David Janowsky:Cholinergic muscarinic mechanisms in depression and mania 

Samuel Gershon’s opening comments

          I was invited to comment on Dr. Janowsky’s recent review of cholinergic muscarinic mechanisms of depression and mania. Janowsky notes at the outset that his current review appears 47 years after one presented by Tom Ban in 1974.

          His review follows a chronological format for his presentation. I found this style to be very useful and worthwhile in viewing this history through a longer and broader lens. I must state at the outset that this review by Janowsky is exceptionally, carefully and meticulously researched and presented.

          Janowsky’s own dramatic demonstration of the clinical effects seen with physostigmine (Phy) offers an anchor for his presentation. His group’s 1973 report  showed that the injection of Phy to manic and depressed patients produced clear clinical findings. Firstly and most clearly, they found that Phy given to manic patients produced a very measurable and readily observable reduction or even elimination of manic features, whereas in depressed patients it induced or increased the depressive symptoms at the outset.

          I was at NYU at the time of their publication and contacted David and John Davis to raise a simple point suggesting that their manic patients could have been mildly overactive and not as ill as the ones we saw at Bellevue Hospital; this was a  slim argument for us to present to them. However, they both agreed it was worth a trial and came to Bellevue with their medical bags and we selected several very actively manic patients as the challenge group. Our visitors proceeded with the trial and again clearly demonstrated the same Phy effects. My colleague, Burt Angrist, participated in these observations and noted the result of the Phy injection was, sort of, classically impressive. These personal observations clearly registered these findings (in our mind) as indicating that acetylcholine was an important factor in any construction of any causes and effects in mania and depression.

          We first became aware of the dramatic effects of acetylcholine when we reported a study of workers exposed to some insecticides in a government laboratory in Australia in a paper published in 1961 in the Lancet. These circumstances were presented  to  us in the Pharmacology department at the university of Melbourne by the Commonwealth Scientific and Industrial Research Organization (CSIRO), an agency of the federal government.  The situation they encountered was the effect observed by some scientists working in one of their labs on insecticides and their effects on various insects and plants. The compound that was being used in this lab was an organophosphorus (OP) insecticide. They became concerned that workers were reporting sick and were routinely sent for a thorough physical, medical and psychiatric evaluation by physicians outside of the CSIRO.

          We were provided with all of the observations and findings of these medical records, yet were essentially blind. The specific observations are reported in our 1961 Lancet  paper. The findings were that the chronic exposure of OP insecticides produced psychiatric changes in some of this population. The most clearly manifest and clearly defined was the production of a depressive illness, including some cases of severe suicidal depression. After the paper was published, we received a number of reprint requests from other countries indicating that they may be seeing similar effects in their agricultural areas.

          In preparing to write up our Lancet paper we carried out a literature search and found a paper by Rowntree, Nevin and Wilson dated 1950. Interestingly, this work was done at the Maudsley Hospital in England and the investigators were able  to study schizophrenic, manic and depressive subjects to whom they administered diisopropylflurophophonate. They reported that the psychiatric effects observed were primarily depressive illness and, in some cases, with other psychiatric features. The dramatic findings in this study are very important as the subjects studied were inpatients. This paper is cited by Janowsky as well.

          The other event that followed our 1961 paper was the publication of a famous book by Rachel Carson titled “Silent Spring.” This book cited our 1961 paper as one example of the possible dangers of the use of these chemical agents in routine agriculture and their possible serious effects on the population at large; this is still a matter of concern throughout the world in regard to the use of a large variety of herbicides, etc.

          Janowsky’s paper presented here makes an indelible mark on the important possibility of a major role for acetylcholine in relation to manic-depressive illness. Janowsky also extensively considers the other possible internal effects from these compounds that may occur in the CNS. His paper and its comprehensive nature and elegant style creates another question. What place does other data, such as that presented by the catecholamine hypothesis, have in regard to affective disorders?

          My colleagues and I at NYU, when faced with this question, decided we would try and set up a series of experiments that might shed light on these two hypotheses. One of our clinical studies used synthesis inhibitors such as alpha-methyl-p-tyrosine (AMPT), a synthesis inhibitor of noradrenaline, and phencyclidine (PCP), a synthesis inhibitor of serotonin, on two groups of depressed patients. The design was to treat the patients diagnosed with major depression with imipramine and, when improved to an established clinical level and HAMD score, one group would be given AMPT and the other PCP. This 1975 paper was titled “The Use of Synthesis Inhibitors for Finding a Role for Biogenic Amines during Imipramine Treatment in Depressed Patients.” A similar set of experiments was carried out using the MAO inhibitor tranylcypromine (Shopsin, Friedman and Gershon 1976) confirming the previous findings. This suggested that the lack of production of norepinephrine in this group of patients did not affect their improved mental state but the inhibition with PCP on another group of depressed patients caused a relapse of depression. When the PCP was removed their improvement began to return. We also reported several other papers furthering this work (Friedman, Shopsin, Goldstein and Gershon 1974; Gershon and Shaw 1961; Rowntree, Nevin and Wilson 1950).  After we digested these findings, together with a number of experiments in animals, we had to conclude that there were some new questions that must be examined in regard to the widely held catecholamine hypothesis.

          So now, in 2019, must we reevaluate all the data available to us to ascertain what our etiological understanding of affective disorders should be.

References:

Ban TA. Depression and the Tricyclic Antidepressants. Montreal: Ronalds Federated; 1974, pp. 45-6.

Carson R. Silent Spring. 1962. Mariner Books.

Friedman E, Shopsin B, Goldstein M, Gershon S. Interactions of imipramine and synthesis inhibitors of biogenic amine. J. Pharm. Pharmacol. 1974;26(12):995-6.

Gershon, S, Shaw F. Psychiatric sequelae of chronic exposure to organophosphorus insecticide. Lancet 1961;1:1371-4.

Janowski DS, El Yousef MK, Davis JM Sekerke J. Parasympathetic suppression of   manic symptoms by Physostigmine. Arch Gen Psychiatry. 1973;28(4):542-7.

Rowntree DW, Nevin S, Wilson A. The effects of disopropylfluorophosphonate in schizophrenia and manic depressive psychosis. J. Neurol. Neurosurg. Psychiat.1950;13:47-62.

Shopsin B, Gershon S, Goldstein M, Friedman E, Wilk S. Use of synthesis inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients. Psychopharmacol Commun. 1975;1(2):239-49.

Shopsin B, Friedman E, Gershon S. Parachlorophenylomine reversal of tranylcyclomine effects in depressed patients. Arch. Gen. Psychiat. 1976;33(7):811-9.

October 10, 2019