted at 6 US academic and community clinics from 2000 - 2006 . INTERVENTIONS Twelve weeks of : ( 1 ) switch to a second , different SSRI ( paroxetine , citalopram , or fluoxetine , 20 - 40 mg ) ; ( 2 ) switch to a different SSRI plus cognitive behavioral therapy ; ( 3 ) switch to venlafaxine ( 150 - 225 mg ) ; or ( 4 ) switch to venlafaxine plus cognitive behavioral therapy . MAIN OUTCOME MEASURES Clinical Global Impressions-Improvement score of 2 or less ( much or very much improved ) and a decrease of at least 50 % in the Children 's Depression Rating Scale-Revised ( CDRS-R ) ; and change in CDRS-R over time . RESULTS Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate ( 54.8 % ; 95 % confidence interval [ CI ] , 47%-62 % ) than a medication switch alone ( 40.5 % ; 95 % CI , 33%-48 % ; P = .009 ) , but there was no difference in response rate between venlafaxine and a second SSRI ( 48.2 % ; 95 % CI , 41%-56 % vs 47.0 % ; 95 % CI , 40%-55 % ; P = .83 ) . There were no differential treatment effects on change in the CDRS-R , self-rated depressive symptoms , suicidal ideation , or on the rate of harm-related or any other adverse events . There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment . CONCLUSIONS For adolescents with depression not responding to an adequate initial treatment with an SSRI , the combination of cognitive behavioral therapy and a switch to another antidepressant result ed in a higher rate of clinical response than did a medication switch alone . However , a switch to another SSRI was just as efficacious as a switch to venlafaxine and result ed in fewer adverse effects . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00018902 OBJECTIVE Previous reports suggesting that selective serotonin reuptake inhibitor ( SSRI ) use is associated with increased suicidal risk have not assessed completed suicides . The authors analyzed reports from r and omized controlled trials to compare suicide rates among depressed patients assigned to an SSRI , other antidepressants , or placebo .  METHOD Food and Drug Administration ( FDA ) summary reports of the controlled clinical trials for nine modern FDA -approved antidepressants provided data for comparing rates of suicide . RESULTS Of 48,277 depressed patients participating in the trials , 77 committed suicide . Based on patient exposure years , similar suicide rates were seen among those r and omly assigned to an SSRI ( 0.59 % , 95 % confidence interval [CI]=0.31%-0.87 % ) , a st and ard comparison antidepressant ( 0.76 % , 95 % CI=0.49%-1.03 % ) , or placebo ( 0.45 % , 95 % CI=0.01%-0.89 % ) . CONCLUSIONS These findings fail to support either an overall difference in suicide risk between  antidepressant- and placebo-treated depressed subjects in controlled trials or a difference between SSRIs and either other types of antidepressants or placebo BACKGROUND Patients with depression have higher rates of cardiac morbidity and mortality . Alterations of cardiac autonomic functions associated with depression may partly explain this . Prospect i ve studies comparing the effects of antidepressants on these abnormalities are limited due to confounding factors and co-morbidities . METHODS Cardiac autonomic functions were studied in  antidepressant naïve patients with major depression ( without co-morbid medical or psychiatric disorders ) before and after treatment with repetitive transcranial magnetic stimulation ( rTMS ; n=30 ) , specific serotonin reuptake inhibitors ( SSRIs ; n=32 ) and tricyclic antidepressants ( TCAs ; n=32 ) . Conventional autonomic function tests and time- and frequency-domain measures of heart rate variability ( HRV ) were measured using st and ard procedures . Changes in autonomic functions were compared across the three treatment groups using repeated measures analysis of variance ( ANOVA ) using sex and age as covariates . RESULTS Depression improved by comparable extent across patients treated with the three treatments . Overall , there was no change in cardiac autonomic functions . However , significant group × occasion interactions were noted for HRV measures . Both time- and frequency-domain HRV measures showed increase with rTMS and decrease with TCAs ; they remained virtually unchanged with SSRIs . LIMITATIONS One of the major limitations of our work being we could not r and omize the treatment groups . CONCLUSIONS The effects of antidepressant treatments on cardiac autonomic function abnormalities found in depression vary with the mode of treatment used . Long-term clinical implication s of these effects on cardiac health of patients with depression need further studies Rationale Premature discontinuation of antidepressant drugs is a frequent clinical problem . Adverse effects are common , occur early on in treatment and are reported to be one of the main reasons for discontinuation of antidepressant treatment . Objectives To investigate the association between adverse effects occurring in the first 2 weeks of antidepressant treatment and discontinuation by 6 weeks as the outcome . To investigate the time profile of adverse effects induced by the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine over 12 weeks of treatment . Methods Six hundred and one depressed individuals were r and omly allocated to either citalopram ( 20 mg daily ) or reboxetine ( 4 mg twice daily ) . A modified version of the Toronto Side Effects Scale was used to measure 14 physical symptoms at baseline ( medication free ) and at 2 , 6 and 12 weeks after r and omisation . Results Individuals r and omised to reboxetine reported a greater number of adverse effects and were more likely to stop treatment than individuals receiving citalopram . Dizziness ( OR 1.83 ; 95 % CI 1.09 , 3.09 ; p = 0.02 ) and the total number of adverse effects ( OR 1.12 ; 95 % CI 1.00 , 1.25 ; p = 0.06 ) reported at 2 weeks were associated with discontinuation from overall antidepressant treatment by 6 weeks . Reports of adverse effects tended to reduce throughout the 12 weeks for both antidepressants . Conclusions The majority of adverse effects were not individually associated with discontinuation from antidepressant treatment . Reports of physical symptoms tended to reduce over time . The physical symptoms that did not reduce over time may represent symptoms of depression rather than antidepressant-induced adverse effects Background The efficacy of antidepressants in irritable bowel syndrome ( IBS ) is controversial . No trials have directly compared a tricyclic with a selective serotonin reuptake inhibitor . Our aim was to determine whether imipramine and citalopram are efficacious in IBS . Methods This was a r and omized , double-blind , placebo-controlled , parallel group pilot trial with imipramine ( 50 mg ) and citalopram ( 40 mg ) . Results Of 51 IBS patients r and omized , baseline characteristics were comparable among the treatment arms ; the majority was diarrhea-predominant . Adequate relief of IBS symptoms ( primary endpoint ) was similar for each treatment arm . Improvements in bowel symptom severity rating for interference ( P = 0.05 ) and distress ( P = 0.02 ) were greater with imipramine versus placebo , but improvements in abdominal pain were not . There was a greater improvement in depression score ( P = 0.08 ) and in the SF-36 Mental Component Score ( P = 0.07 ) , with imipramine . Citalopram was not superior to placebo . Approximately 20 % of the variance in scores was explained by treatment differences for abdominal pain , bowel symptom severity disability , depression and the mental component of the SF-36 . Conclusion Neither imipramine nor citalopram significantly improved global IBS endpoints over placebo & NA ; Two selective serotonin reuptake inhibitors ( SSRIs ) , citalopram and fluoxetine , both at a daily dose of 20 mg , were compared in patients with unipolar major depression treated in general practice . This was a multicentre , double‐blind , r and omized trial carried out in France . The duration of treatment was 8 weeks . Patients were assessed by means of the Montgomery‐Åsberg Depression Rating Scale ( MADRS ) , the 17 items Hamilton Depression Rating Scale ( HAMD ) and the investigator 's Clinical Global Impressions ( CGI ) . Observed and spontaneously reported adverse events were also recorded . A total of 357 patients of both sexes , aged between 21 and 73 years , entered the double‐blind phase of the trial . A clear reduction of both the MADRS and the HAMD mean total scores was observed in both treatment groups with no statistically significant differences between treatments . Apart from back pain recorded more frequently in the citalopram group , no significant difference was found between the two treatment groups with regard to adverse events , and both citalopram and fluoxetine were considered to be well tolerated . It was concluded that citalopram was as effective as fluoxetine in the treatment of unipolar major depression . Citalopram showed an earlier onset of recovery than fluoxetine From theoretical and clinical perspectives , it is important to know if selected serotonin-reuptake inhibitors ( SSRIs ) , often administered concurrently with electroconvulsive therapy ( ECT ) , modify seizure duration . In a study with a double-blind , cross-over design , the authors evaluated the effect of citalopram , the most selective SSRI available , on the length of electrically induced seizures and on hormone secretion during ECT . Ten depressed women were given either 20 mg citalopram or placebo orally 2 hours before the third and fourth ECT sessions . Seizure duration was assessed by the cuff technique and from electroencephalographic recordings , whereas blood for prolactin , thyrotropin , and cortisol assessment was sample d before ECT and 5 , 10 , 20 , 30 , 40 , and 60 minutes after ECT . No adverse effects after the administration of citalopram were recorded . The length of seizures was not statistically different in the citalopram ( 29.3 ± 8.4 seconds ) and placebo sessions ( 28.2 ± 9.4 seconds ) . Neither pre-ECT plasma hormone levels measured 2 hours after citalopram or placebo administration nor the patterns of ECT-induced hormone secretions differed between the two drug and placebo conditions . The lack of effect of citalopram on hormones in this study may be a result of possible deficiencies of the monoaminergic ( i.e. , serotoninergic ) systems in depression . Although safety and efficacy issues were not fully addressed by coadministering citalopram for the long term and throughout the course of ECT , these findings support the view that challenges the typical clinical practice of discontinuing SSRIs before ECT Fluoxetine is the first selective serotonin reuptake inhibitor antidepressant to be marketed in the U.S. In this double-blind trial fluoxetine was compared with imipramine and placebo among 198 out patients with DSM-III major depression , of whom 145 completed at least 2 weeks of active treatment and were evaluated for efficacy . Significantly fewer patients in each active drug group terminated early due to lack of efficacy compared to placebo . Both imipramine and fluoxetine were significantly superior to placebo on most measures . There were no consistently significant differences between the two active drugs although a trend favored imipramine on a number of measures . Fluoxetine was generally well tolerated . Significantly more imipramine than placebo patients terminated early due to side-effects while the fluoxetine-placebo difference was not significant . The results support previous studies which suggest fluoxetine 's superior side-effect profile and the approximate antidepressant equivalence of fluoxetine and TCAs Paroxetine , a selective serotonin reuptake inhibitor ( SSRI ) antidepressant , is considered to have fewer side-effects than a typical tricyclic antidepressant . As the elderly frequently suffer from adverse effects of psychotropic drugs , safeties and tolerance of paroxetine and their relationship with dose were studied in a double-blind study . Sixteen nondashhospitalised depressed patients , aged 72 - 86 years , were recruited but 12 patients completed the study . Patients were r and omly selected to receive either 15 mg or 30 mg paroxetine daily for 42 days in a double-blind study . A trained nurse made weekly home visits to monitor their medication and general conditions . Patients were assessed at the hospital on days 1 , 7 , 14 , 28 and 42 . There were four drop-outs during the first week of study due to lack of motivation , skin rash and upper gastrointestinal symptoms ( n=2 ) . Plasma levels of paroxetine  showed a dose-related increase in concentrations and indicated a good compliance . At the dosages used , no changes in blood pressure , heart rate , salivary volume , visual choice reaction time , critical flicker fusion threshold and short-term memory were observed in these patients . However , there was a significant improvement in their subjective symptoms ( as assessed by a symptom check list and Hamilton Rating Scale ) in the 30 mg group , indicating a feeling of well-being Context Does augmentation with an atypical antipsychotic improve symptoms in patients with major depression that is suboptimally responsive to antidepressant monotherapy ? Contribution This double-blind r and omized trial found that 6 weeks of treatment with risperidone improved symptoms more than placebo in 274 adults with major depression that was suboptimally responsive to antidepressant monotherapy . Risperidone , compared with placebo , result ed in more remissions ( 25 % vs. 11 % ) , as well as more cases of somnolence ( 5 % vs. 2 % ) and dry mouth ( 5 % vs. 1 % ) . Caution The trial duration was short , and 19 % of risperidone recipients did not complete treatment . Implication Risperidone augmentation may improve symptoms in some patients with suboptimal response to antidepressant monotherapy . The Editors Major depressive disorder is the leading cause of disability worldwide ( 1 ) , affecting nearly 121 million people . It is associated with increased overall mortality ( 2 , 3 ) ; premature cardiovascular-related death ( 4 , 5 ) ; and morbidity , including disability , lost productivity , and decreased wages , compared with individuals without depression ( 6 ) . Selective serotonin reuptake inhibitors ( SSRIs ) and serotoninnorepinephrine reuptake inhibitors are generally considered first-line treatments for depression . Despite a sufficient dose and duration of antidepressant treatment , symptoms do not resolve in 30 % to 40 % of patients with major depressive disorder ( 710 ) . Remission , defined as the virtual absence of depressive symptoms , is important because it is associated with improved patient prognosis and functioning relative to response ( generally defined as 50 % reduction in symptoms ) ( 11 , 12 ) . In an effort to improve the therapeutic efficacy of antidepressant monotherapy , several pharmacologic strategies to modulate different or additional neurotransmitters ( 1315 ) are commonly used , despite a paucity of evidence from r and omized clinical trials . These strategies include switching monotherapy within ( 10 , 1618 ) or between antidepressant classes ( 10 , 1921 ) , combination regimens consisting of 2 antidepressants ( 2226 ) , and augmentation of antidepressants with nonst and ard treatmentsfor example , thyroid hormone ( 27 ) ; S-adenosyl-l-methionine ( 28 ) ; lithium ( 29 ) ; cyclooxygenase-2 inhibitors ( 30 ) ; or an atypical antipsychotic ( 3133 ) , such as risperidone . Findings of several open-label studies ( 3135 ) suggest that atypical antipsychotic augmentation provides benefit in major depressive disorder that is suboptimally responsive to antidepressant monotherapy . Risperidone , whose activity includes blockade of certain serotonin and dopamine receptors , is considered an atypical antipsychotic . It is approved in the United States for treatment of bipolar mania and schizophrenia and in other countries for additional uses . The efficacy of risperidone has also been studied for various psychoses and behavioral disorders , including treatment-resistant depression and anxiety spectrum disorders ( 34 , 3639 ) . We hypothesized that low-dose risperidone augmentation would reduce symptoms of major depressive disorder , enhance clinical response and remission rates , and reduce disability and improve quality of life compared with continued antidepressant monotherapy . Preliminary data suggest that persons with a confirmed suboptimal response to previous treatment may respond to risperidone augmentation within 4 to 6 weeks ( 38 ) . We therefore conducted a large , multicenter , double-blind , placebo-controlled trial to assess the clinical efficacy of risperidone augmentation from the clinician and patient perspectives and to evaluate tolerability in patients with major depressive disorder who continue to experience symptoms despite an adequate trial of st and ard antidepressants . Methods Design Consenting persons entered a 4-week prospect i ve open-label run-in period during which they received their current antidepressant monotherapy at the dosages recommended in product labeling , so that we could confirm an insufficient response to st and ard monotherapy . The run-in period was followed by a 6-week double-blind treatment phase ; during this phase , patients who continued to experience depressive symptoms , defined as a Clinical Global ImpressionSeverity of illness ( CGI-S ) score of 4 or greater and a Carroll Depression Scale ( 40 ) score of 20 or greater , were r and omly assigned to receive risperidone augmentation therapy or placebo . A 4-week follow-up phase of open-label risperidone augmentation therapy was available to participants who completed at least 4 weeks of double-blind treatment ( results not shown ) . Setting and Participants Out patients 18 to 65 years of age who had received antidepressant monotherapy for at least 4 weeks and met the Diagnostic and Statistical Manual of Mental Disorders , fourth edition ( 41 ) , criteria for unremitting major depressive disorder ( single or recurrent episodes ) and a CGI-S score of 4 or more ( 42 ) at the start of both the open-label and double-blind phases were eligible . The CGI-S is scored on a scale of increasing intensity from 1 to 7 , with 4 representing moderate illness . We recruited participants by using various methods , including media advertisements , and enrolled persons from 75 public and private primary care ( n= 41 ) and psychiatric ( n= 34 ) centers in the United States between 19 October 2004 and 17 November 2005 . Ethical approval was obtained from the institutional review board of each site , and written informed consent was obtained from all patients . Exclusion criteria were pregnancy ; serious suicidal risk or serious medical or neurologic illness ; active substance or alcohol use disorders ; or current treatment with a tricyclic antidepressant , monoamine oxidase inhibitor , mood stabilizer , antiepileptic , or a central ly acting agent for attention deficit disorder/attention deficit hyperactivity disorder or narcolepsy . R and omization and Interventions Patients who were eligible for r and omization continued their st and ard antidepressant regimen and dosage and were assigned to receive risperidone or placebo . Tablets were identical in appearance . The investigators , study staff , and patients were blinded to the treatment assignment . The r and omization code was central ly generated and administered by a telephone interactive voice response system , was stratified by antidepressant class ( SSRI or non-SSRI ) and center , and occurred in r and om permuted blocks . An independent statistician provided the r and omization codes . The dosing schedule was 0.25 mg for the first 3 days , 0.5 mg on days 4 to 15 , and 1.0 mg on days 16 to 28 . On day 29 , patients with insufficient treatment response in the opinion of the investigator could continue augmentation at the current dosage , have the dosage increased to 2 mg/d , or discontinue double-blind treatment . Concomitant medications were allowed as necessary for medical conditions . Sedative agents ( zolpidem , 2.5 to 10 mg/d , or zaleplon , 5 to 20 mg/d , as needed ) were allowed for insomnia . During double-blind treatment , benztropine mesylate was permitted as needed for potential treatment-emergent motor effects . Measurements and Outcomes At each visit ( end of the open-label phase and weeks 1 , 2 , 4 , and 6 ) , trained personnel administered the grid version of the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) ( 43 , 44 ) and the CGI-S ( 42 ) , both clinician-rated instruments . Scores on the HRSD-17 range from 0 to 52 ; higher scores indicate more severe depression . Patients also independently rated their response by using the telephone interactive voice response system at baseline and weekly thereafter . Other patient-reported outcomes were scores on 3 vali date d instruments : the Quality of Life Enjoyment and Satisfaction Question naire ( Q-LES-Q ) ( 45 ) , the Patient Global Improvement Scale ( 7-point rating from 1 [ very much improved ] to 7 [ very much worse ] ) , and the Sheehan Disability Scale ( SDS ) . Change in HRSD-17 total score from baseline to study end was the a priori primary efficacy measure . Response ( 50 % reduction in HRSD-17 total score from baseline ) and remission ( HRSD-17 total score 7 ) were assessed at each time point . Secondary measures were changes in the CGI-S , Q-LES-Q , SDS , and Patient Global Improvement Scale scores . Follow-up Patients underwent physical examination , including assessment of vital signs , at regular intervals . Research staff maintained records of trial medication and assessed treatment compliance by matching doses taken with the number of treatment days . To assess adverse effects , patients were interviewed at each study visit with open-ended questions about potential adverse events ; spontaneous reports were also taken into account . All adverse events were recorded , and the investigator assessed each event for severity and relationship to the study drug ( probable , possible , not related ) . Statistical Analysis A sample of 116 patients per group was anticipated to have 90 % power to detect an arbitrary difference in change in mean HRSD-17 total score of 3.0 units , assuming a common SD of 7.0 using a 2-group t test and a 2-sided significance level of 0.05 . We also assumed that approximately 30 % of the participants would not complete double-blind treatment and planned for 332 persons to undergo r and omization . We further assumed that during the open-label run-in phase , 30 % of participants would discontinue the study and 20 % would respond to st and ard antidepressant treatment and therefore be ineligible for r and omization ; thus , we sought 592 persons for the open-label run-in phase . All analyses were performed by using SAS , version 8.2 ( SAS Institute , Cary , North Carolina ) , and statistical analysis personnel were blinded to patient group assignment . Baseline patient characteristics were summarized by using descriptive statistics . Efficacy and safety analyses were based on the intention-to-treat population ( that is , all persons who underwent r and omization and received at least 1 dose of medication in the double-blind phase ) . INTRODUCTION Fluoxetine , a selective serotonin reuptake inhibitor ( SSRI ) , and trimipramine , a tricyclic antidepressant ( TCA ) , were compared in terms of efficacy and tolerability in a six-week , parallel group , double-blind pilot study in 41 geriatric patients with major depression ( 61 - 85 years old ) . METHOD The Hamilton Rating Scale for Depression ( HAMD-17 ) , the Montgomery-Asberg Rating Scale ( MADRS ) , the Adjective Mood Scale ( Bf-S ) , the Clinical Global Impression ( CGI ) , and the Patients Global Impression ( PGI ) were used to measure changes in depressive symptoms . RESULTS Improvement with treatment was found on all scales . Efficacy and tolerability were similar in both groups . No statistically significant differences were found . CONCLUSION These findings suggest that fluoxetine and trimipramine are comparable in terms of efficacy and tolerability in the treatment of major depression in geriatric patients Mr. B , age 20 , has taken a semester leave from college because of gradually worsening depressed mood . Over the past 2 months he has lost interest in jogging and playing piano -- which he usually enjoys . He reports reduced libido , middle insomnia , loss of appetite , feeling as if his head is " full of cotton , " trouble concentrating , and waking in the morning with a sense of dread . His anxiety dissipates during the day , but he continues to feel sad and sometimes weepy , which is unusual for him . [ ILLUSTRATION OMITTED ] Mr. B reports feeling hopeless at times and has had vague thoughts about life being " not worth it if I continue to feel like this " but denies specific suicide plans . Your initial impression is that Mr. B is in the midst of a major depressive episode and that a selective serotonin reuptake inhibitor ( SSRI ) is indicated . As you finish taking his history , you run through your mind the pros and cons of the recommendation you will make to him . Do SSRIs raise or lower the risk for suicidal behavior in young adults such as Mr. B ? The answer is complicated and goes beyond an " either/or " question , as the FDA acknowledged in May 2007 when it : * extended the black-box warning of increased suicidality risk with antidepressants to cover adults age 18 to 24 as well as children and adolescents * included language in the warning about the benefits of treating depression and the suicide risk associated with untreated depression , given concerns about declining antidepressant prescriptions and rising suicides among youth . ( 1 ) To help you make informed decisions when treating depression in adults , this article review s the studies leading up to and following the FDA 's meta- analysis of antidepressant trial data in patients age 18 and older . Our goal is to provide a framework for clinical treatment of adults age 18 to 24 and those age [ greater than or equal to]25 . First hints of suicidality  SSRIs revolutionized depression treatment . From 1985 to 1999 , annual U.S. antidepressant prescriptions quadrupled , with SSRIs accounting for 70 % of the increase ( see " Antidepressants and suicide risk , 1985 to 2007 , " pages 36 - 37 ) . At the same time , the age-adjusted suicide rate : * dropped 22.5 % for women ( who account for twice as many antidepressant prescriptions as men ) * dropped 12.8 % for men ( without change in the rank order of suicide methods ) . ( 2 ) For many patients , increased antidepressant use improved treatment of major depressive and other antidepressant-responsive disorders . In 1990 , however , case reports suggested SSRIs might cause suicidal thoughts or behavior . ( 3 ) Hypothesized mechanisms included increased aggression ( 4 ) and akathisia . ( 5 ) An FDA review found no proof , and a meta- analysis of data from 17 double-blind , r and omized , controlled trials found no association between fluoxetine and suicidal thoughts or behavior . ( 6 ) The debate rekindled in June 2003 when the British Committee on Safety of Medicines warned against using paroxetine or venlafaxine in children . After conducting its own meta- analysis , the FDA in 2004 ordered a black-box warning about suicidality and the use of  antidepressants in children and adolescents ( Box ) . ( 7 ) After the pediatric ' black box . '  Antidepressant prescriptions for  children and adolescents declined in the years 2003 to 2004 , as did diagnosis of pediatric depression . ( 8 - 10 ) Antidepressant prescribing also showed signs of shifting from general practitioners to psychiatrists . ( 8) At the same time , the suicide rate  among youth age 60 ,  SSRI prescriptions continued to rise and suicide rates fell , ( 9 ) a pattern of change consistent with antidepressants protecting against suicide . An independent meta- analysis by Bridge et al ( 12 ) examined the pediatric trial data used in the FDA meta- analysis plus 7 additional studies . BACKGROUND Case reports and open studies have reported beneficial therapeutic effects of adding buspirone to a selective serotonin reuptake inhibitor ( SSRI ) in the management of treatment-refractory depression .  This is the first placebo-controlled study to evaluate the efficacy and safety of this combination . METHOD One hundred nineteen patients ( 82 women , 37 men ) who fulfilled criteria for a major depressive episode according to DSM-IV and who had failed to respond to a minimum of 4 weeks ( mean = 211 days ) of treatment with citalopram or paroxetine  were r and omly assigned to 4 weeks of treatment with an SSRI plus buspirone ( N = 58 ) or an SSRI plus placebo ( N = 61 ) . In addition , 97 patients participated in an optional open-label post study treatment phase with the SSRI plus buspirone for 2 weeks . The primary outcome measure was the score on the Clinical Global Impressions-Improvement ( CGI-I ) scale . RESULTS A total of 50.9 % of patients in the buspirone group and 46.7 % in the placebo group responded after 4 weeks of treatment . The difference in response rate was not statistically significant . No statistically significant differences were found in the frequency of adverse events . At the follow-up of the open SSRI plus buspirone treatment , 69.4 % of patients had responded . CONCLUSION Adding buspirone to an SSRI is a safe and well-tolerated drug regimen . This study failed to demonstrate any difference in efficacy between buspirone or placebo augmentation of an SSRI . It could be argued , however , that the study was inconclusive due to the unusually high placebo response BACKGROUND This study aim ed to identify the predictors and outcomes of SSRI antidepressant continuation , discontinuation and switching over a 9-month period of naturalistic observation . METHODS Primary care patients ( n=573 ) with physician-diagnosed depression from 37 practice s were r and omized to an open-label trial of one of three selective serotonin reuptake inhibitors ( SSRIs ) managed in their primary care setting .  Psychiatric characteristics and treatment course were assessed at baseline and at 1 , 3 , 6 and 9 months after medication initiation . RESULTS Nineteen percent of patients switched SSRIs , which occurred significantly sooner than discontinuation ( median : 41 vs.100 days ) . Time to discontinuation was primarily explained by baseline patient skepticism about taking an antidepressant ( 62 % increase in discontinuation risk ) . In contrast , time to switch was associated with greater impairment at baseline and lesser improvement in impairment during the first month on medication . Patients who discontinued were significantly less likely to be depressed 9 months after starting medication than those who either continued or switched medication , and were less symptomatic and impaired than patients who switched . CONCLUSIONS Baseline impairment may increase the risk for SSRI antidepressant switching . Additionally , patient skepticism about antidepressants predicts early SSRI discontinuation and may predict rapid recovery . Intent-to-treat analyses in nonr and omized clinical trials may paradoxically inflate antidepressant effect sizes OBJECTIVE Citalopram and sertraline are widely prescribed selective serotonin reuptake inhibitors ( SSRIs ) . There is no conclusive evidence to show superiority of citalopram or sertraline in terms of efficacy or tolerability . Hence this study was design ed to compare short term efficacy and safety of citalopram and sertraline in major depressive disorder ( MDD ) in Indian patients . METHODS In an open , r and omized study , 100 patients were divided into two groups . In Group A ( n = 50 ) patients received citalopram ( 20 - 60 mg/day ) for 6 weeks . In Group B ( n = 50 ) patients received sertraline ( 50 - 150 mg/day ) for 6 weeks . Patients were evaluated at baseline and then at 1 , 2 , 3 , 4 , 5 , and 6 weeks . RESULTS There was significant improvement in Hamilton depression rating scale ( HDRS ) , Montgomery and Asberg depression rating scale ( MADRS ) and Amritsar depressive inventory ( ADI ) scores ( p < 0.05 ) with both the drugs . However , the decrease in score was more with citalopram ( p < 0.05 ) . Onset of action of citalopram  was earlier as compared to sertraline ( p < 0.05 ) . The number of responders and remitters was also more with citalopram ( p < 0.05 ) . No serious adverse event was reported in either of the groups . CONCLUSION Citalopram had shown better efficacy , earlier onset of action and more number of responders and remitters as compared to sertraline in MDD in Indian patients CONTEXT The high percentage of failed clinical trials in depression may be due to high placebo response rates and the failure of st and ard statistical approaches to capture heterogeneity in treatment response . OBJECTIVE To assess whether growth mixture modeling can provide insights into antidepressant and placebo responses in clinical trials of patients with major depression . DESIGN We reanalyzed clinical trials of duloxetine to identify distinct trajectories of Hamilton Scale for Depression ( HAM-D ) scores during treatment . We analyzed the trajectories in the entire sample and then separately in all active arms and in all placebo arms . Effects of duloxetine hydrochloride , selective serotonin reuptake inhibitor ( SSRI ) , and covariates on the probability of following a particular trajectory were assessed . Outcomes in different trajectories were compared using mixed-effects models . SETTING Seven r and omized double-blind clinical trials of duloxetine vs placebo and comparator SSRI . Patients A total of 2515 patients with major depression . INTERVENTIONS Duloxetine and comparator SSRI . Main Outcome Measure Total score on the HAM-D. RESULTS In the entire sample and in the antidepressant-treated sub sample , we identified trajectories of responders ( 76.3 % of the sample ) and nonresponders ( 23.7 % of the sample ) . However , placebo-treated patients were characterized by a single response trajectory . Duloxetine and SSRI did not differ in efficacy , and compared with placebo they significantly decreased the odds of following the nonresponder trajectory . Antidepressant responders had significantly better HAM-D scores over time than placebo-treated patients , but antidepressant nonresponders had significantly worse HAM-D scores over time than the placebo-treated patients . CONCLUSIONS Most patients treated with serotonergic antidepressants showed a clinical trajectory over time that is superior to that of placebo-treated patients . However , some patients receiving these medications did more poorly than patients receiving placebo . These data highlight the importance of ongoing monitoring of medication risks and benefits during serotonergic antidepressant treatment . They should further stimulate the search for biomarkers or other predictors of responder status in guiding antidepressant treatment BACKGROUND Major depressive disorder is a recurrent illness that often requires maintenance antidepressant treatment . Escitalopram is a selective serotonin reuptake inhibitor ( SSRI ) that has shown efficacy in both acute and continuation treatment of major depressive disorder . The current trial examined the efficacy of maintenance escitalopram treatment in preventing depression recurrence in patients who responded to acute SSRI therapy . METHOD Patients with recurrent DSM-IV-defined major depressive disorder ( > or= 2 previous episodes ; baseline Montgomery-Asberg Depression Rating Scale [ MADRS ] score > or= 22 ) who had responded ( MADRS score < or= 12 ) to acute open-label treatment ( 8 weeks ) with 1 of 4 SSRIs ( fluoxetine , sertraline , paroxetine , or citalopram )  received open-label , flexible-dose continuation treatment ( 16 weeks ) with escitalopram ( 10 - 20 mg/day ) . At the end of continuation treatment , patients maintaining response criteria were r and omly assigned to 52 weeks of double-blind , fixed-dose maintenance treatment with escitalopram ( 10 or 20 mg/day ) or placebo .  Recurrence was defined as a MADRS score > or= 22 or insufficient therapeutic response during the double-blind phase . The study was conducted between October 16 , 2000 , and February 4 , 2003 . RESULTS A total of 234 patients who responded to acute open-label treatment with 1 of 4 SSRIs received at least 1 dose of open-label escitalopram continuation treatment . Of 164 patients who completed escitalopram continuation treatment , 139 were r and omly assigned to double-blind maintenance treatment with escitalopram ( N = 73 ) or placebo ( N = 66 ) . Mean baseline MADRS scores at the start of the maintenance phase were < 5 for both the placebo- and escitalopram-treatment groups . Time to recurrence was significantly longer in patients who received maintenance treatment with escitalopram compared with patients switched to placebo ( hazard ratio = 0.26 , 95 % CI = 0.13 to 0.52 , p < .001 ) . Long-term escitalopram treatment was well tolerated . CONCLUSION Maintenance treatment with escitalopram was well tolerated and significantly reduced the risk for recurrence of depression . Patients with few residual symptoms following continuation treatment with escitalopram experienced a high rate of depression recurrence when switched to placebo , demonstrating the need for maintenance therapy of recurrent major depressive disorder beyond 4 to 6 months of initial symptom resolution even if few residual symptoms are present BACKGROUND Selective serotonin reuptake inhibitors ( SSRIs ) and venlafaxine have been regarded as less toxic in overdose than tricyclic antidepressants ( TCAs ) . Within the TCAs , dothiepin has greater toxicity . Venlafaxine may be more toxic than SSRIs . AIM To assess the toxicity in overdose of venlafaxine and SSRIs compared to TCAs , and of dothiepin compared to other TCAs . DESIGN Cohort study of prospect ively collected data from the Hunter area , NSW , Australia . METHODS First admissions with antidepressant deliberate self-poisoning ( DSP ) ( November 1994 to April 2000 ) were identified ; the presence of seizures , life-threatening arrhythmias , coma , serotonin toxicity or ICU admission , and QRS duration were noted . RESULTS There were 538 admissions , with no deaths . The odds ratio ( OR ) for seizures with dothiepin vs. other TCAs was 3.4 ( 95%CI 1.2 - 9.9 ) . Seizures occurred in 7/51 ( 14 % ) venlafaxine overdoses ; all patients with seizures consumed > or = 900 mg . The OR for seizures vs. TCAs was 4.4 ( 95%CI 1.4 - 13.8 ) . Coma was less likely with venlafaxine and SSRIs . SSRIs , but not venlafaxine , were less likely to prolong the QRS to > or = 100 ms . ICU admission was less likely for SSRIs . Serotonin toxicity was much more common with venlafaxine and SSRIs . DISCUSSION Venlafaxine and dothiepin are pro-convulsant in overdose . Venlafaxine is more likely to cause serotonin toxicity , but less likely to cause coma than TCAs . SSRIs are less likely to cause coma , require ICU admission , or prolong the QRS , but are more likely to cause serotonin toxicity . Antidepressants other than TCAs or venlafaxine should be considered in patients at risk of seizure or suicide Objective Major depression is a mood disorder that causes changes in physical activity , appetite , sleep and weight . Regarding the role of zinc in the pathology of depression , the present study was aim ed to investigate the effects of zinc supplementation in the treatment of this disease . Methods This study was a double-blind r and omized clinical trial . Forty four patients with major depression were r and omly assigned to groups receiving zinc supplementation and placebo . Patients in Zinc group received daily supplementation with 25 mg zinc adjunct to antidepressant ; Selective Serotonin Reuptake Inhibitors ( SSRIs ) , while the patients in placebo group received placebo with antidepressants ( SSRIs ) for twelve weeks . Severity of depression was measured using the Beck Depression Inventory at baseline and was repeated at the sixth and twelfth weeks . ANOVA with repeated measure was used to compare and track the changes during the study . Results The mean score of Beck test decreased significantly in the zinc supplement group at the end of week 6 ( P < 0.01 ) and 12 ( P < 0.001 ) compared to the baseline . The mean score of Beck Depression Inventory reduced significantly compared to the placebo group at the end of 12th week ( P < 0.05 ) Conclusion The results of the present study indicate that zinc supplementation together with SSRIs antidepressant drug improves major depressive disorders more effectively in patients with placebo plus antidepressants ( SSRIs ) Background Despite recent advancements in the pharmacological treatment of major depressive disorder ( MDD ) , over half of patients who receive treatment with antidepressant medication do not achieve full remission of symptoms . There is evidence that exercise can reduce depressive symptomatology when used as a treatment for MDD . However , no r and omized controlled trials have evaluated exercise as an augmentation strategy for patients with carefully diagnosed MDD who remain symptomatic following an adequate acute phase trial of antidepressant therapy . Purpose TReatment with Exercise Augmentation for Depression  ( TREAD ) is an NIMH-funded , r and omized , controlled trial design ed to assess the relative efficacy of two doses of aerobic exercise to augment selective serotonin reuptake inhibitor ( SSRI ) treatment of MDD . Methods The TREAD study includes 12 weeks of acute phase treatment with a 12-week post-treatment follow-up . In addition to looking at change in depressive symptoms as a primary outcome , it also includes comprehensive assessment of psychosocial function and treatment adherence . Results This paper review s the rationale and design of TREAD and illustrates how we address several key issues in contemporary patient-oriented research on MDD : 1 ) the use of augmentation strategies in the treatment of depressive disorders in general , 2 ) the use of non-pharmacological strategies in the treatment of depressive disorders , 3 ) the considerations of design ing a well-controlled trial using two active treatment groups , and 4 ) the implementation of an adherence program for the use of exercise as a treatment strategy . Conclusions The TREAD study is uniquely design ed to overcome sources of potential bias and threats to internal and external validity that have limited prior research on the mental health effects of exercise . The study is facilitated by the development of a multidisciplinary research team that includes experts in both depression treatment and exercise physiology , as well as other related fields OBJECTIVE The first objective of this paper was to describe the pattern of remission , response and recovery in patients with major depression who were r and omised for treatment with fluoxetine ornortriptyline .  The second objective was to report on the demographic and diagnostic predictors of the response and recovery in these depressed patients . METHOD One hundred and ninety-five patients with major depression were recruited for this outpatient study . After a detailed clinical and neurobiological evaluation patients were r and omized to receive either fluoxetine or nortiptyline as an initial antidepressant treatment . RESULTS Of the 195 depressed patients r and omised to treatment,154 completed an adequate 6-week trial of either fluoxetine or nortriptyline as their initial antidepressant . Of the 41 patients who did not complete an adequate trial the dropout rate was higher on those r and omized to nortriptyline ( p = 0.02 ) . There was also an important interaction of drug and gender in determining dropouts in that women did not complete an adequate trial with nortriptyline and men did not complete an adequate trial with fluoxetine ( p = 0.002 ) . Of the 154 patients who completed an adequate 6-week antidepressant trial there were no significant differences in 6-week measures of depression severity or of percentage improvement . However , if we use an intention to treat analysis and dichotomise outcomes into response , remission or recovery ; then recovery rates were significantly higher with fluoxetine than nortriptyline ( p = 0.005 ) . Using an intention to treat analysis fluoxetine was superior tonortriptyline in women , in those less than 25-years old , and in those with atypical depression . Independent of drug , those with chronic depressions had a poorer outcome . CONCLUSION In this sample of depressed patients r and omized tonortriptyline or fluoxetine the change in depressive symptoms over 6 weeks were comparable between fluoxetine and nortriptyline . However , when we look at the more clinical ly important variable of recovery then fluoxetine was superior to nortriptyline . Predictors of a poorer response to nortriptyline were gender , young age and atypical depression . The results challenge traditional beliefs that selective serotonin re-uptake inhibitors ( SSRIs ) and tricyclic antidepressant have comparable efficacy CONTEXT Little is known about selecting among second-step medications for major depressive disorder after intolerance or lack of remission with an initial selective serotonin reuptake inhibitor . OBJECTIVE To determine whether sociodemographic , clinical , or first-step treatment features predict remission with or intolerance overall or differentially to any 1 of 3 second-step medications after an unsatisfactory outcome with citalopram hydrobromide . DESIGN An equipoise stratified r and omized study . Participants were recruited from July 17 , 2001 , through April 20 , 2004 . SETTING Public or private sector primary care ( n = 18 ) and psychiatric care ( n = 23 ) setting s across the United States . PARTICIPANTS Representative out patients aged 18 to 75 years with nonpsychotic major depressive disorder ( N = 727 ) . INTERVENTIONS Sustained-release bupropion hydrochloride was started at 150 mg/d and incrementally increased to 400 mg/d . Sertraline hydrochloride was started at 50 mg/d and incrementally increased to 200 mg/d . Extended-release venlafaxine hydrochloride was started at 37.5 mg/d and incrementally increased to 375 mg/d . MAIN OUTCOME MEASURES The 16-item Quick Inventory of Depressive Symptomatology , Self-Rated and the Frequency , Intensity , and Burden of Side Effects Rating . RESULTS Remission was more likely among participants who were white , employed , cohabiting or married , or privately insured or who had prior intolerance to citalopram or at least a response to citalopram , and no prior suicide attempts . Remission was less likely among participants with concurrent generalized anxiety , obsessive-compulsive , panic , or posttraumatic stress disorders ; social phobia ; anxious or melancholic features ; or more severe depression . Intolerance was less likely for Hispanic participants , but more likely for participants with previous suicide attempts or intolerance to citalopram . Participants with concurrent substance use were less likely to remit ( odds ratio , 0.37 ) and more likely not to tolerate extended-release venlafaxine . Intolerance to citalopram was associated with intolerance to sertraline ( P = .04 ) . CONCLUSIONS Clinical , demographic , and treatment history were of little value in recommending 1 medication vs another as a second-step treatment for major depressive disorder . Participants most likely to remit in the second step had less Axis I psychiatric disorder comorbidity , less social disadvantage , and at least a response to citalopram in the first step . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00021528 Serotonergic and noradrenergic pathways are the main targets of antidepressants . Their differential effects on emotion processing-related brain activation are , however , to be further characterized . We aim ed at elucidating the neural sites of action of an acute differential serotonergic and noradrenergic influence on an emotion-processing task , which was earlier shown to be associated with depressiveness . In a single-blind pseudo-r and omized crossover study , 21 healthy subjects ( 16 subjects finally included in the analysis ) participated to ingest a single dose at three time points of either 40 mg citalopram , a selective serotonin-reuptake inhibitor , 8 mg reboxetine , a selective noradrenaline-reuptake inhibitor , or placebo 2–3 h before functional magnetic resonance imaging ( fMRI ) . During fMRI , subjects performed a task comprising the anticipation and perception of pictures of either ‘ known ’ ( positive , negative , neutral ) or ‘ unknown ’ valence ( r and omly 50 % positive or negative ) . In direct comparison with citalopram and with placebo , reboxetine increased brain activity in the medial thalamus . Citalopram modulated certain prefrontal and insular areas more prominently . Other frontal and parieto-occipital areas were modulated by both drugs . In conclusion , the functional network involved in emotional information processing could be modulated by the acute application of selective noradrenergic and serotonergic drugs revealing a noradrenergic effect in thalamic and frontal areas , and a prefrontal and insular focus of serotonergic modulation . These findings could have implication s for future selection criteria concerning personalized antidepressant medication in depression OBJECTIVE Few controlled studies have addressed the issue of which antidepressant medications should be recommended for out patients who have not responded to multiple treatment trials . This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant ( nortriptyline ) following two prospect i ve , consecutive , unsuccessful medication treatments for nonpsychotic major depressive disorder . METHOD Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks ( first step ) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone ( second step ) , adult out patients ( N=235 ) with nonpsychotic major depressive disorder were r and omly assigned to 14 weeks of treatment with mirtazapine ( up to 60 mg/day ) ( N=114 ) or nortriptyline ( up to 200 mg/day ) ( N=121 ) . The primary outcome , symptom remission , was defined a priori as a total exit score of < /=7 on the 17-item Hamilton Rating Scale for Depression . The 16-item Quick Inventory of Depressive Symptomatology-Self-Report ( QIDS-SR(16 ) ) , obtained at treatment visits , provided secondary outcomes of remission ( score < /=5 at exit ) and response ( > /=50 % reduction in score from baseline ) . RESULTS For mirtazapine , remission rates were 12.3 % and 8.0 % per the Hamilton and QIDS-SR(16 ) scores , respectively . For nortriptyline , remission rates were 19.8 % and 12.4 % , respectively . QIDS-SR(16 ) response rates were 13.4 % for mirtazapine and 16.5 % for nortriptyline . Neither response nor remission rates statistically differed by treatment , nor did these two treatments differ in tolerability or adverse events . CONCLUSIONS Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials result ed in low remission rates ( < 20 % ) among patients with major depressive disorder Antidepressant effects and unintended effects of paroxetine ( 30 mg/day ) and clomipramine ( 150 mg/day ) were compared in a double-blind , r and omized , inpatient , fixed-dose , plasma-level-controlled study . Patients with a DSM-III diagnosis of major depressive disorder participated . After 1 week of single-blind placebo treatment  120 patients fulfilled the criterion of a Hamilton ( 17-item ) score of greater than or equal to 18 and were started on active treatment for 6 weeks . Drop-outs on paroxetine ( n = 12 ) were largely due to lack of effect , and on clomipramine ( n = 19 ) due to lack of effect ( n = 7 ) , adverse reactions or severe side effects ( n = 10 ) and development of mania ( n = 2 ) . According to the protocol , non-responders ( Hamilton total greater than or equal to 16 ) after 4 weeks active treatment were terminated , and this occurred to 23 patients on paroxetine and four patients on clomipramine . Categorical response measures and group averages of rating scores showed a significantly better therapeutic effect of clomipramine from the second week of treatment on . These results are very similar to our earlier results with another selective serotonin reuptake inhibitor ( citalopram ) , but generally at variance with the literature on this class of antidepressants , which , however , mostly deals with outpatient studies Findings from the National Institute of Mental Health 's Sequenced Treatment Alternatives to Relieve Depression trial indicate that approximately 50 % of patients with major depressive disorder do not experience a treatment response after adequate first-line treatment with a selective serotonin reuptake inhibitor ( SSRI ) . This study was design ed to test the hypothesis that , after treatment failure with an SSRI , switching to venlafaxine extended release ( ER ) would offer advantages over switching to another SSRI , citalopram . The objectives of this trial were to compare the efficacy and safety of venlafaxine ER and citalopram in the treatment of moderate-to-severe depression in patients who did not experience a treatment response to an SSRI other than citalopram  and to investigate the effects of severity of depression by categorizing treatment groups according to baseline severity . This was a 12-week , double-blind , r and omized , parallel-group , multicenter study . Participants were adult out patients who , following 8 weeks of monotherapy with an adequate dosing regimen of an SSRI other than citalopram  and had not responded , met the diagnostic criteria for depression as described in the Diagnostic and statistical manual of mental disorders , fourth edition , and had a score ≥20 on the 21-item Hamilton Rating Scale for Depression ( HAM-D21 ) . After a 7-day screening period , patients were r and omly assigned to receive venlafaxine ER 75 mg/day or citalopram 20 mg/day for the first 2 weeks . Doses could be increased every 2 weeks through week 6 . Treatment lasted 12 weeks and was followed by a 1-week tapering period . Maximum dosages were venlafaxine ER 300 mg/day or citalopram 60 mg/day . The primary end point was the final on-therapy total HAM-D21 score . To investigate the treatment effects of the severity of depression on efficacy , a subgroup analysis was performed for baseline HAM-D21 total score ≤31 and > 31 . The analyses for HAM-D21 , Montgomery – Åsberg Depression Rating Scale ( MADRS ) , Clinical Global Impressions – Severity ( CGI-S ) , and Clinical Global Impressions – Improvement scores were based on intent-to-treat ( ITT ) population , for both the primary analysis and subgroup analysis according to baseline HAM-D21 total scores ≤31 or > 31 . Safety assessment s included the recording of adverse events ( AEs ) . A total of 406 patients ( 200 venlafaxine ER , 206 citalopram ) were r and omly assigned and 396 patients were included in the ITT population ( 194 venlafaxine ER , 202 citalopram ) . Treatment groups were similar in terms of demographics and baseline psychiatric assessment s. Two hundred and eighty-four patients ( 137 venlafaxine ER , 147 citalopram ) were present in the ITT population with a baseline HAM-D21 total score ≤31 and 112 patients ( 57 venlafaxine ER , 55 citalopram ) in the > 31 group . In the primary analysis , there was no statistical difference between groups . The group with a baseline HAM-D21 total score of 20–31 did not differ significantly in any efficacy parameters . In the group with a baseline HAM-D21 total score > 31 , the venlafaxine ER group differed significantly from the citalopram group on the primary end point HAM-D21 total score ( P=0.0121 ) . The secondary end point CGI-S score was statistically significant ( P=0.0359 ) , although the MADRS total score ( P=0.0930 ) was not . AEs were reported by 57.8 and 63.4 % of venlafaxine ER and citalopram patients , respectively . Overall discontinuation rates were 24.5 % for venlafaxine ER and 20.9 % for citalopram  . Discontinuation rates owing to an AE as a primary or secondary reason were 5.5 % for venlafaxine ER and 5.3 % for citalopram . Overall , venlafaxine ER and citalopram showed similar efficacy in patients who had an inadequate response to an SSRI . In the subset of more severely depressed patients , venlafaxine ER was significantly more effective on a number of efficacy measures . Patients who remain severely depressed following treatment with an SSRI may gain more benefit from the dual-action drug venlafaxine , rather than switching to another SSRI Background The US Food and Drug Administration ’s meta-analyses of placebo-controlled antidepressant trials found approximately twice the rate of suicidal behaviors among children and adults aged 24 years and younger who were r and omized to receive antidepressant medication  than among those who were r and omized to placebo .  Rates of suicidal behavior were similar for subjects aged 25–64 years whether they received antidepressants or placebo , and subjects aged 65 years or older r and omized to antidepressants were found to have lower rates of suicidal behavior . The age-stratified FDA meta-analyses did not have adequate power to investigate rates of suicidal behaviors by antidepressant drug class . Objective Our objective was to assess the risk of deliberate self-harm associated with the two most commonly prescribed classes of antidepressant agents . Design Propensity score matched cohort study of incident users of antidepressant agents . Setting Population -based healthcare utilization data of US residents . Patients US residents aged 10–64 years with a recorded diagnosis of depression who initiated use of selective serotonin reuptake inhibitors ( SSRIs ) or serotonin norepinephrine reuptake inhibitors ( SNRIs ) between 1 January 1998 and 31 December 2010.Main Outcome Measures ICD-9 external cause of injury codes E950.x – E958.x ( deliberate self-harm ) . Results A total of 102,647 patients aged between 10 and 24 years , and 338,021 aged between 25 and 64 years , initiated therapy with antidepressants . Among 10–24 year olds , prior to propensity score matching , 75,675 initiated therapy with SSRIs and 5,344 initiated SNRIs . After matching , there were 5,344 SNRI users and 10,688 SSRI users . Among the older cohort , 36,037 SNRI users were matched to 72,028 SSRI users ( from an unmatched cohort of 225,952 SSRI initiators ) . Regardless of age cohort , patients initiating SSRIs and patients initiating SNRIs had similar rates of deliberate self-harm . Restriction to patients with no antidepressant use in the past 3 years did not alter our findings . Conclusions Our findings of similar rates of deliberate self-harm for depressed patients who initiate treatment with either an SSRI or an SNRI suggests that physicians who have decided that their patients would benefit from initiating antidepressant therapy need not weigh differential suicide risk when deciding which class of antidepressant to prescribe Brain catecholamines can be rapidly reduced by inhibiting their synthesis with alpha-methyl-para-tyrosine ( AMPT ) . In order to assess the role of catecholamines in antidepressant action  AMPT challenges were administered in a double-blind , placebo-controlled , crossover fashion to 14 depressed patients having maintained a therapeutic antidepressant response for > or = 2 weeks ( 3 desipramine , 2 mazindol , 5 fluoxetine , 4 sertraline ) . Each patient participated in two challenges one week apart . Each challenge included a baseline , two days of either AMPT or diphenhydramine ( active placebo ) , and a followup . Antidepressant drugs were continued throughout testing . The 3 desipramine- and 2 mazindol-responders had a rapid increase in depression score during AMPT but not placebo ( diphenhydramine ) challenge whereas only 1 of 9 selective serotonin reuptake inhibitor (SSRI)-treated patients did . The implication of this is that the antidepressant response to desipramine may be more acutely dependent on brain catecholamine content than the response to SSRIs . In the context of our previous work with tryptophan depletion , these results suggest that the neurobiological mechanisms underlying the antidepressant responses to different drugs involve alterations in the functioning of different neurotransmitter systems and reinforce the importance of changes in both the serotonin and catecholamine systems for successful antidepressant responses In the context of chronic physical illness , such as breast cancer , depression is associated with increased morbidity , longer periods of hospitalization , and greater overall disability . Prompt diagnosis and effective treatment is , therefore , essential . Several small studies have established the efficacy of tricyclic antidepressants ( TCAs ) in this setting , and the selective serotonin reuptake inhibitors ( SSRIs ) would appear to be an alternative therapeutic option because of their established efficacy and better tolerability profile . This was a multicenter , double-blind , parallel-group study in which 179 women with breast cancer were r and omized to treatment with either the SSRI paroxetine ( 20–40mg/day ) , or the TCA , amitriptyline ( 75–150mg/day ) . After 8-weeks treatment , depressive symptomatology had improved markedly and to a similar extent in both groups on the Montgomery Asberg Depression Rating Scale . Clinical global impression ( CGI ) Global improvement and Patient global evaluation scales indicated that patients were minimally to much improved at study endpoint ; a change from moderately/mildly ill to borderline ill on the CGI severity of Illness scale . A steady improvement in quality of life was also observed in both groups . There were no clinical ly significant differences between the groups . In total , 47 ( 53.4 % ) patients in the paroxetine group and 53 ( 59.6 % ) patients in the amitriptyline group had adverse experiences , the most common of which were the well-recognized side-effects of the antidepressant medications or chemotherapy . Anticholinergic effects were almost twice as frequent in the amitriptyline group ( 19.1 % ) compared with paroxetine ( 11.4 % ) . This study has demonstrated that paroxetine is a suitable alternative to amitriptyline for the treatment of depression in patients with breast cancer We reported an independent association of the short variant of the serotonin transporter gene‐linked polymorphic region ( SERTPR ) and tryptophan hydroxylase ( TPH ) genes with antidepressant response to  selective serotonin reuptake inhibitors ( SSRIs ) . The aim of the present study was to confirm the effect of the SERTPR and TPH gene variants on the  SSRIs antidepressant activity in a new sample of major and bipolar depressives . Two hundred and twenty one in patients ( major depressives = 128 , bipolar disorder = 93 ) were treated with SSRIs ( fluvoxamine or paroxetine ) for 6 weeks ; the severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression ( HAMD ) . SERTPR and TPH variants were determined using PCR‐based techniques , 220 subjects genotyped for SERTPR and 221 for TPH that were never included in previous studies . SERTPR*s/s variant association with a poor response to SSRI treatment was confirmed , even if with less significant P values ( P = 0.034 ) , independently from clinical variables ; pooling the present sample with previous ones we observed a highly significant effect ( P < 0.000001 ) . TPH*A/A variants showed higher HAMD scores throughout the trial but with only a trend in the same direction of our previous study in terms of a worse response of A/A genotypes . Thus , the previous positive association was not fully replicated for TPH . The present independent replication confirms SERTPR variants as a liability factor for antidepressant efficacy while the TPH effect is not unequivocal . © 2004 Wiley‐Liss , OBJECTIVE To investigate whether differences in antidepressant efficacy are moderated by an interaction of age and gender . METHODS A pooled data set from eight r and omized , controlled trials of patients with major depressive disorder ( MDD ) was reanalyzed to compare remission rates following therapy with venlafaxine  ( n = 851 ) , one of several selective serotonin reuptake inhibitors ( SSRIs )  ( n = 748 ) , or placebo  ( n = 446 ) . Remission was defined as a final Hamilton Rating Scale for Depression ( HAM-D ) score < or = 7 . Pairwise comparisons were conducted using stepwise multiple logistic regression models with main effect and interaction terms for treatment , sex , and age ( younger : < 50 ; older : > or = 50 ) . Among older women , the impact of hormone replacement therapy ( HRT ) on remission rates also was examined . RESULTS Remission rates on venlafaxine therapy were not affected by age , sex , or HRT use . Among women , but not men , there was a significant interaction reflecting poorer SSRI response in the older age group ( Wald chi-square = 4.21 , df = 1 , p = 0.04 ) ; HRT appeared to eliminate this difference . Whereas the advantage in remission rates favoring venlafaxine was modest for men and younger women ( 6%-9 % ) , the difference among older women not taking HRT was 23 % . CONCLUSIONS These findings provide further evidence that age , gender , and HRT moderate response to antidepressant medications Serotonin-norepinephrine reuptake inhibitors ( SNRIs ) may be used as an alternative treatment for depressed patients who do not tolerate or respond adequately to treatment with a conventional antidepressant . This r and omized , open-label , multicenter study compared the effectiveness of the SNRI venlafaxine extended release ( VXR ) with that of conventional antidepressants ( CA ) in patients who were referred to an outpatient psychiatric specialty care setting for treatment after failure to tolerate or respond to at least 4 weeks of treatment with a CA in a primary care setting . Patients with a Hamilton Depression Rating Scale ( HAM-D17 ) score > or = 17 were r and omly assigned to treatment with an alternative CA or VXR .  Remission was defined as a score < or = 7 on the HAM-D17 . Efficacy analyses were carried out on 3,097 patients from the intent-to-treat ( ITT ) population ( 1,632 VXR ; 1,465 CA ) . The antidepressants prescribed most frequently in the CA group were paroxetine ( 21.3 % ) , citalopram ( 20.1 % ) , sertraline ( 19.1 % ) , fluoxetine ( 17.0 % ) , and mirtazapine ( 7.9 % ) . After 24 weeks of treatment , the VXR group demonstrated a significantly higher remission rate than did the CA group ( 59.3 % VXR ; 51.5 % CA ; P<.0001 ; odds ratio : 1.37 ; 95 % CI : 1.19 - 1.58 ; P<.01 ) . Despite the limitations of the open design , the results of this study suggest that venlafaxine extended release may be more effective than the conventional antidepressants used in this study when treating depressed patients who do not tolerate or respond adequately to treatment with a conventional antidepressant This study was aim ed at resolving the time course of clinical action of antidepressants ( ADs ) and the type of early behavioral changes that precede recovery in treatment-responsive depressed patients . The first goal was to identify , during the first 2 weeks of treatment , the onset of clinical actions of the selective serotonin reuptake inhibitor ( SSRI ) , paroxetine , and the selective noradrenergic reuptake inhibitor , desipramine ( DMI ) . The second aim was to test the hypothesis that the two pharmacologic subtypes would induce different early behavioral changes in treatment-responsive patients . The design was a r and omized , parallel group , placebo-controlled , double-blind study for 6 weeks of treatment following a 1-week washout period . The study utilized measures of the major behavioral components of the depressive disorder as well as overall severity . The results indicated that the onset of clinical actions of DMI ranged from 3 to 13 days , averaged 13 days for paroxetine , and was 16–42 days for placebo . Furthermore , as hypothesized , the different types of ADs initially impacted different behavioral aspects of the disorder . After 1 week of treatment , DMI produced greater reductions in motor retardation and depressed mood than did paroxetine and placebo , and this difference persisted at the second week of treatment . Early improvement in depressed mood – motor retardation differentiated patients who responded to DMI after 6 weeks of treatment from those that did not . Paroxetine initially reduced anxiety more in responders than in nonresponders , and by the second week , significantly improved depressed mood and distressed expression in responders to a greater extent . Depressed patients who responded to placebo showed no consistent early pattern of behavior improvement . Early drug-specific behavioral changes were highly predictive of ultimate clinical response to the different ADs , results that could eventually be applied directly to clinical practice Objective : This is a retrospective study to add to the existing body of clinical information regarding male sexual side effects associated with antidepressants . From the chart review , thirty-four out of eighty male patients were identified to have reported loss of libido , erectile difficulty , anorgasmia , and delayed ejaculation while receiving pharmacotherapy of selective serotonin reuptake blockers ( fluoxetine , paroxetine , and sertraline ) ; tricyclic antidepressants ( nortriptyline , imipramine , amitriptyline , desipramine , and clomipramine ) ; and a monoamine oxidase inhibitor ( phenelzine ) . Method : The authors also discussed the management of these sexual side effects by waiting for spontaneous remission , reducing the dosage level , and substituting the offending drug with other antidepressants . Results : This article underscores the underreported nature of antidepressant-associated sexual dysfunction , the high incidence of SSRI-associated sexual side effects , equal potentials in causing sexual side effects among the three SSRI 's , the low incidence rate of sexual adverse effects from bupropion , and the minimal need to add an antidote if the side effects are to be managed systematic ally . Conclusions : Finally , male sexual side effects can occur r and omly and involve any sexual phase r and omly , and the treatment approaches are similar , regardless of the types of sexual dysfunction associated with antidepressants BACKGROUND There has been a paucity of well- design ed studies comparing selective serotonin reuptake inhibitor ( SSRI ) medications in the treatment of depression in the elderly . This multicenter study was design ed to examine the efficacy and safety of sertraline and fluoxetine in depressed elderly out patients . A secondary objective was to examine the effects of SSRI treatment on quality of life and cognitive function . METHOD Two hundred thirty-six out patients 60 years of age and older who met DSM-III-R criteria for major depressive disorder received 1 week of single-blind placebo before being r and omly assigned to 12 weeks of double-blind , parallel-group treatment with flexible daily doses of either sertraline ( range , 50 - 100 mg ) or fluoxetine ( range , 20 - 40 mg ) . Primary efficacy measures consisted of the 24-item Hamilton Rating Scale for Depression and Clinical Global Impressions scale ratings . Secondary outcome assessment s included clinician- and patient-rated measures of depression symptoms and factors , cognitive functioning , and quality of life , as well as plasma drug concentrations , which were correlated with clinical response . RESULTS Both drugs produced a similarly positive response on the primary efficacy measures , with 12-week responder rates of 73 % for sertraline and 71 % for fluoxetine . Sertraline-treated patients showed statistically greater cognitive improvement on several measures . Both drugs were safe and well tolerated . CONCLUSION Data indicate that both drugs are effective antidepressants for the treatment of depressed elderly out patients . Differences in cognitive performance effects deserve further investigation We assessed the tolerability and antidepressant response to citalopram in a group of patients who could not tolerate a recent trial of paroxetine therapy . Sixty-one out patients with major depressive disorder and a confirmed history of intolerance to paroxetine ( mean final dose : 26.7 mg/day ) were switched after at least a 1 week washout to citalopram therapy ( 20 mg/day ) . During the 6-week , open label treatment protocol , citalopram could be titrated up to a maximum dose of 40 mg/day . Response was evaluated using the Clinical Global Impressions CGI scale , the 24-item Hamilton Rating Scale for Depression , and several other measures of symptoms and quality of life . Fifty-three patients ( 87 % ) completed 6 weeks of citalopram therapy ( mean intent-to-treat dose : 23.9 mg/day ) . The specific side effects that were reported to be intolerable during the earlier paroxetine trial typically recurred only less than 30 % of the time during citalopram therapy ; only 6 patients ( 10 % ) dropped out because of adverse events . The intent-to-treat CGI response rate was 56 % at study endpoint ; 62 % of the completers responded . Significant improvement from pretreatment was observed on various symptom measures after two weeks of citalopram therapy . Citalopram therapy was well tolerated , and more than one half of the patients who began treatment improved significantly . Although further work is necessary to assess the relative merits of this within-class switching strategy ( as compared to other options ) , these data provide further evidence that the various selective serotonin reuptake inhibitors do not have interchangeable tolerability profiles Background Selective serotonin reuptake inhibitors ( SSRIs ) are popular medications for anxiety and depression , but their effectiveness , particularly in patients with prominent symptoms of loss of motivation and pleasure , has been question ed . There are few studies of the effect of SSRIs on neural reward mechanisms in humans . Methods We studied 45 healthy participants who were r and omly allocated to receive the SSRI citalopram , the noradrenaline reuptake inhibitor reboxetine , or placebo for 7 days in a double-blind , parallel group design . We used functional magnetic resonance imaging to measure the neural response to rewarding ( sight and /or flavor of chocolate ) and aversive stimuli ( sight of moldy strawberries and /or an unpleasant strawberry taste ) on the final day of drug treatment . Results Citalopram reduced activation to the chocolate stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex . In contrast , reboxetine did not suppress ventral striatal activity and in fact increased neural responses within medial orbitofrontal cortex to reward . Citalopram also decreased neural responses to the aversive stimuli conditions in key “ punishment ” areas such as the lateral orbitofrontal cortex . Reboxetine produced a similar , although weaker effect . Conclusions Our findings are the first to show that treatment with SSRIs can diminish the neural processing of both rewarding and aversive stimuli . The ability of SSRIs to decrease neural responses to reward might underlie the question ed efficacy of SSRIs in depressive conditions characterized by decreased motivation and anhedonia and could also account for the experience of emotional blunting described by some patients during SSRI treatment OBJECTIVE Nonadherence to antidepressant treatment may contribute to poor outcome and to suicidal adverse events in adolescent depression . We examine the relationship between adherence and both clinical response and suicidal events in participants in the Treatment of Resistant Depression in Adolescents ( TORDIA ) study . METHOD The relationship between adherence to medication and clinical outcome was assessed in 190 treatment-resistant depressed adolescents who were r and omized to one of four cells : switch to another selective serotonin reuptake inhibitor ( SSRI ) , switch to venlafaxine , or either of these two medication switches plus cognitive behavioral therapy .  Plasma levels of antidepressant drug and metabolites were determined after 6 and 12 weeks of treatment . A twofold or greater variation in the dose-adjusted concentration of drug plus metabolites ( level/dose ratio [ LDR ] ) was defined as nonadherence . Nonadherence was also determined by clinician pill counts ( CPC ) of the proportion of prescribed pills that were unused and was defined as having greater than 30 % of the prescribed pills remaining . RESULTS LDR and CPC showed low concordance . LDR was unrelated to clinical response .  CPC adherence was related to a higher response rate overall ( adherent , 63.0 % versus nonadherent , 47.2 % , p = .03 ) . Approximately half ( 50.8 % ) of the sample surveyed showed evidence of nonadherence by CPC . Neither measure of adherence was related to the occurrence of suicidal events or to the pace of decline in suicidal ideation . CONCLUSIONS Clinician pill counts may be a relevant measure of adherence that is related to outcome under formal clinical trial conditions in depressed adolescents . Nonadherence appears to be a common and significant source of treatment nonresponse . Clinical Trial Registration Information-Treatment of SSRI-Resistant Depression in Adolescents ( TORDIA ) ; http://www . clinical trials.gov ; NCT00018902 Background Selective serotonin reuptake inhibitors ( SSRIs ) are typically thought to have a delay of several weeks in the onset of their clinical effects . However , recent reports suggest they may have a much earlier therapeutic onset . A reduction in amygdala responsivity has been implicated in the therapeutic action of SSRIs . Aims To investigate the effect of a single dose of an SSRI on the amygdala response to emotional faces . Method Twenty-six healthy volunteers were r and omised to receive a single oral dose of citalopram ( 20 mg ) or placebo . Effects on the processing of facial expressions were assessed 3 h later using functional magnetic resonance imaging . Results Volunteers treated with citalopram displayed a significantly reduced amygdala response to fearful facial expressions compared with placebo . Conclusions Such an immediate effect of an SSRI on amygdala responses to threat supports the idea that antidepressants have an earlier onset of therapeutically relevant effects than conventionally thought AIM To identify the incidence and risk of suicide and self harm , among patients prescribed antidepressant drugs .  METHODS A retrospective cohort study , with nested case control , of patients identified from a nonr and om sample of general practice s in New Zeal and from 1996 to 2001 . A total of 57 361 patients who received a prescription for a single antidepressant were identified from the RNZCGP Research Unit Data base .  Suicides within 120 days of a prescription were identified from the New Zeal and National Mortality Data base and self-harm events within 120 days of a prescription were identified from the New Zeal and Hospital discharge data base . RESULTS 26 suicides and 330 episodes of self-harm were identified within 120 days of an antidepressant prescription . On univariate analysis the association , expressed as OR ( 95 % CI ) , between  selective serotonin reuptake inhibitors ( SSRIs ) and self harm and suicide were 2.26 ( 1.27 - 4.76 ) and 1.92 ( 0.77 - 4.83 ) , respectively . When corrected for the confounding effects of age , gender and depression/suicidal ideation there was an association between SSRIs and self harm , OR 1.66 ( 95 % CI 1.23 - 2.23 ) , but not for suicide , 1.28 ( 0.38 - 4.35 ) . Paroxetine was a significant risk factor for suicide on univariate analysis , 4.23 ( 1.19 - 14.95 ) , but not when corrected for age , gender and depression/suicidal ideation , 2.76 ( 0.30 - 24.87 ) . CONCLUSIONS Age , gender and pre-existing depression/suicidal ideation are important confounders in observational studies of the association between antidepressants and suicide or self harm BACKGROUND Paroxetine is a potent and selective serotonin reuptake inhibitor ( SSRI ) . The present study assessed the efficacy and tolerability of paroxetine against placebo in depressed out patients . METHOD A double-blind , parallel-group study was undertaken in four st and -alone centers . Patients aged 18 - 65 years , meeting DSM-III criteria for major depression , and having a Hamilton Rating Scale for Depression ( HAM-D ) score > or = 18 on the first 17 items of the HAM-D-21 were r and omized to paroxetine or placebo for 6 weeks of treatment . Efficacy outcome variables included the HAM-D , the Montgomery-Asberg Depression Rating Scale , the Clinical Global Impressions Scale ( CGI ) , and the Covi Anxiety Scale . Tolerability was assessed by asking a non-leading question . Routine laboratory safety and vital sign data from all four centers were pooled . The primary analysis used the intention-to-treat sample and for efficacy variables the last-observation-carried-forward data set was employed . Statistical methods included one-way analysis of variance for parametric and Fisher exact test for nonparametric variables . RESULTS Significant differences ( p < or = .05 ) were found between paroxetine and placebo on the HAM-D and CGI by Week 2 and on all efficacy outcome variables by Week 4 . Improvement on the HAM-D sleep factor occurred 2 weeks prior to that seen on the retardation factor . Similar results were obtained when an adequate treatment group ( therapy for > or = 28 days ) was considered . A full clinical response ( CGI-severity of illness score 1 or 2 ) was seen in over 40 % of subjects . Adverse events were more common for paroxetine compared with placebo ( p < or = .01 ) . Somnolence was twice more common than nervousness . Dropout due to adverse events was similar between therapies . Paroxetine had no clinical ly significant effect on laboratory safety data or vital signs . CONCLUSION Paroxetine was an effective , well tolerated , and safe antidepressant . Side effects were typical of the SSRI class of drugs . Symptoms indicative of a nonalerting profile were more common than those associated with alerting effects Objective To assess the potential economic impact of new and more expensive antidepressants on the overall cost of treatment using cost-effectiveness analysis . Method For this analysis , a computerized decision tree of clinical practice was developed to model the 12-month treatment of moderate to severe depression in Canada . To complete the model , data were obtained from physician panels , the Ontario Ministry of Health , and clinical comparative trials of paroxetine , a selective serotonin reuptake inhibitor , and Imipramine , a tricyclic antidepressant . Results The overall cost of treatment when paroxetine 30 mg per day was used first-line was found to be lower than when generic imipramine was used as the initial therapy ( $ 1697 versus $ 1793 ) . The higher drug cost of paroxetine ( $ 1.69 per day ) versus imipramine ( $ 0.05 per day ) was offset by a higher rate of treatment failures with the tricyclic necessitating an alternate therapy , additional physician visits and /or hospitalization . Sensitivity analysis of key variables determined that drug price and relapse rates after discontinuation were relatively insensitive predictors of the overall cost of care . More important was the continuation rate while on different therapies . Conclusion Paroxetine demonstrated a cost-benefit relative to Imipramine when the continuation rate was ≥ 47 % . Clinical trials of paroxetine have reported continuation rates of 41 % to 65 % , suggesting that paroxetine is a cost-effective alternative to Imipramine in the 1-year management of patients with moderate to severe depression Background : Interferon-induced depression represents a major complication in antiviral treatment of chronic hepatitis C virus ( HCV ) infection . Aim : To evaluate in a placebo-controlled study the efficacy of a selective serotonin reuptake inhibitor ( SSRI ) in HCV patients on antiviral therapy with interferon-associated depression . Methods : 100 HCV out patients were included in a r and omised , double-blind , placebo-controlled study . During interferon therapy ( peginterferon alfa-2b plus ribavirin ) , depression was monitored using the Hospital Anxiety and Depression Scale ( HADS ) .  Patients with clinical ly relevant interferon-induced depression ( HADS ⩾9 ) were r and omly assigned to placebo or citalopram ( SSRI , 20 mg/day ) . Results : In 28 patients ( 28 % ) , HADS scores increased to > 8 during interferon therapy . They were treated with placebo ( n = 14 ) or SSRI ( n = 14 ) . HADS scores declined significantly in SSRI patients within four weeks of therapy ( p<0.001 ) but not in placebo patients . This difference between subgroups was statistically significant ( p = 0.032 ) . Unblinding became necessary in five placebo patients as a result of intolerable depression . Rescue medication ( 20 mg citalopram ) led to a significant decrease in HADS scores ( p = 0.008 ) . All citalopram patients were able to complete interferon therapy as planned . As an interim analysis showed a significant superiority of SSRI over placebo , the study was terminated prematurely . Three patients , who became depressed afterwards , were treated in an unblinded fashion with citalopram . Conclusions : The findings demonstrate clearly that citalopram treatment is highly effective in HCV patients on interferon therapy , when initiated after the onset of clinical ly relevant depressive symptoms . This suggests that a general SSRI prophylaxis is not necessary in these patients BACKGROUND Many patients with major depression are non-adherent to antidepressant medication and do not receive care according to current guidelines . There is increasing evidence that treatment of depression in primary care can be improved . Comparison between effective interventions may help to establish the active ingredients of such interventions . METHOD In a r and omized trial two interventions to improve treatment of major depression in primary care were compared ( 1 ) a depression care programme , targeting general practitioners ( GPs ) , patients , and systematic follow-up , and ( 2 ) a systematic follow-up programme .  Thirty GPs were r and omized and 211 primary -care patients with current major depression were included . All patients were prescribed a selective serotonin reuptake inhibitor . Outcome measures included adherence to antidepressant medication , and depression outcome . RESULTS No significant differences in adherence rates and treatment outcome measures were demonstrated between interventions at week 10 or week 26 . Adherence rates were high and treatment outcome was favourable . CONCLUSIONS The depression care programme was not superior to the systematic follow-up programme . Systematic follow-up in depression treatment in primary care seems to be an intervention per se , having the potential to improve adherence and treatment outcome Background : Parkinson disease ( PD ) is a common neurodegenerative disease affecting up to 1 million individuals in the United States . Depression affects up to 50 % of these patients and is associated with a variety of poor outcomes for patients and their families . Despite this , there are few evidence -based data to guide clinical care . Methods : An NIH-funded , r and omized , controlled trial of paroxetine CR , nortriptyline , and placebo in 52 patients with PD and depression . The primary outcomes were the change in the Hamilton Depression Rating Scale ( HAM-D ) and the percentage of depression responders at 8 weeks . Results : Nortriptyline was superior to placebo for the change in HAM-D ( p < 0.002 ) ; paroxetine CR was not . There was a trend for superiority of nortriptyline over paroxetine CR at 8 weeks ( p < 0.079 ) . Response rates favored nortriptyline ( p = 0.024 ) : nortriptyline 53 % , paroxetine CR 11 % , placebo 24 % . In planned contrasts of response rates , nortriptyline was superior to paroxetine CR ( p = 0.034 ) . Nortriptyline was also superior to placebo in many of the secondary outcomes , including sleep , anxiety , and social functioning , while paroxetine CR was not . Both active drug treatments were well tolerated . Conclusions : Though relatively modest in size , this is the largest placebo-controlled trial done to date in patients with Parkinson disease ( PD ) and depression .  Nortriptyline was efficacious in the treatment of depression and paroxetine CR was not . When compared directly , nortriptyline produced significantly more responders than did paroxetine CR . The trial suggests that depression in patients with PD is responsive to treatment and raises questions about the relative efficacy of dual reuptake inhibitors and selective serotonin reuptake inhibitors . ARR = absolute risk reduction ; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders , 4th edition ; HAM-A = Hamilton Anxiety Scale ; HAM-D = Hamilton Depression Rating Scale ; MMSE = Mini-Mental State Examination ; NNT = number needed to treat ; PD = Parkinson disease ; PDQ = Parkinson ’s Disease Question naire ; PSQI = Pittsburgh Sleep Quality Index ; SCID = Structured Clinical Interview ; SSRI = selective serotonin reuptake inhibitor ; TCA = tricyclic antidepressant ; UPDRS = Unified Parkinson ’s Disease Rating Scale Neuropathic pain ( NeP ) , generated by disorders of the peripheral and central nervous system , can be particularly severe and disabling . Prevalence estimates indicate that 2 % to 3 % of the population in the developed world suffer from NeP , which suggests that up to one million Canadians have this disabling condition . Evidence -based guidelines for the pharmacological management of NeP are therefore urgently needed . R and omized , controlled trials , systematic review s and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting . Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one method ologically sound , r and omized , controlled trial showing significant benefit relative to placebo or another relevant control group . Recommendations for treatment are based on degree of evidence of analgesic efficacy , safety , ease of use and cost-effectiveness .  Analgesic agents recommended for first-line treatments are certain antidepressants ( tricyclics ) and anticonvulsants ( gabapentin and pregabalin ) . Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine . Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain . Recommended fourth-line treatments include cannabinoids , methadone and anticonvulsants with lesser evidence of efficacy , such as lamotrigine , topiramate and valproic acid . Treatment must be individualized for each patient based on efficacy , side-effect profile and drug accessibility , including cost . Further studies are required to examine head-to-head comparisons among analgesics , combinations of analgesics , long-term outcomes , and treatment of pediatric and central Fluoxetine , a selective serotonin ( 5-HT ) reuptake inhibitor ( SSRI ) , and trazodone , a heterocyclic antidepressant , are effective in the treatment of major depression and treatment resistant depression ( TRD ) . Chronic treatment with both drugs causes increases in extracellular 5-HT through 5-HT reuptake inhibition and desensitization of inhibitory 5-HT1A autoreceptors . It has been shown that pindolol , a serotonin (5-HT)1A-receptor antagonist , may shorten the latency of onset of SSRIs in depression . The aim of the present study was to examine whether pindolol may increase the efficacy of a subtherapeutical dosage of trazodone in the treatment of major depression and TRD , defined according to the Thase and Rush criteria ( 1995 ) . Thirty-three major depressed in patients of whom 26 with TRD participated in this study . Ten days after hospitalization , treatment with trazodone 100 mg/day was started . After 1 week trazodone treatment , patients were r and omized-using a double blind placebo controlled design -to receive trazodone 100 mg/day+placebo ; trazodone 100 mg/day+pindolol 7.5 mg/day : or trazodone 100 mg/day+fluoxetine 20 mg/day and treated during 4 weeks . The 17-item Hamilton Depression Rating Scale ( HDRS ) was used as outcome measure . It was found that trazodone+pindolol was as effective as trazodone+fluoxetine in the treatment of major depression and TRD and significantly more effective than trazodone+placebo . Using an outcome measure of 50 % reduction in the HDRS , we found that 72.5 % of the depressed patients treated with trazodone+pindolol and 75 % of depressed patients treated with trazodone+fluoxetine showed a clinical ly significant response compared with 20.0 % of trazodone+placebo-treated patients A growing body of evidence implicates a derangement of zinc homeostasis in mood disorders . In general , unipolar depression is connected with low blood zinc levels that are increased by effective antidepressant therapy . A placebo-controlled , double blind pilot study of zinc supplementation in antidepressant therapy was conducted in patients who fulfilled DSM IV criteria for major ( unipolar ) depression . Patients received zinc supplementation ( 6 patients ; 25 mg of  Zn2 + once daily ) or  placebo  ( 8 patients ) and were treated with st and ard antidepressant therapy ( tricyclic antidepressants , selective serotonin reuptake inhibitors ) . Hamilton Depression Rating Scale ( HDRS ) and Beck Depression Inventory ( BDI ) were used to assess efficacy of antidepressant therapy , and patients ' status was evaluated before the treatment and 2 , 6 and 12 weeks after its commencement . Antidepressant treatment significantly reduced HDRS scores by the 2nd week of treatment in both groups , and lowered BDI scores at the 6th week in zinc-treated group . Zinc supplementation significantly reduced scores in both measures after 6- and 12-week supplementation when compared with placebo treatment . This preliminary study is the first demonstration of the benefit of zinc supplementation in antidepressant therapy . The mechanism(s ) may be related to modulation of glutamatergic or immune systems by zinc ion Depression with psychotic features has been shown to respond to selective serotonin reuptake inhibitors ( SSRIs ) . The serotonin transporter ( 5-HTT ) is a prime target for SSRIs . A functional polymorphism within the promoter region of the 5-HTT gene , leading to different transcriptional efficiency , was recently reported . We tested the hypothesis that allelic variation of the 5-HTT promoter could be related to the antidepressant response to fluvoxamine and /or augmentation with pindolol ( a serotonin autoreceptors antagonist ) which has been suggested as an augmentation therapy for nonresponders . One hundred and two in patients with major depression with psychotic features were r and omly assigned to treatment with a fixed dose of fluvoxamine and either placebo or pindolol for 6 weeks . Depression severity was assessed once a week using the Hamilton Depression Rating Scale . Allelic variation in each subject was determined using a PCR-based method . Data were analyzed with a three-way repeated measures analysis of variance . Both homozygotes for the long variant ( l/l ) of the 5-HTT promoter and heterozygotes ( l/s ) showed a better response to fluvoxamine than homozygotes for the short variant ( s/s ) . In the group treated with fluvoxamine plus pindolol all the genotypes acted like l/l treated with fluvoxamine alone .  Fluvoxamine efficacy in delusional depression seems to be related to allelic variation within the promoter of the 5-HTT gene . Even though other factors may be implicated , genotyping at 5-HTT promoter may represent a promising tool to individualize the pharmacological treatment of depression CONTEXT Selective serotonin reuptake inhibitors ( SSRIs ) are the most commonly prescribed class of antidepressant , yet it is not known whether one SSRI is more effective than another . OBJECTIVE To compare the effectiveness of 3 SSRIs ( paroxetine , fluoxetine , and sertraline ) in depressed primary care patients . DESIGN Open-label , r and omized , intention-to-treat trial , with patient enrollment occurring in April-November 1999 . SETTING Thirty-seven clinics in 2 US primary care research networks . PATIENTS A total of 573 depressed adult patients for whom their primary care physician thought that antidepressant therapy was warranted and who completed a baseline interview . INTERVENTIONS Patients were r and omly assigned to receive paroxetine ( n = 189 ) , fluoxetine ( n = 193 ) , or sertraline ( n = 191 ) for 9 months . Primary care physicians were allowed to switch patients to a different SSRI or non-SSRI antidepressant if they did not adequately respond to or tolerate the initial SSRI . MAIN OUTCOME MEASURES The primary outcome measure was change in the Medical Outcomes Study 36-Item Short-Form Health Survey ( SF-36 ) Mental Component Summary score ( range , 0 - 100 ) , compared across treatment groups at 1 , 3 , 6 , and 9 months . Secondary outcomes included other depression and psychological measures , multiple measures of social and work functioning , and other domains of health-related quality of life , such as physical functioning , concentration and memory , vitality , bodily pain , sleep , and sexual functioning . RESULTS Follow-up interviews were successfully completed in 94 % of patients at 1 month , 87 % at 3 months , 84 % at 6 months , and 79 % at 9 months . Responses to the 3 SSRIs were comparable on all measures and at all time points . The mean change in the SF-36 Mental Component Summary score at 9 months was + 15.8 in the paroxetine group , + 15.1 in the fluoxetine group , and + 17.4 in the sertraline group . The drugs were also associated with similar incidences of adverse effects and discontinuation rates . CONCLUSIONS The SSRI antidepressants paroxetine , fluoxetine , and sertraline were similar in effectiveness for depressive symptoms as well as multiple domains of health-related quality of life over the entire 9 months of this trial BACKGROUND This r and omized , open-label , rater-blinded , multicenter study compared treatment outcomes with the serotonin-norepinephrine reuptake inhibitor ( SNRI ) venlafaxine extended release ( ER ) with selective serotonin reuptake inhibitors ( SSRIs ) in primary care patients with major depressive disorder . METHOD Study data were collected from November 29 , 2000 , to March 4 , 2003 . Out patients who met diagnostic criteria for major depressive disorder according to the Mental Health Screener , a computer-administered telephone interview program that screens for the most common mental disorders , and had a total score on the 17-item Hamilton Depression Rating Scale ( HDRS(17 ) ) ≥ 20 were r and omly assigned to receive up to 6 months of open-label venlafaxine ER 75 - 225 mg/d ( n = 688 ) or an SSRI ( n = 697 ) : fluoxetine 20 - 80 mg/d , paroxetine 20 - 50 mg/d , citalopram 20 - 40 mg/d , and sertraline 50 - 200 mg/d . The primary outcome was remission ( HDRS(17 ) score ≤ 7 ) at study end point using the last-observation-carried-forward method to account for early termination . A mixed-effects model for repeated measures ( MMRM ) analysis evaluated secondary outcome measures . RESULTS Fifty-one percent of patients completed the study . Month 6 remission rates did not differ significantly for venlafaxine ER and the SSRIs ( 35.5 % vs 32.0 % , respectively ; P = .195 ) . The MMRM analysis of HDRS(17 ) scores also did not differ significantly ( P = .0538 ) . Significant treatment effects favoring the venlafaxine ER group were observed for remission rates at days 30 , 60 , 90 , and 135 and a survival analysis of time to remission ( P = .006 ) , as well as Clinical Global Impressions-severity of illness scale ( P = .0002 ) ; Hospital Anxiety and Depression Scale-Anxiety subscale ( P = .03 ) ; 6-item Hamilton Depression Rating Scale , Bech version ( P = .009 ) ; and Quick Inventory of Depressive Symptomatology-Self-Report ( P = .0003 ) . CONCLUSIONS Remission rates for patients treated with venlafaxine ER or an SSRI did not differ significantly after 6 months of treatment . Results of most secondary analyses suggested that SNRI treatment had a greater antidepressant effect versus the SSRIs studied OBJECTIVE The aim of this study was to compare the growth of infants born to women with antenatal major depressive disorder , either untreated or treated with selective serotonin reuptake inhibitor ( SSRI ) antidepressants , and infants born to a nondepressed , nonmedicated comparison group across the first year of life . METHOD In this prospect i ve observational study , pregnant women were evaluated at weeks 20 , 30 , and 36 of gestation , and mother and infant pairs were assessed at 2 , 12 , 26 , and 52 weeks postpartum . Three nonoverlapping groups of women were defined according to their pregnancy exposures : 1 ) no SSRI and no depression ( N=97 ) , 2 ) SSRI ( N=46 ) , and 3 ) major depression without SSRI ( N=31 ) . Maternal demographic and clinical characteristics and newborn outcomes were compared across exposure groups . Infant weight , length , and head circumference were measured by a physician or physician 's assistant who was blind to depression and SSRI exposure status at each postpartum time point . RESULTS Both adjusted and unadjusted analyses revealed neither antenatal major depression nor SSRI exposure was significantly associated with infant weight , length , or head circumference relative to nonexposure to either . In addition , the interaction of group and prepregnancy body mass index was also evaluated , and no significant synergistic effect was identified . Similarly , no differential effect of group over time was observed for weight , length , or head circumference . CONCLUSIONS In utero exposure to major depression or SSRI antidepressants did not affect infant growth with respect to weight , length , or head circumference from birth through 12 months of age BACKGROUND Depression has emerged as a contrastive area of gender differences in psychiatry , as epidemiological data has consistently shown depression is twice as common in women as men . The pharmacodynamic effect of antidepressants may also show gender differences , as suggested by reports of better response of young women to non-tricyclic antidepressants . METHODS The antidepressive effect of an SSRI ( fluoxetine ) and a tetracyclic antidepressant with selective norepinephrine reuptake inhibitory effect ( maprotiline ) was compared in a 6-week , double-blind trial of 105 depressed patients . RESULTS No significant difference was observed in the change of HAMD17 total score from baseline to week 6 between fluoxetine- and maprotiline-treated patients . A significant difference was observed in females ( fluoxetine , -17.8 ; maprotiline , -13.9 ; P=0.017 ) between treatment groups , but not in males . Amongst females , the difference was significant in women aged < 44 years  ( fluoxetine , -18.4 ; maprotiline , -12.9 ; P=0.023 ) but not > or = 44 years . CONCLUSIONS Females in their reproductive period are more responsive to SSRI ( fluoxetine ) than norepinephrinergic tetracyclic antidepressant ( maprotiline ) treatment . Normal cyclical ovulation , and estrogen release may have a clinical ly relevant pharmacodynamic interaction with serotonergic antidepressants Antidepressants are used to treat chronic daily headache disorders such as  migraine  and chronic tension-type headache ( TTH ) , which are often associated with depression and anxiety . Here , we studied the efficacy and tolerability of amitriptyline and citalopram , given alone or in combination , in patients with ‘ triple ’ comorbidity of depression , TTH , and migraine . Eighty-eight patients were enrolled in the study and r and omly divided into two groups . The first group received amitriptyline and the second citalopram for 16 weeks . Patients were assessed at weeks 0 , 4 , 8 , and 16 . The two drugs were equally efficacious in relieving depressive symptoms , although amitriptyline was more efficacious than citalopram in reducing migraine and TTH attacks . Patients who did not respond to monotherapy ( < 30 % of improvement in the clinical scores ) were treated with a combination of the two drugs for 16 additional weeks . In these selected patients , the combined treatment produced a substantial improvement in depression , migraine and TTH without producing major side effects such as those commonly related to the ‘ serotonergic ’ syndrome . The results indicate that a combined therapy with amitriptyline and citalopram may be particularly beneficial for patients with TTH , migraine and comorbid depression that do not respond to monotherapy Selective serotonin-reuptake inhibitors ( SSRIs ) and tricyclic antidepressants ( TCAs ) have been reported to induce extrapyramidal signs and symptoms ( EPS ) . The authors examined the change from baseline EPS , measured by an objective rating scale , in a group of elderly depressed patients participating in an ongoing r and omized , double-blind comparison of nortriptyline and paroxetine .  Mild baseline EPS were present in both groups . After 6 weeks of antidepressant treatment , patients in the nortriptyline group showed a significant decrease in total EPS scores . Patients in the paroxetine group showed a similar decrease in EPS from baseline , which did not reach statistical significance . There was no significant difference between nortriptyline and paroxetine in the change in EPS The effects of trimipramine , a tricyclic antidepressant ( TCA ) with atypical pharmacological properties , and fluoxetine , a selective serotonine reuptake inhibitor ( SSRI ) , were compared in an exploratory analysis using mood and polysomnographic parameters during a six-week double-blind trial in 19 depressed geriatric patients . In sleep EEG measures , trimipramine demonstrated clear-cut effects on sleep measures result ing in higher values for sleep efficiency , total sleep time , stage 2 sleep , and shorter wake time . Under fluoxetine treatment , the proportion of REM sleep was decreased and REM latency was lengthened , whereas no change in REM sleep parameters was observed in the trimipramine group . The present data suggest that early antidepressant effects of medication occur independently of drug-induced changes in objective measures of sleep , i.e. suppression of REM sleep Unidimensional subscales for assessment of  major depression  may be more sensitive to antidepressant drug effects than the Hamilton Depression Rating Scale ( HAM-D ) . To further examine this possibility , we analyzed pooled data from eight comparable , well-controlled clinical trials of venlafaxine  and compared such subscales and the 17-item HAM-D ( HAM-D(17 ) ) based on effect size and number of patients required for 80 % power . Symptoms of depression were assessed using the HAM-D among intent-to-treat patients ( 2045 ) r and omly assigned to receive venlafaxine ( immediate release , n = 474 ; extended release , n = 377 ) , one of several selective serotonin reuptake inhibitors ( SSRIs ) ( n = 748 ) , or placebo ( n = 446 ) for up to 8 weeks . With SSRIs or venlafaxine vs. placebo , subscales yielded effect sizes ( 0.328 - 0.528 ) 16 to 76 % larger than the HAM-D(17 ) did ( 0.237 and 0.396 , respectively ) , and required 31 to 64 % fewer patients for 80 % power . With venlafaxine vs. SSRIs , the subscales showed no advantage over the HAM-D(17 ) ; all devices yielded comparable , positive effect sizes ( 0.183 - 0.195 ) . Final subscale scores significantly predicted ( all P < 0.05 ) whether patients met criteria for remission ( eg , HAM-D(17 ) score of < or = 7 ) . These findings suggest that unidimensional subscales are more sensitive to antidepressant drug effects than the HAM-D(17 ) is , but only in active agent/placebo comparisons . Our data further suggest the subscales can predict the presence of remission . Given these findings , prudent use of these subscales may be appropriate , cost-effective , and informative The firing rate of dorsal raphe serotonergic neurons is modulated by somatodendritic 5-hydroxytryptamine 1A ( HTR1A ) autoreceptors . Evidence from animal and clinical studies has suggested that desensitization of HTR1A is implicated in the antidepressant therapeutic mechanism of selective serotonin reuptake inhibitors ( SSRIs ) . Recent studies , including our recent findings , have reported that a functional HTR1A C-1019 G polymorphism in the promoter region , as well as a nonsynonymous polymorphism , Gly272Asp , may be associated with SSRI pharmacogenetics . In this study , we tested whether Gly272Asp genetic variants are related to a 4-week fluoxetine  antidepressant effect in 222 Chinese major depressive patients . We also tested the linkage disequilibrium ( LD ) measurement between HTR1A Gly272Asp and C-1019 G polymorphisms , and haplotype analysis was conducted to assess the association between the two markers within the HTR1A gene and  fluoxetine antidepressant response . The results show that the HTR1A Gly272Asp polymorphism was not associated with fluoxetine therapeutic response . The two markers are in strong LD and the HTR1A haplotype of the two polymorphisms is associated with fluoxetine therapeutic response . This association is gender-specific and mostly arises from the effect of HTR1A C-1019 G polymorphism : female patients with -1019C/C genotype showed a better response than -1019 G carriers . These findings need to be confirmed in other ethnic population Depression is associated with considerable morbidity and mortality . As depressive disorders carry a high risk of relapse , treatment strategies include the use of a 6-month continuation period after resolution of the acute episode . Tolerability is of major importance when determining compliance and outcome during long-term therapy . Due to the superior tolerability profile of the selective serotonin reuptake inhibitors ( SSRIs ) over the older tricyclic antidepressants ( TCAs ) , the former may be more suitable for extended therapy . Comparative studies have not shown differences between the SSRIs in terms of efficacy , but side-effect profiles may vary . A multicenter , double-blind , comparative study of sertraline and fluoxetine was carried out in out patients fulfilling DSM-III-R criteria for major depressive disorder . Patients were r and omised to receive sertraline ( 50 - 150 mg , n = 118 ) or fluoxetine ( 20 - 60 mg , n = 120 ) for 24 weeks . Assessment s for depression ( HAM-D , HAD , CGI-I , CGI-S ) , anxiety ( Covi ) , sleep ( Leeds Sleep Evaluation scale ) and quality of life ( SIP ) were made at study entry and at weeks 2 , 4 , 8 , 12 , 18 and 24 . All adverse events were recorded to allow evaluation of tolerability . In total , 88 patients in the sertraline group completed the study compared with 79 in the fluoxetine group .  Side effects were responsible for the premature treatment withdrawal of seven ( 6 % ) sertraline patients and 12 ( 10 % ) fluoxetine patients . Two-hundred and thirty-four patients were included in an ITT analysis up to last visit ( 116 sertraline , 118 fluoxetine ) . At study endpoint , both treatments produced a significant improvement over baseline on all efficacy variables ( P < 0.001 ) . Although the magnitude of global changes in depression , anxiety , and quality of life was larger with sertraline than fluoxetine , none of the between-group differences reached statistical significance . However , significant differences in favour of sertraline were observed for individual HAM-D items including item 4 ( insomnia onset ) ( P = 0.04 ) , item 9 ( agitation ) ( P = 0.02 ) , and item 13 ( general somatic symptoms ) ( P = 0.008 ) . In addition , sertraline was associated with significantly superior performance on the Leeds Sleep Evaluation scale and on SIP items relating to sleep and rest , emotional behaviour and ambulation . Both sertraline and fluoxetine were well tolerated with no significant differences between treatments This multicentre , double-blind , r and omised trial in 109 patients compared the efficacy and tolerance of the novel selective serotonin and noradrenaline reuptake inhibitor ( SNRI ) antidepressant milnacipran ( 50 mg twice daily , n=53 ) with the established tricyclic agent imipramine ( 75 mg twice daily , n=56 ) over a period of 6 weeks , in patients with major depression ( Montgomery-Asberg depression rating score ( MADRS ) > or = 25 ) . Initiation of antidepressant medication was conducted during a 2-week period of hospitalisation , after a 3- to 7-day washout period . Concomitant psychiatric medication was limited to lorazepam , cyamemazine , chloral hydrate and long-term uncomplicated lithium therapy . Assessment for efficacy using the MADRS and Hamilton rating scales of depression , a visual analogue scale and global evaluation revealed both agents to be highly effective ( P=0.0001 ) in this group of patients . Milnacipran was found to be of similar efficacy to imipramine .  Tolerance , assessed by physiological and biochemical examinations with routine inventory and spontaneous report of adverse events , revealed a clear advantage for milnacipran . The incidence of anticholinergic events with milnacipran was about half that with imipramine and the overall incidence of adverse events by either reporting method was markedly lower with milnacipran than with imipramine . Furthermore , the patient drop-out rate with imipramine was double that experienced with milnacipran . Milnacipran appears to possess equal antidepressant efficacy to imipramine but with markedly superior tolerance . Therefore , milnacipran constitutes an important new treatment option in major depression After 1 mg DST , 25 major depressive patients ( DSM-III ) received at r and om either a specific inhibitor of noradrenaline reuptake ( Maprotiline ) or an inhibitor of serotinin reuptake ( Indalpine or Citalopram ) . After at least 3 weeks of treatment , no difference was found in treatment response between suppressors and non suppressors . This study is unable to confirm the usefulness of the DST in selection of treatment according to its central activity on serotonin or noradrenaline-reuptake OBJECTIVE Some evidence indicates that an immune response with an increased production of proinflammatory cytokines often accompanies major depression . The objective of this study was to examine the serum levels of IL-6 in patients with major depression and the changes occurring in IL-6 levels during treatment with selective serotonin reuptake inhibitors ( SSRI ) . METHOD Twenty-three patients with a DSM-IV diagnosis of major depressive disorder and 23 healthy matched controls were included in the study . The severity of depression was measured with the Hamilton rating scale for depression . Blood sample s for IL-6 levels were obtained at baseline and at week 6 of treatment and IL-6 concentrations were evaluated using a solid phase s and wich enzyme immunoassay . All patients were treated with an SSRI . RESULTS The IL-6 levels showed no statistically significant difference between the patients and the controls at baseline . However , IL-6 levels after treatment with SSRIs were significantly lower compared with the baseline IL-6 levels of both the patients and the controls . CONCLUSION The results of this study suggest that proinflammatory cytokines show some changes during the course of treatment of major depression . These findings might also be considered as supporting the hypothesis of a modulatory role of antidepressants on the immune system Selective serotonin reuptake inhibitors may be less efficacious than tricyclic antidepressants in the treatment of severe depression in older patients . The authors compared the 12-week clinical outcome of older depressed patients treated with nortriptyline or paroxetine in a double-blind r and omized comparison in 116 psychiatric in patients and out patients ( mean age : 72+/-8 years ) who presented with a major depressive episode or melancholic depression .  Discontinuation and response rates were compared in patients who began or who completed treatment . The discontinuation rate due to side effects was significantly higher with nortriptyline than with paroxetine ( 33 % vs. 16 % ) . There were no significant differences between the rates of response in the Intent-to-Treat analysis ( nortriptyline : 57 % vs. paroxetine : 55 % ) , or the Completer analysis ( nortriptyline : 78 % vs. paroxetine : 84 % ) . Although paroxetine appears to be better tolerated than nortriptyline , the efficacy of these two drugs does not appear to differ in the acute treatment of older depressed patients , including hospitalized patients and those with melancholic features Abstract Antidepressant drugs are increasingly used in the management of  chronic pain .  They are mainly prescribed for cancer‐related pain and central pain , e.g. phantom or stump pain , post‐herpetic neuropathy . However , no controlled clinical trials have vali date d their in either pathology . Thus , physicians still do not know whether antidepressants are really effective and which might be best . It is still debated whether the effect of antidepressants in the management of chronic pain is limited to the amelioration of frequently concomitant depression or extends to pain itself . To verify both the analgesic effect of tricyclic antidepressants , and the possible relationship between their antidepressant effect and the relief of central pain , we carried out a r and omized , within‐patient ( cross‐over ) placebo‐controlled study in patients suffering from central pain . The results clearly indicate the better analgesic effect of tricyclic antidepressants over placebo ( p < 0.0001 ) . Within the antidepressants tested , chlorimipramine , a blocker of serotonin reuptake , is significantly more effective ( p < 0.0001 ) than nortriptyline , a blocker of noradrenaline reuptake . Finally , the antinociceptive effect is independent of the effects of the two drugs on the symptoms of depression Objective : To review the mechanism of selective serotonin reuptake inhibitor (SSRI)–mediated serotonergic neurotransmission , focusing on serotonin 1A ( 5-HT1A ) autoreceptors , which are proposed to be involved in delaying therapeutic efficacy . Vilazodone was specifically design ed to function both as an SSRI and a partial agonist at 5-HT1A receptors . This combined mechanism is proposed to decrease time to efficacy , minimize sexual side effects , and provide concomitant anxiolytic properties . Data Sources : A PubMed search of all English- language articles from January 1990 to January 2013 was conducted using the search terms depression and 5-HT1A , depression and buspirone , depression and pindolol , and vilazodone . Study Selection : We found 47 articles and abstract s that were selected for inclusion on the basis of information about the pharmacology of 5-HT1A receptors and the clinical data on pindolol , buspirone , and vilazodone in depression . Data Extraction : This review summarizes current literature involving antidepressant activity , the role of 5-HT1A autoreceptors , and clinical trials involving serotonin reuptake inhibition in conjunction with 5-HT1A agonists and partial agonists , with a focus on vilazodone . Results : Vilazodone has demonstrated efficacy in 2 large , r and omized , double-blind , placebo-controlled trials in major depressive disorder . Results suggest that vilazodone has a low incidence of sexual side effects and is effective in patients with high levels of anxiety . A pooled analysis shows evidence of significant symptom reduction after only 1 week of therapy . Conclusions : If future studies corroborate the clinical benefits attributed to its mechanism of action , vilazodone may show potential advantages in terms of onset of action , sexual side effects , and anxiolytic activity in patients with major depressive disorder BACKGROUND There is great heterogeneity of clinical presentation and outcome in paediatric depression . AIMS To identify which clinical and environmental risk factors at baseline and during treatment predicted major depression at 28-week follow-up in a sample of adolescents with depression . METHOD One hundred and ninety-two British adolescents with unipolar major depression were enrolled in a r and omised controlled trial ( the Adolescent Depression Antidepressants and Psychotherapy Trial , ADAPT ) . Participants were treated for 28 weeks with routine psychosocial care and selective serotonin reuptake inhibitors ( SSRIs ) , with half also receiving cognitive-behavioural therapy ( CBT ) . Full clinical and demographic assessment was carried out at baseline and 28 weeks . RESULTS Depression at 28 weeks was predicted by the additive effects of severity , obsessive-compulsive disorder and suicidal ideation at entry together with presence of at least one disappointing life event over the follow-up period . CONCLUSIONS Clinicians should assess for severity , suicidality and comorbid obsessive-compulsive disorder at presentation and should monitor closely for subsequent life events during treatment OBJECTIVE The authors used magnetic resonance spectroscopy ( MRS ) to assess the effect of acute administration of the selective serotonin reuptake inhibitor ( SSRI ) citalopram on cortical levels of gamma-aminobutyric acid ( GABA ) . METHOD Ten healthy volunteers received either intravenous citalopram ( 10 mg ) or saline in a r and omized , double-blind , crossover design . The occipital GABA/creatine ratio was measured with a proton MR spectral editing technique . RESULTS In comparison with saline , citalopram produced a mean increase of 35 % in relative brain GABA concentration in the occipital cortex . CONCLUSIONS These findings extend previous work showing that SSRI treatment increases cortical GABA in depressed patients and suggest that this results from an action of SSRIs on GABA neurons rather than as a secondary consequence of mood improvement BACKGROUND Antidepressants , especially selective serotonin reuptake inhibitors ( SSRIs ) , venlafaxine , and clomipramine , are frequently associated with sexual dysfunction . Other antidepressants ( nefazodone , mirtazapine , bupropion , amineptine , and moclobemide ) with different mechanisms of action seem to have fewer sexual side effects . The incidence of sexual dysfunction is underestimated , and the use of a specific question naire is needed . METHOD The authors analyzed the incidence of antidepressant-related sexual dysfunction in a multicenter , prospect i ve , open-label study carried out by the Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction . The group collected data from April 1995 to February 2000 on patients with previously normal sexual function who were being treated with antidepressants alone or antidepressants plus benzodiazepines . One thous and twenty-two out patients ( 610 women , 412 men ; mean age = 39.8 + /- 11.3 years ) were interviewed using the Psychotropic-Related Sexual Dysfunction Question naire , which includes questions about libido , orgasm , ejaculation , erectile function , and general sexual satisfaction . RESULTS The overall incidence of sexual dysfunction was 59.1 % ( 604/1022 ) when all antidepressants were considered as a whole . There were relevant differences when the incidence of any type of sexual dysfunction was compared among different drugs : fluoxetine , 57.7 % ( 161/279 ) ; sertraline , 62.9 % ( 100/159 ) ; fluvoxamine , 62.3 % ( 48/77 ) ; paroxetine , 70.7 % ( 147/208 ) ; citalopram , 72.7 % ( 48/66 ) ; venlafaxine , 67.3 % ( 37/55 ) ; mirtazapine , 24.4 % ( 12/49 ) ; nefazodone , 8 % ( 4/50 ) ; amineptine , 6.9 % ( 2/29 ) ; and moclobemide , 3.9 % ( 1/26 ) . Men had a higher frequency of sexual dysfunction ( 62.4 % ) than women ( 56.9 % ) , although women had higher severity . About 40 % of patients showed low tolerance of their sexual dysfunction . CONCLUSION The incidence of sexual dysfunction with SSRIs and venlafaxine is high , ranging from 58 % to 73 % , as compared with serotonin-2 ( 5-HT2 ) blockers ( nefazodone and mirtazapine ) , moclobemide , and amineptine BACKGROUND Sexual dysfunction commonly occurs during  antidepressant treatment .  However , the reported rates of sexual dysfunction vary across antidepressants and are typically underreported in product literature . The objectives of this study were ( 1 ) to estimate the prevalence of  sexual dysfunction among patients taking newer antidepressants ( bupropion immediate release [ IR ] , bupropion sustained release [ SR ] , citalopram , fluoxetine , mirtazapine , nefazodone , paroxetine , sertraline , venlafaxine , and venlafaxine extended release [ XR ] )  and ( 2 ) to compare physician-perceived with patient-reported prevalence rates of antidepressant-associated sexual dysfunction . METHOD This cross-sectional , observational study was conducted in 1101 U.S. primary care clinics . Adult out patients ( 4534 women and 1763 men ) receiving antidepressant monotherapy were enrolled . The prevalence of sexual dysfunction was measured using the Changes in Sexual Functioning Question naire . RESULTS In the overall population , bupropion IR ( 22 % ) and SR ( 25 % ) and nefazodone ( 28 % ) were associated with the lowest risk for sexual dysfunction , whereas selective serotonin reuptake inhibitor ( SSRI ) antidepressants , mirtazapine , and venlafaxine XR were associated with higher rates ( 36%-43 % ) . In a prospect ively defined sub population unlikely to have predisposing factors for sexual dysfunction , the prevalence of sexual dysfunction ranged from 7 % to 30 % , with the odds of having sexual dysfunction 4 to 6 times greater with SSRIs or venlafaxine XR than with bupropion SR . Physicians consistently underestimated the prevalence of antidepressant-associated sexual dysfunction . CONCLUSION Ours is the first study to assess sexual dysfunction across the newer antidepressants using consistent methodology and a vali date d rating scale . Overall , SSRIs and venlafaxine XR were associated with higher rates of sexual dysfunction than bupropion or nefazodone . Because antidepressant-associated sexual dysfunction is considerably underestimated by physicians , greater recognition and education are imperative when prescribing antidepressant treatment This study is a comparison across treatment setting s of two previously published trials , namely the Danish University Antidepressant Group ( DUAG ) study on citalopram vs. clomipramine in hospitalized patients with major depression , and the Nordic citalopram vs. imipramine  study of depressed patients treated by their family doctors . The Hamilton Depression Scale ( HAM‐D ) had the same level of inter‐rater reliability and construct validity in the two setting s. Using a HAM‐D score of 7 or less as the criterion for full remission , clomipramine was superior to imipramine and citalopram . Using a reduction of the baseline HAM‐D score by 50 % or more as a response criterion , there were no differences between the three antidepressants after 5 or 6 weeks of treatment . Citalopram  showed superior tolerability to the tricyclic antidepressants BACKGROUND Concerns about possible risks of switching to mania associated with antidepressants continue to interfere with the establishment of an optimal treatment paradigm for bipolar depression . METHOD The response of 44 patients meeting DSM-IV criteria for bipolar disorder to naturalistic treatment was assessed for at least 6 weeks using the Montgomery-Asberg Depression Rating Scale and the Bech-Rafaelson Mania Rating Scale . Patients who experienced a manic or hypomanic switch were compared with those who did not on several variables including age , sex , diagnosis ( DSM-IV bipolar I vs. bipolar II ) , number of previous manic episodes , type of antidepressant therapy used ( electroconvulsive therapy vs. antidepressant drugs and , more particularly , selective serotonin reuptake inhibitors [ SSRIs ] ) , use and type of mood stabilizers ( lithium vs. anticonvulsants ) , and temperament of the patient , assessed during a normothymic period using the hyperthymia component of the Semi-structured Affective Temperament Interview . RESULTS Switches to hypomania or mania occurred in 27 % of all patients ( N = 12 ) ( and in 24 % of the subgroup of patients treated with SSRIs [ 8/33 ] ) ; 16 % ( N = 7 ) experienced manic episodes , and 11 % ( N = 5 ) experienced hypomanic episodes . Sex , age , diagnosis ( bipolar I vs. bipolar II ) , and additional treatment did not affect the risk of switching . The incidence of mood switches seemed not to differ between patients receiving an anticonvulsant and those receiving no mood stabilizer . In contrast , mood switches were less frequent in patients receiving lithium ( 15 % , 4/26 ) than in patients not treated with lithium ( 44 % , 8/18 ; p = .04 ) . The number of previous manic episodes did not affect the probability of switching , whereas a high score on the hyperthymia component of the Semistructured Affective Temperament Interview was associated with a greater risk of switching ( p = .008 ) . CONCLUSION The frequency of mood switching associated with acute antidepressant therapy may be reduced by lithium treatment . Particular attention should be paid to patients with a hyperthymic temperament , who have a greater risk of mood switches The aim of the present study was to determine whether , in patients with depression who had responded favourably to the selective serotonin reuptake inhibitor citalopram  , there was a therapeutic benefit in continuation treatment . Three hundred and ninety-one depressive patients were included in an open short-term citalopram treatment period . Only patients who responded to treatment at 8 weeks ( total score of 12 or less on the MADRS scale ) were r and omized to the 24 week double-blind phase . Seventy-four patients were treated with placebo and 152 with citalopram at the same constant dose to which the patient had responded in the first phase . Relapse was defined as a total score of 25 or more on the MADRS scale . Twenty-one patients ( 13.8 % ) continuing to receive citalopram  relapsed compared with 18 patients ( 24.3 % ) receiving placebo . The log rank test for survival data used to test the e quality of relapse hazards between the placebo group and the citalopram group showed that patients treated with citalopram had a significantly lower relapse rate { p = 0.04 ) . The results of this study are in general agreement with those of other studies on antidepressants , and support the hypothesis that full dose continuation treatment is more effective than placebo in preventing relapse of depression Finding predictors of the response to antidepressant therapy  is a major goal of molecular psychiatry . The genes encoding the serotonin ( SERT ) and dopamine ( DAT1 ) transporters are among the possible c and i date genes modulating an individual 's antidepressant response . In a naturalistic prospect i ve cohort study with a total of 190 fully assessed patients , improvement of depression symptoms during the 3 weeks following initiation of antidepressant therapy was recorded using the 21-item Hamilton Depression Rating Scale ( HDRS ) . The SLC6A3 3′ UTR 40-bp variable number of t and em repeats ( VNTR ) and the SLC6A4 5′ 44-bp insertion/deletion polymorphism were analyzed by polymerase chain reaction . There was a significantly smaller number of rapid responders among homozygous carriers of the DAT1 9-repeat allele ( 9/9 ) than among heterozygous ( 9/10 ) and homozygous ( 10/10 ) carriers of the 10-repeat allele ( 19 versus 37 versus 52 % , respectively , P=0.0037 ) . Median decline in HDRS score was 35 , 40 , and 52 % in patients with the 9/9 , 9/10 , and 10/10 genotypes , respectively ( P=0.013 ) . The effect was found in all classes of medications ( selective serotonin reuptake inhibitors ( SSRIs ) , tricyclics , mirtazapine , venlafaxine ) and statistically significant also within the subgroup of patients having received SSRIs . The serotonin promoter insertion/deletion genotype had no effect in the entire study group , but there was an insignificant trend of better response in the l/l and l/s carriers who received SSRIs or mirtazapine . In conclusion , the dopamine transporter VNTR polymorphism influenced rapid response to antidepressant therapy . Compared with homozygous carriers of the 10-repeat allele , carriers of the 9/10 genotype had an odds ratio ( OR ) calculated by logistic regression analysis of 1.6 ( 95 % CI 0.8–3.2 ) and carriers of the 9/9 genotype had an OR of 6.0 ( 1.5–24.4 ) for no or poor response . Further studies are required to confirm this clinical association and to eluci date the underlying mechanisms BACKGROUND Major depression is an important and costly problem among adolescents , yet evidence to support the provision of cost-effective treatments is lacking . AIMS To assess the short-term cost-effectiveness of combined selective serotonin reuptake inhibitors ( SSRIs ) and cognitive-behavioural therapy ( CBT ) together with clinical care compared with SSRIs and clinical care alone in adolescents with major depression . METHOD Pragmatic r and omised controlled trial in the UK .  Outcomes and costs were assessed at baseline , 12 and 28 weeks . RESULTS The trial comprised 208 adolescents , aged 11 - 17 years , with major or probable major depression who had not responded to a brief initial psychosocial intervention . There were no significant differences in outcome between the groups with and without CBT .  Costs were higher in the group with CBT , although not significantly so ( P=0.057 ) . Cost-effectiveness analysis and exploration of the associated uncertainty suggest there is less than a 30 % probability that CBT plus SSRIs is more cost-effective than SSRIs alone . CONCLUSIONS A combination of CBT plus SSRIs is not more cost-effective in the short-term than SSRIs alone for treating adolescents with major depression in receipt of routine specialist clinical care BACKGROUND We compared citalopram and clomipramine against placebo with respect to recurrence prevention as opposed to relapse prevention in patients with recurrent depression , independently of any acute response to the test drug(s ) . METHODS Patients with recurrent depressive disorder with a current depressive episode of moderate to severe degree were recruited over a period of 6.5 years . After 6 - 15 months of routine open acute and continuation therapy , and a discontinuation/drug-free period of one month following sustained response ( at least 3 consecutive monthly ratings with a HAM-D-17-score below 13 ) , patients were r and omised under double-blind conditions , with a follow-up period of 2 years . The major endpoint was recurrence ( HAM-D-17-score of 16 or above ) . RESULTS A total of 307 patients were included in the open phase and 174 patients completed at least 6 months of treatment and achieved sustained response . Out of these , only 59 patients ( 34 % ) could be r and omised to placebo ( n=22 ) , citalopram ( n=19 ) or clomipramine ( n=22 ) , with protocol violation and /or non-consent being the major reasons for non-r and omisation . There were no between-group differences in outcome ; almost half of the r and omised patients met the criterion for recurrence . LIMITATIONS The size of the r and omised sample was considerably smaller than the planned size . CONCLUSIONS The high risk of drop out prior to r and omisation among the eligible patients was presumably caused by an interaction between the study design and the study population . The findings suggest that long-term trial design s interposing a drug-free period prior to r and omisation are not feasible and recommendable in severely ill patients BACKGROUND Antidepressant medication efficacy remains a major research challenge . Here , we explored four questions : whether noradrenergic antidepressants are more effective than serotonergic antidepressants ; whether the addition of 100 mg acetylsalicylic acid ( ASA ) changes antidepressant efficacy ; whether the long-term efficacy differs depending on the antidepressant and the addition of ASA ; and whether serum levels of brain-derived neurotrophic factor ( BDNF ) are clinical ly informative . SUBJECTS AND METHODS In a two-year study , forty people with major depressive disorder were r and omly assigned to groups that received an SSRI ( escitalopram ) or an SNRI ( duloxetine ) , each group received concomitant ASA ( 100 mg ) or a placebo . Sociodemographic data were recorded and patients under went regular assessment s with the Hamilton depression scale ( HDS ) and clinical global impression ( CGI ) scale . Serum levels of BDNF were measured four times per year . RESULTS There was no significant difference in efficacy between the two antidepressants or between antidepressant treatment with and without ASA . However , subgroup comparisons revealed that the duloxetine + ASA ( DASA ) subgroup showed a more rapid improvement in HDS score as early as 2 months ( t=-3.114 , p=0.01 ) , in CGI score at 5 months ( t=-2.119 , p=0.05 ) , and a better remission rate ( χ2=6.296 , p 0.012 ) than the escitalopram + placebo ( EP ) subgroup . Serum BDNF before treatment was also higher in the DASA subgroup than in the EP subgroup ( t=3.713 ; p=0.002 ) . CONCLUSION This suggest two hypotheses : either a noradrenergic agent combined with ASA is more effective in treating depression than a serotonergic agent alone , or the level of serum BDNF before treatment is a precursor marker of the response to antidepressants . Further research is needed to test these hypotheses INTRODUCTION Although a significant amount of evidence indicates the efficacy of some antidepressants in treating psychogenic pain and somatoform disorder , very few studies have investigated their possible therapeutic action in burning mouth syndrome ( BMS ) . The purpose of this 8-week , single-blind study was to provide preliminary data on the efficacy and tolerability of amisulpride and the selective serotonin reuptake inhibitors ( SSRIs ) paroxetine and sertraline for patients with BMS . METHOD Seventy-six patients with BMS ( diagnosed according to the criteria in the literature and integrating the Diagnostic Interview Schedule-Revised for a complete psychiatric assessment ) , with no possible local or systemic causes and without concurrent major depression , were r and omly assigned to receive amisulpride ( 50 mg/day ) , paroxetine ( 20 mg/day ) , or sertraline ( 50 mg/day ) . Efficacy assessment s included a visual analogue scale ( VAS ) for pain intensity , the Hamilton Rating Scale for Depression ( HAM-D ) , the Hamilton Rating Scale for Anxiety ( HAM-A ) , and the Clinical Global Impressions scale ( CGI ) . RESULTS All 3 treatment regimens result ed in a significant improvement from baseline in burning mouth symptoms at week 8 as demonstrated by the quantitative ( mean reduction in VAS , HAM-D , and HAM-A scores ) and qualitative ( percentage of responders ) analyses . Amisulpride showed a shorter response latency than the SSRIs . No serious adverse events were reported , and the incidence of side effects did not differ among the 3 groups . None of the patients who received amisulpride withdrew from the trial , whereas withdrawal from the trial occurred within the first week of treatment in 11.5 % of patients ( N = 3 ) treated with paroxetine and in 21.7 % of patients ( N = 5 ) treated with sertraline . CONCLUSION The data suggest that amisulpride and SSRIs may be effective treatments for BMS ; they are equally effective and equally well tolerated in the short-term treatment of BMS . Amisulpride is associated with better compliance within the first week of treatment and with a shorter response latency in comparison with SSRIs . This finding may indicate that amisulpride is especially useful at the beginning of drug therapy of BMS . Double-blind , placebo-controlled trials are needed to further document the efficacy of amisulpride and SSRIs in the treatment of BMS
Some statistically significant differences between citalopram and other antidepressants for the acute phase treatment of major depression were found in terms of efficacy , tolerability and acceptability .
Citalopram was more efficacious than paroxetine and reboxetine and more acceptable than tricyclics , reboxetine and venlafaxine , however , it seemed to be less efficacious than escitalopram .
BACKGROUND Recent US and UK clinical practice guidelines recommend that second-generation antidepressants should be considered amongst the best first-line options when drug therapy is indicated for a depressive episode .
Systematic review s have already highlighted some differences in efficacy between second-generation antidepressants .
Citalopram , one of the first selective serotonin reuptake inhibitors ( SSRI ) introduced in the market , is one of these antidepressant drugs that clinicians use for routine depression care .
OBJECTIVES To assess the evidence for the efficacy , acceptability and tolerability of citalopram in comparison with tricyclics , heterocyclics , other SSRIs and other conventional and non-conventional antidepressants in the acute-phase treatment of major depression .