Reply (Martin M. Katz)

Syndromes and Neurotransmitters

Martin M. Katz’s reply to Donald F. Klein’s 4th comment/question on his book Depression and Drugs

Don Klein’s question is: “if each neurotransmitter (nt) system controls a particular behavioral domain, then, distinctive arrays of behaviors (or syndromes) should each be mapped onto a particular complex of neurotransmitters”.  But he says “if neurotransmitter systems vary without regard to any supervening syndrome then syndromes are either due to other non-nt processes or the syndrome notion is useless”.

To respond to his question it is necessary to reexamine the background evidence of the relationships of the monaminergic systems and behavior. There is no evidence currently, that diagnostic syndromes are associated with any specific underlying pattern of dysfunctional neurotransmitter systems.  The evidence shows, however, that each of the various of the monoaminergic systems, dopaminergic, serotonergic (5-HT), and noradrenergic (NE) are associated with or regulate different, but potentially, overlapping patterns of behavior and mood. As summarized in the 2004 paper by Morilak and Frazer, 5-HT, primarily with anxiety and impulsive aggression, and NE with “arousal”, mood, and motor activity.  Further, the nt systems do not operate independently, but interact with each other, thus, complicating the nature of specific nt-behavioral associations. There is no current evidence that nt systems vary in accord with any clinical syndromes or diagnoses but disturbed patterns of behavior and mood that are identified as syndromes, may yet be found to be associated with a pattern of dysfunctions in several of the nt systems (Katz and Maas 1994).

Applying this evidence to treatment issues, we note that because patients vary in their clinical profiles of the disorder, some, e.g., with peaks in anxiety, others with feelings of anger, it is possible and now done with some success, to select drug(s) in any given case, based not on the diagnosis, but on the agent’s targeted action on major behavioral component(s) of the disorder, i.e., the drug is selected because of its action on a specific nt system or systems and that system’s evidenced association with that behavioral component, e.g.,  an SSRI or a selective NE agent, a dual action, or possibly, an agent with a new pattern of specific clinical actions, expecting, through this pattern of associations, to achieve the most effective therapeutic result .

So it is not yet clear whether a particular complex of neurotransmitters underlies any of the clinical syndromes. The evidence regarding the interactions of the nt systems and behavior generally, and the soundness of the syndrome concept, however, point to the strong possibility that such patterns may well be eventually uncovered.  What is needed to achieve an answer is to set aside the syndrome concept and to first apply in future neurobehavioral studies, the same level of precision in describing the profile of psychopathology, i.e., the disturbed behavior, affect, and cognition, associated with the syndrome,that is applied to the measurement of the neurochemistry.  Until then, we will have to, as Klein suggests, defer judgment on this important issue.



Katz MM. Depression and Drugs: The Neurobehavioral Structure of a Psychological Storm. Springer, New York: Springer; 2013.

Katz MM, Maas JW.  Psychopharmacology and the etiology of psychopathologic states: Are we looking in the right way? Neuropsychopharmacology 1994; 10: 139-44.

Morilak D, Frazer A. Antidepressant brain monoaminergic systems: A dimensional approach to understanding their effects in depression and anxiety disorders. International Journal of Neuropsychopharmacology 2004; 7:193-218.


Martin M. Katz

October 23, 2014