Potent Dopamine D2 Antagonists Block the Reward-Enhancing Effects of Nicotine in Smokers With Schizophrenia

Alexis E. Whitton; Alan I. Green; Diego A. Pizzagalli; Robert M. Roth; Jill M. Williams; Mary F. Brunette


Schizophr Bull. 2019;45(6):1300-1308. 

In This Article


The use of potent DA D2 receptor antagonists has been linked to increased smoking and difficulty quitting in smokers with schizophrenia.[24–26] The aim of our study was to evaluate a putative mechanism for these effects by examining whether taking potent DA D2 receptor antagonists was associated with a reduction in nicotine's ability to enhance reward learning. Consistent with predictions, smoking increased reward learning, but only in individuals who were not taking potent DA D2 antagonists. This effect was specific to reward learning, as effects were not observed on a measure of general task performance (ie, discriminability). Effects were also not attributable to demographic or clinical differences between the medication groups, or differences in nicotine dependence (FTND scores, expired CO, cigarettes per day), urges to smoke (QSU scores), or to post-smoking breath CO readings. Taken together, these findings point to a potential mechanistic explanation for increased smoking in individuals with schizophrenia who are treated with potent DA D2 receptor antagonists. Specifically, these antagonists appear to diminish the effects of tobacco smoking on reward processing. Although not directly assessed in this study, we suggest that this may be a factor that drives compensatory increases in smoking behavior in order to achieve the same level of reward/stimulation.

Our findings align with prior work linking greater tobacco smoking in patients with schizophrenia to the use of first-generation antipsychotics,[52] and research showing reductions in dependence and craving severity in individuals prescribed second-generation antipsychotics, such as aripiprazole and clozapine.[26,29] Although we are the first to show that increased smoking in those treated with potent DA D2 receptor antagonists may be related to a blunting of nicotine's effects on reward processing, our interpretation is consistent with findings from an earlier study, which examined links between antipsychotic-related DA D2 receptor occupancy and smoking in schizophrenia. Specifically, in patients who were randomized to olanzapine or risperidone, de Hann and colleagues[53] found that striatal D2 receptor occupancy following antipsychotic treatment (stable dose for at least 6 weeks) was associated with future smoking, where greater D2 receptor blockade predicted greater smoking frequency in the following 3 years. Recent studies suggest that nicotine may enhance associative conditioning.[54,55] Therefore, a possible alternative explanation for our findings is that rather than blocking the effects of nicotine on reward sensitivity, potent DA D2 receptor antagonists may diminish nicotine's ability to facilitate the formation of an association between the rich stimulus and reward receipt. This, and other studies linking use of typical antipsychotics to blunted striatal activation in response to monetary reward cues,[56] supports the notion that potent DA D2 receptor antagonists induce changes in the brain reward pathways, which may confer increased risk for nicotine dependence in individuals with schizophrenia.

Our initial hypothesis was based around evidence pointing to increased smoking in schizophrenia patients taking potent DA D2 receptor antagonists;[4,5] however, the 2 medication groups did not differ in smoking urges, dependence, or average number of cigarettes smoked per day. This may be because medication grouping occurred on a naturalistic basis, which meant that many participants were receiving several medications. It is possible that the polypharmacological profile of our sample may have reduced the magnitude of group differences in overt smoking behavior by comparison to other studies that have, for example, compared the effects of haloperidol monotherapy to no medication.[24] Additionally, other measures of smoking behavior may be more sensitive to group differences in nicotine dependence. For example, although de Haan and colleagues[53] found a relationship between antipsychotic-induced DA D2 receptor occupancy and future smoking, they failed to find an association between D2 receptor occupancy and smoking frequency at the time of scanning. As such, longitudinal measures of smoking may be more sensitive to medication-related differences in smoking behavior.

Our findings have important clinical implications for treating individuals with schizophrenia and co-occurring nicotine dependence. All patients with schizophrenia should be advised to quit and offered pharmacologic assistance with quitting. If a patient is unable to quit with evidence-based cessation treatment and is taking a potent DA D2 receptor antagonist, switching to a different antipsychotic with lower affinity DA D2 antagonism (eg, clozapine) or partial DA D2 agonism (eg, aripiprazole) may be appropriate prior to a second trial of evidence-based cessation treatment. This recommendation aligns with recent findings suggesting that clozapine may be an effective treatment for comorbid schizophrenia and nicotine dependence.[57] In addition, when considering the use of a potent DA 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.

Some limitations must be kept in mind when interpreting our findings. In our study, medication groupings were naturalistic rather than randomly assigned. Although the groups did not differ in terms of major demographic, clinical, or smoking characteristics, future research is needed to determine whether the blunted effect of smoking on reward processing observed in the D2 antagonism+ group is specifically caused by potent DA D2 receptor antagonism. It is possible that separate factors may cause a weaker effect of smoking on reward processing in certain individuals who are also more likely to be prescribed potent DA D2 receptor antagonists. Future studies could also use direct administration of nicotine, rather than tobacco smoking, to ensure that effects are not confounded by ingestion of other substances in tobacco. Furthermore, in the pre-smoking condition, participants were tested after a 60-minute period of smoking abstinence. Because this corresponds approximately with the half-life of nicotine (1–2 hours), it is possible that the baseline response bias would have been influenced by some residual levels of nicotine. Additional studies should incorporate a longer abstinence period, while avoiding withdrawal, which worsens reward function.[58] Finally, we did not examine smoking-induced changes in response bias in a non-psychiatric control sample. Future studies using a comparison sample are needed to determine whether the effects of smoking on response bias in patients not taking potent DA D2 receptor antagonists is normative or blunted in comparison with control smokers.

In sum, our findings indicate that the use of potent DA D2 receptor antagonists may reduce the ability of tobacco smoking to enhance reward-related processes in smokers with schizophrenia. Future longitudinal research is needed to examine the role of specific antipsychotic pharmacotherapies in the pharmacological management of schizophrenia and co-occurring tobacco smoking.