Examining the efficacy of adjunctive aripiprazole in major depressive disorder: a pooled analysis of 2 studies. Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of Physicians Efficacy of risperidone augmentation to antidepressants in the management of suicidality in major depressive disorder: a randomized, double-blind, placebo-controlled pilot study. Comparing augmentation with non-antidepressants over sticking to antidepressants after treatment failure in depression: a naturalistic study. The prevalence of major depressive and bipolar disorders in Hungary. Results from a national epidemiologic survey. Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. Exercise and Pharmacotherapy in Patients With Major Depression: One-Year Follow-Up of the SMILE Study Clinical response augments NK cell activity independent of treatment modality: a randomized double-blind placebo controlled antidepressant trial. Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia. Lisdexamfetamine dimesylate augmentation for adults with major depressive disorder and inadequate response to antidepressant monotherapy: Results from 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. TREAD: TReatment with Exercise Augmentation for Depression: study rationale and design Exercise and Pharmacotherapy in the Treatment of Major Depressive Disorder Risperidone for Treatment-Refractory Major Depressive Disorder Adjunctive Lanicemine (AZD6765) in Patients with Major Depressive Disorder and History of Inadequate Response to Antidepressants: A Randomized, Placebo-Controlled Study Efficacy and Tolerability of Reboxetine Compared with Citalopram: A Double-blind Study in Patients with Major Depressive Disorder Effect of cognitive therapy with antidepressant medications vs antidepressants alone on the rate of recovery in major depressive disorder: a randomized clinical trial. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery. A randomized double-blind placebo-controlled trial of treatment as usual plus exogenous slow-release melatonin (6 mg) or placebo for sleep disturbance and depressed mood Comorbid Depression, Chronic Pain, and Disability in Primary Care Antidepressant Efficacy of Adjunctive Aerobic Activity and Associated Biomarkers in Major Depression: A 4-Week, Randomized, Single-Blind, Controlled Clinical Trial Residual symptoms after remission of major depressive disorder with fluoxetine and risk of relapse
BACKGROUND Patients with major depressive disorder ( MDD ) who fail to achieve complete remission with antidepressant therapy  may benefit from augmentation therapy with an atypical antipsychotic . METHOD A pooled analysis was performed on 2 identical 14-week studies ( 8-week prospect i ve antidepressant therapy treatment phase followed by 6-week r and omized double-blind phase ) evaluating the efficacy of adjunctive aripiprazole ( 2 - 20 mg/day ) in DSM-IV-TR-defined MDD patients with an inadequate response to antidepressant therapy . Primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score from end of the prospect i ve phase ( week 8) to end of r and omized phase ( week 14 , last observation carried forward ) . Subgroup analyses were performed . The key secondary endpoint was mean change in Sheehan Disability Scale ( SDS ) mean score . RESULTS At endpoint , mean change in MADRS total score was significantly greater with adjunctive aripiprazole ( -8.7 ) than with adjunctive placebo ( -5.7 ; p < .001 ) . Except for a differential treatment-by-sex interaction , change in MADRS total scores were consistently greater with adjunctive aripiprazole than with adjunctive placebo , regardless of race , age , episode duration , prior antidepressant therapy response , number of historical treatment failures , severity of depressive symptoms , and antidepressant . At endpoint , MADRS remission rates were significantly greater with adjunctive aripiprazole than with placebo ( 25.7 % vs. 15.4 % ; p < .001 ) . Adjunctive aripiprazole also demonstrated significantly greater improvements in mean change from baseline in SDS total score than adjunctive placebo ( -1.2 vs. -0.6 ; p = .001 ) . CONCLUSION Augmentation of antidepressant therapy with the atypical antipsychotic aripiprazole result ed in significant efficacy benefits across a range of subgroups of patients with MDD . Further study of a treatment-by-sex interaction is needed . TRIAL REGISTRATION www . clinical trials.gov Identifiers : NCT00095823 and NCT00095758 Depressive disorders are a major health care issue and one of the foremost causes of disability in adults around the world , result ing in significant costs to society and health care systems ( 1 ) . The estimated economic burden associated with depression was $ 83.1 billion in 2000 and is probably higher today ( 2 ) . Depressive disorders include major depressive disorder ( MDD ) ; dysthymia ; and subsyndromal depression , including minor depression . Major depressive disorder is the most prevalent depressive disorder , with an estimated lifetime prevalence of 16 % in the United States ( 3 ) . An average of 8 million ambulatory care visits per year result in a primary diagnosis of MDD ( 4 ) . The American Psychiatric Association ( 5 ) defines MDD as depressed mood or loss of pleasure or interest along with other symptoms , including significant change in weight or appetite , insomnia or hypersomnia , psychomotor agitation or retardation nearly every day , fatigue or loss of energy , feelings of worthlessness or excessive or inappropriate guilt , indecisiveness or decreased ability to concentrate , and recurrent thoughts of death or suicide , that last for at least 2 weeks and affect normal functioning . Dysthymia is less severe , but symptoms last for 2 or more years . In contrast , subsyndromal depression is associated with less severe symptoms of depression that do not qualify for MDD or dysthymia diagnoses . The treatment of depression can be characterized by 3 phases ( Figure 1 ) : acute ( 6 to 12 weeks ) , continuation ( 4 to 9 months ) , and maintenance ( 1 year ) ( 7 ) . Relapse is defined as the return of depressive symptoms during the acute or continuation phases and is therefore considered part of the same depressive episode , whereas recurrence is defined as the return of depressive symptoms during the maintenance phase and is considered a new , distinct episode . Response to treatment ( typically defined as 50 % reduction in measured severity ) can be quantified using various tools , such as the Patient Health Question naire-9 ( PHQ-9 ) ( 7 ) or the Hamilton Depression Rating Scale ( HAM-D ) ( 8) . Figure 1 . Phases of treatment of major depression . Adapted from reference 6 . TX = treatment . Various treatment approaches can be used to manage MDD , such as psychotherapy , complementary and alternative medicine ( CAM ) , exercise , and pharmacotherapy . The psychological interventions used to treat depression include acceptance and commitment therapy , cognitive therapy , cognitive behavioral therapy ( CBT ) , interpersonal therapy , and psychodynamic therapies ( Table 1 ) . The CAM treatments include acupuncture , meditation , -3 fatty acids , S-adenosyl-l-methionine ( SAMe ) , St. John 's wort , and yoga . Exercise includes a broad range of activities that can be done for varying duration s , in classes , individually , or in informal groups . For pharmacologic therapy , the scope of this guideline is limited to second-generation antidepressants ( SGAs ) ( selective serotonin reuptake inhibitors , serotonin norepinephrine reuptake inhibitors , and selective serotonin norepinephrine reuptake inhibitors ) . First-generation antidepressants ( tricyclic antidepressants and monoamine oxidase inhibitors ) are very rarely used because SGAs have lower toxicity in overdose than first-generation antidepressants and similar efficacy . Table 1 . Common Psychological Interventions to Treat Depression Guideline Focus and Target Population The purpose of this guideline from the American College of Physicians ( ACP ) is to summarize and grade the evidence on the comparative effectiveness and safety of nonpharmacologic treatments and SGAs ( including serotonin reuptake inhibitors , serotonin norepinephrine reuptake inhibitors , bupropion , mirtazapine , nefazodone , and trazodone ) , alone or in combination , for MDD . The target audience for this guideline includes all clinicians , and the target patient population includes all adults with MDD . These recommendations are based on a background evidence article ( 9 ) and a systematic evidence review sponsored by the Agency for Healthcare Research and Quality ( AHRQ ) ( 6 ) . Methods Systematic Review of the Evidence The systematic evidence review was conducted by the AHRQ 's RTI InternationalUniversity of North Carolina at Chapel Hill Evidence -based Practice Center ( 6 ) . Additional method ological details can be found in the Appendix ) , accompanying background evidence article ( 9 ) , and full report ( 6 ) . Review ers search ed several data bases for studies published in English , German , or Italian from 1 January 1990 through September 2015 . Studies on efficacy were limited to r and omized , controlled trials and systematic review s and meta-analyses , although evidence on harms included observational studies . Review ers combined data when possible using meta- analysis and assessed the risk of bias and quality of studies according to established methods . The study population included adult out patients ( aged 18 years ) with MDD during either an initial or a second treatment attempt who did not remit after an initial adequate trial with an SGA . The review evaluated the following classes of interventions : depression-focused psychotherapy , CAM , exercise , and SGAs . Outcomes assessed included benefits in response ( often defined as 50 % improvement in HAM-D scores ) , remission ( often defined as a HAM-D score 7 ) , speed of response , speed of remission , relapse , quality of life , functional capacity ( as assessed by various scales ) , reduction of suicidality , or reduction of hospitalization . Harms assessed included overall adverse events , withdrawals because of adverse events , serious adverse events , and specific adverse events . Quality of life , functional status , suicidality , and hospitalizations were rarely reported . Grading the Evidence and Developing Recommendations This guideline was developed by the ACP Clinical Guidelines Committee according to the ACP guideline development process , which has been described ( 10 ) . The Clinical Guidelines Committee used the evidence tables in the accompanying systematic review and full report ( 9 ) when reporting the evidence and grade d the recommendations using ACP 's guideline grading system ( Table 2 ) . Table 2 . The American College of Physicians ' Guideline Grading System * Peer Review The AHRQ evidence review was sent to invited peer review ers and posted on the AHRQ Web site for public comments . The guideline was peer- review ed through the journal and was posted online for comments from ACP Governors and Regents . Comparative Benefits of Pharmacologic Versus Nonpharmacologic Treatment Options for Initial Management Refer to Appendix Table 1 and the accompanying systematic review ( 9 ) for additional details of the evidence . Appendix Table 1 . First-Line Treatment for MDD : SGAs Versus Nonpharmacologic Therapies * SGA Versus Psychological Interventions SGA Versus CBT Monotherapy . Moderate- quality evidence from 5 trials ( 1115 ) showed no difference in response when comparing SGAs ( fluoxetine , fluvoxamine , paroxetine , or sertraline ) with CBT in patients with MDD after 8 to 52 weeks of treatment . Low- quality evidence from 3 trials ( 11 , 14 , 15 ) showed no difference between remission rates ( fluoxetine , fluvoxamine , and paroxetine ) and functional capacity ( 14 ) ( fluvoxamine and paroxetine ) for SGAs compared with CBT . Combination Therapy . Low- quality evidence from 2 trials ( 14 , 16 ) showed no difference in response or remission when comparing monotherapy using SGAs ( escitalopram , fluvoxamine , or paroxetine ) with combination therapy using SGAs plus CBT ( problem-solving therapy or telephone-based CBT ) in patients with MDD after 12 to 52 weeks of treatment . Low- quality evidence from 2 trials ( 14 , 16 ) assessed function , and 1 trial showed that patients who received the combination therapy reported more improvement on 3 of 5 work-functioning measures than those who received SGA monotherapy , although clinical ly important differences on these measures are uncertain . SGA Versus Interpersonal Therapy Monotherapy . Low- quality evidence showed no difference in response ( 1 trial ; escitalopram ) ( 17 ) or remission ( 2 trials ; citalopram , escitalopram , or sertraline ) ( 17 , 18 ) for SGAs compared with interpersonal therapy for patients with MDD after 12 weeks of treatment . Combination Therapy . Low- quality evidence from 1 trial ( 19 ) showed increased remission for SGA monotherapy compared with SGA combined with interpersonal therapy ( with nefazodone ) in patients with MDD after 12 weeks of treatment . SGA Versus Psychodynamic Therapies Monotherapy . Low- quality evidence from 1 trial ( 20 ) showed no difference in remission for fluoxetine compared with psychodynamic monotherapy in patients with MDD after 16 weeks of treatment . Low- quality evidence from 2 trials ( 20 , 21 ) showed few differences in functional capacity between the treatments . Combination Therapy . Low- quality evidence from 1 trial ( 21 ) showed no difference in functional capacity for SGA monotherapy compared with SGA plus psychodynamic combination therapy . SGA Versus CAM Interventions SGA Versus Acupuncture Monotherapy . Low- quality evidence from 2 trials ( 22 , 23 ) showed no difference in treatment response when comparing fluoxetine with acupuncture monotherapy for patients with MDD after 6 weeks of treatment . Combination Therapy . Low- quality evidence from 2 trials ( 24 , 25 ) showed that combination therapy of SGAs with acupuncture improved treatment response compared with monotherapy with SGAs ( fluoxetine or paroxetine ) in patients with MDD after 6 weeks of treatment . However , low- quality evidence from 1 trial ( 24 ) showed no difference in remission when comparing paroxetine monotherapy with paroxetine plus acupuncture combination therapy . SGA Versus -3 Fatty Acids Monotherapy . Low- quality evidence from network meta- analysis showed that SGAs ( fluoxetine ) were associated with a greater response than -3 fatty acids in patients with MDD .  SGA Versus SAMe Monotherapy . Low- quality evidence from network meta- analysis showed no difference in response between treatment with escitalopram OBJECTIVE Major depressive disorder ( MDD ) is a severe mental illness with high risk of suicidality . Antidepressant treatment alone is not sufficient for the acute management of risk-taking symptoms of depression . This pilot study was design ed to investigate the efficacy of risperidone augmentation to antidepressants in the acute management of suicidality and other core symptoms in MDD with suicidality . METHOD Twenty-four adult men and women diagnosed with MDD ( DSM-IV ) , having a depressive episode with suicidality despite taking an antidepressant , were enrolled in an 8-week double-blind , placebo-controlled study . Subjects were r and omly assigned to receive risperidone ( 0.25 - 2 mg/day ) or placebo while continuing on their antidepressant therapy .  Clinical efficacy in suicidality , depressive symptoms , and impulsivity were assessed after treatment with study drugs for 4 days , weekly for 4 weeks , then every other week for 4 weeks . Adverse events were also recorded at each visit . The study was conducted from June 2004 to April 2007 . RESULTS Risperidone significantly reduced suicidal ideations in MDD patients , and the overall effect of risperidone appeared to be superior to placebo . The effect of risperidone was rapid , with onset at 2 weeks ' treatment , and was sustained along the course of 8 weeks ' treatment . Furthermore , risperidone demonstrated superiority to placebo in improving other symptoms related to suicidality and having better trial completion rate , and the low dose risperidone was well tolerated by subjects in this study . CONCLUSION Data from this pilot study suggest that risperidone is beneficial as an augmenting treatment in MDD patients who have developed high-risk suicidal ideation during a depressive episode . The antisuicidality effect of risperidone is especially valuable in the acute management of severe depressive symptoms . Although the pilot study is limited by small sample size , the promising results warrant further larger scale investigation in the efficacy of atypical antipsychotics in the treatment of severe depression with suicidality . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00167154 INTRODUCTION Non-response to an antidepressant monotherapy in unipolar depression is quite common . Therefore strategies for subsequent treatment steps are necessary . However , there is a lack of direct comparisons of these different strategies . In this naturalistic study we compared the outcome to different strategies after failure of the primary antidepressant treatment . METHODS Failure of primary antidepressant monotherapy occurred in 135 patients . 98 of these patients have been administered 4 treatment strategies of the physicians ' choice : lithium augmentation ( Li-Augm ) , switching to another antidepressant ( AD-Switch ) , combination of 2 antidepressants ( AD-Comb ) or augmentation with second generation antipsychotic ( SGA-Augm ) . Primary outcome measure was the 17-item Hamilton rating scale for depression ( HRSD ) . RESULTS Patients who received Li-Augm or augmentation with SGAs showed significantly greater improvement in HRSD and BDI compared to patients with antidepressant switch or antidepressant combination . Remission rates for Li-Augm and SGA-Augm were 89.3 % and 86.2 % compared to 40.7 % for AD-Switch and 42.9 % for AD-Comb . DISCUSSION Changing to another pharmacological class ( Li-Augm or augmentation with SGAs ) showed better treatment results than sticking to the class of antidepressants ( AD-Switch and AD-Comb ) after primary failure in response to antidepressant monotherapy in unipolar depression . The lack of r and omization and absence of a non-response definition are design flaws . Controlled studies are required to confirm the findings of this trial In order to estimate the prevalence of affective disorders in Hungary a sample of the Hungarian adult population ( 18 - 64 years ) selected at r and om was interviewed using the Diagnostic Interview Schedule ( DIS ) which generated DSM-III-R diagnoses . The lifetime rate for Major Depressive Disorder ( MDD ) was 15.1 % , and for Bipolar Disorders ( BD ) 5.1 % . The female-to-male ratio was 2.7 for MDD and nearly equal for BD . The 1-year and 1-month period prevalence rates were 7.1 % and 2.6 % for MDD and 0.9 % and 0.5 % for manic episodes . A higher rate of divorced or separated persons was found among individuals with a lifetime diagnosis of MDD . Besides these , the lifetime diagnosis of BD coexisted with higher rates of the never-married state . The highest hazard rate for the development of BD or MDD was in the range 15 - 19 years but in MDD another peak was also found in the range 45 - 50 years . The first peak was characteristic of the recurrent , and the other one of the single form of MDD . Insomnia , loss of energy , decreased interest , concentration problems were the most common symptoms during the depressive episode , independent of polarity . Higher rates of lifetime diagnosis of dysthymia and all kinds of anxiety disorder were revealed among persons with MDD . BD was associated with GAD ( Generalized Anxiety Disorder ) , and panic disorder more often than chance INTRODUCTION Effective management of  major depressive disorder ( MDD ) continues to be a challenging task for psychiatrists and primary care physicians . This trial evaluated the efficacy and safety of adjunctive aripiprazole versus antidepressant monotherapy in patients with MDD and independently replicated the positive findings of two similar trials . METHODS Patients ( N=1,147 ) with MDD experiencing a major depressive episode and a history of inadequate response to antidepressant monotherapy were enrolled ( week 0 ) ; 827 received single-blind adjunctive placebo plus open-label antidepressant ( escitalopram , fluoxetine , paroxetine controlled release , sertraline , or venlafaxine extended release ) for 8 weeks to confirm inadequate response to antidepressants ; 349 patients with inadequate response were r and omized ( 1:1 ) to double-blind , adjunctive placebo ( n=172 ) or adjunctive aripiprazole ( n=177 ; 2 - 20 mg/day ) . Primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale ( MADRS ) Total score from baseline ( week 8) to endpoint ( week 14 ) . RESULTS Clinical ly significant improvements in depressive symptoms as assessed by decreases in the MADRS Total score were greater with adjunctive aripiprazole ( -10.1 ) than placebo ( -6.4 ; P<.001 ) . Remission rates were greater for adjunctive aripiprazole than for adjunctive placebo ( week 14 , 36.8 % vs 18.9 % ; P<.001 ) . Completion rates with adjunctive aripiprazole and placebo were high ( 83 % vs. 87 % ) and discontinuations due to adverse events were low ( 6.2 % vs 1.7 % ) . CONCLUSION For some patients with MDD who do not obtain adequate symptom relief with antidepressant monotherapy , adjunctive therapies can significantly improve depressive symptoms . As reported , adjunctive aripiprazole was associated with a two-fold higher remission rate than adjunctive placebo . This , and previous studies , have shown that discontinuations due to adverse events were low and completion rates were high , and has indicated that both antidepressant and aripiprazole in combination were relatively well-tolerated and safe . This is the third consecutive clinical trial , in the absence of a failed trial , to demonstrate that aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for patients with MDD who do not respond adequately to st and ard antidepressant monotherapy ( Clinical Trials.gov study NCT00105196 ) Objective : To examine a 1-year follow-up of a 4-month , controlled clinical trial of exercise and antidepressant medication in patients with major depressive disorder ( MDD ) . Methods : In the original study , 202 sedentary adults with MDD were r and omized to : a ) supervised exercise ; b ) home-based exercise ; c ) sertraline ; or d ) placebo pill . We examined two outcomes measured at 1-year follow-up ( i.e. , 16 months post r and omization ) : 1 ) continuous Hamilton Depression Rating Scale score ; and 2 ) MDD status ( depressed ; partial remission ; full remission ) in 172 available participants ( 85 % of the original cohort ) . Regression analyses were performed to examine the effects of treatment group assignment , as well as follow-up antidepressant medication use and self-reported exercise ( Godin Leisure-Time Exercise Question naire ) , on the two outcomes . Results : In the original study , patients receiving exercise achieved similar benefits compared with those receiving sertraline . At the time of the 1-year follow-up , rates of MDD remission increased from 46 % at post treatment to 66 % for participants available for follow-up . Neither initial treatment group assignment nor antidepressant medication use during the follow-up period were significant predictors of MDD remission at 1 year . However , regular exercise during the follow-up period predicted both Hamilton Depression Rating Scale scores and MDD diagnosis at 1 year . This relationship was curvilinear , with the association concentrated between 0 minute and 180 minutes of weekly exercise . Conclusion : The effects of aerobic exercise on MDD remission seem to be similar to sertraline after 4 months of treatment ; exercise during the follow-up period seems to extend the short-term benefits of exercise and may augment the benefits of antidepressant use . Trial Registration : clinical trials.gov Identifier : NCT00331305 . MDD = major depressive disorder ; HAM-D = Hamilton Depression Rating Scale ; SCID = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition Axis I Disorders ; PSSS = Perceived Social Support Scale BACKGROUND Major depressive disorder ( MDD ) has been associated with alterations in immune function . Suppression of natural killer ( NK ) cell activity ( NKCA ) reliably characterizes immunological alterations observed in MDD . Antidepressant pharmacotherapy has been associated with modulation of NKCA . Previous investigations into antidepressant modulation of NKCA have not employed r and omized double-blind placebo controlled design s. Thus , it is unknown whether treatment-associated changes in immune function are due to drug , placebo , or spontaneous remission effects . The present investigation examined the effect of antidepressant treatment on NKCA utilizing a r and omized double-blind placebo controlled experimental design . METHOD Patients ( N = 16 ) met DSM-IV criteria for MDD and were r and omly assigned to drug ( N = 8 ; citalopram , 20 mg/day ) or placebo ( N = 8) under double-blind conditions . Severity and pattern of depressive symptoms were assessed by the Hamilton Depression Rating Scale ( HDRS ) . NK cell function was measured using a st and ard chromium-release assay and NK cell number assessed by flow cytometry . HDRS scores , NK cell function , and NK cell numbers were collected at 0 , 1 , 2 and 4 weeks of treatment . RESULTS Clinical response was associated with augmented NKCA independent of treatment condition . Failure to respond to treatment result ed in significantly reduced NKCA over treatment interval . CONCLUSIONS The present results suggest that alterations in the depressive syndrome , regardless of therapeutic modality , may be sufficient to modulate NKCA during antidepressant trials and thus may significantly impact on co-morbid health outcomes in MDD STUDY OBJECTIVE Insomnia impacts the course of major depressive disorder ( MDD ) , hinders response to treatment , and increases risk for depressive relapse . This study is an initial evaluation of adding cognitive behavioral therapy for insomnia ( CBTI ) to the antidepressant medication escitalopram ( EsCIT ) in individuals with both disorders . DESIGN AND SETTING A r and omized , controlled , pilot study in a single academic medical center . PARTICIPANTS 30 individuals ( 61 % female , mean age 35 + /- 18 ) with MDD and insomnia . INTERVENTIONS EsCIT and 7 individual therapy sessions of CBTI or CTRL ( quasi-desensitization ) . MEASUREMENTS AND RESULTS Depression was assessed with the HRSD17 and the depression portion of the SCID , administered by raters masked to treatment assignment , at baseline and after 2 , 4 , 6 , 8 , and 12 weeks of treatment . The primary outcome was remission of MDD at study exit , which required both an HRSD17 score < or = 7 and absence of the 2 core symptoms of MDD . Sleep was assessed with the insomnia severity index ( ISI ) , daily sleep diaries , and actigraphy . EsCIT + CBTI result ed in a higher rate of remission of depression ( 61.5 % ) than EsCIT + CTRL ( 33.3 % ) . EsCIT + CBTI was also associated with a greater remission from insomnia ( 50.0 % ) than EsCIT + CTRL ( 7.7 % ) and larger improvement in all diary and actigraphy measures of sleep , except for total sleep time . CONCLUSIONS This pilot study provides evidence that augmenting an antidepressant medication with a brief , symptom focused , cognitive-behavioral therapy for insomnia is promising for individuals with MDD and comorbid insomnia in terms of alleviating both depression and insomnia BACKGROUND The efficacy , safety , and tolerability of lisdexamfetamine dimesylate ( LDX ) augmentation of antidepressant monotherapy in adults with major depressive disorder ( MDD ) from two phase 3 studies are reported . METHODS Across study 1 (  placebo  , n=201 ; LDX , n=201 ) and study 2 ( placebo , n=213 ; LDX , n=211 ) , most participants ( placebo and LDX ) in the safety analysis set were female ( study 1 : 66.2 % and 64.2 % ; study 2 : 67.1 % and 66.8 % ) ; mean±SD ages were 41.8±12.04 with placebo and 42.2±12.32 with LDX in study 1 and 42.6±11.41 with placebo and 42.0±11.63 with LDX in study 2 . Participants ( 18 - 65 y ) had DSM-IV-TR-diagnosed MDD and lead-in baseline Montgomery-Åsberg Depression Rating Scale ( MADRS ) total scores ≥24 . Eight-week antidepressant lead-in phases prospect ively assessed antidepressant response . Then , 8 weeks of r and omized ( 1:1 ) , double-blind treatment with dose-optimized LDX ( 20 - 70 mg ) or placebo in participants exhibiting inadequate antidepressant monotherapy responses ( augmentation baseline MADRS total scores ≥18 and < 50 % MADRS total score reductions from lead-in baseline to augmentation baseline ) was initiated . The primary endpoint was MADRS total score change from augmentation baseline to week 16 . Safety and tolerability measures included the occurrence of treatment-emergent adverse events ( TEAEs ) . RESULTS Least squares mean ( 95 % CI ) treatment differences ( LDX-placebo ) for MADRS total score changes from augmentation baseline to week 16 were not statistically significant in study 1 ( 0.1 [ -1.7 , 2.0 ] , P=0.883 ) or study 2 ( -0.5 [ -2.3 , 1.3 ] , P=0.583 ) . The only TEAE reported by > 5 % of LDX participants at twice the placebo rate in both studies was dry mouth . LIMITATIONS Limitations include the exclusion of participants with psychiatric comorbidities/active medical disorders , the inability to assess specific MDD symptom domains ( eg , anhedonia , cognition ) or subtypes , the use of telephone-based depression assessment s , and the potential influence of placebo response . CONCLUSION Contrary to expectations , LDX augmentation was not superior to placebo in reducing depressive symptoms in individuals with MDD exhibiting inadequate responses to antidepressant monotherapy Major depressive disorder ( MDD ) is a prevalent and disabling condition , and many patients do not respond to available treatments . Deep transcranial magnetic stimulation ( dTMS ) is a new technology allowing non-surgical stimulation of relatively deep brain areas . This is the first double-blind r and omized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD . We recruited 212 MDD out patients , aged 22 - 68 years , who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode . They were r and omly assigned to monotherapy with active or sham dTMS . Twenty sessions of dTMS ( 18 Hz over the prefrontal cortex ) were applied during 4 weeks acutely , and then biweekly for 12 weeks . Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale ( HDRS-21 ) score and response/remission rates at week 5 , respectively . dTMS induced a 6.39 point improvement in HDRS-21 scores , while a 3.28 point improvement was observed in the sham group ( p=0.008 ) , result ing in a 0.76 effect size . Response and remission rates were higher in the dTMS than in the sham group ( response : 38.4 vs. 21.4 % , p=0.013 ; remission : 32.6 vs. 14.6 % , p=0.005 ) . These differences between active and sham treatment were stable during the 12-week maintenance phase . dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred . These results suggest that dTMS constitutes a novel intervention in MDD , which is efficacious and safe in patients not responding to antidepressant medications , and whose effect remains stable over 3 months of maintenance treatment Background Despite recent advancements in the pharmacological treatment of major depressive disorder ( MDD ) , over half of patients who receive treatment with antidepressant medication do not achieve full remission of symptoms . There is evidence that exercise can reduce depressive symptomatology when used as a treatment for MDD . However , no r and omized controlled trials have evaluated exercise as an augmentation strategy for patients with carefully diagnosed MDD who remain symptomatic following an adequate acute phase trial of antidepressant therapy . Purpose TReatment with Exercise Augmentation for Depression  ( TREAD ) is an NIMH-funded , r and omized , controlled trial design ed to assess the relative efficacy of two doses of aerobic exercise to augment selective serotonin reuptake inhibitor ( SSRI ) treatment of MDD . Methods The TREAD study includes 12 weeks of acute phase treatment with a 12-week post-treatment follow-up . In addition to looking at change in depressive symptoms as a primary outcome , it also includes comprehensive assessment of psychosocial function and treatment adherence . Results This paper review s the rationale and design of TREAD and illustrates how we address several key issues in contemporary patient-oriented research on MDD : 1 ) the use of augmentation strategies in the treatment of depressive disorders in general , 2 ) the use of non-pharmacological strategies in the treatment of depressive disorders , 3 ) the considerations of design ing a well-controlled trial using two active treatment groups , and 4 ) the implementation of an adherence program for the use of exercise as a treatment strategy . Conclusions The TREAD study is uniquely design ed to overcome sources of potential bias and threats to internal and external validity that have limited prior research on the mental health effects of exercise . The study is facilitated by the development of a multidisciplinary research team that includes experts in both depression treatment and exercise physiology , as well as other related fields Objective : To assess whether patients receiving aerobic exercise training  performed either at home or in a supervised group setting achieve reductions in depression comparable to st and ard antidepressant medication ( sertraline ) and greater reductions in depression compared to placebo controls . Methods : Between October 2000 and November 2005 , we performed a prospect i ve , r and omized controlled trial ( SMILE study ) with allocation concealment and blinded outcome assessment in a tertiary care teaching hospital . A total of 202 adults ( 153 women ; 49 men ) diagnosed with major depression were assigned r and omly to one of four conditions : supervised exercise in a group setting ; home-based exercise ; antidepressant medication ( sertraline , 50–200 mg daily ) ; or placebo pill for 16 weeks . Patients underwent the structured clinical interview for depression and completed the Hamilton Depression Rating Scale ( HAM-D ) . Results : After 4 months of treatment , 41 % of the participants achieved remission , defined as no longer meeting the criteria for major depressive disorder ( MDD ) and a HAM-D score of < 8 . Patients receiving active treatments tended to have higher remission rates than the placebo controls : supervised exercise = 45 % ; home-based exercise = 40 % ; medication = 47 % ; placebo = 31 % ( p = .057 ) . All treatment groups had lower HAM-D scores after treatment ; scores for the active treatment groups were not significantly different from the placebo group ( p = .23 ) . Conclusions : The efficacy of exercise in patients seems generally comparable with patients receiving antidepressant medication and both tend to be better than the placebo in patients with MDD . Placebo response rates were high , suggesting that a considerable portion of the therapeutic response is determined by patient expectations , ongoing symptom monitoring , attention , and other nonspecific factors . BDI = Beck Depression Inventory ; CI = confidence interval ; HAM-D = Hamilton Depression Rating Scale ; ITT = intention-to-treat ; MDD = major depressive disorder ; SD = st and ard deviation ; SSRIs = selective serotonin reuptake inhibitors ; TSH = thyroid stimulating hormone Context Does augmentation with an atypical antipsychotic improve symptoms in patients with major depression that is suboptimally responsive to antidepressant monotherapy ? Contribution This double-blind r and omized trial found that 6 weeks of treatment with risperidone improved symptoms more than placebo in 274 adults with major depression that was suboptimally responsive to antidepressant monotherapy . Risperidone , compared with placebo , result ed in more remissions ( 25 % vs. 11 % ) , as well as more cases of somnolence ( 5 % vs. 2 % ) and dry mouth ( 5 % vs. 1 % ) . Caution The trial duration was short , and 19 % of risperidone recipients did not complete treatment . Implication Risperidone augmentation may improve symptoms in some patients with suboptimal response to antidepressant monotherapy . The Editors Major depressive disorder is the leading cause of disability worldwide ( 1 ) , affecting nearly 121 million people . It is associated with increased overall mortality ( 2 , 3 ) ; premature cardiovascular-related death ( 4 , 5 ) ; and morbidity , including disability , lost productivity , and decreased wages , compared with individuals without depression ( 6 ) . Selective serotonin reuptake inhibitors ( SSRIs ) and serotoninnorepinephrine reuptake inhibitors are generally considered first-line treatments for depression . Despite a sufficient dose and duration of antidepressant treatment , symptoms do not resolve in 30 % to 40 % of patients with major depressive disorder ( 710 ) . Remission , defined as the virtual absence of depressive symptoms , is important because it is associated with improved patient prognosis and functioning relative to response ( generally defined as 50 % reduction in symptoms ) ( 11 , 12 ) . In an effort to improve the therapeutic efficacy of antidepressant monotherapy , several pharmacologic strategies to modulate different or additional neurotransmitters ( 1315 ) are commonly used , despite a paucity of evidence from r and omized clinical trials . These strategies include switching monotherapy within ( 10 , 1618 ) or between antidepressant classes ( 10 , 1921 ) , combination regimens consisting of 2 antidepressants ( 2226 ) , and augmentation of antidepressants with nonst and ard treatmentsfor example , thyroid hormone ( 27 ) ; S-adenosyl-l-methionine ( 28 ) ; lithium ( 29 ) ; cyclooxygenase-2 inhibitors ( 30 ) ; or an atypical antipsychotic ( 3133 ) , such as risperidone . Findings of several open-label studies ( 3135 ) suggest that atypical antipsychotic augmentation provides benefit in major depressive disorder that is suboptimally responsive to antidepressant monotherapy . Risperidone , whose activity includes blockade of certain serotonin and dopamine receptors , is considered an atypical antipsychotic . It is approved in the United States for treatment of bipolar mania and schizophrenia and in other countries for additional uses . The efficacy of risperidone has also been studied for various psychoses and behavioral disorders , including treatment-resistant depression and anxiety spectrum disorders ( 34 , 3639 ) . We hypothesized that low-dose risperidone augmentation would reduce symptoms of major depressive disorder , enhance clinical response and remission rates , and reduce disability and improve quality of life compared with continued antidepressant monotherapy . Preliminary data suggest that persons with a confirmed suboptimal response to previous treatment may respond to risperidone augmentation within 4 to 6 weeks ( 38 ) . We therefore conducted a large , multicenter , double-blind , placebo-controlled trial to assess the clinical efficacy of risperidone augmentation from the clinician and patient perspectives and to evaluate tolerability in patients with major depressive disorder who continue to experience symptoms despite an adequate trial of st and ard antidepressants . Methods Design Consenting persons entered a 4-week prospect i ve open-label run-in period during which they received their current antidepressant monotherapy at the dosages recommended in product labeling , so that we could confirm an insufficient response to st and ard monotherapy . The run-in period was followed by a 6-week double-blind treatment phase ; during this phase , patients who continued to experience depressive symptoms , defined as a Clinical Global ImpressionSeverity of illness ( CGI-S ) score of 4 or greater and a Carroll Depression Scale ( 40 ) score of 20 or greater , were r and omly assigned to receive risperidone augmentation therapy or placebo . A 4-week follow-up phase of open-label risperidone augmentation therapy was available to participants who completed at least 4 weeks of double-blind treatment ( results not shown ) . Setting and Participants Out patients 18 to 65 years of age who had received antidepressant monotherapy for at least 4 weeks and met the Diagnostic and Statistical Manual of Mental Disorders , fourth edition ( 41 ) , criteria for unremitting major depressive disorder ( single or recurrent episodes ) and a CGI-S score of 4 or more ( 42 ) at the start of both the open-label and double-blind phases were eligible . The CGI-S is scored on a scale of increasing intensity from 1 to 7 , with 4 representing moderate illness . We recruited participants by using various methods , including media advertisements , and enrolled persons from 75 public and private primary care ( n= 41 ) and psychiatric ( n= 34 ) centers in the United States between 19 October 2004 and 17 November 2005 . Ethical approval was obtained from the institutional review board of each site , and written informed consent was obtained from all patients . Exclusion criteria were pregnancy ; serious suicidal risk or serious medical or neurologic illness ; active substance or alcohol use disorders ; or current treatment with a tricyclic antidepressant , monoamine oxidase inhibitor , mood stabilizer , antiepileptic , or a central ly acting agent for attention deficit disorder/attention deficit hyperactivity disorder or narcolepsy . R and omization and Interventions Patients who were eligible for r and omization continued their st and ard antidepressant regimen and dosage and were assigned to receive risperidone or placebo . Tablets were identical in appearance . The investigators , study staff , and patients were blinded to the treatment assignment . The r and omization code was central ly generated and administered by a telephone interactive voice response system , was stratified by antidepressant class ( SSRI or non-SSRI ) and center , and occurred in r and om permuted blocks . An independent statistician provided the r and omization codes . The dosing schedule was 0.25 mg for the first 3 days , 0.5 mg on days 4 to 15 , and 1.0 mg on days 16 to 28 . On day 29 , patients with insufficient treatment response in the opinion of the investigator could continue augmentation at the current dosage , have the dosage increased to 2 mg/d , or discontinue double-blind treatment . Concomitant medications were allowed as necessary for medical conditions . Sedative agents ( zolpidem , 2.5 to 10 mg/d , or zaleplon , 5 to 20 mg/d , as needed ) were allowed for insomnia . During double-blind treatment , benztropine mesylate was permitted as needed for potential treatment-emergent motor effects . Measurements and Outcomes At each visit ( end of the open-label phase and weeks 1 , 2 , 4 , and 6 ) , trained personnel administered the grid version of the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) ( 43 , 44 ) and the CGI-S ( 42 ) , both clinician-rated instruments . Scores on the HRSD-17 range from 0 to 52 ; higher scores indicate more severe depression . Patients also independently rated their response by using the telephone interactive voice response system at baseline and weekly thereafter . Other patient-reported outcomes were scores on 3 vali date d instruments : the Quality of Life Enjoyment and Satisfaction Question naire ( Q-LES-Q ) ( 45 ) , the Patient Global Improvement Scale ( 7-point rating from 1 [ very much improved ] to 7 [ very much worse ] ) , and the Sheehan Disability Scale ( SDS ) . Change in HRSD-17 total score from baseline to study end was the a priori primary efficacy measure . Response ( 50 % reduction in HRSD-17 total score from baseline ) and remission ( HRSD-17 total score 7 ) were assessed at each time point . Secondary measures were changes in the CGI-S , Q-LES-Q , SDS , and Patient Global Improvement Scale scores . Follow-up Patients underwent physical examination , including assessment of vital signs , at regular intervals . Research staff maintained records of trial medication and assessed treatment compliance by matching doses taken with the number of treatment days . To assess adverse effects , patients were interviewed at each study visit with open-ended questions about potential adverse events ; spontaneous reports were also taken into account . All adverse events were recorded , and the investigator assessed each event for severity and relationship to the study drug ( probable , possible , not related ) . Statistical Analysis A sample of 116 patients per group was anticipated to have 90 % power to detect an arbitrary difference in change in mean HRSD-17 total score of 3.0 units , assuming a common SD of 7.0 using a 2-group t test and a 2-sided significance level of 0.05 . We also assumed that approximately 30 % of the participants would not complete double-blind treatment and planned for 332 persons to undergo r and omization . We further assumed that during the open-label run-in phase , 30 % of participants would discontinue the study and 20 % would respond to st and ard antidepressant treatment and therefore be ineligible for r and omization ; thus , we sought 592 persons for the open-label run-in phase . All analyses were performed by using SAS , version 8.2 ( SAS Institute , Cary , North Carolina ) , and statistical analysis personnel were blinded to patient group assignment . Baseline patient characteristics were summarized by using descriptive statistics . Efficacy and safety analyses were based on the intention-to-treat population ( that is , all persons who underwent r and omization and received at least 1 dose of medication in the double-blind phase ) . The objective of this study was to investigate the efficacy and safety of adjunctive lanicemine ( NMDA channel blocker ) in the treatment of major depressive disorder ( MDD ) over 12 weeks . This phase IIb , r and omized , parallel-arm , double-blind , placebo-controlled study was conducted at 49 centers in four countries between December 2011 and August 2013 in 302 patients aged 18–70 years , meeting criteria for single episode or recurrent MDD and with a history of inadequate treatment response . Patients were required to be taking an allowed antidepressant for at least four weeks prior to screening . Patients were r and omized equally to receive 15 double-blind intravenous infusions of adjunctive lanicemine 50 mg , lanicemine 100 mg , or saline over a 12-week course , in addition to ongoing antidepressant . The primary efficacy end point was change in Montgomery-Åsberg Depression Rating Scale ( MADRS ) total score from baseline to week 6 . Secondary efficacy outcome variables included change in MADRS score from baseline to week 12 , response and remission rates , and changes in Clinical Global Impression scale , Quick Inventory of Depressive Symptomology Self-Report score , and Sheehan Disability Scale score . Of 302 r and omized patients , 240 ( 79.5 % ) completed treatment . Although lanicemine was generally well tolerated , neither dose was superior to placebo in reducing depressive symptoms on the primary end point or any secondary measures . There was no significant difference between lanicemine and placebo treatment on any outcome measures related to MDD . Post hoc analyses were performed to explore the possible effects of trial design and patient characteristics in accounting for the contrasting results with a previously reported trial The objective of this study was to compare efficacy and tolerability of the selective noradrenalin reuptake inhibitor reboxetine with the selective serotonin reuptake inhibitor citalopram , in the treatment of major depressive disorder ( MDD ) . In total , 357 out patients with MDD were r and omized to treatment with reboxetine 8 - 10 mg or citalopram 20 - 40 mg per day during 24 weeks . Primary end-point was change from baseline in the Hamilton Depression Rating Scale ( HAM-D , 21 items ) . Sexual function/dysfunction was measured by the Sexual Function scale ( SF ) . Observed case analysis showed that both treatments yielded a gradual reduction of HAM-D scores : reboxetine with -21.4 and citalopram with -22.1 points ( NS ) . LOCF analysis showed a greater reduction of the HAM-D scores with citalopram compared with reboxetine ( -19.6 vs. -17.8 ; P = 0.034 ) . The response rate was 90.3 % for reboxetine and 92.7 % for citalopram ( NS ) . The most common side effect in the reboxetine group was dry mouth , and in the citalopram group sexual dysfunction . At week 24 , anorgasmia was reported by 5.9 % of the sexually active women in the reboxetine group vs 39 % in the citalopram group . The  dropout number  was 91 in the  reboxetine group , and 54 in the citalopram group . To summarize , both treatments gave a satisfactory antidepressant effect . The side effect profile differed between the groups , with a notably high prevalence of sexual dysfunctions in the citalopram group . The high number of dropouts in the reboxetine group , is considered as a result of the non-titration starting dose of 8 mg reboxetine per day , which gave a high incidence of early side-effects .  Depressive disorders including major depression ( MDD ) is very common , with a lifetime prevalence of at least 15 % in men and 25 % in women.1,2 Depression can be treated effectively by a range of antidepressant agents . Recent review s have suggested that the selective serotonin reuptake inhibitors ( SSRIs ) offer equal efficacy to the older antidepressant agents , such as tricyclic antidepressants , with the advantage of greater tolerability.3 - 5 Other review ers have reported that non-SSRI antidepressants , such as clomipramine , have been found to be significantly more effective than fluoxetine for the treatment of patients with severe depression.6  Reboxetine ( reboxetine mesylate , Edronax ; Pfizer , New York ) is a highly selective noradrenaline reuptake inhibitor , and the efficacy of reboxetine has been independently demonstrated in multiple r and omized , double-blind , placebo-controlled studies .7 - 9 In addition to improvements in depressive symptoms , treatment-associated improvements in social behavior ( measured using the Social Adaptation Self-evaluation Scale [SASS]),10 were noticed in one of these studies .8 In this study , reboxetine was statistically and clinical ly superior to both placebo and fluoxetine in improving social functioning . The primary objective of the current study was to assess efficacy and tolerability of reboxetine  in comparison with those of citalopram ( Cipramil ; H. Lundbeck , Copenhagen , Denmark ) in patients with MDD .  Citalopram is a highly SSRI . The antidepressant mechanism is presumed to be a result of stimulation of serotonergic neurotransmission in the central nervous system as a consequence of higher serotonin levels result ing from inhibition of the serotonin transporter . The therapeutic efficacy of citalopram in patients with MDD has been investigated in several placebo-controlled studies and in long-term and extension studies .11 The underlying rationale for this comparison was to study 2 different drug profiles , 1 drug being pure " adrenergic " and the other pure " serotonergic . " A secondary objective was to analyze the correlation between the types of depression ( ie , degree of melancholia and the efficacy of the 2 drugs ) IMPORTANCE Antidepressant medication ( ADM ) is efficacious in the treatment of depression , but not all patients achieve remission and fewer still achieve recovery with ADM alone . OBJECTIVE To determine the effects of combining cognitive therapy ( CT ) with ADM vs ADM alone on remission and recovery in major depressive disorder ( MDD ) . DESIGN , SETTING , AND PARTICIPANTS A total of 452 adult out patients with chronic or recurrent MDD participated in a trial conducted in research clinics at 3 university medical centers in the United States . The patients were r and omly assigned to ADM treatment alone or CT combined with ADM treatment . Treatment was continued for up to 42 months until recovery was achieved . INTERVENTIONS Antidepressant medication with or without CT . MAIN OUTCOMES AND MEASURES Blind evaluations of recovery with a modified version of the 17-item Hamilton Rating Scale for Depression and the Longitudinal Interval Follow-up Evaluation . RESULTS Combined treatment enhanced the rate of recovery vs treatment with ADM alone ( 72.6 % vs 62.5 % ; t451 = 2.45 ; P = .01 ; hazard ratio [ HR ] , 1.33 ; 95 % CI , 1.06 - 1.68 ; number needed to treat [ NNT ] , 10 ; 95 % CI , 5 - 72 ) . This effect was conditioned on interactions with severity ( t451 = 1.97 ; P = .05 ; NNT , 5 ) and chronicity ( χ2 = 7.46 ; P = .02 ; NNT , 6 ) such that the advantage for combined treatment was limited to patients with severe , nonchronic MDD ( 81.3 % vs 51.7 % ; n = 146 ; t145 = 3.96 ; P = .001 ; HR , 2.34 ; 95 % CI , 1.54 - 3.57 ; NNT , 3 ; 95 % CI , 2 - 5 ) . Fewer patients dropped out of combined treatment vs ADM treatment alone ( 18.9 % vs 26.8 % ; t451 = -2.04 ; P = .04 ; HR , 0.66 ; 95 % CI , 0.45 - 0.98 ) . Remission rates did not differ significantly either as a main effect of treatment or as an interaction with severity or chronicity . Patients with comorbid Axis II disorders  took longer to recover than did patients without comorbid Axis II disorders regardless of the condition ( P = .01 ) . Patients who received combined treatment reported fewer serious adverse events than did patients who received ADMs alone ( 49 vs 71 ; P = .02 ) , largely because they experienced less time in an MDD episode . CONCLUSIONS AND RELEVANCE Cognitive therapy combined with ADM treatment enhances the rates of recovery from MDD relative to ADMs alone , with the effect limited to patients with severe , nonchronic depression . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00057577 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 We used in vitro neurogenesis-based human neural stem cell ( hNSCs ) assays and rodent in vivo behavioral assays to identify potential novel antidepressants . A combination of buspirone and melatonin displayed antidepressant activity in these assays whereas neither buspirone nor melatonin alone showed any antidepressant-like profile . After evaluating numerous combination ratios , we determined that low dose buspirone 15 mg combined with melatonin-SR 3 mg yielded optimal antidepressant efficacy in our pre- clinical platform . The low dose of buspirone suggested that antidepressant efficacy might be achieved with only minimal adverse event liability . Based on these data , we conducted an exploratory 6-week , multi-center , double-blind , r and omized , placebo- and comparator-controlled study of the combination of buspirone and melatonin in subjects with acute Major Depressive Disorder ( MDD ) . The combination treatment revealed a significant antidepressant response in subjects with MDD on several measures ( Clinical Global Impression of Severity and Improvement , Inventory of Depressive Symptomatology ) compared to either placebo or buspirone 15 mg monotherapy . These preliminary findings have clinical implication s and suggest that a platform of pre- clinical neurogenesis matched with confirmatory behavioral assays may be useful as a drug discovery strategy Sleep disturbance is common in major depressive disorder ( MDD ) , and is often characterized by early-morning waking . Melatonin is a hypnotic and synchronizes circadian rhythms . It may also be an antidepressant . The melatonin agonists , ramelteon and agomelatine , have hypnotic and antidepressant properties , but there is a dearth of trials investigating the use of melatonin in MDD . This r and omized , controlled trial aim ed to determine whether exogenous melatonin is a sleep promoter and antidepressant . Thirty-three participants with a Diagnostic and Statistical Manual of Mental Disorders ( fourth edition ) diagnosis of MDD and early-morning waking were selected for a 4-week , r and omized , double-blind trial of slow-release melatonin ( 6 mg ; vs. placebo ) given at bedtime over 4 weeks . Sleep was measured subjectively using  sleep diaries  and the Leeds Sleep Evaluation Question naire and objective ly using  wrist actigraphy .  Of the 33 participants , 31 completed the trial . General Linear Modelling showed significant improvements in depression and sleep over time , but this was not specific to melatonin . However , there was a trend towards an improvement in mood with melatonin , and no adverse side effects were observed . In conclusion , melatonin may be beneficial for treating MDD , it seems to be safe and well tolerated , but its potential for treating  depression in people who do not wish to take antidepressants requires further evaluation Objectives : The objectives of this study were to provide estimates of the prevalence and strength of association between major depression and chronic pain in a primary care population and to examine the clinical burden associated with the two conditions , singly and together . Methods : A r and om sample of Kaiser Permanente patients who visited a primary care clinic was mailed a question naire assessing major depressive disorder ( MDD ) , chronic pain , pain-related disability , somatic symptom severity , panic disorder , other anxiety , probable alcohol abuse , and health-related quality of life ( HRQL ) . Instruments included the Patient Health Question naire , SF-8 , and Grade d Chronic Pain Question naire .  A total of 5808 patients responded ( 54 % of those eligible to participate ) . Results : Among those with MDD , a significantly higher proportion reported chronic ( i.e. , nondisabling or disabling ) pain than those without MDD ( 66 % versus 43 % , respectively ) . Disabling chronic pain was present in 41 % of those with MDD versus 10 % of those without MDD . Respondents with comorbid depression and disabling chronic pain had significantly poorer HRQL , greater somatic symptom severity , and higher prevalence of panic disorder than other respondents . The prevalence of probable alcohol abuse/dependence was significantly higher among persons with MDD compared with individuals without MDD regardless of pain or disability level . Compared with participants without MDD , the prevalence of other anxiety among those with MDD was more than sixfold greater regardless of pain or disability level . Conclusions : Chronic pain is common among those with MDD . Comorbid MDD and disabling chronic pain are associated with greater clinical burden than MDD alone . MDD = major depressive disorder ; HRQL = health-related quality of life ; HMO = health maintenance organization ; PHQ = Patient Health Question naire ; GCPS = Grade d Chronic Pain Scale ; CP = chronic pain ; DCP = disabling chronic pain ; GAD = generalized anxiety disorder ; SCID = Structured Clinical Interview for DSM-III-R ; PRIME-MD = Primary Care Evaluation of Mental Disorders ; CI = confidence interval ; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition ; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders , Third Edition Revised Background Major depressive disorder ( MDD ) is a highly prevalent , heterogeneous and systemic medical condition . Treatment options are limited , and recent studies have suggested that physical exercise can play an important role in the therapeutics of MDD . The aim of this study was to evaluate the antidepressant efficacy of adjunctive aerobic activity in association with pharmacotherapy ( selective serotonin reuptake inhibitor ) in symptomatic MDD as well as its association with physiological biomarkers . Methods In this r and omized , single-blind , add-on , controlled clinical trial , 57 patients ( 18–55 years of age ) were followed-up for 28 days . All patients were drug-free , had been diagnosed with symptomatic MDD and received flexible dose of sertraline during the trial . Patients were r and omized to either a 4-week program ( 4x/week ) of add-on aerobic exercise ( exercise group , N = 29 ) or no activity ( control group , N = 28 ) . Depression severity was assessed using the Hamilton Rating Scale for Depression ( HAM-D ) as the primary outcome . At baseline and endpoint , all patients underwent a comprehensive metabolic/cardiopulmonary exercise testing — including determination of maximal oxygen uptake ( VO2max ) , VO2 at the second ventilatory threshold ( VO2-VT2 ) , and oxygen pulse ( O2 pulse ) . Results Depression scores significantly decreased in both groups after intervention . Importantly , patients in the aerobic exercise group required lower  sertraline dose compared to the control group ( sertraline monotherapy ) . The VO2max and O2 pulse parameters increased over time only in the exercise group and remained unchanged in the control group . Conclusions The present findings suggest that a 4-week training of aerobic exercise significantly improves functional capacity in patients with MDD and may be associated with antidepressant efficacy . This approach may also decrease the need for higher doses of antidepressants to achieve response . Further studies in unmedicated and treatment-resistant MDD patients are needed in order to confirm the utility of short-term aerobic exercise as an alternative therapeutic approach in MDD . Trial Registration Clinical Trials.gov Background : Many patients with major depressive disorder ( MDD ) who achieve full remission after  antidepressant treatment  still have residual depressive symptoms . In this study , we assess the type and frequency of residual symptoms and their relationship to subsequent depressive relapses after remission of major depression with fluoxetine . Method : Five hundred seventy‐six patients with MDD were openly treated with fluoxetine for 12 weeks . Those who responded underwent r and om assignment , under double‐blind conditions , to continue taking fluoxetine or to switch to placebo for 52 weeks or until relapse . The presence of residual symptoms in patients who achieved remission at the end of the acute phase ( N=203 ) was assessed using the 28‐item Hamilton Depression Rating Scale . Survival analysis was used to examine the effect of residual symptoms on relapse in remitters . Results : More than 90 % of patients who met criteria for remission had at least one residual depressive symptom ( median=4 ) . The most common were sleep disturbances ( insomnia 48.2 % , hypersomnia 35.9 % ) and anxiety ( 52.7 % ) . The most common individual symptom was middle insomnia ( 33.5 % ) . No statistically or clinical ly significant differences in baseline variables were found between remitters with and without residual symptoms . The presence of residual symptoms , the presence of residual insomnia and the global number of residual symptoms did not predict relapse during the continuation phase of the study . Conclusion : The great majority of patients with remission of MDD after treatment with fluoxetine  continue to experience selected residual depressive symptoms . The presence of residual symptoms is not significantly associated with an increased risk of relapse . Depression and Anxiety , 2011 . © 2010 Wiley‐Liss ,
There were some beneficial effects compared to placebo or antidepressants but tolerability was worse .
Quetiapine was more effective than placebo treatment .
Aripiprazole and quetiapine and partly also olanzapine and risperidone augmentation showed beneficial effects compared to placebo .
Some evidence indicated beneficial effects of low-dose amisulpride for dysthymic people .
Most SGAs showed worse tolerability
BACKGROUND Major depressive disorder ( MDD ) is a common condition with a lifetime prevalence of 15 % to 18 % , which leads to considerable suffering and disability .
Some antipsychotics have been reported to induce remission in major depression , when added to an antidepressant .
OBJECTIVES To evaluate the effects of second-generation antipsychotic ( SGA ) drugs ( alone or augmentation ) compared with placebo or antidepressants for people with MDD or dysthymia .