Antipsychotic medications, psychological side effects and treatment engagement.

Patient complaints of antipsychotic-induced apathy, emotional indifference, mental “fogginess,” “blankness,” and “clouding,” among others, are undoubtedly familiar to practicing psychiatric clinicians. This “family” of subjective psychological side effects, variously dubbed “neuroleptic dysphoria” (Awad & Voruganti, 2005; Singh & Smith, 1976), “behavioral toxicity” (Hollister, 1957; Van Putten & Marder, 1987), and “neurolepticinduced psychic indifference” (Healy, 1989; Kalinowsky, 1958) has been noted by clinicians and studied by researchers since the introduction of chlorpromazine in the 1950s. Although dopamine has been suspected to play a role in this negative subjective “syndrome” for over half a century, direct links between dopamine antagonism—antipsychotics, primary mechanism of action—and dysphoria have been clarified only recently. As Awad and Voruganti (2005) detail, research regarding subjective dysphoria has mostly taken one of two approaches: (1) comparing correlations between side effects and rates of dopamine receptor occupancy, utilizing antipsychotics with differing receptor occupancy profiles (e.g., Kirsch, Ronshausen, Mier & Gallhofer, 2007; Mizrahi et al., 2007), and (2) using selective dopamine depleting drugs such as alphamethyl-para-tyrosine (AMPT) to induce phenomenologically identical “neuroleptic dysphoria.” With respect to the second approach, Voruganti and colleagues (Voruganti & Awad, 2006; Voruganti et al., 2001) have used AMPT in medication-free schizophrenia patients to successfully trigger a cascade of negative affects beginning with anhedonia, “clouded thinking,” and amotivation and ultimately leading to social withdrawal and a state of explicit subjective distress. de Haan, Booij, Lavalye, van Amelsvoort, and Linszen (2005) have also produced AMPT-induced dysphoria in a health subject, documenting a similarly complex array and cognitive and behavioral effects. The complexity of these effects—impacting emotion, cognition, motivation, and behavior—cannot be overemphasized, an unsurprising fact given the complexity and controversy