Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study A one-year open-label trial of risperidone augmentation in lithium nonresponder youth with preschool-onset bipolar disorder. Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder. Adjunctive treatment of manic agitation with lorazepam versus haloperidol: a double-blind study. Lithium treatment of acute mania in adolescents: a large open trial. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). Efficacy and tolerability of lithium in treating acute mania in youth with bipolar disorder: protocol for a systematic review Treatment of suicide attempters with bipolar disorder: a randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. Post-acute effectiveness of lithium in pediatric bipolar I disorder. Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Patterns of pharmacological maintenance treatment in a community mental health services bipolar disorder cohort study (SIN-DEPRES). Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. A Consecutive Series of Treated Affected Offspring of Parents with Bipolar Disorder: Is Response Associated with the Clinical Profile? A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Olanzapine versus lithium in the acute treatment of bipolar mania: a double-blind, randomized, controlled trial. Lithium use and discontinuation in a health maintenance organization. A double-blind, placebo-controlled study with quetiapine as adjunct therapy with lithium or divalproex in bipolar I patients with coexisting alcohol dependence. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Lamotrigine Compared with Lithium in Mania: A Double-Blind Randomized Controlled Trial Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics
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 The aim of this study was to assess the safety and efficacy of risperidone augmentation of lithium in preschool-onset bipolar disorder ( BD ) among youth who insufficiently respond to lithium monotherapy .  METHOD Thirty-eight subjects between the ages of 4 and 17 years ( mean age = 11.37 + /- 3.8 years ) with onset of BD in preschool years ( manic or mixed episode ) entered this 12-month trial . All subjects received lithium monotherapy . Patients who failed to adequately respond to lithium monotherapy after 8 weeks and those who relapsed after an initial response were given risperidone augmentation for up to 11 months . The Young Mania Rating Scale ( YMRS ) was the primary outcome measure . Response was defined as a > or = 50 % decrease from baseline . Additional data were collected on diagnostic comorbidity , family history , number of hospitalizations , perinatal risk factors , history of physical or sexual abuse , Child Depression Rating Scale-Revised ( CDRS-R ) , Clinical Global Impression ( CGI ) scale for BD ( CGI-BP ) , Children 's Global Assessment Scale ( C-GAS ) , and adverse medication effects . RESULTS Of the 38 subjects treated with lithium monotherapy , 17 responded , whereas 21 required augmentation with risperidone .  Response rate in the youths treated with lithium + risperidone was 85.7 % ( n = 18/21 ) . Significant predictors of inadequate response to lithium monotherapy requiring augmentation were : ( 1 ) attention-deficit/hyperactivity disorder ( ADHD ) , ( 2 ) severity at baseline , ( 3 ) history of sexual or physical abuse , and ( 4 ) preschool age . Combination treatment of lithium and risperidone was found to be safe and well tolerated . CONCLUSIONS A substantial proportion of youth with a history of preschool-onset BD treated with lithium  were either nonresponders or partial responders . Subsequent augmentation of lithium with risperidone in these cases was well tolerated and efficacious . Potential predictors of lithium nonresponse identified in this study may guide the choice of medications earlier in the treatment process 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 BACKGROUND While lithium is effective in treating the majority of bipolar patients during a manic episode , the addition of neuroleptic during the early phase of treatment has been common clinical practice in inpatient setting s. In an earlier open study , we demonstrated the utility of the short-acting benzodiazepine lorazepam as an adjunct to lithium for the clinical management of manic agitation . METHOD We now present data from a r and omized , double-blind clinical study of lorazepam versus haloperidol in 20 hospitalized patients with a DSM-III-R diagnosis of bipolar disorder who were being treated concomitantly with lithium .  Patients were rated using the Mania Rating Scale , Brief Psychiatric Rating Scale , Physician Global Impression Scale , and side effects scales . Data were analyzed using st and ard group comparisons and survival analysis . RESULTS There was no evidence for a significant difference between the two treatment groups in the magnitude of or time to response ( 5.0 + /- .82 days for haloperidol ; 6.5 + /- .93 days for lorazepam ) . Of the patients who were terminated from the protocol early , nonresponse was the primary reason in the lorazepam group while side effects were the reason in the haloperidol group . CONCLUSION Lorazepam may offer an efficacious and safe alternative to haloperidol as an adjunctive treatment to lithium in the clinical management of the early phase of manic agitation in a subgroup of bipolar patients OBJECTIVE To 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 OBJECTIVE The aim of this study was to compare the efficacy and tolerability of quetiapine and lithium monotherapy with that of placebo for a major depressive episode in bipolar disorder . METHOD 802 patients with DSM-IV-defined bipolar disorder ( 499 bipolar I , 303 bipolar II ) were r and omly allocated to quetiapine 300 mg/d ( n = 265 ) , quetiapine 600 mg/d ( n = 268 ) , lithium 600 to 1800 mg/d ( n = 136 ) , or placebo ( n = 133 ) for 8 weeks . Primary endpoint was the change in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score . The study was conducted from August 2005 to May 2007 . RESULTS Mean MADRS total score change from baseline at week 8 was -15.4 for quetiapine 300 mg/d , -16.1 for quetiapine 600 mg/d , -13.6 for lithium , and -11.8 for placebo ( P < .001 for both quetiapine doses , P = .123 for lithium , vs placebo ) . Quetiapine 600 mg/d was significantly more effective than lithium in improving MADRS total score at week 8 ( P = .013 ) . Quetiapine-treated ( both doses ) , but not lithium-treated , patients showed significant improvements ( P < .05 ) in MADRS response and remission rates , Hamilton Depression Rating Scale ( HDRS ) , Clinical Global Impressions-Bipolar-Severity of Illness and -Change , and Hamilton Anxiety Rating Scale ( HARS ) scores at week 8 versus placebo . Both quetiapine doses were more effective than lithium at week 8 on the HDRS and HARS . The most common adverse events were somnolence , dry mouth , and dizziness with quetiapine ( both doses ) and nausea with lithium . CONCLUSIONS Quetiapine ( 300 or 600 mg/d ) was more effective than placebo for the treatment of episodes of acute depression in bipolar disorder . Lithium did not significantly differ from placebo on the main measures of efficacy . Both treatments were generally well tolerated . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00206141 Background Epidemiological , clinical , and high-risk studies have provided evidence that the peak period for onset of diagnosable episodes of mania and hypomania starts in mid-to-late adolescence . Moreover , clinical ly significant manic symptoms may occur even earlier , especially in children at familial risk . Lithium is the gold st and ard treatment for acute mania in adults , yet to our knowledge , there is no published systematic review assessing lithium treatment of mania in children or adolescents . This is a major gap in knowledge needed to inform clinical practice . Aim As a working group within the ISBD Task Force on Lithium Treatment ( http://www.isbd.org/active-task-forces ) , our aim is to complete a systematic review of the efficacy , tolerability , and acceptability of lithium compared with placebo and other active drugs in treating mania in children and adolescents diagnosed with bipolar disorder . Methods We will include double- or single-blind r and omized controlled trials in patients aged less than 18 years . No restrictions will be made by study publication date or language . Several electronic data bases will be search ed along with secondary sources such as bibliographies and trial registry websites for published and unpublished studies . Response rates to lithium compared with placebo or other active drugs will be the primary efficacy outcome . Primary tolerability and acceptability outcomes will be rates of serious adverse events and dropouts , respectively . Secondary outcomes will include rates of remission , severity of manic symptoms at different time points , and incidence of specific adverse events . Discussion Findings from this systematic review are critically needed to inform clinical practice . We should not generalize findings from adult studies , as children and adolescents are undergoing accelerated physiological and brain development . Therefore , efficacy , tolerability , and acceptability of lithium treatment of acute mania in children compared to adults may be very different . This systematic review has been registered in PROSPERO ( CRD42017055675 ) OBJECTIVE Bipolar disorder is associated with high risk for  suicidal acts . Observational studies suggest a protective effect of lithium against suicidal behavior . However , testing this effect in r and omized clinical trials is logistically and ethically challenging . The authors tested the hypothesis that lithium offers bipolar patients with a history of suicide attempt greater protection against suicidal behavior compared to valproate . METHOD Patients with bipolar disorder and past suicide attempts ( N=98 ) were r and omly assigned to treatment with lithium or valproate , plus adjunctive medications as indicated , in a double-blind 2.5-year trial . An intent-to-treat analysis was performed using the log-rank test for survival data . Two models were fitted : time to suicide attempt and time to suicide event ( attempt or hospitalization or change in medication in response to suicide plans ) . RESULTS There were 45 suicide events in 35 participants , including 18 suicide attempts made by 14 participants , six from the lithium group and eight from the valproate group . There were no suicides . Intent-to-treat analysis using the log-rank test showed no differences between treatment groups in time to suicide attempt or to suicide event . Post hoc power calculations revealed that the modest sample size , reflective of challenges in recruitment , only permits detection of a relative risk of 5 or greater . CONCLUSIONS Despite the high frequency of suicide events during the study , this r and omized controlled trial detected no difference between lithium and valproate in time to suicide attempt or suicide event in a sample of suicide attempters with bipolar disorder . However , smaller clinical ly significant differences between the two drugs were not ruled out 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 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 OBJECTIVE Withdrawal of bipolar mood disorder ( BP-I ) patients from prolonged , stable lithium maintenance has a high risk of early recurrence , particularly of mania . We thus compared risks of stopping lithium rapidly vs gradually . DESIGN Out patients undergoing clinical ly determined discontinuation of lithium treatment at different rates were followed up prospect ively to 5 years . Risks and timing of new episodes were analyzed . PATIENTS Subjects ( N = 64 ) with a DSM-III-R BP disorder , previously stable on lithium monotherapy for 18 to 120 months ( mean , 3.6 years ) were followed up clinical ly after discontinuing lithium ( elected in prolonged wellbeing in 67 % ) . None was unavailable for follow-up , and subtyping ( BP-I or BP-II ) remained stable . RESULTS Within 5 years , 75 % had a recurrent episode ; BP-I patients were 1.5-times less likely than BP-II to remain in remission . Polarity of first-recurrent and onset episodes was 80.8 % concordant . Overall risk of a new episode of mania was significantly greater after rapid ( < 2 ) than gradual ( 2 to 4 weeks discontinuation ( 5-year hazard ratio = 2.8 ) ; the difference in risk of depression was even greater hazard ratio = 5.4 ) . Recurrence rate was more elevated within months of rapid discontinuation ( 12-month hazard ratio = 5.4 ) . Recurrence rate was more elevated within months of rapid discontinuation ( 12-month hazard ratio = 4.3 ) than at later times ( 2 to 5 years ) , when courses of " survival " over time were nearly parallel in both discontinuation groups . CONCLUSIONS Risk of early recurrence of BP disorder following discontinuation of lithium maintenance is elevated , but may be both predictable ( timing and polarity ) and modifiable by gradual discontinuation Maintenance therapy in bipolar disorder ( BD ) is usually required to prevent relapses and improve residual symptoms . Therefore , in this study , we describe patterns of pharmacological maintenance treatment and identify associated clinical features . This prospect i ve multicentre epidemiological study recruited a cohort of 739 consecutive out- patients with clinical ly stable BD . Clinical stability was assessed at baseline with the Clinical Global Impression scale for BD and depressive symptoms with the Hamilton Depression Rating Scale .  Psychotropic medications were classified and analysed according to their mechanism as well as use . Logistic regression models were used to examine the associations between pharmacological strategies and clinical features . Longer time since last episode [ odds ratio ( OR ) 1.002 , p < 0.0001 ] and family history of psychiatric disorders ( OR 1.911 , p = 0.028 ) were associated with lithium in monotherapy ;  manic polarity of the most recent episode ( OR 3.300 , p = 0.006 ) and longer duration of clinical stability ( OR 1.009 , p = 0.034 ) with antipsychotic in monotherapy ;  depressive polarity of the most recent episode ( OR 2.567 , p = 0.003 ) and bipolar II disorder diagnosis ( OR 2.278 , p = 0.008 ) with antidepressant combination ;  no ongoing psychiatric co-morbidity ( OR 0.230 , p = 0.004 ) with lithium and anticonvulsant ;  manic polarity of the most recent episode ( OR 3.774 , p < 0.0001 ) with lithium and antipsychotic ;  manic polarity of the most recent episode ( OR 2.907 , p = 0.028 ) with lithium , anticonvulsant and antipsychotic . The pharmacological patterns followed published recommendations , except for the excessive use of antidepressants . This study reveals clinical factors closely related to prescription patterns BACKGROUND 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 A subgroup of children and adolescents with conduct disorder are characterized by severe and persistent aggression . Although there is no agreed on treatment for such aggression , lithium carbonate has shown promise in some studies involving children . Our study was design ed to critically assess the efficacy of lithium in the treatment of aggression in children and adolescents using a measure specific for aggression . METHODS Subjects were in patients with conduct disorder hospitalized because of severe and chronic aggression . A parallel-groups design was used in this double-blind , placebo-controlled trial with r and omization to lithium or placebo . Only those who met the aggression criterion during the 2-week placebo-baseline period were r and omized to 4 weeks of treatment . Outcome measures included Clinical Global Impressions , the Global Clinical Judgements ( Consensus ) Scale , and the Overt Aggression Scale . RESULTS Eighty-six in patients enrolled in the study ; 40 ( 33 male and 7 female ; median age , 12.5 years ) entered and completed the treatment phase . Lithium was statistically and clinical ly superior to placebo . Sixteen of 20 subjects in the lithium group were responders on the Consensus ratings vs 6 of 20 in the placebo group ( P=.004 ) . Ratings on the Overt Aggression Scale decreased significantly for the lithium group vs the placebo group ( P=.04 ) . More than half of the subjects in the lithium group experienced nausea , vomiting , and urinary frequency . CONCLUSIONS Lithium is a safe and effective short-term treatment for aggression in in patients with conduct disorder , although its use is associated with adverse effects Objective : In adults with established bipolar disorder ( BD ) , differential response to  mood stabilizers  has been associated with the clinical profile . Long-term treatment studies of youth with BD are lacking . This paper provides longitudinal observations of response to  mood stabilizers  early in the course of illness in youth with BD . Method : We report on 15 research patients who , as adolescents , met DSM-IV lifetime criteria for a bipolar spectrum disorder and required long-term treatment . These youths derived from families with one parent having BD whose course and long-term treatment response were determined in accordance with research criteria . The patients were offered lithium , and if they failed to respond or refused it , they were treated with either an anticonvulsant or an atypical antipsychotic . Using a vali date d scale , an independent rater retrospectively blindly scored the response to long-term treatment . Results : Those patients who stabilized on  lithium  derived from lithium-responsive families , whereas those who stabilized on an  antipsychotic  derived from lithium-nonresponsive families . The clinical course in the youths stabilized by lithium differed from that in the youths stabilized by an atypical antipsychotic . Conclusions : Our findings suggest that the clinical profile may help in selecting effective stabilizing treatment and that a proportion of youth can be stabilized on monotherapy . This is a small case series with nonr and om treatment assignment , and the findings should be considered tentative 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 BACKGROUND This multicenter , double-blind , r and omized , controlled study conducted in China examined the efficacy and safety of olanzapine versus lithium in the treatment of patients with bipolar manic/mixed episodes . METHODS Patients with bipolar manic or mixed episode ( DSM-IV criteria ) and Young Mania Rating Scale ( YMRS ) score > or = 20 at screening received olanzapine ( 5 - 20 mg/day , n=69 ) or lithium carbonate ( 600 - 1800 mg/day , n=71 ) for 4 weeks . The primary outcome was mean change from baseline in Clinical Global Impressions-Bipolar Version Overall Severity of Illness ( CGI-BP ) score . Secondary efficacy measures included YMRS , Brief Psychiatric Rating Scale ( BPRS ) , and Montgomery-Asberg Depression Rating Scale ( MADRS ) scores . Safety was also assessed . RESULTS A significantly greater mean change was observed in olanzapine versus lithium patients in CGI-BP ( Overall Severity ) ( P=0.009 ) , YMRS ( P=0.013 ) , BPRS ( P=0.032 ) , and CGI-BP ( Severity of Mania ) ( P=0.012 ) scores . More olanzapine than lithium patients experienced at least one adverse event possibly related to study drug ( P=0.038 ) . More olanzapine patients had a clinical ly significant weight increase ( > or = 7 % of baseline weight ) compared to lithium patients ( P=0.009 ) . More olanzapine patients completed the study than lithium patients , although this difference was not statistically significant ( olz , 91.3 % ; lith , 78.9 % ; P=0.057 ) . LIMITATIONS No placebo arm was included ; however both treatments have previously been reported to be more effective than placebo . CONCLUSIONS These results suggest that olanzapine has superior efficacy to lithium in the acute treatment of patients with bipolar mania over a 4-week period . However , adverse events were experienced by a greater number of olanzapine patients than lithium patients OBJECTIVE For decades , lithium has been prescribed to treat bipolar disorder . Its efficacy has been documented by clinical trials and by data from specialized clinics . An issue of considerable interest is the use of lithium in managed care systems . This project examined the use of lithium and its continuity of use by enrollees of a health maintenance organization ( HMO ) . METHOD In a 6-year longitudinal cohort study , 1,594 lithium users aged 15 years and older who were enrolled in an HMO were followed from 1986 - 1991 . Data were obtained from automated data bases and from medical record review of a r and om 5 % sub sample of the group ( N = 74 ) . RESULTS Bipolar disorder was the most frequent morbidity treated . Eighty-four percent ( N = 62 or 74 ) received services from a psychiatrist . Annual prevalence of lithium use increased over the 6-year period from 1.4 to 2.3 persons per thous and HMO members . Duration of use varied widely with some long-term but many short-term users . Discontinuation of treatment was associated with evaluated rates of psychiatric hospitalization and use of psychiatric emergency services .  Lithium users were much more likely to receive a variety of other psychotropic drugs than nonusers of the same sex and age . CONCLUSIONS Lithium use in this population was more often sporadic than continuous . Discontinuation of lithium was associated with psychiatric hospitalization . If lithium is to be a cost-effective treatment for bipolar disorder , managed care systems will need to improve adherence to drug treatment regimens BACKGROUND This study evaluated the efficacy of quetiapine versus placebo as an adjunct to lithium or divalproex in reducing alcohol consumption in patients with bipolar I disorder and coexisting alcohol dependence . METHODS Male and female out patients ( 21 to 60 years ) with a history of bipolar I disorder and alcohol dependence were included in this 12-week , placebo-controlled study . Patients treated with lithium or divalproex ( ongoing or assigned at screening ) were r and omized to receive quetiapine ( dosed up to 400 mg/d over 7 days , followed by 300 to 800 mg/d flexible dosing until study end ) or placebo . The primary outcome measure was the change in the proportion of heavy drinking days from baseline to Week 12 ( as derived from the Timeline Followback method ) . Secondary outcome measures included time to the first consecutive 2 weeks of abstinence , changes from baseline to Week 12 in the proportion of nondrinking days , mean number of st and ardized drinks per day , and Clinical Global Impressions-Severity of Illness score . RESULTS Of 362 enrolled patients ( mean 38.6 years ) , 176 were r and omized to receive quetiapine and 186 to placebo .  The mean proportion of heavy drinking days at baseline was 0.66 in the quetiapine group and 0.67 in the placebo group . At Week 12 , the mean change in the proportion of heavy drinking days was -0.36 with quetiapine and -0.36 with placebo ( p = 0.93 ) . No statistically significant differences in any of the secondary outcome measures were noted between the quetiapine and placebo groups . The incidence of adverse events was consistent with the previously known tolerability profile of quetiapine . CONCLUSIONS The efficacy of quetiapine in the treatment of bipolar disorder is already well established . In this study , however , quetiapine added to lithium or divalproex did not result in significantly greater improvement compared with placebo in measures of alcohol use and dependence in patients with bipolar I disorder and alcohol dependence OBJECTIVE This study compared the efficacy and safety of paroxetine and imipramine with that of placebo in the treatment of bipolar depression in adult out patients stabilized on a regimen of lithium . METHOD In a double-blind , placebo-controlled study , 117 out patients with DSM-III-R bipolar disorder , depressive phase , were r and omly assigned to treatment with paroxetine ( N=35 ) , imipramine ( N=39 ) , or placebo ( N=43 ) for 10 weeks . In addition to lithium monotherapy , patients may have received either carbamazepine or valproate in combination with lithium for control of manic symptoms . Patients were stratified on the basis of trough serum lithium levels determined at the screening visit ( high : > 0.8 meq/liter ; low : < /=0.8 meq/liter ) . Primary efficacy was assessed by change from baseline in scores on the Hamilton Rating Scale for Depression and the Clinical Global Impression illness severity scale . RESULTS Differences in overall efficacy among the three groups were not statistically significant . For patients with high serum lithium levels  , antidepressant response at endpoint also did not significantly differ from placebo . However , both paroxetine and imipramine were superior to placebo for patients with low serum lithium levels . Compared to imipramine , paroxetine result ed in a lower incidence of adverse events , most notably emergence of manic symptoms . CONCLUSIONS Antidepressants may not be useful adjunctive therapy for bipolar depressed patients with high serum lithium levels . However , antidepressant therapy may be beneficial for patients who can not tolerate high serum lithium levels or who have symptoms that are refractory to the antidepressant effects of lithium 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 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 Background Lithium is a well-established treatment for bipolar I disorder in adults . However , there is a paucity of information on its pharmacokinetics/pharmacodynamics in children and adolescents . We aim ed to develop the first lithium dosage regimens based on population pharmacokinetics/pharmacodynamics for paediatric patients . Methods Lithium concentrations , Young Mania Rating Scale ( YMRS ) and Clinical Global Impressions-Improvement ( CGI-I ) scores over 24 weeks were available from 61 paediatric patients with bipolar I disorder . The population pharmacokinetics/pharmacodynamics were co-modelled . Concentrations and clinical effects following several dosage regimens were predicted by Monte Carlo simulations . Results The pharmacokinetics were well characterised by a two compartment model with linear elimination . Including the effect of total body weight ( TBW ) or lean body weight ( LBW ) on clearance and volume of distribution decreased the unexplained inter-individual variability by up to 12 % . The population mean ( inter-individual variability ) clearance was 1.64 L/h/53 kg LBW0.75 ( 19 % ) and central volume of distribution 23.6 L/53 kg LBW ( 6.8 % ) . The average lithium concentration over a dosing interval required for a 50 % reduction in YMRS was 0.711 mEq/L ( 59 % ) . A maintenance dose of 25 mg/kg TBW/day lithium carbonate in two daily doses was predicted to achieve a ≥50 % reduction in YMRS in 74 % of patients , while ~8 % of patients would be expected to have trough concentrations above the nominal safety threshold of 1.4 mEq/L. Therefore , therapeutic drug monitoring will still be required even with these dosing strategies . Conclusions When accounting for body size , the pharmacokinetic parameters in paediatric patients were within the range of estimates from adults . Pharmacokinetic/pharmacodynamic modelling supported development of practical scientifically-based dosage regimens for paediatric patients
Conclusions Lithium continues as the st and ard and most extensively evaluated treatment for bipolar disorder , especially for long-term prophylaxis
Background Lithium has been used clinical ly for 70 years , mainly to treat bipolar disorder .
Competing treatments and exaggerated impressions about complexity and risks of lithium treatment have led to its declining use in some countries , encouraging this up date about its safe clinical use .