Neuroleptic dysphoria: towards a new synthesis

Rationale. Neuroleptic dysphoria (ND) is a subtle and under-recognized side effect of antipsychotic drugs. It is an all-inclusive descriptive phrase that encompasses a variety of unpleasant subjective changes in arousal, mood, thinking and motivation induced by neuroleptic drugs. Understanding this phenomenon has wide ranging clinical and research implications. Objective. The present review examined the themes identified in the original studies from the neuroleptic era in the light of recent findings from neuroimaging research, cumulative experience with second generation antipsychotic drugs, and new concepts such as pleasure responsivity, hedonic regulation and subjective tolerability. Methods. Empirical studies on neuroleptic drugs involving clinical populations treated for schizophrenia, Tourette's disorder and stuttering, studies performed on normal healthy volunteers and selected experimental studies in animals, are reviewed. Results. Dysphoric responses occur early during treatment and typically manifest as a dislike towards medication (drug aversiveness). Dysphoria persisting over time, may lead to adverse clinical consequences such as treatment non-adherence, substance abuse, poor clinical outcome, increased suicidality and compromised quality of life. Interference with the physiological processes of hedonic capacity by the neuroleptics due to their dopaminergic blocking action in the prefrontal cortex and the shell of nucleus accumbens is the putative mediating mechanism underlying the occurrence of dysphoric responses. Second generation antipsychotic drugs with an atypical receptor blocking profile are less likely to elicit dysphoric responses. Conclusion. Viewing neuroleptic dysphoria within a broader spectrum of disorders of subjective tolerability and exploring its neurobiological mechanisms is relevant to addressing the nuances of antipsychotic therapy, and could help unravel the questions surrounding the pathophysiology of depression, substance abuse and other dysphoric clinical states.