Efficacy and tolerability of lithium in treating acute mania in youth with bipolar disorder: protocol for a systematic review A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Number needed to treat analyses of drugs used for maintenance treatment of bipolar disorder Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder. Allopurinol for mania: a randomized trial of allopurinol versus placebo as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder. Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. A history of substance abuse complicates remission from acute mania in bipolar disorder. GERI-BD: A Randomized Double-Blind Controlled Trial of Lithium and Divalproex in the Treatment of Mania in Older Patients With Bipolar Disorder. A 12-week, open, randomized trial comparing sodium valproate to lithium in patients with bipolar I disorder suffering from a manic episode Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study. Antidepressant-induced mania in bipolar patients: identification of risk factors. Post-acute effectiveness of lithium in pediatric bipolar I disorder. Efficacy and mood conversion rate during long-term fluoxetine v. lithium monotherapy in rapid- and non-rapid-cycling bipolar II disorder. Lithium treatment of acute mania in adolescents: a large open trial. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial Maintenance Efficacy of Divalproex in the Prevention of Bipolar Depression Differential Efficacy of Lithium and Carbamazepine in the Prophylaxis of Bipolar Disorder: Results of the MAP Study Adjunctive treatment of manic agitation with lorazepam versus haloperidol: a double-blind study. Depression and Suicidality Outcomes in the Treatment of Early Age Mania Study. Olanzapine versus lithium in the acute treatment of bipolar mania: a double-blind, randomized, controlled trial. Does lithium protect against dementia? A 40-week double-blind aripiprazole versus lithium follow-up of a 12-week acute phase study (total 52 weeks) in bipolar I disorder. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Lithium carbonate and imipramine in prevention of affective episodes. A comparison in recurrent affective illness. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: A possible role for lithium antioxidant effects Open-label prospective trial of risperidone in combination with lithium or divalproex sodium in pediatric mania. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. Paliperidone extended-release as adjunctive therapy to lithium or valproate in the treatment of acute mania: a randomized, placebo-controlled study. Adjunctive topiramate therapy in patients receiving a mood stabilizer for bipolar I disorder: a randomized, placebo-controlled trial. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Patterns of pharmacological maintenance treatment in a community mental health services bipolar disorder cohort study (SIN-DEPRES). Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial. Maintenance treatment for patients with bipolar I disorder: results from a north american study of quetiapine in combination with lithium or divalproex (trial 127).
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 ) 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 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 To evaluate the efficacy and tolerability of topiramate monotherapy in adults with acute manic or mixed episodes of bipolar I disorder . METHODS In four trials , adults hospitalized with acute mania , a diagnosis of bipolar I disorder , history of > or = 1 previous manic or mixed episodes , and > or = 20 Young Mania Rating Scale ( YMRS ) score were r and omized to double-blind treatment with topiramate ( target doses : 200 , 400 , or 600 mg/day ) or placebo ; two trials included an active comparator ( lithium , 1500 mg/day ) . The core study duration in all trials was 3 weeks ; three trials also had 9-week double-blind extensions . The primary efficacy variable was mean change from baseline in YMRS in the core 3-week study . RESULTS Changes in YMRS score during 3 weeks were not significantly different for topiramate versus placebo ( mean YMRS reductions , -5.1 to -8.4 ) . Mean YMRS reductions in lithium-treated groups were significantly greater ( p < or = 0.001 versus placebo and topiramate ) . A similar pattern was observed after 12 weeks of double-blind treatment in studies with double-blind extensions . Paresthesia , appetite decrease , dry mouth , and weight loss were more frequently associated with topiramate than with placebo . CONCLUSIONS These studies do not support the efficacy of topiramate as monotherapy in acute mania or mixed episodes in adults with bipolar I disorder . Topiramate was not associated with mood destabilization measured as mania exacerbation or treatment-emergent depression . Lithium was confirmed as an effective therapy in this population OBJECTIVE The therapeutics for bipolar disorders are still far from adequate , and new options with improved effectiveness , safety , and tolerability in a wide range of patients are necessary . Preliminary data have suggested a role for dysfunctions targeting the purinergic system in mood disorders . This study aim ed to evaluate the efficacy and tolerability of the purinergic agents allopurinol and dipyridamole combined with lithium in bipolar mania . METHOD A r and omized , placebo-controlled , double-blind study was performed in adult in patients ( N = 180 ) with a DSM-IV-TR diagnosis of bipolar I disorder , current episode manic with or without psychotic features ( rapid cyclers and mixed episodes were not included ) . No antipsychotic agent was used during the study . Subjects were given fixed oral doses of either allopurinol 600 mg/day ( N = 60 ) , dipyridamole 200 mg/day ( N = 60 ) , or placebo ( N = 60 ) added to lithium for 4 weeks . Subjects were rated at baseline and days 7 , 14 , 21 , and 28 using the Young Mania Rating Scale ( YMRS ) as the primary efficacy measure . The study was conducted between September 2003 and September 2006 . RESULTS Allopurinol result ed in greater mean reductions in YMRS scores from baseline to day 21 ( p < .001 ) and day 28 ( p = .003 ) compared with placebo using a linear model analysis ( d = 0.32 , 95 % CI = 0.07 to 0.57 ) . Remission rates were significantly higher for allopurinol compared with dipyridamole and placebo ( p = .008 ) . Lithium showed a significant antimanic efficacy even in the placebo group . Decrease in plasma uric acid levels showed a significant positive association with antimanic effects in the allopurinol group ( p < .001 ) . CONCLUSION Allopurinol is clinical ly effective and well-tolerated adjunctively with lithium in manic episodes and may represent an alternative approach in the treatment of acute mania , especially for those presenting tolerability and safety issues with antipsychotics . The present results strongly support the involvement of the purinergic system in the pathophysiology and therapeutics of bipolar disorder . Further placebo-controlled studies with allo-purinol compared with st and ard mood stabilizers in mania and maintenance are warranted . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00560079 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 To develop effect sizes for 3 mood stabilizers -- lithium , divalproex sodium , and carbamazepine -- for the acute-phase treatment of bipolar I or II disorder , mixed or manic episode , in children and adolescents aged 8 to 18 years . METHOD Forty-two out patients with a mean age of 11.4 years ( 20 with bipolar I disorder and 22 with bipolar II disorder ) were r and omly assigned to 6 weeks of open treatment with either lithium , divalproex sodium , or carbamazepine . The primary efficacy measures were the weekly Clinical Global Impression Improvement scores and the Young Mania Rating Scale ( Y-MRS ) . RESULTS Using a > or = 50 % change from baseline to exit in the Y-MRS scores to define response , the effect size was 1.63 for divalproex sodium , 1.06 for lithium , and 1.00 for carbamazepine . Using this same response measure with the intent-to-treat sample , the response rates were as follows : sodium divalproex , 53 % ; lithium , 38 % ; and carbamazepine , 38 % ( chi 2(2 ) = 0.85 , p = .60 ) . All 3 mood stabilizers were well tolerated , and no serious adverse effects were seen . CONCLUSIONS Divalproex sodium , lithium , and carbamazepine all showed a large effect size in the open treatment of children and adolescents with bipolar I or II disorder in a mixed or manic episode OBJECTIVE An emerging body of evidence supports a role for dysfunctional purinergic neurotransmission in mood disorders . Adenosine agonists have been shown to have properties similar to those of dopamine antagonists ; there is a well-characterized interaction between adenosine and dopamine receptors in the ventral striatum , and increasing adenosinergic transmission has been demonstrated to reduce the affinity of dopamine agonists for dopamine receptors . Allopurinol increases adenosine levels in the brain , and hence is hypothesized to reduce the symptoms of mania . Two r and omized , placebo-controlled trials administering add-on allopurinol to manic patients showed significantly greater improvements in Young Mania Rating Scale ( YMRS ) scores for drug compared to placebo , while a more recent , relatively small , add-on study showed negative results . Based on these data , our objective was to examine the efficacy of allopurinol as add-on treatment to mood stabilizers and /or antipsychotic agents in manic patients with bipolar disorder . METHODS We performed a large , well-powered , multicenter , six-week , r and omized , placebo-controlled trial of allopurinol added to mood stabilizers and /or antipsychotic agents in 180 patients with bipolar disorder in an acute manic episode . RESULTS Both groups showed improvement on the YMRS ( effect size of 1.5 for placebo and 1.6 for allopurinol ) , with no difference observed between groups on YMRS scores ( t = 0.28 , p = 0.78 ) . There was no difference in the proportion of patients who responded to treatment ( defined as showing at least 50 % improvement in YMRS score ) between the two groups ( p = 0.92 ) , or in dropout rates ( p = 0.84 ) . LIMITATIONS None of our patients received lithium . However , the side effects of lithium and its narrow therapeutic index made the use of lithium less common and , therefore , our study results reflect common current clinical practice . In the present study , we used a variety of antipsychotic and /or mood stabilizing treatments , to which we added allopurinol ; one might hypothesize that add-on allopurinol has a different effect in combination with different antipsychotic agents or mood stabilizers . CONCLUSIONS The findings of this large , well-powered study do not support add-on allopurinol as a treatment for acute mania . This study did not test the efficacy of allopurinol as monotherapy BACKGROUND : Lithium is a benchmark treatment for bipolar disorder in adults . Definitive studies of lithium in pediatric bipolar I disorder ( BP-I ) are lacking . METHODS : This multicenter , r and omized , double-blind , placebo-controlled study of pediatric participants ( ages 7–17 years ) with BP-I/manic or mixed episodes compared  lithium ( n = 53 )  versus placebo ( n = 28 ) for up to 8 weeks . The a priori primary efficacy measure was change from baseline to the end of study ( week 8/ET ) in the Young Mania Rating Scale ( YMRS ) score , based on last-observation-carried-forward analysis . RESULTS : The change in YMRS score was significantly larger in lithium-treated participants ( 5.51 [ 95 % confidence interval : 0.51 to 10.50 ] ) after adjustment for baseline YMRS score , age group , weight group , gender , and study site ( P = .03 ) . Overall Clinical Global Impression – Improvement scores  favored lithium ( n = 25 ; 47 % very much/much improved ) compared with placebo ( n = 6 ; 21 % very much/much improved ) at week 8/ET ( P = .03 ) . A statistically significant increase in thyrotropin concentration was seen with lithium ( 3.0 ± 3.1 mIU/L ) compared with placebo ( –0.1 ± 0.9 mIU/L ; P < .001 ) . There was no statistically significant between-group difference with respect to weight gain . CONCLUSIONS : Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial . Lithium was generally well tolerated in this patient population and was not associated with weight gain , distinguishing it from other agents commonly used to treat youth with bipolar disorder BACKGROUND A 6-week double-blind , r and omized , placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes . METHODS The primary objective was to evaluate the efficacy of olanzapine ( 5 - 20 mg/d ) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale ( YMRS ) scores . Patients with bipolar disorder ( n = 344 ) , manic or mixed episode , who were inadequately responsive to more than 2 weeks of lithium or valproate therapy , were r and omized to receive cotherapy  ( olanzapine + mood-stabilizer ) or monotherapy ( placebo + mood-stabilizer ) . RESULTS Olanzapine cotherapy improved patients ' YMRS total scores significantly more than monotherapy ( -13.11 vs -9.10 ; P = .003 ) . Clinical response rates ( > or = 50 % improvement on YMRS ) were significantly higher with cotherapy ( 67.7 % vs 44.7 % ; P < .001 ) . Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale ( HAMD-21 ) total scores significantly more than monotherapy ( 4.98 vs 0.89 points ; P < .001 ) . In patients with mixed-episodes with moderate to severe depressive symptoms ( DSM-IV mixed episode ; HAMD-21 score of > or = 20 at baseline ) , olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy ( P < .001 ) . Extrapyramidal symptoms ( Simpson-Angus Scale , Barnes Akathisia Scale , Abnormal Involuntary Movement Scale ) were not significantly changed from baseline to end point in either treatment group . Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence , dry mouth , weight gain , increased appetite , tremor , and slurred speech . CONCLUSION Compared with the use of valproate or lithium alone , the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes 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 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 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 Clinicians treating older patients with bipolar disorder with mood stabilizers need evidence from age-specific r and omized controlled trials . The authors describe findings from a first such study of late-life mania . METHOD The authors compared the tolerability and efficacy of lithium carbonate and divalproex in 224 in patients and out patients age 60 or older with bipolar I disorder who presented with a manic , hypomanic , or mixed episode . Participants were r and omly assigned , under double-blind conditions , to treatment with lithium ( target serum concentration , 0.80 - 0.99 mEq/L ) or divalproex ( target serum valproate concentration , 80 - 99 μg/mL ) for 9 weeks . Participants with an inadequate response after 3 weeks received open adjunctive risperidone . The authors hypothesized that divalproex would be better tolerated and more efficacious than lithium  . Tolerability was assessed based on a measure of sedation and on the proportions of participants achieving target concentrations . Efficacy was assessed with the Young Mania Rating Scale ( YMRS ) . RESULTS Attrition rates were similar for lithium and divalproex ( 14 % and 18 % at week 3 and 51 % and 44 % at week 9 , respectively ) . The groups did not differ significantly in sedation . Participants in the lithium group tended to experience more tremor . Similar proportions of participants in the lithium and divalproex groups achieved target concentrations ( 57 % and 56 % , respectively ) . A longitudinal mixed model of improvement ( change from baseline in YMRS score ) favored lithium ( change in score , 3.90 ; 97.5 % CI=1.71 , 6.09 ) . Nine-week response rates did not differ significantly between the lithium and divalproex groups ( 79 % and 73 % , respectively ) . The need for adjunctive risperidone was low and similar between groups ( 17 % and 14 % , respectively ) . CONCLUSIONS Both lithium and divalproex  were adequately tolerated and efficacious ; lithium was associated with a greater reduction in mania scores over 9 weeks On the basis of 3-week studies , lithium and valproate are both recommended for first-line treatment of acute mania . It is , however , also important to demonstrate that antimanic efficacy can be maintained . This study has been design ed to compare the efficacy and tolerability of valproate and lithium over 12 weeks in the treatment of acute mania in patients with type I bipolar disorder . Three hundred patients with bipolar I disorder presenting with acute mania were r and omized to open treatment with lithium ( starting dose : 400 mg/day ) or valproate ( starting dose : 20 mg/kg/day ) for 12 weeks . The primary efficacy criterion was remission ( YMRS score ≤12 at study end and a reduction of ≥2 on the CGI-BP severity scale ) . Remission rates were 65.5 % ( lithium group ) and 72.3 % ( valproate  group ) . Noninferiority  of  valproate with respect to lithium was demonstrated [ between-group difference : 6.78 % ( 95 % confidence intervals : −3.80 to 17.36 % ) ] . Remission rates assessed by the secondary mixed model repeated measures analysis were significantly greater with valproate than with lithium . Adverse events were reported in 44 % of patients in both  groups . Valproate and lithium showed comparable efficacy and tolerability in the treatment of acute mania over 12 weeks OBJECTIVE The authors compared the efficacy of olanzapine and lithium in the prevention of  mood episode relapse/recurrence . METHOD Patients with a diagnosis of bipolar disorder ( manic/mixed ) , a history of two or more manic or mixed episodes within 6 years , and a Young Mania Rating Scale total score > or = 20 entered the study and received open-label co-treatment with olanzapine and lithium for 6 - 12 weeks . Those meeting symptomatic remission criteria ( Young Mania Rating Scale score < or = 12 ; 21-item Hamilton depression scale score < or = 8) were r and omly assigned to 52 weeks of double-blind monotherapy with olanzapine , 5 - 20 mg/day ( N=217 ) , or lithium ( target blood level : 0.6 - 1.2 meq/liter ) ( N=214 ) . RESULTS Symptomatic relapse/recurrence ( score > or = 15 on either the Young Mania Rating Scale or Hamilton depression scale ) occurred in 30.0 % of olanzapine-treated and 38.8 % of lithium-treated patients . The noninferiority of olanzapine relative to lithium ( primary objective ) in preventing relapse/recurrence was met , since the lower limit of the 95 % confidence interval on the 8.8 % risk difference ( -0.1 % to 17.8 % ) exceeded the predefined noninferiority margin ( -7.3 % ) . Secondary results showed that compared with lithium , olanzapine had significantly lower risks of manic episode and mixed episode relapse/recurrence . Depression relapse/recurrence occurred in 15.7 % of olanzapine-treated and 10.7 % of lithium-treated patients . Mean weight gain during open-label co-treatment was 2.7 kg ; during double-blind monotherapy , weight gain was significantly greater with olanzapine ( 1.8 kg ) than with lithium ( -1.4 kg ) . CONCLUSIONS These results suggest that olanzapine was significantly more effective than lithium in preventing manic and mixed episode relapse/recurrence in patients acutely stabilized with olanzapine and lithium co-treatment . Both agents were comparable in preventing depression relapse/recurrence Maintenance studies in bipolar disorder have received increased attention in recent years . The interest is driven by apparent contradictions between results of early placebo-controlled trials of lithium and recent open studies , as well as interest in a new group of drugs with mood-stabilizing properties . The multiple outcome indices that require attention in prophylactic bipolar disorder studies add a dimension not present in acute studies of bipolar disorder . We present the methodology of a recently completed r and omized , double-blind , placebo-controlled , parallel-group comparison of divalproex and lithium . We examine the consequences of salient design features , along with their implication s for future studies . A fundamental conclusion is that such maintenance studies should be design ed and executed to emphasize enrollment of patients with relatively active , severe forms of the illness . This goal is not achieved simply , as inherent features of long-term , placebo-controlled studies drive recruitment and enrollment in the direction of patients with milder forms of bipolar disorder . Attention to the frequency of both manic and depressive episodes and the severity of an index manic episode may aid in the selection of patients most suitable for studies design ed to achieve adequate statistical power 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 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 BACKGROUND Controversy exists over antidepressant use in rapid-cycling bipolar disorder . AIMS Exploratory analysis of safety and efficacy of fluoxetine v. lithium monotherapy in individuals with rapid- v. non-rapid-cycling bipolar II disorder . METHOD R and omised , double-blind , placebo-controlled comparison of fluoxetine v. lithium monotherapy in patients initially stabilised on fluoxetine monotherapy ( trial registration NCT00044616 ) . RESULTS The proportion of participants with depressive relapse was similar between the rapid- and non-rapid-cycling groups ( P = 0.20 ) . The odds of relapse were similar between groups ( P = 0.36 ) . The hazard of relapse was similar between groups ( hazard ratio 0.87 , 95 % CI 0.40 - 1.91 ) . Change in mania rating scores was similar between groups ( P = 0.86 ) . There was no difference between groups in the rate of syndromal ( P = 0.27 ) or subsyndromal ( P = 0.82 ) hypomania . CONCLUSIONS Depressive relapse and treatment-emergent mood conversion episode rates were similar for lithium and fluoxetine monotherapy and placebo during long-term , relapse-prevention therapy of rapid- and non-rapid-cycling bipolar II disorder OBJECTIVE To examine initial response to treatment in a large sample of acutely manic bipolar I adolescents and to examine potential predictors of nonresponse , such as the presence of prominent depressive features , psychosis , or psychiatric comorbidity . METHOD Adolescents , 12 to 18 years of age , with an acute manic episode were treated with open lithium . Response was defined as a decline in Young Mania Rating Scale total score of > or=33 % and a rating of " much improved " or " very much improved " on the Clinical Global Impressions Improvement item at week 4 . Remission of mania was defined as a Young Mania Rating Scale score of < or=6 . Axis I diagnoses were assessed using the Lifetime Schedule for Affective Disorders and Schizophrenia for Adolescents . RESULTS Of 100 subjects , 63 met response criteria and 26 achieved remission of manic symptoms at the week 4 assessment . Prominent depressive features , age at first mood episode , severity of mania , and comorbidity with attention-deficit/hyperactivity disorder did not distinguish responders from nonresponders . When treated with adjunctive antipsychotic medication , subjects with psychotic features at baseline responded as well as subjects without psychosis . CONCLUSIONS In this largest systematic treatment trial of acutely manic adolescents to date , lithium appears effective for acute stabilization of symptoms . Controlled treatment studies in adolescents with acute mania are needed BACKGROUND This study examined the efficacy and safety of quetiapine in combination with lithium or divalproex compared with placebo with lithium or divalproex in the prevention of recurrent mood events in bipolar I patients , most recent episode mania , depression , or mixed . METHODS Patients received open-label quetiapine  ( 400 - 800 mg/day ; flexible , divided doses ) with lithium or divalproex ( target serum concentrations 0.5 - 1.2 mEq/L and 50 - 125 microg/mL , respectively ) for up to 36 weeks to achieve at least 12 weeks of clinical stability . Patients were subsequently r and omized to double-blind treatment with quetiapine ( 400 - 800 mg/day ) plus lithium/divalproex or placebo plus lithium/divalproex for up to 104 weeks . The primary endpoint was time to recurrence of any mood event . RESULTS Treatment with quetiapine in combination with lithium/divalproex significantly increased the time to recurrence of any mood event compared with placebo plus lithium/divalproex . The proportion of patients having a mood event was markedly lower in the quetiapine than in the placebo group ( 18.5 % versus 49.0 % ) . The hazard ratio for time to recurrence of a mood event was 0.28 ( P<0.001 ) , a mania event 0.30 ( P<0.001 ) , and a depression event 0.26 ( P<0.001 ) corresponding to risk reductions of 72 % , 70 % , and 74 % , respectively . During the r and omization phase , the most common adverse events occurring in > or = 5 % in the quetiapine group were somnolence , nasopharyngitis , and headache . Insomnia was more common in the placebo group . During the r and omization phase , there was an increase in weight of 0.5 kg in the quetiapine group and a reduction of 1.9 kg in the placebo group . The incidence and incidence density of a single emergent fasting blood glucose value > or = 126 mg/dL was higher with quetiapine than with placebo ( 9.3 % versus 4.1 % ; 17.6 versus 9.5 patients per 100 patient-years ) . LIMITATIONS This was an enriched sample of patients with bipolar I disorder responding to treatment with quetiapine plus lithium/divalproex . CONCLUSIONS Maintenance treatment with quetiapine in combination with lithium/divalproex significantly increased time to recurrence of any event ( mania , depression , or mixed ) irrespective of the polarity of the index episode compared with placebo with lithium/divalproex . Long-term treatment with quetiapine was generally well-tolerated .  Quetiapine with lithium/divalproex can provide an effective long-term treatment option for bipolar I disorder to prevent recurrences not only of mania but also depression The objective of this study was to compare the efficacy and safety of valproate and lithium in bipolar I patients experiencing a manic or a mixed episode . This international , r and omized , open-label , parallel-group , equivalence study included 268 patients with bipolar I disorder . The starting dose of valproate was 20 mg/kg/day and that of lithium was 800 mg/day . Treatment duration was 12 weeks . The primary outcome measure was mean change in Young Mania Rating Scale score between baseline and study end . Secondary outcome measures were response and remission rates , change in Montgomery and Åsberg Depression Rating Scale and Clinical Global Impression Bipolar Disorder instrument score , and occurrence of adverse events . The mean change from baseline in Young Mania Rating Scale score was 15.8±5.3 in the lithium group and 17.3±9.4 in the valproate group . The 90 % confidence interval of the intergroup difference ( −0.69 ; 3.31 ) was within prespecified equivalence limits . Response rates were 72.6 % in the lithium group and 79.5 % in the valproate  group . Remission rates were 58.5 and 71.9 % , respectively . No intergroup differences were observed in median time to treatment response ( 21 days ) or change in Clinical Global Impression Bipolar Disorder instrument or Montgomery and Åsberg Depression Rating Scale scores . Adverse events were reported in 42.8 % of patients in the lithium group and 41.5 % in the valproate group . Valproate and lithium showed comparable efficacy and tolerability in the treatment of acute mania over 12 weeks 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 In a r and omized clinical trial with an observation period of 2.5 years , the differential efficacy of lithium versus carbamazepine was compared in 171 bipolar patients ( DSM-IV ) . In order to investigate the efficacy of the two drugs in clearly defined sub sample s , a series of subgroup analyses was carried out . First , patients with a bipolar I disorder ( n = 114 ) were analyzed separately . In these patients , lithium was superior to carbamazepine . In contrast , carbamazepine was at least equally as efficacious as lithium in the sub sample of patients with bipolar II disorder or bipolar disorder not otherwise specified ( n = 57 ) . In a second analysis on differential efficacy , the whole sample was subdivided into a classical subgroup ( bipolar I patients without mood-incongruent delusions and without comorbidity ; n = 67 ) and a nonclassical subgroup including all other patients ( n = 104 ) . Classical bipolar patients had a significantly lower hospitalization rate under lithium than under carbamazepine prophylaxis ( 26 vs. 62 % , p = 0.012 ) . For the nonclassical group , a tendency in favor of carbamazepine was found . In a third step , we analyzed the impact of episode sequence on differential efficacy . In a global view , the episode sequence prior to the index episode was not correlated to differential efficacy . Our results might , however , indicate that patients with an episode sequence of mania-depression-free interval responded better to lithium . Besides differential efficacy , suicidal behavior and patients ’ satisfaction with treatment were investigated . Regarding suicidal behavior , a trend in favor of lithium was found . The data on patients ’ satisfaction were significantly in favor of carbamazepine . In conclusion , lithium appears to be superior to carbamazepine in classical bipolar cases and might have additional impact on proneness to suicide . The distinctly larger group of patients with nonclassical features might profit more from carbamazepine which seems to be well accepted by the patients . Hence , treatment alternatives to lithium are desirable for the majority of bipolar patients BACKGROUND While lithium is effective in treating the majority of bipolar patients during a manic episode , the addition of neuroleptic during the early phase of treatment has been common clinical practice in inpatient setting s. In an earlier open study , we demonstrated the utility of the short-acting benzodiazepine lorazepam as an adjunct to lithium for the clinical management of manic agitation . METHOD We now present data from a r and omized , double-blind clinical study of lorazepam versus haloperidol in 20 hospitalized patients with a DSM-III-R diagnosis of bipolar disorder who were being treated concomitantly with lithium .  Patients were rated using the Mania Rating Scale , Brief Psychiatric Rating Scale , Physician Global Impression Scale , and side effects scales . Data were analyzed using st and ard group comparisons and survival analysis . RESULTS There was no evidence for a significant difference between the two treatment groups in the magnitude of or time to response ( 5.0 + /- .82 days for haloperidol ; 6.5 + /- .93 days for lorazepam ) . Of the patients who were terminated from the protocol early , nonresponse was the primary reason in the lorazepam group while side effects were the reason in the haloperidol group . CONCLUSION Lorazepam may offer an efficacious and safe alternative to haloperidol as an adjunctive treatment to lithium in the clinical management of the early phase of manic agitation in a subgroup of bipolar patients 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 This multicenter , double-blind , r and omized , controlled study conducted in China examined the efficacy and safety of olanzapine versus lithium in the treatment of patients with bipolar manic/mixed episodes . METHODS Patients with bipolar manic or mixed episode ( DSM-IV criteria ) and Young Mania Rating Scale ( YMRS ) score > or = 20 at screening received olanzapine ( 5 - 20 mg/day , n=69 ) or lithium carbonate ( 600 - 1800 mg/day , n=71 ) for 4 weeks . The primary outcome was mean change from baseline in Clinical Global Impressions-Bipolar Version Overall Severity of Illness ( CGI-BP ) score . Secondary efficacy measures included YMRS , Brief Psychiatric Rating Scale ( BPRS ) , and Montgomery-Asberg Depression Rating Scale ( MADRS ) scores . Safety was also assessed . RESULTS A significantly greater mean change was observed in olanzapine versus lithium patients in CGI-BP ( Overall Severity ) ( P=0.009 ) , YMRS ( P=0.013 ) , BPRS ( P=0.032 ) , and CGI-BP ( Severity of Mania ) ( P=0.012 ) scores . More olanzapine than lithium patients experienced at least one adverse event possibly related to study drug ( P=0.038 ) . More olanzapine patients had a clinical ly significant weight increase ( > or = 7 % of baseline weight ) compared to lithium patients ( P=0.009 ) . More olanzapine patients completed the study than lithium patients , although this difference was not statistically significant ( olz , 91.3 % ; lith , 78.9 % ; P=0.057 ) . LIMITATIONS No placebo arm was included ; however both treatments have previously been reported to be more effective than placebo . CONCLUSIONS These results suggest that olanzapine has superior efficacy to lithium in the acute treatment of patients with bipolar mania over a 4-week period . However , adverse events were experienced by a greater number of olanzapine patients than lithium patients OBJECTIVE To investigate whether treatment with lithium in patients with mania or bipolar disorder is associated with a decreased rate of subsequent dementia . METHODS Linkage of register data on prescribed lithium in all patients discharged from psychiatric health care service with a diagnosis of mania or bipolar disorder and subsequent diagnoses of dementia in Denmark during a period from 1995 to 2005 . RESULTS A total of 4,856 patients with a diagnosis of a manic or mixed episode or bipolar disorder at their first psychiatric contact were included in the study . Among these patients , 2,449 were exposed to lithium ( 50.4 % ) , 1,781 to anticonvulsants ( 36.7 % ) , 4,280 to antidepressants ( 88.1 % ) , and 3,901 to antipsychotics ( 80.3 % ) during the study period . A total of 216 patients received a diagnosis of dementia during follow-up ( 103.6/10,000 person-years ) . During the period following the second prescription of lithium , the rate of dementia was decreased compared to the period following the first prescription . In contrast , the rates of dementia during multiple prescription periods with anticonvulsants , antidepressants , or antipsychotics , respectively , were not significantly decreased compared to the rate of dementia during the period with one prescription of these drugs . CONCLUSIONS Continued treatment with lithium was associated with a reduced rate of dementia in patients with bipolar disorder in contrast to continued treatment with anticonvulsants , antidepressants , or antipsychotics . Method ological reasons for these findings can not be excluded due to the nonr and omized nature of the data BACKGROUND This study followed manic or mixed bipolar I subjects for an additional 40 weeks after initial r and omization to 12 weeks of lithium versus aripiprazole monotherapy . This is the only long-term , double-blind study comparing lithium and aripiprazole . METHODS Patients continued receiving either aripiprazole 15 or 30 mg/day , or lithium 900 , 1200 or 1500 mg/day in a double-blind fashion for 40 weeks after completing a 12-week double-blind study ( 52 weeks total treatment ) . Efficacy endpoints included adjusted mean change from baseline to Week 52 in Young Mania Rating Scale ( YMRS ) total score and Montgomery-Åsberg Depression Rating Scale ( MADRS ) total scores ( observed cases ) . Remission was defined as YMRS total score≤12 . Safety and tolerability were also assessed . RESULTS Of the 66 patients who entered the extension phase , only 20 patients ( 30.3 % ) completed the entire phase ( aripiprazole n=7 ; lithium n=13 ) . The significant improvement that occurred over the first 12 weeks was maintained over the 40 weeks of blinded continuation ( from Week 12 through Week 52 ) . The most common treatment-emergent adverse events in the extension phase for aripiprazole  were akathisia , headache , somnolence , anxiety and nasopharyngitis ( all 8 % ) , and for lithium  were insomnia ( 15.8 % ) , headache ( 13.2 % ) , diarrhea ( 13.2 % ) and vomiting ( 10.5 % ) . Mean weight change was + 2.71 kg for lithium and + 5.66 kg for aripiprazole ( p=0.46 ) . LIMITATIONS This trial was not powered to statistically compare active treatments , and long-term completion rates were low in both groups . CONCLUSIONS Aripiprazole monotherapy appears to be equivalently useful to lithium for the extended treatment of mixed or manic bipolar disorder patients OBJECTIVE The study assessed the efficacy and safety of risperidone as an adjunctive agent to mood stabilizers in the treatment of acute mania .  METHOD This 3-week r and omized , double-blind , placebo-controlled study included 156 bipolar disorder patients with a current manic or mixed episode who received a mood stabilizer ( lithium or divalproex ) and placebo , risperidone , or haloperidol .  The primary efficacy measure was the Young Mania Rating Scale . Other assessment s used the Brief Psychiatric Rating Scale , the Clinical Global Impression scale , and safety measures . RESULTS The trial was discontinued by 25 ( 49 % ) of the 51 placebo group patients , 18 ( 35 % ) of the 52 risperidone group patients , and 28 ( 53 % ) of the 53 haloperidol group patients . Mean modal doses were 3.8 mg/day ( SD=1.8 ) of risperidone and 6.2 mg/day ( SD=2.9 ) of haloperidol . Significantly greater reductions in Young Mania Rating Scale scores at endpoint and over time were seen in the risperidone group and in the haloperidol group , compared with the placebo group . Young Mania Rating Scale total scores improved with risperidone and with haloperidol both in patients with psychotic features and in those without psychotic features at baseline . Extrapyramidal Symptom Rating Scale total scores at endpoint were significantly higher in the haloperidol patients than in the placebo patients . Antiparkinsonian medications were received by 8 % , 17 % , and 38 % of patients in the placebo , risperidone , and haloperidol groups , respectively . CONCLUSIONS Risperidone plus a mood stabilizer was more efficacious than a mood stabilizer alone , and as efficacious as haloperidol plus a mood stabilizer , for the rapid control of manic symptoms and was well tolerated Patients with recurrent affective illness ( N-122 ) were r and omly assigned to lithium carbonate , imipramine , or placebo therapy for two years following discharge from hospitalization for acute depression . Patients were classified as bipolar or unipolar based on the presence or absence of a history of mania . With bipolar patients lithium carbonate was significantly more effective than imipramine or placebo in preventing affective episodes ( ie , manic or depressive attacks severe enough to require hospitalization or use of non study drugs ) . There was a relatively high incidence of manic episodes on imipramine . Unipolar patients responded equally well to lithium carbonate or imipramine . Both treatments were significantly more effective than placebo . The difference between treatments was due primarily to depressive episodes ; manic episodes occurred infrequently and were evenly distributed across treatment groups . There was no significant difference between  lithium carbonate and imipramine  among unipolar patients BACKGROUND Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder . Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse , compared with lithium or valproate alone . METHOD Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium ( 0.6 - 1.2 mmol/l ) or valproate ( 50 - 125 microg/ml )  received lithium or valproate plus either olanzapine 5 - 20 mg/day ( combination therapy ) or placebo ( monotherapy ) , and were followed in a double-masked trial for 18 months . RESULTS The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse ( median time to relapse : combination therapy 94 days , monotherapy 40.5 days ; P=0.742 ) , but was significant for symptomatic relapse ( combination therapy 163 days , monotherapy 42 days ; P=0.023 ) . CONCLUSIONS Patients taking olanzapine  added to lithium or valproate experienced sustained symptomatic remission , but not syndromic remission , for longer than those receiving lithium or valproate monotherapy Studies have proposed the involvement of oxidative stress and neuronal energy dysfunctions in the pathophysiology of bipolar disorder ( BD ) . This study evaluates plasma levels of the oxidative/energy metabolism markers , thiobarbituric acid reactive substances ( TBARS ) , superoxide dismutase ( SOD ) , catalase ( CAT ) , and neuron-specific enolase ( NSE ) during initial episodes of mania compared to controls in 75 subjects . Two groups of manic subjects ( unmedicated n=30 , and lithium-treated n=15 ) were age/gender matched with healthy controls ( n=30 ) .  TBARS and antioxidant enzymes activity ( SOD and CAT ) were increased in unmedicated manic patients compared to controls . Conversely , plasma NSE levels were lower during mania than in the controls . In contrast , acute treatment with lithium showed a significant reduction in both SOD/CAT ratio and TBARS levels . These results suggest that initial manic episodes are associated with both increased oxidative stress parameters and activated antioxidant defenses , which may be related to dysfunctions on energy metabolism and neuroplasticity pathways . Antioxidant effects using lithium in mania were shown , and further studies are necessary to evaluate the potential role of these effects in the pathophysiology and therapeutics of BD OBJECTIVE This prospect i ve 6-month open trial examined the safety and efficacy of two combination therapies for manic or mixed episodes of pediatric bipolar disorder : ( 1 ) divalproex sodium plus risperidone ( DVPX+Risp ) , or ( 2 ) lithium plus risperidone ( Li+Risp ) . METHODS Thirty-seven ( 37 ) subjects aged 5 and 18 ( age=12.1+/-3.5 years ) with DSM IV current mixed or manic episode and Young Mania Rating Scale ( YMRS ) score > 20 were sequentially assigned to either DVPX+Risp or Li+Risp in a 6-month , prospect i ve open-label trial . Outcome measures included the YMRS , Clinical Global Impression Scale for Bipolar Disorder ( CGI-BP ) , Child Depression Rating Scale-Revised ( CDRS-R ) as well as measures of safety and tolerability . RESULTS Effect sizes ( Cohen 's d ) based on change of YMRS scores from baseline were 4.36 for DVPX+Risp and 2.82 for Li+Risp .  Response rates ( > or=50 % change from baseline YMRS score at the end of study ) were 80 % for DVPX+Risp and 82.4 % for Li+Risp . Both combination treatments were well tolerated . Significant improvements ( p<0.001 ) from baseline were seen for mean scores on all efficacy measures , i.e. , YMRS , CGI-BP , and CDRS-R. There were no significant group differences in safety or tolerability , and no serious adverse events during the 6-month trial . CONCLUSION Both DVPX+Risp and Li+Risp show strong effects coupled with safety and tolerability in treating children and adolescents with manic or mixed episodes associated with type I bipolar disorder OBJECTIVE To evaluate the efficacy and tolerability of quetiapine monotherapy versus placebo for the treatment of mania associated with bipolar disorder . METHOD In an international , multicenter , double-blind , parallel-group , 12-week study , patients with a DSM-IV diagnosis of bipolar I disorder ( manic episode ) were r and omly assigned to treatment with quetiapine ( flexibly dosed up to 800 mg/day ) , placebo , or lithium . The primary efficacy measure was change from baseline in Young Mania Rating Scale ( YMRS ) score at day 21 . Data were gathered from April 2001 to May 2002 . RESULTS More patients in the quetiapine ( 72/107 ) and lithium ( 67/98 ) groups completed the study compared with the placebo group ( 35/97 ) . Improvement ( reduction ) in YMRS score was significantly greater for quetiapine than placebo at day 7 ( -8.03 vs. -4.89 ; p < .01 ) , and the difference between groups continued to increase over time to day 21 ( -14.6 vs. -6.7 ; p < .001 ) and to endpoint at day 84 ( -20.3 vs. -9.0 ; p < .001 ) . Significantly more quetiapine patients compared with placebo patients fulfilled YMRS response criteria at day 21 ( 53.3 % vs. 27.4 % ; p < .001 ) and at day 84 ( 72.0 % vs. 41.1 % ; p < .001 ) . Quetiapine was also superior to placebo in efficacy at day 21 and day 84 by all secondary measures . Lithium-treated patients improved significantly compared with placebo patients and similarly to quetiapine-treated patients on the primary efficacy measure . The most common adverse events for quetiapine were dry mouth , somnolence , and weight gain , while lithium was associated with tremor and insomnia . The quetiapine and placebo groups had similar , low levels of extrapyramidal symptom-related adverse events . CONCLUSIONS Quetiapine demonstrated superior efficacy to placebo in patients with bipolar mania and was well tolerated BACKGROUND Combination treatment with atypical antipsychotics and a mood stabilizer is often recommended for treatment of manic or mixed episodes associated with bipolar I disorder . METHODS Eligible patients ( n=300 ) with a Young Mania Rating Scale ( YMRS ) total score ≥20 were r and omly allocated ( 1:1 ) to continue mood stabilizer monotherapy or receive flexibly-dosed paliperidone ER ( 3 - 12 mg/day ) in addition ( combination treatment ) for 6 weeks . The primary efficacy variable was the change from baseline to endpoint in the YMRS total score . RESULTS The mean ( SD ) YMRS total score at baseline was 26.7 ( 5.26 ) ; 33 % of patients presented with a mixed ( as distinct from a manic ) episode and 62 % were on valproate and 38 % on lithium . The mean ( SD ) change from baseline to endpoint in the YMRS total score was not significantly different for combination treatment ( -14.3 [ 10.0 ] ) compared with mood stabilizer monotherapy ( -13.2 [ 10.9 ] ; p=0.16 ) . Combination treatment also failed to separate from mood stabilizer monotherapy for the secondary efficacy measures . The incidence of treatment-emergent adverse events was higher with combination treatment ( 70 % ) than with mood stabilizer monotherapy ( 54 % ) ; insomnia was the most common adverse event in both treatment groups ( 11 % ) . LIMITATIONS The relatively low doses of paliperidone ER used in this study and the conduct across different countries may have contributed to its failure to differentiate combination treatment from mood stabilizer monotherapy for the primary and secondary efficacy measures . CONCLUSIONS In this study , flexibly-dosed paliperidone ER used as adjunctive therapy to mood stabilizers did not demonstrate efficacy over mood stabilizer monotherapy . No new safety signals were observed with combination treatment in this population OBJECTIVE To investigate the efficacy and safety of topiramate versus placebo as adjunctive therapy for the outpatient management of bipolar I disorder . METHOD In this 12-week , r and omized , double-blind , placebo-controlled trial , adults with bipolar I disorder ( DSM-IV criteria ) experiencing a manic or mixed episode with a Young Mania Rating Scale ( YMRS ) score of > or= 18 while taking therapeutic levels of valproate or lithium received adjunctive topiramate or placebo . Topiramate was titrated from 25 to 400 mg/day over 8 weeks and was continued for 4 additional weeks . The study was conducted from October 2001 through October 2003 . The primary outcome measure was the change in YMRS score from baseline to last study visit during the double-blind phase . RESULTS The mean + /- SD change in YMRS score from baseline was -10.1 + /- 8.7 ( -40.1 % ) in the topiramate group ( N = 143 ) and -9.6 + /- 8.2 ( -40.2 % ) in the placebo group ( N = 144 , p = .797 ) . Greater than 50 % reduction in YMRS was achieved by 39 % of the topiramate group and 38 % of the placebo group ( p = .914 ) . No significant treatment differences were observed for secondary efficacy measures . Compared with adjunctive placebo , adjunctive topiramate did not worsen mania or induce depression . Paresthesia , diarrhea , and anorexia were more common in the topiramate group . The topiramate group achieved greater reductions than the placebo group in body weight ( -2.5 vs. 0.2 kg , p < .001 ) and body mass index ( -0.84 vs. 0.07 kg/m(2 ) , p < .001 ) . CONCLUSION In patients treated with lithium or valproate , there was no difference in the reduction of YMRS score in the topiramate and placebo groups . Both groups showed declines of 40 % . Topiramate reduced body weight significantly relative to placebo without worsening depressive or manic symptoms 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 OBJECTIVE This study compared the efficacy and safety of paroxetine and imipramine with that of placebo in the treatment of bipolar depression in adult out patients stabilized on a regimen of lithium . METHOD In a double-blind , placebo-controlled study , 117 out patients with DSM-III-R bipolar disorder , depressive phase , were r and omly assigned to treatment with paroxetine ( N=35 ) , imipramine ( N=39 ) , or placebo ( N=43 ) for 10 weeks . In addition to lithium monotherapy , patients may have received either carbamazepine or valproate in combination with lithium for control of manic symptoms . Patients were stratified on the basis of trough serum lithium levels determined at the screening visit ( high : > 0.8 meq/liter ; low : < /=0.8 meq/liter ) . Primary efficacy was assessed by change from baseline in scores on the Hamilton Rating Scale for Depression and the Clinical Global Impression illness severity scale . RESULTS Differences in overall efficacy among the three groups were not statistically significant . For patients with high serum lithium levels  , antidepressant response at endpoint also did not significantly differ from placebo . However , both paroxetine and imipramine were superior to placebo for patients with low serum lithium levels . Compared to imipramine , paroxetine result ed in a lower incidence of adverse events , most notably emergence of manic symptoms . CONCLUSIONS Antidepressants may not be useful adjunctive therapy for bipolar depressed patients with high serum lithium levels . However , antidepressant therapy may be beneficial for patients who can not tolerate high serum lithium levels or who have symptoms that are refractory to the antidepressant effects of lithium CONTEXT There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder , manic or mixed phase , in children and adolescents . OBJECTIVE To investigate which medication to administer first to antimanic medication-naive subjects . DESIGN , SETTING , AND PARTICIPANTS The Treatment of Early Age Mania ( TEAM ) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder ( manic or mixed phase ) at 5 US sites from 2003 to 2008 into a controlled , r and omized , no-patient-choice , 8-week protocol . Blinded , independent evaluators conducted all baseline and end-point assessment s. INTERVENTIONS Subjects received a titrated schedule of lithium , divalproex sodium , or risperidone . Medications were increased weekly only if there was inadequate response , and no dose-limiting adverse effects , to maximum doses of lithium carbonate ( 1.1 - 1.3 mEq/L ) , divalproex sodium ( 111 - 125 μg/mL ) , and risperidone ( 4 - 6 mg ) . MAIN OUTCOME MEASURES Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents . RESULTS There were 279 antimanic medication-naive subjects ( mean [ SD ] age , 10.1 [ 2.8 ] years ; 50.2 % female ) who had the following characteristics : 100 % elated mood and /or gr and iosity , 77.1 % psychosis , 97.5 % mixed mania , 99.3 % daily rapid cycling , and mean ( SD ) mania duration of 4.9 ( 2.5 ) years .  The mean ( SD ) titrated lithium level was 1.09 ( 0.34 ) mEq/L , and the mean ( SD ) divalproex sodium level was 113.6 ( 23.0 ) μg/mL. The mean ( SD ) titrated risperidone dose was 2.57 ( 1.21 ) mg . Higher response rates occurred with risperidone vs lithium ( 68.5 % vs 35.6 % ; χ(2)(1 ) = 16.9 , P < .001 ) and vs divalproex sodium ( 68.5 % vs 24.0 % ; χ(2)(1 ) = 28.3 , P < .001 ) . Response to lithium vs divalproex sodium did not differ . The discontinuation rate was higher for lithium than for risperidone ( χ(2)(1 ) = 6.4 , P = .011 ) . Increased weight gain , body mass index , and prolactin level occurred with risperidone vs lithium ( F(1,212 ) = 45.5 , P < .001 ; F(1,212 ) = 39.1 , P < .001 ; and F(1,213 ) = 191.4 , P < .001 , respectively ) and vs divalproex sodium ( F(1,212 ) = 34.7 , P < .001 ; F(1,212 ) = 45.3 , P < .001 ; and F(1,213 ) = 209.4 , P < .001 , respectively ) . The thyrotropin level increased in subjects taking lithium ( t(62 ) = 11.3 , P < .001 ) . CONCLUSIONS Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects . TRIAL REGISTRATION clinical trials.gov Identifier : 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 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 OBJECTIVE The authors evaluated the efficacy and safety of quetiapine plus lithium or divalproex in the prevention of recurrent mood events in patients with stabilized bipolar I disorder . METHOD A total of 1,953 patients received open-label  quetiapine ( 400 - 800 mg/day in flexible , divided doses ) with either lithium or divalproex ( target serum concentrations 0.5 - 1.2 meq/liter and 50 - 125 microg/ml , respectively ) for up to 36 weeks . After at least 12 weeks of clinical stability , 628 patients were r and omly assigned to double-blind treatment with quetiapine or placebo , in combination with lithium or divalproex , for up to 104 weeks . The primary efficacy measure was time to recurrence of any mood event ( mania , depression , or a mixed episode ) . RESULTS Fewer patients in the quetiapine group experienced a mood event compared with the placebo group ( 20.3 % versus 52.1 % ) . The hazard ratio for time to recurrence of a mood event was 0.32 . Hazard ratios were similar for mania and depression events ( 0.30 and 0.33 , respectively ) . Sedation , weight increase , and hypothyroidism occurred more frequently in the quetiapine group , as did discontinuations due to adverse events . The incidence and incidence density of a single emergent blood glucose value > or = 126 mg/dl were higher in the quetiapine group ( 12.6 % versus 5.4 % ; 18.44 versus 9.56 patients per 100 patient-years ) . Adverse events were generally consistent with the known tolerability profile of quetiapine . CONCLUSIONS In patients stabilized on quetiapine plus lithium or divalproex  , continued treatment was associated with a significant risk reduction in the time to recurrence of any mood event compared with placebo and lithium or divalproex
This systematic review indicates that lithium is more effective than placebo as a treatment for acute mania but increases the risk for somnolence and tremor .
Limited evidence suggests little or no difference between lithium and other mood stabilisers ( valproate , carbamazepine ) or antipsychotics ( risperidone , quetiapine , haloperidol ) .
Olanzapine may be an exception , as it is probably slightly more effective than lithium .
There is uncertain evidence that risperidone may also be more effective than lithium .
Lithium is probably more effective at treating acute mania than topiramate .
When compared to placebo , lithium was more likely to cause adverse events .
More , rigorously design ed , large-scale studies are needed to definitively conclude if lithium is superior to other interventions in treating acute mania
BACKGROUND Bipolar disorder is a common condition associated with high morbidity ; developing efficacious , safe treatments is therefore essential .
Lithium is an effective maintenance treatment for bipolar disorder .
It acts as mood stabiliser and reduces the risk of suicide .
However , evidence assessing the efficacy of lithium in the treatment of acute mania is less robust .
Current evidence -based guidelines cite multiple anti-dopaminergic and mood-stabilising agents as initial treatments : more definite evidence is needed to decide if lithium should be the first-line therapy .
OBJECTIVES 1 .
To assess the effects of lithium in comparison with placebo or other active treatment in alleviating the acute symptoms of a manic or mixed episode in people with bipolar disorder.2 .
To review the acceptability and tolerability of treatment with lithium in comparison with placebo or other active treatments in alleviating the acute symptoms of a manic or mixed episode in people with bipolar disorder .