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Saturday, 06.03.2021

Mogens Schou: My journey with lithium
Written on the invitation of Johan Schioldann

Barry Blackwell’s comment

 

       Professor Johan Schioldann is generous to share his treasure trove of information about the history of lithium, on this occasion with a priceless brief autobiography written by Mogens Schou before his death in 2005.

       Much of the controversies concerning lithium have been aired on the INHN website over the last few years with contributions from many members (Blackwell 2017).

       In addressing Schou’s intimate autobiography I shall keep reference to the collated material to a minimum to avoid repetition, although a brief synopsis will help understand both our roles.

       Much of Mogen’s commentary hinges on the prelude and outcome of a critical analysis (Blackwell and Shepherd 1968) of the original study (Baastrup and Schou 1967) that launched the concept of lithium prophylaxis in recurrent depression and bipolar disorder, one of the most important original contributions in the modern field of psychopharmacology.  

       Our Lancet article was unkindly and incorrectly titled “Prophylactic Lithium: Another therapeutic myth,” in which we catalogued our concerns about trial design and analysis.

       More than 40 years later I offered a partial apology: “We had been wrong but for the right reasons.” This acknowledged that anyone prescribing lithium to prevent recurrence would be so quickly convinced of its efficacy that a controlled double-blind study was unnecessary.

       Interestingly, this is a truism applicable to almost all the original discoveries by pioneers in the field of psychopharmacology – both chlorpromazine and imipramine were in worldwide use before their benefits were confirmed by a double-blind placebo-controlled studies: chlorpromazine by Joel Elkes and his wife (Elkes and Elkes 1954) and imipramine by Heinz Lehmann and colleagues in Canada (Lehman, Cahn and DeVerteuil 1958).

       But we were right because the history of our field also teaches us that the only way to distinguish panaceas, snake oil, placebos and toxic compounds from safe and effective drugs is to eliminate bias, false optimism and unfounded enthusiasm with placebo-controlled double-blind studies.

       The toxic effects of lithium confirm this caution – fortunately they were well-recognized by Schou from his very first acquaintance with lithium shortly after John Cade’s original discovery of lithium’s efficacy in manic psychosis (Schou, Juel-Nielson, Stromgren and Voldby 1954). But elsewhere and more recently, despite this knowledge, serious toxicity and occasional fatalities have been reported in Britain (Kores and Lader 1997) and America (Hampton, Daubresse, Chang et al. 2014), probably attributable  to the fact a simple metallic ion could not be patented, no pharmaceutical company is responsible for promulgating safety measures and perhaps academic training programs fall short. In America the journal JAMA also failed to recommend appropriate measures based on its own publication (Blackwell 2017).

       Mogens’ autobiography suggests that his career choice was determined by childhood experiences as the son of a distinguished psychiatrist and medical director of a hospital for psychotic patients in the days before effective treatment: “I have vivid memories of depressed patients wandering the hospital park with bent heads and anguished faces, waiting for the depression to lift and fearing manic and depressive recurrences. It is difficult to imagine the torment of these drawn-out depressions.”

       Mogens’ father established a research laboratory to study “biological and physiological changes in manic-depressive patients” and shared beliefs of his countrymen about a biological etiology for them.

       Two years after graduating from high school at age 16 Mogen’s contemplated a career in either engineering or medicine and shortly after decided on medicine. Two years later his father “Spoke to me with exhilaration about electro-convulsive therapy.” He graduated from medical school at age 26 and, following in his father’s footsteps, spent three-four years in Scandinavian psychiatric hospitals, learning about the lack of effective treatment for the disorders he saw there.

       At around age 30 Mogens spent an unspecified period studying experimental biology and cytophysiology in Copenhagen then neurochemistry and the experimental approach in New York. During this time he was mentored by Erik Stromgren who he eventually joined at Aarhus University in Risskov, Denmark, first as a research associate (with the rank of Associate Professor) where Mogens founded a laboratory of biological psychiatry .

       In 1951, at age 33, Stromgren drew Schou’s attention to Cade’s publication on lithium in psychotic mania, as well as Edward M. Trautner and colleague’s work on plasma monitoring rendering it safe to use. “Here was a welcome opportunity to study a supposedly effective drug but I felt that the studies reported until then were insufficiently stringent.”  Mogens designed the study (Schou, Juel-Nielsen, Stromgren and Voldby 1954) which was partly randomized and placebo controlled. He describes his own role: “I did not see the patients, but I threw dice to allocate them randomly to lithium or placebo and carried out the serum lithium determinations.  The results fully confirmed the anti-manic effects of lithium and it was the beginning of my almost lifelong journey with the drug.” It doing so he joined Elkes and Lehmann, scientifically confirming the efficacy and safety of a novel treatment already in wide use.

        I also imagine this was a turning point, back from primarily functioning as a lab scientist to becoming also a fully committed clinician.  A memorial to Mogens Schou after his death (Per Bech 2006) states: “Schou was not a psychiatrist but a physician specialized in clinical chemistry.” This invites further comparison to Elkes (born 2013) and Lehmann (born 2011), neither of whom underwent a formal residency training in psychiatry, but who both learned the clinical discipline by seeking out their own exposure to patients. Joel Elkes’ career trajectory was remarkably similar to Schou’s. Elkes began in medical school with electrophysiology, followed by neurochemistry and only then moving to clinical work (Blackwell 2016).

       Mogens Schou’s earliest interest was in identifying the mechanisms underlying a disorder that might lead to effective treatment. But once he had found lithium his life became devoted to the clinical arena. Nevertheless, in describing his collaboration with Baastrup practical considerations sometimes interfered. His involvement was “despite the geographical distance between Risskov and Glostrup” as a result of which he was “co-operating only with serum lithium analyses and methodology.”

       Understandably, “the outcome of the trial gave Baastrup and me an intense feeling of fulfillment. For the first time we had come on a maintenance treatment that could break the almost inexorable development of recurrences.”

       In appropriate defense against criticism that they avoided a double-blind study he notes: “40% of the patients had attempted suicide before they were given lithium.” His opinion that our “skepticism was purely speculative” is partly correct, although seldom acknowledged in the ensuing debate was the fact that we demonstrated equivalent efficacy for imipramine using the same statistical methodology on a small sample of bipolar patients from the Maudsley data base.

       Much to his credit Schou comments: “I went over the first paper’s many misunderstandings and erroneous calculations” which included the caveat: “It was the general practitioners who decided when there had been a recurrence and we had no influence over this.” This constitutes a significant weakness in the design I do not recall mentioned in the original article.

       Finally, Mogens Schou must be commended for implementing a follow-up study that resolved concerns about the first study with an elegant, original and creative design yielding convincing results (Baastrup, Poulson, Schou et al. 1970).

       A few remaining miscellaneous thoughts arising from Schou’s biography are worth noting.

      Shepherd never confided in me the source of his knowledge about the Schou family history of bipolar disorder but neither did he imply that Mogens himself or his brother suffered. 

      Mogens compares the personas of the three primary actors in the lithium saga. He categorizes Cade as “artistic,” Baastrup as “persevering” and himself as a “scientist.” I agree with what this brief autobiography confirms and note that all were outstanding clinicians.

       During a long career I successfully treated many people suffering bipolar disorder with lithium thanks to the work of all three pioneers. Based on personal experience, that of colleagues and those I supervised, a consensus would be that lithium was an excellent effective remedy at stifling and preventing the manic phase of bipolar disorders, but its antidepressant property is weak, inviting the use of more potent antidepressants but with the risk of provoking mania.

     As Schou’s own data indicate suicide is a serious risk in the natural history of bipolar disorder - perhaps 40% before lithium and significantly less since. Common sense (not science) suggests this is less likely due to lithium’s weak antidepressant component and more likely to its ability to stifle or prevent symptoms that occur in severe mania, often coupled with lack of insight; eroticism that destroys marriages; errors of judgement lead to economic disaster or bankruptcy; and bizarre behaviors disrupt occupation and incur job loss.

     The “anti-suicidal” effect of lithium is likely due to its effect on the natural history of the disorder, preventing symptoms and behaviors that impair or destroy quality of life and invite attempts to end it.

      Had he lived longer Schou’s late life interest in this topic might have led him to a closer look at the natural  history of the disorder which, like the sufferers themselves, tends to ignore or even welcome  symptoms of euphoria often coupled with agnosia that delays or denies seeking help in a timely manner.

       Lastly, without using the term “serendipity,” Mogens Schou attributes his contribution of lithium prophylaxis to the “felicitous juxtaposition of observation, circumstance and a tuned mind.” Sounds like serendipity to me, without a hint of implied disparagement.

     Thanks again to Professor Schioldann for sharing this thought-provoking autobiography by Mogens Schou with INHN readers.

 

References:

Baastrup PC, Poulson JC, Schou M, Thompson K, Amidsen A. Prophylactic lithium; double-blind discontinuation in manic-depressive disorders. Lancet 1970; 2: 326-30.

Baastrup PC, Schou M. Lithium as a prophylactic agent; its effects against recurrent depressions and manic-depressive psychosis. Arch.Gen. Psychiat. 1967; 16: 162.

Bech P. The full story of lithium. A tribute to Mogens Schou (1918-2005). Psychother. Psychosom. 2006; 75: 265-9.

Blackwell B. Joel Elkes, an integrative life. inhn.org collated December 22, 2016.

Blackwell B. The lithium controversy: A historical autopsy. inhn.org collated January 2, 2017. 

Blackwell B. Risk and relevance of lithium usage. inhn.org collated July 20, 2017.

Blackwell B, Shepherd M. Prophylactic lithium; another therapeutic myth? Lancet 1968, 1: 968-71.

Elkes J, Elkes C. Effects of chlorpromazine on the behavior of chronically overactive psychotic patients. Brit. M. J. 1954; 560-5.

Hampton LM, Daubresse M, Chang HY, Alexander GC, Budnitz DS. Emergency department visits by adults for psychiatric adverse events. JAMA Psychiatry 2014; 71:1006-14.

Kores B, Lader MH. Irreversible lithium toxicity; an overview. Clin Neuropsychopharm 1997; 20: 283-99.

Lehmann HE, Cahn CH, DeVertuil RL. The treatment of depressive conditions with imipramine (G22355), Can. Psychiat.Ass.J. Ass.J. 1958;3:155-64.

Schou M, Juel-Nielson N, Stromgren E Voldby H. The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatr 1954; 17: 250-60.

Trautner EM, Morris R, Noack CH, Gershon S, The excretion and retention of ingested lithium and its effects on ionic balance in man. Med J Aust 1955;2:280-91.

 

March 21, 2019