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
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
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 .