Patterns of pharmacological maintenance treatment in a community mental health services bipolar disorder cohort study (SIN-DEPRES). The study protocol of the Norwegian randomized controlled trial of electroconvulsive therapy in treatment resistant depression in bipolar disorder Suicide attempts in patients with bipolar I disorder during acute and maintenance phases of intensive treatment with pharmacotherapy and adjunctive psychotherapy. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. Efficacy and tolerability of lithium in treating acute mania in youth with bipolar disorder: protocol for a systematic review A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Study design and methodology for a multicentre, randomised controlled trial of transcranial direct current stimulation as a treatment for unipolar and bipolar depression. Impact of antidepressant continuation after acute positive or partial treatment response for bipolar depression: a blinded, randomized study. Safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for relapse-prevention of bipolar II depression: A randomized, double-blind, parallel-group, prospective study. Antidepressant-induced mania in bipolar patients: identification of risk factors. Why do clinicians maintain antidepressants in some patients with acute mania? Hints from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM), a large naturalistic study. Depression and Suicidality Outcomes in the Treatment of Early Age Mania Study. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. A sham-controlled randomized trial of adjunctive light therapy for non-seasonal depression. Post-acute effectiveness of lithium in pediatric bipolar I disorder. Efficacy and Safety of Transcranial Direct Current Stimulation as an Add-on Treatment for Bipolar Depression: A Randomized Clinical Trial Differential outcome of bipolar patients receiving antidepressant monotherapy versus combination with an antimanic drug.
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 The treatment of depressive phases of bipolar disorder is challenging . The effects of the commonly used antidepressants in bipolar depression are question able . Electroconvulsive therapy is generally considered to be the most effective treatment even if there are no r and omized controlled trials of electroconvulsive therapy in bipolar depression . The safety of electroconvulsive therapy is well documented , but there are some controversies as to the cognitive side effects . The aim of this study is to compare the effects and side effects of electroconvulsive therapy to pharmacological treatment in treatment resistant bipolar depression .  Cognitive changes and quality of life during the treatment will be assessed . Methods / Design A prospect i ve , r and omised controlled , multi-centre six- week acute treatment trial with seven clinical assessment s. Follow up visit at 26 weeks or until remission ( max 52 weeks ) . A neuropsychological test battery design ed to be sensitive to changes in cognitive function will be used . Setting : Nine study centres across Norway , all acute psychiatric departments . Sample : n = 132 patients , aged 18 and over , who fulfil criteria for treatment resistant depression in bipolar disorder , Montgomery Åsberg Depression Rating Scale Score of at least 25 at baseline . Intervention : Intervention group : 3 sessions per week for up to 6 weeks , total up to 18 sessions . Control group : algorithm-based pharmacological treatment as usual . Discussion This study is the first r and omized controlled trial that aims to investigate whether electroconvulsive therapy is better than pharmacological treatment as usual in treatment resistant bipolar depression . Possible long lasting cognitive side effects will be evaluated . The study is investigator initiated , without support from industry . Trial registration OBJECTIVE Lifetime rates of  suicide attempts among patients with bipolar I disorder were compared to rates during a 2-year period of intensive treatment with pharmacotherapy and with one of two adjunctive psychosocial interventions . METHOD Subjects entered the study during an acute mood episode . Subjects were treated with primarily lithium pharmacotherapy and with either psychotherapy specific to bipolar disorder , which included help in regularizing daily routines , or nonspecific , intensive clinical management involving regular visits with empathic clinicians . Data on prior suicide attempts were obtained retrospectively from interviews with the NIMH-Life-Chart method . Data on suicide attempts during the clinical trial were collected systematic ally throughout the protocol . RESULTS The rate of suicide attempts  was 1.05 per 100 person-months before patients entered the trial . Patients experienced a threefold reduction in the rate of suicide attempts during the acute treatment phase ( until the patient achieved stabilization , defined by completion of 4 weeks during which the patient had a mean score of < or = 7 on the 17-item Hamilton Depression Rating Scale and < or = 7 on the Bech-Rafaelsen Mania Scale ) and a 17.5-fold reduction during maintenance treatment . Poisson loglinear regression analysis modeling the relationship between the observed rates and the three protocol stages ( pretreatment , acute , and maintenance ) showed that the reductions were significant in the acute and maintenance phases , compared with the pretreatment phase . No patient with one or more suicide attempts before entering the trial attempted suicide during the protocol . CONCLUSIONS A treatment program in a maximally supportive clinical environment can significantly reduce suicidal behavior in high-risk patients with bipolar I disorder 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 Background Epidemiological , clinical , and high-risk studies have provided evidence that the peak period for onset of diagnosable episodes of mania and hypomania starts in mid-to-late adolescence . Moreover , clinical ly significant manic symptoms may occur even earlier , especially in children at familial risk . Lithium is the gold st and ard treatment for acute mania in adults , yet to our knowledge , there is no published systematic review assessing lithium treatment of mania in children or adolescents . This is a major gap in knowledge needed to inform clinical practice . Aim As a working group within the ISBD Task Force on Lithium Treatment ( http://www.isbd.org/active-task-forces ) , our aim is to complete a systematic review of the efficacy , tolerability , and acceptability of lithium compared with placebo and other active drugs in treating mania in children and adolescents diagnosed with bipolar disorder . Methods We will include double- or single-blind r and omized controlled trials in patients aged less than 18 years . No restrictions will be made by study publication date or language . Several electronic data bases will be search ed along with secondary sources such as bibliographies and trial registry websites for published and unpublished studies . Response rates to lithium compared with placebo or other active drugs will be the primary efficacy outcome . Primary tolerability and acceptability outcomes will be rates of serious adverse events and dropouts , respectively . Secondary outcomes will include rates of remission , severity of manic symptoms at different time points , and incidence of specific adverse events . Discussion Findings from this systematic review are critically needed to inform clinical practice . We should not generalize findings from adult studies , as children and adolescents are undergoing accelerated physiological and brain development . Therefore , efficacy , tolerability , and acceptability of lithium treatment of acute mania in children compared to adults may be very different . This systematic review has been registered in PROSPERO ( CRD42017055675 ) OBJECTIVE The authors tested the hypothesis that divalproex would be more effective than lithium in the long-term management of patients with recently stabilized rapid-cycling bipolar disorder . METHOD A 20-month , double-blind , parallel-group comparison was carried out in recently hypomanic/manic patients who had experienced a persistent bimodal response to combined treatment with lithium and divalproex . Sixty patients were r and omly assigned to lithium or divalproex monotherapy in a balanced design after stratification for illness type ( bipolar I versus bipolar II disorder ) . RESULTS Of the 254 patients enrolled in the open-label acute stabilization phase , 76 % discontinued the study prematurely ( poor adherence : 28 % ; nonresponse : 26 % [ of whom 74 % remained depressed and 26 % remained in a hypomanic/manic/mixed episode ] , intolerable side effects : 19 % ) . Of the 60 patients ( 24 % ) r and omly assigned to double-blind maintenance monotherapy , 53 % relapsed ( 59 % into depression and 41 % into a hypomanic/manic/mixed episode ) , 22 % completed the study , 10 % had intolerable side effects , and 10 % were poorly adherent . The rates of relapse into any mood episode for those given lithium versus divalproex were 56 % and 50 % , respectively ; the rates were 34 % and 29 % for a depressive relapse and 19 % and 22 % for a hypomania/mania relapse . There were no significant differences in time to relapse . The proportion discontinuing prematurely because of side effects was 16 % for lithium and 4 % for divalproex . CONCLUSIONS The hypothesis that divalproex is more effective than lithium in the long-term management of rapid-cycling bipolar disorder is not supported by these data . Preliminary data suggest highly recurrent refractory depression may be the hallmark of rapid-cycling bipolar disorder 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 To assess long-term outcome in bipolar disorder , subjects were prospect ively followed after receiving acute treatment for bipolar depression . METHOD Eighty-three out patients with DSM-IV bipolar depression who were enrolled between March 1996 and November 2002 and were treated in a 10-week acute double-blind antidepressant treatment trial agreed to participate in a 1-year double-blind continuation of their medication . In the acute antidepressant treatment trial , subjects were treated with a mood stabilizer plus 1 of 3 r and omly assigned antidepressants .  Sixty-one subjects had attained an acute positive antidepressant response ( 50 % improvement on the Inventory for Depressive Symptomatology [ IDS ] or 2-point improvement on the Clinical Global Impression for Bipolar Disorder [ CGI-BP ] ) and 22 subjects achieved only acute partial improvement at the end of the 10-week acute trial . In the blinded continuation phase immediately following the acute trial , subjects continued on the same medications and were rated monthly for up to 1 year using the IDS , CGI-BP , and the Young Mania Rating scale . RESULTS At study endpoint , 42 ( 69 % ) of the 61 acute positive responders maintained positive response and 32 ( 53 % ) achieved remission . Compared to the acute positive responders , 6 ( 27 % ) of the 22 acute partial responders had achieved positive treatment response at study endpoint ( p < .001 ) . Eight acute positive responders ( 13 % ) and 5 acute partial responders ( 22 % ) developed mania . CONCLUSION Patients who achieve a positive acute antidepressant response to 10 weeks of antidepressant treatment adjunctive to a mood stabilizer will probably maintain response with the same continued treatment . Patients who achieve only a partial acute antidepressant response are less likely to further improve when the same treatment is sustained . The switch rate into mania for patients being treated with an antidepressant adjunctive to a mood stabilizer is not higher than the reported rate for patients on mood stabilizer monotherapy OBJECTIVE Compare the safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for preventing  depressive relapse in bipolar II disorder . METHODS Subjects ≥18 years old with bipolar II depression ( n=129 ) were r and omized to double-blind venlafaxine or lithium monotherapy for 12 weeks . Responders with a ≥50 % reduction in depression score were continued for an additional 6 months of relapse-prevention monotherapy . Primary outcome was depressive relapse during continuation monotherapy . Secondary outcomes included sustained response rate from initiation of treatment to study end-point , relapse hazard , time to relapse , change in mania ratings , and frequency of treatment-emergent sub-syndromal hypomania and /or depressive episodes . RESULTS Venlafaxine produced greater sustained response rate  versus lithium ( p<0.0001 ) ; however , there was no difference in relapse rate  for venlafaxine ( 7.5 % ) versus lithium ( 26.7 % ) ( p=0.079 ) ; relapse hazard ( p=0.073 ) , or time to relapse ( p=0.090 ) between treatment conditions during continuation monotherapy . There were no group differences in mania rating scores over time and no difference in frequency or duration of syndromal or sub-syndromal hypomanic episodes . There were more sub-syndromal depressive episodes  during lithium monotherapy ( p=0.03 ) . LIMITATIONS Sample size was limited by the lower sustained response rate  for lithium versus venlafaxine ; study was not specifically powered to detect differences in treatment-emergent hypomanic or depressive episodes between groups . CONCLUSION Results suggest that continuation venlafaxine monotherapy may provide similar prophylactic effectiveness relative to lithium , with no difference in treatment-emergent hypomanic episodes and without the need for frequent serum lithium level and metabolic monitoring . Larger , prospect i ve trials are needed to confirm these observations BACKGROUND Concerns about possible risks of switching to mania associated with antidepressants continue to interfere with the establishment of an optimal treatment paradigm for bipolar depression . METHOD The response of 44 patients meeting DSM-IV criteria for bipolar disorder to naturalistic treatment was assessed for at least 6 weeks using the Montgomery-Asberg Depression Rating Scale and the Bech-Rafaelson Mania Rating Scale . Patients who experienced a manic or hypomanic switch were compared with those who did not on several variables including age , sex , diagnosis ( DSM-IV bipolar I vs. bipolar II ) , number of previous manic episodes , type of antidepressant therapy used ( electroconvulsive therapy vs. antidepressant drugs and , more particularly , selective serotonin reuptake inhibitors [ SSRIs ] ) , use and type of mood stabilizers ( lithium vs. anticonvulsants ) , and temperament of the patient , assessed during a normothymic period using the hyperthymia component of the Semi-structured Affective Temperament Interview . RESULTS Switches to hypomania or mania occurred in 27 % of all patients ( N = 12 ) ( and in 24 % of the subgroup of patients treated with SSRIs [ 8/33 ] ) ; 16 % ( N = 7 ) experienced manic episodes , and 11 % ( N = 5 ) experienced hypomanic episodes . Sex , age , diagnosis ( bipolar I vs. bipolar II ) , and additional treatment did not affect the risk of switching . The incidence of mood switches seemed not to differ between patients receiving an anticonvulsant and those receiving no mood stabilizer . In contrast , mood switches were less frequent in patients receiving lithium ( 15 % , 4/26 ) than in patients not treated with lithium ( 44 % , 8/18 ; p = .04 ) . The number of previous manic episodes did not affect the probability of switching , whereas a high score on the hyperthymia component of the Semistructured Affective Temperament Interview was associated with a greater risk of switching ( p = .008 ) . CONCLUSION The frequency of mood switching associated with acute antidepressant therapy may be reduced by lithium treatment . Particular attention should be paid to patients with a hyperthymic temperament , who have a greater risk of mood switches OBJECTIVE Antidepressants are supposed to be withdrawn during a manic episode . The aim of this study was to analyze the characteristics of manic patients who received antidepressants during a manic phase in a large , naturalistic study . METHOD The European Mania in Bipolar Longitudinal Evaluation of Medication was a 2-year prospect i ve observational study of in patients and out patients with acute mania/mixed mania ( DSM-IV or ICD-10 criteria ) conducted in 14 European countries . Of 2,416 manic patients who continued into the maintenance phase of the study , 345 ( 14 % ) were taking an antidepressant  and 2,071 ( 86 % ) were not taking an antidepressant at baseline , week 1 , and /or week 2 postbaseline . Demographic and clinical variables were collected at baseline and each study visit up to 24 months . Outcome measures included the Clinical Global Impressions-Bipolar Disorder scale ( CGI-BP overall , mania , and depression scores ) at 12 weeks and 24 months , the 5-item Hamilton Depression Rating Scale ( HDRS-5 ) , and the Young Mania Rating Scale ( YMRS ) at 12 weeks only . The present study was conducted from December 2002 to June 2004 . RESULTS More antidepressant maintenance use was seen in patients with mixed episodes ( P < .001 ) , rapid cyclers ( P < .02 ) , patients with more previous depressive episodes ( P < .001 ) , and patients with higher mean HDRS-5 score at baseline ( P < .001)-specifically patients with anxiety ( P = .013 ) . Patients in the antidepressant group had significantly higher CGI-BP depression scores ( P < .001 ) and a significantly higher rate of depression relapse ( P < .001 ) at both 12 weeks and 24 months . CONCLUSIONS Patients with mania receiving antidepressants are more likely to be out patients with mixed episodes , anxiety , or rapid cycling and have a higher risk of depression relapse during follow-up OBJECTIVE To assess the efficacy of mood-stabilizing medications for depression and suicidality in pediatric bipolar disorder . METHOD The Treatment of Early Age Mania ( TEAM ) study is a multicenter , prospect i ve , r and omized , masked comparison of divalproex sodium ( VAL ) , lithium carbonate ( LI ) , and risperidone ( RISP ) in an 8-week parallel clinical trial . A total of 279 children and adolescents with DSM-IV diagnoses of bipolar I disorder , mixed or manic , aged 6 to 15 years were enrolled . The primary outcome measure was improvement on the Clinical Global Impression scale for depression ( CGI-BP-I-D ) . Secondary outcome measures included the Children 's Depression Rating Scale ( CDRS-R ) and suicidality status . Statistics included longitudinal analysis of outcomes using generalized linear mixed models with r and om intercept both for the complete data set and by using last observation carried forward . RESULTS CGI-BP-I-D ratings were better in the RISP group ( 60.7 % ) as compared to the LI ( 42.2 % ; p = .03 ) or VAL ( 35.0 % ; p = .003 ) groups from baseline to the end of the study . CDRS scores in all treatment groups improved equally by study end . In week 1 , scores were lower with RISP compared to VAL ( mean = 4.72 , 95 % CI = 2.67 , 6.78 ) , and compared to LI ( mean = 3.63 , 95 % CI = 1.51 , 5.74 ) , although group differences were not present by the end of the study . Suicidality was infrequent , and there was no overall effect of treatment on suicidality ratings . CONCLUSION Depressive symptoms , present in the acutely manic or mixed phase of pediatric bipolar disorder , improved with all 3 medications , though RISP appeared to yield more rapid improvement than LI or VAL and was superior using a global categorical outcome . Clinical trial registration information- Study of Outcome and Safety of Lithium , Divalproex and Risperidone for Mania in Children and Adolescents ( TEAM ) ; http:// clinical trials.gov ; NCT00057681 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 BACKGROUND The aim of the study was to examine the efficacy and safety of morning bright light therapy ( BLT ) in the treatment of patients with a current major depressive episode ( MDE ) in bipolar and unipolar disorder without a seasonal pattern . It was a r and omized , sham-controlled trial . METHODS Adults , ages 18 - 70 years were r and omized to treatment either with BLT or a sham negative ion generator ( as a placebo control ) . The subjects were required to be on a stable and therapeutic dose of psychotropic medication for at least 4 weeks prior to enrollment and their treatment had to be insufficiently effective . Their clinical state was monitored at the baseline and at the end of treatment . The Hamilton Depression Rating Scale-21 items ( HDRS-21 ) , Montgomery-Asberg Depression Rating Scale ( MADRS ) , Beck Depression Inventory ( BDI-II ) , Clinical Global Impression-Severity ( CGI-S ) and Patient Global Impression ( PGI ) were used . The results were analyzed with an intention-to-treat ( ITT ) analysis . RESULTS Ninety-five patients were enrolled ( 50 diagnosed with bipolar disorder and 45 with unipolar depression ) . Fifty-two patients were r and omized to treatment with BLT and forty-three were in the placebo group ( ITT population ) . Eighty-three subjects completed the study . There were 12 dropouts ( 5 in the light group and 7 in the placebo group ) . After 14 days of treatment , a significant improvement was found in all groups ( p<0.001 ) . The subjects treated with BLT did not significantly differ in terms of improvement in HDRS-21 scores at the endpoint when compared to patients treated with placebo ( p=0.2 ) . However , further analysis demonstrated significantly higher response ( 50 % v. 27.9 % , p=0.02 ) and remission rates ( 28.8 % v. 11.6 % , p=0.04 ) among patients treated with morning BLT when compared to placebo group . It should be noted that in the population of drug-resistant patients , BLT was more efficacious than placebo . There were no statistically significant differences between unipolar and bipolar disorders ( p=0.4 ) . CONCLUSION Although overall improvement in HDRS-21 scores were not superior in the BLT group , both response and remission rates were significantly higher among patients treated with BLT relative to those receiving the sham intervention . BLT was also more efficacious than placebo in the population of patients with drug-resistant depression . Further studies to define the sub population of patients with non-seasonal depression who may benefit the most from BLT are needed OBJECTIVE This study examined the long-term effectiveness of lithium for the treatment of pediatric bipolar disorder within the context of combination mood stabilizer therapy for refractory mania and pharmacological treatment of comorbid psychiatric conditions . METHODS Out patients , ages 7 - 17 years , meeting American Psychiatric Association , diagnostic and statistical manual of mental disorders , 4th ed . ( DSM-IV ) diagnostic criteria for bipolar disorder I ( BP-I ) ( manic or mixed ) who demonstrated at least a partial response to 8 weeks of open-label treatment with lithium ( phase I ) were eligible to receive open-label lithium for an additional 16 weeks ( phase II ) . Up to two adjunctive medications could be prescribed to patients experiencing residual symptoms of mania or comorbid psychiatric conditions , following a st and ardized algorithm . RESULTS Forty-one patients received continued open-label long-term treatment with lithium for a mean of 14.9 ( 3.0 ) weeks during phase II . The mean weight-adjusted total daily dose at end of phase II was 27.8 ( 6.7 ) mg/kg/day , with an average lithium concentration of 1.0 ( 0.3 ) mEq/L. Twenty-five of the 41 patients ( 60.9 % ) were prescribed adjunctive psychotropic medications for residual symptoms . The most frequent indications for adjunctive medications were refractory mania ( n=13 ; 31.7 % ) and attention-deficit/hyperactivity disorder ( ADHD ) ( n=15 ; 36.6 % ) . At the end of this phase 28 ( 68.3 % ) patients met a priori criteria for response ( ≥50 % reduction from phase I baseline in young mania rating scale [ YMRS ] summary score and a clinical global impressions-improvement [ CGI-I ] score of 1 or 2 ) , with 22 ( 53.7 % ) considered to be in remission ( YMRS summary score≤12 and CGI-severity score of 1 or 2 ) . These data suggest that patients who initially responded to lithium  maintained mood stabilization during continuation treatment , but partial responders did not experience further improvement during Phase II , despite the opportunity to receive adjunctive medications . The most commonly reported ( ≥20 % ) adverse events associated with lithium treatment were vomiting , headache , abdominal pain , and tremor .  CONCLUSIONS Lithium may be a safe and effective longer-term treatment for patients with pediatric bipolar disorder who respond to acute treatment with lithium . Partial responders to acute lithium did not appear to experience substantial symptom improvement during the continuation phase , despite the possibility that adjunctive medications could be prescribed Importance More effective , tolerable interventions for bipolar depression treatment are needed . Transcranial direct current stimulation ( tDCS ) is a novel therapeutic modality with few severe adverse events that showed promising results for unipolar depression . Objective To determine the efficacy and safety of tDCS as an add-on treatment for bipolar depression . Design , Setting , and Participants A r and omized , sham-controlled , double-blind trial ( the Bipolar Depression Electrical Treatment Trial [ BETTER ] ) was conducted from July 1 , 2014 , to March 30 , 2016 , at an outpatient , single-center academic setting . Participants included 59 adults with type I or II bipolar disorder in a major depressive episode and receiving a stable pharmacologic regimen with 17-item Hamilton Depression Rating Scale ( HDRS-17 ) scores higher than 17 . Data were analyzed in the intention-to-treat sample . Interventions Ten daily 30-minute , 2-mA , anodal-left and cathodal-right prefrontal sessions of active or sham tDCS on weekdays and then 1 session every fortnight until week 6 . Main Outcomes and Measures Change in HDRS-17 scores at week 6 . Results Fifty-nine patients ( 40 [ 68 % ] women ) , with a mean ( SD ) age of 45.9 ( 12 ) years participated ; 36 ( 61 % ) with bipolar I and 23 ( 39 % ) with bipolar II disorder were r and omized and 52 finished the trial . In the intention-to-treat analysis , patients in the active tDCS condition showed significantly superior improvement compared with those receiving sham ( & bgr;int = −1.68 ; number needed to treat , 5.8 ; 95 % CI , 3.3 - 25.8 ; P = .01 ) . Cumulative response rates were higher in the active vs sham groups ( 67.6 % vs 30.4 % ; number needed to treat , 2.69 ; 95 % CI , 1.84 - 4.99 ; P = .01 ) , but not remission rates ( 37.4 % vs 19.1 % ; number needed to treat , 5.46 ; 95 % CI , 3.38 - 14.2 ; P = .18 ) . Adverse events , including treatment-emergent affective switches , were similar between groups , except for localized skin redness that was higher in the active group ( 54 % vs 19 % ; P = .01 ) . Conclusions and Relevance In this trial , tDCS was an effective , safe , and tolerable add-on intervention for this small bipolar depression sample . Further trials should examine tDCS efficacy in a larger sample . Trial Registration clinical trials.gov Identifier : INTRODUCTION Despite antidepressants are widely used in treating bipolar depression , there is much debate about their utility and their potential dangers , involving mood switches and suicidality . Our hypothesis was that the pattern of initial antidepressant prescription , i.e. , alone ( AM ) or in combination with stabilizers ( AC ) might impact the long-term outcome of patients with bipolar disorder ( BP ) . We aim ed to test this hypothesis and to identify outcome measures that could be predicted by initial AM or AC treatment in patients with BP . METHODS We included 95 patients with DSM-IV BP from a pool of 138 patients following a BP program .  Patients were rated for initial AM vs. AC treatment when they were first seen in primary care and subdivided into two groups accordingly . Differences in their clinical course were sought investigating course both retrospectively and prospect ively ( mean follow-up 10 years ) . Primary outcome measures comprised suicidality and switch rate . RESULTS There were significantly more patients who switched in the AM group than in the AC group . The number of suicide attempts was higher in the AM group . Significance was retained after performing logistic regression . LIMITATIONS Sample size was small and severe BP patients might be overrepresented in this sample . DISCUSSION Initial AM treatment of patients subsequently diagnosed as BP may entrain a course characterized by higher proneness to switch and suicidal behaviour . Accurate initial diagnosis of bipolar depression should prompt combined treatment with antimanic drugs
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 .