Dopamine D₂ Antagonists Impact Nicotine Reward Processing in Schizophrenia

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Dopamine D₂ antagonists impact nicotine reward processing in schizophrenia.

Patients with schizophrenia who are prescribed potent dopamine D₂ receptor antagonists often increase smoking and experience difficulty quitting. Possibly, this is due to a mechanism of these medications to reduce the reward-enhancing effect of nicotine, according to a study published in Schizophrenia Bulletin.

Researchers evaluated patients with schizophrenia who were taking potent dopamine D₂ receptor antagonists and chronic tobacco smokers using a probabilistic reward task before and after smoking. All patients were enrolled in the Randomized Controlled Trial of a Motivational Decision Support System study (RCTEDSS; NCT02086162). All study participants completed demographic and clinical assessments, had their medication classified by potency of the dopamine D₂ receptor antagonist, were analyzed for nicotine dependence, and completed a probabilistic reward task before and after smoking.

Of the 184 patients included in the study, 50.5% were black, 90.2% were unemployed, 66.3% were men, and the mean age was 45.73 years old. Over the previous 3 months, patients smoked an average of 15.57 cigarettes per day. After analyzing the probabilistic reward task, 114 patients had valid pre- and post-smoking data, and out of this group, 71 were classified as taking a potent dopamine D₂ receptor antagonist and 27 were classified as not taking potent dopamine D₂ receptor antagonist. Most characteristics of the 2 groups were similar except for gender and ethnicity, with more men (P =.04) and Hispanics (P =.01) in the potent dopamine D₂ receptor antagonist arm.

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A repeated measures analysis of variance, the Fagerström Test for Nicotine Dependence, indicated a significant interaction between type of medication classification, smoking, and blocking of reward-enhancing effects (F[1,96]=8.17, P =.005, η²=0.08). In the potent dopamine D₂ receptor antagonist arm, there was a significant interaction between smoking and blocking of reward-enhancing effects (F[1,26]=8.56, P =.007, η²=0.25), and in the post-smoking time frame, there was a significant interaction between type of medication classification and blocking of reward-enhancing effects (F[1,96]=9.07, P =.003, η²=0.09).

Some limitations of this study include the naturalistic characterization of medications vs randomly assigning medications to control for group covariates, only using smoking as a nicotine measure and not direct administration of nicotine, and a relatively short abstinence period as a pre-smoking time frame given a longer half-life of nicotine.

The researchers concluded a clinical implication of these findings indicate “when considering the use of a potent [dopamine] D₂ receptor antagonist for a patient with schizophrenia who smokes, it may be beneficial to implement concurrent efforts aimed at minimizing increases in smoking behavior.”


Whitton AE, Green AI, Pizzagalli DA, Roth RM, Williams JM,Brunette MF. Potent dopamine D₂ antagonists block the reward-enhancing effects of nicotine in smokers with schizophrenia [published online January 22, 2019]. Schizophr Bull. doi: 10.1093/schbul/sby185