Samuel Gershon: Events and Memories. 8. Neuropathology



       Since our earliest reports (Mackiewicz and Gershon, 1964;Singer, Sanghvi and Gershon, 1971), perhaps a hundred new antipsychotic compounds have been introduced. Each reports a lengthy list of side effects; many are direct actions on the brain, others may be caused via other neuronal mechanisms. Well publicized CNS effects include tardive dyskinesia, Parkinson’s syndrome, neuroleptic malignant syndrome and serious neurotoxicity along with drug interactions, including irreversible effects with lithium. A detailed compilation of these adverse effects should cause more concern than seems to be the case. Furthermore, increasing proposals to treat younger and younger children should arouse more alarm in our present state of ignorance.


        Our early study on rabbits treated with chlorpromazine showed neuropathology and nerve loss (Manckiewicz and Gershon, 1964). More recently, rats treated with haloperidol showed similar neuronal changes in the substantia nigra and striatum (Mitchell et al, 2002).  Here is the crux of the problem; we do not know the etiology of the psychotic disorders we are treating, we cannot label them reliably and the treatments are almost certainly harmful to the brain and other organ systems. Yet we blithely persist as if there were no problems.


      Psychiatrists, like physicians in the rest of medicine, informed by the Hippocratic Oath to, “First, do no harm”, struggle with the task of balancing benefits against risks. Perhaps the best example was when insulin coma was deemed the best and most effective treatment for schizophrenia, a worldwide pandemic delusion. Insulin coma was accompanied by protracted or irreversible coma, degrees of dementia, and occasional death. When a colleague and I questioned its efficacy based on patient follow ups at John Cade’s hospital in Melbourne, we were attacked as irresponsible, ignorant and punished. Our claim it was not effective was validated by the Maudsley study comparing insulin coma with barbiturate induced sleep, showing no difference between treatments (Ackner, Harris and Oldham 1957) (Bourne 1953) (Fink, Shaw, Gross and Oldham 1958). Yet insulin coma continued worldwide until the antipsychotics arrived in 1954. Whatever perceived benefits insulin coma bestowed were probably due to the care and attention devoted to the treatment of patients in coma.

       The situation with the anti-psychotics has been more nuanced and complex but also slow to evolve and clarify. The initial benefits appeared revolutionary, and within a decade, the old asylums were closing and “deinstitutionalization” was underway. The drugs primarily stifled the acute and disturbing features of schizophrenia that required institutionalization; hallucinations, delusions, paranoia and aggression (the so called positive symptoms).

       Only later did we fully appreciate the obverse side of the risk-benefit coin. Patients, often alone and bereft of family, living in an unwelcoming community and sometimes on the streets, became victims of side effects and stopped taking the drugs, relapsed and were re-hospitalized (the so-called revolving door). This was aggravated by an increasing awareness among patients and prescribers that anti-psychotic medication often did little to benefit the cognitive difficulties, social skill deficits, apathy and poor motivation that combined to complicate earning a living and thriving in community (the so called negative symptoms).

       The similarities between these two historic events, insulin coma and antipsychotic medication, are disturbingly similar; the benefits were overinflated and the risks underestimated. We seem unable to assimilate that lesson and pass it along. What is needed is a textbook on the neurological and neuropathological effects of anti-psychotic drugs, coupled with the clinical skill and knowledge to use them wisely in both a hospital and a supportive community setting.


Ackner B, Harris A, Oldham AJ. Insulin treatment of schizophrenia. Lancet 1957; 1: 607-11.

Bourne H. The insulin myth. Lancet 1953; 2: 964-8.

Fink M, Shaw R, Gross G, Coleman FS. Comparative study of chlorpromazine and insulin in the therapy of psychosis. JAMA 1958; 166: 1846-50.

Mackiewicz J, Gershon S., An experimental study of the neuropathological and toxicological effects of chlorpromazine and reserpine. J. Neuropsychiat. 1964; 5: 159-69.

Singer G, Sanghvi I, Gershon S., Exploration of certain behavioral patter ns induced by psychotropic agents in the rat. Psychopharmacol. Bull. 1971; 7: 32

Mitchell IJ, Cooper AC, and Griffith MR., Acute administration of haloperidol induces apoptosis of neurons in the striatum and substantia of rats. Neuroscience 2002: 89


Samuel Gershon

November 5, 2015