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.
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
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 .