title: A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study. The long-term natural history of the weekly symptomatic status of bipolar I disorder. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Influence of sub-syndromal symptoms after remission from manic or mixed episodes. Carbamazepine in manic-depressive illness: a new treatment. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Adjunctive herbal medicine with carbamazepine for bipolar disorders: A double-blind, randomized, placebo-controlled study. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Levetiracetam in the management of bipolar depression: a randomized, double-blind, placebo-controlled trial. Number needed to treat analyses of drugs used for maintenance treatment of bipolar disorder Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Maintenance Efficacy of Divalproex in the Prevention of Bipolar Depression Antidepressant effects of carbamazepine. Acute efficacy of divalproex sodium versus placebo in mood stabilizer-naive bipolar I or II depression: a double-blind, randomized, placebo-controlled trial. Divalproex in the treatment of bipolar depression: a placebo-controlled study. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. Long-term outcome of bipolar depressed patients receiving lamotrigine as add-on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo-controlled trial with a novel design. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. Randomized, double-blind pilot trial comparing lamotrigine versus citalopram for the treatment of bipolar depression. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials.
abstract: There is a pressing need for additional treatment options for refractory mood disorders . This controlled comparative study evaluated the efficacy of lamotrigine ( LTG ) and gabapentin ( GBP ) monotherapy versus placebo ( PLC ) .  Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind , r and omized , crossover series of three 6-week monotherapy evaluations including LTG , GBP , and PLC . There was a st and ardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose ( LTG 500 mg or GBP 4,800 mg ) . The primary outcome measure was the Clinical Global Impressions Scale ( CGI ) for Bipolar Illness as supplemented by other st and ard rating instruments . The mean doses at week 6 were 274 + /- 128 mg for LTG and 3,987 + /- 856 mg for GBP . Response rates ( CGI ratings of much or very much improved ) were the following : LTG , 52 % ( 16/31 ) ; GBP , 26 % ( 8/31 ) ; and PLC , 23 % ( 7/31 ) ( Cochran 's Q = 6.952 , df = 2 , N = 31 , p = 0.031 ) . Post hoc Q differences ( df = 1 , N = 31 ) were the following : LTG versus GBP ( Qdiff = 5.33 , p = 0.011 ) ; LTG versus PLC ( Qdiff = 4.76 , p = 0.022 ) ; and GBP versus PLC ( Qdiff = 0.08 , p = 0.70 ) . With respect to anticonvulsant dose and gender , there was no difference between the responders and the nonresponders . The agents were generally well tolerated . This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients . Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study OBJECTIVE To determine the efficacy of divalproex ( extended release ) in the treatment of acute nonrefractory bipolar depression . METHOD In a stratified , double-blind , r and omized , placebo-controlled trial , 18 acutely depressed bipolar out patients ( DSM-IV criteria ) received either divalproex monotherapy ( target dose level , 70 - 90 ng/dL ) ( N = 9 ) or placebo ( N = 9 ) for 6 weeks . Patients were recruited between January 2004 and May 2005 . Clinical assessment on the Montgomery-Asberg Depression Rating Scale ( MADRS ) determined primary efficacy . RESULTS The divalproex treatment group showed significantly greater reduction in MADRS scores compared to placebo ( group x time interaction , p = .0078 ) . Absolute effect size of estimated MADRS total score reduction over time was 13.6 points with divalproex versus 1.4 points with placebo ( p = .003 , linear growth curve model ) . St and ardized effect size was large ( Cohen d = 0.81 ) . MADRS item analyses demonstrated improvement in core mood symptoms more than in anxiety or insomnia symptoms . There was also a modest but significant association between MADRS and Mania Rating Scale scores in the divalproex group ( r = 0.29 , df = 51 , p = .03 ) , but not in the placebo group ( r = -0.15 , df = 35 , p = .36 ) . CONCLUSIONS Divalproex appeared to be an effective treatment for acute nonrefractory bipolar depression , which is consistent with previous small r and omized studies . Some evidence of benefit in the depressive mixed state was observed . Confirmation or refutation with larger r and omized clinical trials is warranted . CLINICAL TRIAL REGISTRATION Clinical Trials.gov identifier NCT00226343 BACKGROUND To our knowledge , this is the first prospect i ve natural history study of weekly symptomatic status of patients with bipolar I disorder ( BP-I ) during long-term follow-up . METHODS Analyses are based on ongoing prospect i ve follow-up of 146 patients with Research Diagnostic Criteria BP-I , who entered the National Institute of Mental Health ( Bethesda , Md ) Collaborative Depression Study from 1978 through 1981 .  Weekly affective symptom status ratings were analyzed by polarity and severity , ranging from asymptomatic , to subthreshold levels , to full-blown major depression and mania . Percentages of follow-up weeks at each level as well as number of shifts in symptom status and polarity during the entire follow-up period were examined . Finally , 2 new measures of chronicity were evaluated in relation to previously identified predictors of chronicity for BP-I. RESULTS Patients with BP-I were symptomatically ill 47.3 % of weeks throughout a mean of 12.8 years of follow-up . Depressive symptoms ( 31.9 % of total follow-up weeks ) predominated over manic/hypomanic symptoms ( 8.9 % of weeks ) or cycling/mixed symptoms ( 5.9 % of weeks ) . Subsyndromal , minor depressive , and hypomanic symptoms combined were nearly 3 times more frequent than syndromal-level major depressive and manic symptoms ( 29.9 % vs 11.2 % of weeks , respectively ) . Patients with BP-I changed symptom status an average of 6 times per year and polarity more than 3 times per year . Longer intake episodes and those with depression-only or cycling polarity predicted greater chronicity during long-term follow-up , as did comorbid drug-use disorder . CONCLUSIONS The longitudinal weekly symptomatic course of BP-I is chronic . Overall , the symptomatic structure is primarily depressive rather than manic , and subsyndromal and minor affective symptoms predominate . Symptom severity levels fluctuate , often within the same patient over time . Bipolar I disorder is expressed as a dimensional illness featuring the full range ( spectrum ) of affective symptom severity and polarity BACKGROUND Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials . This double-blind , placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder . METHODS After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued , patients were r and omized to lamotrigine ( 100 - 400 mg daily ) , lithium ( 0.8 - 1.1 mEq/L ) , or placebo as double-blind maintenance treatment for as long as 18 months . RESULTS Of 349 patients who met screening criteria and entered the open-label phase , 175 met stabilization criteria and were r and omized to double-blind maintenance treatment  ( lamotrigine , 59 patients ; lithium , 46 patients ; and placebo , 70 patients ) . Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode  ( lamotrigine vs placebo , P = .02 ; lithium vs placebo , P = .006 ) . Lamotrigine was superior to placebo at prolonging the time to a depressive episode ( P = .02 ) . Lithium was superior to placebo at prolonging the time to a manic , hypomanic , or mixed episode ( P = .006 ) . The most common adverse event reported for lamotrigine was headache . CONCLUSIONS Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode . The results indicate that lamotrigine is an effective , well-tolerated maintenance treatment for bipolar disorder , particularly for prophylaxis of depression OBJECTIVE Clinicians have few evidence -based options for the management of treatment-resistant bipolar depression .  This study represents the first r and omized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine , inositol , and risperidone . METHOD Participants ( N=66 ) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder ( STEP-BD ) . All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant . Patients were r and omly assigned to open-label adjunctive treatment with lamotrigine , inositol , or risperidone for up to 16 weeks . The primary outcome measure was the rate of recovery , defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks . RESULTS No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure . However , the recovery rate with lamotrigine was 23.8 % , whereas the recovery rates with inositol and risperidone were 17.4 % and 4.6 % , respectively . Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone . CONCLUSIONS No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine , inositol , or risperidone . Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression BACKGROUND Sub-syndromal symptoms in bipolar disorder impair functioning and diminish quality of life . AIMS To examine factors associated with time spent with sub-syndromal symptoms and to characterise how these symptoms influence outcomes . METHOD In a double-blind r and omised maintenance trial , patients received either olanzapine or lithium monotherapy for 1 year . Stepwise logistic regression models were used to identify factors that were significant predictors of percentage time spent with sub-syndromal symptoms . The presence of sub-syndromal symptoms during the first 8 weeks was examined as a predictor of subsequent relapse . RESULTS Presence of sub-syndromal depressive symptoms during the first 8 weeks significantly increased the likelihood of depressive relapse ( relative risk 4.67 , P<0.001 ) . Patients with psychotic features and those with a greater number of previous depressive episodes were more likely to experience sub-syndromal depressive symptoms ( RR=2.51 , P<0.001 and RR=2.35 , P=0.03 respectively ) . CONCLUSIONS These findings help to identify patients at increased risk of affective relapse  and suggest that appropriate therapeutic interventions should be considered even when syndromal-level symptoms are absent The authors evaluated carbamazepine ( Tegretol ) , a drug of choice for treatment of temporal lobe epilepsy , in a double-blind placebo-controlled trial in patients with manic-depressive illness . Seven of 9 manic patients had a partial to marked response ; several also showed relapses when placebo was substituted and improvement when carbamazepine was reinstituted . Five of 13 depressed patients showed significant improvement in depression ratings ; 3 additional patients experienced partial relapse when placebo was substituted . Carbamazepine might also have prophylactic as well as acute efficacy in patients with both phases of manic-depressive illness , including some patients who do not respond to lithium . Therapeutic effects were achieved with 600 - 1600 mg/day at blood levels of 8 - 12 microgram/ml with relatively few side effects .  Carbamazepine may prove to be a useful additional treatment for affective illness OBJECTIVE Determine the efficacy and tolerability of olanzapine/fluoxetine combination ( OFC ) for treatment of acute bipolar I depression compared with lamotrigine . METHOD The 7-week , acute phase of a r and omized , double-blind study compared OFC ( 6/25 , 6/50 , 12/25 , or 12/50 mg/day ; N = 205 ) with lamotrigine ( [ LMG ] titrated to 200 mg/day ; N = 205 ) in patients with DSM-IV-diagnosed bipolar I disorder , depressed . The study was conducted from November 2003 to August 2004 . RESULTS Completion rates were similar between treatments ( OFC , 66.8 % vs. LMG , 65.4 % ; p = .835 ) . OFC-treated patients had significantly greater improvement than lamotrigine-treated patients in change from baseline across the 7-week treatment period on the Clinical Global Impressions-Severity of Illness scale ( primary outcome ) ( p = .002 , effect size = 0.26 ) , Montgomery-Asberg Depression Rating Scale ( MADRS ) ( p = .002 , effect size = 0.24 ) , and Young Mania Rating Scale total scores ( p = .001 , effect size = 0.24 ) . Response rates did not significantly differ between groups when defined as > or = 50 % reduction in MADRS score ( OFC , 68.8 % vs. LMG , 59.7 % ; p = .073 ) . Time to response was significantly shorter for OFC-treated patients ( median days [ 95 % CI ] = OFC , 17 [ 14 to 22 ] vs. LMG , 23 [ 21 to 34 ] ; p = .010 ) . There was a significant difference in incidence of " suicidal and self-injurious behavior " adverse events ( OFC , 0.5 % vs. LMG , 3.4 % ; p = .037 ) . Somnolence , increased appetite , dry mouth , sedation , weight gain , and tremor occurred more frequently ( p < .05 ) in OFC-treated patients than lamotrigine-treated patients . Weight , total cholesterol , and triglyceride levels were significantly elevated in OFC-treated patients compared with lamotrigine-treated patients ( all p < or = .001 ) . CONCLUSIONS Patients with acute bipolar I depression had statistically significantly greater improvement in depressive and manic symptoms , more treatment-emergent adverse events , greater weight gain , and some elevated metabolic factors with OFC than lamotrigine . Treatment differences were of modest size 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 Chinese herbal medicines possess the therapeutic potential for mood disorders . This double-blind , r and omized , placebo-controlled study was design ed to evaluate the efficacy and side effects of the herbal medicine called Free and Easy W and erer Plus ( FEWP ) as an adjunct to carbamazepine ( CBZ ) in patients with bipolar disorders . One hundred and twenty-four bipolar depressed and 111 manic patients were r and omized to treatment with CBZ alone , CBZ plus FEWP , or equivalent placebo  for 12 weeks . CBZ was initiated at 300mg/day and FEWP was given at a fixed dose of 36g/day . Efficacy measures included the Hamilton Rating Scale for Depression , Montgomery-Asberg Depression Rating Scale , Young Mania Rating Scale , Bech-Rafaelsen Mania Scale , and Clinical Global Impression-Severity ( CGI-S ) .  CBZ monotherapy produced significantly greater improvement on manic measures at week 2 through endpoint and CGI-S of depression at endpoint compared to placebo . CBZ monotherapy also yielded significantly higher clinical response rates than placebo on bipolar depression ( 63.8 % vs. 34.8 % , p=0.044 ) and mania ( 87.8 % vs. 57.1 % , p=0.012 ) . Compared to CBZ monotherapy , adjunctive FEWP with CBZ result ed in significantly better outcomes on the three measures of depression at week 4 and week 8 and significantly greater clinical response rate in depressed subjects ( 84.8 % vs. 63.8 % , p=0.032 ) , but failed to produce significantly greater improvement on manic measures and the response rate in manic subjects . There was a lesser incidence of dizziness and fatigue in the combination therapy compared to CBZ monotherapy . These results suggest that adjunctive FEWP has additive beneficial effects in bipolar patients , particularly for those in depressive phase BACKGROUND This is the first prospect i ve longitudinal study , to our knowledge , of the natural history of the weekly symptomatic status of bipolar II disorder ( BP-II ) . METHODS Weekly affective symptom status ratings for 86 patients with BP-II were based on interviews conducted at 6- or 12-month intervals during a mean of 13.4 years of prospect i ve follow-up . Percentage of weeks at each symptom severity level and the number of shifts in symptom status and polarity were examined . Predictors of chronicity for BP-II were evaluated using new chronicity measures . Chronicity was also analyzed in relation to the percentage of follow-up weeks with different types of somatic treatment . RESULTS Patients with BP-II were symptomatic 53.9 % of all follow-up weeks : depressive symptoms ( 50.3 % of weeks ) dominated the course over hypomanic ( 1.3 % of weeks ) and cycling/mixed ( 2.3 % of weeks ) symptoms . Subsyndromal , minor depressive , and hypomanic symptoms combined were 3 times more common than major depressive symptoms . Longer intake episodes , a family history of affective disorders , and poor previous social functioning predicted greater chronicity . Prescribed somatic treatment did not correlate significantly with symptom chronicity .  Patients with BP-II of brief ( 2 - 6 days ) vs longer ( > or = 7 days ) hypomanias were not significantly different on any measure . CONCLUSIONS The longitudinal symptomatic course of BP-II is chronic and is dominated by depressive rather than hypomanic or cycling/mixed symptoms . Symptom severity fluctuates frequently within the same patient over time , involving primarily symptoms of minor and subsyndromal severity . Longitudinally , BP-II is expressed as a dimensional illness involving the full severity range of depressive and hypomanic symptoms . Hypomania of long or short duration in BP-II seems to be part of the same disease process BACKGROUND Long-term outcomes are often poor in patients with bipolar disorder despite treatment ; more effective treatments are needed to reduce recurrences and morbidity . This study compared the efficacy of divalproex , lithium , and placebo as prophylactic therapy . METHODS A r and omized , double-blind , parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period . Patients who met the recovery criteria within 3 months of the onset of an index manic episode ( n = 372 ) were r and omized to maintenance treatment with divalproex , lithium , or placebo in a 2:1:1 ratio . Psychotropic medications were discontinued before r and omization , except for open-label divalproex or lithium , which were gradually tapered over the first 2 weeks of maintenance treatment . The primary outcome measure was time to recurrence of any mood episode . Secondary measures were time to a manic episode , time to a depressive episode , average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania , and Global Assessment of Function scores . RESULTS The divalproex group did not differ significantly from the placebo group in time to any mood episode .  Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode .  Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores . CONCLUSIONS The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy . Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures OBJECTIVE To study the efficacy of adjunctive levetiracetam therapy compared with placebo in the treatment of subjects with depression with bipolar disorder . METHOD This double-blind , placebo-controlled clinical trial r and omly assigned out patients with bipolar disorder type I and type II who were experiencing a major depressive episode ( Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version criteria ) to treatment with either placebo or adjunctive levetiracetam ( up to 2,500 mg/d flexibly dosed ) for 6 weeks . The subjects were recruited from October 2005 to June 2008 . The primary efficacy measure was mean change from baseline to week 6 in the Hamilton Depression Rating Scale ( 21-item ) . Secondary efficacy assessment s included the Montgomery-Åsberg Depression Rating Scale , the Beck Depression Inventory , the Clinical Global Impressions-Bipolar Version scale , the Hamilton Anxiety Rating Scale , and the Young Mania Rating Scale . RESULTS Of 42 subjects r and omly assigned to placebo or drug , 32 received at least 1 postbaseline assessment and thus were included in the analysis . The mean ( SD ) levetiracetam daily dose at endpoint evaluation was 1,132 ( 425 ) mg/d . There was no significant difference in the mean change from baseline to week 6 in the Hamilton Depression Rating Scale scores for levetiracetam compared with placebo . There were no significant differences in any of the secondary outcome measures . CONCLUSIONS Levetiracetam adjunctive therapy was not superior to placebo in the short-term treatment of subjects with depression with bipolar disorder in the population studied . TRIAL REGISTRATION Clinical trials.gov Identifier : NCT00566150 Rationale Due to the episodic and chronic nature of bipolar disorder ( BD ) , maintenance therapy represents a critical part of treatment ; however , there is a paucity of studies comparing effectiveness of available long-term treatments . Objective The aim of this study is to determine and compare the efficacy of pharmacological treatments for maintenance treatment of BD by means of the number needed to treat ( NNT ) . Methods The efficacy of drugs used for maintenance treatment of BD , as emerging from the results of r and omized controlled trials , was assessed using the size effect measure of NNT . PubMed search es were conducted on English- language articles published until May 2010 using the search terms “ bipolar disorder , ” “ mania , ” “ mixed episode , ” or “ bipolar depression , ” cross-referenced with trial characteristic search phrases and generic names of medications . The search was supplemented by manually review ing reference lists from identified publications . Results In 15 studies , aripiprazole , olanzapine , quetiapine , risperidone long-acting injection , lithium , lamotrigine , and divalproex proved effectiveness in terms of NNTs ( ≥10 % advantage over placebo ) for prevention of relapse into any mood episode . Quetiapine , lithium , risperidone long-acting injection , aripiprazole , and olanzapine are effective in manic recurrence prevention .  Lamotrigine , quetiapine , and lithium present significant NNTs for prevention of depressive relapses . Conclusions All of the pharmacological agents assessed were effective in the prevention of any kind of mood episode ; however , different efficacy profiles were found for prevention of manic and /or depressive relapses . The comparison of NNT values of the available agents may represent a useful tool in clinical setting s , in order to facilitate implementation of long-term pharmacological interventions in patients with BD OBJECTIVE Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines . The authors looked for the features associated with risk of recurrence . METHOD The authors examined prospect i ve data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder ( STEP-BD ) study for up to 24 months . For those who were symptomatic at study entry but subsequently achieved recovery , time to recurrence of mania , hypomania , mixed state , or a depressive episode was examined with Cox regression . RESULTS Of 1,469 participants symptomatic at study entry , 858 ( 58.4 % ) subsequently achieved recovery . During up to 2 years of follow-up , 416 ( 48.5 % ) of these individuals experienced recurrences , with more than twice as many developing depressive episodes ( 298 , 34.7 % ) as those who developed manic , hypomanic , or mixed episodes ( 118 , 13.8 % ) . The time until 25 % of the individuals experienced a depressive episode was 21.4 weeks and until 25 % experienced a manic/hypomanic/mixed episode was 85.0 weeks . Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence . Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic , hypomanic , or mixed episode recurrence . CONCLUSIONS Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery . Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence 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 Thirty-five depressed patients diagnosed by DSM-III criteria participated in a double-blind study of the acute antidepressant effects of the anticonvulsant carbamazepine , at average doses of 971 mg/day , achieving mean + /- SD blood levels of 9.3 + /- 1.9 micrograms/ml ( range , 3 - 12.5 micrograms/ml ) . Twenty patients ( 57 % ) showed at least mild improvement , and 12 showed more substantial improvement . Possible clinical predictors of antidepressant response to carbamazepine are discussed . These preliminary data suggest that carbamazepine has some acute antidepressant efficacy in addition to the growing evidence that it has acute antimanic and longer-term prophylactic efficacy in both phases of manic-depressive illness OBJECTIVE To conduct an exploratory evaluation of the acute efficacy of extended-release divalproex sodium compared to placebo in patients with bipolar I or II depression . METHOD Out patients aged 18 - 70 years with mood stabilizer-naive bipolar I or II disorder experiencing a major depressive episode ( DSM-IV ) were r and omly assigned to 6 weeks of divalproex sodium monotherapy or placebo . The primary outcome measure was mean change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale ( MADRS ) total score . Secondary outcomes included rates of response and remission , changes in the Clinical Global Impressions-Bipolar ( CGI-BP ) Severity of Illness scores , and changes in anxiety symptoms as measured by the Hamilton Anxiety Rating Scale . The study was conducted between 2003 and 2007 . RESULTS Fifty-four subjects with bipolar I ( n = 20 ) or bipolar II ( n = 34 ) disorder were r and omly assigned to divalproex or placebo ; 67 % ( 36 of 54 ) met DSM-IV criteria for rapid cycling . Divalproex treatment produced statistically significant improvement in MADRS scores compared with placebo from week 3 onward . The proportions of patients meeting response criteria were 38.5 % ( 10 of 26 ) in the divalproex group versus 10.7 % ( 3 of 28 ) for the placebo group ( P = .017 ) . The proportions of patients meeting remission criteria were 23.1 % ( 6 of 26 ) for divalproex versus 10.7 % ( 3 of 28 ) for placebo ( P = .208 ) . Subgroup analysis revealed no separation between divalproex and placebo for those with bipolar II diagnoses . Nausea , increased appetite , diarrhea , dry mouth , and cramps were the most common side effects . CONCLUSIONS These data suggest that divalproex sodium is efficacious and reasonably well tolerated in the acute treatment of mood stabilizer-naive patients with bipolar depression , particularly for those with rapid-cycling type I presentations , and that confirmatory large-scale studies are indicated . TRIAL REGISTRATION Clinical trials.gov Identifier : NCT00194116 BACKGROUND The treatment of bipolar disorder in the depressed phase is complicated by a tendency for conventional antidepressant drugs to worsen the course of the illness by precipitating a manic episode or increasing cycle frequency . Thus , the potential antidepressant efficacy of mood stabilizers , such as divalproex , which is an effective treatment for the manic phase of bipolar disorder , is of considerable interest . METHODS The clinical efficacy of divalproex ( valproate , Depakote ) was tested in an 8-week , double-blind , placebo-controlled , r and omized clinical trial in 25 out patients with bipolar I depression . The primary outcome measure was the 17-item Hamilton Rating Scale for Depression , and secondary measures included the Hamilton Rating Scale for Anxiety , the Clinician Administered Rating Scale for Mania , and the Clinical Global Impression scale . RESULTS Using repeated measures ANOVA with last observation carried forward , divalproex was more effective than placebo in improving symptoms of depression ( p = 0.0002 ) and symptoms of anxiety ( p = 0.0001 ) than placebo . LIMITATIONS The sample size was small , and most patients were male . CONCLUSIONS These pilot results indicate that divalproex is effective in reducing the symptoms of depression and anxiety in bipolar I , depressed phase . These positive results support the need to perform a larger , multisite study of divalproex treatment for bipolar depression BACKGROUND More treatment options for bipolar depression are needed . Currently available antidepressants may increase the risk of mania and rapid cycling , and mood stabilizers appear to be less effective in treating depression than mania . Preliminary data suggest that lamotrigine , an established antiepileptic drug , may be effective for both the depression and mania associated with bipolar disorder . This is the first controlled multicenter study evaluating lamotrigine monotherapy in the treatment of bipolar I depression . METHODS Out patients with bipolar I disorder experiencing a major depressive episode ( DSM-IV , N = 195 ) received lamotrigine ( 50  or  200 mg/day ) or placebo as monotherapy for 7 weeks . Psychiatric evaluations , including the Hamilton Rating Scale for Depression ( HAM-D ) , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , Mania Rating Scale , and the Clinical Global Impressions scale for Severity ( CGI-S ) and Improvement ( CGI-I ) were completed at each weekly visit . RESULTS Lamotrigine 200 mg/day demonstrated significant antidepressant efficacy on the 17-item HAM-D , HAM-D Item 1 , MADRS , CGI-S , and CGI-I compared with placebo . Improvements were seen as early as week 3 . Lamotrigine 50 mg/day also demonstrated efficacy compared with placebo on several measures . The proportions of patients exhibiting a response on CGI-I were 51 % , 41 % , and 26 % for lamotrigine 200 mg/day , lamotrigine 50 mg/day , and placebo groups , respectively . Adverse events and other safety results were similar across treatment groups , except for a higher rate of headache in the lamotrigine groups . CONCLUSION Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression OBJECTIVE In two previous manuscripts , we described the efficacy of lamotrigine versus placebo as add-on to lithium ( followed by the addition of paroxetine in nonresponders ) in the short-term treatment of bipolar depression . In this paper we describe the long-term ( 68 weeks ) outcome of that study . METHODS A total of 124 bipolar depressed patients receiving lithium  were r and omized to addition of lamotrigine or placebo . After eight weeks , paroxetine was added to nonresponders for another eight weeks . Responders continued medication and were followed for up to 68 weeks or until a relapse or recurrence of a depressive or manic episode . RESULTS After eight weeks , the addition of lamotrigine to lithium was significantly more efficacious than addition of placebo , while after addition of paroxetine in nonresponders both groups further improved with no significant difference between groups at week 16 . During follow-up the efficacy of lamotrigine was maintained : time to relapse or recurrence was longer for the lamotrigine group [ median time 10.0 months ( confidence interval : 1.1 - 18.8 ) ] versus the placebo group [ 3.5 months ( confidence interval : 0.7 - 7.0 ) ] . CONCLUSION In patients with bipolar depression , despite continued use of lithium , addition of lamotrigine revealed a continued benefit compared to placebo throughout the entire study 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 OBJECTIVE Lamotrigine is one of the pharmacologic options for the treatment of bipolar depression but has only been studied as monotherapy . This study compared the acute effects of lamotrigine and placebo as add-on therapy to ongoing treatment with lithium in patients with bipolar depression . METHOD Out patients ( N = 124 ) aged 18 years and older with a DSM-IV bipolar I or II disorder and a major depressive episode ( Montgomery-Asberg Depression Rating Scale [ MADRS ] score > or = 18 and Clinical Global Impressions-Bipolar Version [ CGI-BP ] severity of depression score > or = 4 ) while receiving lithium treatment ( 0.6 - 1.2 mmol/L ) were r and omly assigned to 8 weeks of double-blind treatment with lamotrigine ( titrated to 200 mg/d ) or placebo . The primary outcome measure was mean change from baseline in total score on the MADRS at week 8 . Secondary outcome measures were response ( defined as a reduction of > or = 50 % on the MADRS and /or change of depression score on the CGI-BP of " much improved " or " very much improved " compared to baseline ) and switch to mania or hypomania ( defined as a CGI-BP severity of mania score of at least mildly ill at any visit ) . Patients were included in the study between August 2002 ( Spain started in October 2003 ) and May 2005 . RESULTS Endpoint mean change from baseline MADRS total score was -15.38 ( SE = 1.32 ) points for lamotrigine and -11.03 ( SE = 1.36 ) points for placebo ( t = -2.29 , df = 104 , p = .024 ) . Significantly more patients responded to lamotrigine than to placebo on the MADRS ( 51.6 % vs. 31.7 % , p = .030 ) , but not on the CGI-BP change of depression ( 64.1 % vs. 49.2 % , p = .105 ) . Switch to mania or hypomania occurred in 5 patients ( 7.8 % ) receiving lamotrigine and 2 patients ( 3.3 % ) receiving placebo ( p = .441 ) . CONCLUSION Lamotrigine was found effective and safe as add-on treatment to lithium in the acute treatment of bipolar depression . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00224510 BACKGROUND Uncertainty exists regarding the best approach for treating bipolar depression among patients already receiving a first-line mood stabilizer . The aim of this pilot study was to compare adding a second mood stabilizer or an antidepressant at this treatment decision point . METHODS Twelve-week , r and omized , double-blind pilot trial comparing the addition of lamotrigine or citalopram for bipolar depressed patients on mood stabilizer medication . Change in depressive symptoms and risk of switch were examined . RESULTS Twenty subjects were r and omized . Each treatment group experienced a significant mean reduction in total MADRS scores  ( citalopram Delta - 14.2 , p=0.002 ; lamotrigine Delta - 13.3 , p= 0.001 ) , and there was no significant difference between treatment groups ( p=0.78 ) . Total response rates increased from 31.6 % at week 6 to 52.6 % at week 12 . One out of ten patients in each group experienced a switch to hypomania . LIMITATIONS Small sample size . Lack of a placebo arm . CONCLUSIONS Results of this small trial suggest that both lamotrigine and citalopram appear to be reasonable choices as add-on acute treatment for bipolar depression , with response rates continuing to rise considerably past 6 weeks of treatment BACKGROUND Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers , relatively few controlled studies have examined treatment strategies for bipolar depression . OBJECTIVE To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression . DESIGN Double-blind , 8-week , r and omized controlled trial . SETTING Eighty-four sites ( inpatient and outpatient ) in 13 countries . Patients A total of 833 r and omized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale ( MADRS ) score of at least 20 . Intervention Patients were r and omly assigned to receive placebo ( n = 377 ) ; olanzapine , 5 to 20 mg/d ( n = 370 ) ; or olanzapine-fluoxetine combination , 6 and 25 , 6 and 50 , or 12 and 50 mg/d ( n = 86 ) . MAIN OUTCOME MEASURE Changes in MADRS total scores using mixed-effects model repeated- measures analyses . RESULTS During all 8 study weeks , the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group ( P<.001 for all ) . The olanzapine-fluoxetine group also showed statistically greater improvement than the olanzapine group at weeks 4 through 8 . At week 8 , MADRS total scores were lower than at baseline by 11.9 , 15.0 , and 18.5 points in the placebo , olanzapine , and olanzapine-fluoxetine groups , respectively . Remission criteria were met by 24.5 % ( 87/355 ) of the placebo group , 32.8 % ( 115/351 ) of the olanzapine group , and 48.8 % ( 40/82 ) of the olanzapine-fluoxetine group . Treatment-emergent mania ( Young Mania Rating Scale score < 15 at baseline and > or = 15 subsequently ) did not differ among groups ( placebo , 6.7 % [ 23/345 ] ; olanzapine , 5.7 % [ 19/335 ] ; and olanzapine-fluoxetine , 6.4 % [ 5/78 ] ) . Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea . CONCLUSIONS Olanzapine is more effective than placebo , and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of  bipolar I depression without increased risk of developing manic symptoms 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
target: 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 .
background: 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 .