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Sunday, 28.02.2021

Samuel Gershon: Events and Memories.

Bernard Lerer’s comments

 

        I came to Detroit in 1982 to work with Sam Gershon at Lafayette Clinic. I had completed my residency in psychiatry two years earlier and then did a research fellowship with Robert (Haim) Belmaker at Ezrath Nashim Hospital in Jerusalem. I met Sam in 1981 during one of his visits to Israel and talked to him about my interest in the biology of depression and bipolar disorder and the mechanism of action of ECT. Sam offered me a fellowship on the spot. Without even checking other options, I made arrangements to do my training with Sam in Detroit. When I arrived in July 1982 and started work Sam did not assign me to any projects. Instead, he listened to my ideas and helped me implement what I wanted to do.

        My first study was an open trial of the tetracycline antibiotic, demeclocycline, in patients with acute mania.  The study was motivated by the focus of the Belmaker group on inhibition of adenylate cyclase as a possible mechanism of action of lithium in bipolar disorder. Since demeclocycline inhibits adenylate cyclase and causes diabetes insipidus, as does lithium, a trial of demeclocycline in mania was an excellent test of the hypothesis. Unfortunately, good ideas do not always pay off. Demeclocycline did not have any effect on manic symptoms. Very soon I had used up all my credit with the nursing staff as manic patients receiving the drug did not improve and then grew significantly worse. Sam supported me as best he could but it soon became clear that the study had to be disbanded.

        My next clinical research venture was also in bipolar disorder and was enthusiastically supported by Sam. While with the Belmaker group in Jerusalem I had been part of a study that compared add-on of the anticonvulsant, carbamazepine, to placebo add-on in patients with “excited psychosis.” Bipolar manic and schizoaffective manic patients as well schizophrenia patients with manic-like symptoms were included in the study. The addition of carbamazepine was significantly better than placebo (Klein, Bental, Lerer and Belmaker 1984).

        Encouraged by these results I wanted to undertake a randomized controlled trial  (RCT) comparing lithium and carbamazepine in patients with acute mania. Sam liked the study because it could test his hypothesis that patients with “typical” bipolar disorder, characterized by predominant mood symptoms in the acute phases and high quality remissions, are those who respond best to lithium. Having rehabilitated my stature with nursing staff, Norman Moore and I set out to do the study. The fact that both drugs worked equally well helped keep the peace on the ward. We published the results in the Journal of Clinical Psychiatry (Lerer, Moore, Meyendorff et al. 1987). As the first RCT of carbamazepine versus lithium in mania it aroused a lot of interest. The number of patients was not large enough to substantively test Sam’s hypothesis but there definitely was a trend for those patients who responded to lithium to be more “typical” in their clinical picture as well as during remission than those who responded to carbamazepine.

        Another study I initiated with Sam’s encouragement also supported a different profile of action of lithium and carbamazepine in bipolar disorder. It had been previously shown that pretreatment with lithium inhibited the mood enhancing effects of stimulants in euthymic patients with bipolar disorder. Together with Elaine Meyendorff, I examined the effect of carbamazepine pretreatment on methylphenidate-induced behavioral activation and euphoria. Seven euthymic bipolar patients received two weeks of pretreatment with carbamazepine or placebo in a double-blind crossover design. After each pretreatment period, the subjects received methylphenidate, 30 mg i.v.; mood and behavior changes were monitored for a period of five hours after each infusion. Methylphenidate induced a striking psychostimulant effect that was not attenuated by carbamazepine pretreatment. This clearly differs from the effect of lithium in the same paradigm and supports the hypothesis of different therapeutic profiles for lithium and carbamazepine in bipolar disorder (Meyendorff, Lerer, Moore et al. 1985; Lerer, Moore, Meyendorff et al. 1985).

        I did a lot more in those amazing years in Detroit. In 1984 I received deeply appreciated recognition of my preclinical studies on the mechanism of action of ECT (encouraged and supported by Sam) for which I was awarded the A.E. Bennet Prize for Preclinical Research in Biological Psychiatry (Lerer 1984).

        I returned to Israel in 1984 and never forgot Sam’s dictum regarding “typical bipolarity” and its exquisite responsiveness to lithium. I have taught this approach to my students and see it regularly in my clinical work. I am firmly convinced there is a population of bipolar patients who respond extraordinarily well to lithium and are never ill again after starting the drug.

        At this time I am in the process of conducting an extensive, systematic analysis of all available data comparing carbamazepine and lithium in bipolar disorder. I am working with two talented younger colleagues in the Department of Psychiatry at Hadassah – Hebrew University Medical Center in Jerusalem. Beyond assessing the overall effect of carbamazepine as compared to lithium, one of our cardinal objectives is to determine whether there are unique characteristics that differentiate patients who respond to the two drugs.

        More than 40 years after they were first expressed to me, Sam’s ideas remain a powerful motivating factor for my own research and that of others in psychopharmacology and biological psychiatry. And that is only a drop in the ocean of his achievements.

 

References:

 

Klein E, Bental E, Lerer B, Belmaker RH.  Combination of carbamazepine and haloperidol versus placebo and haloperidol in excited psychoses: A controlled study. Archives of General Psychiatry 1984; 41:165-70. 

Lerer B.  Studies on the role of brain cholinergic systems in the therapeutic mechanisms and adverse effects of ECT and lithium (Winning Paper, A.E. Bennet Award, Basic Science, 1984). Biological Psychiatry 1985; 20:20-40.

Lerer B, Moore N, Meyendorff E, Cho S-R, Gershon S.  Carbamazepine and lithium: Different profiles in affective disorders? Psychopharmacology Bulletin 1985; 21:18-22.

Lerer B, Moore N, Meyendorff E, Cho S-R, Gershon S.  Carbamazepine versus lithium in mania: A double blind study. Journal of Clinical Psychiatry 1987; 48:89-93.

Meyendorff E, Lerer B, Moore N, Bow J, Gershon S.  Methylphenidate infusion in euthymic bipolars: Effect of carbamazepine pretreatment. Psychiatry Research 1985; 16:303-8.

 

July 9, 2020