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. 2001;2001(2):CD003013.
doi: 10.1002/14651858.CD003013.

Lithium for maintenance treatment of mood disorders

S Burgess  1 , J Geddes, K Hawton, E Townsend, K Jamison, G Goodwin
Affiliations

Lithium for maintenance treatment of mood disorders

S Burgess et al. Cochrane Database Syst Rev. 2001.

Update in

Abstract

Background: Mood disorders are common, disabling and tend to be recurrent. They carry a high risk of suicide. Maintenance treatment, aimed at the prevention of relapse, is therefore of vital importance. Lithium has been used for some years as the mainstay of maintenance treatment in bipolar affective disorder, and to a lesser extent in unipolar disorder. However, the efficacy and effectiveness of prophylactic lithium therapy has been disputed. Low suicide rates in lithium-treated patients have led to claims that lithium has a specific anti-suicidal effect. If so, this is of considerable importance as treatments for mental disorders in general have not been shown convincingly to be effective in suicide prevention.

Objectives: 1. To investigate the efficacy of lithium treatment in the prevention of relapse in recurrent mood disorders. 2. To examine the effect of lithium treatment on consumers' general health and social functioning, its acceptability to consumers, and the side-effects of treatment. 3. To investigate the hypothesis that lithium has a specific effect in reducing the incidence of suicide and deliberate self-harm in persons with mood disorders.

Search strategy: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) and The Cochrane Controlled Clinical Trials Register (CCTR) were searched. Reference lists of relevant papers and major text books of mood disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable trials, published or unpublished. Specialist journals concerning lithium were hand searched.

Selection criteria: Randomised controlled trials comparing lithium with placebo, where the stated intent of treatment was maintenance or prophylaxis. Participants were males and females of all ages with diagnoses of mood disorder. Discontinuation studies (in which all participants had been stable on lithium for some time before being randomised to either continued lithium treatment or placebo substitution) were excluded.

Data collection and analysis: Data were extracted from the original reports independently by two reviewers. The main outcomes studied were related to the objectives stated above. Data were analysed for all diagnoses of mood disorder and for bipolar and unipolar disorder separately. Data were analysed using Review Manager version 4.0.

Main results: Nine studies were included in the review, reporting on 825 participants randomly allocated to lithium or placebo. Lithium was found to be more effective than placebo in preventing relapse in mood disorder overall, and in bipolar disorder. The most consistent effect was found in bipolar disorder (random effects OR 0.29; 95% CI 0.09 to 0.93 ). In unipolar disorder, the direction of effect was in favour of lithium, but the result (when heterogeneity between studies was allowed for) did not reach statistical significance. Considerable heterogeneity was found between studies in all groups of patients. The direction of effect was the same in all studies; no study found a negative effect for lithium. Heterogeneity may have been due to differences in selection of participants, and to differing exposures to lithium in the pre-study phase resulting in variable influence of a discontinuation effect. There was little reported data on overall health and social functioning of participants under the different treatment conditions, or on the participants' own views of their treatment. Descriptive analysis showed that assessments of general health and social functioning generally favoured lithium. Small absolute numbers of deaths and suicides, and the absence of data on non-fatal suicidal behaviours, made it impossible to draw meaningful conclusions about the place of lithium therapy in suicide prevention.

Reviewer's conclusions: This systematic review indicates that lithium is an efficacious maintenance treatment for bipolar disorder. In unipolar disorder the evidence of efficacy is less robust. This review does not cover the relative efficacy of lithium compared with other maintenance treatments, which is at present unclear. There is no definitive evidence from this review as to whether or not lithium has an anti-suicidal effect. Systematic reviews and large scale randomised studies comparing lithium with other maintenance treatments (e.g. anti-convulsants, antidepressants) are necessary. Outcomes relating to death and suicidal behaviour should be included in all future maintenance studies of mood disorder.

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Conflict of interest statement

Kay Jamison has given lectures sponsored by Solvay Pharmaceuticals, a manufacturer of lithium. Guy Goodwin has on two occasions acted as an advisor to Solvay Pharmaceuticals. JG has received research funding and support from Sanofi‐Aventis and GlaxoSmithKline and is currently in discussion with several other companies that manufacture SSRIs about collaboration on planned independent trials and systematic reviews.

Figures

1.1
1.1. Analysis
Comparison 1 Lithium v. placebo all mood disorders, Outcome 1 All relapses.
1.2
1.2. Analysis
Comparison 1 Lithium v. placebo all mood disorders, Outcome 2 Manic relapse.
1.3
1.3. Analysis
Comparison 1 Lithium v. placebo all mood disorders, Outcome 3 Depressive relapse.
1.6
1.6. Analysis
Comparison 1 Lithium v. placebo all mood disorders, Outcome 6 Suicide.
1.8
1.8. Analysis
Comparison 1 Lithium v. placebo all mood disorders, Outcome 8 Mortality.
1.9
1.9. Analysis
Comparison 1 Lithium v. placebo all mood disorders, Outcome 9 Drop‐out.
1.10
1.10. Analysis
Comparison 1 Lithium v. placebo all mood disorders, Outcome 10 Drop‐out due to treatment failure.
1.11
1.11. Analysis
Comparison 1 Lithium v. placebo all mood disorders, Outcome 11 Drop out due to side‐effects.
1.12
1.12. Analysis
Comparison 1 Lithium v. placebo all mood disorders, Outcome 12 Side‐effects.
2.1
2.1. Analysis
Comparison 2 Lithium v. placebo ‐ bipolar disorder, Outcome 1 All relapses.
2.2
2.2. Analysis
Comparison 2 Lithium v. placebo ‐ bipolar disorder, Outcome 2 Manic relapse.
2.3
2.3. Analysis
Comparison 2 Lithium v. placebo ‐ bipolar disorder, Outcome 3 Depressive relapse.
3.1
3.1. Analysis
Comparison 3 Lithium v. placebo ‐ unipolar disorder, Outcome 1 All relapses.
3.2
3.2. Analysis
Comparison 3 Lithium v. placebo ‐ unipolar disorder, Outcome 2 Manic relapse.
3.3
3.3. Analysis
Comparison 3 Lithium v. placebo ‐ unipolar disorder, Outcome 3 Depressive relapse.
3.4
3.4. Analysis
Comparison 3 Lithium v. placebo ‐ unipolar disorder, Outcome 4 relapse excluding imipramine.
4.1
4.1. Analysis
Comparison 4 Lithium v. placebo studies including bipolar patients, Outcome 1 All relapses.
5.2
5.2. Analysis
Comparison 5 Lithium v. placebo studies including unipolars, Outcome 2 All relapses.
6.1
6.1. Analysis
Comparison 6 Discontinuation studies, Outcome 1 Lithium vs placebo‐relapse stated.
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References

References to studies included in this review

Baastrup 1970 a {published data only}
    1. Baastrup PC, Poulsen JC, Schou M, Thomsen K, Amdisen A. Prophylactic lithium: double blind discontinuation in manic‐depressive and recurrent‐depressive disorders. Lancet 1970;2(668):326‐30. - PubMed
    1. Schou M, Baastrup PC. Lithium prophylaxis in recurrent affective disorders. British Journal of Psychiatry 1971;118(542):133‐4. - PubMed
Bowden 1995 {published and unpublished data}
    1. Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, et al. A randomized, placebo‐controlled 12‐month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Archives of General Psychiatry 2000;57(5):481‐9. - PubMed
    1. Bowden CL, Swann AC, Calabrese JR, McElroy SL, Morris D, Petty F, et al. Maintenance clinical trials in bipolar disorder: Design implications of the divalproex‐lithium‐placebo study. Psychopharmacology Bulletin 1997;33(4):693‐9. - PubMed
Coppen 1971 {published data only}
    1. Coppen A, Noguera R, Bailey J, et al. Controlled Trial. The Lancet 1971;2(719):275‐279. - PubMed
Cundall 1972 {published data only}
    1. Cundall RL, Brooks PW, Murray LG. A controlled evaluation of lithium prophylaxis in affective disorders. Psychological Medicine 1972;2:308‐11. - PubMed
Glen 1984 {published data only}
    1. Glen A, Johnson A, Shepherd M. Continuation therapy with lithium and amitriptyline in unipolar depressive illness: a randomized, double‐blind controlled trial. Psychological Medicine 1984;14(1):37‐50. - PubMed
    1. Medical Research Council Drug Trials Subcommittee. Preliminary report. Continuation therapy with lithium and amitriptyline in unipolar depressive illness: a controlled clinical trial. Psychological Medicine 1981;11(2):409‐16. - PubMed
Hardy 1997 {published data only}
    1. Hardy BG, Shulman KI, Zucchero C. Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression. Journal of Clinical Psychopharmacology 1997;17(1):22‐6. - PubMed
Hullin 1972 {published data only}
    1. Hullin RP, McDonald R, Allsopp MN. Prophylactic lithium in recurrent affective disorders. Lancet 1972;1(7759):1044‐6. - PubMed
Laurell 1968 {published data only}
    1. Laurell B, Ottosson J. Prophylactic lithium?. Lancet 1968;2(7580):1245‐6. - PubMed
Melia 1970 {published data only}
    1. Melia P, O'Sullivan D, Barry D. Lithium and rapid‐cycling affective disorder: A report on six cases. Irish Journal of Psychological Medicine 1988;5(2):79‐83.
    1. Melia PI. Prophylactic lithium: A double‐blind trial in recurrent affective disorders. British Journal of Psychiatry 1970;116(535):621‐4. - PubMed
Mendlewicz 1972 {published data only}
    1. Dunner DL, Stallone F, Fieve RR. Lithium carbonate and affective disorders V. A double blind study of lithium prophylaxis of depression in bipolar illness. Archives of General Psychiatry 1976;33(1):117‐20. - PubMed
    1. Dunner DL, Stallone F, Fieve RR. Prophylaxis with lithium carbonate‐an update. Archives of General Psychiatry 1982;39(11):1344‐5. - PubMed
    1. Fieve RR, Dunner DL, Kumbaraci T, Stallone F. Lithium carbonate in affective disorders IV. A double‐blind study of prophylaxis in unipolar recurrent depression. Archives of General Psychiatry 1975;32(12):1541‐5. - PubMed
    1. Fieve RR, Dunner DL, Kumbaraci T, Stallone F. Lithium carbonate prophylaxis of depression in three subtypes of primary affective disorder.. Pharmakopsychiatrie Neuropsychopharmakologie 1976;9(3):100‐7. - PubMed
    1. Fieve RR, Kumbaraci T, Dunner DL. Lithium prophylaxis of depression in bipolar I, bipolar II and unipolar patients. American Journal of Psychiatry 1976;133(8):925‐9. - PubMed
Prien 1973a {published data only}
    1. Caffey E, Prien R. The VA‐NIMH study of lithium in affective disorders. Psychosomatics, 1970;11(5):409‐412. - PubMed
    1. Pokorny A, Prien R. Lithium in the treatment and prevention of affective disorder. Diseases of the Nervous System, 1974;35:327‐333. - PubMed
    1. Prien R, Caffey E, Klett J. Factors associated with treatment success in lithium carbonate prophylaxis. Archives of General Psychiatry, 1974;31:189‐192. - PubMed
    1. Prien R, Caffey E, Klett J. Prophylactic efficacy of lithium carbonate in manic‐depressive illness. Archives of General Psychiatry 1973;28:337341. - PubMed
    1. Prien R, Klett J, Caffey E. Lithium prophylaxis in recurrent affective illness. American Journal of Psychiatry 1974;131:198‐202. - PubMed
Prien 1973b {published data only}
    1. Caffey E, Prien R. The VA‐NIMH study of lithium in affective disorders. Psychosomatics, 1970;11(5):409‐412. - PubMed
    1. Pokorny A, Prien R. Lithium in the treatment and prevention of affective disorder. Diseases of the Nervous System, 1974;35:327‐333. - PubMed
    1. Prien R, Klett J, Caffey E. Lithium carbonate and imipramine in prevention of affective episodes. Archives of General Psychiatry, 1973;29:420‐425. - PubMed
    1. Prien R, Klett J, Caffey E. Lithium prophylaxis in recurrent affective illness. American Journal of Psychiatry 1974;131:198‐202. - PubMed
Prien 1984 {published and unpublished data}
    1. Frank E, Prien R, Kupfer D, Alberts L. Implications of non‐compliance on research in affective disorders. Psychopharmacology Bulletin 1985;21(1):37‐42. - PubMed
    1. Greenhouse J, Stangl D, Kupfer D, Prien R. Methodologic issues in maintenance therapy clinical trials. Archives of General Psychiatry 1991;48(4):313‐8. - PubMed
    1. Prien RF, Kupfer DJ, Mansky PA, Small JG, Tuason VB, Voss CB, et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Archives of General Psychiatry, 1984;41(11):1096‐104. - PubMed
Quitkin 1978 {published data only}
    1. Kane JM, Quitkin FM, Rifkin A, Ramos‐Lorenzi JR, Nayak DD, Howard A. Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: A prospective, placebo‐controlled comparison. Archives of General Psychiatry, 1982;39(9):1065‐9. - PubMed
    1. Quitkin FM, Kane JM, Rifkin A, Ramos‐Lorenzi JR, Saraf K, Howard A, et al. Lithium and imipramine in the prophylaxis of unipolar and bipolar II depression: A prospective, placebo‐controlled comparison. Psychopharmacology Bulletin 1981;17(1):142‐4. - PubMed

References to studies excluded from this review

Naylor 1974 {published data only}
    1. Naylor G, Mcdonald J, Poidevin D, Reid A. A double‐blind trial of long‐term lithium therapy in mental defectives. British Journal of Psychiatry 1974;124(578):52‐7. - PubMed

References to studies awaiting assessment

Coppen 1981 {published data only}
    1. Coppen A, Abou‐Saleh MT, Milln P, Bailey J, Metcalfe M, Burns BH, et al. Lithium continuation therapy following electroconvulsive therapy. British Journal of Psychiatry 1981;139:284‐7. - PubMed
Dorus 1989 {published data only}
    1. Dorus W, Ostrow DG, Anton R, Cushman P, Collins JF, Schaefer M, et al. Lithium treatment of depressed and non‐depressed alchoholics. JAMA 1989;262(15):1646‐52. - PubMed
Wilson 1995 b {published data only}
    1. Wilson KC, Scott M, Abou‐Saleh MT, Burns R, Copeland JR. Long‐term effects of cognitive‐behavioural therapy and lithium therapy on depression in the elderly. British Journal of Psychiatry 1995;167:653‐8. - PubMed

Additional references

Abou‐Saleh 1982
    1. Abou‐Saleh M. Lithium. In: Paykel E editor(s). Handbook of Affective Disorders. Edinburgh: Churchill Livingstone, 1982:369.
Abou‐Saleh 1992
    1. Abou‐Saleh M.T. Lithium. Handbook of Affective Disorders. 2nd Edition. Edinburgh: Churchill Livingstone, 1992.
APA 1994
    1. American Psychiatric Association. Diagnostic and Statistical Manual of mental disorders DSM‐IV. 4th Edition. Washington DC: American Psychiatric Association, 1994.
Barraclough 1974
    1. Barraclough B, Bunch J, Nelson B, Sainsbury P. A hundred cases of suicide: Clinical aspects. British Journal of Psychiatry 1974;125:355‐73. - PubMed
Blackwell 1968
    1. Blackwell B, Shepherd M. Prophylactic lithium: Another therapeutic myth?. Lancet 1968;1(7549):968‐71. - PubMed
Causemann 1988
    1. Causemann B, Muller‐Oerlinghausen B. Does lithium prevent suicides and suicide attempts?. In: Birch NJ editor(s). Lithium: Inorganic pharmacology and psychiatric use. Oxford: IRL Press, 1988:23‐4.
Clarke 1999
    1. Clarke M, Oxman AD. Cochrane Reviewers' Handbook 4.0. Oxford: Cochrane Collaboration, 1999.
Cochran 1988
    1. Cochran S, Gitlin M. Attitudinal correlates of lithium compliance in bipolar affective disorders. Journal of Nervous and Mental Disorders 1988;176(8):457‐64. - PubMed
Coppen 1991
    1. Coppen A, Standish‐Barry H, Bailey J, Houston G, Silcocks P, Hermon C. Does lithium reduce the mortality of recurrent mood disorders?. Journal of Affective Disorders 1991;23(1):1‐7. - PubMed
Crundwell 1994
    1. Crundwell J. Lithium and its potential benefit in reducing increased mortality due to suicide. Lithium 1994;5(4):193‐204.
DerSimonian 1986
    1. DerSimonian R, Laird N. Meta‐analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177‐88. - PubMed
DOH 1992
    1. Department of Health. The health of the nation: a strategy for health in England. London: HMSO, 1992.
Fieve 1983
    1. Fieve R, Peselow E. Lithium: clinical applications. In: Burrows GD, Norman TR, Davies B editor(s). Antidepressants. Drugs in Psychiatry 1. Amsterdam: Elsevier, 1983:277‐321.
Gelder 1989
    1. Gelder M, Gath D, Mayou R. Oxford Textbook of Psychiatry. 2nd Edition. Oxford: Oxford University Press, 1989:666‐7.
Goodwin 1990
    1. Goodwin F, Jamison K. Manic depressive illness. New York: Oxford University Press, 1990.
Goodwin 1994
    1. Goodwin G. Recurrence of mania after lithium withdrawal. British Journal of Psychiatry 1994;164:149‐52. - PubMed
Gunnell 1994
    1. Gunnell D, Frankel S. Prevention of suicide: aspirations and evidence. BMJ 1994;308(6938):1227‐33. - PMC - PubMed
Guscott 1994
    1. Guscott R, Taylor L. Lithium prophylaxis in recurrent affective illness: efficacy, effectiveness and efficiency. British Journal of Psychiatry 1994;164:741‐6. - PubMed
Guze 1970
    1. Guze S, Robins E. Suicide and primary affective disorders. British Journal of Psychiatry 1970;117:437‐8. - PubMed
Harris 1997
    1. Harris E, Barraclough B. Suicide as an outcome for mental disorders. British Journal of Psychiatry 1997;170:205‐28. - PubMed
Jadad 1996
    1. Jadad A, Moore A, Carroll D, Jenkinson C, Reynolds D, Gavaghan D, et al. Assessing the quality of reports of randomised clinical trials: Is blinding necessary?. Controlled Clinical Trials 1996;17(1):1‐12. - PubMed
Juni 1999
    1. Juni P, Witschi A, Bloch R, Egger M. The hazards of scoring the quality of clinical trials for meta‐analysis. JAMA 1999;282(11):1054‐60. [MEDLINE: ] - PubMed
Katona 1995
    1. Katona C. Refractory depression: a review with particular reference to the use of lithium augmentation. European Neuropsychopharmacology 1995;5(Suppl):109‐13. - PubMed
Kay 1977
    1. Kay D, Petterson U. VI. Mortality in: U Petterson: Manic‐depressive illness: A clinical social and genetic study. Acta Psychiatrica Scandanavica 1977;Supplementum 269:55‐60. - PubMed
Klein 1980
    1. Klein D, Gittelman R, Quitkin F, Rifkin A. Diagnosis and drug treatment of psychiatric disorders: adults and children. Baltimore: Williams and Wilkins, 1980.
Lonnqvist 1995
    1. Lonnqvist J, Henriksson M, Isometsa E, Marttunen M, Heikkinen M, Aro H, et al. Mental disorders and suicide prevention. Psychiatry and Clinical Neurosciences 1995;49(Suppl 1):111‐6. - PubMed
Markar 1989
    1. Markar H, Mander A. Efficacy of lithium prophylaxis in clinical practice. British Journal of Psychiatry 1989;155:496‐500. - PubMed
Moncrieff 1997
    1. Moncrieff J. Lithium: evidence reconsidered. British Journal of Psychiatry 1997;171:113‐9. - PubMed
Newson‐Smith 1979
    1. Newson‐Smith J, Hirsch S. Psychiatric symptoms in self‐poisoning patients. Psychological Medicine 1979;9(3):493‐500. - PubMed
NIMH‐NIH 1985
    1. NIMH‐NIH Consensus Development Conference Statement. Mood disorders: Pharmacologic prevention of recurrences. American Journal of Psychiatry 1985;142(4):469‐72. - PubMed
Prien 1979
    1. Prien R. Lithium in the prophylactic treatment of affective disorders. Archives of General Psychiatry 1979;36(8 Spec No):847‐8. - PubMed
Stokes 1971
    1. Stokes P, Shamoian C, Stoll P, Patton MJ. Efficacy of lithium as an acute treatment of manic‐depressive illness. Lancet 1971;1(7713):1319‐25. - PubMed
Suppes 1991
    1. Suppes T, Ross J, Baldessarini R, Faedda G, Tohen M. Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Archives of General Psychiatry 1991;48(12):1082‐8. - PubMed
Thies‐Flechtner 1996
    1. Thies‐Flechtner K, Muller‐Oerlinghausen B, Seibert W, Walther A, Greil W. Effect of prophylactic treatment on suicide risk in patients with major affective disorders. Pharmacopsychiatry 1996;29(3):103‐7. - PubMed
Tondo 1997
    1. Tondo L, Jamison K, Ross J, Baldessarini R. Effect of lithium maintenance on suicidal behaviour in major mood disorders. Annals of the New York Academy of Sciences 1997;836:339‐51. - PubMed
WHO 1992
    1. World Health Organisation. The ICD‐10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Geneva: WHO, 1992.
Yusuf 1985
    1. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta‐blockade during and after myocardial infarction: an overview of the randomised trials. Progress in Cardiovascular Diseases 1985;27(335):371. - PubMed

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