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Wednesday, 28.10.2020

Samuel Gershon: Events and Memories

Edward Shorter’s comments

 

        This fascinating series of Sam Gershon will soon be a book.  This is the best news I’ve had all day.

        Few are the clinicians who write memoirs and Dr. Gershon’s is on par with Michael Alan Taylor’s 2013 Hippocrates Cried and Barry Blackwell’s 2012 Bits and Pieces as critical reassessments of the field.  When historians 50 years from now try to figure out what went wrong in psychiatry in the last decades of the old century and the first decades of the new, they will turn to these precious documents as offering some clue.  What clues does Sam give us?

        Sam Gershon was born in Poland in 1927.  He went to high school in Sydney, then received a medical degree from the University of Sydney in 1950.  He trained in psychiatry in Victoria and Melbourne starting in 1952, then in child psychiatry at Melbourne’s Travancore Child Psychiatric Clinic.  In 1959-60 he was chief of the child psychopharmacology section of the University of Michigan’s Joint Research Program in Schizophrenia and Psychopharmacology.  The mid-1960s took him to the Missouri Institute of Psychiatry in St Louis to work with Max Fink and Turan Itil,  then on to the New York University Medical Center where he founded a Psychopharmacology Research Unit.  In 1975 he joined the Department of Psychiatry of the University of Missouri and in 1980 became professor and chair of psychiatry at Wayne State University in Detroit.  From 1988 until his emeriting in 2004 he was vice-president for research and research director for neurosciences at the University of Pittsburgh, then onward to the University of Miami to serve as professor and vice chair of academic affairs.

        Gershon was the first elected president of the International Society for Bipolar Disorders and editor of its journal, Bipolar Disorders.  In this context, one of his main achievements was bringing lithium from Australia, where John Cade had discovered its clinical efficacy, to the United States.  Cade ended up turning his back on lithium but Sam Gershon became one of its main apostles.

        Fittingly, this memoir begins with Gershon’s encounter with lithium in Australia.   Everybody, of course, was talking about Cade’s discovery and Gershon, as a resident at the Royal Park Psychiatric Receiving Hospital in Melbourne, wanted to study it.  A difficulty was that Cade had just banned it from the hospital.  Gershon would have to try an end run, so he went upstairs to see “Trautie,” Dr Edward Trautner in the department of physiology, who led the first large-scale lithium study that monitored lithium levels with a flame photometer.  They had no deaths and, says Gershon, kept lithium alive in psychiatry.

        Once at the University of Michigan he became further convinced that “Lithium is one of the few examples of psychopharmacological specificity in psychiatric treatment.”  They also determined that lithium could replace maintenance treatments with ECT (after initial ECT) in following bipolar cases.   Gershon closes this section with a pregnant sentence, “All of the studies cited were conducted without grants or research funds, contributed to by the faculty and the meager resources of their labs.  They were all unblinded because we could not afford elaborate designs.” 

        Thus it is possible to conduct important work without huge NIMH grants and lavish industry support.   So many psychiatrists have become Key Opinion Leaders, the derisive term for researchers who have become de facto shills for industry.  In fact, becoming a KOL is probably a guarantee that one will not end up doing work of scientific significance.  The Gershon memoir is instructive.

        The section on succinic acid delves into his research on insulin coma, a procedure that he completely rejects:   “Not all woke up after the glucose, some had protracted comas, some died and others developed neurological impairments.  This treatment was dangerous and had not been established anywhere in the world as effective treatment for schizophrenia.”  And barbiturate-sleep treatment for schizophrenia produced the same (paltry) results!   This is really a shattering indictment of a therapy that has, in fact, produced some positive studies in otherwise intractable cases of “schizophrenia” (Doroshow 2007).  Maybe there are different schizophrenias that respond  differently to different treatments.  Sam Gershon came of age in a era where everyone believed implicity in “schizophrenia,” which is not the case today, and the last word has not been written on the effects of insulin on the brain.

        The depression study.  As a resident, Gershon added depression to schizophrenia and other disorders treated with succinic acid.  It influences depression, but then most treatments influence depression, given the ease with which one can shift patients a few points down the Hamilton scale.  (Unfortunately, placebo moves them along with equal ease.)  There is an intellectual problem here: treating “depression” as though it were a unitary disorder.  But it is very difficult to leave one’s training behind.  Gershon’s memoir has some lessons.  Unhappily, some of them are warning lessons.

        Their work on bemegride showed promise in reversing barbiturate poisoning, which had been very common until the benzodiazepines replaced the barbiturates after 1960.  If it not been for Librium and Valium, bemegride would have become a standard antidote used in emergency departments everywhere.  Instead, it has now sunk into oblivion, as has succinate.  Gershon looks back on these experiences with resignation.  But a wry shrug is premature!  The state of drug discovery in psychopharmacology today is so parlous that we should seize these forgotten’s hints, left at history’s wayside, and have another look.

        Morphine.  At several points in Gershon’s life the market has determined the ultimate fate of a promising molecule:  combining morphine and aminphenazole showed promise in pain control while antagonizing depressed vital functions.   A small company brought the combo treatment out but slow sales caused it to be withdrawn in a year or so.   “The market determined the outcome and so we returned to the laboratory.”  This is not the way it’s supposed to be.  That’s why we have NIMH.  Yet the government agency wastes hundreds of millions of dollars in useless SSRI trials while neglecting the kind of pioneering pharmacology that could produce real breakthroughs (as opposed to phony “breakthroughs” like ketamine.  Don’t get me started).

        He ends the THA section (tetrahydroaminoacridine)  with the “belief that all these antagonists have considerable therapeutic value and deserve further study.”  I hope that Joshua Gordon, head of NIMH, can suspend his self-congratulation over ketamine long enough to read these pregnant lines.

        Indole alkaloids: yohimbine, harmine and ibogaine.  Gershon spent a lot of time with these analeptic agents, possibly useful in relieving depression.  All three showed promise, yet have been largely forgotten (as harmine had in the 1920s – before sodium amytal – success in reversing catatonia). 

        The section at pp. 18-21 will be read with interest by those currently wrestling with the diagnosis and treatment of “Havana Syndrome,” the American and Canadian diplomats who became ill after possible exposure to insecticides.  Researchers in Melbourne confronted similar clinical pictures in the 1950s.  At NYU they were able to treat some of these symptoms with physostigmine, which led to a restoration of choline acetylase.  “[This] supported the role of acetylcholine in the biochemical etiology of both schizophrenia and bipolar disorder.”

        The etiology of bipolar disorder.   Here I bite my tongue.  That a researcher of such eminence as Sam Gershon believes in the existence of “bipolar disorder” as a separate disease, should cause me to modulate my own scepticism (or at least not be so noisy about it).  He asks the question “norepinephrine or serotonin” in the etiology of affective disorders?  It would be fair to say that this was a burning question in the 1960s and ‘70s but no longer is. 

        Neuropathology.  Here the “risk-benefit” balance in treatment with antipsychotics is discussed.  Sam Gershon justly observes that the risks have been underemphasized, the benefits exaggerated.  It is a neat bridge over which to segue into a final discussion of model psychoses obtained with amphetamine.  Here Burton Angrist enters the picrture at Bellevue as a young psychiatrist who had just finished training with Don Klein and wanted to do more with “the psychopharmacology of psychotomimetics and drugs of abuse.”  They focused on amphetamine abuse.  Bellevue was the right place for this.  They arrived at the controversial conclusion that amphetamine psychosis was virtually identical to the schizophrenic variety.  They also found clozapine to be “a very interesting and effective antipsychotic.” 

        Gershon fires a final Parthian shot:  “All the studies in this broad arena were created by a talented group of scientists working collabofratively in a supportive academic setting.  (i.e., no industry money).   This form of interaction is less frequent now and I believe science has suffered a loss.”

 

Bravo!

 

        Two comments by Burton Angrist follow: “ I liked Sam immediately.  He was gracious, utterly without pretense, and often hilariously funny.  Over time, this fondness continued to grow but I also recognized some of his other qualities, his remarkable astuteness and clarity of thought…”   Under Sam’s tutelage, Angrist thrived.  Amphetamine psychosis turned out to be very common indeed at Bellevue. 

        There is a logical problem that plagues this kind of research.  It supposes that the essence of schizophrenia is psychosis and that one might usefully study schizophrenia by inducing “model” psychoses.  This work has generally been unproductive because emotional blunting, executive disfunction and thought disorder are thought by many to be the core features of “schizophrenia” rather than psychosis.   Indeed, it is possible that schizophrenia as a unitary disease does not exist.  So, good luck reproducing it experimentally!  It may, however, be – as Angrist points out – that amphetamine can faithfully reproduce psychotic mania.

        A tiny pedantic correction.  Angrist writes, “I fell back on Kraepelin’s concept that recovery in schizophrenia is not a full restitutio ad integrum.”   That residual symptoms remain.  It was not Kraepelin who believed this but Bleuler. Kraepelin thought that patients with “dementia praecox” (Bleuler’s schizophrenia) went irreversibly downhill.

        On balance, Gershon’s memoir and Angrist’s coda will give researchers 50 years from now a good image of what scientifically-oriented, industry-independent psychiatrists, who were capable of lateral thinking and commited to interdisciplinary collaboration, were accomplishing at the turn of the new century.  It was not all nonsense.

 

References:

Blackwell B.  Bits and Pieces of a Psychiatrist’s Life.  United StatesL Xlibris, 2012.

Doroshow DB.  Performing a Cure for Schizophrenia: Insulin Coma Therapy on the Wards.  J Hist Med Allied Sci. 2007;62(2):213-43.

Taylor MA.  Hippocrates Cried: The Decline of American Psychiatry.  New York, Oxford University Press, 2013.

 

March 5, 2020