Antidepressant Withdrawal Syndromes: Phenomenology and Pathophysiology

The discontinuation of tricyclic antidepresants (TCAs) produces a broad array of symptoms which can be grouped to form 4 categories or syndroms(1) general somatic distress with anxiety or agitation, (2) sleep disturbance characterized by excessive, vivid dreaming and initial or middle insomnia, (3) movement disorder, and (4) behavioral activation on a continuum to mania. Syndromes (1H3) may be due to withdrawal-induced cholinergic overdrive at peripheral (e.g. the gastrointestinal system) and central (e.g. the gigantocellular tegmental field and the mesocortical, nigrostriatal and mesolimbic tracts) sites. The cholinergic overdrive hypothesis is supported by reports that anticholinergic agents produce tolerance, all TCAs block the physiological effects of acetylcholine and competitively displace radiolabeled muscarinic receptor antagonists in vitro and antidepressant withdrawal symptoms respond to centrally active antimuscarinics. Withdrawal-triggered abnormalities in the interaction of cholinergic and monoaminergic systems may contribute to the development of TCA-withdrawal associated mania but the pathophysiology of this syndrome remains unknown. The development of these syndromes indicates that TCAs can produce heuristically important modifications in cholinergic systems and that they might be used to model those aspects of the pathophysiology of depression which may have a cholinergic component. Phenomenological, physiological, biochemical and receptor binding variables which are pertinent to the biology of depression and partially regulated by cholinergic mechanisms are prime targets for strategies employing TCAs to supersensitize cholinergic systems. Both clinical and basic aspects of TCA withdrawal phenomena are discussed in detail.This article reviews signs and symptoms produced by the withdrawal of tricyclic antidepressants (TCAs), the management and pathophysiology of TCA-withdrawal phenomena and the use of TCAs and classical antimuscarinic agents to model cholinergic abnormalities which may be involved in the pathogenesis of depression. The phenomenology of TCA withdrawal syndromes is first illustrated using case examples. Evidence that TCAs produce cholinergic system supersensitivity and their withdrawal cholinergic overdrive is then presented. The “cholinergic overdrive hypothesis,” does not explain TCA withdrawal-induced hypomania. It is possible, however, that withdrawal of TCAs mobilizes monoaminergic pathways via the activation of choliner