Center for Depression, Anxiety, and Stress Research, McLean Hospital, Belmont, MA.
Department of Psychiatry, Harvard Medical School, Boston, MA.
Schizophr Bull. 2019 Oct 24;45(6):1300-1308. doi: 10.1093/schbul/sby185.
Antipsychotics that are potent dopamine (DA) D2 receptor antagonists have been linked to elevated levels of nicotine dependence in smokers with schizophrenia. Because activation of D2 receptors mediates motivation for nicotine, we examined whether potent D2 antagonists would diminish nicotine's ability to stimulate reward processing-a mechanism that may drive compensatory increases in smoking. Smokers with schizophrenia (n = 184) were recruited and stratified into medication groups based on D2 receptor antagonist potency. The effects of smoking on reward function were assessed using a probabilistic reward task (PRT), administered pre- and post-smoking. The PRT used an asymmetrical reinforcement schedule to produce a behavioral response bias, previously found to increase under conditions (including smoking) that enhance mesolimbic DA signaling. Among the 98 participants with valid PRT data and pharmacotherapy that could be stratified into D2 receptor antagonism potency, a medication × smoking × block interaction emerged (P = .005). Post-hoc tests revealed a smoking × block interaction only for those not taking potent D2 antagonists (P = .007). This group exhibited smoking-related increases in response bias (P < .001) that were absent in those taking potent D2 antagonists (P > .05). Our findings suggest that potent D2 antagonists diminish the reward-enhancing effects of nicotine in smokers with schizophrenia. This may be a mechanism implicated in the increased rate of smoking often observed in patients prescribed these medications. These findings have important clinical implications for the treatment of nicotine dependence in schizophrenia.
具有强效多巴胺 (DA) D2 受体拮抗作用的抗精神病药物与精神分裂症吸烟者尼古丁依赖水平升高有关。由于 D2 受体的激活介导了对尼古丁的动机，我们研究了强效 D2 拮抗剂是否会降低尼古丁刺激奖励处理的能力-这种机制可能会导致吸烟量的补偿性增加。招募了患有精神分裂症的吸烟者（n = 184），并根据 D2 受体拮抗剂的效力将他们分层到药物治疗组中。使用概率奖励任务（PRT）评估吸烟对奖励功能的影响，该任务在吸烟前和吸烟后进行。PRT 使用不对称强化计划来产生行为反应偏差，先前发现这种偏差在增强中隔侧多巴胺信号的条件（包括吸烟）下会增加。在有有效 PRT 数据和可以分层为 D2 受体拮抗作用强度的药物治疗的 98 名参与者中，出现了药物×吸烟×块交互作用（P =.005）。事后检验仅发现那些未服用强效 D2 拮抗剂的人存在吸烟×块交互作用（P =.007）。该组表现出与吸烟相关的反应偏差增加（P <.001），而服用强效 D2 拮抗剂的人则没有（P >.05）。我们的发现表明，强效 D2 拮抗剂可降低精神分裂症吸烟者尼古丁的奖励增强作用。这可能是在服用这些药物的患者中经常观察到吸烟率增加的一个机制。这些发现对治疗精神分裂症中的尼古丁依赖具有重要的临床意义。
