lack of funding

Tobacco smokers with schizophrenia are known to be resistant smokers, with high rates of smoking and inability to quit in the long-term, often related to smoking relapse. This may relate to problems with frontal lobe function associated with schizophrenia, which make these patients have great difficulty in dealing with smoking withdrawal, urges and cravings. The current study will develop a combination approach that takes advantage of brain stimulation of the frontal lobes (repetitive transcranial magnetic stimulation (rTMS), in combination with the anti-smoking drug varenicline, to prevent smoking lapse using a well-established human laboratory method. Results from this study may have important implications for developing novel treatment approaches for smokers with schizophrenia.

Tobacco smokers with schizophrenia (SWS) represent a subset of smokers with high smoking prevalence compared to the general population, and reduced ability to quit smoking and to resist smoking relapse. There is some evidence that first-line treatments for tobacco use disorder are safe and effective for smoking cessation and smoking relapse-prevention in SWS, but these treatments do not appear to be as effective in smokers with a mental illness as compared to non-psychiatric tobacco smokers. Novel approaches to identify safe and effective treatments using human laboratory models may be an efficient strategy towards this important clinical goal.

The proposed human laboratory study will test the effects of standard pharmacotherapy for tobacco use disorder, the nicotinic partial agonist varenicline, in combination with an established brain stimulation method (repetitive transcranial magnetic stimulation;; rTMS) in SWS. This will allow for the determination of the benefits of combining rTMS with varenciline in SWS using a validated smoking lapse paradigm developed by the collaborator Sherry McKee, Ph.D. at Yale University. The present study represents a novel neuroscience-based strategy for targeting dorsolateral prefrontal cortex (DLPFC) dysfunction in schizophrenia, and is consistent with a target engagement and validation approach as endorsed by NIDA/NIH. Moreover, the subject population the investigators are targeting (SWS) are prone to quit attempt failures and rapid relapse to tobacco smoking, and are in need of novel and effective anti-smoking lapse interventions. The investigators' preliminary data support the use of the combination of varenicline and high-frequency (20 Hz) rTMS to target smoking lapse and craving outcomes in SWS. Accordingly, the investigators believe that the proposed goals, approach and implications for treatment development are substantial and likely to impact positively on clinical treatment research outcomes in this marginalized population of tobacco smokers. Specifically, using a randomized, double-blind, placebo-controlled parallel groups experimental design, the investigators will determine whether the combination of varenicline (2 mg/day) and high-frequency (20 Hz) rTMS versus varenicline and sham rTMS directed to the DLPFC will be superior for the prevention of tobacco smoking lapse behaviors in cigarette smokers with schizophrenia (N=80).

Hypothesis 1 (H1): Active (20 Hz) versus Sham rTMS will increase the time to smoking lapse in combination with varenicline in SWS.

Hypothesis 2 (H2): Active (20 Hz) versus Sham rTMS will improve prefrontal cognition in SWS, and this will be associated with increased ability to resist smoking lapse.

Inclusion Criteria:

• smokers with schizophrenia, non-treatment seeking (i.e., not trying to quit as indicated by <7 on the contemplation ladder)
• ages 18-55
• IQ ≥80 on the Weschler Test of Adult Reading
• Fagerstrom Test for Nicotine Dependence (FTND) ≥5
• smoke ≥ 10 cigarettes per day
• must meet SCID for DSM-5 diagnosis criteria for schizophrenia
• must be in stable remission from positive symptoms of psychosis as judged by a PANSS positive score total score <70
• must be receiving a stable dose of antipsychotics for >1month.

Exclusion Criteria:

• substance use (except nicotine or caffeine) in the last month
• a history of alcohol/drug abuse in the 3 months before study enrolment and use of opioids (e.g., meperidine, oxycodone, methadone)
• current use of smoking cessation aids (e.g., nicotine replacement therapy, bupropion or varenicline)
• pregnancy or nursing
• a history of renal insufficiency or a hypersensitivity to varenicline (Chantix®)
• a history of neurological illness like epilepsy or medical condition known to significantly influence neurocognitive function, at the discretion of the PI
• any other medical condition deemed relevant by the PI

The investigators will have a sham rTMS coil to provide full blinding for the active rTMS condition.