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Lithium -
- D B Double (3 May 1998)
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Lithium
- Mogens Schou (6 May 1998)
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Discontinuation does contribute to relapse
- D B Double (12 May 1998)
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Antisuicidal effects of lithium
- B Mueller-Oerlinghausen (22 June 1998)
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Re: Antisuicidal effects of lithium - bias in interpreting the effectiveness of lithium
- D B Double (6 July 1998)
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D B Double, Consultant Psychiatrist, Norfolk mental Health Care NHS Trust Hellesdon Hospital, Norwich NR6 5BE
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EDITOR-Jefferson's justification of lithium as a "tried remedy" requires scrutiny.1 Impeaching clinical trials because of methodological problems is easy game, but Moncrieff's determined scepticism is refreshing,2 and a counterbalance to the bias of proving that psychotropic medication is effective. Jefferson does not mention that doubts have also been raised about the value of lithium from evidence in routine clinical practice.3 A meta-analysis of more recent placebo controlled lithium discontinuation studies did not find as great a difference between relapse rates on lithium and placebo (37.5%-53.5%) as previous reviews.4 Rapid withdrawal is associated with higher relapse than gradual withdrawal (62%-29%).4 The finding of such a difference suggests that nonspecific factors are important. Unblinding can occur in clinical trials of lithium, compromising their results.5 Despite Jefferson, the issue of the effectiveness of lithium prophylaxis has not been foreclosed. No withdrawal study has included a no drug control group as an addition to the standard double-blind placebo design, so that withdrawal to placebo and no drug can be compared, giving an estimation of the placebo effect of withdrawal of medication when the primary treatment is merely tablet taking. Nor has any study of the discontinuation of lithium attempted to measure whether the blind has been broken. Correlation can be made with relapse and symptom ratings to determine whether degree of unblinding is associated with measured efficacy. This improved design should provide more data to evaluate the evidence for the effectiveness of lithium, even if it does not give the certainty that Jefferson would like. Denial of the extent to which lithium is a placebo effect in clinical practice does not serve the interests of the many patients who are reliant on this medication. Jefferson quotes Ambroise Paré who readily discarded ineffective remedies and was also critical of remedies that were highly esteemed by others. D B Double, Consultant Psychiatrist, Norfolk Mental Health Care, Hellesdon Hospital, Drayton High Road, Norwich NR2 2AE. (Duncan_Double@bigfoot.com) 1. Jefferson JW. Lithium. Still effective despite its detractors. BMJ 1998;316:1330-1 2. Moncrieff J. Lithium: evidence reconsidered. Br J Psychiatry 1997;171:113-9 3. Greenberg RP, Fisher S. Mood-mending medicines: Probing drug, psychotherapy, and placebo solutions. In: Fisher S, Greenberg RP, ed. From placebo to panacea - Putting psychiatric drugs to the test. New York: Wiley, 1997:115-172 4. Baker JP. Outcomes of lithium discontinuation: a meta-analysis. Lithium 1994;5:187-192 5. Double DB. Lithium revisited. [letter] Br J Psychiatry 1996; 168: 381-2 |
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Mogens Schou, Emeritus professor Psychiatric Hospital, Skocagervej 2, 8240 Risskov, Denmark
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EDITOR - Jefferson's editorial of 2 May should be supplemented with the following considerations. Moncrieff(1) saw the increased frequency of recurrences after discontinution of lithium exclusively as a withdrawal phenomenon. This was faulty logic; the increased frequency could have been caused by a combination of a withdrawal effect and the removal of a prophylactic effect. It has been shown that when lithium is discontinued abruptly in patients who responded to it, some of them may develop recurrences at a rate greater than they had before lithium treatment (2). It should be noted, however, that the patients involved in this and similar studies were diagnosed according to DSM criteria with their broad boundaries for bipolar illness. The boundaries are considerably narrower in the ICD (Krapelinean) diagnostic system, and the patients in whom lithium has been shown prophylactically efficacious were diagnosed according to the latter criteria. Studies carried out in Czechoslovakia (3), Denmark (4), Sweden, England, Belgium, and Germany (5) have shown that discontinuation of lithium, also abrupt discontinuation, in such patients leads to re-emergence of recurrences at a rate which does not exceed that experienced by the patients before they started on lithium. The two sets of observations concerning withdrawal-induced recurrences are probably both correct, but they were made on differently diagnosed groups of patients. Moncrieff extrapolated without any reservations findings from one group to the other group, and her rejection of the discontinuation trials with lithium was unfounded. The principal argument in Moncrieff's 'case' against prophylactic lithium treatment has fallen through. Paul Grof Professor of Psychiatry University of Ottawa, Royal Ottawa Hospital, 1145 Carling Ave, Ottawa, Ont., Canada K1Z 7E4 (pgrof@rohcg.on.ca) Mogens Schou Emeritus professor The Psychiatric Hospital, Skovagervej 2, DK.8240 Risskov, Denmark (sch@post9.tele.dk) 1 Moncrieff J. Lithium revisited: A re-examination of the placebo-controlled trials of lithium prophylaxis in manic-depressive disorder. Brit J Psychiatry 1995;167:569-574. 2 Suppes T, Baldessarini RJ, Faedda GI, Tondo L, Tohen M. Discontinuation of maintenance treatmet in bipolar disorder: Risks and implications. Harvard Res Psychiatry 1993;1:131-144.. 3 Grof P, Cakuls P, Dostal T. Lithium drop-outs: A follow-up study of patients who discontinued prophylactic treatment. Int Pharmacopsychiatr 1970;5:162-169. 4 Schou M, Thomsen K, Baastrup PC. Studies on the course of recurrent endogenous affective disorders. Int Pharmacother 1970;5:100-106. 5 Berghöfer A, Kossman B, Müller-Oerlinghausen B. Course of illness and pattern of recurrences in patients with affective disorders during long-term lithium prophylaxis: A retrospective analysis over 15 years. Acta Psychiatr Scand 1995;93:349-354. |
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D B Double, Consultant Psychiatrist Norfolk Mental Health Care NHS Trust
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EDITOR-Grof and Schou attempt to explain the discepancies in the evidence about lithium by suggesting that the withdrawal syndrome only occurs in those with more broadly defined bipolar disorder.1 Schou has been an enthusiast for lithium and was involved in an influential double-blind lithium discontinuation study, which had remarkably favourable results for lithium (21 placebo patients relapsed and none on lithium).2 In that study patients were not informed they were in a clinical trial and were deceived into believing they had received tablets from an unreliable batch so that concealed trial medication could be reissued. Although this procedure would now be regarded as unethical because of lack of consent, it does have the advantage that patient expectancies are not created if they remain unaware of the trial. Four placebo patients were excluded from the analysis because for some reason they used some of their old tablets or supplementary lithium from outside sources. Particular detail was paid to methodological issues because of criticism of the inferences made from previous non-blind trials.3 Patients were matched on total number of previous episodes, and assigned randomly to lithium or placebo, although no details were given of the randomisation procedure. Although it was anticipated that side-effects might compromise the blindness of the trial, and the protocol required that patients with side-effects must be excluded, none were eliminated. Lithium blood results were reported to assessors, but care was reported to have been taken to ensure that fictitious values for the placebo patients approximated to those recorded before the trial and showed variations similar to those found in the patients receiving lithium. No attempt was made to measure the degree of unblinding. Despite the lack of evidence for unblinding or incomplete randomisation it is difficult to believe that bias did not in some way affect the results as they are so strikingly favourable to lithium, particularly in the context of the need to counter criticism at the time and produce an unequivocal answer. One of the reasons proposed for the striking difference is that all patients had well-diagnosed affective disorders of the endogenous type, the same point about effectiveness as Grof and Schou make about the presence of the withdrawal syndrome. The assumption seems to be that lithium is a specific prophylactic treatment for the biological diseases of manic-depressive and recurrent-depressive disorders. Evidence for lithium withdrawal has not always been found and heightened anxiety, sleep disturbances and irritability have been associated.4 The presence of withdrawal symptoms seems to also be influenced by clinicians and experimenters and not just patients alone. It seems appropriate and timely to propose further research of the implications that drug discontinuation itself contributes to relapse, including the study of nonspecific effects. This is the same conclusion reached by the group, quoted by Grof and Schou, who found that recurrences are greater than before lithium treatment in patients abruptly discontinuing lithium.5 DB Double, Consultant Psychiatrist, Norfolk Mental Health Care NHS Trust, Hellesdon Hospital, Drayton High Road, Norwich NR6 5BE (Duncan_Double@bigfoot.com) 1. Grof P, Schou M. Re: Lithium. http://www.bmj.com/cgi/eletters/316/7141/1330#EL1. 2. Baastrup PC, Poulsen JC, Schou M, Thomsen K, Amdisen A. Prophylactic lithium: Double blind discontinuation in manic-depressive and recurrent-depressive disorders. Lancet 1970;ii:326-330 3. Blackwell B, Shepherd M. Prophylactic lithium: another therapeutic myth? Lancet 1968;i:968-971 4. Balon R, Yeragani VK, Pohl RB, Gershon S. Lithium discontinuation: Withdrawal or relapse? Comp Psychiatry 1988;29:330-334 5. Baldessarini RJ, Tondo L, Viguera AC. Forty years of lithium treatment. Arch Gen Psychiatry 1998;55:93 |
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B Mueller-Oerlinghausen, Professor of Clinical Psychopharmacology Freie Universitaet Berlin
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ref.: Editorial "Lithium", BMJ, 1998; 316:1330 After so much confusion and misunderstandings induced by articles published in BMJ, particularly by J. Montcrieff regarding the position of lithium therapy was overdue. One can only hope that harm possibly done to patients who did not receive an adequate treatment because of this hostile attitude expressed in the BMJ can be compensated and repaired in the future. An important aspect of lithium prophylaxis should be added to the editorial of Dr. Jefferson, namely the antiaggressive and suicide preventive effects of lithium long-term medication. During the last 10 years it has been clearly demonstrated by various independent authors and also an international lithium research group (IGSLi) that adequate lithium prophylaxis administered and controlled according to the state of the art can reduce or even completely suppress suicidality and reduce or even normalize the high excess mortality observed in untreated or off-lithium patients with affective disorders. Most of these data were reviewed recently by Tondo et al., Annals of the New York Academy of Science, 836; 1997:339-351, and by M. Schou, Journal of Affective Disorders, in press. Bruno Mueller-Oerlinghausen, MD Professor of Clinical Psychopharmacology Head, Lithium Clinic Berlin, Department of Psychiatry, Freie Universitaet Berlin |
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D B Double, Consultant Psychiatrist Norfolk Mental Health Care NHS Trust
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EDITOR-Mueller-Oerlinghausen makes a causal statement about the link between lithium prophylaxis and suicide prevention (1), whereas the evidence is only correlational. The strength of Joanna Moncrieff’s critique of lithium is the scepticism she has for the literature and her recognition of the bias, such as that displayed by Mueller-Oerlinghausen, for favourable interpretation of the effectiveness of lithium. The evidence about suicide prevention to which Mueller-Oerlinghausen refers includes the finding that patients prescribed long-term lithium do not have increased mortality, particularly due to suicide, generally found in patients with manic-depressive disorder (2,3). Such results, of course, should be understood with caution, not least because patients in these studies might be unusual in some way. Compliant, consistent attenders at dedicated lithium clinics are not necessarily typical of all patients on lithium. In an unselected sample of patients treated with lithium for more than 2 months, excess mortality was found to be similar to that noted in earlier studies of manic-depressive patients before lithium was widely introduced (4). Similarly, there should be reservations about the finding that the mortality of patients who discontinue lithium treatment is significantly higher than those in the general population (5). Patients who drop out of treatment may be more at risk of suicide because of factors unrelated to lithium treatment. Propagating spurious conclusions about the effectiveness of lithium encourages dependence on this medication. Further randomised controlled trials measuring degree of unblinding are required to help clarify the extent to which lithium is placebo treatment. D B Double, Consultant Psychiatrist, Norfolk Mental Health Care, Hellesdon Hospital, Drayton High Road, Norwich NR6 5BE. (Duncan_Double@bigfoot.com) 1. Mueller-Oerlinghausen B. Re: Antisuicidal effects of lithium. http://www.bmj.com/cgi/eletters/316/7141/1330#EL6 2. Coppen A, Standish-Barry H, Bailey J, Houston G, Silcocks P, Hermon C. Does lithium reduce the mortality of recurrent mood disorders? J Affect Dis 1991;23:1-7. 3. Mueller-Oerlinghausen B, Ahrens B, Grof E, Grof P, Lenz G, Schou M, Simhandl C, Thau K, Volk J, Wolf R, Wolf T. The effect of long-term lithium treatment on the mortality of patients with manic-depressive and schizoaffective illness. Acta Psychiatr Scand 1992;86:218-222. 4. Norton B, Whalley LJ. Mortality of a lithium-treated population. Br J Psychiatr 1984;145:277-282. 5. Mueller-Oerlinghausen B, Wolf T, Ahrens B, Glaenz T, Schou M, Grof E, Grof P, Lenz G, Simhandl C, Thau K, Vestergaard P, Wolf R. Mortality of patients who dropped out from regular lithium prophylaxis: a collaborative study of the International Group for the Study of Lithium_Treated Patients (IGSLI). Acta Psychiatr Scand 1996; 94:344-347 |
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