Lithium prophylaxis in recurrent affective illness. Lithium as a prophylactic agent in unipolar affective illness: comparison with cyclic antidepressants. Methodologic issues in maintenance therapy clinical trials. Combination tricyclic antidepressant and lithium maintenance medication in unipolar and bipolar depressed patients. Comparative efficacy of lithium and amitriptyline in the maintenance treatment of recurrent unipolar depression: a randomised study. 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. The use of lithium in affective disorders. I. Acute endogenous depression. Patterns of pharmacological maintenance treatment in a community mental health services bipolar disorder cohort study (SIN-DEPRES). Prophylactic therapy with lithium in elderly patients with unipolar major depression. Prophylactic lithium in affective disorders. Controlled trial. Lithium carbonate and imipramine in prevention of affective episodes. A comparison in recurrent affective illness. 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. Continuation therapy with lithium and amitriptyline in unipolar depressive illness: a randomized, double-blind, controlled trial. How Long Should the Lithium Augmentation Strategy be Maintained? A 1-Year Follow-up of a Placebo-Controlled Study in Unipolar Refractory Major Depression Safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for relapse-prevention of bipolar II depression: A randomized, double-blind, parallel-group, prospective study.
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 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 . 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 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 The present study , including 81 depressive patients , compares the prophylactic efficacy of lithium and amitriptyline in recurrent unipolar depression over a treatment period of 2.5 years in a r and omised multicentre design .  Hospitalisation , re-emergence of depressive or subdepressive recurrences , unwanted side-effects and need of concomitant psychotropic medication were considered to indicate treatment failures . Average dosage for amitriptyline  was 98 + /- 37 mg/day , average  lithium blood level was 0.59 + /- 0.12 mmol/l . Survival analyses demonstrated a significant superiority of lithium ( P = 0.015 ) regarding the outcome criteria ' recurrences and /or sub clinical recurrences ' and non-significantly better results of lithium compared to amitriptyline concerning ' recurrence ' ( P = 0.059 ) or ' recurrence and /or concomitant medication ' ( P = 0.066 ) 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 A double-blind study involving 29 patients was design ed to investigate the efficacy of lithium compared with imipramine in the treatment of acute endogenous depression . After two to three weeks , there was evidence of a moderate to strong antidepressant effect of imipramine  , while lithium produced only a weak to mild antidepressant effect . The authors discuss these findings in the light of other reports on the use of lithium in the treatment of acute endogenous depression 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 OBJECTIVES To compare the relapse rate of elderly depressed patients taking low dose lithium as an additional therapy with antidepressant medication  to those receiving antidepressant medication alone . METHODS Fifty elderly subjects recovering from a major depressive illness taking continuation antidepressants  were r and omised , in a double blind study , to receive additional lithium carbonate or placebo and followed up over a two year period for evidence of relapse . RESULTS Relapse rate was significantly greater in those subjects taking antidepressant medication alone compared to subjects taking additional lithium therapy . After six months four ( 17 % ) subjects taking antidepressant medication alone had relapsed , whereas none of the subjects taking additional lithium had relapsed . After two years eight ( 33 % ) subjects taking antidepressant medication alone had relapsed , whereas only one ( 4 % ) of the subjects taking additional lithium had relapsed . CONCLUSION This preliminary study suggests that long-term low dose lithium therapy is well tolerated and protects elderly patients from a relapse of depressive illness 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 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 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 A detailed analysis of the results of a multi-centre clinical trial shows that , while the relapse rate following recovery from an operationally defined depressive illness was smaller among patients subsequently treated with either amitryptiline or lithium  than with a placebo , there was no clinical ly significant difference between the prophylactic efficacy of the 2 antidepressants . An account is given of the relative adverse effects of the treatments , and the implication s of the findings are discussed 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 OBJECTIVE Compare the safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for preventing  depressive relapse in bipolar II disorder . METHODS Subjects ≥18 years old with bipolar II depression ( n=129 ) were r and omized to double-blind venlafaxine or lithium monotherapy for 12 weeks . Responders with a ≥50 % reduction in depression score were continued for an additional 6 months of relapse-prevention monotherapy . Primary outcome was depressive relapse during continuation monotherapy . Secondary outcomes included sustained response rate from initiation of treatment to study end-point , relapse hazard , time to relapse , change in mania ratings , and frequency of treatment-emergent sub-syndromal hypomania and /or depressive episodes . RESULTS Venlafaxine produced greater sustained response rate  versus lithium ( p<0.0001 ) ; however , there was no difference in relapse rate  for venlafaxine ( 7.5 % ) versus lithium ( 26.7 % ) ( p=0.079 ) ; relapse hazard ( p=0.073 ) , or time to relapse ( p=0.090 ) between treatment conditions during continuation monotherapy . There were no group differences in mania rating scores over time and no difference in frequency or duration of syndromal or sub-syndromal hypomanic episodes . There were more sub-syndromal depressive episodes  during lithium monotherapy ( p=0.03 ) . LIMITATIONS Sample size was limited by the lower sustained response rate  for lithium versus venlafaxine ; study was not specifically powered to detect differences in treatment-emergent hypomanic or depressive episodes between groups . CONCLUSION Results suggest that continuation venlafaxine monotherapy may provide similar prophylactic effectiveness relative to lithium , with no difference in treatment-emergent hypomanic episodes and without the need for frequent serum lithium level and metabolic monitoring . Larger , prospect i ve trials are needed to confirm these observations
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 .