Is an Adaptation of NMDA Receptors an Obligatory Step in Antidepressant Action?

Abstract

Clinically effective antidepressants are structurally diverse, ranging from phenylcycloalkylamines (e.g., tranylcypromine), and tri- and tetracyclics (e g, imipramine and mianserin, respectively) to nonfused polyaromatic molecules (e.g., zimelidine) (Fig. 1). Most antidepressants have well-documented effects on either biogenic amine reuptake or metabolism, and it is these neurochemical properties (e.g., blockade of serotonin reuptake, inhibition of monoamine oxidase), rather than structutal considerations, that most often form the basis of classification schemes for these agents. Despite the unequivocal evidence that antidepressants can perturb biogenic amine metabolism and disposition, establishing a causal link between these actions and therapeutic response has been problematic (1–4). Thus, although effects on biogenic amine metabolism and reuptake are generally readily demonstrable both in vitro and in vivo, there is an apparent requirement for sustained treatment to achieve an antidepressant effect. This therapeutic lag cannot be defined with certainty, but most double-blind, well-controlled clinical trials indicate a latent period of ≥2 wk, with a general (albeit conservative) estimate of 3–6 wk of drug therapy required to obtain significant therapeutic effects. The symptomatology associated with major depression is complex, and the rating scales used to assess clinical improvement may not be sufficiently sensitive to detect a more rapid improvement within the constraints imposed by a well-controlled trial. Both open trials and clinical impressions suggest that certain individuals may respond more rapidly than the norm (for example, clinical improvement following electroconvulsive therapy (ECT) has been observed following 3–4 seizures—that is, in ≤2 wk [5]), but, based on the large number of well-controlled studies demonstrating a therapeutic lag, the hypothesis that one or more adaptive changes must precede a therapeutic response has become a tenet of biological psychiatry.KeywordsNMDA ReceptorRadioligand BindingAntidepressant ActionChronic Mild StressGlycine SiteThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.