Lithium as a prophylactic agent in unipolar affective illness: comparison with cyclic antidepressants. Cognitive-behavioral management of patients with bipolar disorder who relapsed while on lithium prophylaxis. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Mortality of patients with mood disorders: follow-up over 34-38 years. Methodologic issues in maintenance therapy clinical trials. Controlled studies of the acute antidepressant effects of lithium. How Long Should the Lithium Augmentation Strategy be Maintained? A 1-Year Follow-up of a Placebo-Controlled Study in Unipolar Refractory Major Depression Long-term symptomatic status of bipolar I vs. bipolar II disorders. Number needed to treat analyses of drugs used for maintenance treatment of bipolar disorder Prophylactic lithium in affective disorders. Controlled trial. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Lithium carbonate and imipramine in prevention of affective episodes. A comparison in recurrent affective illness. A double-blind comparison of lithium carbonate and maprotiline in the prophylaxis of the affective disorders. Lithium prophylaxis in recurrent affective illness. Cognitive impairment in the euthymic phase of affective disorder. 5-HT brain function in affective disorder: d,l-fenfluramine-induced hormone release and clinical outcome in long-term lithium/carbamazepine prophylaxis. Suicide in 406 Mood-Disorder Patients With and Without Long-Term Medication: A 40 to 44 Years' Follow-Up A Consecutive Series of Treated Affected Offspring of Parents with Bipolar Disorder: Is Response Associated with the Clinical Profile? Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Efficacy and mood conversion rate during long-term fluoxetine v. lithium monotherapy in rapid- and non-rapid-cycling bipolar II disorder. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). The Bipolar Interactive Psychoeducation (BIPED) study: trial design and protocol The use of lithium in affective disorders. II. Prophylaxis of depression in chronic recurrent affective disorder. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Clinical responses to antidepressants among 1036 acutely depressed patients with bipolar or unipolar major affective disorders Diagnostic conversion to bipolar disorder in unipolar depressed patients participating in trials on antidepressants. Efficacy and safety of long-term fluoxetine versus lithium monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study. Addition of monoamine oxidase inhibitors to carbamazepine: preliminary evidence of safety and antidepressant efficacy in treatment-resistant depression. Combination tricyclic antidepressant and lithium maintenance medication in unipolar and bipolar depressed patients. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Long-term effectiveness of lithium in bipolar disorder: a multicenter investigation of patients with typical and atypical features. Lithium use and discontinuation in a health maintenance organization. Effect of prophylactic treatment on suicide risk in patients with major affective disorders. Data from a randomized prospective trial. Maintenance Efficacy of Divalproex in the Prevention of Bipolar Depression Risk for switch from unipolar to bipolar disorder in youth with ADHD: a long term prospective controlled study.
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 . BACKGROUND The application of cognitive-behavioral treatment ( CBT ) to patients with bipolar disorder who had an affective episode while on lithium prophylaxis has received little research attention . The aim of this preliminary study was to test whether reduction of residual symptomatology by cognitive-behavioral methods could yield long-term beneficial effects in patients with bipolar disorder , as was found to be the case in recurrent unipolar depression . METHOD Fifteen patients with RDC bipolar disorder , type I , who relapsed while on lithium prophylaxis despite initial response and adequate compliance were treated by cognitive-behavioral methods in an open trial . A 2- to 9-year follow-up was performed . RESULTS Five of the 15 patients had a new affective episode during follow-up . CBT was associated with a significant reduction of residual symptomatology . CONCLUSION These preliminary results suggest that a trial of CBT may enhance lithium prophylaxis and improve long-term outcome of bipolar disorder In a double-blind , long-term follow-up study , 117 bipolar patients received lithium carbonate , imipramine hydrochloride , or both and 150 unipolar patients received lithium carbonate , imipramine , both lithium carbonate and imipramine , or placebo . With bipolar patients , lithium carbonate and the combination treatment were superior to imipramine in preventing manic recurrences and were as effective as imipramine in preventing manic recurrences and were as effective as imipramine in preventing depressive episodes . The combination treatment provided no advantage over lithium carbonate alone . With unipolar patients , imipramine and the combination treatment were more effective than lithium carbonate and placebo in preventing depressive recurrences . The combination treatment provided no advantage over imipramine alone . The lithium carbonate-treated group had fewer manic episodes than the other groups . Treatment outcome , which was evaluated primarily in terms of the occurrence of major depression or manic episodes , was significantly related to characteristics of the index episode , ie , the episode that brought the patient into the study BACKGROUND All follow-up studies of causes of death in affective disordered patients have found they have markedly elevated suicide rates and a less reproducible increased mortality from other causes . The reported rates by gender , disorder type and treatment are more variable . METHODS Hospitalised affective disordered patients ( n=406 ) were followed prospect ively for 22 years or more . Later , mortality was assessed for 99 % of them at which time 76 % had died . RESULTS St and ardised Mortality Rates ( observed deaths/expected deaths ) for patients were elevated especially for suicide and circulatory disorders in both men and women . Women actually had higher suicide rates but that did not take into account the twofold increase in general population rates for men . Unipolar patients had significantly higher rates of suicide than bipolar Is or IIs . In all groups long term medication treatment with antidepressants alone or with a neuroleptic , or with lithium in combination with antidepressants and /or neuroleptics significantly lowered suicide rates even though the treated were more severely ill . Although at the age of onset the suicide rates were most elevated , from ages 30 to 70 the rates were remarkably constant despite the different courses of illness . LIMITATIONS The patients were identified as in patients and followed prospect ively . The treatments were uncontrolled and are not quantifiable but were documented during the follow-up . CONCLUSIONS Men and women hospitalised for affective disorders have elevated mortality rates from suicide and circulatory disorders . Unipolars have higher suicide rates than bipolar Is or IIs . Long term medication treatment lowers the suicide rates , despite the fact that it was the more severely ill who were treated In the early 1980s , the National Institute of Mental Health supported a multicenter , r and omized , controlled , clinical trial on unipolar and bipolar disorder to evaluate the comparative efficacies of lithium carbonate , imipramine hydrochloride , a lithium-imipramine combination , and placebo in preventing the recurrence of affective disorders . The objective of this report is to present a re analysis of the relative efficacies of these treatments in patients with unipolar disorder to focus attention on general issues related to the design and conduct of maintenance therapy trials . We show that the earlier conclusions of that study that imipramine and the combination therapy are more effective than lithium and placebo in preventing the recurrence of depression in unipolar patients can be accounted for by alternative explanations that are a consequence of the design of the study . Our findings have important implication s for the design , conduct , and interpretation of results of maintenance therapy clinical trials in general In two r and omized double-blind controlled trials on 63 depressed female in- patients subject to recurrent affective disorder ( bipolar and unipolar manic-depressive psychosis )  lithium was shown to have major acute antidepressant effects . At the end of three weeks lithium produced more uniform improvement than did imipramine ; lithium in combination with tryptophan ( in the form of Optimax ) was superior to tryptophan alone -- the latter drug having no discernible antidepressant activity in this group of patients . Lithium did not produce an antidepressant effect until the second and third week of both trials There is compelling evidence from placebo-controlled studies that lithium augmentation is an effective strategy in the acute and continuation treatment of refractory unipolar major depression . Authors prospect ively investigated the 1-year outcome of 22 subjects diagnosed with unipolar major depression who had participated in a 4-month placebo-controlled , double-blind continuation study of lithium augmentation without relapse . At the end of the double-blind phase , the blinded medication ( lithium in 14 patients , placebo in 8 patients ) was tapered off over a 1-week period , while the antidepressant was continued at the same dosage for another 4 weeks . Subsequently , the antidepressant was gradually discontinued over a 4-week period . Clinical status was assessed at regular follow-up visits . During the open 6-month follow-up period , seven subjects suffered an affective recurrence , five of whom had received lithium during the placebo-controlled , double-blind phase of the study . Study data suggest that active medication should be maintained for at least 1 year after successful lithium augmentation in patients with unipolar major depressive disorder Weekly affective symptom severity and polarity were compared in 135 bipolar I ( BP I ) and 71 bipolar II ( BP II ) patients during up to 20 yr of prospect i ve symptomatic follow-up . The course of BP I and BP II was chronic ; patients were symptomatic approximately half of all follow-up weeks ( BP I 46.6 % and BP II 55.8 % of weeks ) . Most bipolar disorder research has concentrated on episodes of MDD and mania and yet minor and subsyndromal symptoms are three times more common during the long-term course . Weeks with depressive symptoms predominated over manichypomanic symptoms in both disorders ( 31 ) in BP I and BP II at 371 in a largely depressive course ( depressive symptoms=59.1 % of weeks vs. hypomanic=1.9 % of weeks ) . BP I patients had more weeks of cyclingmixed polarity , hypomanic and subsyndromal hypomanic symptoms . Weekly symptom severity and polarity fluctuated frequently within the same bipolar patient , in which the longitudinal symptomatic expression of BP I and BP II is dimensional in nature involving all levels of affective symptom severity of mania and depression . Although BP I is more severe , BP II with its intensely chronic depressive features is not simply the lesser of the bipolar disorders ; it is also a serious illness , more so than previously thought ( for instance , as described in DSM-IV and ICP-10 ) . It is likely that this conventional view is the reason why BP II patients were prescribed pharmacological treatments significantly less often when acutely symptomatic and during intervals between episodes . Taken together with previous research by us on the long-term structure of unipolar depression , we su bmi t that the thrust of our work during the past decade supports classic notions of a broader affective disorder spectrum , bringing bipolarity and recurrent unipolarity closer together . However the genetic variation underlying such a putative spectrum remains to be clarified Rationale Due to the episodic and chronic nature of bipolar disorder ( BD ) , maintenance therapy represents a critical part of treatment ; however , there is a paucity of studies comparing effectiveness of available long-term treatments . Objective The aim of this study is to determine and compare the efficacy of pharmacological treatments for maintenance treatment of BD by means of the number needed to treat ( NNT ) . Methods The efficacy of drugs used for maintenance treatment of BD , as emerging from the results of r and omized controlled trials , was assessed using the size effect measure of NNT . PubMed search es were conducted on English- language articles published until May 2010 using the search terms “ bipolar disorder , ” “ mania , ” “ mixed episode , ” or “ bipolar depression , ” cross-referenced with trial characteristic search phrases and generic names of medications . The search was supplemented by manually review ing reference lists from identified publications . Results In 15 studies , aripiprazole , olanzapine , quetiapine , risperidone long-acting injection , lithium , lamotrigine , and divalproex proved effectiveness in terms of NNTs ( ≥10 % advantage over placebo ) for prevention of relapse into any mood episode . Quetiapine , lithium , risperidone long-acting injection , aripiprazole , and olanzapine are effective in manic recurrence prevention .  Lamotrigine , quetiapine , and lithium present significant NNTs for prevention of depressive relapses . Conclusions All of the pharmacological agents assessed were effective in the prevention of any kind of mood episode ; however , different efficacy profiles were found for prevention of manic and /or depressive relapses . The comparison of NNT values of the available agents may represent a useful tool in clinical setting s , in order to facilitate implementation of long-term pharmacological interventions in patients with BD Abstract The prophylactic effect of lithium was studied in a group of sixty-five patients with recurrent affective disorders in four centres . Patients were r and omly allocated to lithium or identical-looking placebo tablets for periods of up to 112 weeks . In addition , patients received any further medication or treatment which the psychiatrist in charge of the case thought was necessary . Patients receiving lithium had very significantly less affective illness than patients receiving placebo tablets , whether this was measured by time spent as an inpatient or by the duration of outpatient episodes . The amount of antidepressant or of antimanic medication prescribed was also significantly less in the lithium group . No patient on lithium was given  electroconvulsive therapy  ( E.C.T. ) , whereas 43 % of the placebo group received one or more courses of E.C.T. A global rating was made independently by two assessors who did not know whether the patient was in the lithium or in the placebo group . These assessors , the psychiatrist in charge of the case and a psychiatric social worker , showed a very high concordance in their ratings . 86 % of patients on lithium were rated as showing little or no affective disorders ( global rating 1 and 2 ) during the trial , as compared to only 8 % of the placebo group . Only 11 % of the lithium group was rated as unchanged or worse than during the 2 years previous to the trial , as compared with 75 % of the placebo group . Lithium seemed to be as effective in patients with unipolar recurrent depressive illness as in patients with both mania and depression BACKGROUND Long-term outcomes are often poor in patients with bipolar disorder despite treatment ; more effective treatments are needed to reduce recurrences and morbidity . This study compared the efficacy of divalproex , lithium , and placebo as prophylactic therapy . METHODS A r and omized , double-blind , parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period . Patients who met the recovery criteria within 3 months of the onset of an index manic episode ( n = 372 ) were r and omized to maintenance treatment with divalproex , lithium , or placebo in a 2:1:1 ratio . Psychotropic medications were discontinued before r and omization , except for open-label divalproex or lithium , which were gradually tapered over the first 2 weeks of maintenance treatment . The primary outcome measure was time to recurrence of any mood episode . Secondary measures were time to a manic episode , time to a depressive episode , average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania , and Global Assessment of Function scores . RESULTS The divalproex group did not differ significantly from the placebo group in time to any mood episode .  Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode .  Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores . CONCLUSIONS The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy . Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures Patients with recurrent affective illness ( N-122 ) were r and omly assigned to lithium carbonate , imipramine , or placebo therapy for two years following discharge from hospitalization for acute depression . Patients were classified as bipolar or unipolar based on the presence or absence of a history of mania . With bipolar patients lithium carbonate was significantly more effective than imipramine or placebo in preventing affective episodes ( ie , manic or depressive attacks severe enough to require hospitalization or use of non study drugs ) . There was a relatively high incidence of manic episodes on imipramine . Unipolar patients responded equally well to lithium carbonate or imipramine . Both treatments were significantly more effective than placebo . The difference between treatments was due primarily to depressive episodes ; manic episodes occurred infrequently and were evenly distributed across treatment groups . There was no significant difference between  lithium carbonate and imipramine  among unipolar patients A double-blind prospect i ve study was carried out comparing the prophylactic effect of maprotiline and lithium carbonate over a period of one year in patients suffering from recurrent affective disorders . The average Affective Morbidity Index was lower , but not significantly so , in patients treated with lithium .  A further analysis , based on dividing patients into those with no affective morbidity and those who showed some affective morbidity during the study , demonstrated lithium carbonate to be significantly superior to maprotiline both in the group as a whole and in unipolar depressives . A correlation between high plasma maprotiline concentration and low morbidity was observed and was in line with an earlier report . A highly significant negative correlation ( r=-0 - 97 ; p less than 0 - 001 ) was found between plasma maprotiline concentration and body weight . Although the results showed lithium carbonate to be superior to maprotiline in the study , it should be emphasized that the plasma levels of lithium  were constantly monitored and maintained at what is considered to be its optimum concentration , whereas the maprotiline treated patients were kept on a fixed dosage regime irrespective of plasma levels 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 BACKGROUND A review of studies of cognition in the euthymic phase of unipolar and bipolar affective disorder reveals diverging results . METHODS The study was design ed as a controlled cohort study , with the Danish psychiatric case register of admissions used to identify patients and the Danish civil register to identify controls . Patients who were hospitalized between 19 and 25 years ago with an affective diagnosis and who at interviews fulfilled criteria for a primary affective unipolar or bipolar disorder , according to ICD-10 , were compared with age- and gender-matched controls . Interviews and assessment of the cognitive function  were made in the euthymic phase of the disorder . In all , 118 unipolar patients , 28 bipolar patients and 58 controls were included . Analyses were adjusted for differences in the level of education and for sub clinical depressive and anxiety symptoms . RESULTS Patients with recurrent episodes were significantly more impaired than patients with a single episode and more impaired than controls . Also , within patients the number of prior episodes seemed to be associated with cognitive outcome . There was no difference in the severity of the dysfunction between unipolar and bipolar patients . CONCLUSIONS Cognitive impairment in out- patients with unipolar and bipolar disorder appears to be associated with the number of affective episodes Prolactin ( PRL ) and Cortisol ( CORT ) responses to d , l-fenfluramine ( FEN ) challenge ( 60 mg ) were examined in patients with affective disorders on two occasions under euthymic conditions : drug-free before admission to prophylactic treatment and after about 9 months of medication with lithium or carbamazepine .  Response to treatment was assessed by a complex algorithm using continuous ratings in outpatient clinic over a period of 2 years . In general , treatment result ed in a delayed and diminished CORT release ( n.s . ) ; subgroup analysis revealed an attenuated CORT response ( P < 0.05 ) in responders , whereas nonresponders showed no change in CORT secretion pattern except an enhanced CORT baseline value ( P < 0.05 ) . Cross-sectional comparison of responders with nonresponders under medication yielded a trend for greater CORT stimulation in nonresponders . This result was not affected by  FEN/NorFEN or lithium/carbamazepine serum levels , baseline CORT values , age , sex , diagnostic distribution , number of appointments to the outpatient clinic or duration of medication at the time of FEN test session . Before onset of prophylactic medication responders and nonresponders could not be discriminated significantly regarding stimulated hormone release , probably due to the small sample size ( n = 17 ) . CORT response to FEN was increased in drugfree unipolar patients compared to bipolar ( P < 0.05 ) and to schizoaffective patients ( P < 0.1 ) . In accordance with its well-documented presynaptic 5-HT-agonistic action lithium medication result ed in a significantly greater increase in CORT release than carbamazepine ( P < 0.05 ) . Evaluation of PRL stimulation showed patterns of secretion quite similar to those of CORT , without reaching statistical significance in most cases . Perhaps due to method ological differences in assessing treatment response , these data do not confirm former results , which supposed an enhanced 5-HT net activity in long-term prophylactic lithium treatment . Because of high interindividual variances of hormone parameters , the FEN-test procedure is not a useful tool for the prediction of therapeutical outcome in terms of clinical routine use . Relations of stimulated hormone response as a marker of central serotoninergic activity and clinical outcome are discussed ABSTRACT There is no data on the variation in the suicide risk over lifetime and on the suicide-preventive effect of the long-term treatment of mood-disorder patients with antidepressants and neuroleptics .  Our research focused on 186 unipolar ( D ) , 60 bipolar II ( Dm ) , 130 nuclear bipolar I ( MD ) , and 30 preponderantly manic patients ( M/Md ) ; that were followed-up from 1963 to 2003 . By 2003 , 45 ( 11.1 % ) of the 406 patients had committed suicide . Suicide rates were highest among D patients ( St and ardized Mortality Ratio , SMR = 26.4 ) , MD ( SMR = 13.6 ) , Dm ( SMR = 10.6 ) and lowest among M/Md patients ( SMR = 4.7 ) . Prospect ively , the suicide rate decreased over the 44 years ' follow-up ; Lithium , neuroleptics and antidepressants reduced suicides significantly . Long-term treatment also reduced overall mortality , and combined treatments proved more effective than mono-therapy 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 OBJECTIVE Studies have reported that countries with high rates of fish oil consumption have low rates of depressive disorder . The authors studied a specific omega-3 fatty acid , the ethyl ester of eicosapentaenoic acid ( E-EPA ) , as an adjunct to treatment for depressive episodes occurring in patients with recurrent unipolar depressive disorder who were receiving maintenance antidepressant therapy . METHOD Twenty patients with a current diagnosis of major depressive disorder participated in a 4-week , parallel-group , double-blind addition of either placebo or E-EPA to ongoing antidepressant therapy .  Seventeen of the patients were women , and three were men . RESULTS Highly significant benefits of the addition of the omega-3 fatty acid compared with placebo were found by week 3 of treatment . CONCLUSIONS It is not possible to distinguish whether E-EPA augments antidepressant action in the manner of lithium or has independent antidepressant properties of its own BACKGROUND Controversy exists over antidepressant use in rapid-cycling bipolar disorder . AIMS Exploratory analysis of safety and efficacy of fluoxetine v. lithium monotherapy in individuals with rapid- v. non-rapid-cycling bipolar II disorder . METHOD R and omised , double-blind , placebo-controlled comparison of fluoxetine v. lithium monotherapy in patients initially stabilised on fluoxetine monotherapy ( trial registration NCT00044616 ) . RESULTS The proportion of participants with depressive relapse was similar between the rapid- and non-rapid-cycling groups ( P = 0.20 ) . The odds of relapse were similar between groups ( P = 0.36 ) . The hazard of relapse was similar between groups ( hazard ratio 0.87 , 95 % CI 0.40 - 1.91 ) . Change in mania rating scores was similar between groups ( P = 0.86 ) . There was no difference between groups in the rate of syndromal ( P = 0.27 ) or subsyndromal ( P = 0.82 ) hypomania . CONCLUSIONS Depressive relapse and treatment-emergent mood conversion episode rates were similar for lithium and fluoxetine monotherapy and placebo during long-term , relapse-prevention therapy of rapid- and non-rapid-cycling bipolar II disorder 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 Bipolar disorders affect between 3–5 % of the population and are associated with considerable lifelong impairment . Since much of the morbidity associated with bipolar disorder is caused by recurrent depressive symptoms , which are often only poorly responsive to antidepressants , there is a need to develop alternative , non-pharmacological interventions . Psychoeducational interventions have emerged as promising long-term therapeutic options for bipolar disorder . Methods / design The study is an exploratory , individually r and omised controlled trial . The intervention known as ' Beating Bipolar ' is a psychoeducational programme which is delivered via a novel web-based system . We will recruit 100 patients with a diagnosis of DSM-IV bipolar disorder ( including type I and type II ) currently in clinical remission . The primary outcome is quality of life . This will be compared for those patients who have participated in the psychoeducational programme with those who received treatment as usual . Quality of life will be assessed immediately following the intervention as well as 10 months after r and omisation . Secondary outcomes include current depressive and manic symptoms , number of episodes of depression and mania/hypomania experienced during the follow-up period , global functioning , functional impairment and insight . An assessment of costs and a process evaluation will also be conducted which will explore the feasibility and acceptability of the intervention as well as potential barriers to effectiveness . Discussion Bipolar disorder is common , under-recognised and often poorly managed . It is a chronic , life-long , relapsing condition which has an enormous impact on the individual and the economy . This trial will be the first to explore the effectiveness of a novel web-based psychoeducational intervention for patients with bipolar disorder which has potential to be easily rolled out to patients .Trial registration Current Controlled Trials IS RCT 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 OBJECTIVE Use of lithium to augment antidepressant medication has been shown to be beneficial in the acute treatment of depression . The authors examined the efficacy of lithium augmentation in the continuation treatment of unipolar major depressive disorder . METHOD Thirty patients with a refractory major depressive episode who had responded to acute lithium augmentation during an open 6-week study participated in a r and omized , parallel-group , double-blind , placebo-controlled trial of lithium augmentation during continuation treatment . After a 2 - 4-week stabilization period following remission , patients were r and omly assigned to receive either lithium or placebo for a 4-month period . Antidepressant medication was continued throughout the study . RESULTS Relapses ( including one suicide ) occurred in seven ( 47 % ) of the 15 patients who received placebo in addition to antidepressants . None ( 0 % ) of the 14 patients who received lithium augmentation with antidepressants suffered a relapse during the double-blind phase of the study . Five of the seven relapsing patients in the placebo group developed a depressive episode , and the other two experienced a manic episode . CONCLUSIONS Lithium augmentation in the continuation phase of treatment of unipolar major depressive disorder effectively protects patients against a relapse .  Patients who respond to lithium augmentation  should be maintained on lithium augmentation for a minimum of 6 months or even longer 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 Whether responses to antidepressants  differ in bipolar and unipolar depression remains unresolved OBJECTIVE In unipolar depressed patients participating in trials on antidepressants , we investigated if illness characteristics at baseline could predict conversion to bipolar disorder . METHOD A long-term register-based follow-up study of 290 unipolar depressed patients with a mean age of 50.8 years ( SD=11.9 ) participating in three r and omized trials on antidepressants conducted in the period 1985 - 1994 . The independent effects of explanatory variables were examined by applying Cox regression analyses . RESULTS The overall risk of conversion was 20.7 % , with a mean follow-up time of 15.2 years per patient . The risk of conversion was associated with an increasing number of previous depressive episodes at baseline , [ HR 1.18 , 95 % CI ( 1.10 - 1.26 ) ] . No association with gender , age , age at first depressive episode , duration of baseline episode , subtype of depression or any of the investigated HAM-D subscales included was found . LIMITATIONS The patients were followed-up through the Danish Psychiatric Central Research Register , which result ed in inherent limitations such as possible misclassification of outcome . CONCLUSION In a sample of middle-aged hospitalized unipolar depressed patients participating in trials on antidepressants , the risk of conversion was associated with the number of previous depressive episodes . Therefore , this study emphasizes that unipolar depressed patients experiencing a relatively high number of recurrences should be followed more closely , or at least be informed about the possible increased risk of conversion OBJECTIVE The authors examined the safety and efficacy of long-term fluoxetine monotherapy , lithium monotherapy , and placebo therapy in preventing relapse and recurrence of bipolar type II major depressive episode . The authors hypothesized that fluoxetine monotherapy would be superior to lithium monotherapy with a similar hypomanic mood conversion rate . METHOD Patients at least 18 years old who recovered from their major depressive episode during initial open-label fluoxetine monotherapy were r and omly assigned to receive 50 weeks of double-blind monotherapy with fluoxetine at 10 - 40 mg/day , lithium at 300 - 1200 mg/day , or placebo . The primary outcome measure was time to relapse or recurrence . Secondary outcome measures included the proportion of patients remaining well and the frequency of hypomanic symptoms . RESULTS There were no significant differences in clinical or demographic characteristics among the fluoxetine ( N=28 ) , lithium ( N=26 ) , and placebo ( N=27 ) groups . The mean time to relapse was 249.9 days for the fluoxetine group , 156.4 days for the lithium group , and 186.9 days for the placebo group . The hazard of relapse was significantly lower with fluoxetine compared with lithium , and the estimated hazard of relapse with lithium was 2.5 times greater than with fluoxetine . There were no statistically significant or clinical ly meaningful differences in hypomanic symptoms among treatment groups over time . One patient taking fluoxetine and one patient taking placebo discontinued treatment because of hypomania . CONCLUSIONS These findings suggest that long-term fluoxetine monotherapy may provide superior relapse-prevention benefit relative to lithium monotherapy after recovery from bipolar II major depressive episode without an increase in hypomanic mood conversion episodes BACKGROUND Depression is often resistant to treatment with mood stabilizers . The antidepressant effects of carbamazepine can be potentiated by lithium supplementation , but some patients fail to respond to the combination . Although monoamine oxidase inhibitors ( MAOIs ) appear useful in atypical and bipolar depressions , concerns have been raised regarding safety and pharmacokinetic interactions when they are combined with carbamazepine . METHOD Ten in patients ( 7 bipolar , 3 unipolar ) with refractory DSM-III-R major depression , also resistant to double-blind treatment with carbamazepine , plus lithium augmentation in 8 , received double-blind MAOI augmentation ( phenelzine in 4 , tranylcypromine in 6 ) . RESULTS All 10 patients tolerated the addition of an MAOI well , and mean self-rated side effect scores did not change significantly . Four of 10 patients improved substantially and became euthymic , allowing discharge from hospital on the carbamazepine + /- lithium plus MAOI combination . These 4 patients improved in spite of prior inadequate responses to the same MAOI without carbamazepine and carbamazepine without an MAOI . CONCLUSION This preliminary evidence suggests that the addition of MAOIs to carbamazepine + /- lithium may be well tolerated , may not affect carbamazepine and lithium pharmacokinetics , and may provide relief of refractory depressive symptoms in some patients . Further studies are needed to establish the safety and efficacy of combining carbamazepine with MAOIs In a small study of up to 3 years ' duration comparison of the value of amitriptyline alone versus amitriptyline + lithium in unipolar cases ( 27 patients ) and of that of lithium alone versus amitriptyline + lithium in bipolar cases ( 13 patients ) showed no advantage for the combination treatments in terms of efficacy in reducing depressive relapses . There was no effect of treatment , developing depression or developing hypothyroidism upon the psychological tests which were conducted during this prolonged study . Observer and self ratings detected an increase in depression before relapse was clearly present , but of the various psychological assessment s conducted only arousal showed changes in association with developing and definite relapse . The prescription of lithium but not amitriptyline + lithium or amitriptyline alone was associated with significant increases in blood pressure 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 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 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 Recent findings have indicated that lithium treatment markedly reduces  suicide risk in major affective disorders . To compare the effect of lithium with carbamazepine and amitriptyline , suicidal behavior was analyzed during the r and omized prospect i ve long-term MAP study ( N = 378 ; duration 2.5 years ) . Of the nine suicides and five attempted suicides , none took place during lithium treatment . The findings support the view that lithium has a specific antisuicidal effect over and above its prophylactic benefit Breakthrough depression is a common problem in the treatment of bipolar disorder . Only one , recently published , double-blind , placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients . This report describes , in further detail , the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder . A r and omized , double-blind , parallel-group , multicenter study was conducted over a 52-week maintenance period . Bipolar I patients , who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode , were r and omized to maintenance treatment with divalproex , lithium , or placebo in a 2 : 1 : 1 ratio . Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase . Outcome measures were the rate of early discontinuation for depression , time to depressive relapse , proportion of patients with depressive relapse , mean change in Depressive Syndrome Scale score , proportion of patients receiving antidepressants , and time in the study . Among patients taking an antidepressant , a higher percentage of patients on placebo than divalproex discontinued early for depression .  Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period . Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance . Indices of severity of pre study illness course predicted worse outcome in all treatment groups . Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder , particularly in patients who had responded to divalproex when manic , and among patients with a more severe course of illness BACKGROUND To investigate whether ADHD is a risk factor for switches from unipolar to bipolar disorder over time . METHODS Data from two large controlled longitudinal family studies of boys and girls with and without ADHD and their siblings were used . Subjects ( n=168 ) were followed prospect ively and blindly over an average follow-up period of 7 years . Comparisons were made between youth with unipolar major depression who did and did not switch to full or subthreshold BP-I disorder at the follow-up assessment . Subjects were assessed at baseline and follow-up on multiple domains of functioning . Positive family history of parental psychiatric disorders was also compared between groups . RESULTS ADHD was associated with a significantly higher risk for switches from unipolar to bipolar disorder ( 28 % versus 6 % ; z=2.80 , p=0.005 ) . In subjects with ADHD , switches from unipolar to bipolar disorder were predicted by baseline comorbid conduct disorder , school behavior problems , and a positive family history of parental mood disorder . LIMITATIONS Psychosis was an exclusionary criterion in the original ascertainment of the studies of ADHD prob and s , so we were unable to test this as a predictor of switching to BPD . CONCLUSIONS ADHD is a risk factor for switches from unipolar to bipolar disorder , and switches could be predicted by the presence of baseline conduct disorder , school behavior problems , and a positive family history of a mood disorder in a parent . These characteristics can aid clinicians in their treatment of youth with MDD
There were no other statistically significant differences between lithium and antidepressants according to all other outcomes considered .
AUTHORS ' CONCLUSIONS There was adequate efficacy evidence for lithium or antidepressants preventing relapse in unipolar affective disorder , however their relative efficacy was unknown .
BACKGROUND The main rationale for the use of lithium in the long-term treatment of unipolar affective disorder is its efficacy in treating bipolar affective disorder and resistant depression .
However , there is considerable uncertainty about which pharmacological intervention is most effective in the long-term treatment of recurrent unipolar affective disorder .
OBJECTIVES To assess the effects of lithium versus antidepressants for the long-term treatment of recurrent affective disorder .