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



Participants were 184 chronic tobacco smokers with schizophrenia (122 male) enrolled in a multisite smoking cessation study (Randomized Controlled Trial of a Motivational Decision Support System [RCTEDSS]; ClinicalTrials.gov #NCT02086162). The aim of this multisite study was to evaluate whether the use of a web-based decision support system resulted in higher rates of initiation of smoking cessation treatment compared to use of a computerized educational pamphlet. The primary outcomes of this study will be reported separately. To be eligible, participants had to be English speaking, daily smokers, with a diagnosis of schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV)[36] and stable in mental health treatment. Exclusion criteria were psychiatric instability (a score >75 on the Brief Psychiatric Rating Scale [BPRS][37]); current moderate/severe alcohol/drug dependence; pregnancy/breastfeeding.


Demographic and Clinical Assessments. Demographics and psychiatric history were assessed with a structured interview at baseline. Diagnosis of schizophrenia, schizoaffective disorder, and current drug/alcohol dependence was determined using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-IV). Psychotic symptom severity was assessed using the BPRS. All assessments were administered by trained interviewers.

Classification of Antipsychotic Medication. Current antipsychotic medications were obtained by self-report and confirmed by record review. Medications were classified into groups based on the potency with which they blocked the DA D2 receptor. This classification was carried out based on a theoretical hypothesis that the relative potency of DA D2 receptor antagonism might contribute to the reward-enhancing effects of nicotine in patients with schizophrenia. Medications known to be potent DA D2 receptor antagonists included haloperidol, fluphenazine, chlorpromazine, risperidone, olanzapine, and paliperidone.[38] Participants who were taking a combination of antipsychotics that included a potent D2 receptor antagonist and other types of antipsychotics were included in this class. Medications were considered "non-potent DA D2 antagonists" if they were known to have lower DA D2 antagonism (clozapine and quetiapine)[38–40] or DA D2 partial agonism, resulting in a lack of "functional antagonism" at DA D2 receptors (aripiprazole).[41–44] Patients who were not taking antipsychotic medication were excluded, as were those taking lurasidone, due to its complex pharmacologic profile.

Measures of Nicotine Dependence. Nicotine dependence was assessed using the Fagerström Test for Nicotine Dependence (FTND),[45] and smoking urges were assessed using the Tiffany Questionnaire of Smoking Urges (QSU).[46] Both measures have been found to have adequate psychometric properties among smokers with schizophrenia.[47] Expired carbon monoxide (CO)—associated with greater levels of smoking[48]—was obtained using a Smokerlyzer monitor (Bedfont Scientific).

Probabilistic Reward Task. To probe reward responsiveness, all participants completed the PRT.[32] Rooted within signal detection theory, the PRT allows for an objective assessment of the propensity to modulate behavior based on prior reinforcement. The PRT consisted of schematic faces presented on a monitor, each with 2 eyes, a nose, and a horizontal line for a mouth. On each trial, a fixation cross appeared for 500 ms, followed by a mouthless face. After 500 ms, either a "short mouth" (10 mm) or "long mouth" (11 mm) was presented for 100 ms. Participants indicated via keypress whether the short or long mouth appeared. There were 2 blocks of 100 trials, and 40 correct trials in each block were followed by a monetary reward (Correct!! You won 20 cents). Long mouths and short mouths were presented at equal frequencies; however, unbeknownst to participants, one of the mouth lengths (the "rich stimulus") was rewarded 3 times more frequently than the other mouth length (the "lean stimulus"). Participants were told to try and win as much money as possible, as they would be given the money that they earned. To avoid practice effects from pre- to post-smoking, 2 versions of the PRT were used—a version where the length of the mouth varied, and a version where the length of the nose varied, with different versions administered in a counterbalanced order across participants.


Participants were recruited through flyers and clinician referral. After providing informed consent, demographic, smoking, diagnostic, and symptom information was collected. Eligible participants returned to do the PRT and other cognitive assessments. They were instructed to smoke prior to the study visit. At the beginning of the visit, participants indicated that they had smoked within the past hour, which was confirmed with a breath CO sample ≥10 ppm. They then completed cognitive assessments, and after being abstinent for at least 1 hour, completed the PRT for the first time. They then smoked one of their own cigarettes over a period of 15 minutes. After this smoking period, a second breath CO sample was taken, and participants repeated a counterbalanced version of the PRT performed within 10 minutes of finishing smoking.