title: Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology A double-blind comparison of valproate and lithium in the treatment of acute mania. Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Report of the Veterans Administration and National Institute of Mental Health Collaborative Study Group. Trials of lithium, chlorpromazine and amitriptyline in schizoaffective patients. Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial Sulpiride treatment of acute mania with a comparison of the effects on plasma hormone concentrations of lithium and sulpiride treatment. A comparison of haloperidol, lithium carbonate and their combination in the treatment of mania. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. Psychoactive drugs in mania. A controlled comparison of lithium carbonate, chlorpromazine, and haloperidol. A 12-week, open, randomized trial comparing sodium valproate to lithium in patients with bipolar I disorder suffering from a manic episode Treatment of manic episodes: Zuclopenthixol and Clonazepam versus Lithiim and Clonazepam Response and remission rates in Chinese patients with bipolar mania treated for 4 weeks with either quetiapine or lithium: a randomized and double-blind study Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population-based UK cohort study using electronic health records. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Carbamazepine versus lithium in mania: a double-blind study. Olanzapine versus lithium in the acute treatment of bipolar mania: a double-blind, randomized, controlled trial. A 40-week double-blind aripiprazole versus lithium follow-up of a 12-week acute phase study (total 52 weeks) in bipolar I disorder. Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Open-label prospective trial of risperidone in combination with lithium or divalproex sodium in pediatric mania. Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder. Electroconvulsive treatment compared with lithium in the management of manic states. Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. Comparative effects of lithium and chlorpromazine in the treatment of acute manic states. Carbamazepine vs lithium in the treatment and prophylaxis of mania. GERI-BD: A Randomized Double-Blind Controlled Trial of Lithium and Divalproex in the Treatment of Mania in Older Patients With Bipolar Disorder. Single Dose Pharmacokinetics of 5 Formulations of Lithium: a Controlled Comparison in Healthy Subjects Bioavailability of lithium from lithium citrate syrup versus conventional lithium carbonate tablets Lithium in the treatment of mania: comparisons with neuroleptics. Comparison of the antimanic efficacy of carbamazepine and lithium carbonate by double-blind controlled study. A comparison of lithium carbonate and chlorpromazine in mania. Lamotrigine Compared with Lithium in Mania: A Double-Blind Randomized Controlled Trial Acute mania: haloperidol dose and augmentation with lithium or lorazepam. Olanzapine vs. lithium in management of acute mania. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients. Comparison of efficacy of lithium carbonate and chlorpromazine in mania. Report of collaborative study group on treatment of mania in Japan. Frequency of hospitalisations and inpatient care costs of manic episodes Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study. A double-blind comparison of lithium and chlorpromazine in the treatment of manic states. Carbamazepine compared with lithium in the treatment of mania. Risperidone Compared with Both Lithium and Haloperidol in Mania: A Double‐Blind Randomized Controlled Trial 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. Incidence and predictors of suicide attempts in bipolar I and II disorders: A 5‐year follow‐up study
abstract: The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder . The third version is based explicitly on the available evidence and presented , like previous Clinical Practice Guidelines , as recommendations to aid clinical decision making for practitioners : it may also serve as a source of information for patients and carers , and assist audit . The recommendations are presented together with a more detailed review of the corresponding evidence . A consensus meeting , involving experts in bipolar disorder and its treatment , review ed key areas and considered the strength of evidence and clinical implication s. The guidelines were drawn up after extensive feedback from these participants . The best evidence from r and omized controlled trials and , where available , observational studies employing quasi-experimental design s was used to evaluate treatment options . The strength of recommendations has been described using the GRADE approach . The guidelines cover the diagnosis of bipolar disorder , clinical management , and strategies for the use of medicines in short-term treatment of episodes , relapse prevention and stopping treatment . The use of medication is integrated with a coherent approach to psychoeducation and behaviour change OBJECTIVE This study was carried out to compare the efficacy of lithium carbonate with that of valproate in acute mania and to determine whether pretreatment clinical characteristics , such as the presence of a mixed affective state , might predict a differential response to the two drugs . METHOD Twenty-seven patients meeting DSM-III-R criteria for acute manic episodes underwent a 3-week , r and omized , double-blind , parallel-groups trial of treatment with lithium carbonate or valproate .  Symptom severity was measured by using the Schedule for Affective Disorders and Schizophrenia , change version ( SADS-C ) , the Global Assessment Scale ( GAS ) , and the Brief Psychiatric Rating Scale ( BPRS ) . Drug effects were compared by using repeated measures analysis of variance ( ANOVA ) . RESULTS At the end of the study , nine of 14 patients treated with valproate and 12 of 13 patients treated with lithium had responded favorably , as measured by changes in the SADS-C mania , BPRS , and GAS scores . Elevated pretreatment SADS-C depression scores were associated with good response to valproate . ANOVA revealed a significant interaction between drug and mixed affective state with respect to treatment response . CONCLUSIONS Lithium and valproate were both effective in improving manic symptoms , and lithium was slightly more efficacious overall . Unlike the case with lithium , favorable response to valproate was associated with high pretreatment depression scores . Therefore , treatment with valproate alone may be particularly effective in manic patients with mixed affective states In an 18-hospital collaborative study , 255 newly admitted manic patients were r and omly assigned to lithium carbonate or chlorpromazine for a three-week period . Patients were classified as highly active or mildly active on the basis of degree of motor activity shown at admission . Treatments were compared in terms of early terminations , symptom change , and toxicity . The following results were obtained : ( 1 ) Chlorpromazine was clearly superior to lithium carbonate in treating the highly active patient . Chlorpromazine acted more quickly , produced significantly fewer dropouts , and had a lower incidence of severe side effects . ( 2 ) The difference between lithium carbonate and chlorpromazine was less pronounced among mildly active patients . Lithium carbonate , however , appeared to be the better treatment . Both drugs effectively reduced manic symptomatology but lithium carbonate left the patient feeling less sluggish and fatigued .  Lithium carbonate also produced fewer severe side effects than chlorpromazine Two drug trials in schizoaffective patients are reported . Nineteen " schizomanic " patients were treated for one month , on a double blind basis , with chlorpromazine or lithium and 41 " schizodepressive " patients with amitriptyline , chlorpromazine or both . In the schizodepressive patients there was a trend to a better response to chlorpromazine , but drug response generally was poor , only 20 per cent of patients recovering within the month . In the schizomanic patients lithium seemed as effective as chlorpromazine , which supports the view that these patients were suffering from a variant of mania 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 Sulpiride , in this open study of acute manic patients , had a clear antimanic action with all eight patients responding to sulpiride treatment without the need for other antipsychotic drugs . Plasma prolactin concentrations were increased and oestrogen-stimulated neurophysin concentrations decreased by sulpiride but were unchanged by lithium treatment , whereas TSH concentrations showed a rapid increase following the introduction of lithium therapy Previous investigations of the treatment of mania have result ed in uncertainty about the efficacy of lithium versus a neuroleptic . In addition there have been reports of toxicity with a haloperidol -- lithium combination . In order to determine the comparative efficacy of lithium vs haloperidol vs a combination of haloperidol -- lithium , we studied 21 severely ill manic patients who all met rigorous criteria for bipolar illness and who required in hospital treatment . Subjects were r and omly assigned to 3 groups : ( A ) Lithium plus placebo ( B ) Placebo plus haloperidol and ( C ) Lithium plus haloperidol . The study was conducted in double blind fashion for 3 weeks with the dosages of the medications varied according to clinical response or untoward effects . Subjects on haloperidol and placebo or the haloperidol -- lithium combination were significantly improved after 7 days in comparison to the lithium-treated group . Groups B and C did not differ from each other , either in degree of improvement or in side effects . Inspite of the relatively small sample size the results suggest ( 1 ) that haloperidol is superior to lithium for treating severely ill acute mania and ( 2 ) that while a haloperidol -- lithium combination does not result in a significant increase in side effects , it is not superior to haloperidol alone 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 Lithium carbonate , haloperidol , and chlorpromazine hydrochloride were compared in a double-blind controlled study with severely ill hospitalized manics .  Lithium carbonate and haloperidol produced a highly significant improvement of manic symptoms without sedation . Although producing considerable sedation , chlorpromazine did little to alter the underlying mania qualitatively . Qualitative differences between lithium carbonate and haloperidol indicate that , while haloperidol has a more dramatically rapid impact on behavior-motor activity , lithium carbonate acted more evenly on the entire manic picture , with total normalization realized during active treatment . The majority of lithium carbonate-treated patients met discharge criteria at study termination , but not the patients receiving either neuroleptic drug . The rating scales are not sensitive enough to monitor manic psychopathology ; this accounts for the lack of statistically significant differences among drug groups at treatment termination , despite the widely disparate discharge rates 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 For the treatment of acute mania , no single drug is sufficiently effective in daily clinical routine for all patients . Drug combinations are often prescribed but poorly investigated . The present study examined whether a treatment with a neuroleptic drug ( zuclopenthixol ) combined with a benzodiazepine ( clonazepam ) was superior to a treatment with lithium and the same benzodiazepine ( lithium citrate and clonazepam ) .  Twenty‐eight hospitalized patients with a DSM‐III‐R manic episode were included , r and omized to fixed drug doses and observed up to 28 days . Degree of mania , side effects and patients satisfaction with the treatment were registered . Approximately two thirds of the patients improved fully or partially on both drug combinations . Furthermore no statistically significant differences were found regarding acceptance and tolerance of the two drug combinations . The present drug combination are only two among several which deserve a thorough examination in order to prevent a r and om polypharmacy for treatment of mania ABSTRACT Objective : To assess the efficacy and tolerability of quetiapine in Chinese patients hospitalized with acute bipolar mania . Methods : This was a 4-week , multicenter , r and omized , double-blind , lithium-controlled , parallel-group study . Secondary endpoints in the primary analysis were : response rate ( ≥ 50 % decrease from baseline in YMRS total score ) and remission rate as defined using 3 criteria : YMRS total score ≤ 12 , YMRS total score ≤ 12 + MADRS total score ≤ 8 , and YMRS total score ≤ 8 . Other measures included : change from baseline at Day 28 in YMRS , PANSS , and MADRS total score . Adverse event ( AE ) data were collected throughout the study . Results : 73 ( 94.8 % ) quetiapine and 62 ( 80.5 % ) lithium patients completed the study .  Mean ( SD ) quetiapine  doses for the ITT population and responders were 648.2 ( 111.84 ) mg/day and 637.5 ( 118.78 ) mg/day , respectively , while mean lithium concentrations for the ITT population and responders were 0.80 ( 0.28 ) mmol/L and 0.80 ( 0.22 ) mmol/L , respectively . Of patients who responded to quetiapine at Day 28 , 88.3 % were receiving 600–800 mg/day . At Day 28 YMRS response rate was significantly greater with quetiapine than lithium ( 77.9 % vs. 59.7 % , p = 0.0132 ) , and remission rates using the 3 criteria were significantly greater with quetiapine than lithium  : YMRS total score ≤ 12 ( 70.1 % vs. 48.1 % , p = 0.0071 ) , YMRS ≤ 12 + MADRS ≤ 8 ( 70.1 % vs. 48.1 % ; p = 0.0071 ) , and YMRS ≤ 8 ( 51.9 % vs. 32.5 % ; p = 0.0147 ) . Significant decreases were observed in PANSS , YMRS , and MADRS total scores for both groups . The most common AEs experienced by patients receiving quetiapine  were constipation , dizziness , diarrhea , alanine aminotransferase increase , palpitations , aspartate aminotransferase increase , pharyngolaryngeal pain , upper respiratory tract infection and dry mouth . In patients receiving lithium , the most common AEs were nausea ( 16.9 % ) , constipation ( 13.0 % ) , vomiting ( 13.0 % ) , nasopharyngitis ( 11.7 % ) , dizziness ( 6.5 % ) , diarrhea ( 6.5 % ) , and upper respiratory tract infection ( 6.5 % ) . Conclusion : Quetiapine was shown to be clinical ly effective in patients with acute bipolar mania . There were side effects with quetiapine similar to those reported in other studies that included other ethnic population s of patients It is unclear which maintenance treatment for bipolar disorder is superior in clinical practice . R and omized controlled head-to-head trials of available drugs either do not exist or are inconclusive . We aim ed to compare rates of monotherapy treatment failure in individuals prescribed lithium , valproate , olanzapine or quetiapine  by a population -based cohort study using electronic health records . 5,089 patients with bipolar disorder were prescribed  lithium ( N=1,505 ) , valproate ( N=1,173 ) olanzapine ( N=1,366 ) or quetiapine ( N=1,075 ) as monotherapy . Treatment failure was defined as time to stopping medication or add-on of another mood stabilizer , antipsychotic , antidepressant or benzodiazepine . In unadjusted analyses , the duration of successful monotherapy was longest in individuals treated with lithium .  Treatment failure had occurred in 75 % of those prescribed lithium by 2.05 years ( 95 % CI : 1.63 - 2.51 ) , compared to 0.76 years ( 95 % CI : 0.64 - 0.84 ) for those prescribed quetiapine , 0.98 years ( 95 % CI : 0.84 - 1.18 ) for those prescribed valproate , and 1.13 years for those prescribed olanzapine ( 95 % CI : 1.00 - 1.31 ) . Lithium 's superiority remained in a propensity score matched analysis ; when treatment failure was defined as stopping medication or add-on of a mood stabilizer or antipsychotic ; and when treatment failure was restricted to more than three months after commencing the study drug . Lithium appears to be more successful as monotherapy maintenance treatment than valproate , olanzapine or quetiapine . Lithium is often avoided because of its side effect profile , but alternative treatments may reduce the time to being prescribed more than one drug , with potential additive side effects of these treatments 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 Thirty-four manic patients were r and omly assigned to treatment with carbamazepine or lithium . Clinical response was rated over 4 weeks . Twenty-eight patients , 14 in each group , completed the full protocol .  Serum levels for both drugs were within the accepted therapeutic range . The overall response to treatment was not significantly different between the two groups . Comparison of individual Clinical Global Impressions , Brief Psychiatric Rating Scale , and Beigel-Murphy Manic State Rating Scale change scores showed a more consistent level of improvement across patients in the lithium-treated group compared to a minority of good responders in the carbamazepine-treated group . The findings suggest that carbamazepine has antimanic potential in specific bipolar patients whose clinical characteristics remain to be clearly defined 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 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 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 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 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 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 Thirty-four hospitalized manic patients were r and omized to treatment with either lithium carbonate or an average series of nine bilateral electroconvulsive treatments ( ECTs ) , followed by maintenance with lithium carbonate . Weekly ratings of manic , depressive , and psychotic symptoms were obtained for eight weeks , and patients were followed up monthly for up to two years . Ratings by nonblind and blind observers indicated that the patients who underwent ECT  improved more during the first eight weeks than did patients who were treated with lithium carbonate . This was especially true of patients with mixed symptoms of mania and depression and /or extreme manic behavior . Clinical ratings after eight weeks showed no significant differences between the lithium carbonate- and ECT-treated patients . Likewise , the two groups had comparable rates of relapse , recurrence , and rehospitalization during the follow-up period Neuroleptics are of established efficacy in mania . Controlled data on the use of olanzapine in mania is however , absent . In this study , 30 patients meeting DSM-IV criteria for mania were r and omly allocated to receive either olanzapine or lithium in a 4 week double-blind r and omized controlled design . There were no significant outcome differences between the two groups on any of the primary outcome measures , the Brief Psychiatric Rating Scale  ( lithium 28.2 ; olanzapine 28.0 ; P = 0.44 ) ; Clinical Global Impression ( CGI ) improvement scale  ( lithium 2.75 , olanzapine 2.36 ; P = 0.163 ) or the Mania Scale  ( lithium 13.2 , olanzapine 10.2 ; P = 0.315 ) . Olanzapine was however , significantly superior to lithium on the CGI-severity scale at week 4 ( lithium 2.83 , olanzapine 2.29 ; P = 0.025 ) . Olanzapine did not differ from lithium in terms of treatment emergent extrapyramidal side-effects as measured by the Simpson-Angus Scale .  Olanzapine appears to be at least as effective as lithium in the treatment of mania A controlled double-blind evaluation of lithium and chlorpromazine in acute manic states is reported . Analysis of the results shows that lithium produced a highly significant improvement in the  manic-depressive ( manic phase ) patients but no significant change in the  schizoaffective ( excited ) patients .  Chlorpromazine produced significant improvement in both diagnostic groups . An analysis of the differences of the two treatments showed that lithium produced the greater change in the manic-depressives , whereas chlorpromazine produced more change than lithium in the schizoaffective group . These differences , however , did not reach statistical significance . The importance of diagnosis for treatment outcome is discussed . Lithium is an effective and specific agent for the control of the manic phase of manic-depressive illness Fifty-four acutely manic patients were allocated to treatment on a double-blind basis with either carbamazepine or lithium carbonate . The short-term effects of treatment were studied over a period of six weeks and the longer term , prophylactic , effects over a period of up to a year . Additional ' rescue ' medication was allowed when clinical ly indicated . There was a high drop-out rate from the trial . Despite this , it appeared that valid comparisons between the two treatments could be made . No statistically significant differences were found , but carbamazepine appeared slightly less effective as a treatment for acute mania and more effective as a prophylactic treatment in this group of patients . Possible predictors of individual responsiveness to each treatment are discussed 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 The single dose pharmacokinetics of  4 lithium preparations ( Camcolit-400 , Priadel , Liskonum , Litarex ) and a new micro-encapsulated formulation were compared in normal volunteers using a balanced cross-over design . The data show an inverse relationship between rate of release and bioavailability . The pharmacokinetic characteristics of Camcolit-400 and Priadel were similar ; both showed earlier and greater peak serum concentrations than the other 3 . The new formulation , which accounted for most of the significant variance , had the slowest rate of release and the lowest bioavailability . Statistical analysis showed significant differences between the 5 preparations for C-max , T-max , 12-h serum levels , AUC and urinary excretion , but not for the 24-h serum levels . No serious untoward side-effects were noted The bioavailability of lithium citrate syrup was compared with that of regular lithium carbonate tablets in 18 healthy male human volunteers . Blood sample s were collected up to 48 h after dosing . Lithium serum concentrations were determined by means of AAS . The absorption rate following oral administration of the syrup was greater ( tmax 0·8 h ) than following administration of regular tablets ( tmax 1·4 h ) . Maximum lithium serum concentrations , however , were only about 10 per cent higher after syrup dosing and serum concentrations result ing from syrup and tablets were almost superimposable from 2 h after dosing . The terminal half‐life of lithium  was found to be 22 h after syrup as well as after tablet dosing . No side‐effects were observed during the study . The bioavailability of lithium from syrup relative to tablets was found to be bioequivalent with respect to the maximum lithium serum concentration and the extent of drug absorption ( AUC ) Since the original discovery of the antimanic properties of lithium nearly 30 years ago , 1 a large number of studies , as well as extensive clinical experience , have confirmed the efficacy of this drug for the treatment of the manic phase of manic-depressive illness . The recent focus of questions concerning the role of lithium in the treatment of mania has shifted from efficacy per se to comparisons with other drug treatments and the related issue of specificity . This review will , therefore , focus on controlled studies comparing lithium with neuroleptics , following a brief historical review of the earlier studies . The studies comparing lithium with neuroleptics are of special importance not only from a practical point of view but also theoretically , in that they bear on the question of the specificity of  lithium  against the manic syndrome — a question with implication for the underlying pathophysiology of mania . OPEN SINGLE-BLIND STUDIES Table 1 summarizes A multi-institutional study comparing the antimanic effect of carbamazepine ( CBZ ) and lithium carbonate ( Li ) was performed using a double-blind group comparison design in a series of 105 patients with bipolar disorders .  CBZ and Li were given for four weeks using a fixed-flexible method at an equipotent dose ratio of 1:1 , starting from an initial dosage of 400 mg with a maximum dosage of 1200 mg . The final global improvement rate , based on the number of cases showing moderate to marked amelioration of manic symptoms , was 62 % in the CBZ group and 59 % in the Li group , with no significant difference being found between the two groups . Incidence of cutaneous side-effects was significantly higher in the CBZ group . The mean daily dosage and serum level of CBZ  in the fourth week were 674 + /- 239 mg and 7.3 + /- 2.4 micrograms/ml respectively ; these were within the therapeutic range . The daily dose and serum level of Li  , however , were 710 + /- 239 mg and 0.46 + /- 0.22 mEq/l , and the  Li level seemed to be too low to compare its therapeutic effect with that of CBZ . Prior to the present study , approximately 80 % of the patients in both groups had been receiving antipsychotic medication , equivalent to 8.0 mg of haloperidol on average , without favorable response . This medication was maintained unchanged during treatment . While the shortcomings of the present study limit the interpretation of the data , it may be suggested that the usefulness of CBZ as a drug for the treatment of manic states is comparable to that of Li Thirteen manic patients were treated with  lithium carbonate  and ten manic patients with chlorpromazine in a double-blind , r and omly selected drug trial .  Lithium carbonate proved superior to chlorpromazine on all six parameters selected from an objective rating scale . The author discusses the problems militating against a valid research trial utilizing these medications in this type of patient Background : Preliminary data from case reports and small open trials suggest a role for lamotrigine in the treatment of bipolar disorder , although controlled data for the manic phase are lacking . Method : Thirty in patients with a DSM-IV diagnosis of bipolar I disorder , currently manic , were r and omly allocated to receive either lamotrigine ( 25 mg once daily for 1 week , 50 mg once daily for the second week , and 100 mg once daily for the last 2 weeks ) or lithium ( 400 mg twice daily ) in a 4-week r and omized , double-blind , clinical trial . Results : Both treatments improved symptoms of mania , as assessed by the Mania Rating Scale , Brief Psychiatric Rating Scale , Clinical Global Impression severity and improvement scales , and the Global Assessment of Functioning scale . There were no significant differences between groups at any time point , suggesting that the dose escalation required for lamotrigine did not adversely affect its onset of action . Secondary outcome measures , including the use of lorazepam as rescue medication , did not differ between the groups . No significant adverse events were noted in either group . Conclusion : In this pilot study , lamotrigine was as effective as lithium in the treatment of patients with bipolar disorder hospitalised for acute mania Antipsychotic dosing for acute mania has not been well studied . Combined treatment with lithium and an antipsychotic is the most common treatment , but additional antimanic efficacy of a lithium-antipsychotic combination beyond that of an antipsychotic alone has not been well demonstrated . Furthermore , the possibility that lithium could affect antipsychotic dose requirement is believed to have never been studied . In this study , 63 acutely psychotic bipolar manic in patients were r and omly assigned to receive double-blind treatment with 1 of 2 haloperidol doses , 25 mg/day or 5 mg/day , for 21 days . In addition to haloperidol , subjects were r and omly assigned to receive concomitant treatment with placebo , st and ard lithium , or lorazepam 4 mg/day . The high haloperidol dose produced greater improvement and more side effects than did the low dose . Lithium added to the low dose produced a markedly greater clinical response than did the low dose alone . Lorazepam did not improve the outcome for the patients receiving low-dose haloperidol . The clinical response produced by high-dose haloperidol was not enhanced by adding either lithium or lorazepam . All treatment effects emerged by the fourth day of treatment and persisted . Used alone , a haloperidol dose of 5 mg/day is too low for most manic patients , but concomitant lithium produces a dose-dependent enhancement of haloperidol response .  Lorazepam 4 mg/day was insufficient to produce an advantage when added to low-dose haloperidol OBJECTIVE Among the available mood stabilizers , it appears that lithium may share an important role for treatment of acute mania . In a study from Sep. 2007 to Apr. 2008 at Razi Psychiatric Hospital we evaluated the efficiency of olanzapine vs. lithium . METHODS Forty ( 40 ) female in patients meeting DSM-IV-TR criteria for acute mania were entered into a 3-week parallel group , double-blind study for r and om assignment to olanzapine or lithium carbonate in a 1:1 ratio . Primary outcome measurements were the changes in Manic State Rating Scale ( MSRS ) at baseline and weekly intervals up to the third week . Similarly , overall illness severity was rated using the Clinical Global Impression-Severity of illness scale ( CGI-S ) at baseline and at the end of the third week . Analysis of the data was accomplished by means of split-plot ( mixed ) and repeated measures analysis of variance ( ANOVA ) and t test . RESULTS While both olanzapine and lithium were found to be significantly helpful in the improvement of manic symptoms ( p<0.05 ) , lithium was considerably more successful by the end of the third week ( p<0.0002 and p<0.003 , for frequency and intensity of the symptoms ) . CGI-S also showed important improvements with both olanzapine and lithium ( p<0.043 and p<0.015 for olanzapine and lithium ) . CONCLUSION Though both olanzapine and lithium were effective in the improvement of manic symptoms , lithium was more beneficial BACKGROUND Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder , but are not individually fully effective in many patients . If combination therapy with both agents is better than monotherapy , many relapses and consequent disability could be avoided . We aim ed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder . METHODS 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK , France , USA , and Italy were r and omly allocated to open-label lithium monotherapy ( plasma concentration 0.4 - 1.0 mmol/L , n=110 ) , valproate monotherapy ( 750 - 1250 mg , n=110 ) , or both agents in combination ( n=110 ) , after an active run-in of 4 - 8 weeks on the combination . R and omisation was by computer program , and investigators and participants were informed of treatment allocation . All outcome events were considered by the trial management team , who were masked to treatment assignment . Participants were followed up for up to 24 months . The primary outcome was initiation of new intervention for an emergent mood episode , which was compared between groups by Cox regression . Analysis was by intention to treat . This study is registered , number IS RCT N 55261332 . FINDINGS 59 ( 54 % ) of 110 people in the combination therapy group , 65 ( 59 % ) of 110 in the lithium group , and 76 ( 69 % ) of 110 in the valproate group had a primary outcome event during follow-up . Hazard ratios for the primary outcome were 0.59 ( 95 % CI 0.42 - 0.83 , p=0.0023 ) for combination therapy versus valproate , 0.82 ( 0.58 - 1.17 , p=0.27 ) for combination therapy versus lithium , and 0.71 ( 0.51 - 1.00 , p=0.0472 ) for lithium versus valproate . 16 participants had serious adverse events after r and omisation : seven receiving valproate monotherapy ( three deaths ) ; five lithium monotherapy ( two deaths ) ; and four combination therapy ( one death ) . INTERPRETATION For people with bipolar I disorder , for whom long-term therapy is clinical ly indicated , both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy . This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years . BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy . FUNDING Stanley Medical Research Institute ; Sanofi-Aventis BACKGROUND Achieving therapeutic blood levels of a mood stabilizer as quickly as possible is desirable in patients with acute mania . We examined the feasibility and safety of an accelerated oral loading strategy ( divalproex , 30 mg/kg/day , on days 1 and 2 , followed by 20 mg/kg/day on days 3 - 10 ) design ed to bring serum valproate concentrations to therapeutic levels ( i.e. , above 50 microg/mL ) . METHOD Fifty-nine patients who met DSM-IV diagnostic criteria for current manic episode and who had a Mania Rating Scale score > or = 14 were r and omly assigned on a double-blind basis to receive divalproex oral loading ( N = 20 ) ; divalproex nonloading ( N = 20 ) at a starting dose of 250 mg t.i.d . on days 1 and 2 , followed by st and ard dose titration for days 3 to 10 ; or lithium carbonate ( N = 19 ) at a starting dose of 300 mg t.i.d . , followed by st and ard dose titration for days 3 to 10 . RESULTS Eighty-four percent of the divalproex-loading patients , but only 30 % of the divalproex-nonloading patients , had valproate serum levels above 50 microg/mL at day 3 of the study . None of the lithium-treated patients had serum lithium levels above 0.8 mEq/L at study day 3 . No patient was removed from the study because of an adverse event . There were no significant differences between the groups in the frequencies or types of adverse events . CONCLUSION Accelerated oral loading with divalproex sodium is a feasible and safe method to bring serum valproate concentrations to effective levels rapidly A  multi-institutional cooperative study comparing lithium carbonate with chlorpromazine was conducted , using a controlled double-blind design in a series of 80 cases of endogenous manic psychosis , to evaluate the drugs ' clinical utility and efficacy , characteristics of therapeutic effect , and side-effects . Dosages employed were consistently at an equipotent ratio of 4:1 ( lithium carbonate : chlorpromazine ) . Physicians ' overall ratings showed lithium carbonate as significantly superior to chlorpromazine in efficacy for manic psychosis . Improvements of basic mood and of disturbance in speech and voice were prominent with lithium carbonate .  Onset of the therapeutic effect of lithium carbonate was within ten days of medication in 65 % of the patients , significantly faster than with chlorpromazine .  Side-effects encountered with lithium carbonate therapy at dose levels not higher than 1,800 mg/day were milder and less frequent compared with those seen with chlorpromazine Abstract Background : Bipolar disorder is a chronic illness that may involve multiple relapses and result in substantial psychosocial impairment . However , very few recent studies have investigated the economic burden of the disease . Objective : To assess the frequency of hospitalisation and the inpatient care costs associated with manic episodes in patients with bipolar I disorder in France . Method : A cost-of-illness study was conducted based on available data using a hospital payer perspective . The lifetime prevalence of manic episodes was estimated from published epidemiological data using a r and om-effects meta- analysis . Data were obtained by a computerised literature search using the main scientific and medical data bases . Additional epidemiological references were identified from published studies and textbooks . Data on frequency of hospitalisation and length of stay were collected from a large psychiatric university hospital . Data on unit costs for inpatient care were obtained from the accounting system of the largest hospital group in Paris , France for the year 1999 . Results : Extrapolating from international data on the average prevalence of bipolar I disorder , the proportion of rapid cycling patients and the average cycle duration , we estimated the annual number of manic episodes in patients with bipolar I disorder to be around 265 000 in France . Based on hospital data in Paris , the proportion of manic episodes that require hospitalisation was estimated to be around 63 % . The average length of stay was 32.4 days and the hospitalisation-related costs were estimated to be around 8.8 billion French francs ( € 1.3 billion ) [ 1999 values ] . Conclusion : Our study highlights the lack of medical and economic data on the frequency and hospitalisation-related costs of manic episodes in patients with bipolar I disorder in France . As the lifetime prevalence of bipolar I disorder may be as high as 3 % among adults , further studies are required in order to provide representative national data and to allow economic evaluations of costs related to bipolar I disorder in France OBJECTIVES To evaluate the efficacy and safety of aripiprazole as acute and maintenance of effect monotherapy for acute bipolar mania . METHODS Patients with acute bipolar I mania ( DSM-IV-TR : YMRS > or = 20 ) , manic or mixed ( with or without psychotic features ) were r and omized to double-blind aripiprazole ( 15 - 30 mg/day ; n=155 ) , placebo ( n=165 ) or lithium ( 900 - 1500 mg/day ; n=160 ) ( 1:1:1 ) for 3 weeks . Aripiprazole- and lithium-treated patients remained on blinded treatment for 9 additional weeks . The primary outcome was the mean change from baseline in YMRS Total score ( LOCF ) to Week 3 . Secondary outcomes included the mean change from baseline in YMRS Total score ( LOCF ) at all other timepoints up to Week 12 . RESULTS Aripiprazole demonstrated significantly greater improvement than placebo in mean YMRS Total score from baseline to Day 2 ( -4.3 vs.-2.8 ; p=0.003 ) , and up to Week 3 ( -12.6 vs. -9.0 ; p<0.001 ) . Significant improvement in YMRS Total score was also seen with lithium versus placebo at Week 3 ( -12.0 vs. -9.0 ; p=0.005 ) . Improvements in YMRS Total score were maintained to Week 12 for aripiprazole ( -14.5 ) and lithium ( -12.7 ) . Response rates at Week 3 were significantly higher with aripiprazole ( 46.8 % ) and lithium ( 45.8 % ) than placebo ( 34.4 % ; both p<0.05 , LOCF ) ; increasing to Week 12 with aripiprazole ( 56.5 % ) and lithium ( 49.0 % ) . Most common adverse events with aripiprazole were headache , nausea , akathisia , sedation , and constipation ; with lithium were nausea , headache , constipation , and tremor . CONCLUSIONS Aripiprazole provided statistically significant improvement of acute mania within 2 days , continuing over 3 weeks and sustained over 12 weeks . The magnitude of improvement to Week 12 was similar with aripiprazole and lithium Lithium , at a dosage of 1,800 mg . daily , was found to be effective in the treatment of  acute manic states .  However , when compared with chlorpromazine by means of a double-blind technique using stringent diagnostic criteria , no significant difference between the two drugs was noted . In regard to the prophylactic effect of lithium , the data presented indicate that this question is still unresolved Fifty-two hospitalized manic patients were r and omized to treatment with either carbamazepine or lithium carbonate after a 2-week drug withdrawal period . All of the prob and s were tertiary referrals with a high proportion of failures of previous lithium and other treatment .  Weekly ratings of manic , depressive , and psychotic symptoms were obtained for 8 weeks , and responders were followed up for up to 2 years . One third of patients responded favorably . Double-blind assessment s revealed no statistically reliable differences between the two treatment groups . Patients receiving carbamazepine were somewhat more manageable than patients treated with lithium early in the study , whereas lithium-treated patients remained longer in the follow-up phase . However , numbers of long-term survivors were too small to be conclusive . This study adds to the growing body of evidence that acutely manic patients  respond as well to  carbamazepine  as to lithium . However , monotherapy with either drug is not sufficient for the majority of manic patients who are referred for tertiary care Case reports and studies of other neuroleptics suggest the efficacy of risperidone in the treatment of mania . Forty-five in patients with DSM-IV mania were studied in a 28-day r and omized , controlled , double-blind trial of either 6 mg daily of risperidone , 10 mg daily of haloperidol , or 800 to 1200 mg daily of lithium . The patients in all three groups showed a similar improvement on the total score for all rating scales at day 28 ( Brief Psychiatric rating scale :  lithium 9.1 , haloperidol 4.9 , risperidone 6.5 , F = 1.01 , df = 2 , p = 0.37 ; Mania rating scale :  lithium 15.7 , haloperidol 10.2 , risperidone 12.4 , F = 1.07 , df = 2 , p = = 0.35 [ analysis of variance ] ) . The Global Assessment of Functioning and Clinical Global Impression data showed a similar pattern of improvement . This study suggests that risperidone is of equivalent efficacy to lithium and haloperidol in the management of acute mania . The extrapyramidal side effects of risperidone and haloperidol were not significantly different 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 : Few long‐term studies on bipolar disorder ( BD ) have investigated the incidence and risk factors of suicide attempts ( SAs ) specifically related to illness phases . We examined the incidence of SAs during different phases of BD in a long‐term prospect i ve cohort of bipolar I ( BD‐I ) and bipolar II ( BD‐II ) patients , and risk factors specifically for SAs during major depressive episodes ( MDEs )
target: 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: 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 .