Patterns of pharmacological maintenance treatment in a community mental health services bipolar disorder cohort study (SIN-DEPRES). Efficacy and tolerability of lithium in treating acute mania in youth with bipolar disorder: protocol for a systematic review Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Post-acute effectiveness of lithium in pediatric bipolar I disorder. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Lithium in the treatment of mania: comparisons with neuroleptics. Differential Efficacy of Lithium and Carbamazepine in the Prophylaxis of Bipolar Disorder: Results of the MAP Study A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Allopurinol for mania: a randomized trial of allopurinol versus placebo as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics Lithium treatment of acute mania in adolescents: a large open trial. Long-term effectiveness of lithium in bipolar disorder: a multicenter investigation of patients with typical and atypical features. Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial
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 Epidemiological , clinical , and high-risk studies have provided evidence that the peak period for onset of diagnosable episodes of mania and hypomania starts in mid-to-late adolescence . Moreover , clinical ly significant manic symptoms may occur even earlier , especially in children at familial risk . Lithium is the gold st and ard treatment for acute mania in adults , yet to our knowledge , there is no published systematic review assessing lithium treatment of mania in children or adolescents . This is a major gap in knowledge needed to inform clinical practice . Aim As a working group within the ISBD Task Force on Lithium Treatment ( http://www.isbd.org/active-task-forces ) , our aim is to complete a systematic review of the efficacy , tolerability , and acceptability of lithium compared with placebo and other active drugs in treating mania in children and adolescents diagnosed with bipolar disorder . Methods We will include double- or single-blind r and omized controlled trials in patients aged less than 18 years . No restrictions will be made by study publication date or language . Several electronic data bases will be search ed along with secondary sources such as bibliographies and trial registry websites for published and unpublished studies . Response rates to lithium compared with placebo or other active drugs will be the primary efficacy outcome . Primary tolerability and acceptability outcomes will be rates of serious adverse events and dropouts , respectively . Secondary outcomes will include rates of remission , severity of manic symptoms at different time points , and incidence of specific adverse events . Discussion Findings from this systematic review are critically needed to inform clinical practice . We should not generalize findings from adult studies , as children and adolescents are undergoing accelerated physiological and brain development . Therefore , efficacy , tolerability , and acceptability of lithium treatment of acute mania in children compared to adults may be very different . This systematic review has been registered in PROSPERO ( CRD42017055675 ) BACKGROUND : 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 therapeutics for bipolar disorders are still far from adequate , and new options with improved effectiveness , safety , and tolerability in a wide range of patients are necessary . Preliminary data have suggested a role for dysfunctions targeting the purinergic system in mood disorders . This study aim ed to evaluate the efficacy and tolerability of the purinergic agents allopurinol and dipyridamole combined with lithium in bipolar mania . METHOD A r and omized , placebo-controlled , double-blind study was performed in adult in patients ( N = 180 ) with a DSM-IV-TR diagnosis of bipolar I disorder , current episode manic with or without psychotic features ( rapid cyclers and mixed episodes were not included ) . No antipsychotic agent was used during the study . Subjects were given fixed oral doses of either allopurinol 600 mg/day ( N = 60 ) , dipyridamole 200 mg/day ( N = 60 ) , or placebo ( N = 60 ) added to lithium for 4 weeks . Subjects were rated at baseline and days 7 , 14 , 21 , and 28 using the Young Mania Rating Scale ( YMRS ) as the primary efficacy measure . The study was conducted between September 2003 and September 2006 . RESULTS Allopurinol result ed in greater mean reductions in YMRS scores from baseline to day 21 ( p < .001 ) and day 28 ( p = .003 ) compared with placebo using a linear model analysis ( d = 0.32 , 95 % CI = 0.07 to 0.57 ) . Remission rates were significantly higher for allopurinol compared with dipyridamole and placebo ( p = .008 ) . Lithium showed a significant antimanic efficacy even in the placebo group . Decrease in plasma uric acid levels showed a significant positive association with antimanic effects in the allopurinol group ( p < .001 ) . CONCLUSION Allopurinol is clinical ly effective and well-tolerated adjunctively with lithium in manic episodes and may represent an alternative approach in the treatment of acute mania , especially for those presenting tolerability and safety issues with antipsychotics . The present results strongly support the involvement of the purinergic system in the pathophysiology and therapeutics of bipolar disorder . Further placebo-controlled studies with allo-purinol compared with st and ard mood stabilizers in mania and maintenance are warranted . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00560079 OBJECTIVE The authors compared the efficacy of olanzapine and lithium in the prevention of  mood episode relapse/recurrence . METHOD Patients with a diagnosis of bipolar disorder ( manic/mixed ) , a history of two or more manic or mixed episodes within 6 years , and a Young Mania Rating Scale total score > or = 20 entered the study and received open-label co-treatment with olanzapine and lithium for 6 - 12 weeks . Those meeting symptomatic remission criteria ( Young Mania Rating Scale score < or = 12 ; 21-item Hamilton depression scale score < or = 8) were r and omly assigned to 52 weeks of double-blind monotherapy with olanzapine , 5 - 20 mg/day ( N=217 ) , or lithium ( target blood level : 0.6 - 1.2 meq/liter ) ( N=214 ) . RESULTS Symptomatic relapse/recurrence ( score > or = 15 on either the Young Mania Rating Scale or Hamilton depression scale ) occurred in 30.0 % of olanzapine-treated and 38.8 % of lithium-treated patients . The noninferiority of olanzapine relative to lithium ( primary objective ) in preventing relapse/recurrence was met , since the lower limit of the 95 % confidence interval on the 8.8 % risk difference ( -0.1 % to 17.8 % ) exceeded the predefined noninferiority margin ( -7.3 % ) . Secondary results showed that compared with lithium , olanzapine had significantly lower risks of manic episode and mixed episode relapse/recurrence . Depression relapse/recurrence occurred in 15.7 % of olanzapine-treated and 10.7 % of lithium-treated patients . Mean weight gain during open-label co-treatment was 2.7 kg ; during double-blind monotherapy , weight gain was significantly greater with olanzapine ( 1.8 kg ) than with lithium ( -1.4 kg ) . CONCLUSIONS These results suggest that olanzapine was significantly more effective than lithium in preventing manic and mixed episode relapse/recurrence in patients acutely stabilized with olanzapine and lithium co-treatment . Both agents were comparable in preventing depression relapse/recurrence 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 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 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 In a r and omized clinical trial with an observation period of 2.5 years , the differential efficacy of lithium versus carbamazepine was compared in 171 bipolar patients ( DSM-IV ) . In order to investigate the efficacy of the two drugs in clearly defined sub sample s , a series of subgroup analyses was carried out . First , patients with a bipolar I disorder ( n = 114 ) were analyzed separately . In these patients , lithium was superior to carbamazepine . In contrast , carbamazepine was at least equally as efficacious as lithium in the sub sample of patients with bipolar II disorder or bipolar disorder not otherwise specified ( n = 57 ) . In a second analysis on differential efficacy , the whole sample was subdivided into a classical subgroup ( bipolar I patients without mood-incongruent delusions and without comorbidity ; n = 67 ) and a nonclassical subgroup including all other patients ( n = 104 ) . Classical bipolar patients had a significantly lower hospitalization rate under lithium than under carbamazepine prophylaxis ( 26 vs. 62 % , p = 0.012 ) . For the nonclassical group , a tendency in favor of carbamazepine was found . In a third step , we analyzed the impact of episode sequence on differential efficacy . In a global view , the episode sequence prior to the index episode was not correlated to differential efficacy . Our results might , however , indicate that patients with an episode sequence of mania-depression-free interval responded better to lithium . Besides differential efficacy , suicidal behavior and patients ’ satisfaction with treatment were investigated . Regarding suicidal behavior , a trend in favor of lithium was found . The data on patients ’ satisfaction were significantly in favor of carbamazepine . In conclusion , lithium appears to be superior to carbamazepine in classical bipolar cases and might have additional impact on proneness to suicide . The distinctly larger group of patients with nonclassical features might profit more from carbamazepine which seems to be well accepted by the patients . Hence , treatment alternatives to lithium are desirable for the majority of bipolar patients BACKGROUND 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 The anticonvulsant lamotrigine was previously shown to be effective for bipolar depression . This study assessed the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of mood episodes in bipolar disorder . METHOD During an 8- to 16-week open-label phase , lamotrigine ( titrated to 200 mg/day ) was added to current therapy for currently or recently depressed DSM-IV-defined bipolar I out patients ( N = 966 ) and concomitant drugs were gradually withdrawn . Patients stabilized on open-label treatment ( N = 463 ) were then r and omly assigned to lamotrigine ( 50 , 200 , or 400 mg/day ; N = 221 ) , lithium ( 0.8 - 1.1 mEq/L ; N = 121 ) , or placebo ( N = 121 ) monotherapy for up to 18 months . The primary outcome measure was time from r and omization to intervention ( addition of pharmacotherapy ) for any mood episode ( depressive , manic , hypomanic , or mixed ) . Data were gathered from September 1997 to August 2001 . RESULTS Time to intervention for any mood episode was statistically superior ( p = .029 ) for both lamotrigine and lithium compared with placebo-median  survival times were 200 , 170 , and 93 days , respectively . Intervention for depression was more frequent than for mania by a factor of nearly 3:1 . Lamotrigine was statistically superior to placebo at prolonging the time to intervention for a depressive episode ( p = .047 ) . The proportions of patients who were intervention-free for depression at 1 year were lamotrigine 57 % , lithium 46 % , and placebo 45 % . Lithium was statistically superior to placebo at prolonging the time to intervention for a manic or hypomanic episode ( p = .026 ) . The proportions of patients who were intervention-free for mania at 1 year were lamotrigine 77 % , lithium 86 % , and placebo 72 % . Headache was the most frequent adverse event for all 3 treatment groups . CONCLUSION Lamotrigine and lithium were superior to placebo for the prevention of mood episodes in bipolar I patients , with lamotrigine predominantly effective against depression and lithium predominantly effective against mania OBJECTIVE An emerging body of evidence supports a role for dysfunctional purinergic neurotransmission in mood disorders . Adenosine agonists have been shown to have properties similar to those of dopamine antagonists ; there is a well-characterized interaction between adenosine and dopamine receptors in the ventral striatum , and increasing adenosinergic transmission has been demonstrated to reduce the affinity of dopamine agonists for dopamine receptors . Allopurinol increases adenosine levels in the brain , and hence is hypothesized to reduce the symptoms of mania . Two r and omized , placebo-controlled trials administering add-on allopurinol to manic patients showed significantly greater improvements in Young Mania Rating Scale ( YMRS ) scores for drug compared to placebo , while a more recent , relatively small , add-on study showed negative results . Based on these data , our objective was to examine the efficacy of allopurinol as add-on treatment to mood stabilizers and /or antipsychotic agents in manic patients with bipolar disorder . METHODS We performed a large , well-powered , multicenter , six-week , r and omized , placebo-controlled trial of allopurinol added to mood stabilizers and /or antipsychotic agents in 180 patients with bipolar disorder in an acute manic episode . RESULTS Both groups showed improvement on the YMRS ( effect size of 1.5 for placebo and 1.6 for allopurinol ) , with no difference observed between groups on YMRS scores ( t = 0.28 , p = 0.78 ) . There was no difference in the proportion of patients who responded to treatment ( defined as showing at least 50 % improvement in YMRS score ) between the two groups ( p = 0.92 ) , or in dropout rates ( p = 0.84 ) . LIMITATIONS None of our patients received lithium . However , the side effects of lithium and its narrow therapeutic index made the use of lithium less common and , therefore , our study results reflect common current clinical practice . In the present study , we used a variety of antipsychotic and /or mood stabilizing treatments , to which we added allopurinol ; one might hypothesize that add-on allopurinol has a different effect in combination with different antipsychotic agents or mood stabilizers . CONCLUSIONS The findings of this large , well-powered study do not support add-on allopurinol as a treatment for acute mania . This study did not test the efficacy of allopurinol as monotherapy BACKGROUND Lithium 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 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 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 Poor response to long-term lithium treatment has been reported to be associated with atypical features of bipolar disorder . The purpose of this study was to investigate the influence of atypical symptoms on the effectiveness and stability of long-term lithium treatment  in a prospect i ve , multicenter cohort of bipolar patients in a naturalistic setting . METHOD Patients were initially selected according to International Classification of Diseases , 8th Revision , criteria for bipolar disorder and required long-term treatment .  Their diagnoses were reconfirmed according to DSM-IV upon its publication . They were prospect ively followed for an approximately 20-year period ending in 2004 in 5 centers participating in the International Group for the Study of Lithium-Treated Patients . Examinations included a comprehensive psychiatric evaluation , an assessment of typical and atypical features on an 8-item scale , and an evaluation of clinical course using the morbidity index . Unbalanced repeated- measures regression models with structured covariance matrices were used to assess the extent to which the morbidity index was influenced by atypical symptoms , duration of treatment , and pretreatment features . RESULTS A total of 242 patients were followed for a mean period of 10 years . In 142 patients , the number of typical features was greater than the number of atypical features , whereas in 100 patients the number of atypical features was greater than or equal to the number of typical features . The mean morbidity index remained stable over a period of 20 years in both groups of patients and was not significantly associated with the presence of atypical features , the duration of lithium treatment , the number or frequency of episodes , or latency from the onset of bipolar disorder to the start of lithium treatment . CONCLUSION Our study suggests that long-term response to lithium maintenance treatment is stable both in patients with typical and in patients with atypical features . The predominance of either typical or atypical features did not result in different responses to long-term lithium treatment in this sample of bipolar patients The objective of this study was to compare the efficacy and safety of valproate and lithium in bipolar I patients experiencing a manic or a mixed episode . This international , r and omized , open-label , parallel-group , equivalence study included 268 patients with bipolar I disorder . The starting dose of valproate was 20 mg/kg/day and that of lithium was 800 mg/day . Treatment duration was 12 weeks . The primary outcome measure was mean change in Young Mania Rating Scale score between baseline and study end . Secondary outcome measures were response and remission rates , change in Montgomery and Åsberg Depression Rating Scale and Clinical Global Impression Bipolar Disorder instrument score , and occurrence of adverse events . The mean change from baseline in Young Mania Rating Scale score was 15.8±5.3 in the lithium group and 17.3±9.4 in the valproate group . The 90 % confidence interval of the intergroup difference ( −0.69 ; 3.31 ) was within prespecified equivalence limits . Response rates were 72.6 % in the lithium group and 79.5 % in the valproate  group . Remission rates were 58.5 and 71.9 % , respectively . No intergroup differences were observed in median time to treatment response ( 21 days ) or change in Clinical Global Impression Bipolar Disorder instrument or Montgomery and Åsberg Depression Rating Scale scores . Adverse events were reported in 42.8 % of patients in the lithium group and 41.5 % in the valproate group . Valproate and lithium showed comparable efficacy and tolerability in the treatment of acute mania over 12 weeks
This systematic review indicates that lithium is more effective than placebo as a treatment for acute mania but increases the risk for somnolence and tremor .
Limited evidence suggests little or no difference between lithium and other mood stabilisers ( valproate , carbamazepine ) or antipsychotics ( risperidone , quetiapine , haloperidol ) .
Olanzapine may be an exception , as it is probably slightly more effective than lithium .
There is uncertain evidence that risperidone may also be more effective than lithium .
Lithium is probably more effective at treating acute mania than topiramate .
When compared to placebo , lithium was more likely to cause adverse events .
More , rigorously design ed , large-scale studies are needed to definitively conclude if lithium is superior to other interventions in treating acute mania
BACKGROUND Bipolar disorder is a common condition associated with high morbidity ; developing efficacious , safe treatments is therefore essential .
Lithium is an effective maintenance treatment for bipolar disorder .
It acts as mood stabiliser and reduces the risk of suicide .
However , evidence assessing the efficacy of lithium in the treatment of acute mania is less robust .
Current evidence -based guidelines cite multiple anti-dopaminergic and mood-stabilising agents as initial treatments : more definite evidence is needed to decide if lithium should be the first-line therapy .
OBJECTIVES 1 .
To assess the effects of lithium in comparison with placebo or other active treatment in alleviating the acute symptoms of a manic or mixed episode in people with bipolar disorder.2 .
To review the acceptability and tolerability of treatment with lithium in comparison with placebo or other active treatments in alleviating the acute symptoms of a manic or mixed episode in people with bipolar disorder .