Table 2.

Reported neuropsychiatric adverse events during varenicline use in clinical trials

	Sample size	Exclusion criteria	Intervention	Trial Design	Adverse events	Mood Outcomes	Smoking Outcomes
McClure (2009)	N=1117 661 had probable lifetime history of depression (DH+) vs. no history (DH-)	Psychosis, bipolar disorder, drug or heavy alcohol use	Telephone and/or web-based counseling	Open label varenicline up to 90 days	DH + more self-reported tension, irritability, difficulty concentrating, nausea, sleep disturbance, and confusion	Indices of mood not different between groups. Depression decreased in both groups over time	No difference in quit smoking rates between groups with and without history of depression
Philip (2009)	N=18 Axis I Depression (unipolar, bipolar or substance induced) and Nicotine Dependence	N/A	Adjunct to depression treatment; No smoking cessation counseling	Open label varenicline for 8 weeks	Sleep disturbance, GI, and irritability	No change in suicide ratings during study. Mean mood scores improved in study. One patient discontinued due to worse mood.	8 stopped smoking (44%), 9 reduced significantly and 1 had no change
Stapleton (2008)	N=111 (depression, bipolar disorder, psychosis, eating disorder)	N/A	Group counseling	Open label varenicline or NRT up to 12 weeks	Nausea and sleep disturbance	No evidence that varenicline exacerbated mental illness	Varenicline equally effective in those with and without mental illness. Short-term cessation rates were higher with varenicline than NRT.
Purvis (2009)	N=50 veterans 24 with mental illness (depression, PTSD, bipolar disorder, anxiety disorder, psychosis, ADHD)	N/A	Telephone counseling	Open label varenicline for up to 12 weeks		No suicidal ideation or attempts in study. Five self- reported worsening of psychiatric symptoms (depression, agitation, impulsivity)	Smokers with mental illness less likely to quit than those without history.
McClure (2010)	N=542 271 had prior psychiatric diagnosis (PH+) from chart review (depression, anxiety, other) vs. no history PH-	Psychosis, bipolar disorder, drug or heavy alcohol use	Telephone and/or web-based counseling	Open label varenicline up to 90 days	No difference in side effects in PH+ and PH- smokers	No difference in depression and anxiety in PH+ and PH- smokers	No difference in cessation rates in PH+ vs. PH- smokers
Poling (2010)	N=31 smokers on methadone maintenance also using cocaine	Psychosis, bipolar disorder	Substance abuse CBT counseling	DB-PC varenicline vs. placebo for 12 weeks	None	Varenicline treatment was not associated with increases in negative affect, measured with the PANAS	Significant smoking reduction and more weeks without smoking in varenicline group. No change in cocaine use
Steinberg (2011)	N=723 smokers assessed with K6 scale of SPD	N/A	Individual or group counseling	N=168 (23%) treated with open-label varenicline for up to 6 months	Not reported	Varenicline not associated with increases in scores of serious psychological distress vs. other medications	Smokers with SPD less likely to quit smoking than those without
Gunnell (2009)	80,660 smokers in UK primary care network Included 2244 (3.5%) taking an antidepressant	N/A	Not reported	10973 received open-label varenicline up to 12 weeks (vs NRT or bupropion)	Not reported	No difference in self-harm between medication treatment groups. No evidence of increased depression in patients taking varenicline with history of depression.	Not reported
Tonstad (2010)	N= 5096 smokers from 10 studies	Past year depression, alcohol or drug dependence or lifetime panic disorder, psychosis, bipolar disorder	Individual counseling	DB-PC varenicline vs. placebo for 6, 12 or 52 weeks	Varenicline associated with more sleep disturbance	No higher rate of psychiatric adverse events in varenicline group. No cases of suicidal ideation or behavior in varenicline-treated subjects.	Not reported
Garza (2011)	N=110	Current/past psychiatric illness by SCID; h/o suicidal thoughts or behavior		DB-PC varenicline vs. placebo for 12 weeks	Nausea, insomnia, somnolence, and abnormal dreams were more frequent in the varenicline group	Comprehensive weekly assessments for neuropsychiatric symptoms. No differences in rating for anxiety, depression, agitation, other symptoms between groups. No reports of suicidality.
Weiner (2011)	N=9 smokers with schizophrenia or schizoaffective disorder	N/A	Individual counseling	DB-PC varenicline vs. placebo for 12 weeks	Constipation, nausea and insomnia	No worsening of psychotic, depressive or other psychiatric symptoms or suicidal ideation.	Reduced smoking in varenicline group

NRT= nicotine replacement therapy; SPD=serious psychological distress

PTSD= post traumatic stress disorder; ADHD= attention deficit hyperactivity disorder; SCID= Structured Clinical Interview for DSM for Axis I and II disorders