Lithium use and discontinuation in a health maintenance organization. Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. The use of lithium in affective disorders. 3. A double-blind study of prophylaxis in bipolar illness. Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. Lithium in the treatment of mania: comparisons with neuroleptics. Efficacy and tolerability of lithium in treating acute mania in youth with bipolar disorder: protocol for a systematic review Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders. Lithium prophylaxis in recurrent affective illness. Post-acute effectiveness of lithium in pediatric bipolar I disorder. Patterns of pharmacological maintenance treatment in a community mental health services bipolar disorder cohort study (SIN-DEPRES). The use of lithium in affective disorders. II. Prophylaxis of depression in chronic recurrent affective disorder. Lithium combined with carbamazepine or haloperidol in the treatment of mania. Lithium as a prophylactic agent in unipolar affective illness: comparison with cyclic antidepressants. RAPID RECURRENCE OF MANIA FOLLOWING ABRUPT DISCONTINUATION OF LITHIUM Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population-based UK cohort study using electronic health records.
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 : 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 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 The authors studied 52 manic-depressive patients who were assigned to either lithium or placebo during their normal interval phases for periods up to 28 months . Patients receiving lithium had fewer manic and depressive episodes per patient-year than placebo patients . However , this difference may have been due to a sample bias produced by a large dropout rate among patients who had manic episodes . The findings also suggest a relationship between response to lithium and family history of bipolar illness OBJECTIVE To perform a double-blind , placebo-controlled , r and om assignment , parallel group , pharmacokinetically dosed study of lithium for adolescents with bipolar disorders ( BP ) and temporally secondary substance dependency disorders ( SDD ) . METHOD Subjects were 16.3 + /- 1.2 years old and were comprehensively assessed during a 6-week outpatient protocol that included r and om weekly urine collection for drug assays and r and om and weekly serum collection for lithium levels . RESULTS Using both intent-to-treat ( N = 25 ) and completer ( n = 21 ) analyses , there were significant differences on continuous and categorical measures between the active and placebo groups for both psychopathology measures and weekly r and om urine drug assays . The mean scheduled weekly serum lithium level of active responders was 0.9 mEq/L. Addiction to both alcohol and marijuana was the most frequent category of SDD . Mean age at onset of BP was 9.6 + /- 3.9 years and of SDD was 15.3 + /- 1.3 years . There were multigenerational mood disorders in 96 % and multigenerational SDD in 56 % of families . CONCLUSIONS Lithium treatment of BP with secondary SDD in adolescents was an efficacious treatment for both disorders . These results warrant replication with a long-term maintenance phase . The mean 6-year interval between the onset of BP and onset of SDD strongly argues for earliest recognition of BP 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 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 ) Abstract Fifty manic-depressive patients and thirty-four patients with recurrent endogenous depression who had been on open lithium treatment for at least a year took part in double-blind discontinuance studies to compare lithium carbonate and placebo . Within each diagnostic group matched pairs were allocated at r and om to lithium carbonate or placebo .  Relapses occurring first in the lithium partners constituted placebo preferences and those occurring first in the placebo parners lithium preferences . Relapses were recorded when requiring hospital admission or supervision with additional therapy at home . Serum-lithium levels were monitored . The trials terminated in significant preference for lithium both in manic-depressive and in recurrent-depressive disorder ; this happened when nine patients in each group had relapsed on placebo and none on lithium . During the whole trial , which lasted five months , twenty-one placebo patients relapsed and none of the lithium patients . Before the trials , patients had been on lithium for up to 7 years ; even after this long period there was still risk of relapse on withdrawal of the drug The authors report on two recent two-year studies that attempted to determine the effectiveness of lithium carbonate  in treating recurrent affective illness . In study I , 205 bipolar ( manic-depressive ) patients were r and omly assigned to lithium or placebo ; in study 2 , 44 bipolar and 78 unipolar ( depressive ) patients were r and omly assigned  lithium , imipramine , or placebo . The results showed lithium to be effective in treating both manic and depressive episodes and imipramine to be effective in treating depressive episodes . The findings emphasize the importance of considering the patient 's previous course of illness in selecting a program of maintenance treatment 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 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 In a longitudinal outpatient study , the authors found that lithium produced a mild decrease in depth of depression scores among patients who had been on the drug for more than seven months , as compared with patients who had been receiving lithium less than seven months . They assess the factors contributing to reported positive clinical results of maintenance lithium treatment in recurrent affective disorder Hospitalized manic patients were withdrawn from psychoactive medications for 2 weeks after which they were r and omized to double-blind treatment with carbamazepine plus lithium [ CBZ-Li ] or haloperidol plus lithium [ HAL-Li ] with benztropine . Unit dosages of Li 300 mg , CBZ 200 mg and HAL 2 mg were titrated to therapeutic plasma levels and maintained for 8 weeks . No rescue medications were permitted after 3 weeks . St and ard ratings of psychopathology and side effects were accomplished weekly . Sixty patients entered the study but only 33 remained for r and omization after drug washout . By 8 weeks both groups were improved from baseline without statistically reliable differences between them . However HAL-Li patients had more extrapyramidal side effects that were major reasons for dropout , whereas CBZ-Li patients were more often noncompliant and initially required more rescue medications . We conclude that either combination treatment can be beneficial but CBZ-Li has the advantage because of fewer neurologic side effects As reported by Prien ( see p 847 ) , two United States committees concluded in 1975 that lithium is prophylactically efficacious , ie , significantly better than placebo , in recurrent bipolar affective illness . The committees felt , however , that they could not recommend the prophylactic use of lithium in recurrent unipolar affective illness ( 1 ) because there is uncertainty as to what a unipolar disorder represents and ( 2 ) because the evidence for the efficacy of lithium in this disease type is based on a relatively small number of patients . With the first reason given , the committees more or less acknowledge that lack of trust in the psychiatrists ' ability to diagnose recurrent unipolar affective illness played a role in their decision . I have no comment to offer on this . As regards the second reason : It might be worth comparing the evidence now available for prophylactic efficacy of lithium and of cyclic antidepressants  in unipolar affective illness . Fourteen patients with a history of mania satisfying DSM-III criteria were entered into a r and omised double-blind placebo-controlled crossover trial , spending four weeks on each of lithium and placebo .  All patients had been well and stable on lithium for at least 18 months and were not taking any other psychotropic drugs . Seven patients ( 50 % ) had a relapse of their manic illness and a further two had to be withdrawn because they recognised signs of incipient relapse . One of these became overtly manic after restarting lithium . The seven definite and the two possible relapses occurred in the placebo phase ; this finding was unlikely to have arisen by chance . The relapses started 13 - 19 days after placebo substitution . These results have important implication s in the management of lithium prophylaxis by all doctors , particularly those who , for any reason , are considering withdrawal of lithium from their patients 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 It is unclear which maintenance treatment for bipolar disorder is superior in clinical practice . R and omized controlled head-to-head trials of available drugs either do not exist or are inconclusive . We aim ed to compare rates of monotherapy treatment failure in individuals prescribed lithium , valproate , olanzapine or quetiapine  by a population -based cohort study using electronic health records . 5,089 patients with bipolar disorder were prescribed  lithium ( N=1,505 ) , valproate ( N=1,173 ) olanzapine ( N=1,366 ) or quetiapine ( N=1,075 ) as monotherapy . Treatment failure was defined as time to stopping medication or add-on of another mood stabilizer , antipsychotic , antidepressant or benzodiazepine . In unadjusted analyses , the duration of successful monotherapy was longest in individuals treated with lithium .  Treatment failure had occurred in 75 % of those prescribed lithium by 2.05 years ( 95 % CI : 1.63 - 2.51 ) , compared to 0.76 years ( 95 % CI : 0.64 - 0.84 ) for those prescribed quetiapine , 0.98 years ( 95 % CI : 0.84 - 1.18 ) for those prescribed valproate , and 1.13 years for those prescribed olanzapine ( 95 % CI : 1.00 - 1.31 ) . Lithium 's superiority remained in a propensity score matched analysis ; when treatment failure was defined as stopping medication or add-on of a mood stabilizer or antipsychotic ; and when treatment failure was restricted to more than three months after commencing the study drug . Lithium appears to be more successful as monotherapy maintenance treatment than valproate , olanzapine or quetiapine . Lithium is often avoided because of its side effect profile , but alternative treatments may reduce the time to being prescribed more than one drug , with potential additive side effects of these treatments
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 .