Neuroleptic Dysphoria, Comorbid Drug Abuse in Schizophrenia and the Emerging Science of Subjective Tolerability—Towards a New Synthesis

Abstract One of the frequent but under-recognized side effects of antipsychotic medications is the subtle subjective changes including feelings of anxiety, distress and lack of pleasure, which are collectively labeled as neuroleptic-induced dysphoria and, ultimately, often lead to dislike and aversions to medications, with serious clinical consequences. Yet, those very patients take to frequent abuse of illicit drugs. Several surveys estimated the association of drug abuse in schizophrenia as ranging somewhere between 10–70%. One popular and frequently accepted explanation for such high association has been the self-medication hypothesis. In other words, patients take to illicit drugs as a way of dalleviating symptoms of the illness as well as medication-induced side effects, particularly neuroleptic dysphoria. Recent clinical and neuro-imaging studies have, for the first time, directly linked the genesis of neuroleptic dysphoria to the dopamine-binding ratios in the nigrostriatal complex. This recent evidence comes from the study of dopamine receptor occupancy using PET scanning as well as from dopamine depletion SPECT studies. Meanwhile, emerging evidence from research in the addiction field has implicated dopamine in the same neural circuitry in motivational and reinforcement behaviour, which is central to initiation and continuation of dependency states. As the self-medication hypothesis proved incapable of explaining all the varied pictures of dysphoria and comorbid addictions, a unifying hypothesis is put forward to argue that both vulnerability to drug addictions and medication-induced dysphoria vary on independent facets of the illness itself. The mechanism that possibly links both lies in a dysregulated dopamine signaling in the nucleus accumbens resulting from frontal/cortical and hippocampal dysfunction. Besides the neurochemical argument, clinical and epidemiological data seem also to add support to this proposition. Such proposal not only represents a major rethinking of the concept of schizophrenia and its varied domains and manifestations but has also significant clinical implications in understanding and better management of comorbid drug abuse in the context of the illness itself. The recent intensified research efforts to understand the central mechanisms related to the role of dopamine in reward, punishment and pleasurable experiences as well as motivational and reinforcement behaviour, opens a new vista in understanding how and why patients like or dislike their medications based on their subjective responses to medication-taking. It is possible that the field is on the verge of a new science, which can collectively be called: "The Science of Subjective Tolerability Disorders." Key Words: Schizophrenianeuroleptic dysphoriacomorbid drug abuseantipsychotic medicationsdopamine dysregulationnucleus accumbensmotivational and reinforcement behaviour