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Mr. J. is a 38-year-old Caucasian male with chronic schizoaffective disorder, alcohol use disorder in sustained remission, tobacco use disorder and tardive dyskinesia. His psychotic disorder has been stable on clozapine. He has smoked cigarettes, 1-2 packs per day, for the past 20 years. Mr. J. also has mild orofacial tardive dyskinesia. At a recent outpatient visit, Mr. J. requested a trial of varenicline for smoking cessation. He underwent a 4-week trial of varenicline, which was overall well-tolerated, and his tobacco used decreased from 1.5 to 1 pack per day. During that time, his tardive dyskinesia remained unchanged, with an Abnormal Involuntary Movement Scale score of 6 at both baseline before and 4 weeks after starting varenicline.
The mechanism(s) underlying tardive dyskinesia (TD) are unclear. Beyond the dopamine D2-receptor supersensivity/upregulation hypothesis, one theory posits decreased cholinergic activity within striatal motor circuits, raising the possibility of treatments that normalize cholinergic signaling and restore the balance of acetylcholine and dopamine.1 The cholinergic system—which is inordinately complex—is divided into 2 main branches: muscarinic and nicotinic cholinergic receptors.2 Muscarinic cholinergic receptors have 5 sub-families (M1 to M5), all of which are G-protein coupled receptors. Benztropine and other M1 receptor antagonists worsen TD. By contrast, there are 17 vertebrate sub-units with 5 different families (alpha, beta, delta, gamma, and epsilon) of nicotinic cholinergic receptors, all of which are all ion channels, and have different physiologic functions than muscarinic cholinergic receptors.
Clinical evidence supporting a potential role of cholinergic deficiency includes the observation that anticholinergic agents worsen TD.3 In an animal model of TD, administration of varenicline, a partial α-4-β-2 and full α-7 nicotinic acetylycholine receptor (nAChR) agonist, attenuates haloperidol-induced vacuous chewing movements.2 However, effects of varenicline on TD in humans is unclear.
Caroff and colleagues conduced an open-label, pilot study investing the impact of varenicline on TD.4 Three outpatients with schizophrenia, no change in antipsychotic medication for 2 months, TD, and active smoking based on cigarette consumption and exhaled carbon monoxide (CO). After a 2-week baseline period, participants were titrated to 1 mg varenicline twice daily over 1 week, and were maintained on this dose for 4 weeks. The primary outcome was mean change in the Abnormal Involuntary Movement Scale (AIMS) total score from baseline to week 4. Other outcome measure were 7-day prevalence of daily mean cigarette use, CO, and akathisia.
Study authors recruited 3 males, mean age 59 years, who were all receiving long-acting injectable antipsychotic medication (paliperidone). The mean AIMS score at baseline was 9.7 (range 6-12). Participants showed a significant decrease in mean daily cigarette consumption (-6.3 cigarettes/day) and CO (-6.0 ppm) from baseline to week 4. There were no clinically significant changes from in TD (mean change in AIMS total score of +1) or akathisia.
The authors concluded that treatment with varenicline was associated with reduced smoking, but not TD, in a small, open-label pilot study. The authors noted it is uncertain whether results would have been different if patients were taking antipsychotics associated with marked changes in blood levels after smoking cessation (due to smoking-induced enzyme induction). Preclinical investigations of the complex dynamics underlying striatal regulation of movement may transform understanding of TD and identify novel potential cholinergic therapeutic targets, given that varenicline targets only a small slice of the cholinergic pie.
The Bottom Line
Trials of agents for smoking cessation in patients taking antipsychotic medications should include measures of drug-induced movement disorders.
Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.
1. Conti MM, Chambers N, Bishop C. A new outlook on cholinergic interneurons in Parkinson's disease and L-DOPA-induced dyskinesia. Neurosci Biobehav Rev. 2018;92:67-82.
2. Quik M, Boyd JT, Bordia T, Perez X. Potential therapeutic application for nicotinic receptor drugs in movement disorders. Nicotine Tob Res. 2019;21(3):357-369.
3. Caroff SN, Campbell EC, Carroll B. Pharmacological treatment of tardive dyskinesia: recent developments. Expert Rev Neurother. 2017;17(9):871-881.
4. Caroff SN, Gutman AR, Northrop J, et al. Effect of varenicline on tardive dyskinesia: a pilot study. Clin Psychopharmacol Neurosci. 2021;19(2):355-360.