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Tuesday, 25.01.2022

Martin M. Katz’s comment on Lithium Controversy

I am not an expert on the literature relevant to the discovery and establishment of lithium as a specific treatment for manic-depressive psychosis. I have been asked to comment on the distinct complications that this treatment has posed methodologically for investigators in the field. If one goes no further than the dialogue between experienced clinicians like the late Mogens Schou and JF Cade and clinical scientists, like Barry Blackwell and Sam Gershon, you are easily made aware of the complicated issues they confronted in determining the validity or non-validity of lithium as a prophylactic treatment for any of the affective disorders.

It reminds us that there has been no single way in clinical science to achieve discovery of a new or novel treatment or specifically, a drug. The newly found drugs in the 1950’s that revolutionized psychiatry were uncovered by working clinicians in non-controlled clinical settings. These clinicians were, in treating their patients, having little success and very open to testing new agents. The clinicians were, based on their extensive experience with intractable disorders and the response to inadequate treatments, alert to detecting positive effects of a new drug, not immediately visible to less trained eyes.  Certain astute clinicians because of this experience were prepared and able to identify promising new treatments when they appeared, for disorders as varied as schizophrenia, depression and anxiety disorders, and also strong enough to then overcome the barriers imposed by establishment psychiatry.

One of those treatments was lithium and its apparent specificity for M-D states.  Although no one formula for discovering new drugs exists, we fortunately, have a model for validating in a scientifically controlled short term study or trial, the changes induced by a novel treatment in an acutely, disturbed mental disorder. Although we also have a model for evaluating a longterm treatment, the complications of the longterm course of the illness itself and the lengthy treatment period, in contrast, creates difficult to solve problems for a controlled treatment evaluation.

More concretely, on the critical issue for a controlled evaluation treatment trial of how seriously ill patients in a placebo control group are maintained over an extended clinical trial period, there is as yet no satisfying solution.

These methodological problems have been analyzed in the chapter on Maintenance treatment trials for bipolar disorders” in the volume: Prien & Robinson (eds) “Clinical Evaluation of Psychotropic Drugs” (Raven Press: NY, 1994, pgs. 331-336). The articles in Prien et al. “Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders” (Arch gen Psychiatry 1984, 41:1096-1011), Burgess et al. “Lithium for maintenance treatment of mood disorders”, based on the Cochrane Database System Review [(3):CD003013, 2001], and Berghofer et al “Stability of lithium treatment in bipolar disorder long term follow up of 346 patients” (Int J Bipolar Dis, 2013, 1:11),summarize the results of controlled studies up to that time, establishing lithium and the combination with imipramine as efficacious and stable for preventing recurrences of manic episodes and equal to imipramine alone in preventing depressive episodes. And from the Cochrane data analysis, based on 9 studies, as efficacious as a maintenance treatment for bipolar disorder, if not for the unipolar form.

These studies follow earlier confirmation that although not universally effective (some 30% of patients do not respond), lithium is efficacious in resolving acute manic episodes.

More recent studies compare newer therapies, such as valproate, which although effective are not found to be superior to lithium and may involve a wider range of side effects.

These studies are by definition difficult to carry off, in view of the time demands and patient selection issues that see too many placebo-treated patients drop out early in the treatment trial. Nevertheless, the findings reassure experts like Fawcett and Goodwin that lithium is probably the most effective treatment maintenance treatment for manic-depressive patients. I see the wide range of studies now available in this area, as providing a network of results and research strategies that can serve as guide and foundation for evaluating new treatments for this chronic disorder.

It appears that the clinicians who uncovered the role of lithium and the clinical investigators who were successful in developing controlled trials for its assessment, should now be more in accord about the strengths and weaknesses of this treatment going into the future.


Martin M. Katz
March 5, 2015