Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. Nine-month predictors and outcomes of SSRI antidepressant continuation in primary care. Citalopram versus desipramine in treatment resistant depression: Effect of continuation or switching strategies. A randomized open study 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† Antidepressant Exposure as a Predictor of Clinical Outcomes in the Treatment of Resistant Depression in Adolescents (TORDIA) Study Response to an open trial of a second SSRI in major depression. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. Efficacy and safety of mirtazapine in major depressive disorder patients after SSRI treatment failure: an open-label trial. Mirtazapine substitution in SSRI-induced sexual dysfunction. Switching to bupropion in fluoxetine-resistant major depressive disorder. Impact of treatments for depression on comorbid anxiety, attentional, and behavioral symptoms in adolescents with selective serotonin reuptake inhibitor-resistant depression. Treatments for Poststroke Motor Deficits and Mood Disorders: A Systematic Review for the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Guidelines for Stroke Rehabilitation Further evidence of a combined effect of SERTPR and TPH on SSRIs response in mood disorders Treatment of selective serotonin reuptake inhibitor-resistant depression in adolescents: predictors and moderators of treatment response. Cardiac side‐effects of two selective serotonin reuptake inhibitors in middle- aged and elderly depressed patients 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. The treatment of SSRI-resistant depression in adolescents (TORDIA): in search of the best next step. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. Male Sexual Side Effects Associated with Antidepressants: A Descriptive Clinical Study of 32 Patients Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. A Review of Vilazodone, Serotonin, and Major Depressive Disorder 5-HTTLPR modulates antidepressant efficacy in depressed women Comparison of moclobemide with selective serotonin reuptake inhibitors (SSRIs) on sexual function in depressed adults Pharmacokinetically and clinician-determined adherence to an antidepressant regimen and clinical outcome in the TORDIA trial. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression SECOND-STAGE TREATMENTS FOR RELATIVE NONRESPONDERS TO COGNITIVE BEHAVIORAL THERAPY (CBT) FOR PANIC DISORDER WITH OR WITHOUT AGORAPHOBIA-CONTINUED CBT VERSUS SSRI: A RANDOMIZED CONTROLLED TRIAL. Effect of Vortioxetine vs. Escitalopram on Sexual Functioning in Adults with Well-Treated Major Depressive Disorder Experiencing SSRI-Induced Sexual Dysfunction. Venlafaxine extended release versus citalopram in patients with depression unresponsive to a selective serotonin reuptake inhibitor Escitalopram maintenance treatment for prevention of recurrent depression: a randomized, placebo-controlled trial. Polymorphism of the 5-HT transporter and response to antidepressants: randomised controlled trial. Antidepressant-induced mania in bipolar patients: identification of risk factors. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. Brain-derived neurotrophic factor Val66Met polymorphism and 6-month antidepressant remission in depressed Caucasian patients. Does fetal exposure to SSRIs or maternal depression impact infant growth? Clinical and Neurobiological Effects of Tianeptine and Paroxetine in Major Depression GENetic and clinical Predictors Of treatment response in Depression: the GenPod randomised trial protocol Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline Effective components of TORDIA cognitive-behavioral therapy for adolescent depression: preliminary findings. 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 Reboxetine and citalopram in panic disorder: a single-blind, cross-over, flexible-dose pilot study IL-6 levels decrease with SSRI treatment in patients with major depression. The diagnosis and treatment of generalized anxiety disorder. Comparison of desipramine and citalopram treatments for depression in Parkinson's disease: a double-blind, randomized, placebo-controlled study. 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. Incremental cost-effectiveness of combined therapy vs medication only for youth with selective serotonin reuptake inhibitor-resistant depression: treatment of SSRI-resistant depression in adolescents trial findings. Efficacy outcomes from 3 clinical trials of edivoxetine as adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment. Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients Remission with venlafaxine extended release or selective serotonin reuptake inhibitors in depressed patients: a randomized, open-label study. Safe use of SSRIs in young adults: how strong is evidence for new suicide warning? 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 controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine. Effects of Zinc Supplementation in Patients with Major Depression: A Randomized Clinical Trial Cost-effectiveness and cost-utility of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine: randomised controlled trial. Association between -1438G/A Promoter Polymorphism in the 5-HT2A Receptor Gene and Fluvoxamine Response in Japanese Patients with Major Depressive Disorder Safety and Tolerability of Dexmecamylamine (TC-5214) Adjunct to Ongoing Antidepressant Therapy in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy: Results of a Long-Term Study A randomized effectiveness trial of brief cognitive-behavioral therapy for depressed adolescents receiving antidepressant medication.
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 BACKGROUND This study aim ed to identify the predictors and outcomes of SSRI antidepressant continuation , discontinuation and switching over a 9-month period of naturalistic observation . METHODS Primary care patients ( n=573 ) with physician-diagnosed depression from 37 practice s were r and omized to an open-label trial of one of three selective serotonin reuptake inhibitors ( SSRIs ) managed in their primary care setting .  Psychiatric characteristics and treatment course were assessed at baseline and at 1 , 3 , 6 and 9 months after medication initiation . RESULTS Nineteen percent of patients switched SSRIs , which occurred significantly sooner than discontinuation ( median : 41 vs.100 days ) . Time to discontinuation was primarily explained by baseline patient skepticism about taking an antidepressant ( 62 % increase in discontinuation risk ) . In contrast , time to switch was associated with greater impairment at baseline and lesser improvement in impairment during the first month on medication . Patients who discontinued were significantly less likely to be depressed 9 months after starting medication than those who either continued or switched medication , and were less symptomatic and impaired than patients who switched . CONCLUSIONS Baseline impairment may increase the risk for SSRI antidepressant switching . Additionally , patient skepticism about antidepressants predicts early SSRI discontinuation and may predict rapid recovery . Intent-to-treat analyses in nonr and omized clinical trials may paradoxically inflate antidepressant effect sizes Abstract Objectives . Evidence in favour of switching between selective serotonin reuptake inhibitor ( SSRI ) and tricyclic ( TCA ) antidepressants in treatment resistant depression has been tested in a few studies only , consequently a prospect i ve study was undertaken to evaluate the impact of switching strategies . Methods . One hundred eighty-nine patients who failed to respond to a previous antidepressant were r and omised to four arms : firstly they received citalopram or desipramine for a 4-week period ; secondly , those who failed to respond were treated for a further 4-week period with the same antidepressant ( citalopram-citalopram and desipramine-desipramine arms ) or switched to the alternate one ( citalopram-desipramine and desipramine-citalopram arms ) . Results . There was no difference in the first 4-week phase between patients receiving citalopram versus desipramine in Hamilton Rating Scale for Depression ( HRSD ) , Montgomery – Asberg Depression Rating Scale ( MADRS ) , and Clinical Global Impression ( CGI ) scores . In the second 4-week phase remitter rates were higher among non-switched patients ( P = 0.04 ) . Moreover , considering HRSD and MADRS , switched patients reported significantly higher scores ( P ≤ 0.02 for both scales at each time-point ) . Conclusions . This study supports the thesis that switching from an SSRI to a TCA ( and vice versa ) in non-responders to a 4-week trial of an SSRI/TCA is not associated with improved response . The result goes in the opposite direction to that predicted by current guidelines 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 This paper examines the relationship between plasma concentration of antidepressant and both clinical response and adverse effects in treatment-resistant depressed adolescents . Adolescents ( n = 334 ) with major depression who had not responded to a selective serotonin reuptake inhibitor ( SSRI )  were r and omized to 1 of 4 treatments : switch to another SSRI ( fluoxetine , citalopram , or paroxetine ) , switch to venlafaxine , switch to SSRI plus cognitive behavior therapy , or switch to venlafaxine plus cognitive behavior therapy . Adolescents who did not improve by 6 weeks had their dose increased . Plasma concentrations of medication and metabolites were measured at 6 weeks in 244 participants and at 12 weeks in 204 participants . Adolescents treated with citalopram whose plasma concentration was equal to or greater than the geometric mean ( GM ) showed a higher response rate compared to those with less than the GM , with parallel but nonsignificant findings for fluoxetine . A dose increase of citalopram or fluoxetine at week 6 was most likely to result in response when it led to a change in concentration from less than the GM at 6 weeks to the GM or greater at week 12 . Plasma levels of paroxetine , venlafaxine , or O-desmethylvenlafaxine were not related to clinical response . Exposure was associated with more cardiovascular and dermatologic side effects in those receiving venlafaxine . Antidepressant concentration may be useful in optimizing treatment for depressed adolescents receiving fluoxetine or citalopram 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 After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor ( SSRI ) , it is not known whether switching to one antidepressant is more effective than switching to another . METHODS We r and omly assigned 727 adult out patients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram  to receive one of the following drugs for up to 14 weeks : sustained-release bupropion ( 239 patients ) at a maximal daily dose of 400 mg , sertraline ( 238 patients ) at a maximal daily dose of 200 mg , or extended-release venlafaxine ( 250 patients ) at a maximal daily dose of 375 mg . The study was conducted in 18 primary and 23 psychiatric care setting s. The primary outcome was symptom remission , defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) at the end of the study . Scores on the Quick Inventory of Depressive Symptomatology - Self Report ( QIDS-SR-16 ) , obtained at treatment visits , determined secondary outcomes , including remission ( a score of 5 or less at exit ) and response ( a reduction of 50 percent or more on baseline scores ) . RESULTS Remission rates as assessed by the HRSD-17 and the QIDS-SR-16 , respectively , were 21.3 percent and 25.5 percent for sustained-release bupropion , 17.6 percent and 26.6 percent for sertraline , and 24.8 percent and 25.0 percent for extended-release venlafaxine . QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion , 26.7 percent for sertraline , and 28.2 percent for extended-release venlafaxine . These treatments did not differ significantly with respect to outcomes , tolerability , or adverse events . CONCLUSIONS After unsuccessful treatment with an SSRI , approximately one in four patients had a remission of symptoms after switching to another antidepressant . Any one of the medications in the study provided a reasonable second-step choice for patients with depression . ( Clinical Trials.gov number , NCT00021528 . ) 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 BACKGROUND Sexual side effects are a common and bothersome reaction to selective serotonin reuptake inhibitors ( SSRIs ) , frequently leading to cessation of treatment . Mirtazapine , an alpha2-adrenoceptor and serotonin-2/3 receptor antagonist , appears to cause few sexual problems . METHOD Nineteen patients ( 12 women and 7 men ) , with SSRI-induced sexual dysfunction who were in remission from major depressive disorder ( total Hamilton Rating Scale for Depression [ HAM-D ] score < or = 10 ) , were switched to open-label mirtazapine for up to 6 weeks . Mirtazapine was titrated from 7.5 mg to 45 mg daily , as tolerated . Sexual functioning was measured weekly with the Arizona Sexual Experiences Scale ( ASEX ) , and depression was measured weekly with the HAM-D. RESULTS Eleven patients ( 58 % ) had a return of normal sexual functioning ( mean + /- SD ASEX score = 12+/-3 ) , and another 2 ( 11 % ) reported significant improvement in sexual functioning ( mean ASEX score reduced from 24+/-1 to 20+/-0 ) . All nineteen patients maintained their antidepressant response ( HAM-D score after 6 weeks of mirtazapine = 6+/-3 ) . The most commonly reported side effects ( using moderate/severe rating on a symptom checklist ) were initial sedation ( N = 3 ) , irritability ( N = 6 ) , and muscle soreness and stiffness ( N = 3 ) . Weight gain of 10 to 20 lb ( 4.5 - 9 kg ) was seen in 3 patients ( 2 women and 1 man ) . CONCLUSION Mirtazapine is an effective antidepressant for many patients experiencing SSRI-induced sexual dysfunction 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 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 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 We reported an independent association of the short variant of the serotonin transporter gene‐linked polymorphic region ( SERTPR ) and tryptophan hydroxylase ( TPH ) genes with antidepressant response to  selective serotonin reuptake inhibitors ( SSRIs ) . The aim of the present study was to confirm the effect of the SERTPR and TPH gene variants on the  SSRIs antidepressant activity in a new sample of major and bipolar depressives . Two hundred and twenty one in patients ( major depressives = 128 , bipolar disorder = 93 ) were treated with SSRIs ( fluvoxamine or paroxetine ) for 6 weeks ; the severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression ( HAMD ) . SERTPR and TPH variants were determined using PCR‐based techniques , 220 subjects genotyped for SERTPR and 221 for TPH that were never included in previous studies . SERTPR*s/s variant association with a poor response to SSRI treatment was confirmed , even if with less significant P values ( P = 0.034 ) , independently from clinical variables ; pooling the present sample with previous ones we observed a highly significant effect ( P < 0.000001 ) . TPH*A/A variants showed higher HAMD scores throughout the trial but with only a trend in the same direction of our previous study in terms of a worse response of A/A genotypes . Thus , the previous positive association was not fully replicated for TPH . The present independent replication confirms SERTPR variants as a liability factor for antidepressant efficacy while the TPH effect is not unequivocal . © 2004 Wiley‐Liss , OBJECTIVE To 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 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 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 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 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 Objective : This is a retrospective study to add to the existing body of clinical information regarding male sexual side effects associated with antidepressants . From the chart review , thirty-four out of eighty male patients were identified to have reported loss of libido , erectile difficulty , anorgasmia , and delayed ejaculation while receiving pharmacotherapy of selective serotonin reuptake blockers ( fluoxetine , paroxetine , and sertraline ) ; tricyclic antidepressants ( nortriptyline , imipramine , amitriptyline , desipramine , and clomipramine ) ; and a monoamine oxidase inhibitor ( phenelzine ) . Method : The authors also discussed the management of these sexual side effects by waiting for spontaneous remission , reducing the dosage level , and substituting the offending drug with other antidepressants . Results : This article underscores the underreported nature of antidepressant-associated sexual dysfunction , the high incidence of SSRI-associated sexual side effects , equal potentials in causing sexual side effects among the three SSRI 's , the low incidence rate of sexual adverse effects from bupropion , and the minimal need to add an antidote if the side effects are to be managed systematic ally . Conclusions : Finally , male sexual side effects can occur r and omly and involve any sexual phase r and omly , and the treatment approaches are similar , regardless of the types of sexual dysfunction associated with antidepressants 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 Objective : To review the mechanism of selective serotonin reuptake inhibitor (SSRI)–mediated serotonergic neurotransmission , focusing on serotonin 1A ( 5-HT1A ) autoreceptors , which are proposed to be involved in delaying therapeutic efficacy . Vilazodone was specifically design ed to function both as an SSRI and a partial agonist at 5-HT1A receptors . This combined mechanism is proposed to decrease time to efficacy , minimize sexual side effects , and provide concomitant anxiolytic properties . Data Sources : A PubMed search of all English- language articles from January 1990 to January 2013 was conducted using the search terms depression and 5-HT1A , depression and buspirone , depression and pindolol , and vilazodone . Study Selection : We found 47 articles and abstract s that were selected for inclusion on the basis of information about the pharmacology of 5-HT1A receptors and the clinical data on pindolol , buspirone , and vilazodone in depression . Data Extraction : This review summarizes current literature involving antidepressant activity , the role of 5-HT1A autoreceptors , and clinical trials involving serotonin reuptake inhibition in conjunction with 5-HT1A agonists and partial agonists , with a focus on vilazodone . Results : Vilazodone has demonstrated efficacy in 2 large , r and omized , double-blind , placebo-controlled trials in major depressive disorder . Results suggest that vilazodone has a low incidence of sexual side effects and is effective in patients with high levels of anxiety . A pooled analysis shows evidence of significant symptom reduction after only 1 week of therapy . Conclusions : If future studies corroborate the clinical benefits attributed to its mechanism of action , vilazodone may show potential advantages in terms of onset of action , sexual side effects , and anxiolytic activity in patients with major depressive disorder Background As compared with the long variant ( L ) , the short variant ( S ) of the functional polymorphic region of the serotonin transporter gene ( 5-HTTLPR ) has been associated with a lower antidepressant efficacy in major depression , but some replication studies have evidence d contradictory results . Sex differences may explain these contradictory results . Methods One hundred and three in patients ( 74 women and 29 men ) with a major depressive episode were assessed prospect ively for antidepressant efficacy after 4 weeks of treatment with selective serotonin reuptake inhibitors ( SSRI ) and non-SSRI drugs . Results As compared with LL/LS , the SS genotype of the 5-HTTLPR was associated with a lower antidepressant efficacy in depressed women ( 79 vs. 50 % responders , P = 0.035 ) . This result was shown with both SSRI and non-SSRI antidepressants . The logistic regression performed in women showed that response to treatment was related to genotype ( odds ratio=0.15 ; 95 % confidence interval=0.03–0.85 ; P = 0.03 ) and not to other variables . No effect of 5-HTTLPR was found in depressed men . Conclusion Despite a low power , this study suggests a significant effect of 5-HTTLPR genotype on antidepressant efficacy in depressed women but not in men , with both SSRI and non-SSRI drugs . Further research is needed to confirm this result and investigate its underlying mechanisms OBJECTIVE To compare the emergent sexual effects of moclobemide and selective serotonin reuptake inhibitors ( SSRIs ) during acute and maintenance therapy in routine practice . METHOD 268 patients were evaluated for sexual function  at baseline , 6 weeks , 3 and 6 months of treatment using physician ratings and self-rating question naires . Patients received moclobemide , an reversible monoamine oxidase A inhibitor ( RIMA ) , or a SSRI ( fluoxetine , fluvoxamine , paroxetine , sertraline ) . RESULTS Baseline values were similar in all groups . Incidences of impairments of sexual functioning with treatment , whether clinical ly relevant or not , were 24.3 % with moclobemide and 61.5 % with SSRIs ( physician ratings ) , with no significant tolerance to these effects . There was a suggestion of differences between the SSRIs in their specific dysfunctions they cause . SSRIs ( 21.6 % of patients ) had about ten times the moclobemide rate ( 1.9 % ) of sexual dysfunction reported as adverse events . Antidepressant efficacy was comparable between treatments . CONCLUSION In patients for whom sexual function  is important or sexual dysfunction  is present , moclobemide should be considered a first line antidepressant OBJECTIVE Nonadherence to antidepressant treatment may contribute to poor outcome and to suicidal adverse events in adolescent depression . We examine the relationship between adherence and both clinical response and suicidal events in participants in the Treatment of Resistant Depression in Adolescents ( TORDIA ) study . METHOD The relationship between adherence to medication and clinical outcome was assessed in 190 treatment-resistant depressed adolescents who were r and omized to one of four cells : switch to another selective serotonin reuptake inhibitor ( SSRI ) , switch to venlafaxine , or either of these two medication switches plus cognitive behavioral therapy .  Plasma levels of antidepressant drug and metabolites were determined after 6 and 12 weeks of treatment . A twofold or greater variation in the dose-adjusted concentration of drug plus metabolites ( level/dose ratio [ LDR ] ) was defined as nonadherence . Nonadherence was also determined by clinician pill counts ( CPC ) of the proportion of prescribed pills that were unused and was defined as having greater than 30 % of the prescribed pills remaining . RESULTS LDR and CPC showed low concordance . LDR was unrelated to clinical response .  CPC adherence was related to a higher response rate overall ( adherent , 63.0 % versus nonadherent , 47.2 % , p = .03 ) . Approximately half ( 50.8 % ) of the sample surveyed showed evidence of nonadherence by CPC . Neither measure of adherence was related to the occurrence of suicidal events or to the pace of decline in suicidal ideation . CONCLUSIONS Clinician pill counts may be a relevant measure of adherence that is related to outcome under formal clinical trial conditions in depressed adolescents . Nonadherence appears to be a common and significant source of treatment nonresponse . Clinical Trial Registration Information-Treatment of SSRI-Resistant Depression in Adolescents ( TORDIA ) ; http://www . clinical trials.gov ; NCT00018902 BACKGROUND Inositol has been reported to be an effective treatment in depression , and we hypothesized that inositol addition might enhance or speed up response to  serotonin selective reuptake inhibitors ( SSRI ) . METHODS Twenty-seven depressed patients completed a double-blind controlled 4-week trial of SSRI plus placebo or SSRI plus inositol .  Hamilton Depression Rating Scale was used as an assessment tool at baseline , and 1 , 2 , 3 , and 4 weeks . RESULTS No significant difference was found between the two treatment groups . CONCLUSIONS Previous studies combining different effective antidepressant therapies similarly found no evidence for additive effects [ e.g. , monoamine oxidase inhibitors ( MAOI ) plus tricyclic antidepressants ( TCA ) , TCA plus lithium ] . By contrast , augmentation by lithium or MAOI after a failed course of antidepressant treatment is effective and should be studied with inositol BACKGROUND Cognitive behavioral therapy ( CBT ) and pharmacotherapy are efficacious for the short-term treatment of panic disorder . Less is known about the efficacy of these therapies for individuals who do not respond fully to short-term CBT .  METHOD The current trial is a second-step stratified r and omized design comparing two treatment conditions-selective serotonin reuptake inhibitor ( SSRI ; paroxetine or citalopram ; n = 34 ) and continued CBT  ( n = 24)-in a sample of individuals classified as treatment nonresponders to an initial course of CBT for panic disorder . Participants were r and omized to 3 months of treatment and then followed for an additional 9 months . Only treatment responders after 3 months were maintained on the treatment until 12-month follow-up . Data analysis focused on panic disorder symptoms and achievement of response status across the first 3 months of treatment . Final follow-up data are presented descriptively . RESULTS Participants in the SSRI condition showed significantly lower panic disorder symptoms as compared to continued CBT at 3 months . Results were similar when excluding individuals with comorbid major depression or analyzing the entire intent-to-treat sample . Group differences disappeared during 9-month naturalistic follow-up , although there was significant attrition and use of non study therapies in both arms . CONCLUSIONS These data suggest greater improvement in panic disorder symptoms when switching to SSRI after failure to fully respond to an initial course of CBT . Future studies should further investigate relapse following treatment discontinuation for nonresponders who became responders . Clinical trials.gov Identifier : NCT00000368 ; https:// clinical trials.gov/show/NCT00000368 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 Findings from the National Institute of Mental Health 's Sequenced Treatment Alternatives to Relieve Depression trial indicate that approximately 50 % of patients with major depressive disorder do not experience a treatment response after adequate first-line treatment with a selective serotonin reuptake inhibitor ( SSRI ) . This study was design ed to test the hypothesis that , after treatment failure with an SSRI , switching to venlafaxine extended release ( ER ) would offer advantages over switching to another SSRI , citalopram . The objectives of this trial were to compare the efficacy and safety of venlafaxine ER and citalopram in the treatment of moderate-to-severe depression in patients who did not experience a treatment response to an SSRI other than citalopram  and to investigate the effects of severity of depression by categorizing treatment groups according to baseline severity . This was a 12-week , double-blind , r and omized , parallel-group , multicenter study . Participants were adult out patients who , following 8 weeks of monotherapy with an adequate dosing regimen of an SSRI other than citalopram  and had not responded , met the diagnostic criteria for depression as described in the Diagnostic and statistical manual of mental disorders , fourth edition , and had a score ≥20 on the 21-item Hamilton Rating Scale for Depression ( HAM-D21 ) . After a 7-day screening period , patients were r and omly assigned to receive venlafaxine ER 75 mg/day or citalopram 20 mg/day for the first 2 weeks . Doses could be increased every 2 weeks through week 6 . Treatment lasted 12 weeks and was followed by a 1-week tapering period . Maximum dosages were venlafaxine ER 300 mg/day or citalopram 60 mg/day . The primary end point was the final on-therapy total HAM-D21 score . To investigate the treatment effects of the severity of depression on efficacy , a subgroup analysis was performed for baseline HAM-D21 total score ≤31 and > 31 . The analyses for HAM-D21 , Montgomery – Åsberg Depression Rating Scale ( MADRS ) , Clinical Global Impressions – Severity ( CGI-S ) , and Clinical Global Impressions – Improvement scores were based on intent-to-treat ( ITT ) population , for both the primary analysis and subgroup analysis according to baseline HAM-D21 total scores ≤31 or > 31 . Safety assessment s included the recording of adverse events ( AEs ) . A total of 406 patients ( 200 venlafaxine ER , 206 citalopram ) were r and omly assigned and 396 patients were included in the ITT population ( 194 venlafaxine ER , 202 citalopram ) . Treatment groups were similar in terms of demographics and baseline psychiatric assessment s. Two hundred and eighty-four patients ( 137 venlafaxine ER , 147 citalopram ) were present in the ITT population with a baseline HAM-D21 total score ≤31 and 112 patients ( 57 venlafaxine ER , 55 citalopram ) in the > 31 group . In the primary analysis , there was no statistical difference between groups . The group with a baseline HAM-D21 total score of 20–31 did not differ significantly in any efficacy parameters . In the group with a baseline HAM-D21 total score > 31 , the venlafaxine ER group differed significantly from the citalopram group on the primary end point HAM-D21 total score ( P=0.0121 ) . The secondary end point CGI-S score was statistically significant ( P=0.0359 ) , although the MADRS total score ( P=0.0930 ) was not . AEs were reported by 57.8 and 63.4 % of venlafaxine ER and citalopram patients , respectively . Overall discontinuation rates were 24.5 % for venlafaxine ER and 20.9 % for citalopram  . Discontinuation rates owing to an AE as a primary or secondary reason were 5.5 % for venlafaxine ER and 5.3 % for citalopram . Overall , venlafaxine ER and citalopram showed similar efficacy in patients who had an inadequate response to an SSRI . In the subset of more severely depressed patients , venlafaxine ER was significantly more effective on a number of efficacy measures . Patients who remain severely depressed following treatment with an SSRI may gain more benefit from the dual-action drug venlafaxine , rather than switching to another SSRI BACKGROUND 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 Antidepressants exhibit a variety of pharmacological actions including inhibition of the serotonin and noradrenaline transporters . We wished to investigate whether genetic variation could be used to target or personalise treatment , in a comparison of selective serotonin reuptake inhibitors ( SSRIs ) with noradrenaline reuptake inhibitors ( NARIs ) . AIMS To test the hypothesis that patients homozygous for the long ( insertion ) polymorphism of the serotonin transporter ( 5-HTTLPR ) have an increased response to SSRI antidepressants but not to NARI antidepressants . METHOD In an individually r and omised , parallel-group controlled trial , people meeting criteria for a depressive episode who were referred by their general practitioner were r and omised to receive either citalopram ( an SSRI ) or reboxetine ( an NARI ) . R and omisation was by means of a remote automated system accessed by telephone . The main outcome was depressive symptoms , measured by Beck Depression Inventory ( BDI ) total score 6 weeks after r and omisation . The trial was registered with the International St and ard R and omised Controlled Trials Number registry ( IS RCT N31345163 ) . RESULTS Altogether 298 participants were r and omised to receive citalopram and 303 were r and omised to reboxetine . At 6 weeks follow-up , complete data were available for 258 participants taking citalopram and 262 taking reboxetine . We found no evidence to support an influence of 5-HTTLPR on outcome following antidepressant treatment . The interaction term for BDI score at 6 weeks was 0.50 ( 95 % CI -2.04 to 3.03 , P = 0.70 ) , which indicated that responses to the SSRI and NARI were similar irrespective of 5-HTTLPR genotype . CONCLUSIONS It is unlikely that the 5-HTTLPR polymorphism alone will be clinical ly useful in predicting response to antidepressants in people with depression BACKGROUND Concerns about possible risks of switching to mania associated with antidepressants continue to interfere with the establishment of an optimal treatment paradigm for bipolar depression . METHOD The response of 44 patients meeting DSM-IV criteria for bipolar disorder to naturalistic treatment was assessed for at least 6 weeks using the Montgomery-Asberg Depression Rating Scale and the Bech-Rafaelson Mania Rating Scale . Patients who experienced a manic or hypomanic switch were compared with those who did not on several variables including age , sex , diagnosis ( DSM-IV bipolar I vs. bipolar II ) , number of previous manic episodes , type of antidepressant therapy used ( electroconvulsive therapy vs. antidepressant drugs and , more particularly , selective serotonin reuptake inhibitors [ SSRIs ] ) , use and type of mood stabilizers ( lithium vs. anticonvulsants ) , and temperament of the patient , assessed during a normothymic period using the hyperthymia component of the Semi-structured Affective Temperament Interview . RESULTS Switches to hypomania or mania occurred in 27 % of all patients ( N = 12 ) ( and in 24 % of the subgroup of patients treated with SSRIs [ 8/33 ] ) ; 16 % ( N = 7 ) experienced manic episodes , and 11 % ( N = 5 ) experienced hypomanic episodes . Sex , age , diagnosis ( bipolar I vs. bipolar II ) , and additional treatment did not affect the risk of switching . The incidence of mood switches seemed not to differ between patients receiving an anticonvulsant and those receiving no mood stabilizer . In contrast , mood switches were less frequent in patients receiving lithium ( 15 % , 4/26 ) than in patients not treated with lithium ( 44 % , 8/18 ; p = .04 ) . The number of previous manic episodes did not affect the probability of switching , whereas a high score on the hyperthymia component of the Semistructured Affective Temperament Interview was associated with a greater risk of switching ( p = .008 ) . CONCLUSION The frequency of mood switching associated with acute antidepressant therapy may be reduced by lithium treatment . Particular attention should be paid to patients with a hyperthymic temperament , who have a greater risk of mood switches 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 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 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 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 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 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 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 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 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 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 Both noradrenergic and serotonergic systems have been implicated in the pathophysiology of panic disorder . The advent of selective serotonin ( 5-HT ) reuptake inhibitors ( SSRIs ) ( e.g. citalopram ) and , more recently , selective noradrenergic ( NA ) reuptake inhibitors ( NRIs ) ( e.g. reboxetine ) has provided potentially important avenues of treatment for the disorder . To date , the comparative efficacy of selective NA and 5-HT reuptake inhibitors for panic disorder remains unresolved . Nineteen patients with panic disorder were r and omized in a single-blind , cross-over design to either citalopram or reboxetine for 8 weeks and after a 2-week washout were switched to the other study drug . At week 18 , seven of 13 patients ( 54 % ) in the intent-to-treat sample responded to reboxetine and nine of 11 patients responded to citalopram ( 82 % ) . Both citalopram and reboxetine led to significant improvements in panic attack severity with no apparent between-drug differences in efficacy . However , citalopram demonstrated superior efficacy in treating depressive symptoms . One non-responder to citalopram responded to reboxetine and three non-responders to reboxetine responded to citalopram . Although SSRIs are viewed as a first-line treatment for panic disorder , these results suggest that a NA agent such as reboxetine may also have a role . These data also suggest an advantage for citalopram in treating comorbid depressive symptoms , although some patients may respond preferentially to an SSRI and other patients to an NRI OBJECTIVE 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 BACKGROUND Generalized anxiety disorder  ( GAD ) is a common and serious disease with a lifetime prevalence of 4.3 % to 5.9 % . It is underdiagnosed in primary care . METHODS Recommendations on the treatment of GAD are given on the basis of all available findings from pertinent r and omized trials , retrieved by a selective search of the literature . RESULTS Among psychotherapeutic techniques , various kinds of cognitive behavioral therapy ( CBT ) have been found useful in controlled trials . The drugs of first choice include selective serotonin reuptake inhibitors ( SSRIs ) , serotonin-norepinephine reuptake inhibitors ( SNRIs ) , and the calcium-channel modulator pregabalin . Tricyclic antidepressants are also effective but have more adverse effects than SSRIs . Although benzodiazepines are effective anxiolytic agents for short-term use , they should not be given over the long term because of the danger of addiction . Buspirone , an azapirone , was found to be effective in a small number of trials , but the findings across trials are inconsistent . The response rate of GAD to CBT in published studies lies between 47 % and 75 % , while its response rate to drug treatment lies between 44 % and 81 % . CONCLUSION The treatment of GAD with CBT and drugs is evidence -based and has a good chance of improving the manifestations of the disorder 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 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 CONTEXT Many youth with depression do not respond to initial treatment with selective serotonin reuptake inhibitors ( SSRIs ) , and this is associated with higher costs . More effective treatment for these youth may be cost-effective . OBJECTIVE To evaluate the incremental cost-effectiveness over 24 weeks of combined cognitive behavior therapy plus switch to a different antidepressant medication vs medication switch only in adolescents who continued to have depression despite adequate initial treatment with an SSRI . DESIGN R and omized controlled trial . SETTING Six US academic and community clinics . PATIENTS Three hundred thirty-four patients aged 12 to 18 years with SSRI-resistant depression . INTERVENTION Participants were r and omly assigned to ( 1 ) switch to a different medication only or ( 2 ) switch to a different medication plus cognitive behavior therapy . MAIN OUTCOME MEASURES Clinical outcomes were depression-free days ( DFDs ) , depression-improvement days ( DIDs ) , and quality -adjusted life-years based on DFDs ( DFD-QALYs ) . Costs of intervention , non protocol services , and families were included . RESULTS Combined treatment achieved 8.3 additional DFDs ( P = .03 ) , 0.020 more DFD-QALYs ( P = .03 ) , and 11.0 more DIDs ( P = .04 ) . Combined therapy cost $ 1633 more ( P = .01 ) . Cost per DFD was $ 188 ( incremental cost-effectiveness ratio [ ICER ] = $ 188 ; 95 % confidence interval [ CI ] , -$22 to $ 1613 ) , $ 142 per DID ( ICER = $ 142 ; 95 % CI , -$14 to $ 2529 ) , and $ 78,948 per DFD-QALY ( ICER = $ 78,948 ; 95 % CI , -$9261 to $ 677,448 ) . Cost-effectiveness acceptability curve analyses suggest a 61 % probability that combined treatment is more cost-effective at a willingness to pay $ 100,000 per QALY . Combined treatment had a higher net benefit for subgroups of youth without a history of abuse , with lower levels of hopelessness , and with comorbid conditions . CONCLUSIONS For youth with SSRI-resistant depression , combined treatment decreases the number of days with depression and is more costly . Depending on a decision maker 's willingness to pay , combined therapy may be cost-effective , particularly for some subgroups . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00018902 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 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 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 Mr. B , age 20 , has taken a semester leave from college because of gradually worsening depressed mood . Over the past 2 months he has lost interest in jogging and playing piano -- which he usually enjoys . He reports reduced libido , middle insomnia , loss of appetite , feeling as if his head is " full of cotton , " trouble concentrating , and waking in the morning with a sense of dread . His anxiety dissipates during the day , but he continues to feel sad and sometimes weepy , which is unusual for him . [ ILLUSTRATION OMITTED ] Mr. B reports feeling hopeless at times and has had vague thoughts about life being " not worth it if I continue to feel like this " but denies specific suicide plans . Your initial impression is that Mr. B is in the midst of a major depressive episode and that a selective serotonin reuptake inhibitor ( SSRI ) is indicated . As you finish taking his history , you run through your mind the pros and cons of the recommendation you will make to him . Do SSRIs raise or lower the risk for suicidal behavior in young adults such as Mr. B ? The answer is complicated and goes beyond an " either/or " question , as the FDA acknowledged in May 2007 when it : * extended the black-box warning of increased suicidality risk with antidepressants to cover adults age 18 to 24 as well as children and adolescents * included language in the warning about the benefits of treating depression and the suicide risk associated with untreated depression , given concerns about declining antidepressant prescriptions and rising suicides among youth . ( 1 ) To help you make informed decisions when treating depression in adults , this article review s the studies leading up to and following the FDA 's meta- analysis of antidepressant trial data in patients age 18 and older . Our goal is to provide a framework for clinical treatment of adults age 18 to 24 and those age [ greater than or equal to]25 . First hints of suicidality  SSRIs revolutionized depression treatment . From 1985 to 1999 , annual U.S. antidepressant prescriptions quadrupled , with SSRIs accounting for 70 % of the increase ( see " Antidepressants and suicide risk , 1985 to 2007 , " pages 36 - 37 ) . At the same time , the age-adjusted suicide rate : * dropped 22.5 % for women ( who account for twice as many antidepressant prescriptions as men ) * dropped 12.8 % for men ( without change in the rank order of suicide methods ) . ( 2 ) For many patients , increased antidepressant use improved treatment of major depressive and other antidepressant-responsive disorders . In 1990 , however , case reports suggested SSRIs might cause suicidal thoughts or behavior . ( 3 ) Hypothesized mechanisms included increased aggression ( 4 ) and akathisia . ( 5 ) An FDA review found no proof , and a meta- analysis of data from 17 double-blind , r and omized , controlled trials found no association between fluoxetine and suicidal thoughts or behavior . ( 6 ) The debate rekindled in June 2003 when the British Committee on Safety of Medicines warned against using paroxetine or venlafaxine in children . After conducting its own meta- analysis , the FDA in 2004 ordered a black-box warning about suicidality and the use of  antidepressants in children and adolescents ( Box ) . ( 7 ) After the pediatric ' black box . '  Antidepressant prescriptions for  children and adolescents declined in the years 2003 to 2004 , as did diagnosis of pediatric depression . ( 8 - 10 ) Antidepressant prescribing also showed signs of shifting from general practitioners to psychiatrists . ( 8) At the same time , the suicide rate  among youth age 60 ,  SSRI prescriptions continued to rise and suicide rates fell , ( 9 ) a pattern of change consistent with antidepressants protecting against suicide . An independent meta- analysis by Bridge et al ( 12 ) examined the pediatric trial data used in the FDA meta- analysis plus 7 additional studies . BACKGROUND 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 To determine the relative cost-effectiveness of three classes of antidepressants : tricyclic antidepressants ( TCAs ) , selective serotonin reuptake inhibitors ( SSRIs ) , and the modified TCA lofepramine , as first choice treatments for depression in primary care . DESIGN Open , pragmatic , controlled trial with three r and omised arms and one preference arm . Patients were followed up for 12 months . SETTING UK primary care : 73 practice s in urban and rural areas in Engl and . PARTICIPANTS Patients with a new episode of depressive illness according to GP diagnosis . INTERVENTIONS Patients were r and omised to receive a TCA ( amitriptyline , dothiepin or imipramine ) , an SSRI ( fluoxetine , sertraline or paroxetine ) or lofepramine . Patients or GPs were able to choose an alternative treatment if preferred . MAIN OUTCOME MEASURES At baseline the Clinical Interview Schedule , Revised ( CIS-R PROQSY computerised version ) was administered to establish symptom profiles . Outcome measures over the 12-month follow-up included the Hospital Anxiety and Depression Scale self-rating of depression ( HAD-D ) , CIS-R , EuroQol ( EQ-5D ) for quality of life , Short Form ( SF-36 ) for generic health status , and patient and practice records of use of health and social services . The primary effectiveness outcome was the number of depression-free weeks ( HAD-D less than 8 , with interpolation of intervening values ) and the primary cost outcome total direct NHS costs . Quality -adjusted life-years ( QALYs ) were used as the outcome measure in a secondary analysis . Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were computed . Estimates were bootstrapped with 5000 replications . RESULTS In total , 327 patients were r and omised . Follow-up rates were 68 % at 3 months and 52 % at 1 year . Linear regression analysis revealed no significant differences between groups in number of depression-free weeks when adjusted for baseline HAD-D. A higher proportion of patients r and omised to TCAs entered the preference arm than those allocated to the other choices . Switching to another class of antidepressant in the first few weeks of treatment occurred significantly more often in the lofepramine arm and less in the preference arm . There were no significant differences between arms in mean cost per depression-free week . For values placed on an additional QALY of over 5000 pounds , treatment with SSRIs was likely to be the most cost-effective strategy .  TCAs were the least likely to be cost-effective as first choice of antidepressant for most values of a depression-free week or QALY respectively , but these differences were relatively modest . CONCLUSIONS When comparing the different treatment options , no significant differences were found in outcomes or costs within the sample , but when outcomes and costs were analysed together , the result ing cost-effectiveness acceptability curves suggested that SSRIs were likely to be the most cost-effective option , although the probability of this did not rise above 0.6 . Choosing lofepramine is likely to lead to a greater proportion of patients switching treatment in the first few weeks . Further research is still needed on the management of depressive illness in primary care . This should address areas such as the optimum severity threshold at which medication should be used ; the feasibility and effectiveness of adopting structured depression management programmes in the UK context ; the importance of factors such as physical co-morbidity and recent life events in GPs ' prescribing decisions ; alternative ways of collecting data ; and the factors that give rise to many patients being reluctant to accept medication and discontinue treatment early 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 The cost-effectiveness of tricyclic antidepressants ( TCAs ) and selective serotonin reuptake inhibitors ( SSRIs ) has not been compared in a prospect i ve study in primary care . AIMS To determine the relative cost-effectiveness of TCAs , SSRIs and lofepramine in UK primary care . METHOD An open-label , three-arm r and omised trial with a preference arm . Practitioners referred 327 patients with incident depression . RESULTS No significant differences were found in effectiveness or cost-effectiveness . The numbers of depression-free weeks over 12 months ( on the Hospital Anxiety and Depression Scale ) were 25.3 ( 95 % CI 21.3 - 29.0 ) for TCAs , 28.3 ( 95 % CI 24.3 - 32.2 ) for SSRIs and 24.6 ( 95 % CI 20.6 - 28.9 ) for lofepramine .  Mean health service costs per patient were pound 762 ( 95 % CI 553 - 1059 ) for TCAs , pound 875 ( 95 % CI 675 - 1355 ) for SSRIs and pound 867 ( 95 % CI 634 - 1521 ) for lofepramine .  Cost-effectiveness acceptability curves suggested SSRIs were most cost-effective ( with a probability of up to 0.6 ) . CONCLUSIONS The findings support a policy of recommending SSRIs as first-choice antidepressants in primary care 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 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 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
The number of previous treatments with antidepressants was negatively correlated with treatment outcome .
After a first SSRI , any switch within or between classes of antidepressants appears legitimate ( second SSRI , novel dual-acting antidepressants , selective norepinephrine or nor-adrenergic/dopaminergic agents , or tricyclic anti-depressant or mianserin ) .
No unequivocal evidence is available to prove an advantage of a between-class switch .
OBJECTIVE Selective serotonin reuptake inhibitors ( SSRIs ) are frequently used as a first antidepressant for major depressive disorder but have response rates of 50 % to 60 % in daily practice .
For patients with insufficient response to SSRIs , switching is often applied .
This article aims to systematic ally review the evidence for switching pharmacotherapy after a first SSRI .