By Donald F. Klein
To quote Marty Katz, "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-neurotransmitter processes or the syndrome notion is useless”.
Marty says with regard to my question: "To respond to his question it is necessary to re-examine the background evidence of the relationships of the monaminergic systems and behavior.....So it is not yet clear whether a particular complex of neurotransmitters underlies any of the clinical syndromes…….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."
It is here that we deeply disagree. I do not think this belief is well supported. Most apparent is our disagreement regarding onset of anti-depressant action, since the various anti-depressants have their ultra-quick uptake blockade while the modal clinical response occurs weeks later. Further, how can one speak about serotonin effects when there are 14 serotonin receptors or NE effects when dopamine is taken up in frontal lobe NE receptors, etc.? The simple rheostatic view of regulating behavioral/affective action, up or down, in step with neurotransmitter concentration --without regard for the intricacies of pathophysiology-- seems wrong. Elsewhere, I have suggested that certain manifest syndromes are due to an impaired adaptive function --that there are a host of ways to impair a function so simple genetic linkages will not do and that for those syndromes marked by spontaneous remissions-- effective medication can also normalize a dysfunction--such as can be accomplished for impaired negative and positive feedback loops. We have emphasized this view in our texts and concisely in: Klein DF. Cybernetics, activation, and drug effect. Acta Psychiatrica Scandinavica 1988; 77: 126-137.
Further, Marty suggests, "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."
I agree with more detailed phenotypic description --but of who? Note Marty puts aside the syndrome concept but nevertheless describes the phenotypic description "associated with the syndrome". I believe the most striking evidence for the syndrome concept is the fact of spontaneous remission, which contradicts the notion of a simple aggregate of difficulties.
Note that the current NIMH RDoC template eschews the syndrome concept, "supporting dimensional assessments" without concern for the nature of the subjects --who may be normal children, aged folk, demented patients, depressives, those who happen to come into the clinic,etc. All will be dimensionally informative, affirming the presumptive structure of the current problematic granting assessments.
Is there an alternative to dimensional phenotypic or endophenotypic analysis? I believe so. Current parallel group placebo controlled studies, that indicate a medication is or is not effective are very FDA useful --but do not specify which patient requires medication to remit and maintain gains.
This is possible through intensive design, varying the dose of apparently effective medications while ascertaining fluctuations in benefit. This is described in detail in: Klein DF (2011) Causal Thinking for Objective Psychiatric Diagnostic Criteria. Shrout PE, Keyes K, Ornstein K (Eds) Causality and Psychopathology . New York City: Oxford University Press, pp 321-337.
Finally,a well accepted (DSM 4 & 5) notion is that under the general label of depression there is a subgroup with “atypical depression” manifestations, that have a differential onset (early), course (chronic but reactive), and vegetative (hypersomnia, hyperphagia, severe fatigue, rejection sensitivity) symptoms. Almost the converse of melancholia as described in: Stewart JW, McGrath PJ, Quitkin FM, Klein DF: Atypical depression: current status and relevance to melancholia. Acta Psychiatr Scand 115 (Suppl. 433): 58–71; 2007.
Striking, those with an adolescent onset or chronic course have a specific psychopharmacological response to MAOIs, but not to TCAs. Strangely, late onset patients with atypical features may respond equivalently well to TCAs or MAOIs.
MAOIs are supposed to inhibit the catabolism of many (NE, 5HT, Dopamine) neurotransmitters. How would “Atypical Depression”and MAOIs fit into Marty Katz’s schema?
Donald F. Klein
January 1, 2015