Physiologic Mechanisms Underlying the Antidepressant Discontinuation Syndrome
Pierre Blier, MD, PhD, and Philippe Tremblay, MD
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The rate at which serotonin reuptake inhibitor (SRI) treatment is terminated and the duration of
treatment appear to be key factors in predicting discontinuation symptoms. The development of animal
models to explain the mechanisms of this clinical problem has proved challenging, because less
than half of all patients experience any discontinuation symptoms, many of which are subjective in
nature. One explanation is that SRI discontinuation symptoms may arise from the rapid decrease in
serotonin (5-HT) availability when treatment ends abruptly. Yet, it would appear that discontinuation
discomforts may not be mediated exclusively through 5-HT receptors, given the major regulatory role
5-HT exerts on a number of specific chemical receptor systems in the brain. As a result, attempts to
explain the determinants of this phenomenon rely on a certain level of speculation. This article examines
the possible physiologic bases for the antidepressant discontinuation syndrome and briefly describes
these adaptations. It discusses the 3 systems most likely to account for at least part of the
symptomatology—the 5-HT, the norepinephrine, and the cholinergic systems—and the possible interactions
among them. It also attempts to explain their implications in the therapeutic actions of antidepressants
in patients with affective and anxiety disorders.
J Clin Psychiatry 2006;67(suppl 4):8-13
© Copyright 2006 Physicians Postgraduate Press, Inc.
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