White matter tract integrity is associated with antidepressant response to lurasidone in bipolar depression Efficacy and safety of aripiprazole in the treatment of bipolar disorder: a systematic review Antidepressant-induced mania in bipolar patients: identification of risk factors. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Aripiprazole augmentation in treatment-resistant bipolar depression: Early response and development of akathisia Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Who will benefit from antidepressants in the acute treatment of bipolar depression? A reanalysis of the STEP-BD study by Sachs et al. 2007, using Q-learning Antidepressants in bipolar depression: The clinical debate The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial. Interpersonal and social rhythm therapy for adolescents with bipolar disorder: treatment development and results from an open trial Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Patterns of pharmacological maintenance treatment in a community mental health services bipolar disorder cohort study (SIN-DEPRES). Clinical efficacy, onset time and safety of bright light therapy in acute bipolar depression as an adjunctive therapy: A randomized controlled trial. Efficacy and safety of quetiapine extended release monotherapy in bipolar depression: a multi-center, randomized, double-blind, placebo-controlled trial Bipolar vaporization of the prostate: is it ready for the primetime? A history of substance abuse complicates remission from acute mania in bipolar disorder. Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study. Maintenance Efficacy of Divalproex in the Prevention of Bipolar Depression Study design and methodology for a multicentre, randomised controlled trial of transcranial direct current stimulation as a treatment for unipolar and bipolar depression. Efficacy and safety of extended-release quetiapine fumarate in youth with bipolar depression: an 8 week, double-blind, placebo-controlled trial. International randomized-controlled trial of transcranial Direct Current Stimulation in depression Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study.
Patients with bipolar disorder spend the most time in the depressed phase , and that phase is associated with the most morbidity and mortality . Treatment of bipolar depression lacks a test to determine who will respond to treatment . White matter disruptions have been found in bipolar disorder . Previous reports suggest that white matter disruptions may be associated with resistance to  antidepressant medication  , but this has never been investigated in a prospect i ve study using a Food and Drug Administration ( FDA ) ‐approved medication Background The current article is a systematic review concerning the efficacy and safety of aripiprazole in the treatment of bipolar disorder . Methods A systematic Medline and repositories search concerning the usefulness of aripiprazole in bipolar disorder was performed , with the combination of the words ' aripiprazole ' and ' bipolar ' . Results The search returned 184 articles and was last up date d on 15 April 2009 . An additional search included repositories of clinical trials and previous systematic review s specifically in order to trace unpublished trials . There were seven placebo-controlled r and omised controlled trials ( RCTs ) , six with comparator studies and one with add-on studies . They assessed the usefulness of aripiprazole in acute mania , acute bipolar depression and during the maintenance phase in comparison to placebo , lithium or haloperidol . Conclusion Aripiprazole appears effective for the treatment and prophylaxis against mania . The data on bipolar depression are so far negative , however there is a need for further study at lower dosages . The most frequent adverse effects are extrapyramidal signs and symptoms , especially akathisia , without any significant weight gain , hyperprolactinaemia or laboratory test changes BACKGROUND Concerns about possible risks of switching to mania associated with antidepressants continue to interfere with the establishment of an optimal treatment paradigm for bipolar depression . METHOD The response of 44 patients meeting DSM-IV criteria for bipolar disorder to naturalistic treatment was assessed for at least 6 weeks using the Montgomery-Asberg Depression Rating Scale and the Bech-Rafaelson Mania Rating Scale . Patients who experienced a manic or hypomanic switch were compared with those who did not on several variables including age , sex , diagnosis ( DSM-IV bipolar I vs. bipolar II ) , number of previous manic episodes , type of antidepressant therapy used ( electroconvulsive therapy vs. antidepressant drugs and , more particularly , selective serotonin reuptake inhibitors [ SSRIs ] ) , use and type of mood stabilizers ( lithium vs. anticonvulsants ) , and temperament of the patient , assessed during a normothymic period using the hyperthymia component of the Semi-structured Affective Temperament Interview . RESULTS Switches to hypomania or mania occurred in 27 % of all patients ( N = 12 ) ( and in 24 % of the subgroup of patients treated with SSRIs [ 8/33 ] ) ; 16 % ( N = 7 ) experienced manic episodes , and 11 % ( N = 5 ) experienced hypomanic episodes . Sex , age , diagnosis ( bipolar I vs. bipolar II ) , and additional treatment did not affect the risk of switching . The incidence of mood switches seemed not to differ between patients receiving an anticonvulsant and those receiving no mood stabilizer . In contrast , mood switches were less frequent in patients receiving lithium ( 15 % , 4/26 ) than in patients not treated with lithium ( 44 % , 8/18 ; p = .04 ) . The number of previous manic episodes did not affect the probability of switching , whereas a high score on the hyperthymia component of the Semistructured Affective Temperament Interview was associated with a greater risk of switching ( p = .008 ) . CONCLUSION The frequency of mood switching associated with acute antidepressant therapy may be reduced by lithium treatment . Particular attention should be paid to patients with a hyperthymic temperament , who have a greater risk of mood switches BACKGROUND The anticonvulsant lamotrigine was previously shown to be effective for bipolar depression . This study assessed the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of mood episodes in bipolar disorder . METHOD During an 8- to 16-week open-label phase , lamotrigine ( titrated to 200 mg/day ) was added to current therapy for currently or recently depressed DSM-IV-defined bipolar I out patients ( N = 966 ) and concomitant drugs were gradually withdrawn . Patients stabilized on open-label treatment ( N = 463 ) were then r and omly assigned to lamotrigine ( 50 , 200 , or 400 mg/day ; N = 221 ) , lithium ( 0.8 - 1.1 mEq/L ; N = 121 ) , or placebo ( N = 121 ) monotherapy for up to 18 months . The primary outcome measure was time from r and omization to intervention ( addition of pharmacotherapy ) for any mood episode ( depressive , manic , hypomanic , or mixed ) . Data were gathered from September 1997 to August 2001 . RESULTS Time to intervention for any mood episode was statistically superior ( p = .029 ) for both lamotrigine and lithium compared with placebo-median  survival times were 200 , 170 , and 93 days , respectively . Intervention for depression was more frequent than for mania by a factor of nearly 3:1 . Lamotrigine was statistically superior to placebo at prolonging the time to intervention for a depressive episode ( p = .047 ) . The proportions of patients who were intervention-free for depression at 1 year were lamotrigine 57 % , lithium 46 % , and placebo 45 % . Lithium was statistically superior to placebo at prolonging the time to intervention for a manic or hypomanic episode ( p = .026 ) . The proportions of patients who were intervention-free for mania at 1 year were lamotrigine 77 % , lithium 86 % , and placebo 72 % . Headache was the most frequent adverse event for all 3 treatment groups . CONCLUSION Lamotrigine and lithium were superior to placebo for the prevention of mood episodes in bipolar I patients , with lamotrigine predominantly effective against depression and lithium predominantly effective against mania There is growing evidence that atypical antipsychotics may be effective in the treatment of acute bipolar depression . Results from r and omized , placebo-controlled trials support the use of quetiapine monotherapy and a combination of olanzapine-fluoxetine in the depressed phase of bipolar disorder , while only limited data exists regarding the use of aripiprazole in this population . To assess the potential effectiveness of aripiprazole in treating acute bipolar depression , a chart review was conducted on 12 patients with treatment-resistant bipolar disorder ( I , II , and not otherwise specified [ NOS ] ) who received aripiprazole augmentation for the relief of an acute major depressive episode . After 8 weeks of treatment , 4 of 12 ( 33 % ) patients demonstrated a response , defined as a 50 % reduction in the Montgomery-Asberg Depression Rating Scale ( MADRS ) score . In addition , 5 of 12 ( 42 % ) patients newly developed akathisia . This report , though limited by its small sample size and naturalistic design , suggests that the usefulness of aripiprazole in the treatment of bipolar depression may be limited by akathisia BACKGROUND Few studies have examined the relative risks of switching into hypomania or mania associated with second-generation antidepressant drugs in bipolar depression . AIMS To examine the relative acute effects of bupropion , sertraline and venlafaxine as adjuncts to mood stabilisers . METHOD In a 10-week trial , participants receiving out-patient treatment for bipolar disorder ( stratified for rapid cycling ) were r and omly treated with a flexible dose of one of the antidepressants , or their respective matching placebos , as adjuncts to mood stabilisers . RESULTS A total of 174 adults with bipolar disorder I , II or not otherwise specified , currently in the depressed phase , were included . All three antidepressants were associated with a similar range of acute response ( 49 - 53 % ) and remission ( 34 - 41 % ) . There was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline . CONCLUSIONS More caution appears indicated in the use of venlafaxine rather than bupropion or sertraline in the adjunctive treatment of bipolar depression , especially if there is a prior history of rapid cycling Background There is substantial uncertainty regarding the efficacy of antidepressants in the treatment of bipolar disorders . Methods Traditional r and omized controlled trials and statistical methods are not design ed to discover if , when , and to whom an intervention should be applied ; thus , other method ological approaches are needed that allow for the practice of personalized , evidence -based medicine with patients with bipolar depression . Results Dynamic treatment regimes operationalize clinical decision-making as a sequence of decision rules , one per stage of clinical intervention , that map patient information to a recommended treatment . Using data from the acute depression r and omized care ( RAD ) pathway of the Systematic Treatment Enhancement Program for Bipolar Disorder ( STEP-BD ) study , we estimate an optimal dynamic treatment regime  via Q-learning . Conclusions The estimated optimal treatment regime presents some evidence that patients in the RAD pathway of STEP-BD who experienced a (hypo)manic episode before the depressive episode may do better to forgo adding an antidepressant to a m and atory mood stabilizer There are scientific , clinical and cultural aspects to the debate about antidepressants in bipolar depression . In prior communications I ’ve focused on scientific aspects . Over time , as I realized how the scientific evidence seemed unconvincing , I concluded that clinical and cultural aspects were important . Here , besides briefly recapitulating the scientific evidence , I will also comment on clinical and cultural factors . To begin with some rules of clinical research worth making explicit : r and omized data are more valid than observational data , because factors that influence the results besides what we are study ing ( confounding factors ) are only removed by r and omization . Sample size is less relevant ; a large observational study does not contradict a smaller r and omized study . Let ’s keep in mind this basic fact of science ( one can call it evidence -based medicine , EBM , if one wants ) . Given that background , risks and benefits of antidepressants need to be assessed in four categories : acute efficacy , maintenance efficacy , acute manic switch and long-term mood destabilization . These different groupings often overlap and are mixed , leading to confusion BACKGROUND Evidence is accumulating to support the presence of redox dysregulation in a number of psychiatric disorders , including bipolar disorder . This dysregulation may be amenable to therapeutic intervention . Glutathione is the predominant non-enzymatic intracellular free radical scavenger in the brain , and the most generic of all endogenous antioxidants in terms of action . N-acetylcysteine ( NAC ) is a glutathione precursor that effectively replenishes brain glutathione . Given the failure of almost all modern trials of antidepressants in bipolar disorder to demonstrate efficacy , and the limited efficacy of mood stabilisers in the depressive phase of the disorder , this is a major unmet need . METHOD This study reports data on the treatment of 149 individuals with moderate depression during the 2 month open label phase of a r and omised  placebo controlled clinical trial of the efficacy of 1 g BID of NAC that examined the use of NAC as a maintenance treatment for bipolar disorder . RESULTS In this trial , the estimated mean baseline Bipolar Depression Rating Scale ( BDRS ) score was 19.7 ( SE=0.8 ) , and the mean BDRS score at the end of the 8 week open label treatment phase was 11.1 ( SE=0.8 ) . This reduction was statistically significant ( p<0.001 ) . Improvements in functioning and quality of life were similarly evident . CONCLUSION These open label data demonstrate a robust decrement in depression scores with NAC treatment . Large placebo controlled trials of acute bipolar depression are warranted INTRODUCTION Bipolar patients with breakthrough major depressive episodes despite ongoing adequately-dosed mood stabilizer medication were r and omized in a double-blind manner to one of three antidepressants with different mechanisms of action : bupropion , sertraline , or venlafaxine . Preliminary data are presented on the switch rates into hypomania or mania for the antidepressants as a group prior to unblinding the specific individual drug efficacy and tolerability data in this ongoing clinical trial . METHODS Subjects included 64 bipolar patients who participated at five sites in a 10-week double-blind trial for depression and a 1-year blinded continuation maintenance phase for responders . Nonresponders were re-r and omized such that there were 95 acute treatment phases . In the acute phase , doses were titrated to clinical response , side effects , or maximum dose of bupropion ( 450 mg/day ) , sertraline ( 200 mg/day ) , or venlafaxine ( 375 mg/day ) . Daily ratings on the National Institute of Mental Health-Life Chart Methodology ( NIMH-LCM ) were inspected for the degree of improvement on the Clinical Global Impressions scale as revised for bipolar illness ( CGI-BP ) and the occurrence of hypomania or mania . RESULTS Thirty-five ( 37 % ) of the 95 acute treatment phases were associated with a much or very much improved rating in depression on the CGI-BP . Thirteen ( 14 % ) of these 95 acute trials of antidepressants as adjuncts to mood stabilizers were associated with switches , seven into hypomania and six into mania . Forty-two patients elected to go into the continuation phase in 48 instances . Sixteen ( 33 % ) of the continuation phase trials were associated with mood switches , 10 into hypomania and six into mania . CONCLUSIONS In this r and omized double-blind prospect i ve study of three second-generation antidepressants ( bupropion , sertraline , and venlafaxine ) in bipolar patients whose depression broke through ongoing treatment with mood stabilizers , switches into hypomania or mania occurred in 14 % of the acute phases and 33 % of the continuation phases . Individual data on each drug will be assessed in the next phase of the study after more subjects are recruited and the blind is broken OBJECTIVE The aim of this study was to compare the efficacy and tolerability of quetiapine and lithium monotherapy with that of placebo for a major depressive episode in bipolar disorder . METHOD 802 patients with DSM-IV-defined bipolar disorder ( 499 bipolar I , 303 bipolar II ) were r and omly allocated to quetiapine 300 mg/d ( n = 265 ) , quetiapine 600 mg/d ( n = 268 ) , lithium 600 to 1800 mg/d ( n = 136 ) , or placebo ( n = 133 ) for 8 weeks . Primary endpoint was the change in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score . The study was conducted from August 2005 to May 2007 . RESULTS Mean MADRS total score change from baseline at week 8 was -15.4 for quetiapine 300 mg/d , -16.1 for quetiapine 600 mg/d , -13.6 for lithium , and -11.8 for placebo ( P < .001 for both quetiapine doses , P = .123 for lithium , vs placebo ) . Quetiapine 600 mg/d was significantly more effective than lithium in improving MADRS total score at week 8 ( P = .013 ) . Quetiapine-treated ( both doses ) , but not lithium-treated , patients showed significant improvements ( P < .05 ) in MADRS response and remission rates , Hamilton Depression Rating Scale ( HDRS ) , Clinical Global Impressions-Bipolar-Severity of Illness and -Change , and Hamilton Anxiety Rating Scale ( HARS ) scores at week 8 versus placebo . Both quetiapine doses were more effective than lithium at week 8 on the HDRS and HARS . The most common adverse events were somnolence , dry mouth , and dizziness with quetiapine ( both doses ) and nausea with lithium . CONCLUSIONS Quetiapine ( 300 or 600 mg/d ) was more effective than placebo for the treatment of episodes of acute depression in bipolar disorder . Lithium did not significantly differ from placebo on the main measures of efficacy . Both treatments were generally well tolerated . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00206141 BACKGROUND Adjunctive antidepressant therapy is commonly used to treat acute bipolar depression but few studies have examined this strategy . AIMS To examine the efficacy of agomelatine v. placebo as adjuncts to lithium or valproate in bipolar depression . METHOD Patients who were currently depressed despite taking lithium or valproate for at least 6 weeks were r and omised to treatment with agomelatine ( n = 172 )  or placebo ( n = 172 ) for 8 weeks of acute therapy and 44 weeks of continuation therapy ( trial registration : IS RCT N28588282 ) . RESULTS No significant differences in improvement of depressive symptoms were observed between the two groups either at 8 weeks or 52 weeks on the primary efficacy measure of change in Montgomery-Åsberg Depression Rating Scale scores from baseline to end-point . Adverse events including switches into mania/hypomania were low and similar in both groups . CONCLUSIONS Agomelatine adjunctive therapy was not superior to placebo adjunctive therapy for acute bipolar depression Background : In adolescents and adults , bipolar disorder ( BD ) is associated with significant morbidity , mortality , and impairment in psychosocial and occupational functioning . IPSRT is an empirically supported adjunctive psychotherapy for adults with bipolar disorder , which has been shown to help delay relapse , speed recovery from a bipolar depressive episode , and increase occupational and psychosocial functioning in adults with BD . This study is design ed to describe the adolescent‐specific developmental adaptations made to IPSRT ( i.e. , IPSRT‐A ) and to report the results from an open trial of IPSRT‐A with 12 adolescents with a bipolar spectrum disorder . Method : Interpersonal and Social Rhythm Therapy was adapted to be developmentally relevant to adolescents with bipolar disorder . Twelve adolescents ( mean age 16.5±1.3 years ) diagnosed with a bipolar spectrum disorder participated in 16–18 sessions of adjunctive IPSRT‐A over 20 weeks . Manic , depressive , and general symptoms and global functioning were measured at baseline , monthly during treatment , and at post‐treatment . Adolescent satisfaction with treatment was also measured . Results : Feasibility and acceptability  of IPSRT‐A were high ; 11/12 participants completed treatment , 97 % of sessions were attended , and adolescent‐rated satisfaction scores were high . IPSRT‐A participants experienced significant decreases in manic , depressive , and general psychiatric symptoms over the 20 weeks of treatment . Participants ' global functioning increased significantly as well . Effect sizes ranged from medium‐large to large . Conclusions : IPSRT‐A appears to be a promising adjunctive treatment for adolescents with bipolar disorder . A current r and omized controlled trial is underway to examine effects of adjunctive IPSRT‐A  on psychiatric symptoms and psychosocial functioning . Depression and Anxiety , 2010 . © 2010 Wiley‐Liss , OBJECTIVE Antiepileptic drugs ( AEDs ) are commonly employed in the treatment of bipolar disorder . The efficacy and tolerability of topiramate , a novel anticonvulsant , and bupropion SR when added to mood stabilizer therapy were compared under single-blind conditions ( rater-blinded ) in patients meeting DSM-IV criteria for bipolar I/II depression . METHODS A total of 36 out- patients with Hamilton Depression Rating Scale ( HDRS-17 ) scores > or = 16 were r and omized to receive escalating doses of either topiramate ( 50 - 300 mg/day ) or bupropion SR ( 100 - 400 mg/day ) for 8 weeks . Data were analyzed on an intent-to-treat basis using the last observation carried forward method . RESULTS The percentage of patients meeting a priori response criteria ( > or = 50 % decrease from baseline in mean HDRS-17 total score ) was significant for both topiramate ( 56 % ) and bupropion SR ( 59 % ) [ t(17 ) = 2.542 , p = 0.04 and t(17 ) = 2.661 , p = 0.03 , respectively ] . Baseline demographic and clinical parameters were comparable between the two treatment groups . The mean doses of study medication were 176 mg/day ( SD = 102 mg/day ) for the topiramate-treated group and 250 mg/day ( SD = 133 mg/day ) for the bupropion SR-treated group . A significant and comparable reduction in depressive symptoms was observed from baseline to endpoint following topiramate and bupropion SR treatment , according to a > or = 50 % reduction in the HDRS-17 . Total mean HDRS-17 scores significantly decreased from baseline to endpoint in both groups ( p = 0.001 ) , however , differences between the topiramate-treated group and the bupropion SR-treated group were not significant [ t(36 ) = 1.754 , p = 0.097 ] . Both topiramate and bupropion SR were generally well tolerated .  Thirteen patients discontinued the study : 2 because of lack of efficacy  , 1 due to withdrawal of consent and 10 following side-effects ( six in the topiramate and four in the bupropion SR-treated group ) . There were no cases of affective switch in either arm . Weight loss was experienced by patients in both groups ( mean weight loss at endpoint was 1.2 kg in bupropion SR and 5.8 kg in topiramate ) [ t(17 ) = 2.325 , p = 0.061 and t(17 ) = 2.481 , p = 0.043 , respectively ] . CONCLUSIONS These preliminary data suggest that adjunctive topiramate may reduce depressive symptom severity in acute bipolar depression . The antidepressant efficacy of this compound requires confirmation via double-blind placebo controlled investigation OBJECTIVES The efficacy of lamotrigine as maintenance treatment for bipolar disorder ( BD ) , particularly for delaying depressive episodes , is well established , but its efficacy in the acute treatment of bipolar depression is less clear . This paper reports the results of five r and omized , double-blind , placebo-controlled trials of lamotrigine monotherapy for the acute treatment of bipolar depression . METHODS Adult subjects with bipolar I or II disorder experiencing a depressive episode were r and omized to placebo or lamotrigine monotherapy ( after titration , at a fixed dose of 50 mg or 200 mg daily in Study 1 ; a flexible dose of 100 - 400 mg daily in Study 2 ; or a fixed dose of 200 mg daily in Studies 3 , 4 and 5 ) for 7 - 10 weeks . RESULTS Lamotrigine did not differ significantly from placebo on primary efficacy endpoints [ 17-item Hamilton Depression Rating Scale in Studies 1 and 2 ; Montgomery-Asberg Depression Rating Scale ( MADRS ) in Studies 3 , 4 and 5 ] . In Study 1 , lamotrigine significantly separated from placebo on some secondary measures of efficacy , including the MADRS , the Clinical Global Impressions-Severity ( CGI-S ) and the CGI-Improvement ( CGI-I ) , but seldom differed on secondary efficacy endpoints for the other studies . CONCLUSIONS Lamotrigine monotherapy did not demonstrate efficacy in the acute treatment of bipolar depression in four out of five placebo-controlled clinical studies . Lamotrigine was well tolerated in the acute treatment of bipolar depression Maintenance therapy in bipolar disorder ( BD ) is usually required to prevent relapses and improve residual symptoms . Therefore , in this study , we describe patterns of pharmacological maintenance treatment and identify associated clinical features . This prospect i ve multicentre epidemiological study recruited a cohort of 739 consecutive out- patients with clinical ly stable BD . Clinical stability was assessed at baseline with the Clinical Global Impression scale for BD and depressive symptoms with the Hamilton Depression Rating Scale .  Psychotropic medications were classified and analysed according to their mechanism as well as use . Logistic regression models were used to examine the associations between pharmacological strategies and clinical features . Longer time since last episode [ odds ratio ( OR ) 1.002 , p < 0.0001 ] and family history of psychiatric disorders ( OR 1.911 , p = 0.028 ) were associated with lithium in monotherapy ;  manic polarity of the most recent episode ( OR 3.300 , p = 0.006 ) and longer duration of clinical stability ( OR 1.009 , p = 0.034 ) with antipsychotic in monotherapy ;  depressive polarity of the most recent episode ( OR 2.567 , p = 0.003 ) and bipolar II disorder diagnosis ( OR 2.278 , p = 0.008 ) with antidepressant combination ;  no ongoing psychiatric co-morbidity ( OR 0.230 , p = 0.004 ) with lithium and anticonvulsant ;  manic polarity of the most recent episode ( OR 3.774 , p < 0.0001 ) with lithium and antipsychotic ;  manic polarity of the most recent episode ( OR 2.907 , p = 0.028 ) with lithium , anticonvulsant and antipsychotic . The pharmacological patterns followed published recommendations , except for the excessive use of antidepressants . This study reveals clinical factors closely related to prescription patterns BACKGROUND Bright light therapy ( BLT ) is an effective treatment for seasonal affective disorder and non- seasonal depression . The efficacy of BLT in treating patients with bipolar disorder is still unknown . AIMS The aim of this study is to examine the efficacy , onset time and clinical safety of BLT in treating patients with acute bipolar depression as an adjunctive therapy ( trial registration at Clinical Trials.gov : NCT02009371 ) . METHODS This was a multi-center , single blind , r and omized clinical trial . Seventy-four participants were r and omized in one of two treatment conditions : BLT and control ( dim red light therapy , dRLT ) .  Sixty-three participants completed the study ( 33 BLT , 30 dRLT ) . Light therapy lasted for two weeks , one hour every morning . All participants were required to complete several scales assessment s at baseline , and at the end of weeks 1 and 2 . The primary outcome measures were the clinical efficacy of BLT  which was assessed by the reduction rate of HAMD-17 scores , and the onset time of BLT  which was assessed by the reduction rate of QIDS-SR16 scores . The secondary outcome measures were rates of switch into hypomania or mania and adverse events . RESULTS 1 ) Clinical efficacy :  BLT showed a greater ameliorative effect on bipolar depression than the control , with response rates of 78.19 % vs. 43.33 % respectively ( p < 0.01 ) . 2 ) Onset day : Median onset day was 4.33 days in BLT group . 3 )  BLT-emergent hypomania : No participants experienced symptoms of hypomania . 4 ) Side effects : No serious adverse events were reported . CONCLUSION BLT can be considered as an effective and safe adjunctive treatment for patients with acute bipolar depression Rationale Quetiapine extended release ( XR ) has been used to treat various psychiatric disorders , including depressive episodes associated with bipolar I and II disorders .  Quetiapine XR is the first approved drug in China for the treatment of bipolar disorder . Objectives The study evaluated the efficacy and safety of short-term quetiapine XR monotherapy in the treatment of depressive episodes of bipolar I and II disorders . Methods This was an 8-week multi-center , r and omized , double-blind , placebo-controlled , fixed-dose phase 3 study . The primary endpoint was the mean change of the Montgomery-Åsberg Depression Rating Scale ( MADRS ) total score . Secondary endpoints included Clinical Global Impressions-Bipolar ( CGI-BP ) and remission rates . Results The study recruited 279 adult bipolar I or II patients currently experiencing depression from 11 Chinese provinces . Of these , 139 received quetiapine XR ( 300 mg/day ) and 140 received placebo for 8 weeks . The mean change in the MADRS total score was significantly greater in the quetiapine XR group than in the placebo group ( −19.00 ± 7.88 vs. −16.20 ± 9.32 ; p = 0.004 ) . Adverse events occurred in 96 patients ( 65.3 % ) in the quetiapine XR group and 72 ( 49.0 % ) in the placebo group . The incidence of serious adverse events did not differ significantly between the groups ( p = 0.247 ) . Conclusions This study , which is the first to evaluate 300 mg/day quetiapine XR monotherapy for depression in Chinese patients with bipolar disorders , found that this drug was superior to the placebo . Quetiapine XR was generally safe and well tolerated ( Clinical Trials.gov number , NCT01256177 ) Although transurethral resection of the prostate is still the ‘ gold st and ard ’ in the surgical management of benign prostatic hyperplasia , it is associated with significant morbidity . This review presents one of its most successful alternatives , bipolar transurethral vaporization of the prostate , a procedure that has emerged during the last decade . The technical principles are presented , together with the trials that compare it with the st and ard resection technique . The review concludes that bipolar vaporization of the prostate is safe and effective , providing very good hemostasis control and low complication rates , at a significantly reduced cost per procedure . Improved vision and hemostasis make it suitable for patients with cardiac pacemakers , bleeding disorders , or those under anticoagulant therapy . However , long-term follow-up and more r and omized trials are still needed , to vali date the value of bipolar vaporization BACKGROUND Substance abuse frequently complicates the course of bipolar illness , promotes mixed states , and contributes to poor outcome in mania . Preliminary open trials suggest that anticonvulsant mood stabilizers may enhance remission rates and outcome for bipolar patients with substance abuse . This study compared remission patterns for mixed or pure manic episodes among bipolar in patients with or without substance abuse histories . METHOD Hospital records were retrospectively review ed for 204 DSM-III-R bipolar I in patients . Clinical features were compared for those with or without substance abuse/dependence histories predating the index manic episode . Time until remission was analyzed by Kaplan-Meier survival analysis . Naturalistic treatment outcome with lithium or anticonvulsant mood stabilizers was compared for those with or without past substance abuse . RESULTS Past substance abuse was evident in 34 % of the bipolar sample and comprised most often alcoholism ( 82 % ) , followed by cocaine ( 30 % ) , marijuana ( 29 % ) , sedative-hypnotic or amphetamine ( 21 % ) , and opiate ( 13 % ) abuse . Substance abuse was more common among men ( p < .05 ) and those with mixed rather than pure mania ( p < .05 ) . Remission during hospitalization was less likely among patients with prior substance abuse ( p < .05 ) , especially alcohol or marijuana abuse , and among mixed manic patients with past substance abuse ( p < .05 ) . Bipolar patients with substance abuse histories who received divalproex or carbamazepine  remitted during hospitalization more often than did those who received lithium as the sole mood stabilizer ( p < .05 ) . CONCLUSION These findings support previous reports suggesting that bipolar patients with past substance abuse have poorer naturalistic treatment outcomes , but may show a better response to anticonvulsant mood stabilizers than lithium OBJECTIVE Cariprazine , a dopamine D3/D2 and 5-HT1A receptor partial agonist , was found to be effective in treating bipolar I depression in a previous phase 2 study . This phase 3 study further assessed the efficacy , safety , and tolerability of cariprazine in bipolar I depression . METHODS In a double-blind placebo-controlled study , adult participants ( 18 - 65 years old ) who met DSM-5 criteria for bipolar I disorder and a current depressive episode were r and omly assigned to receive placebo ( N=158 ) or cariprazine at 1.5 mg/day ( N=157 ) or 3.0 mg/day ( N=165 ) . The primary and secondary efficacy parameters were changes from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale ( MADRS ) score and Clinical Global Impressions severity ( CGI-S ) score , respectively . Least squares mean differences were estimated using a mixed model for repeated measures , and p values were adjusted for multiplicity . RESULTS Both dosages of cariprazine were significantly more effective than placebo in improving depressive symptoms ( reducing MADRS total score ) ; the least squares mean differences were -2.5 ( 95 % CI=-4.6 , -0.4 ) for cariprazine at 1.5 mg/day and -3.0 ( 95 % CI=-5.1 , -0.9 ) for cariprazine at 3.0 mg/day . Both cariprazine dosages were associated with lower CGI-S scores compared with placebo , but the differences did not reach statistical significance after adjustment for multiplicity ( least squares mean difference , -0.2 [ 95 % CI=-0.5 , 0.0 ] for the 1.5 mg/day group and -0.3 [ 95 % CI=-0.5 , 0.0 ] for the 3.0 mg/day group ) . Common treatment-emergent adverse events ( in at least 5 % of participants in either cariprazine treatment group and twice the rate of the placebo group ) were nausea , akathisia , dizziness , and sedation . Mean changes in weight and metabolic parameters were relatively small and comparable across groups . CONCLUSIONS Cariprazine , at both 1.5 mg/day and 3.0 mg/day , was effective , generally well tolerated , and relatively safe in reducing depressive symptoms in adults with bipolar I depression Breakthrough depression is a common problem in the treatment of bipolar disorder . Only one , recently published , double-blind , placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients . This report describes , in further detail , the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder . A r and omized , double-blind , parallel-group , multicenter study was conducted over a 52-week maintenance period . Bipolar I patients , who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode , were r and omized to maintenance treatment with divalproex , lithium , or placebo in a 2 : 1 : 1 ratio . Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase . Outcome measures were the rate of early discontinuation for depression , time to depressive relapse , proportion of patients with depressive relapse , mean change in Depressive Syndrome Scale score , proportion of patients receiving antidepressants , and time in the study . Among patients taking an antidepressant , a higher percentage of patients on placebo than divalproex discontinued early for depression .  Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period . Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance . Indices of severity of pre study illness course predicted worse outcome in all treatment groups . Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder , particularly in patients who had responded to divalproex when manic , and among patients with a more severe course of illness Transcranial Direct Current Stimulation ( tDCS ) is a new , non-invasive neuromodulation approach for treating depression that has shown promising efficacy . The aim of this trial was to conduct the first international , multicentre r and omised controlled trial of tDCS as a treatment for unipolar and bipolar depression . The study recruited 120 participants across 6 sites in the USA and Australia . Participants received active or sham tDCS ( 2.5mA , 20 sessions of 30min duration over 4weeks ) , followed by a 4-week open label active treatment phase and a 4-week taper phase . Mood and neuropsychological outcomes were assessed with the primary antidepressant outcome measure being the Montgomery-Asberg Depression Rating Scale ( MADRS ) . A neuropsychological battery was administered to assess safety and examine cognitive effects . The study also investigated the possible influence of genetic polymorphisms on outcomes . The trial was triple-blinded . Participants , tDCS treaters and study raters were blinded to each participant 's tDCS group allocation in the sham-controlled phase . Specific aspects of tDCS administration , device operation and group allocation were design ed to optimise the integrity of blinding . Outcome measures will be tested using a mixed effects repeated measures analysis with the primary factors being Time as a repeated measure , tDCS condition ( sham or active ) and Diagnosis ( unipolar or bipolar ) . A restricted number of r and om and fixed factors will be included as required to account for extraneous differences . As a promising treatment , tDCS has excellent potential for translation into widespread clinical use , being cost effective , portable , easy to operate and well tolerated OBJECTIVE Quetiapine is an atypical antipsychotic with demonstrated efficacy in the treatment of adolescent schizophrenia and pediatric bipolar mania . Large , placebo-controlled studies of interventions in pediatric bipolar depression are lacking . The current study investigated the efficacy and safety of quetiapine extended-release ( XR ) in patients 10 - 17 years of age , with acute bipolar depression . METHODS This multicenter , double-blind , r and omized , placebo-controlled study investigated quetiapine XR ( dose range , 150 - 300 mg/day ) in pediatric out patients with an American Psychiatric Association , Diagnostic and Statistical Manual of Mental Disorders , 4th ed . , Text Revision ( DSM-IV-TR ) diagnosis of bipolar I or bipolar II disorder ( current or most recent episode depressed ) treated for up to 8 weeks ( Clinical Trials.gov identifier : NCT00811473 ) . The primary study outcome was mean change in Children 's Depression Rating Scale-Revised ( CDRS-R ) total score . Secondary efficacy outcomes included CDRS-R-based response and remission rates . RESULTS Of 193 patients r and omized to treatment , 144 patients completed the study ( 75.3 % of quetiapine XR group [ n=70 ] ; 74.0 % of placebo  group [ n=74 ] ) . Least squares mean changes in CDRS-R total score at week 8 were : -29.6 ( SE , 1.65 ) with quetiapine XR and -27.3 ( SE , 1.60 ) with placebo , a between-treatment group difference of -2.29 ( SE , 1.99 ; 95 % CI , -6.22 , 1.65 ; p=0.25 ; mixed-model for repeated measures analysis ) . Rates of response and remission did not differ significantly between treatment groups . The safety profile of quetiapine XR was broadly consistent with the profile reported previously in adult studies of quetiapine XR and pediatric studies of quetiapine immediate-release ( IR ) . Potentially clinical ly significant elevations in clinical chemistry values included triglycerides ( 9.3 % , quetiapine XR ; 1.4 % , placebo group ) and thyroid stimulating hormone ( 4.7 % , quetiapine XR ; 0 % , placebo group ) . An adverse event potentially related to diabetes mellitus occurred in 3.3 % of the quetiapine XR versus no adverse events in the placebo group . CONCLUSIONS Quetiapine XR did not demonstrate efficacy relative to placebo in this 8 week study of pediatric bipolar depression . Quetiapine XR was generally safe and well tolerated BACKGROUND Evidence suggests that transcranial Direct Current Stimulation ( tDCS ) has antidepressant effects in unipolar depression , but there is limited information for patients with bipolar depression . Additionally , prior research suggests that brain derived neurotrophic factor ( BDNF ) Val66Met genotype may moderate response to tDCS . OBJECTIVE To examine tDCS efficacy in unipolar and bipolar depression and assess if BDNF genotype is associated with antidepressant response to tDCS . METHODS 130 participants diagnosed with a major depressive episode were r and omized to receive active ( 2.5 milliamps ( mA ) , 30 min ) or sham ( 0.034 mA and two 60-second current ramps up to 1 and 0.5 mA ) tDCS to the left prefrontal cortex , administered in 20 sessions over 4 weeks , in a double-blinded , international multisite study . Mixed effects repeated measures analyses assessed change in mood and neuropsychological scores in participants with at least one post-baseline rating in the unipolar ( N = 84 ) and bipolar ( N = 36 ) sample s. RESULTS Mood improved significantly over the 4-week treatment period in both unipolar ( p = 0.001 ) and bipolar groups ( p < 0.001 ) . Among participants with unipolar depression , there were more remitters in the sham treatment group ( p = 0.03 ) . There was no difference between active and sham stimulation in the bipolar sample . BDNF genotype was unrelated to antidepressant outcome . CONCLUSIONS Overall , this study found no antidepressant difference between active and sham stimulation for unipolar or bipolar depression . However , the possibility that the low current delivered in the sham tDCS condition was biologically active can not be discounted . Moreover , BDNF genotype did not moderate antidepressant outcome . CLINICAL TRIALS REGISTRATION www . clinical trials.gov , NCT01562184 BACKGROUND More than half of all individuals with bipolar disorder have a substance abuse problem at some point in their lifetime . Patients with comorbid substance abuse disorders often are excluded from clinical trials . Thus , treatments targeting this high-risk clinical population are lacking . OBJECTIVE To evaluate the efficacy of divalproex sodium ( hereafter referred to as valproate ) in decreasing alcohol use and stabilizing mood symptoms in acutely ill patients with bipolar disorder and alcoholism . DESIGN A 24-week , double-blind , placebo-controlled , r and omized parallel-group trial . SETTING A university hospital serving as a primary catchment-area hospital and tertiary-care facility . PARTICIPANTS Fifty-nine subjects with diagnoses of bipolar I disorder and alcohol dependence . Intervention All study subjects received treatment as usual , including lithium carbonate and psychosocial interventions , and were r and omized to receive valproate or placebo . MAIN OUTCOME MEASURES Primary alcohol use outcomes included changes in alcohol use as indicated by changes in proportion of heavy drinking days and number of drinks per heavy drinking day . Other alcohol use outcomes included proportion of any drinking days , number of drinks per drinking day , and relapse to sustained heavy drinking . Mood outcomes included changes in depressive and manic symptoms . We used the mixed model to analyze longitudinal data . The first model used time of assessment , bipolar subtype ( mixed , manic , or depressed ) , and treatment group ( placebo or valproate ) as covariates . The second nested model included the additional covariate of medication adherence . RESULTS The valproate group had a significantly lower proportion of heavy drinking days ( P = .02 ) and a trend toward fewer drinks per heavy drinking day ( P = .055 ) than the placebo group . When medication adherence was added as covariate , the valproate group had significantly fewer drinks per heavy drinking day ( P = .02 ) and fewer drinks per drinking day ( P = .02 ) . Higher  valproate serum concentration significantly correlated with improved alcohol use outcomes . Manic and depressive symptoms improved equally in both groups . Level of gamma-glutamyl transpeptidase was significantly higher in the placebo group compared with the valproate group . CONCLUSIONS Valproate therapy decreases heavy drinking in patients with comorbid bipolar disorder and alcohol dependence . The results of this study indicate the potential clinical utility of the anticonvulsant mood stabilizer , valproate , in bipolar disorder with co-occurring alcohol dependence
Findings were inconclusive for lamotrigine and carbamazepine although overall lamotrigine may have a beneficial but modest effect .
Negative results were found for levetiracetam and gabapentin but the evidence base on these agents is scant .
All anticonvulsants were generally well tolerated .
No double-blind RCTs were found for the use of other anticonvulsants such as oxcarbazepine , licarbazepine , zonisamide , retigabine , pregabalin , tiagabine , felbamate and vigabatrine in the acute treatment of bipolar depression .
To sum up , taking into consideration the efficacy and tolerability profiles of anticonvulsants , current evidence supports the use of divalproex and lamotrigine in the treatment of acute bipolar depression .
Despite the high morbidity and mortality associated with bipolar depression , the optimal treatment for this phase is still a matter of debate .
The aim of the current review was to provide up date d evidence about the efficacy and tolerability of anticonvulsants in the treatment of acute bipolar depression .