David Janowsky:Cholinergic muscarinic mechanisms in depression and mania 

Edward Shorter’s comments

        Dr. Janowsky’s work on the effects on behaviour of the catecholaminergic-cholinergic balance is very much to be welcomed. And his advocacy of scopolamine as opening new pathways to treatment alongside ketamine should cause the ears of industry chemists to pick up. But. I wonder if, at some level, we aren’t talking past each other.

        There is a difference between “depression” as a disorder of affect and depression as a deep-seated brain disease. This goes deeper than the traditional distinction between affect and mood, because serious depression is a disorder of the entire body involving mood, cognition and behavior. It is a disease that overlaps with “schizophrenia” at several levels and one wonders if the Kraepelinian firewall between the two isn’t a historic mistake, as is the DSM firewall. At some level, depression and the symptoms of schizophrenia may be expressions of the same disease. The Germans classically called this Einheitspsychose. Yet there may, deep down, be several Einheitspsychosen, not just one.

        Now, single-factor biochemical explanations involving particular amine neurotransmitters, or balances in the autonomic nervous system affecting acetylcholine and its various receptors, do not have a long history of success. The brain is simply too complex. We don’t even know how much we don’t know. Yet interwoven somehow into these various layers of complexity is the disease of deep-depression, classically known as melancholia. ECT has remarkable success in treating melancholic depression and some forms of “schizophrenia,” which further reinforces the deep-down hypothesis. Psychopharmacologic agents seem to act mainly on affect. But it is not difficult to get results on affect.

        Ketamine has just been accepted by the FDA. If Dr. Janowsky’s wise suggestions are adopted, some company will soon propose scopolamine for psychiatric indications. Both drugs seem to address only depressive affect, and it is interesting that, when the Psychopharmacologic Drugs Advisory Committee of FDA met on Nov 2, 2018, to consider ketamine, there were no references — zip — to melancholia. For members of the committee and the FDA brass, there was only one depression, “major depression,” and there was no talk of affect vs melancholia.                         I am not in any way critical of Dr. Janowsky’s fine work. But I am saying that, every time I hear the unmodified terms “depression” or “major depression,” “That’s when I reach for my revolver…” (Signals, Calls and Marches. Mission of Burma. Ace of Hearts. 1981)

October 31, 2019