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Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder A pragmatic 12-week, randomized trial of duloxetine versus generic selective serotonin-reuptake inhibitors in the treatment of adult outpatients in a moderate-to-severe depressive episode Effects of Zinc Supplementation in Patients with Major Depression: A Randomized Clinical Trial Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline Bupropion as an augmenting agent in patients of depression with partial response. Cardiac side‐effects of two selective serotonin reuptake inhibitors in middle- aged and elderly depressed patients A double-blind, placebo-controlled study of edivoxetine as an adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment. A randomised, double-blind study in adults with major depressive disorder with an inadequate response to a single course of selective serotonin reuptake inhibitor or serotonin–noradrenaline reuptake inhibitor treatment switched to vortioxetine or agomelatine† Cost-effectiveness of selective serotonin reuptake inhibitors and routine specialist care with and without cognitive behavioural therapy in adolescents with major depression. The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder Efficacy and Tolerability of Reboxetine Compared with Citalopram: A Double-blind Study in Patients with Major Depressive Disorder L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. 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Association between -1438G/A Promoter Polymorphism in the 5-HT2A Receptor Gene and Fluvoxamine Response in Japanese Patients with Major Depressive Disorder Response to an open trial of a second SSRI in major depression. Remission with venlafaxine extended release or selective serotonin reuptake inhibitors in depressed patients: a randomized, open-label study. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Preliminary experience with adjunctive quetiapine in patients receiving selective serotonin reuptake inhibitors Treatment of depression in patients with temporal lobe epilepsy: A pilot study of cognitive behavioral therapy vs. selective serotonin reuptake inhibitors A randomized effectiveness trial of brief cognitive-behavioral therapy for depressed adolescents receiving antidepressant medication. Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients Comparison of desipramine and citalopram treatments for depression in Parkinson's disease: a double-blind, randomized, placebo-controlled study. Effective components of TORDIA cognitive-behavioral therapy for adolescent depression: preliminary findings. Escitalopram maintenance treatment for prevention of recurrent depression: a randomized, placebo-controlled trial. Long-term outcome of adolescent depression initially resistant to selective serotonin reuptake inhibitor treatment: a follow-up study of the TORDIA sample. Treatment of selective serotonin reuptake inhibitor-resistant depression in adolescents: predictors and moderators of treatment response. Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: a randomized, double-blind, placebo-controlled, pilot clinical trial. Brain-derived neurotrophic factor Val66Met polymorphism and 6-month antidepressant remission in depressed Caucasian patients. Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. Exercise and Pharmacotherapy in the Treatment of Major Depressive Disorder Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. Efficacy of venlafaxine in patients with major depressive disorder who have unsustained or no response to selective serotonin reuptake inhibitors: an open-label, uncontrolled study. Impact of treatments for depression on comorbid anxiety, attentional, and behavioral symptoms in adolescents with selective serotonin reuptake inhibitor-resistant depression. Reboxetine, the first selective noradrenaline reuptake inhibitor antidepressant: Efficacy and tolerability in 2613 patients Randomized double-blind comparison of serotonergic (Citalopram) versus noradrenergic (Reboxetine) reuptake inhibitors in outpatients with somatoform, DSM-IV-TR pain disorder. Does fetal exposure to SSRIs or maternal depression impact infant growth? Treatment of Post-Myocardial Infarction Depressive Disorder: A Randomized, Placebo-Controlled Trial With Mirtazapine Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. Efficacy and safety of mirtazapine in major depressive disorder patients after SSRI treatment failure: an open-label trial. Clinical and Neurobiological Effects of Tianeptine and Paroxetine in Major Depression Use of benzodiazepines and selective serotonin reuptake inhibitors in middle-aged and older adults with anxiety disorders: a longitudinal and prospective study. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. Short-term intravenous citalopram augmentation in partial/nonresponders with major depression: a randomized placebo-controlled study fMRI response to negative words and SSRI treatment outcome in major depressive disorder: A preliminary study Association study of two serotonin 1A receptor gene polymorphisms and fluoxetine treatment response in Chinese major depressive disorders Effect of selective serotonin reuptake inhibitors on the risk of fracture. Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder. Effects of selective serotonin reuptake inhibitors on platelet serotonin parameters in major depressive disorder Association between enhanced soluble CD40 ligand and proinflammatory and prothrombotic states in major depressive disorder: pilot observations on the effects of selective serotonin reuptake inhibitor therapy. 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 Diminished Neural Processing of Aversive and Rewarding Stimuli During Selective Serotonin Reuptake Inhibitor Treatment Are patients who are intolerant to one serotonin selective reuptake inhibitor intolerant to another? Treated depression in adolescents: predictors of outcome at 28 weeks. Differential Antidepressant Symptom Efficacy: Placebo-Controlled Comparisons of Duloxetine and SSRIs (Fluoxetine, Paroxetine, Escitalopram) Effect of Vortioxetine vs. Escitalopram on Sexual Functioning in Adults with Well-Treated Major Depressive Disorder Experiencing SSRI-Induced Sexual Dysfunction. Reboxetine and citalopram in panic disorder: a single-blind, cross-over, flexible-dose pilot study Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment. Sertraline and Cognitive Behavioral Therapy for Depressed Alcoholics: Results of A Placebo-Controlled Trial Variations in circulating cytokine levels during 52 week course of treatment with SSRI for major depressive disorder A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease Effects of Sertraline on Sleep Architecture in Patients With Depression S-Adenosyl-L-Methionine (SAMe) as an Adjunct for Resistant Major Depressive Disorder: An Open Trial Following Partial or Nonresponse to Selective Serotonin Reuptake Inhibitors or Venlafaxine 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 Escitalopram in the prevention of posttraumatic stress disorder: a pilot randomized controlled trial (S)-(+)-mecamylamine (TC-5214): a neuronal nicotinic receptor modulator enters phase III trials as an adjunct treatment for Major Depressive Disorder (MDD). Strategy for treating selective serotonin reuptake inhibitor-resistant social anxiety disorder in the clinical setting: a randomised controlled trial protocol of cognitive behavioural therapy in combination with conventional treatment Time to response in panic disorder in a naturalistic setting: combination therapy with alprazolam orally disintegrating tablets and serotonin reuptake inhibitors compared to serotonin reuptake inhibitors alone. Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. Prophylactic efficacy of fluoxetine, escitalopram, sertraline, paroxetine, and concomitant psychotherapy in major depressive disorder: Outcome after long-term follow-up A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. Cytokines and serotonin transporter in patients with major depression Switching to Reboxetine: An Efficacy and Safety Study in Patients With Major Depressive Disorder Unresponsive to Fluoxetine Trajectories of depression severity in clinical trials of duloxetine: insights into antidepressant and placebo responses. Venlafaxine XR demonstrates higher rates of sustained remission compared to fluoxetine, paroxetine or placebo Intramuscular Testosterone Supplementation to Selective Serotonin Reuptake Inhibitor in Treatment-Resistant Depressed Men: Randomized Placebo-Controlled Clinical Trial The treatment of SSRI-resistant depression in adolescents (TORDIA): in search of the best next step. A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of the Augmentation of a Nicotinic Acetylcholine Receptor Partial Agonist in Depression: Is There a Relationship to Leptin Levels? Efficacy and safety of add on low-dose mirtazapine in depression Relation of Serotonin Transporter Genetic Variation to Efficacy of Escitalopram for Generalized Anxiety Disorder in Older Adults Results of a naturalistic longitudinal study of benzodiazepine and SSRI use in the treatment of generalized anxiety disorder and social phobia. Efficacy of venlafaxine in major depression resistant to selective serotonin reuptake inhibitors Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. Switching to bupropion in fluoxetine-resistant major depressive disorder. Dense Cranial Electroacupuncture Stimulation for Major Depressive Disorder—A Single-Blind, Randomized, Controlled Study Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study Safe use of SSRIs in young adults: how strong is evidence for new suicide warning? Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. The expert consensus guideline series. Pharmacotherapy of depressive disorders in older patients. Stop or go? Preventive cognitive therapy with guided tapering of antidepressants during pregnancy: study protocol of a pragmatic multicentre non-inferiority randomized controlled trial GENetic and clinical Predictors Of treatment response in Depression: the GenPod randomised trial protocol
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 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 OBJECTIVE Three studies examined whether edivoxetine ( a highly selective norepinephrine reuptake inhibitor ) had efficacy as adjunctive therapy for patients with major depressive disorder ( DSM-IV-TR ) who were partial responders to selective serotonin reuptake inhibitor ( SSRI ) treatment of at least 6 weeks ' duration . METHOD Studies were 8-week r and omized , placebo-controlled trials with a 3-week double-blind placebo lead-in phase , conducted from December 16 , 2010 , to October 21 , 2013 . Patients entered the double-blind adjunctive treatment phase if they met r and omization criteria ( < 25 % improvement on  Montgomery-Asberg Depression Rating Scale  [  MADRS  ] and  MADRS total score ≥ 14 ) ; patients not r and omized remained on adjunctive placebo . Study 1 compared fixed-dose edivoxetine ( 12 or 18 mg daily ) + SSRI ( N = 231 and N = 230 , respectively ) with placebo + SSRI ( N = 240 ) ; study 2 compared flexible-dose edivoxetine ( 12 - 18 mg daily ) + SSRI ( N = 232 ) and fixed-dose edivoxetine ( 6 mg daily ) + SSRI ( N = 226 ) with placebo + SSRI ( N = 231 ) ; and study 3 compared flexible-dose edivoxetine ( 12 - 18 mg daily ) + SSRI ( N = 230 ) with placebo + SSRI ( N = 219 ) . The primary outcome was mean change from r and omization baseline to week 8 in MADRS total score , analyzed using repeated measures analysis . RESULTS Each trial failed to meet the primary and most of the secondary objectives . The least-squares mean changes in MADRS total score were as follows- study 1 : -8.5 ( edivoxetine 12 mg + SSRI ) , -8.7 ( edivoxetine 18 mg + SSRI ) , and -7.8 ( placebo + SSRI ) ; study 2 : -9.4 ( edivoxetine 12 - 18 mg + SSRI ) , -9.6 ( edivoxetine 6 mg + SSRI ) , and -9.4 ( placebo + SSRI ) ; and study 3 : -8.7 ( edivoxetine 12 - 18 mg + SSRI ) and -8.5 ( placebo + SSRI ) . CONCLUSIONS Adjunctive edivoxetine treatment for patients with major depressive disorder who were partial responders to SSRIs did not significantly improve efficacy outcomes . TRIALS REGISTRATION S Clinical Trials.gov identifiers : NCT01173601 , NCT01187407 , NCT01185340 Objective The aim of the investigation was to study the effects of withdrawing selective serotonin reuptake inhibitor ( SSRI ) drugs in nursing home patients , who had no documented diagnosis or symptoms of depression . Setting The setting of the study was in 11 nursing homes in the county of Stockholm , Sweden . Participants Participants were patients without dementia or history of depression who had received treatment with SSRI drugs for more than 6 months and who had no indications of anxiety disorder or major depression Design The included patients ( n=70 ) were r and omized to either the intervention group  ( withdrawal of SSRI ) or the control group  ( no change in treatment ) , 35 patients to each group . Main outcome measures The patients were subjected to assessment using the following instruments : Montgomery-Åsberg depression rating scale , global assessment for functioning , health index and a symptom assessment form . Assessment was made at the start of the study and at the 3-month and 6-month follow-ups . Results We found no significant difference between the intervention and control groups in any outcome measure . Conclusion Treatment with SSRI drugs in patients without clinical major depression or anxiety disorder is often unjustified and should be discontinued BACKGROUND Due to their favorable side-effect profile , atypical antipsychotic agents offer important therapeutic advantages in mood disorders .  Ziprasidone , an atypical antipsychotic agent with strong 5-HT(1A ) agonist activity , may be particularly useful when used in conjunction with st and ard antidepressants in treatment-resistant depression . The purpose of this study is to test this hypothesis in depressed out patients who have not experienced significant clinical improvement following an adequate trial of a selective serotonin reuptake inhibitor ( SSRI ) . METHOD Twenty patients with major depressive disorder ( MDD ) who had failed to experience a clinical response to an adequate trial of an SSRI were treated with open-label ziprasidone in addition to their SSRI for 6 weeks between February 2002 and December 2002 . MDD was diagnosed with the Structured Clinical Interview for DSM-IV Axis I disorders . Clinical response was defined as a 50 % or greater decrease in depressive symptoms during the course of the trial ( baseline to endpoint ) , as measured by the HAM-D-17 total score . RESULTS Thirteen of 20 patients ( 65.0 % ) completed the trial . Using a completer analysis , 8 patients ( 61.5 % ) were classified as responders . An intent-to-treat ( ITT ) analysis result ed in 10 responders ( 50.0 % ) . The overall proportion of remitters was 5 of 13 ( 38.5 % ) using a completer analysis and 5 of 20 ( 25.0 % ) using the ITT analysis . Ziprasidone administration appeared to be safe , with no clinical ly significant QTc prolongation or severe adverse events observed in any of the study participants . CONCLUSION These results suggest a possible augmentation role for ziprasidone when used in conjunction with SSRIs in SSRI-resistant MDD & NA ; Sexual side‐effects due to antidepressant treatment are an important consideration when selecting a treatment regimen and can influence patient compliance . Sexual function during treatment with the selective noradrenaline reuptake inhibitor reboxetine , the selective serotonin reuptake inhibitor ( SSRI ) fluoxetine and placebo has been assessed in a multicentre , r and omized , 8‐week , double‐blind study of 450 patients diagnosed with major depressive disorder .  Sexual function was measured by the Rush Sexual Inventory completed by male and female patients and administered at baseline , week 4 and week 8 . The results indicate that reboxetine was similar to placebo and superior to fluoxetine in its effect on overall sexual function . There was a greater degree of sexual satisfaction in the reboxetine group compared to fluoxetine ( P = 0.02 ) . The percentage of female patients able to achieve orgasm increased during the study period for women who received reboxetine and placebo , but decreased for those who received fluoxetine . These results suggest that reboxetine may be of particular benefit for patients at risk for sexual dysfunction with SSRIs Some evidence suggests that medications that modulate both serotonin and norepinephrine may be more effective than selective serotonin-reuptake inhibitors ( SSRIs ) in severe major depressive disorder ( MDD ) . This prospect i ve pragmatic trial tests this hypothesis . Patients with severe MDD were r and omly assigned to either duloxetine ( a serotonin and norepinephrine-reuptake inhibitor ) or physicians ’ choice of four generic SSRIs . Nonblinded , flexibly dosed treatment was used to mimic clinical practice . To address potential investigator bias , the patient-reported Quick Inventory of Depressive Symptomatology Self-Report ( QIDS-SR ) was used as the primary efficacy outcome measure . A total of 750 out patients ( 19.2 % , African descent ; 14.8 % , Hispanic ) were r and omized . The primary outcome , remission at week 12 by QIDS-SR , was numerically greater for duloxetine compared with SSRIs ( 36 vs. 32 % ) , but this difference was not statistically significant . Mean changes in secondary outcomes were significantly superior in favor of duloxetine for the Hamilton Depression Scale-17 item , the Brief Pain Inventory , and the Sheehan Disability Scale . Remission superiority on the QIDS-SR was not achieved . Significantly greater benefit for duloxetine compared with SSRIs was demonstrated on measures of pain and functioning . Study demographics suggest a more generalizable racial and ethnic population than is typical in r and omized clinical trials 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 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 objective of this study is to evaluate the effects of bupropion as an add-on therapy to selective serotonin reuptake inhibitor ( SSRI ) on patients of major depressive disorder with partial response . This prospect i ve , r and omized , controlled and single-blind study was conducted in sixty patients suffering from major depressive disorder as per Diagnostic and Statistical Manual (DSM)-IV TR criteria , who were having Hamilton depression rating scale ( HDRS ) score ≥16 after 4 weeks of treatment with SSRIs . Group A received SSRI plus placebo and group B received SSRI plus bupropion . Evaluation was performed based on changes in HDRS score , Montgomery and Asberg depression rating scale ( MADRS ) , Amritsar depressive inventory ( ADI ) and spontaneously reported adverse effects . There was a significant decrease in the HDRS , MADRS and ADI scores as compared to baseline in both groups . However , the mean decrease in depression score was more in group B than in group A. The percentage decrease of remitters was also significantly more in group B ( 60 % as per HDRS score and 63 % as per MADRS score ) , as compared to group A ( 24 % as per HDRS score and 27 % as per MADRS score ) ( p < 0.05 ) , at the end of treatment . In conclusion , bupropion add-on can act as augmenting agent in patients of depression with partial response to SSRIs Selective serotonin reuptake inhibitors ( SSRIs ) are the ‘ new ’ drugs of first choice for the treatment of depression in the older patient . Systematic studies on the effects of SSRIs on cardiac function are scarce , despite the high prevalence of cardiac disorders in the older depressed patient . This is a study which systematic ally assesed cardiac function by echo-cardiography in middle-aged and elderly depressed patients treated with SSRI . In a double-blind r and omized trial , 20 patients were assigned to receive fluvoxamine 20 mg/day or fluoxetine 100mg/day for 6 weeks . Cardiac function was assessed by left ventricle ejection fraction , aortic flow integral and early or passive/late or active mitral inflow , and electrocardiography . Neither SSRI significantly affected cardiac function . Compared with patients without a history of myocardial infa rct ion and /or hypertension , patients with such a history showed a significant improvement in left ventricular ejection fraction . Despite our small study sample , these data indicate that both fluoxetine and fluvoxamine do not affect cardiac function adversely BACKGROUND This phase 2 study examined the efficacy and tolerability of edivoxetine , a highly selective norepinephrine reuptake inhibitor , as an adjunctive treatment for patients with major depressive disorder ( MDD ) who have a partial response to selective serotonin reuptake inhibitor ( SSRI ) treatment . METHODS Study design consisted of double-blind , 10-week therapy of adjunctive edivoxetine ( 6 - 18 mg once daily ) or adjunctive placebo with SSRI .  Inclusion /entry criteria included partial response to current SSRI by investigator opinion and a GRID 17-item Hamilton Rating Scale for Depression ( HAMD17 ) total score ≥16 . The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale ( MADRS ) . Safety measures included treatment-emergent adverse events ( TEAE ) and vital signs . RESULTS For the primary evaluable population ( n=63 for adjunctive edivoxetine and n=68 for adjunctive placebo ) , the treatment groups did not differ significantly on the primary outcome of change from baseline to week 8 in the MADRS total score ; the effect size of edivoxetine treatment was 0.26 . Significant treatment differences , favoring adjunctive edivoxetine ( p≤.05 ) , were shown for improvements in role functioning and the functional impact of fatigue . For the adjunctive edivoxetine r and omized group ( N=111 ) , the most frequent TEAEs were hyperhidrosis ( 7.2 % ) , nausea ( 7.2 % ) , erectile dysfunction ( 6.3 % ) and testicular pain ( 6.3 % ) . Hemodynamic changes were observed in blood pressure and pulse rate between treatment groups . LIMITATIONS Study was underpowered for an alpha 2-sided 0.05 significance level for the primary outcome . CONCLUSIONS For patients with MDD who had a partial response to SSRIs  , adjunctive edivoxetine treatment was not statistically superior to adjunctive placebo on the primary outcome measure . However , pending further study , improved functioning and remission rate suggest a potential role for edivoxetine for patients with depression Objective This r and omised , double-blind , 12-week study compared efficacy and tolerability of flexible-dose treatment with vortioxetine ( 10–20 mg/day ) versus agomelatine ( 25–50 mg/day ) in major depressive disorder patients with inadequate response to selective serotonin reuptake inhibitor (SSRI)/serotonin – noradrenaline reuptake inhibitor ( SNRI ) monotherapy . Methods Patients were switched directly from SSRI/SNRI to vortioxetine or agomelatine . Primary endpoint was change from baseline to week 8 in the Montgomery – Åsberg Depression Rating Scale ( MADRS ) total score analysed by mixed model for repeated measurements , using a noninferiority test followed by a superiority test . Secondary endpoints included response and remission rates , anxiety symptoms ( Hamilton Anxiety Rating Scale ) , Clinical Global Impression , overall functioning ( Sheehan Disability Scale ) , health-related quality of life ( EuroQol 5 Dimensions ) , productivity ( work limitation question naire ) and family functioning ( Depression and Family Functioning Scale ) . Results Primary endpoint noninferiority was established and vortioxetine ( n = 252 ) was superior to agomelatine ( n = 241 ) by 2.2 MADRS points ( p < 0.01 ) . Vortioxetine was also significantly superior in response and remission rates at weeks 8 and 12 ; MADRS , Hamilton Anxiety Rating Scale , Clinical Global Impression , Sheehan Disability Scale and EuroQol 5 Dimensions scores at week 4 onwards ; work limitation question naire at week 8 and Depression and Family Functioning Scale at weeks 8 and 12 . Fewer patients withdrew because of adverse events with vortioxetine ( 5.9 % vs 9.5 % ) . Adverse events ( incidence ≥5 % ) were nausea , headache , dizziness and somnolence . Conclusions Vortioxetine was noninferior and significantly superior to agomelatine in major depressive disorder patients with previous inadequate response to a single course of SSRI/SNRI monotherapy . Vortioxetine was safe and well tolerated 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 Rationale A common polymorphism ( 5HTTLPR ) within the promoter region of the serotonin transporter gene ( LSC6A4 ) has been shown to influence response time as well as overall response to selective serotonin reuptake inhibitors ( SSRIs ) in subjects with major depressive disorder . We hypothesized that a similar effect in response time to sertraline would be observed and that no effect on response time would be seen in a placebo arm . Objectives We tested the hypothesis that subjects homozygous for the long allele at the 5HTTLPR polymorphism would respond more rapidly to sertraline than subjects carrying one or two copies of the short allele . Methods HAM-D and CGI-I responses to sertraline and placebo were measured weekly in the context of an 8-week , placebo-controlled study in elderly depressed subjects . Genotyping of the 5HTTLPR polymorphism was performed to test for correlations with response at each week in the  sertraline  and  placebo groups ( n=206 ) . Results Subjects homozygous for the long allele of 5HTTLPR showed a significant increase in response at week 1 and week 2 , as assessed by the CGI-I scale compared with subjects carrying one or two copies of the short allele ( P=0.01 at both weeks ) . No significant difference was observed in the placebo group . Conclusions These results suggest that genetic variation in the serotonin transporter gene effects the response time to sertraline and provides complementing evidence to previous reports that this polymorphism affects response time to other SSRIs 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 ) OBJECTIVE The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors ( SSRIs ) .  METHOD In the first trial , 148 out patients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods . Patients were r and omly assigned , in a 2:3:3 ratio , to receive L-methylfolate for 60 days ( 7.5 mg/day for 30 days followed by 15 mg/day for 30 days ) , placebo for 30 days followed by L-methylfolate ( 7.5 mg/day ) for 30 days , or placebo for 60 days . SSRI dosages were kept constant throughout the study . In the second trial , with 75 patients , the design was identical to the first , except that the l-methylfolate dosage was 15 mg/day during both 30-day periods . RESULTS In the first trial , no significant difference was observed in outcomes between the treatment groups . In the second trial , adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures ( response rate and degree of change in depression symptom score ) and two secondary outcome measures of symptom severity . The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day . L-Methylfolate was well tolerated , with rates of adverse events no different from those reported with placebo . CONCLUSIONS Adjunctive L-methylfolate at 15 mg/day may constitute an effective , safe , and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs 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 , Patients with major depressive disorder ( MDD ) usually suffer from altered cognitive functions of episodic memory , working memory , mental processing speed and motor response . Diverse studies suggest that different antidepressant agents may improve cognitive functions in patients with MDD . The aim of this work is to study the effects of serotonergic reuptake inhibitors ( SSRIs ) and serotonergic-noradrenergic reuptake inhibitors ( SNRIs ) treatments to improve the performance on memory tasks and mental processing speed in MDD . Seventy-three subjects meeting criteria for major depressive disorder were assessed with the Hamilton depression rating scale and a neuropsychological battery . The subjects were medicated with escitalopram ( n=36 ) or duloxetine ( n=37 ) for 24 weeks . At the end of the trial , the subjects were assessed again with the same neuropsychological battery used prior to the treatment . Both treatments improved importantly the episodic memory and to a lesser extent , working memory , mental processing speed and motor performance . Our results suggest that cognition is partially independent from improvement in clinical symptoms . Both groups achieved remission rates in the HAM-D-17 after 24 weeks of treatment , but SNRI was superior to SSRI  at improving episodic and working memory . Our work indicates that the superiority of SNRI over the SSRI  at episodic memory improvement is clinical ly relevant BACKGROUND This study was conducted to determine if patients with major depressive disorder who had previously failed treatment with one serotonin selective reuptake inhibitor ( SSRI ) would respond to a different SSRI . METHOD Adult out patients ( N = 106 ) with DSM-III-R major depressive disorder and a history of either intolerance ( N = 34 ) or nonresponse ( N = 72 ) to treatment with sertraline  were treated with fluoxetine ( mean dose = 37.2 mg/day ) in a st and ardized , open-label , 6-week clinical trial . Outcome was assessed at each visit using the Hamilton Rating Scale for Depression ( HAM-D ) , the Clinical Global Impressions ( CGI-Improvement and CGI-Severity ) scales , and the Patient 's Global Improvement ( PGI ) scale . RESULTS Ninety-one patients ( 86 % ) completed the study . Sixty-seven patients ( 63 % ) responded to fluoxetine ( i.e. , experienced > or = 50 % reduction in HAM-D28 total score at endpoint versus baseline ) . In addition , clinical ly and statistically significant improvements were noted on all measures of depressive symptoms and global functioning . There was a nonsignificant trend for patients with a history of less vigorous sertraline trials to respond more favorably to fluoxetine . Fluoxetine therapy was generally well tolerated , and there were only slight differences in adverse events reported by patients who had been intolerant to sertraline versus those who were nonresponders . CONCLUSION These findings indicate that fluoxetine and sertraline , two widely used SSRIs , are not interchangeable . Patients who either have had trouble tolerating or have not responded to sertraline may do well on fluoxetine treatment 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 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 Depression and anxiety are common disorders and have substantially overlapping symptom complexes . Not surprisingly , treatment approaches are similar for both conditions with the selective serotonin reuptake inhibitors ( SSRIs ) as the initial therapy of choice . However , after first line treatments have been deployed , residual symptoms are often problematic . Augmentation strategies to address these difficulties are an area of active investigation . This study assessed aripiprazole as adjunctive therapy to SSRIs for patients with persistent anxiety symptoms complicating a depression or anxiety disorder . METHODS Ten patients who had been receiving SSRIs for at least 6 weeks , but still had clinical ly significant anxiety symptoms , were enrolled in an open label , flexibly-dosed study of adjunctive aripiprazole . Clinical status was assessed with the Hamilton Anxiety Rating Scale ( HAM-A ) , Montgomery Asberg Rating Scale ( MADRS ) , and Sheehan Disability Scale ( SDS ) . RESULTS Eighty percent of the subjects had a greater than 50 % reduction of symptoms on these outcome measures by week 2 of therapy , and continued with further decrements in symptoms throughout the course of the study . CONCLUSIONS The results of this trial provide preliminary evidence that aripiprazole may be an effective adjunctive treatment in individuals on SSRIs with residual symptoms of anxiety or depression . More rigorous double-blind studies are warranted to confirm and eluci date the potential role of aripiprazole in these conditions BACKGROUND AND OBJECTIVE Selective serotonin reuptake inhibitors ( SSRIs ) are currently the first-line treatment for panic disorder , although up to 30 % of patients either do not respond to SSRIs or withdraw due to adverse events . Reboxetine , a selective norepinephrine reuptake inhibitor ( selective NRI ) , is effective in treating depression and may alleviate depression-related anxiety . This study aim ed to investigate the efficacy of reboxetine in the treatment of patients with panic disorder who did not respond to SSRIs . METHOD In this 6-week , open-label study , 29 adult out patients with panic disorder who had previously failed to respond to SSRI treatment received reboxetine 2 mg/day , titrated to a maximum of 8 mg/day over the first 10 days .  Efficacy was assessed using the Panic Self- Question naire ( PSQ ) , the Hamilton Rating Scale for Anxiety ( HAM-A ) , the 17-item Hamilton Rating Scale for Depression ( HRSD ) and the Global Assessment of Functioning ( GAF ) Scale . RESULTS The 24 patients who completed the study responded well to reboxetine treatment . Significant improvement ( p < 0.001 ) was observed in the number of daily panic attacks , and on the scales measuring anxiety , depression and functioning . Reboxetine was generally well tolerated . Five patients withdrew due to  adverse events . CONCLUSIONS Reboxetine appears to be effective in the treatment of SSRI-refractory panic disorder patients and warrants further clinical investigation Genetic polymorphism of the serotonin 5-HT2A receptor seems to be associated with therapeutic response to selective serotonin reuptake inhibitors ( SSRIs ) . The present study investigated whether a novel –1438G/A polymorphism in the promoter region of the 5-HT2A receptor gene is associated with therapeutic response to fluvoxamine ( an SSRI ) in 66 Japanese patients with major depressive disorder .  Fluvoxamine ( 50 to 200 mg ) was administered twice daily for 6 weeks . Fifty-four patients completed this study . The genotype distribution and the allele frequencies showed no significant difference between responders and non-responders . The time-course of the Montgomery-Åsberg Depression Rating Scale scores showed no significant difference among –1438G/G , –1438G/A , and –1438A/A genotype groups . The results demonstrated that the –1438G/A promoter polymorphism in the 5-HT2A receptor gene was unlikely to have a major role in therapeutic response to fluvoxamine in Japanese patients with major depressive disorder 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 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 Selective serotonin reuptake inhibitor ( SSRI ) use during pregnancy incurs a low absolute risk for major malformations ; however , other adverse outcomes have been reported . Major depression also affects reproductive outcomes . This study examined whether 1 ) minor physical anomalies , 2 ) maternal weight gain and infant birth weight , 3 ) preterm birth , and 4 ) neonatal adaptation are affected by SSRI or depression exposure . METHOD This prospect i ve observational investigation included maternal assessment s at 20 , 30 , and 36 weeks of gestation . Neonatal outcomes were obtained by blinded review of delivery records and infant examinations . Pregnant women ( N=238 ) were categorized into three mutually exclusive exposure groups : 1 ) no SSRI , no depression ( N=131 ) ; 2 ) SSRI exposure ( N=71 ) , either continuous ( N=48 ) or partial ( N=23 ) ; and 3 ) major depressive disorder ( N=36 ) , either continuous ( N=14 ) or partial ( N=22 ) . The mean depressive symptom level of the group with continuous depression and no SSRI exposure was significantly greater than for all other groups , demonstrating the expected treatment effect of SSRIs . Main outcomes were minor physical anomalies , maternal weight gain , infant birth weight , pregnancy duration , and neonatal characteristics . RESULTS Infants exposed to either SSRIs or depression continuously across gestation were more likely to be born preterm than infants with partial or no exposure . Neither SSRI nor depression exposure increased risk for minor physical anomalies or reduced maternal weight gain . Mean infant birth weights were equivalent . Other neonatal outcomes were similar , except 5-minute Apgar scores . CONCLUSIONS For depressed pregnant women , both continuous SSRI exposure and continuous untreated depression were associated with preterm birth rates exceeding 20 % Treatment of depression and anxiety disorders with selective serotonin reuptake inhibitors ( SSRIs ) has been shown by numerous studies to be generally effective . Less well understood is how clinical ly to address the residual anxiety symptoms a significant minority of such patients treated with SSRIs continue to experience . We assessed quetiapine as adjunctive therapy to SSRIs for patients with anxiety symptoms complicating a depressive or anxiety disorder . Patients receiving a stable dosage of an SSRI for at least 6 weeks who also had persistent anxiety symptoms ( Hamilton Anxiety scale [ HAM‐A ] ≥16 ) , were enrolled in a 9‐week , open‐label , variable dose study . Changes in clinical status were assessed with the Hamilton Depression Rating Scale ( HAM‐D ) , HAM‐A , and State Anxiety Inventory ( SAI ) . Statistically and clinical ly significant reductions of ≥50 % in the HAM‐D and HAM‐A occurred by the second week of treatment in 10 of the 11 patients . These improvements continued throughout the study along with a significant improvement on the SAI scale . The most frequent side effects reported were mild dry mouth , constipation , and transient drowsiness with dose escalation . The results provide evidence that quetiapine may be an effective adjunctive treatment for recalcitrant anxiety symptoms in individuals treated with SSRIs for either anxiety or depressive disorders . Given the open‐label design of the trial , more rigorous studies are clearly indicated . Depression and Anxiety 19:121‐126 , 2004 . © 200 Wiley‐Liss , There is a high prevalence of depression in patients with epilepsy , which negatively impacts their quality of life ( QOL ) and seizure control . Currently , the first-line of treatment for depression in patients with epilepsy is based on selective serotonin reuptake inhibitors ( SSRIs ) . The main objective of this pilot study was to compare cognitive behavioral therapy ( CBT ) versus SSRIs for the treatment of major depressive disorder ( MDD ) in patients with temporal lobe epilepsy ( TLE ) . Seven patients who received group CBT were compared with eight patients treated with SSRIs .  All were diagnosed with MDD and TLE . Patients were assessed at baseline before treatment and at six and 12weeks during treatment with the  Quality of Life in Epilepsy Scale of 31 items ( QOLIE 31 ) , the  Beck Depression Inventory ( BDI )  , and the Hospital Anxiety and Depression Scale ( HADS ) . Seizure records were also taken on a monthly basis . After 12weeks of treatment , both groups showed improved QOL and reduced severity of depression symptoms . There were no statistically significant group differences in the final scores for the BDI ( p=0.40 ) and QOLIE 31 ( p=0.72 ) , although the effect size on QOL was higher for the group receiving CBT . In conclusion , the present study suggests that both CBT and SSRIs may improve MDD and QOL in patients with TLE . We found no significant outcome differences between both treatment modalities . These findings support further study using a double-blind controlled design to demonstrate the efficacy of CBT and SSRIs in the treatment of MDD and QOL in patients with TLE OBJECTIVE To test a collaborative-care , cognitive-behavioral therapy ( CBT ) program adjunctive to selective serotonin reuptake inhibitor ( SSRI ) treatment in HMO pediatric primary care . METHOD A r and omized effectiveness trial comparing a treatment-as-usual ( TAU ) control condition consisting primarily of SSRI medication delivered outside the experimental protocol ( n = 75 ) versus TAU SSRI plus brief CBT ( n = 77 ) . Participants were identified by a recent dispense of SSRI medication followed by telephone screening . Adolescents with a diagnosis of major depressive disorder ( n = 152 ) were enrolled . The CBT program employed cognitive restructuring and /or behavioral activation training . Therapists consulted with prescribing pediatricians to improve medication adherence . RESULTS Through 1-year follow-up , the authors found CBT advantages on the Short Form-12 Mental Component Scale ( p = .04 ) , reductions in  TAU outpatient visits ( p = .02 ) , and days ' supply of all medications ( p = .01 ) . No effects were detected for major depressive disorder episodes ; a nonsignificant trend favoring CBT was detected on the Center for Epidemiology Depression Scale ( p = .07 ) . CONCLUSIONS The authors detected a weak CBT effect , possibly rendered less significant by the small sample and likely attenuated by the unexpected reduction in SSRI pharmacotherapy in the CBT condition . Small , incremental improvements over monotherapy , such as observed in this study , most likely represent the new norm in adolescent depression treatment research More than half of anxiety and depression patients treated with an adequate course of antidepressants fail to fully improve . We retrospectively examined whether treatment-resistant depression and anxiety disorder patients responded to and tolerated augmentation with the atypical antipsychotic , aripiprazole . We report on patients with depression and anxiety disorders , including panic disorder , generalized anxiety disorder , social anxiety and post-traumatic stress disorder , who had an incomplete response to a variety of selective serotonin reuptake inhibitors ( SSRIs ) and who received augmentation with aripiprazole .  The primary outcome measure was the Clinical Global Impression of Improvement ( CGI-I ) . In the intent-to-treat analysis , the mean±SD CGI-S was 3.8±1.3 at endpoint . Fifty-nine percent of subjects received CGI-I ratings of 1 or 2 , ‘ much improved ’ or ‘ very much improved , ’ in terms of their depression and anxiety symptoms at the end of 12 weeks . Several patients showed an early ( weeks 1–5 ) , as well as sustained , response to augmentation with doses of aripiprazole between 15 and 30 mg/day . The results suggest that aripiprazole may be effective as an augmentation for patients with persistent depressive and anxiety disorders despite initial SSRI treatment . Because this is a retrospective case review , further prospect i ve studies are required to confirm these findings 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 In this report , we conducted a secondary analysis of the Treatment of SSRI-Resistant Depression in Adolescents ( TORDIA ) study to explore the impact of specific cognitive-behavioral therapy ( CBT ) treatment components on outcome . In TORDIA , 334 youths ( ages 12 to 18 years ) with major depressive disorder who had failed to respond to an adequate course of selective serotonin reuptake inhibitor ( SSRI ) medication were r and omized to a medication switch ( either to an alternative SSRI or venlafaxine ) with or without 12 weeks of adjunctive CBT . Participants who had more than 9 CBT sessions were 2.5 times more likely to have adequate treatment response than those who had 9 or fewer sessions . CBT participants who received problem-solving and social skills treatment components , controlling for number of sessions and other confounding variables , were 2.3 and 2.6 times , respectively , more likely to have a positive response . These preliminary findings underscore the importance of receiving an adequate number of sessions to attain an adequate clinical response . Finally , social skills and problem solving may be active elements in CBT for adolescent depression and should be considered in treatment by those working with seriously depressed youths 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 We examined the long-term outcome of participants in the Treatment of SSRI-Resistant Depression in Adolescents ( TORDIA ) study , a r and omized trial of 334 adolescents ( aged 12 - 18 years ) with DSM-IV-defined major depressive disorder initially resistant to selective serotonin reuptake inhibitor ( SSRI ) treatment who were subsequently treated for 12 weeks with another SSRI , venlafaxine , another SSRI + cognitive-behavioral therapy ( CBT ) , or venlafaxine + CBT . Responders then continued with the same treatment through week 24 , while nonresponders were given open treatment . METHOD For the current study , patients were reassessed 48 ( n = 116 ) and 72 ( n = 130 ) weeks from intake . Data were gathered from February 2001 to February 2007 . St and ardized diagnostic interviews and measures of depression , suicidal ideation , related psychopathology , and level of functioning were periodically administered . Remission was defined as ≥ 3 weeks with ≤ 1 clinical ly significant symptom and no associated functional impairment ( score of 1 on the adolescent version of the Longitudinal Interval Follow-Up Evaluation [ A-LIFE ] ) , and relapse , as ≥ 2 weeks with probable or definite depressive disorder ( score of 3 or 4 on the A-LIFE ) . Mixed-effects regression models were applied to estimate remission , relapse , and functional recovery . RESULTS By 72 weeks , an estimated 61.1 % of the r and omized youths had reached remission . R and omly assigned treatment ( first 12 weeks ) did not influence remission rate or time to remission , but the group assigned to SSRIs had a more rapid decline in self-reported depressive symptoms and suicidal ideation than those assigned to venlafaxine ( P < .03 ) . Participants with more severe depression  ,  greater  dysfunction , and alcohol or drug use at baseline were less likely to remit . The depressive symptom trajectory of the remitters diverged from that of nonremitters by the first 6 weeks of treatment ( P < .001 ) . Of the 130 participants in remission at week 24 , 25.4 % relapsed in the subsequent year . CONCLUSIONS While most adolescents achieved remission , more than one-third did not , and one-fourth of remitted patients experienced a relapse . More effective interventions are needed for patients who do not show robust improvement early in treatment . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00018902 OBJECTIVE To advance knowledge regarding strategies for treating selective serotonin reuptake inhibitor (SSRI)-resistant depression in adolescents , we conducted a r and omized controlled trial evaluating alternative treatment strategies . In primary analyses , cognitive-behavioral therapy ( CBT ) combined with medication change was associated with higher rates of positive response to short-term ( 12-week ) treatment than medication alone . This study examines predictors and moderators of treatment response , with the goal of informing efforts to match youths to optimal treatment strategies . METHOD Youths who had not improved during an adequate SSRI trial ( N = 334 ) were r and omized to an alternative SSRI , an alternative SSRI plus CBT , venlafaxine , or venlafaxine plus CBT . Analyses examined predictors and moderators of treatment response . RESULTS Less severe depression , less family conflict , and absence of nonsuicidal self-injurious behavior predicted better treatment response status . Significant moderators of response to CBT + medication ( combined ) treatment were number of comorbid disorders and abuse history ; hopelessness was marginally significant . The CBT/combined treatment superiority over medication alone was more evident among youths who had more comorbid disorders ( particularly attention-deficit/hyperactivity disorder and anxiety disorders ) , no abuse history , and lower hopelessness . Further analyses revealed a stronger effect of combined CBT + medication treatment among youths who were older and white and had no nonsuicidal self-injurious behavior and longer pre study pharmacotherapy . CONCLUSIONS Combined treatment with CBT and antidepressant medication may be more advantageous for adolescents whose depression is comorbid with other disorders . Given the additional costs of adding CBT to medication , consideration of moderators in clinical decision making can contribute to a more personalized and effective approach to treatment 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 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 OBJECTIVE Herbal remedies play an important role in treatment of psychiatric disorders . The aim of this study was to assess the efficacy of crocin , the main active constituent of saffron , as an adjunctive treatment in major depressive disorder ( MDD ) . METHOD This study was a r and omized , double-blind , placebo-controlled , pilot clinical trial . It was carried out during 4 weeks in two groups ( placebo and treatment ) on 40 MDD patients between 24 and 50 years old in Ibn-e-Sina psychiatric hospital , Mashhad , Iran , from March 2013 to December 2013 . The crocin group ( n=20 ) was given one selective serotonin reuptake inhibitor ( SSRI ) drug ( fluoxetine 20mg/day or sertraline 50mg/day or citalopram 20mg/day ) plus crocin tablets ( 30mg/day ; 15 mg BID ) and placebo group ( n=20 ) was administered one SSRI ( fluoxetine 20mg/day or sertraline 50mg/day or citalopram 20mg/day ) plus placebo ( two placebo tablets per day ) for 4 weeks . Both groups filled beck depression inventory ( BDI ) , beck anxiety inventory ( BAI ) , general health question naire ( GHQ ) , the mood disorder question naire ( MDQ ) , side effect evaluation question naire , and demographic question naire before and after one month intervention . RESULTS The crocin group showed significantly improved scores on BDI , BAI and GHQ compared to placebo group ( Pvalue<0.0001 ) . The averages of decrease in BDI , BAI and GHQ scores in placebo group were 6.15 , 2.6 and 10.3 respectively , whereas the values in crocin group were 17.6 , 12.7 and 17.2 after 4 weeks trial . LIMITATIONS Poor patient compliance with medications and short trial period , small sample size and self-report assessment s were the major limitations of this study . CONCLUSION These results demonstrated the effect of crocin in depression and could be administered in treatment of MDD patients 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 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 Objective : To assess whether patients receiving aerobic exercise training  performed either at home or in a supervised group setting achieve reductions in depression comparable to st and ard antidepressant medication ( sertraline ) and greater reductions in depression compared to placebo controls . Methods : Between October 2000 and November 2005 , we performed a prospect i ve , r and omized controlled trial ( SMILE study ) with allocation concealment and blinded outcome assessment in a tertiary care teaching hospital . A total of 202 adults ( 153 women ; 49 men ) diagnosed with major depression were assigned r and omly to one of four conditions : supervised exercise in a group setting ; home-based exercise ; antidepressant medication ( sertraline , 50–200 mg daily ) ; or placebo pill for 16 weeks . Patients underwent the structured clinical interview for depression and completed the Hamilton Depression Rating Scale ( HAM-D ) . Results : After 4 months of treatment , 41 % of the participants achieved remission , defined as no longer meeting the criteria for major depressive disorder ( MDD ) and a HAM-D score of < 8 . Patients receiving active treatments tended to have higher remission rates than the placebo controls : supervised exercise = 45 % ; home-based exercise = 40 % ; medication = 47 % ; placebo = 31 % ( p = .057 ) . All treatment groups had lower HAM-D scores after treatment ; scores for the active treatment groups were not significantly different from the placebo group ( p = .23 ) . Conclusions : The efficacy of exercise in patients seems generally comparable with patients receiving antidepressant medication and both tend to be better than the placebo in patients with MDD . Placebo response rates were high , suggesting that a considerable portion of the therapeutic response is determined by patient expectations , ongoing symptom monitoring , attention , and other nonspecific factors . BDI = Beck Depression Inventory ; CI = confidence interval ; HAM-D = Hamilton Depression Rating Scale ; ITT = intention-to-treat ; MDD = major depressive disorder ; SD = st and ard deviation ; SSRIs = selective serotonin reuptake inhibitors ; TSH = thyroid stimulating hormone BACKGROUND Citalopram is a racemic selective serotonin reuptake inhibitor ( SSRI ) indicated for the treatment of depression . Citalopram is a racemate and its serotonin reuptake inhibitory activity resides primarily in the single S-isomer , escitalopram , which is now being evaluated for its potential usefulness in the treatment of depression and other psychiatric disorders . RESULTS from placebo-controlled studies that also included citalopram as an active control have shown that escitalopram is effective in treating depression and associated symptoms of anxiety . However , none of these studies was powered sufficiently to detect differences between active treatment groups . The goal of the present analysis is to evaluate the efficacy of escitalopram compared with citalopram in the treatment of major depressive disorder . METHOD Data were pooled from three similarly design ed , r and omized , double-blind , placebo-controlled trials of escitalopram ( 10 - 20 mg/day ) and citalopram ( 20 - 40 mg/day ) . Patients were male or female , greater than or equal to 18 years of age , who met criteria for a major depressive episode with a Montgomery Asberg Depression Rating Scale ( MADRS ) score greater than or equal to 22 at baseline . Efficacy measures included change from baseline in MADRS score and the Clinical Global Impression of Improvement ( CGI-I ) scale . Improvement in associated symptoms of anxiety was measured using the change from baseline in the MADRS inner tension item . RESULTS Both escitalopram and citalopram significantly improved depression and anxiety symptoms compared with placebo , and there were significantly more MADRS responders ( defined as > /=50 % improvement in MADRS scores at end point ) in the escitalopram and citalopram treatment groups . Escitalopram treatment was associated with statistically significant improvements in all efficacy measures relative to placebo after 1 week of treatment , whereas citalopram treatment statistically separated from placebo at the end of week 4 ( CGI-I and MADRS inner tension ) or week 6 ( MADRS ) . Escitalopram treatment also was statistically significantly superior to citalopram treatment at a number of time points . CONCLUSION These data support the effectiveness of escitalopram and citalopram in the treatment of major depressive disorder , and suggest escitalopram may have a faster onset and greater overall magnitude of effect than citalopram in improving symptoms of depression and anxiety in patients with major depressive disorder BACKGROUND Approximately half of patients who are prescribed selective serotonin re-uptake inhibitors ( SSRIs ) either do not respond to treatment or do not experience a sustained response . OBJECTIVE The purpose of this study was to assess the efficacy of venlafaxine immediate-release ( IR ) and extended-release ( XR ) in out patients who either did not respond to SSRI treatment or did not maintain a sustained response . METHODS Out patients who met the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition ( DSM-IV ) criteria for major depressive disorder who were previously treated with an SSRI ( fluoxetine > or = 20 mg/d ; sertraline > or = 50 mg/d ; paroxetine > or = 20 mg/d ) for > or = 6 weeks , but demonstrated an inadequate or unsustained response , were switched  to venlafaxine ( IR or XR formulation , 50 - 400 mg/d , titrated from 37.5 mg/d ) for > or = 6 weeks . Response at 6 to 8 weeks was defined as total score < or = 10 on the modified 25-item Hamilton Depression ( HAM-D25 ) rating scale or total score > or = 5 on the 21-item Patient Global Improvement ( PGI-21 ) scale . Remission was defined as a HAM-D25 total score < or = 8 or PGI-21 score > or = 7 . Tests were administered by an unblinded , board-certified psychiatrist . RESULTS A total of 73 patients ( 54 women , 19 men ; mean age , 38.6 years ) were enrolled and treated with venlafaxine IR ( n = 63 ) or venlafaxine XR ( n = 10 ) ; 33 were SSRI nonresponders and 36 had an unsustained response to SSRI treatment . Four patients receiving venlafaxine IR discontinued due to drug-related adverse events ( agitation , sedation , or nausea ) . Data from these patients were excluded from the analysis . After 6 to 8 weeks of treatment , 94.2 % ( 65/69 ) of patients were considered responders ( HAM-D25 or PGI-21 criteria ) ; 91.3 % ( 63/69 ) of patients responded to treatment as assessed by both measures . Eighty-seven percent ( 60/69 ) and 85.5 % ( 59/69 ) of patients achieved remission based on HAM-D,5 and PGI-21 criteria , respectively . Response/remission rates were comparable among patients treated with SSRIs , regardless of whether patients had failed to respond to treatment with 1 or 2 SSRIs . CONCLUSION Venlafaxine IR/venlafaxine XR may be effective in out patients with major depressive disorder who do not respond or have an unsustained response to SSRIs . However , r and omized , controlled trials are needed before any conclusions can be drawn about the efficacy of this agent in this population OBJECTIVE To assess the relative efficacy of antidepressant medication , alone and in combination with cognitive behavioral therapy ( CBT ) , on comorbid symptoms of anxiety , attention , and disruptive behavior disorders in participants in the Treatment of Resistant Depression in Adolescents ( TORDIA ) trial . METHOD Adolescents with selective serotonin reuptake inhibitor (SSRI)-resistant depression ( N = 334 ) were r and omly assigned to a medication switch alone ( to another SSRI or to venlafaxine ) or to a medication switch plus CBT .  Anxiety , attention-deficit/hyperactivity disorder ( ADHD ) , and disruptive behavior disorder ( DBD ) symptoms were assessed by psychiatric interview and self-report at regular intervals between baseline and 24 weeks . The differential effects of medication and of CBT , and the impact of remission on the course of comorbid symptoms and diagnoses , were assessed using generalized linear mixed models . RESULTS Remission was associated with a greater reduction in scalar measures of anxiety , ADHD , and DBDs , and a greater decrease in the rate of diagnosed anxiety disorders . The correlations between the changes in symptoms of depression on the CDRS-R and anxiety , ADHD , and oppositional symptoms were modest , ranging from r = 0.12 to r = 0.28 . There were no significant differential treatment effects on diagnoses , or corresponding symptoms . CONCLUSION The achievement of remission had a beneficial effect on anxiety , ADHD , and DBD symptoms , regardless of the type of treatment received . There were no differential effects of medication or CBT on outcome , except for a nonsignificant trend that those adolescents treated with SSRIs showed a greater decrease in rates of comorbid DBDs relative to those treated with venlafaxine . Clinical trial registration information-Treatment of SSRI-Resistant Depression In Adolescents ( TORDIA ) ; http:// clinical trials.gov/ ; NCT00018902 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 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 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 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 CONTEXT The efficacy , safety , and tolerability of selective serotonin reuptake inhibitors ( SSRIs ) in the treatment of adults with major depressive disorder ( MDD ) are well established . Comparatively few data are available on the effects of SSRIs in depressed children and adolescents . OBJECTIVE To evaluate the efficacy and safety of sertraline compared with placebo in treatment of pediatric patients with MDD . DESIGN AND SETTING Two multicenter r and omized , double-blind , placebo-controlled trials were conducted at 53 hospital , general practice , and academic centers in the United States , India , Canada , Costa Rica , and Mexico between December 1999 and May 2001 and were pooled a priori . PARTICIPANTS Three hundred seventy-six children and adolescents aged 6 to 17 years with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition-defined MDD of at least moderate severity . INTERVENTION Patients were r and omly assigned to receive a flexible dosage ( 50 - 200 mg/d ) of sertraline ( n = 189 ) or matching placebo tablets ( n = 187 ) for 10 weeks . MAIN OUTCOME MEASURES Change from baseline in the Children 's Depression Rating Scale-Revised ( CDRS-R ) Best Description of Child total score and reported adverse events . RESULTS Sertraline-treated patients experienced statistically significantly greater improvement than placebo patients on the CDRS-R total score ( mean change at week 10 , -30.24 vs -25.83 , respectively ; P = .001 ; overall mean change , -22.84 vs -20.19 , respectively ; P = .007 ) . Based on a 40 % decrease in the adjusted CDRS-R total score at study end point , 69 % of sertraline-treated patients compared with 59 % of placebo patients were considered responders ( P = .05 ) . Sertraline treatment was generally well tolerated . Seventeen sertraline-treated patients ( 9 % ) and 5 placebo patients ( 3 % ) prematurely discontinued the study because of adverse events . Adverse events that occurred in at least 5 % of sertraline-treated patients and with an incidence of at least twice that in placebo patients included diarrhea , vomiting , anorexia , and agitation . CONCLUSION The results of this pooled analysis demonstrate that sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD OBJECTIVE To evaluate the efficacy and safety of mirtazapine in depressed out patients who have shown nonresponse or intolerance to selective serotonin reuptake inhibitor ( SSRI ) therapy . METHOD In this open-label , 8-week study , the efficacy and safety of mirtazapine among 103 out patients with DSM-IV major depressive disorder who had failed previous therapy with an SSRI ( fluoxetine , paroxetine , or sertraline )  were evaluated . The primary efficacy measure was the 17-item Hamilton Rating Scale for Depression ( HAM-D-17 ) , and safety assessment s included reported adverse events , routine laboratory assessment s , physical examinations , and assessment s of vital signs . A 4-day washout period followed by mirtazapine treatment was compared with an immediate switch from the SSRI to mirtazapine . RESULTS Based on mean HAM-D-17 scores at endpoint and response rates of 48 % based on the criterion of > or = 50 % reduction in HAM-D-17 score , mirtazapine was found to be an effective treatment for a substantial proportion of patients for whom an SSRI was ineffective and /or poorly tolerated . Mirtazapine was well tolerated , with sedation and appetite increase/weight gain the most commonly reported adverse events . In addition , no difference in efficacy , safety , or tolerability was observed for patients undergoing an immediate switch from an SSRI ( after having been tapered to the minimal effective dose ) to mirtazapine , compared with those undergoing the imposition of a 4-day drug-free washout . CONCLUSION These results suggest that an immediate switch to mirtazapine may be a valid therapeutic option among patients who can not tolerate or do not respond to SSRIs 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 OBJECTIVE The purpose of this study was to examine the use of benzodiazepines ( BZs ) and selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors ( SSRIs/SNRIs ) over nine years of follow-up in middle-aged and older adults with diagnoses of panic disorder with or without agoraphobia , social phobia , or generalized anxiety disorder . SETTING AND PARTICIPANTS Participants in this study were enrolled in the Harvard/Brown Anxiety Research Project ( HARP ) . HARP is a naturalistic , longitudinal , multisite study of adults with anxiety disorders who are recruited from psychiatric setting s. The analytic sample consisted of 51 participants with anxiety disorders who were 55 to 70 years old at baseline and a younger cohort of 211 participants added for comparative analysis . DESIGN The authors examined patterns of medication use ( BZs and SSRIs/SNRIs ) in participants with anxiety disorders as they aged , by assessing the proportion of participants taking these medications using generalized estimating equation modeling . MEASUREMENTS The present data were derived from the structured diagnostic interview administered at enrollment using a combination of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders , Third Edition-R Non-Affective Disorder , Patient Version , Research Diagnostic Criteria Schedule for Affective Disorders-Lifetime , and subsequent follow-up interviews over a nine-year period using the Longitudinal Interval Follow-up Evaluation-Pharmacia & Upjohn to assess the weekly course of disorders to indicate syndrome severity and document medication use by specific type and dose on a weekly basis . RESULTS Findings showed that rates of BZ use were high among both the older ( 53 % at baseline ) and the younger ( 57.4 % ) age groups and did not significantly decrease over time , after controlling for time in episode of their anxiety disorders . There was a statistically significant increase in  SSRI/SNRI use over time in both groups . At the beginning of the study , 18 % of the older group and 21 % of the younger group were using SSRIs/SNRIs ; however , at the end of the study , the rates increased to 35 % and 43 % , respectively . CONCLUSIONS Although there was an increase in  SSRI/SNRI use in older participants with anxiety disorders over the course of study , at nine years of follow-up , only 35 % of participants were utilizing SSRI/SNRI medication , while more than one-half of the same participants were continuing to use BZs . To the authors ' knowledge , there are no r and omized clinical trials that have addressed comparative efficacy and safety of BZs and SSRIs/SNRIs in this population . However , there is documented evidence of adverse effects of chronic BZ use and the risk of developing dependency in older population Low folate is associated with poorer response to selective serotonin reuptake inhibitors ( SSRIs ) in major depressive disorder ( MDD ) . Folate supplementation in MDD has been studied in other setting s with promising results . The objective of this study was to assess the efficacy of methylfolate as an adjunctive treatment among adults with MDD and inadequate response to an SSRI . Twenty-two adults ( 59 % female ; mean age 45.2 + /- 11.0 years ) with DSM-IV MDD , partial or nonresponse to an SSRI after at least 4 weeks of treatment , and a 17-item Hamilton Depression Rating Scale ( HAM-D-17 ) score > or = 12 were enrolled in this 8-week prospect i ve open trial . Exclusion criteria included current use of anticonvulsants or psychotropics other than an SSRI , or B12 deficiency .  Leucovorin ( folinic acid ) , which is metabolized to methylfolate , was added to SSRIs at 15 - 30 mg/day .  Folate levels rose from 28 + /- 19 ng/mL to 301 + /- 203 ng/mL ( p < 0.001 ) . HAM-D-17 scores among the 16 completers decreased from 19.1 + /- 3.9 to 12.8 + /- 7.0 ( p < 0.01 ) . However only 31 % of completers and 27 % of the intent-to-treat ( ITT ) sample achieved response ( > or = 50 % reduction in HAM-D-17 scores ) , and only 19 % of completers and 18 % of the ITT sample achieved remission ( HAM-D-17 < or = 7 ) . Leucovorin appears to be modestly effective as an adjunct among SSRI-refractory depressed individuals with normal folate levels . The application of leucovorin as an adjunct in the setting of refractory depression deserves further study OBJECTIVE Approximately 30 % of patients with depression fail to respond to a selective serotonin reuptake inhibitor ( SSRI ) . Few studies have attempted to define these patients from a biological perspective . Studies suggest that overall patients with depression show increased production of proinflammatory cytokines . We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant . METHODS Plasma concentrations of IL-6 , IL-8 , IL-10 , TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays ( ELISA ) in DSM-1V major depressives who were SSRI resistant , in formerly SSRI resistant patients currently euthymic and in healthy controls . RESULTS Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 ( p=0.01 ) and TNF-alpha ( p=0.004 ) compared to normal controls . Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group . Anti-inflammatory cytokine levels did not differ across the 3 groups . CONCLUSION Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery Approximately 30–45 % of patients with major depressive episode ( MDE ) do not fully respond to st and ard recommended treatments and further strategies of intervention , including pharmacological augmentation , have been proposed for these patients . This study was aim ed to evaluate the efficacy of short-term , low-dose ( 10 mg/day ) intravenous ( i.v . ) citalopram augmentation versus placebo in a sample of patients with MDE and partial or no response to selective serotonin reuptake inhibitors ( SSRIs ) . Thirty-six patients with a Diagnostic and Statistical Manual for Mental Disorders , 4th edition , text revision criteria MDE and partial or no response to oral SSRIs were selected and r and omly assigned to citalopram ( n=18 ) or to placebo ( n=18 ) i.v . augmentation . The augmentation regimen lasted 5 consecutive days during which the patients were maintained on their current treatment with oral SSRIs . Analyses of variance with repeated measures on Hamilton Depression Rating Scale and Montgomery – Asberg Depression Rating Scale total scores , administered daily with blind-raters conditions , were done . With regard to the Hamilton Depression Rating Scale total scores , a significant time effect ( F=42.02 , P<0.0001 ) and timextreatment effect ( F=21.17 , P<0.0001 ) were found in favor of citalopram . Similar results were obtained from the analysis on Montgomery – Asberg Depression Rating Scale total scores : time effect ( F=50.07 , P<0.0001 ) , timextreatment effect ( F=19.91 , P<0.0001 ) , and treatment effect ( F=4.07 , P=0.05 ) . Even though referred to a small sample , the present findings seem to suggest that short-term , low-dose , i.v . citalopram augmentation may be effective in depressed patients with partial or no response to oral SSRIs . Further controlled studies performed with double-blind conditions are warranted to confirm the present results Clinical ly useful predictors of treatment outcome in major depressive disorder ( MDD ) remain elusive . We examined associations between functional magnetic resonance imaging ( fMRI ) blood oxygen level dependent ( BOLD ) signal during active negative word processing and subsequent  selective serotonin reuptake inhibitor ( SSRI ) treatment outcome in MDD . Unmedicated MDD subjects ( n=17 ) performed an emotional word processing fMRI task , and then received eight weeks of st and ardized antidepressant treatment with escitalopram . Lower pre-treatment BOLD responses to negative words in midbrain , dorsolateral prefrontal cortex , paracingulate , anterior cingulate , thalamus and cau date nuclei correlated significantly with greater improvement following escitalopram treatment . Activation of these regions in response to negative words correlated significantly with reaction time for rating word relevance . Maximally predictive clusters of voxels identified using a cross-validation approach predicted 48 % of the variance in response to treatment . This study provides preliminary evidence that SSRIs may be most beneficial in patients who are less able to engage cognitive control networks while processing negative stimuli . Differences between these findings and previous fMRI studies of SSRI treatment outcome may relate to differences in task design . Regional BOLD responses to negative words predictive of SSRI outcome in this study were both overlapping and distinct from those predictive of outcome with cognitive behavioral therapy ( CBT ) in previous studies using the same task . Future studies may examine prediction of differential outcome across treatments in the context of a r and omized controlled trial 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 BACKGROUND Depression and osteoporotic fractures are common ailments among elderly persons .  Selective serotonin reuptake inhibitors ( SSRIs ) are frequently used in the treatment of depression in this population , and the association between daily SSRI use and fragility fractures is unclear . Our objective was to examine the effect of daily SSRI use on the risk of incident clinical fragility fracture . METHODS A population -based , r and omly selected , prospect i ve cohort study of 5008 community-dwelling adults 50 years and older , followed up over 5 years for incident fractures . Clinical fragility fractures were classified as minimal trauma fractures that were clinical ly reported and radiographically confirmed . The risk of fragility fracture associated with daily SSRI use was determined while controlling for relevant covariates . RESULTS Daily SSRI use was reported by 137 subjects . After adjustment for many potential covariates , daily SSRI use was associated with substantially increased risk of incident clinical fragility fracture ( hazard rate , 2.1 ; 95 % confidence interval , 1.3 - 3.4 ) . Daily SSRI use was also associated with increased odds of falling ( odds ratio , 2.2 ; 95 % confidence interval , 1.4 - 3.5 ) , lower bone mineral density at the hip , and a trend toward lower bone mineral density at the spine . These effects were dose dependent and were similar for those who reported taking SSRIs at baseline and at 5 years ' follow-up . CONCLUSIONS Daily SSRI use in adults 50 years and older remained associated with a 2-fold increased risk of clinical fragility fracture after adjustment for potential covariates . Depression and fragility fractures are common in this age group , and the elevated risk attributed to daily SSRI use may have important public health consequences BACKGROUND Tricyclic antidepressants and selective serotonin reuptake inhibitors ( SSRIs ) as well as benzodiazepines have been shown to be effective for the treatment of panic disorder . The introduction of SSRIs has enabled a greater underst and ing of the role of serotonin in the etiology of panic disorder ; however , the role of norepinephrine has been more challenging to ascertain . The aim of this study was to determine the efficacy and tolerability of reboxetine , a novel selective norepinephrine reuptake inhibitor , in patients with panic disorder with and without agoraphobia . METHOD Eighty-two patients ( aged 18 - 65 years ) with DSM-III-R panic disorder , with or without agoraphobia , were r and omly assigned to receive 6 to 8 mg/day of reboxetine ( 42 patients ) or placebo ( 40 patients ) for 8 weeks in this placebo-controlled , parallel-group , double-blind clinical trial . RESULTS Of the 82 patients enrolled in the trial , 75 were considered in the analysis ( 37 patients in the reboxetine group and 38 patients in the placebo group ) . At last assessment , there was a significant reduction in the mean number of panic attacks ( range , 9.3 - 1.2 ) and phobic symptoms ( range , 8.1 - 3.2 ) in the reboxetine group compared with the placebo group ( ranges , 8.5 - 5.8 and 7.7 - 5.2 , respectively ; p < .05 ) . Improvement in Hamilton Rating Scale for Depression , Hopkins Symptom Checklist-90 , and Sheehan Disability Scale scores were also greater in the reboxetine group compared with the placebo group . Adverse events reported more frequently with reboxetine than placebo included dry mouth ( 36 % vs. 16 % ) , constipation ( 27 % vs. 22 % ) , and insomnia ( 26 % vs. 22 % ) . CONCLUSION Reboxetine was effective and well tolerated in the treatment of panic disorder The effects of treatment with serotonin ( 5-HT ) reuptake inhibitors on platelet 5-HT2 receptors , 5-HT reuptake sites an 5-HT uptake were studied in a double-blind trial comparing two selective serotonin reuptake inhibitors ( SSRI ) , paroxetine , and fluoxetine , for the treatment of major depression . Hamilton Depression Rating Scale ( HAM-D ) scores and platelet 5-HT parameters were determined in 21 depressed patients at baseline , after 4 and 8 weeks of treatment , and were compared to 21 healthy controls . Antidepressant treatment did not significantly alter the density of 5-HT reuptake sites , labelled with [3H]paroxetine , or 5-HT2 receptors , labelled with [3H]LSD . However , a strong correlation was observed between the HAM-D suicidality item and 5-HT2 receptor density at baseline . A marked increase in platelet 5-HT2 receptors at baseline was observed in suicidal depressed patients compared to those with no suicidal ideation and healthy controls . Changes in [3H]paroxetine Bmax and in [3H]5-HT uptake significantly correlated with change in HAM-D score at 4 and 8 weeks respectively . These results confirm previous reports of an association between suicidality and platelet 5-HT2 receptor upregulation . Our data also lends support to the use of platelet 5-HT parameters as indicators of antidepressant efficacy , particularly in suicidal depressed patients OBJECTIVE Major depressive disorder ( MDD ) is associated with low- grade inflammation , and it is considered a risk factor for coronary artery disease ( CAD ) . CD40 lig and ( CD40L ) plays an important role in inflammation , platelet activation , and clotting system activation . We investigated soluble CD40L ( sCD40L ) expression in MDD and assessed whether it may represent a molecular mechanism that links inflammation and a prothrombotic state and whether this condition may be modified by selective serotonin reuptake inhibitor ( SSRI ) therapy . METHOD Levels of sCD40L , interleukin-1beta ( IL-1beta ) , interleukin-6 ( IL-6 ) , tumor necrosis factor-alpha ( TNF-alpha ) , soluble P-selectin ( sP-selectin ) , activated factor VII ( FVIIa ) , and prothrombin fragment 1 + 2 ( F1 + 2 ) were measured in 46 drug-naïve , first-episode MDD patients without conventional CAD risk factors and in 46 matched healthy controls . Participants were screened between March 2002 and November 2005 . Twenty of the 46 MDD patients were then r and omly assigned to either sertraline 100 mg/day ( N = 10 ) or citalopram 20 mg/day ( N = 10 ) ; the aforementioned variables were measured at baseline and after 6 weeks of treatment . RESULTS Compared with control subjects , MDD patients had higher baseline levels of sCD40L , IL-1beta , IL-6 , TNF-alpha , sP-selectin , FVIIa , and F1 + 2 . In the clinical group , sCD40L levels , HAM-D total scores , and proinflammatory markers were strongly intercorrelated . In contrast , there were no significant correlations in the control group . Mood improvement achieved with SSRI therapy was associated with significant reduction in sCD40L , proinflammatory markers , and prothrombotic markers expression . ( All p values < .0001 . ) CONCLUSIONS This pilot study shows that CD40/ CD40L pathway up-regulation in MDD patients relates increased levels of sCD40L to a prothrombotic state and , preliminarily , indicates that SSRI therapy may significantly reduce sCD40L and CD40L levels associated with proinflammatory and prothrombotic states 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 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 BACKGROUND The question was asked whether patients who discontinue one serotonin selective reuptake inhibitor ( SSRI ) because of side effects can be treated successfully with another SSRI . METHOD 113 patients with major depression who had discontinued fluoxetine because of side effects were enrolled in an open , multicenter , 8-week study design ed to evaluate the tolerability and efficacy of sertraline . After a washout period of at least 3 weeks following fluoxetine discontinuation and an additional 1-week , single-blind , placebo washout period , patients began treatment with 50 mg of sertraline once daily . Doses were titrated upward as necessary to a maximum daily dose of 200 mg . Depressive symptoms and adverse events were evaluated weekly . RESULTS Based on the Clinical Global Impressions Scale , 79 ( 71.8 % ) of 110 patients evaluated for efficacy were " much " or " very much " improved relative to baseline . Only 11 ( 9.8 % ) of 112 patients discontinued sertraline because of adverse reactions . CONCLUSION These results suggest that patients who discontinue one SSRI because of side effects can be treated successfully with another 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 : To test the hypothesis that in patients with major depressive disorder ( MDD ) , the response for specific Hamilton Depression Rating Scale items will differ for duloxetine compared with selective serotonin reuptake inhibitors ( SSRIs ) and that patterns of response will differ based on symptom severity at baseline . Method : Data were pooled from all Lilly-sponsored clinical trials where duloxetine was compared with placebo and an SSRI in patients with MDD : 7 r and omized , double-blind , fixed-dose , 8-week studies of duloxetine  ( n = 1,133 )  versus SSRI  ( n = 689 )  versus placebo  ( n = 641 ) .  Duloxetine doses were 40 , 60 , 80 and 120 mg/day . SSRI doses were 10 mg/day ( escitalopram ) and 20 mg/day ( fluoxetine and paroxetine ) . Results : Compared to SSRI-treated patients , duloxetine-treated patients had a significantly greater ( p ≤ 0.05 ) reduction in the 17-item Hamilton Depression Rating Scale ( HAMD17 ) total score and HAMD17 items of work and activities , psychomotor retardation , genital symptoms and hypochondriasis . Differences favoring the SSRIs approached significance for middle insomnia ( p = 0.057 ) and late insomnia ( p = 0.06 ) , with effect sizes at least twice the magnitude of the corresponding effect sizes for duloxetine . Similarly , the advantage for duloxetine versus the SSRIs approached significance for general somatic symptoms ( p = 0.056 ) , with an effect size twice that observed for the SSRIs . The HAMD17 total score difference was driven mostly by patients with lower baseline MDD severity ( HAMD17 total score ≤19 ) , where the HAMD17 effect size advantage for duloxetine over combined SSRIs was statistically significant ( p = 0.031 ) . Conclusion : Potentially important differences in symptom response patterns were found between duloxetine and the combined SSRIs depending on symptom severity , and different HAMD17 items responded differently to duloxetine compared with SSRIs . Underst and ing these differences may be useful in tailoring antidepressant therapy for individual patients 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 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 BACKGROUND The effects of extended selective serotonin reuptake inhibitor ( SSRI ) treatment on weight are not well characterized . Also unknown is whether different agents have differential effects . To examine these questions , we assessed weight changes in patients r and omly assigned to long-term treatment with  fluoxetine , sertraline , or paroxetine . METHOD Patients ( N = 284 ) with major depressive disorder ( DSM-IV ) were r and omly assigned to double-blind treatment with fluoxetine ( N = 92 ) , sertraline , ( N = 96 ) , or paroxetine ( N = 96 ) for a total of 26 to 32 weeks . The mean percent change in weight was compared for each group , as was the number of patients who had > or = 7 % weight increase from baseline . RESULTS Patients ( fluoxetine , N = 44 ; sertraline , N = 48 ; paroxetine , N = 47 ) who completed the trial were included in these analyses . Paroxetine-treated patients experienced a significant weight increase , fluoxetine-treated patients had a modest but nonsignificant weight decrease , and patients treated with sertraline had a modest but nonsignificant weight increase . The number of patients whose weight increased > 7 % from baseline was significantly greater for paroxetine-treated compared with either fluoxetine-treated or sertraline-treated patients . CONCLUSION Risk of weight gain during extended SSRI treatment differs depending on which SSRI is used Alcoholism and depression are common disorders that frequently cooccur in the same individual . Selective serotonin reuptake inhibitors ( SSRIs ) are effective in the treatment of depression and also had decreased drinking in some studies of heavy drinkers and alcoholics . The reported effect of serotonergic medications on alcohol intake in depressed alcoholics has not been consistent . Most previous studies have not investigated the use of an SSRI in the context of cognitive behavioral therapy ( CBT ) , a known efficacious treatment of both alcoholism and depression . The study presented here was a r and omized placebo-controlled 12-week trial of sertraline combined with individual CBT focused on both alcoholism relapse prevention and depressive symptoms . Subjects were 82 currently depressed , actively drinking alcohol-dependent individuals . Subjects had either primary ( independent ) major depression ( 70 subjects ) or substance-induced mood disorder and at least 1 first-degree relative ( parent , sibling , or child ) with an affective disorder ( 12 subjects ) .  Depression and alcohol consumption outcomes were measured weekly over 12 weeks . Sertraline was well tolerated and all subjects had decreases in both depression and alcohol use during the study compared with baseline . Subjects who received sertraline had fewer drinks per drinking day than subjects who received placebo , but other drinking outcomes were not different between the 2 treatment groups . Treatment with sertraline was associated with less depression at the end of treatment in female subjects compared with female subjects who received placebo .  Less drinking during the study was associated with improved depression outcome . The findings in this study suggest that sertraline , compared with placebo , may provide some modest benefit in terms of drinking outcome and also may lead to improved depression in female alcohol-dependent subjects . Additionally , alcohol relapse prevention CBT , delivered according to manual guidelines with modifications that provide specific attention to depression , appeared to be of benefit to subjects , although this interpretation is limited by the design of the study Major depressive disorder ( MDD ) is a psychiatric condition characterized by hypercortisolism and variations in circulatory cytokines . Previously it has been reported that administration of selective serotonin reuptake inhibitors ( SSRI ) in MDD patients modify cortisol and cytokine levels but these studies only evaluated changes over a short time period . This work reports the long-term effects of administration of SSRI on the cortisol levels and pro-/anti-inflammatory cytokine profile in a group of MDD patients treated for 52 weeks . A total of 31 patients diagnosed with MDD received anti depressant treatment with SSRI . HDRS and BDI were administered over a year , and levels of interleukin IL-1beta , IL-10 , IL-2 , IFN-gamma , IL-4 , IL-13 , and 24-h urine cortisol were determined at weeks ( W ) 0 , 5 , 20 , 36 and 52 of treatment . Before treatment we found high levels of cortisol , IL-4 , IL-13 ( Th2 ) and IL-10 in MDD patients when compared with healthy volunteers . At W20 psychiatric scales indicated a remission of the depressive episode concomitantly with increments in IL-2 and IL-1beta but without changes in cortisol . Towards the end of the treatment ( W52 ) we observed a significant reduction ( p<0.01 ) in cortisol levels , with an increment in IL-1beta and IFN-gamma and a decrease in Th2 cytokines . Our results suggest that depressed patients only reach a partial reestablishment of HPA axis function after the long-term administration of SSRI Objective : To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor ( SSRI ) and a serotonin and norepinephrine reuptake inhibitor ( SNRI ) in the treatment of depression in Parkinson disease ( PD ) . Methods : A total of 115 subjects with PD were enrolled at 20 sites . Subjects were r and omized to receive an SSRI ( paroxetine ; n = 42 ) , an SNRI ( venlafaxine extended release [ XR ] ; n = 34 ) , or placebo ( n = 39 ) . Subjects met DSM-IV criteria for a depressive disorder , or operationally defined subsyndromal depression , and scored > 12 on the first 17 items of the Hamilton Rating Scale for Depression ( HAM-D ) . Subjects were followed for 12 weeks ( 6-week dosage adjustment , 6-week maintenance ) . Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR . The primary outcome measure was change in the HAM-D score from baseline to week 12 . Results : Treatment effects ( relative to placebo ) , expressed as mean 12-week reductions in HAM-D score , were 6.2 points ( 97.5 % confidence interval [ CI ] 2.2 to 10.3 , p = 0.0007 ) in the paroxetine group and 4.2 points ( 97.5 % CI 0.1 to 8.4 , p = 0.02 ) in the venlafaxine XR group . No treatment effects were seen on motor function . Conclusions : Both paroxetine and venlafaxine XR significantly improved  depression in subjects with PD . Both medications were generally safe and well tolerated and did not worsen motor function . Classification of Evidence : This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD Previous studies indicate that selective serotonin reuptake inhibitors ( SSRIs ) , including fluoxetine , fluvoxamine , citalopram and paroxetine , suppress rapid eye movement sleep , and increased nocturnal arousals . There has been no published report of the impact of sertraline on the sleep of depressed patients . This study examines such effects . Forty-seven patients with major depressive disorder , r and omized to double-blind treatment with sertraline or placebo , completed sleep studies before and after 12 weeks of pharmacotherapy . Groups were compared using multivariate analyses of covariance and /or analyses of covariance to examine 4 empirically defined sets of sleep measures . Compared to the placebo-treated group , patients who received sertraline experienced an increase in delta wave sleep in the first sleep cycle and prolonged rapid eye movement ( REM ) sleep latency . Although , sertraline therapy decreased the average number of REM periods ( from 3.86 to 2.40 ) , the activity of both REM period 1 and REM period 2 was significantly increased . Aside from an increase in sleep latency , sertraline therapy was not associated with a worsening of measures of sleep continuity . There was also no significant difference between the groups on a measure of subjective sleepiness . These findings are both similar and different from those observed in previous studies of other SSRIs . The increase in delta sleep ratio and consolidation of REM sleep may have some other clinical implication s. However , the generalizability of these findings is limited because of a number of reasons . Further studies are needed to examine the effects of SSRIs in acute treatment of depressed patients with severe insomnia , and the relationship of acute changes and relapse prevention of recurrent depression Background : The purpose of this open trial was to evaluate the safety , tolerability , and efficacy of oral S-adenosyl-l-methionine as an antidepressant adjunct among partial and nonresponders to serotonin reuptake inhibitors or venlafaxine . Method : Thirty antidepressant-treated adult out patients with persisting major depressive disorder received 800 to 1600 mg of S-adenosyl-l-methionine tosylate over a 6-week trial . Results : Intent-to-treat analyses based on the Hamilton Depression Rating Scale revealed a response rate of 50 % and a remission rate of 43 % following augmentation with S-adenosyl-l-methionine .  Gastrointestinal symptoms and headaches were the most common side effects . Conclusion : Augmentation of selective serotonin reuptake inhibitors or venlafaxine with S-adenosyl-l-methionine warrants a placebo-controlled trial in resistant depression 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 Background A small literature suggests that pharmacotherapy may be useful in the prophylaxis of posttraumatic stress disorder in patients presenting with major trauma . There is relatively little data , however , on the use of selective serotonin reuptake inhibitors ( SSRIs ) in this context . Methods 24 week , double-blind placebo controlled study . 31 participants presenting immediately after trauma , and meeting diagnostic criteria for full or partial acute stress disorder were r and omized to treatment with 10–20 mg of escitalopram or placebo daily for 24 weeks . 2 participants were excluded from the analysis due to early drop out , leaving 29 participants ( escitalopram = 12 , placebo = 17 ) for inclusion in an intent- to- treat analysis . Participants were followed up until 56 weeks , and assessed with the  Clinician Administered PTSD Scale ( CAPS ) . A mixed model repeated measures analysis of variance ( RMANOVA ) was undertaken to determine the efficacy of the intervention on the CAPS score . Results There was a significant reduction in CAPS score over the course of treatment ( F(7 , 142 ) = 41 . 58 , p < 0.001 ) in both the escitalopram and placebo groups , with a greater reduction in CAPS score in the placebo group F(7 , 142 ) = 2.12 , p = 0.045 . There were improvements on all secondary measures , including the Clinical Global Impressions scale , and scales assessing depression , anxiety and disability . Only functional disability outcomes ( F(7 , 141 ) = 2.13 , p = .04 ) , were significantly different between treatment and placebo groups . In the sample as a whole , improvement in scores were maintained at the 52 week follow-up . Side effects were comparable between the groups . Conclusions These data are consistent with other recent work indicating that the SSRIs may not be efficacious in the prevention of PTSD . Nevertheless , the small sample size and baseline differences between groups limit the explanatory power of the study . Although a consideration of the possibility of medication prophylaxis in PTSD remains important , both from conceptual and clinical perspectives , caution is needed with regards to the use of SSRIs until their efficacy can be proven . Trial registration Clinical Trials 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 Introduction Pharmacotherapy and cognitive behavioural therapy ( CBT ) are consistently effective as first-line treatments for  social anxiety disorders ( SADs ) . Nevertheless , pharmacotherapy is often the first choice in clinical practice . In many countries , the first line of pharmacotherapy involves the administration of a selective serotonin reuptake inhibitor ( SSRI ) . Although a significant proportion of patients with SAD fail to respond to the initial SSRI administration , there is no st and ard approach to the management of SSRI-resistant SAD . This paper describes the study protocol for a r and omised controlled trial to evaluate the clinical effectiveness of CBT as a next-step strategy , concomitant with conventional treatment , for patients with SSRI-resistant SAD . Methods and analysis This Prospect i ve R and omized Open Blinded End-point study is design ed with two parallel groups , with dynamic allocation at the individual level . The interventions for the two groups are conventional treatment , alone , and CBT combined with conventional treatment , for 16 weeks . The primary end-point of SAD severity will be assessed by an independent assessor using the Liebowitz Social Anxiety Scale , and secondary end-points include severity of other social anxieties , depressive severity and functional impairment . All measures will be assessed at weeks 0 ( baseline ) , 8 ( halfway point ) and 16 ( postintervention ) and the outcomes will be analysed based on the intent-to-treat . Statistical analyses are planned for the study design stage so that field material s can be appropriately design ed . Ethics and dissemination This study will be conducted at the academic outpatient clinic of Chiba University Hospital . Ethics approval was granted by the Institutional Review Board of Chiba University Hospital . All participants will be required to provide written informed consent . The trial will be implemented and reported in accordance with the recommendations of CONSORT . Clinical Trial Registration Number UMIN000007552 OBJECTIVE This study evaluated time to response in the treatment of panic disorder with a selective serotonin reuptake inhibitor ( SSRI ) or serotonin norepinephrine reuptake inhibitor ( SNRI ) combined with alprazolam orally disintegrating tablets ( ODT ) , or SSRI/SNRI alone . DESIGN Subjects were r and omized to eight weeks open-label treatment with alprazolam ODT ( 4 weeks treatment followed by 3 - 4 week taper ) combined with an SSRI or SNRI , or treatment with SSRI/SNRI alone . SETTING The study was conducted under naturalistic conditions at 62 primary care and 34 psychiatric practice s. PARTICIPANTS Male or female subjects ≥18 years of age diagnosed with panic disorder , with or without agoraphobia . MEASUREMENTS The primary efficacy measure was time to response , defined as ≥50-percent decrease from baseline Hamilton Rating Scale for Anxiety ( HAM-A ) total score . Secondary measures included change from baseline in HAM-A scores and the Clinical Global Impression of Improvement ( CGI-I ) and Patient Global Impression ( PGI ) scales . RESULTS The intent-to-treat ( ITT ) population comprised 245 subjects . There was no statistical difference between treatment groups in time to response in the ITT population ; however , a prospect ively defined per protocol analysis revealed a statistically significant earlier onset of effect in subjects receiving SSRI/SNRI plus alprazolam ODT ( P<0.05 ) . Mean change from baseline in HAM-A total score and clinician and patient measures of global improvement also showed statistically significant early advantages for combination therapy compared with SSRI/SNRI monotherapy . CONCLUSION Combined treatment of panic disorder with alprazolam ODT and an SSRI/SNRI may be associated with more rapid improvement in anxiety symptoms compared with an SSRI/SNRI alone 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 The acute efficacy of selective serotonin reuptake inhibitors ( SSRIs ) in the treatment of major depressive disorder ( MDD ) is well established ; however their role in longer-term prevention of recurrence remains unconfirmed . This study aims at examining : the prophylactic efficacy of four commonly used SSRIs in MDD in a naturalistic setting with long-term follow-up , the effect of concomitant cognitive behavioral therapy ( CBT ) , and the predictors of outcome . In a prospect i ve cohort study , 387 patients who either remitted or responded following treatment with four different SSRIs-fluoxetine , escitalopram , sertraline and paroxetine-were  followed up over several years . During an average follow-up period of 34.5 months , 76.5 % of patients experienced MDD recurrence . Escitalopram and fluoxetine showed a numerically higher prophylactic efficacy than paroxetine and sertraline but the difference was statistically insignificant . The prophylactic efficacy for SSRI-only treatment was limited , with a recurrence rate of 82.0 % , compared to 59.0 % of patient recurrence rate in concomitant Cognitive Behavioral Therapy ( CBT ) . The relatively small size of the CBT group and the lack of r and omization may undermine the extrapolation of its findings to clinical practice . Nevertheless , the study preliminary data may help in defining the clinical utility of antidepressants and CBT in the prophylaxis from MDD recurrence OBJECTIVE This study reports the results of a placebo-controlled , double-blind comparison of bupropion sustained release ( SR ) as an antidote for sexual dysfunction versus placebo in 42 patients with selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction . Exploratory analyses of the association of testosterone and sexual functioning in women in the study were also performed . METHOD Patients with DSM-IV major depression who experienced a therapeutic response to any SSRI and were experiencing medication-induced global or phase-specific sexual dysfunction , as measured by the Changes in Sexual Functioning Question naire ( CSFQ )  , were r and omly assigned to receive either bupropion SR 150 mg b.i.d . or placebo for 4 weeks in addition to the SSRI .  Total testosterone levels were assessed at baseline and week 4 . RESULTS The difference in global sexual functioning , based on the total CSFQ score , was not statistically significant between the 2 groups at week 4 , nor were differences in orgasm , desire/ interest as measured by sexual thoughts , or self-reported arousal . There was a statistically significant difference between the 2 groups at week 4 in desire as measured by self-report feelings of desire and frequency of sexual activity . Desire/ frequency showed a significantly greater improvement among those patients receiving bupropion SR compared with placebo ( Wilk 's F = 5.47 , df = 1 , p = .024 ) . Frequency was significantly correlated to total testosterone level at baseline ( r = 0.36 , p = .027 ) and at week 4 ( r = 0.41 , p = .025 ) . CONCLUSIONS Bupropion SR , as an effective antidote to SSRI-induced sexual dysfunction , produced an increase in desire to engage in sexual activity and frequency of engaging in sexual activity compared with placebo . A larger study is needed to further investigate this finding 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 Altered cytokine secretion as a mechanism in the etiology of depression is still obscure . The serotonin transporter ( 5-HTT ) may play an important role in the termination of serotonergic neurotransmission by serotonin ( 5-HT ) uptaking into presynaptic neurons and representing as an initial action site for selective 5-HTT reuptake inhibitors ( SSRI ) . In our study , we evaluated whether cytokines and 5-HTT acted as biological markers for depression . Blood sample s were collected from 42 participants . The differences in cytokine and 5-HTT mRNA expressions of leukocytes were assessed between the patients with major depression ( n=20 ) and the healthy controls ( n=22 ) , along with the measurements prior and after treatment with a SSRI , fluoxetine , for 3 months in the follow-up patient group ( n=8 ) . The results revealed that the mRNA expressions of IL-1beta , IL-6 , IFNgamma , TNFalpha , and 5-HTT were higher in the depressed patients than those of the healthy controls . The higher level of mRNA expressions of IFNgamma and 5-HTT diminished after fluoxetine treatment . Furthermore , we found a positive correlation between 5-HTT and cytokines mRNA expressions in total participants , which suggested that pro-inflammatory cytokines and 5-HTT might play critical roles in the pathogenesis of major depression and that their levels were affected by chronic treatment with 5-HTT inhibitors The aim of the present study was to evaluate the efficacy and safety of an immediate switch to reboxetine , a selective noradrenaline reuptake inhibitor ( selective NRI ) , in patients with depression unresponsive to the selective serotonin reuptake inhibitor ( SSRI ) fluoxetine . The study included 128 adult out patients with DSM-IV major depressive disorder ( MDD ) who had not responded to at least 6 to 12 weeks of fluoxetine treatment , with at least 3 weeks of treatment on a minimum dose of 40 mg/d . Patients were switched , without a washout period , to reboxetine 4 mg twice daily , with the possibility of increasing the dose to 10 mg/d ( given in divided doses ) after 4 weeks of treatment . Efficacy was assessed using the 17-item Hamilton Rating Scale for Depression ( HAM-D-17 ) and the Clinical Global Impression Improvement ( CGI-I ) and Severity ( CGI-S ) scales . Safety was evaluated by recording spontaneously reported adverse events . A statistically significant ( P < 0.001 ) improvement in the mean total HAM-D-17 score was seen from baseline by week 1 of treatment with reboxetine , and the improvement continue to week 8 . CGI-I and CGI-S scores were similarly improved . The switch to reboxetine was well tolerated ; the most common treatment-emergent adverse events were insomnia , headache , dry mouth , diaphoresis , and constipation , all of which were mild to moderate in severity and decreased in frequency as the study progressed . Immediate switching to reboxetine appears to be a safe and effective treatment for patients with depression who have failed to respond to an adequate dose of fluoxetine 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 The combined serotonin – norepinephrine reuptake inhibitor , venlafaxine XR , has demonstrated significant response and remission in patients diagnosed with depression when measured with the Hamilton Depression Rating Scale ( HAM-D ) . This pooled analysis of data from five studies compared the sustained remission of depressive symptoms in patients treated with venlafaxine XR , the selective serotonin reuptake inhibitors ( SSRIs ) fluoxetine or paroxetine , or placebo .  Data from 1391 subjects enrolled in five active and placebo-controlled studies who met the DSM-III-R or DSM-IV criteria for major depressive disorder were analysed . Three treatment groups were compared : venlafaxine XR ( n=560 ) , fluoxetine/paroxetine ( n=298 ) and placebo ( n=496 ) . Mean treatment duration was 8 weeks . Responders were defined as those patients whose HAM-D-21 score decreased by ≥50 % from baseline . Remission was defined as a HAM-D-17 score ≤7 . Sustained remission was defined as maintenance of remission through week 8 or the end of treatment ( if before week 8) and for ≥2 weeks . Between-group rate comparisons in outcome measures were carried out using Fisher 's exact and log-rank tests . Venlafaxine XR produced significantly higher rates of sustained remission in depressed patients compared to fluoxetine/paroxetine or placebo over this 8-week treatment period . As early as week 2 , a significantly greater proportion of patients treated with venlafaxine  achieved improved depression scores ( remission and response ) . A significantly greater rate of remission and sustained remission  occurred with venlafaxine compared to placebo  . Remission was achieved earlier with venlafaxine and lasted throughout the remainder of the study . These results demonstrate that venlafaxine XR is more effective than fluoxetine/paroxetine for sustaining remission of depressive symptoms Background : Treatment-resistant depression is a persistent clinical problem . Exogenous testosterone therapy has psychotropic effects and has been proposed as an antidepressant supplement , although this strategy has received limited systematic study . Objective : The aim of the study was to examine the mood effects of testosterone supplementation to a serotonergic antidepressant in men with treatment-resistant depression . Method : Twenty-six healthy adult men with major depressive disorder , partial or nonresponse to 2 adequate antidepressant trials during the current episode , and currently using a selective serotonin reuptake inhibitor were r and omized under double-blind conditions to receive intramuscular injections of escalating doses of testosterone or placebo , in addition to their existing selective serotonin reuptake inhibitor regimen , for 6 weeks . The main outcome measure was the Hamilton Rating Scale for Depression score . Results : The mean age was 46.4 ± 10.8 years ; mean total testosterone level , 417.5 ± 197 ng/dL ; mean baseline Hamilton Rating Scale for Depression score , 22.2 ± 5.2 ; and median duration of the current depressive episode , 6.3 ± 10.6 years . Hamilton Rating Scale for Depression scores decreased significantly in both testosterone ( 8.4 ) and placebo ( 7.4 ) groups . Antidepressant response , defined as a 50 % decline in Hamilton Rating Scale for Depression score , was achieved by 53.8 % ( 7/13 ) in the testosterone group and 23.1 % ( 3/13 ) in the placebo group ( P = 0.226 ) . Conclusion : Both injectable testosterone and placebo supplementation to selective serotonin reuptake inhibitor were associated with improvement in mood ; group differences were not distinguishable in this small sample of predominantly eugonadal men with treatment-resistant 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 Abstract This r and omized , double-blind , placebo-controlled trial evaluated the efficacy of CP-601,927 , an & agr;4&bgr;2 nicotinic acetylcholine receptor partial agonist and an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to selective serotonin reuptake inhibitors ( SSRIs ) . After open-label treatment with an SSRI for 8 weeks , subjects with a Hamilton Depression Scale 17 score greater than or equal to 16 were entered into a double-blind phase and r and omized to CP-601,927 2 mg twice daily or placebo  for 6 weeks . The primary end point was the change in Montgomery-Åsberg Depression Rating Scale ( MADRS ) score from double-blind baseline to week 14 . There was no significant difference in change from baseline to week 14 in the MADRS score for CP-610,927 versus placebo ( least square mean difference [ 80 % confidence interval ] , −1.30 [ −3.32–0.71 ] ) . Post hoc analyses revealed that the drug-placebo difference in change from baseline ( SE ) to week 14 in MADRS score was greater in subjects with body mass index ( BMI ) less than or equal to 35 kg/m2 ( −3.43 [ 1.87 ] , P = 0.069 ) than those with BMI greater than 35 kg/m2 ( 3.37 [ 2.8 ] , P = 0.230 ) . Analysis of biomarkers associated with increased BMI suggests that baseline leptin had a significant effect on treatment outcome . P values for the effect of treatment on mean change in MADRS score for subjects with baseline leptin levels below and above the median were 0.055 and 0.0055 , respectively . CP-601,927 was equivalent to placebo as an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to SSRIs . However , post hoc analyses suggest that BMI , particularly elevated leptin levels , may have affected the response to CP-601,927 ; however , further study may be needed to confirm these results 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 Objective : Generalized anxiety disorder ( GAD ) is common in older adults and can be treated with selective serotonin reuptake inhibitors ( SSRIs ) . Genetic variation in the serotonin transporter gene promoter region is posited to be associated with SSRI efficacy : 2 polymorphisms ( 5-HTTLPR S/L and rs25531 g/a ) form a haplotype with the La combination having higher transcription activity than other haplotypes . We hypothesized that GAD patients with no La haplotypes ( La− ) have lower SSRI treatment efficacy than those with 1 to 2 La haplotypes ( La+ ) . Method : The study enrolled subjects aged 60 years or older with a principal diagnosis of GAD into a 12-week , r and omized trial of escitalopram versus placebo . One hundred fifty subjects were genotyped for the serotonin transporter promoter region haplotype and were divided into La− and La+ genotype groups ; the primary analyses were done in European Americans only ( n = 125 ; n = 59 with escitalopram and n = 66 with placebo ) . Results : Escitalopram  had no efficacy in the La− group versus moderate efficacy in the La+ group . This genetic moderation of SSRI efficacy was due to a higher placebo response in La− subjects , compared with La+ subjects . Drug concentration did not affect the genetic results . Exploratory analyses suggest that La− subjects had greater variability of anxiety symptoms unrelated to treatment . Conclusions : The serotonin transporter promoter haplotype is associated with variability in SSRI efficacy for late-life GAD . The variability may result from a genetic effect on anxiety symptom variability unrelated to treatment , rather than a pharmacodynamic effect that has been previously assumed . Further research is needed to underst and the pharmacogenetic mechanism of this haplotype The past decade has brought major new developments in the psychopharmacologic management of generalized anxiety disorder and social phobia . We examined medication-prescribing patterns for the treatment of these anxiety disorders for 12 years to assess changes in patients ' anti-anxiety psychotropic medication usage during that period of evolving practice guidelines . We examined psychotropic medication use in 305 patients with generalized anxiety disorder and 232 with social phobia enrolled in the Harvard/Brown Anxiety Disorders Research Project ( HARP ) , a prospect i ve , longitudinal study of anxiety disorders .  Psychotropic treatment patterns seem to have remained relatively stable over 12 years with benzodiazepines the medications most commonly used for both generalized anxiety disorder and social phobia . Comparatively , selective serotonin reuptake inhibitor ( SSRI ) and venlafaxine usage as st and -alone medications for these disorders remained low throughout the follow-up period . At the 12-year follow-up , 24 % of patients with generalized anxiety disorder and 30 % of patients with social phobia were utilizing neither an  SSRI/selective norepinephrine reuptake inhibitor ( SNRI ) nor a benzodiazepine . Treatment recommendations for use of SSRIs and venlafaxine in the management of generalized anxiety disorder and social phobia initially promulgated in 1998 had a modest impact on changes in psychopharmacologic practice 4 - 5 years later . Difficulties in the implementation of treatment guidelines are discussed 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 OBJECTIVE The authors compared low-dose sustained-release bupropion with placebo for sexual dysfunction induced by selective serotonin reuptake inhibitors ( SSRIs ) . METHOD Thirty adults who had received SSRIs for at least 6 weeks , who were euthymic , and who had sexual dysfunction as determined by a total score greater than 19 out of a possible 30 on the Arizona Sexual Experience Scale were r and omly assigned to receive either 150 mg/day of sustained-release bupropion or placebo at 6:00 p.m. for 3 weeks . RESULTS There were no significant differences between the sustained-release bupropion and placebo groups as measured by change in Arizona Sexual Experiences Scale or Hamilton Depression Rating Scale scores or side effects . CONCLUSIONS Future studies should compare higher doses of bupropion for treating sexual dysfunction and should include a greater number of subjects Up to 50 % of patients with major depressive disorder ( MDD ) fail to respond to an antidepressant trial , with most taking a selective serotonin reuptake inhibitor ( SSRI ) as an initial treatment . Switching to bupropion , for depressed patients not responding to SSRIs , is a popular strategy among clinicians . This study assesses the efficacy of bupropion SR in the management of MDD resistant to a prospect i ve trial of fluoxetine . Twenty-nine patients with MDD refractory to an 8- to 12-week open-trial of fluoxetine  were enrolled in an 8-week open-trial of bupropion SR . Both a completer analysis ( n = 20 ) and a modified intent-to-treat analysis ( n = 26 ) were performed to evaluate  bupropion SR response rates . Using a completer analysis , seven patients ( 35.0 % ) were classified as responders , five ( 25.0 % ) partial responders , and eight ( 40.0 % ) nonresponders . A modified intent to treat analysis result ed in nine ( 34.6 % ) patients classified as responders , eight ( 30.8 % ) partial responders , and nine ( 34.6 % ) nonresponders . The overall proportion of remitters was 6/20 ( 30.0 % ) using a completer analysis and 6/26 ( 23.1 % ) using an MITT analysis . Approximately 60 % of patients with MDD resistant to a prospect i ve trial of fluoxetine experienced a full or partial response to bupropion SR . Bupropion SR should be considered as a potential treatment for patients who remain depressed despite treatment with Background Previous studies suggest that electroacupuncture possesses therapeutic benefits for depressive disorders . The purpose of this study was to determine whether dense cranial electroacupuncture stimulation ( DCEAS ) could enhance the antidepressant efficacy in the early phase of selective serotonin reuptake inhibitor ( SSRI ) treatment of major depressive disorder ( MDD ) . Methods In this single-blind , r and omized , controlled study , patients with MDD were r and omly assigned to 9-session DCEAS or noninvasive electroacupuncture ( n-EA ) control procedure in combination with fluoxetine ( FLX ) for 3 weeks . Clinical outcomes were measured using the 17-item Hamilton Depression Rating Scale ( HAMD-17 ) , Clinical Global Impression-severity ( CGI-S ) , and Self-rating Depression Scale ( SDS ) as well as the response and remission rates . Results Seventy-three patients were r and omly assigned to n-EA ( n = 35 ) and DCEAS ( n = 38 ) , of whom 34 in n-EA and 36 in DCEAS group were analyzed . DCEAS-treated patients displayed a significantly greater reduction from baseline in HAMD-17 scores at Day 3 through Day 21 and in SDS scores at Day 3 and Day 21 compared to patients receiving n-EA . DCEAS intervention also produced a higher rate of clinical ly significant response compared to n-EA procedure ( 19.4 % ( 7/36 ) vs. 8.8 % ( 3/34 ) ) . The incidence of adverse events was similar in the two groups . Conclusions DCEAS is a safe and effective intervention that augments the antidepressant efficacy . It can be considered as an additional therapy in the early phase of SSRI treatment of depressed patients . Trial Registration Controlled-Trials.com IS RCT 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 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 . 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 CONTEXT Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy ( CBT ) or a selective serotonin reuptake inhibitor ( SSRI ) . However , little is known about their relative or combined effectiveness . OBJECTIVE To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial of a volunteer sample of 439 patients between the ages of 12 to 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , diagnosis of major depressive disorder . The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003 . INTERVENTIONS Twelve weeks of ( 1 ) fluoxetine alone ( 10 to 40 mg/d ) , ( 2 ) CBT alone , ( 3 ) CBT with fluoxetine ( 10 to 40 mg/d ) , or ( 4 ) placebo ( equivalent to 10 to 40 mg/d ) . Placebo and fluoxetine alone were administered double-blind ; CBT alone and CBT with fluoxetine were administered unblinded . MAIN OUTCOME MEASURES Children 's Depression Rating Scale-Revised total score and , for responder analysis , a ( dichotomized ) Clinical Global Impressions improvement score . RESULTS Compared with placebo , the combination of fluoxetine with CBT was statistically significant ( P = .001 ) on the Children 's Depression Rating Scale-Revised . Compared with fluoxetine alone ( P = .02 ) and CBT alone ( P = .01 ) , treatment of fluoxetine with CBT was superior . Fluoxetine alone is a superior treatment to CBT alone ( P = .01 ) . Rates of response for fluoxetine with CBT were 71.0 % ( 95 % confidence interval [ CI ] , 62%-80 % ) ; fluoxetine alone , 60.6 % ( 95 % CI , 51%-70 % ) ; CBT alone , 43.2 % ( 95 % CI , 34%-52 % ) ; and placebo , 34.8 % ( 95 % CI , 26%-44 % ) . On the Clinical Global Impressions improvement responder analysis , the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo . Clinical ly significant suicidal thinking , which was present in 29 % of the sample at baseline , improved significantly in all 4 treatment groups . Fluoxetine with CBT showed the greatest reduction ( P = .02 ) . Seven ( 1.6 % ) of 439 patients  attempted suicide ; there were no completed suicides . CONCLUSION The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder 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 Approximately 6.2 % of women in the USA and 3.7 % of women in the UK , use Selective Serotonin Reuptake Inhibitors ( SSRIs ) during their pregnancies because of depression and /or anxiety . In the Netherl and s , this prevalence is around 2 % . Nonetheless , SSRI use during pregnancy is still controversial . On the one h and SSRIs may be toxic to the intrauterine developing child , while on the other h and relapse or recurrence of depression during pregnancy poses risks for both mother and child . Among patients and professionals there is an urgent need for evidence from r and omized studies to make rational decisions regarding continuation or tapering of SSRIs during pregnancy . At present , no such studies exist . Methods / Design ‘ Stop or Go ’ is a pragmatic multicentre r and omized non-inferiority trial among 200 pregnant women with a gestational age of less than 16 weeks who use SSRIs without clinical ly relevant depressive symptoms . Women allocated to the intervention group will receive preventive cognitive therapy with gradual , guided discontinuation of SSRIs under medical management ( STOP ) . Women in the control group will continue the use of SSRIs ( GO ) . Primary outcome will be the ( cumulative ) incidence of relapse or recurrence of maternal depressive disorder ( as assessed by the Structured Clinical Interview for DSM disorders ) during pregnancy and up to three months postpartum . Secondary outcomes will be child outcome ( neonatal outcomes and psychomotor and behavioural outcomes up to 24 months postpartum ) , and health-care costs . Total study duration for participants will be therefore be 30 months . We specified a non-inferiority margin of 15 % difference in relapse risk . Discussion This study is the first to investigate the effect of guided tapering of SSRIs with preventive cognitive therapy from early pregnancy onwards as compared to continuation of SSRIs during pregnancy . We will study the effects on both mother and child with a pragmatic approach . Additionally , the study examines cost effectiveness . If non-inferiority of preventive cognitive therapy with guided tapering of SSRIs compared to intended continuation of SSRIs is demonstrated for the primary outcome , this may be the preferential strategy during pregnancy . Trial registration Netherl and s Trial Register ( NTR ) : NTR4694 ; registration date : 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
SSRIs significantly increase the risk of both serious and non-serious adverse events .
The potential small beneficial effects seem to be outweighed by harmful effects .
Background The evidence on selective serotonin reuptake inhibitors ( SSRIs ) for major depressive disorder is unclear .
Methods Our objective was to conduct a systematic review assessing the effects of SSRIs versus placebo , ‘ active ’ placebo , or no intervention in adult participants with major depressive disorder .