Association between the so-called "activation syndrome" and bipolar II disorder, a related disorder, and bipolar suggestive features in outpatients with depression. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. The treatment of SSRI-resistant depression in adolescents (TORDIA): in search of the best next step. Does comorbid substance use disorder impair recovery from major depression with SSRI treatment? An analysis of the STAR*D level one treatment outcomes. Switching to bupropion in fluoxetine-resistant major depressive disorder. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. (S)-(+)-mecamylamine (TC-5214): a neuronal nicotinic receptor modulator enters phase III trials as an adjunct treatment for Major Depressive Disorder (MDD). Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study Short-term fluoxetine monotherapy for bipolar type II or bipolar NOS major depression - low manic switch rate. Frontal EEG predictors of treatment outcome in major depressive disorder Efficacy and safety of add on low-dose mirtazapine in depression Prophylactic efficacy of fluoxetine, escitalopram, sertraline, paroxetine, and concomitant psychotherapy in major depressive disorder: Outcome after long-term follow-up Short-term intravenous citalopram augmentation in partial/nonresponders with major depression: a randomized placebo-controlled study Vagus Nerve Stimulation (VNS™) for Treatment-Resistant Depression: Efficacy, Side Effects, and Predictors of Outcome Safe use of SSRIs in young adults: how strong is evidence for new suicide warning? Differential Antidepressant Symptom Efficacy: Placebo-Controlled Comparisons of Duloxetine and SSRIs (Fluoxetine, Paroxetine, Escitalopram) Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. fMRI response to negative words and SSRI treatment outcome in major depressive disorder: A preliminary study Efficacy and Tolerability of Reboxetine Compared with Citalopram: A Double-blind Study in Patients with Major Depressive Disorder TREAD: TReatment with Exercise Augmentation for Depression: study rationale and design Venlafaxine inhibits the upregulation of plasma tumor necrosis factor-alpha (TNF-α) in the Chinese patients with major depressive disorder: A prospective longitudinal study Use of SSRIs in "very old" depressed nursing home residents. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials.
BACKGROUND Activation syndrome ( AS ) is a cluster of symptoms listed by the US Food and Drug Administration as possible suicidality precursors during antidepressant treatment . We aim ed to clarify whether AS is associated with bipolar II disorder ( BP-II ) and its related disorder , i.e. , bipolar disorder not otherwise specified ( BP-NOS ) , which are often mistreated as major depressive disorder ( MDD ) , as well as bipolar suggestive features in out patients with depression . METHODS The frequency of AS , bipolar suggestive features , and background variables in consecutive out patients with a major depressive episode ( MDE ) due to BP-II/BP-NOS or MDD , who were naturalistically treated with antidepressants  , were investigated and analyzed retrospectively . RESULTS Of 157 evaluable patients ( 46 BP-II/BP-NOS , 111 MDD ) , 39 ( 24.8 % ) experienced AS . Patients with BP-II/BP-NOS experienced AS significantly more frequently than patients with MDD ( 52.2 % of BP-II/BP-NOS vs. 13.5 % of MDD , p<0.01 ) . Univariate analysis revealed that BP-II/BP-NOS diagnosis , cyclothymic temperament , early age at onset of first MDE , psychiatric comorbidities , and depressive mixed state ( DMX ) were significantly associated with AS development in the entire sample . Multivariate analysis revealed that BP-II/BP-NOS diagnosis and DMX were independent risk factors for AS . LIMITATIONS This is a retrospective and naturalistic study ; therefore , patient selection bias could have occurred . CONCLUSIONS Cautious monitoring of AS is needed during antidepressant trials in patients with BP-II/BP-NOS . Clinicians should re-evaluate underlying bipolarity when they confront AS . Antidepressants should be avoided for treating a current DMX beyond the unipolar-bipolar dichotomy . Prospect i ve studies are needed to confirm these results 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 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 Many patients with major depressive disorder ( MDD ) present with concurrent substance use disorders ( SUDs ) , which has been thought to impair their response to antidepressants . Clinicians often delay antidepressant treatment until sustained sobriety has been established . Unfortunately , these comorbid subjects are typically excluded from depression treatment trials , leaving a gap in underst and ing the treatment outcomes . In the Sequenced Treatment Alternatives to Relieve Depression ( STAR*D ) study , 2876 adult out patients diagnosed with nonpsychotic MDD were prospect ively treated with the selective serotonin-reuptake inhibitor ( SSRI ) , citalopram , and returned for at least one post-baseline visit .  Participants with SUD ( 29 % ) and without SUD ( 71 % ) were compared in regard to baseline clinical and sociodemographic features and treatment response . The group with MDD and SUD was further subdivided into those with alcohol only , drug only , and both alcohol and drug use . Despite clear sociodemographic and clinical differences , there were no significant differences between groups in the time to achieve response or rates of response to citalopram ;  however , those who endorsed both alcohol and drug use had significantly reduced rates of remission and significantly increased times to reach remission compared to the MDD group without SUD . In addition , subjects with MDD and SUD had higher risk of psychiatric serious adverse events ( 3.3 % vs. 1.5 % ) and hospitalization ( 2.8 % vs. 1.2 % ) . The results indicate that first-line treatment with citalopram in depressed patients with alcohol or drug use respond as well as those without SUD . More intensive treatment is most likely needed for MDD patients with both drug and alcohol use disorders Up to 50 % of patients with major depressive disorder ( MDD ) fail to respond to an antidepressant trial , with most taking a selective serotonin reuptake inhibitor ( SSRI ) as an initial treatment . Switching to bupropion , for depressed patients not responding to SSRIs , is a popular strategy among clinicians . This study assesses the efficacy of bupropion SR in the management of MDD resistant to a prospect i ve trial of fluoxetine . Twenty-nine patients with MDD refractory to an 8- to 12-week open-trial of fluoxetine  were enrolled in an 8-week open-trial of bupropion SR . Both a completer analysis ( n = 20 ) and a modified intent-to-treat analysis ( n = 26 ) were performed to evaluate  bupropion SR response rates . Using a completer analysis , seven patients ( 35.0 % ) were classified as responders , five ( 25.0 % ) partial responders , and eight ( 40.0 % ) nonresponders . A modified intent to treat analysis result ed in nine ( 34.6 % ) patients classified as responders , eight ( 30.8 % ) partial responders , and nine ( 34.6 % ) nonresponders . The overall proportion of remitters was 6/20 ( 30.0 % ) using a completer analysis and 6/26 ( 23.1 % ) using an MITT analysis . Approximately 60 % of patients with MDD resistant to a prospect i ve trial of fluoxetine experienced a full or partial response to bupropion SR . Bupropion SR should be considered as a potential treatment for patients who remain depressed despite treatment with BACKGROUND 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 Major Depressive Disorder ( MDD ) is a common illness that affects > 40 million people worldwide , and antidepressants are one of the top 5 leading classes of pharmaceuticals with annual sales in excess of $ 20 billion ( 1,2 ) . The current st and ard of care focuses on serotonin−norepinephrine reuptake inhibitors ( SNRI ) and selective serotonin reuptake inhibitors ( SSRI ) ; however , patients often respond poorly . In fact , the National Institute of Mental Health conducted a large-scale STAR*D study and found that 63 % of patients did not achieve remission with the SSRI Citalopram ( 1,3−5 ) . Citalopram was originally developed in Lundbeck in the late 1980s and sold as a racemate . Lundbeck , in collaboration with Forest Laboratories , has recently released an up date d version called Escitalopram ( also known as Lexapro ) , which is the single (S)-enantiomer of the racemic Citalopram , which provided new patent life . In 2009 , Lexapro garnered ∼$2.7 billion in sales in the US ( Figure ​(Figure1)1 ) ( 2 ) . Figure 1 Structures of Citalopram , Escitalopram , and TC-5214 . An alternative hypothesis for depression emerged over 30 years ago and suggests that a cholinergic imbalance ( hypercholinergic tone ) is a major factor in depression , and both clinical and pre clinical studies have implicated neuronal nicotinic cholinergic receptors ( NNRs ) rather than muscarinic receptors ( 5 ) . On the basis of these data , AstraZeneca and Targacept have explored the role of NNR antagonism in depressive disorders and recently announced the initiation of a phase III trial of TC-5214 , (S)-(+)-mecamylamine , as an adjunct therapy with Citalopram . TC-5214 is a low molecular weight ( 167.3 as free base , 203.8 as the HCl salt ) , basic ( pKa = 11.5 ) compound , freely soluble in water . While TC-5214 displays modest selectivity among the NNRs , its antidepressive properties are presumed to be the result of inhibition of the α4β2 NNRs . Pre clinical ly , TC-5214 demonstrated robust efficacy in rodent models of depression ( forced swim and behavioral despair ) and anxiety ( social interaction and light/dark chamber ) . The (S)-enantiomer showed a superior preclincial safety profile compared to that of either the racemic compound or the (R)-enantiomer . Furthermore , TC-5214 was well tolerated in both acute and chronic toxicity tests , displayed no mutagenic potential , and possessed pharmacokinetic properties suitable for development ( 3−5 ) . In 2009 , Targacept conducted a double blind , placebo controlled phase IIb trial in MMD patients with TC-5214  , as an adjunct treatment with Citalopram demonstrated superiority to placebo in both primary and secondary outcome measures ( 3−5 ) . This positive outcome led to a license agreement in December of 2009 with AstraZeneca for the global development and commercialization of TC-5214 . On June 23 , 2010 , AstraZeneca and Targacept announced the enrollment of the first patients in the phase III trial of TC-4214 . Coined the Renaissance Program , the trial will include two fixed dose and two flexible dose phase III studies of TC-5214 as an adjunct treatment for patients with poor response to st and ard SSRI or SNRI therapy . Each fixed dose and flexible dose phase III study will employ an initial open label phase wherein patients diagnosed with MDD receive one of seven marketed SSRIs or SNRIs for eight weeks to assess therapeutic response . Patients that respond poorly will then be r and omized into a double blind , placebo controlled second phase to receive a fixed or a flexible dose of TC-5214 or placebo , twice daily , while continuing the SSRI or SNRI therapy . A change from double blind baseline for TC-5214 on the Montgomery−Asberg Depression Rating Scale ( MADRS ) as compared to placebo is the primary outcome measure . The program will also include a double blind , placebo controlled study for long-term safety . The companies plan completion of the trial in time to file an IND with the FDA in late 2012 ( 3−5 ) . MMD is the leading cause of disability in the US for people 15−44 , and the burden for MDD in the US in 2000 was in excess of $ 83 billion ( 6 ) . When broken down , the workplace burden for lost time is ∼62 % , treatment costs account for ∼31 % , and suicide related costs average 7 % ( 6 ) . For those suffering from MDD with poor response to SSRIs and SNRIs , the phase III data is anxiously awaited BACKGROUND Vagus Nerve Stimulation ( VNS ) delivered by the NeuroCybernetic Prosthesis ( NCP ) System was examined for its potential antidepressant effects . METHODS Adult out patients ( n = 30 ) with nonpsychotic , treatment-resistant major depressive ( n = 21 ) or bipolar I ( n = 4 ) or II ( n = 5 ; depressed phase ) disorders who had failed at least two robust medication trials in the current major depressive episode ( MDE ) while on stable medication regimens completed a baseline period followed by NCP System implantation .  A 2-week , single-blind recovery period ( no stimulation ) was followed by 10 weeks of VNS . RESULTS In the current MDE ( median length = 4.7 years ) , patients had not adequately responded to two ( n = 9 ) , three ( n = 2 ) , four ( n = 6 ) , or five or more ( n = 13 ) robust antidepressant medication trials or electroconvulsive therapy ( n = 17 ) . Baseline 28-item Hamilton Depression Rating Scale ( HDRS(28 ) ) scores averaged 38.0 . Response rates ( > or = 50 % reduction in baseline scores ) were 40 % for both the HDRS(28 ) and the Clinical Global Impressions-Improvement index ( score of 1 or 2 ) and 50 % for the Montgomery-Asberg Depression Rating Scale . Symptomatic responses ( accompanied by substantial functional improvement ) have been largely sustained during long-term follow-up to date . CONCLUSIONS These open trial results suggest that VNS has antidepressant effects in treatment-resistant depressions OBJECTIVES Current guidelines for the initial treatment of bipolar type II ( BP II ) major depressive episode ( MDE ) recommend using either a mood stabilizer alone or a combination of a mood stabilizer plus a selective serotonin re-uptake inhibitor ( SSRI ) . This recommendation is the result of concern over antidepressant-induced manic switch episodes . However , recent evidence suggests that the manic switch rate may be low in BP II MDE during SSRI therapy . METHODS As part of a r and omized , double-blind ,  placebo-controlled  relapse-prevention study of  fluoxetine  monotherapy in BP II MDE , 37 patients received open-label fluoxetine 20 mg every day for up to 8 weeks . Outcome measures included the Hamilton Depression Rating ( HAM-D 17 ) rating and the Young Mania Rating ( YMR ) scale . RESULTS Eleven of 23 patients ( 48 % ) who completed 8 weeks of fluoxetine treatment showed a HAM-D 17 reduction of > or = 50 % , while 14 ( 38 % ) of all treated patients had > or = 50 % reduction in baseline HAM-D 17 score . Using a conservative YMR score of > or = 8 to identify hypomanic symptoms , the frequency of patients with YMR score > or = 8 during fluoxetine did not differ from that seen during the screen and baseline period . Only three patients ( 7.3 % ) had symptoms suggestive of hypomania , and only one patient stopped treatment because of a rapid mood swing into depression . LIMITATIONS Fluoxetine was given at a fixed dose of 20 mg everyday . Fluoxetine was prescribed in an open-label manner , and the sample size was limited . CONCLUSIONS These observations support the findings of a low manic switch rate during SSRI monotherapy of BP II MDE , and suggest that fluoxetine monotherapy may be a safe and effective initial treatment of BP II MDE OBJECTIVE To investigate the role of frontal EEG as predictor of clinical response to SSRIs or venlafaxine in major depressive disorder ( MDD ) . METHOD 82 subjects ( age 35.9+/-13.0 ; 47.6 % female ) meeting DSM-IV criteria for MDD entered an 8-week prospect i ve treatment with SSRIs or venlafaxine . At baseline and week 1 we recorded serial , 4-channel EEGs ( F7-Fpz , F8-Fpz , A1-Fpz , A2-Fpz ) . We evaluated prospect ively the relative theta power as predictor of treatment outcome . We also developed an Antidepressant Treatment Response ( ATR ) index using EEG parameters assessed at baseline and week 1 . RESULTS 45 subjects ( 54.9 % ) responded to treatment ( HAM-D-17 reduction > or=50 % ) . At baseline , frontal relative theta power ( i.e. , 4 - 8 Hz power/2 - 20 Hz power ) was significantly ( p=0.017 ) lower ( 21 % ) in treatment responders than in non-responders ( 24 % ) . Baseline relative theta power predicted treatment response with 63 % accuracy [ 64 % sensitivity , 62 % specificity , 66 % area under the receiver operator curve ( AUROC ) ( p=0.014 ) ] . Relative theta power at week 1 predicted treatment response with 60 % accuracy [ 62 % sensitivity , 57 % specificity , 61 % AUROC ( p=0.089 ) ] . ATR predicted response with 70 % accuracy [ 82 % sensitivity , 54 % specificity , 72 % AUROC ( p=0.001 ) ] . CONCLUSION Using automated analysis of frontal EEG collected during the first week of antidepressant treatment it may be possible to facilitate prediction of SSRI or venlafaxine efficacy in MDD Objectives : Although antidepressant medications are effective , they have a delayed onset of effect . Mirtazapine , an atypical antidepressant is an important option for add-on therapy in major depression . There is insufficient data on mirtazapine in Indian population ; hence this study was design ed to study the add-on effect of low-dose mirtazapine with selective serotonin reuptake inhibitors ( SSRIs ) in major depressive disorder ( MDD ) in Indian population . Material s and Methods : In an open , r and omized study , 60 patients were divided into two groups . In Group A ( n=30 ) patients received conventional SSRIs for 6 weeks . In Group B ( n=30 ) patients received conventional SSRIs with low-dose mirtazapine for 6 weeks . Patients were evaluated at baseline and then at 1 , 2 , 3 , 4 , 5 , and 6 weeks . Results : There was significant improvement in Hamilton Depression Rating Scale ( HDRS ) , Montgomery and Asberg depression rating scale ( MADRS ) scores ( P<0.05 ) in both groups . Mirtazapine in low dose as add on therapy showed improvement in scores , had earlier onset of action , and more number of responders and remitters as compared to conventional treatment ( P<0.05 ) . No serious adverse event was reported in either of the groups . Conclusion : Low-dose mirtazapine as add-on therapy has shown better efficacy , earlier onset of action and more number of responders and remitters as compared to conventional treatment in MDD in Indian patients The acute efficacy of selective serotonin reuptake inhibitors ( SSRIs ) in the treatment of major depressive disorder ( MDD ) is well established ; however their role in longer-term prevention of recurrence remains unconfirmed . This study aims at examining : the prophylactic efficacy of four commonly used SSRIs in MDD in a naturalistic setting with long-term follow-up , the effect of concomitant cognitive behavioral therapy ( CBT ) , and the predictors of outcome . In a prospect i ve cohort study , 387 patients who either remitted or responded following treatment with four different SSRIs-fluoxetine , escitalopram , sertraline and paroxetine-were  followed up over several years . During an average follow-up period of 34.5 months , 76.5 % of patients experienced MDD recurrence . Escitalopram and fluoxetine showed a numerically higher prophylactic efficacy than paroxetine and sertraline but the difference was statistically insignificant . The prophylactic efficacy for SSRI-only treatment was limited , with a recurrence rate of 82.0 % , compared to 59.0 % of patient recurrence rate in concomitant Cognitive Behavioral Therapy ( CBT ) . The relatively small size of the CBT group and the lack of r and omization may undermine the extrapolation of its findings to clinical practice . Nevertheless , the study preliminary data may help in defining the clinical utility of antidepressants and CBT in the prophylaxis from MDD recurrence Approximately 30–45 % of patients with major depressive episode ( MDE ) do not fully respond to st and ard recommended treatments and further strategies of intervention , including pharmacological augmentation , have been proposed for these patients . This study was aim ed to evaluate the efficacy of short-term , low-dose ( 10 mg/day ) intravenous ( i.v . ) citalopram augmentation versus placebo in a sample of patients with MDE and partial or no response to selective serotonin reuptake inhibitors ( SSRIs ) . Thirty-six patients with a Diagnostic and Statistical Manual for Mental Disorders , 4th edition , text revision criteria MDE and partial or no response to oral SSRIs were selected and r and omly assigned to citalopram ( n=18 ) or to placebo ( n=18 ) i.v . augmentation . The augmentation regimen lasted 5 consecutive days during which the patients were maintained on their current treatment with oral SSRIs . Analyses of variance with repeated measures on Hamilton Depression Rating Scale and Montgomery – Asberg Depression Rating Scale total scores , administered daily with blind-raters conditions , were done . With regard to the Hamilton Depression Rating Scale total scores , a significant time effect ( F=42.02 , P<0.0001 ) and timextreatment effect ( F=21.17 , P<0.0001 ) were found in favor of citalopram . Similar results were obtained from the analysis on Montgomery – Asberg Depression Rating Scale total scores : time effect ( F=50.07 , P<0.0001 ) , timextreatment effect ( F=19.91 , P<0.0001 ) , and treatment effect ( F=4.07 , P=0.05 ) . Even though referred to a small sample , the present findings seem to suggest that short-term , low-dose , i.v . citalopram augmentation may be effective in depressed patients with partial or no response to oral SSRIs . Further controlled studies performed with double-blind conditions are warranted to confirm the present results This open pilot study of vagus nerve stimulation ( VNS ™ ) in 60 patients with treatment-resistant major depressive episodes ( MDEs ) aim ed to : 1 ) define the response rate ; 2 ) determine the profile of side effects ; and , most importantly ; 3 ) establish predictors of clinical outcome . Participants were out patients with nonatypical , nonpsychotic , major depressive or bipolar disorder who had not responded to at least two medication trials from different antidepressant classes in the current MDE . While on stable medication regimens , the patients completed a baseline period followed by device implantation . A 2-week , single blind , recovery period ( no stimulation ) was followed by 10 weeks of VNS . Of 59 completers ( one patient improved during the recovery period ) , the response rate was 30.5 % for the primary HRSD28 measure , 34.0 % for the Montgomery-Äsberg Depression Rating Scale ( MADRAS ) , and 37.3 % for the Clinical Global Impression-Improvement Score ( CGI-I of 1 or 2 ) . The most common side effect was voice alteration or hoarseness , 55.0 % ( 33/60 ) , which was generally mild and related to output current intensity . History of treatment resistance was predictive of VNS outcome . Patients who had never received ECT ( lifetime ) were 3.9 times more likely to respond . Of the 13 patients who had not responded to more than seven adequate antidepressant trials in the current MDE , none responded , compared to 39.1 % of the remaining 46 patients ( p = .0057 ) . Thus , VNS appears to be most effective in patients with low to moderate , but not extreme , antidepressant resistance . Evidence concerning VNS  ' long-term therapeutic benefits and tolerability will be critical in determining its role in treatment-resistant depression 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 . Objective : To test the hypothesis that in patients with major depressive disorder ( MDD ) , the response for specific Hamilton Depression Rating Scale items will differ for duloxetine compared with selective serotonin reuptake inhibitors ( SSRIs ) and that patterns of response will differ based on symptom severity at baseline . Method : Data were pooled from all Lilly-sponsored clinical trials where duloxetine was compared with placebo and an SSRI in patients with MDD : 7 r and omized , double-blind , fixed-dose , 8-week studies of duloxetine  ( n = 1,133 )  versus SSRI  ( n = 689 )  versus placebo  ( n = 641 ) .  Duloxetine doses were 40 , 60 , 80 and 120 mg/day . SSRI doses were 10 mg/day ( escitalopram ) and 20 mg/day ( fluoxetine and paroxetine ) . Results : Compared to SSRI-treated patients , duloxetine-treated patients had a significantly greater ( p ≤ 0.05 ) reduction in the 17-item Hamilton Depression Rating Scale ( HAMD17 ) total score and HAMD17 items of work and activities , psychomotor retardation , genital symptoms and hypochondriasis . Differences favoring the SSRIs approached significance for middle insomnia ( p = 0.057 ) and late insomnia ( p = 0.06 ) , with effect sizes at least twice the magnitude of the corresponding effect sizes for duloxetine . Similarly , the advantage for duloxetine versus the SSRIs approached significance for general somatic symptoms ( p = 0.056 ) , with an effect size twice that observed for the SSRIs . The HAMD17 total score difference was driven mostly by patients with lower baseline MDD severity ( HAMD17 total score ≤19 ) , where the HAMD17 effect size advantage for duloxetine over combined SSRIs was statistically significant ( p = 0.031 ) . Conclusion : Potentially important differences in symptom response patterns were found between duloxetine and the combined SSRIs depending on symptom severity , and different HAMD17 items responded differently to duloxetine compared with SSRIs . Underst and ing these differences may be useful in tailoring antidepressant therapy for individual patients OBJECTIVE Specific genetic or biological markers may predict inadequate response to therapy for major depressive disorder ( MDD ) . The objective of the current post hoc analysis was to evaluate the effect of specific biological and genetic markers on the antidepressant efficacy of adjunctive L-methylfolate 15 mg versus placebo from a trial of inadequate responders to selective serotonin reuptake inhibitors ( SSRIs ) . METHOD The double-blind , r and omized , placebo-controlled trial used the sequential parallel comparison design . Out patients with SSRI-resistant MDD ( DSM-IV criteria ) received L-methylfolate 15 mg/d for 60 days , placebo for 30 days followed by L-methylfolate 15 mg/d for 30 days , or placebo for 60 days . The effects of baseline levels of select biological and genetic markers individually and combined on treatment response to L-methylfolate versus placebo were evaluated ; the primary response measure was the 28-Item Hamilton Depression Rating Scale ( HDRS-28 ) .  The first patient was enrolled July 14 , 2009 , and the last patient completed April 28 , 2011 . RESULTS Seventy-five patients were enrolled . Patients with specific biological ( body mass index ≥ 30 kg/m² , elevated plasma levels of high-sensitivity C-reactive protein or 4-hydroxy-2-nonenal , low S-adenosylmethionine/S-adenosylhomocysteine ratio ) and genetic markers at baseline had significantly ( P ≤ .05 ) greater pooled mean change from baseline on the HDRS-28 with L-methylfolate versus placebo . Pooled mean change from baseline on the Clinical Global Impressions-Severity of Illness scale was significantly ( P < .05 ) greater with L-methylfolate versus placebo for most genetic markers . Most combinations of baseline biological and genetic markers predicted significantly ( P ≤ .05 ) greater reductions in pooled mean change from baseline in HDRS-28 scores  with L-methylfolate versus placebo . CONCLUSIONS Biomarkers associated with inflammation or metabolism and genomic markers associated with L-methylfolate synthesis and metabolism may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with L-methylfolate 15 mg . Confirmatory studies are needed . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00955955 Clinical ly useful predictors of treatment outcome in major depressive disorder ( MDD ) remain elusive . We examined associations between functional magnetic resonance imaging ( fMRI ) blood oxygen level dependent ( BOLD ) signal during active negative word processing and subsequent  selective serotonin reuptake inhibitor ( SSRI ) treatment outcome in MDD . Unmedicated MDD subjects ( n=17 ) performed an emotional word processing fMRI task , and then received eight weeks of st and ardized antidepressant treatment with escitalopram . Lower pre-treatment BOLD responses to negative words in midbrain , dorsolateral prefrontal cortex , paracingulate , anterior cingulate , thalamus and cau date nuclei correlated significantly with greater improvement following escitalopram treatment . Activation of these regions in response to negative words correlated significantly with reaction time for rating word relevance . Maximally predictive clusters of voxels identified using a cross-validation approach predicted 48 % of the variance in response to treatment . This study provides preliminary evidence that SSRIs may be most beneficial in patients who are less able to engage cognitive control networks while processing negative stimuli . Differences between these findings and previous fMRI studies of SSRI treatment outcome may relate to differences in task design . Regional BOLD responses to negative words predictive of SSRI outcome in this study were both overlapping and distinct from those predictive of outcome with cognitive behavioral therapy ( CBT ) in previous studies using the same task . Future studies may examine prediction of differential outcome across treatments in the context of a r and omized controlled trial The 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 ) 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 Although tumor necrosis factor-alpha ( TNF-α ) has been recognized to be involved in the pathogenesis of major depressive disorder ( MDD ) for a long time , only few studies so far investigated the effects of antidepressant , venlafaxine on TNF-α and the results are inconsistent . Moreover , the association between plasma TNF-α levels and suicide accompanied with MDD is entirely unknown . To eluci date these relationships , in the present study , 64 first-episode drug-naïve MDD patients and 64 matched healthy controls were recruited . Total 61 MDD patients received 8-week venlafaxine treatment and they were divided into responders and non-responders according to the reduction rate of HRSD-17 . Prior to venlafaxine treatment , both responders and non-responders shared a similar plasma TNF-α ( p=0.33 ) , which was significantly decreased following venlafaxine treatment ( p<0.001 , p=0.03 , respectively ) . Compared to non-responders , the responder group had a greater reduction in TNF-α ( p=0.01 ) , which was associated with the greater reduction rate of HRSD-17 ( B=1.02 , p=0.01 ) . In addition , the plasma TNF-α levels were equally higher in both suicidal and non-suicidal MDD patients ( p=0.84 ) compared to the healthy controls on admission ( p=0.001 , p=0.03 , respectively ) . Together , our data suggest that MDD per se rather than suicide is associated with the elevated plasma TNF-α , which can be inhibited with venlfaxine monotherapy . The extent of TNF-α reduction may be associated with the efficiency of venlafaxine The authors examined 50 patients , with a mean age of 89 years ( range : 80–98 ) , placed in a prospect i ve , open-label trial of either fluoxetine , sertraline , or paroxetine . At 12-week follow-up , there was a significant overall decline ( 36 % ) in Ham-D scores ; 42 % had at least a 50 % decline in their scores . There were no significant differences in responses to the three antidepressants , and all drugs were well tolerated . However , there were significant differences between diagnostic subgroups in the percentage of persons showing at least a 50 % decrease in their Ham-D scores : major depressive disorder ( MDD ; 93 % ) , Alzheimer 's disease with MDD ( 8 % ) , vascular dementia with MDD ( 6 % ) , and other CNS-related disorders with MDD ( 83 % ) . The findings confirm earlier accounts that antidepressants may be substantially less effective with MDD secondary to dementia in very old patients CONTEXT The efficacy , safety , and tolerability of selective serotonin reuptake inhibitors ( SSRIs ) in the treatment of adults with major depressive disorder ( MDD ) are well established . Comparatively few data are available on the effects of SSRIs in depressed children and adolescents . OBJECTIVE To evaluate the efficacy and safety of sertraline compared with placebo in treatment of pediatric patients with MDD . DESIGN AND SETTING Two multicenter r and omized , double-blind , placebo-controlled trials were conducted at 53 hospital , general practice , and academic centers in the United States , India , Canada , Costa Rica , and Mexico between December 1999 and May 2001 and were pooled a priori . PARTICIPANTS Three hundred seventy-six children and adolescents aged 6 to 17 years with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition-defined MDD of at least moderate severity . INTERVENTION Patients were r and omly assigned to receive a flexible dosage ( 50 - 200 mg/d ) of sertraline ( n = 189 ) or matching placebo tablets ( n = 187 ) for 10 weeks . MAIN OUTCOME MEASURES Change from baseline in the Children 's Depression Rating Scale-Revised ( CDRS-R ) Best Description of Child total score and reported adverse events . RESULTS Sertraline-treated patients experienced statistically significantly greater improvement than placebo patients on the CDRS-R total score ( mean change at week 10 , -30.24 vs -25.83 , respectively ; P = .001 ; overall mean change , -22.84 vs -20.19 , respectively ; P = .007 ) . Based on a 40 % decrease in the adjusted CDRS-R total score at study end point , 69 % of sertraline-treated patients compared with 59 % of placebo patients were considered responders ( P = .05 ) . Sertraline treatment was generally well tolerated . Seventeen sertraline-treated patients ( 9 % ) and 5 placebo patients ( 3 % ) prematurely discontinued the study because of adverse events . Adverse events that occurred in at least 5 % of sertraline-treated patients and with an incidence of at least twice that in placebo patients included diarrhea , vomiting , anorexia , and agitation . CONCLUSION The results of this pooled analysis demonstrate that sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD
Multiple secondary data analyses of TORDIA have identified important predictors of treatment response and relapse .
To up date a comparative effectiveness review ( 1980–2011 ) of treatments for adolescents whose depressive episode or disorder ( MDE/MDD ) did not respond to one or more trials of SSRI antidepressants .