Varenicline Effects on Smoking, Cognition, and Psychiatric Symptoms in Schizophrenia: A Double-Blind Randomized Trial

Abstract

Schizophrenic patients have a high rate of smoking and cognitive deficits which may be related to a decreased number or responsiveness of nicotinic receptors in their brains. Varenicline is a partial nicotinic agonist which is effective as an antismoking drug in cigarette smokers, although concerns have been raised about potential psychiatric side-effects. We conducted a double-blind placebo controlled study in 87 schizophrenic smokers to evaluate the effects of varenicline (2 mg/day) on measures of smoking, cognition, psychiatric symptoms, and side-effects in schizophrenic patients who were cigarette smokers. Varenicline significantly decreased cotinine levels (P<0.001), and other objective and subjective measures of smoking (P < .01), and responses on a smoking urges scale (P = .02), more than placebo. Varenicline did not improve scores on a cognitive battery designed to test the effect of drugs on cognitive performance in schizophrenia (the MATRICS battery), either in overall MATRICS battery Composite or individual Domain scores, more than placebo. There were no significant differences between varenicline vs. placebo effects on total symptom scores on psychiatric rating scales, PANSS, SANS, or Calgary Depression scales, and there were no significant drug effects in any of these scales sub-scores when we used Benjamin-Hochberg corrected significance levels (α = .05). Varenicline patients did not show greater side-effects than placebo treated patients at any time point when controlled for baseline side-effect scores. Our study supports the use of varenicline as a safe drug for smoking reduction in schizophrenia but not as a cognitive enhancer.

Trial registration: ClinicalTrials.gov 00802919.

Trial registration: ClinicalTrials.gov NCT00802919.

Conflict of interest statement

Competing Interests: Dr. Smith has been supported by previous grants from National Institutes of Health, Stanley Foundation, NARSAD, and Individual Investigator Grants from Eli Lilly. He has received travel support from Eli Lilly. Dr. Amiaz participated in research initiated by Jonson & Jonson, Lilly and Biotis. She has received travel support from Astrazenca and Biotis. Dr. Tianmei Si has been supported by previous grants from “12th Five-year-plan” of National Key Technologies R & D Program of China, National Natural Science Foundation of China, Doctoral Program of Higher Education of China, Ministry of Education, and Individual Investigator Grants from Pfizer, AstraZaneca, J & J, and Lundbeck. Dr. Weiser has received consulting fees/honoraria/travel grants/research grants from Jansen, Lilly, Lundbeck, Teva, BiolineRX, Sanofi, Pfizer, and Astra Zenneca. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Flow chart of disposition of patients through the study.

Number of patients who were used for each major outcome measures in main analysis: Cognition: MATRICS battery Composite Score N = 54, Varenicline = 25, Placebo = 29; for number of subjects analyzed for individual Domain scores on MATRICS see Table 3 and Fig 3. Smoking Measures-Cigarettes Smoked and Breathalyzer CO N = 87, Varenicline = 42, Placebo = 45; Nicotine and Cotinine N = 70, Varenicline = 34, Placebo = 36; Smoking Urges QSU N = 85, varenicline = 40, Placebo = 45; Psychopathology Measures—PANSS Scale N = 77, Varenicline = 38, Placebo = 39; SANS Scale n = 64, Varenicline = 30, Placebo = 34; Calgary Depression Scale N = 74, Varenicline = 36, Placebo = 38.

Fig 2. Effects of varenicline and placebo on measures related to cigarette smoking.

Each value represents model adjusted least square mean score ± s.e.m. for that week, from mixed model ANCOVA. Significance of difference between varenicline and placebo means at specific time point (t-test): * P Drug Effect from mixed model ANCOVA: (A) Cigarettes Smoked/Day (N = 87, Varenicline = 42, Placebo = 45) Drug Effect F = 14.88, DF = 1, 81, P = 0.0002; Drug x Time Effect: F = 1.67, DF = 8,532, P = 0.1035. (B) C0 (N = 87, Varenicline = 42, Placebo = 45) Drug Effect: F = 16.27, DF = 1,81, P = 0.0001; Drug x Time Effect: F = 2.08 DF = 8,535, P = 0.0357; (C) Cotinine (N = 70, varenicline = 34, Placebo = 36) Drug Effect: F = 16.30, DF = 1,64, P = 0.0001; Drug X Time Effect: F = 8.81, DF = 2,112, P = .00003,; (D) Smoking Urges (QSU) (N = 85, varenicline = 40, Placebo = 45) Drug Effect: F = 7.20, DF = 1,79, P = 0.0089; Drug X Time Effect: F = 0.86, DF = 8,518, P = 0.5502.

Fig 3. Comparison of MATRICS Battery Domain and Overall Composite Scores In varenicline- and placebo- treated patients.

N's are shown in figure. Each value represents mean ± s.e.m. of Domain or Composite scores of subjects who had complete values on all Domain scores at baseline and week 8. Mean scores are not adjusted for baseline covariate value or site effects. Abbreviations of Domain and Composite scores in figure: SP = speed of processing, AV = attention-vigilance, WM = working memory, VERBL = verbal learning, VISL = visual learning, RP = reasoning-problem solving, COMP = overall composite. Significance of difference for specific Domain or Composite score between baseline and 8 week value: *P < .05, by paired t-test.

Fig 4. Effect of varenicline and placebo on PANSS Total and Depression Scores.

N = 77, Varenicline = 38, Placebo = 39. Each value represents model adjusted least square mean score ± s.e.m. for that week, from mixed model ANCOVA. Overall Drug Effect between varenicline and placebo: PANSS Total F = 2.11, DF = 1, 71, P = 0.151; PANSS Depression Factor F = 4.79, df = 1,71, P = 0.032. Significance of difference from same drug baseline in varenicline treated patients by least square means t-test: * P