Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2012 Apr 16.
Published in final edited form as: J Addict Res Ther. 2011 Dec 20;Suppl 4(1):3045. doi: 10.4172/2155-6105.S4-001

A Review of Varenicline’s Efficacy and Tolerability in Smoking Cessation Studies in Subjects with Schizophrenia

Mahtab Karkhane Yousefi 1, Timothy D Folsom 1, S Hossein Fatemi 1,2,*
PMCID: PMC3327361  NIHMSID: NIHMS356233  PMID: 22514788

Abstract

Schizophrenia is a severe psychiatric disorder affecting 1% of the world’s population. Nicotine addiction is one of the most important health concerns for patients with schizophrenia. An extensive body of evidence points to a high prevalence rate of comorbid nicotine addiction in people with schizophrenia (70–90%), which contributes to significant cardiovascular and cancer risks in this vulnerable population. Therefore, effective smoking cessation strategies could play a major role in preventing significant morbidity and mortality in this population. Two of the most common pharmacological approaches to smoking cessation, bupropion and nicotine replacement therapy (NRT), have been used in psychiatric patients to reduce their smoking. In 2006, varenicline, a partial agonist of α4β2 acetylcholine receptor, was approved for smoking cessation by the FDA. This drug not only has the beneficial effects on withdrawal symptoms, but also reduces craving and rewarding effects of smoking. While varenicline has been shown to be an effective, safe medication for the general population, its efficacy and safety for subjects with schizophrenia is less well characterized. A number of case studies have prompted FDA warnings about the potential exacerbation of psychiatric symptoms. However, other case studies and pilot studies have shown varenicline to be a safe and effective treatment for smoking cessation in subjects with schizophrenia. Varenicline has the potential to reduce smoking in subjects with schizophrenia, however, clinicians should carefully monitor patients receiving varenicline for potential exacerbation of psychiatric symptoms.

Keywords: Schizophrenia, Schizoaffective disorder, Smoking cessation, Varenicline, Bupropion

Schizophrenia and Nicotine Addiction

Schizophrenia is a major debilitating and neurodevelopmental [1] disorder which affects an estimated 1% of the world’s population. Subjects with schizophrenia present with a variety of characteristic symptoms, such as delusions, hallucinations, disorganized speech and behavior (positive symptoms), and/or affective flattening, poverty of thought, and avolition (negative symptoms) [2]. There is a high prevalence of substance abuse in subjects with schizophrenia [3,4]. Several reports find a strong association between smoking and schizophrenia with prevalence rates ranging from 74% [5] to as high as 90% [6–8], as compared to national average of 20% in individuals who do not have a diagnosis of schizophrenia [9]. Smoking cessation rates among patients with schizophrenia are considerably lower than for other psychiatric disorders [10,11]. Not surprisingly, people with schizophrenia have an increased risk for at least three of the most important respiratory diseases: Chronic obstructive pulmonary disease (COPD), pharyngeal cancer, and lung cancer [12–14]. However, others have found reduced rates of cancer among subjects with schizophrenia [15,16].

A number of hypotheses have been proposed to explain the relationship between high smoking rates and schizophrenia [7,17,18], mostly relating to self-medication. Dalack et al. [17] reviewed preclinical and clinical literature and suggested that subjects with schizophrenia were using nicotine as a way of self-medicating, primarily for the negative symptoms of schizophrenia [17]. Similarly, Patkar et al. [7] found significant correlations between smoking and negative symptoms, including blunted affect, social withdrawal, difficulty in abstract thinking, and stereotyped thinking. In contrast, they found no correlation to positive symptoms [7]. Other researchers have hypothesized self-medication of anxiety, depression, and psychotic symptoms [19,20], self-medication to reduce extrapyramidal side effects [5], and to enhance cognition and normalizing attentional and information processing deficits [20,21]. Patients who smoke require a higher dosage of antipsychotics because they metabolize their medication more rapidly than nonsmokers [22].

Psychosocial factors also influence the high rate of smoking in subjects with schizophrenia. Several social factors that increase the risk of smoking in this population are low educational attainment, unemployment, peer influence and the mental health care system [23]. It has been hypothesized that the rewards patients with schizophrenia receive from smoking, particularly the reduction of negative symptoms, might increase the patients’ interactions with others, reducing feelings of isolation [22]. Others have pointed out that mental health settings, including group homes where other smokers live and where smoking is accepted, has possibly contributed to the increased rates of smoking [24]. Indeed, supplying cigarettes has been used to reward positive behavior in psychiatric treatment units [25]. It has only been recently that some psychiatric treatment facilities have begun to address smoking cessation strategies [23].

Nicotine has been shown to increase the release of dopamine in the nucleus accumbens and prefrontal cortex [26–28] via alteration in firing of ventral tegmental dopamine cells from a regular pattern to a burst-firing format. The consequent release of dopamine in nucleus accumbens has been associated with reward mechanisms in the brain [29–31]. Additional studies provide evidence for nicotine stimulation of dopamine release via activation of nicotinic receptors localized on dopaminergic neurons in the mesolimbic system [17], and smoking results in a reduction in activity of the monoamine oxidase B enzyme and the consequent decrease in degradation of dopamine in the brain [32]. Recent evidence [7] links high smoking rates with negative symptoms in subjects with schizophrenia. Negative symptoms are related to a hypodopaminergic state of the brain and are thus relieved by nicotinic stimulation of dopamine release via increased smoking. Finally, nicotine also enhances glutamatergic and GABAergic function in brains of subjects with schizophrenia [33] helping in better transmission of these neurotransmitters implicated in pathophysiology of schizophrenia.

Smoking Cessation Studies in Schizophrenia

Due to the use of nicotine for self-medication by patients with schizophrenia, it may be that the smoking cessation agents which work well for smokers that do not have a diagnosis of schizophrenia may have reduced efficacy among patients with schizophrenia who smoke. For the patients with schizophrenia who smoke and are unwilling or unable to quit, a smoking reduction approach may have benefits, as described by Dalack and Meader-Woodruff’s study on the use of nicotine patch [10]. An alternative approach involves use of psychotropic medications, which affect the dopamine and norepinephrine systems. One such agent is bupropion HCl, a unicyclic aminoketone atypical antidepressant.

A number of reports [34–39], as well as a recent metaanalysis [40], now suggest that bupropion HCl is a safe medication for treatment of smoking in subjects with schizophrenia, although its effectiveness is inconclusive. Evins et al. [35] examined the effect of bupropion HCl combined with cognitive behavioral therapy (CBT) on smoking cessation. They found that subjects treated with bupropion HCl and CBT were more likely to be abstinent a week after the quit date, as well as four weeks of continuous abstinence [35]. Treatment with bupropion HCl also displayed a trend towards improvement in depressive and negative symptoms [35]. However, Evins et al. [35] found a high relapse rate at the end of treatment. More recently, a study by George et al. [38] found that smokers with schizophrenia that received bupropion HCl combined with transdermal nicotine patch were significantly more likely to achieve continuous smoking abstinence than those with the transdermal nicotine patch alone [38]. Importantly, the combination of bupropion HCl and transdermal nicotine patch was well tolerated by smokers with schizophrenia and did not alter positive or negative symptoms of schizophrenia [38].

Several studies have shown an impact of antipsychotics on the smoking behavior of subjects with schizophrenia. Haloperidol has been shown to increase smoking among subjects with schizophrenia and results in a worsening of some of the symptoms ameliorated by nicotine [41–43]. A report by de Leon et al. [44] has shown that, in contrast to earlier studies [45–46], clozapine had no significant effect on smoking cessation. Another study has shown that atypical antipsychotics combined with a nicotine patch had an enhanced rate of smoking cessation [47]. Moreover, George et al. [37] demonstrated that antipsychotic medication (clozapine, risperidone, or olanzapine) and bupropion HCl enhanced smoking cessation outcomes when compared to placebo [37].

Varenicline

Varenicline is a new smoking cessation aide that was approved by the FDA on May 11, 2006. Varenicline is a partial α4β2 and full α7 nicotinic acetylcholine receptor agonist. Animal studies have established that the α4β2 receptor is necessary and sufficient to establish nicotine addiction [48–52]. Stimulation of this receptor by its agonist causes a release of dopamine from the nucleus accumbens and prefrontal cortex [53]. In addition, studies of knockout mice suggested that α5, α7, and β4 acetylcholine receptor subunits have some essential roles in the expression of somatic signs of nicotine withdrawal, and that β2 subunits were instrumental in showing affective aspects of the nicotine withdrawal [48]. As a partial agonist of the α4β2 receptor, varenicline allows for the release of some dopamine, which causes a lessening of withdrawal and craving, while blocking the effects of nicotine in cigarette smoke.

To date, there have been several smoking cessation and maintenance of cessation studies [57–63] to test varenicline’s efficacy. These studies have found varenicline to be more effective than placebo and bupropion as measured by consistently higher continuous abstinence rates both at the end of the initial study periods as well as up to a year following the end of treatment. Furthermore, subjects on varenicline reported reduced craving, withdrawal symptoms, and smoking satisfaction when compared to subjects on nicotine replacement therapy [54,64].

Nausea has been reported as the most common side effect with varenicline [57,59]. Other common side effects include sleep disturbance and constipation [65]. A recent case study has shown that varenicline may trigger severe hyperglycemia in subjects with Type 1 diabetes suggesting that further investigation of the use of varenicline in subjects with diabetes is warranted [66]. Also, a review study has documented 78 adverse events related to aggression/ violence associated with use of varenicline including assault (10 events), homicidal ideation (nine events), and other thoughts or acts of violence and aggression (seven events) [67]. Of these cases, 93% of them were resolved following discontinuation of varenicline [67]. Finally, the FDA has recently issued a statement that “varenicline may be associated with a small increased risk of certain cardiovascular adverse events” in patients with cardiovascular disease [68]. Table 1 summarizes physical side effects associated with varenicline in selected publications.

Table 1.

Commonly reported physical side effects of varenicline.

Study Population Dosage Side Effects (including percentage experiencing a given side effect)
Boudrez et al. [56] Non-psychiatric Not specified Nausea (8.9%), insomnia (2.9%), and sleep disorder (2.2%)
Gonzales et al. [57] Non-psychiatric 1 mg BID Nausea (28%), insomnia (14%), dry mouth (6.7%), headache (15.5%), and dizziness (6%)
Jorenby et al. [59] Non-psychiatric 1 mg BID Nausea (29.4%), insomnia (14.2%), abnormal dreams (13.1%), headache (12.8%), and dry mouth (5.5%)
Nides et al. [61] Non-psychiatric 1 mg BID Nausea (52%), insomnia (35.2%), headache (24%), abnormal dreams (15.2%), and taste perversion (15.2%)
Garza et al. [85] Non-psychiatric 1 mg BID Nausea (37.7%), insomnia (30.9%), somnolence (20%), and abnormal dreams (9.1%)
Evins and Goff, [88] Schizophrenia 1 mg BID Nausea and vomiting (21.1%)
Stapleton et al. [89] Depression, bipolar disorder, psychosis, psychosis and depression, eating disorders Not specified Nausea (32.1%), and sleep disturbances (32.1%)
Smith et al. [90] Schizophrenia, schizoaffective 1 mg BID Mild nausea, shaking, dry mouth, and tiredness-sleepiness (57% of all patients experienced at least one side effect)
Weiner et al. [91] Schizophrenia 1 mg BID Constipation (50%), insomnia (75%), and nausea (75%)
Liu et al. [92] Schizophrenia 1 mg BID Nausea (10%), vomiting (10%), fatigue (5%), dry mouth (5%), muscle stiffness (5%), and headache (5%)
McClure et al. [97] Depression 1 mg BID Tension/agitation (51%), nausea (61.6%), sleep disturbance (46.4%), irritability (47.1%), confusion (19.3%), and difficulty concentrating (33.4%)
Philip et al. [98] Depression 1 mg BID GI problem (21.4%), sleep disturbances, and irritability (7.1%)
Tonstad et al. [99] Non-psychiatric 1 mg BID Sleep disturbance (19.9%)
Open in a new tab

GI: Gastrointestinal

Thus far, there are no published studies that have shown an interaction between varenicline and antipsychotic medications. Indeed, varenicline’s pharmacokinetic properties suggest that there would not be an interaction with antipsychotic medications. It has been demonstrated that 92% of varenicline is excreted unchanged in urine [69]. In vitro studies in human liver microsomes have demonstrated that varenicline does not induce or inhibit human cytochrome P450 activities, thus having no effect on CYP1A2, CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A [70]. Therefore, it is unlikely that varenicline would interact with any medication that is primarily cleared by P450 enzymes. Consequently, drugs like clozapine and olanzapine, that are primarily cleared by CYP1A2 [71], and haloperidol, perphenazine, risperidone, thioridazine, and zuclopenthixol, that are cleared by CYP2D6 [71], are unlikely to interact with varenicline. It is important to emphasize, however, that as a result of smoking cessation, plasma levels of CYP1A2 metabolized drugs may increase to potentially toxic levels [72,73]. Therefore, it is important for clinicians to carefully monitor plasma levels of these drugs for patients undergoing treatment with varenicline or other smoking cessation programs.

Varenicline and Schizophrenia

The use of varenicline to treat smokers with schizophrenia and other psychiatric disorders has been and continues to be considered controversial due to a number of case studies and a small pilot study which showed exacerbation of psychiatric symptoms including psychosis, mania, anxiety, and depression [74–83] (Table 2). An FDA warning, issued February 1, 2008, stated that serious neuropsychiatric symptoms, including changes in behavior, agitation, depressed mood, suicidal ideation, and attempted and completed suicide, have occurred in patients taking varenicline [84]. Because of these case studies and the FDA warning, it is important that people with schizophrenia receiving outpatient care receive close monitoring, especially early in treatment, to ensure that there are no physical or psychiatric side-effects are manifested as a result of varenicline.

Table 2.

Psychiatric side effects of varenicline.

Study Underlying disorder (N) Methods and Dosage Outcome Concomitant medication
Ahmed et al. [74] Bipolar disorder (1) Case report; Duration: 7 days (1mg/day) Acute manic episode mianserin (90 mg/day), oxazepam (10 mg/day), acetylsalicylic acid (80 mg/day), barnidipine (20 mg/day), hydrochlorothiazide (12.5 mg/day), perindopril (8 mg/day) and rosuvastatin (5 mg/day)
Francois et al. [75] None (1) Case report; Duration: 7 days (dose not specified) Grandiose delusions, agitation, insomnia, rapid speech None
Freedman, [76] Schizophrenia (1) Case report; Duration: 5 days (1 mg BID) Exacerbation of psychotic symptoms Thiothixene (10–15mg/day)
Hussain et al. [77] History of mild depression (1) Case report; Duration: approximately three weeks (0.5mg/day) Manic episode Oxycodone (up to 12 pills/day), diazepam (10mg/day)
Ismail et al. [78] Schizophrenia (1) Case report; Duration: 20 days (1 mg BID) Significantly reduced smoking and self-reported craving to smoke. Polydipsia and hyponatremia Depot risperidone (25mg/2 weeks)
Kohen and Kremen, [79] Bipolar disorder (1) Case report; Duration: 7 days (2mg/day) Exacerbation of manic episode valproic acid (dose not specified)
Morstad, [81] Bipolar II disorder, poly-substance abuse (1) Case report; Duration: approximately one month (2mg/day) Hypomanic episode with suicidal ideation bupropion XL (300 mg/day), clonazepam (1 mg/day), oxcarbazepine (450 mg/day), quetiapine (100 mg/day), montelukast (10 mg/day), pantoprazole (40 mg/day)
Popkin, [82] Major depression (1) Case report; Duration: 6 weeks (2mg/day) Hypersomnia, unusual dreams, decreased appetite, irritability, sadness and guilt Fluoxetine (20mg/day), aspirin, niacin and metoprolol
Waldo et al. [83] Schizophrenia (6) Pilot study; Duration: 2 hours (1 mg, once) Varenicline did not improve P50 gating. Study discontinued due to emergence of suicidal ideation, aggressive, erratic behavior Atypical APDs
Anghelescu, [86] Schizophrenia (1) Case report; Duration: 2 weeks (1 mg BID) Complete abstinence confirmed with expired CO level, improvement of negative symptoms 45 to 22 via PANSS Depot risperidone (37.5mg/2 weeks)
Fatemi, [87] Schizophrenia (1) Case report; Duration: >24 weeks (1 mg BID) Meaningful reduction in number of cigarettes smoked Clozapine (700mg/day) and citalopram (40 mg/day)
Evins and Goff, [88] Schizophrenia (16) Case series; Duration: 12 weeks (1 mg BID) Reduced craving to smoke, 13 patients quit smoking (expired CO level <9 ppm), self-reported abstinence ≥ 12 weeks Various antipsychotics
Smith et al. [90] Schizophrenia (9); Schizoaffective (3) Case series; Duration: 9 weeks (1 mg BID) Significant decrease in plasma cotinine (p <0.01), expired CO level (p<0.05), self-reported smoking urges, number of cigarettes smoked and nicotine level. Improvement in some cognitive test score Various antipsychotics
Weiner et al. [91] Schizophrenia (8) Double blind randomized trial; Duration: 12 weeks (1 mg BID) Sustained abstinence and significant reduction in CO level <10 ppm (p=0.02) in Varenicline group Atypical antipsychotics
Dutra et al. [93] Schizophrenia or Schizoaffective disorder (53) Trial combined with CBT; Duration: 12 weeks (1 mg BID) 60.4% attained abstinence, significantly reduced CO levels (p<0.001) compared with baseline Various antipsychotics
Pirmoradi et al. [100] Alcohol abuse and MDD (1) Case report; Duration: 7 days (1mg/day) Experience of severe anxiety eszopiclone (2 mg/day), fluoxetine (20 mg/day), bupropion hydrochloride (300 mg/day), lisinopril (10 mg/day) and hydrochlorothiazide 12.5 mg/day)
Pumariega et al. [101] MDD (1) Case report; Duration: 90 days (dose not specified) Creation of manic episode Sertraline (dose not specified)
DiPaula and Thomas, [102] Bipolar disorder (1) Case report; Duration: 2 days (2mg/day) Exacerbation of psychotic symptoms and agitation Haloperidol, olanzapine, lorazepam and diphenhydramine (dose not specified)
Liu et al. [103] Schizoaffective disorder (1) Case report; Duration: 13 days (dose not specified) Exacerbation of mania episode with psychotic features clothiapine (160 mg/day) and lithium (1,200 mg/day)
Lyon, [104] MDD, GAD, BLPD and marijuana use (1) Case report; Duration: One month (2mg/day) Paranoia and irritability Topiramate (200 mg/day), duloxetine (120 mg/day), modafinil (400 mg/day) and clonazepam (2mg/day)
Alhatem et al. [105] Bipolar and Adult ADHD disorder (1) Case report; Duration: 2 weeks (dose not specified) Exacerbation of mania Quetiapine and amphetamine salts (dose not specified)
Kutscher et al. [106] None (1) Case report; Duration: 10 weeks (dose not specified) Paranoia, anxiety and suicidal ideation Oral contraceptive
Raidoo et al. [107] PTSD, depression, alcohol dependence (1) Case report; Duration: 19 days (2mg/day) Visual hallucination fluoxetine (20 mg/day), nortriptyline (25 mg/day), quetiapine (50 mg/day), prazosin (1 mg/day), pramipexole (0.5 mg/day), terazosin (5 mg/day), atenolol (50 mg/day) and spironolactone (50 mg/day)
Cinemre et al. [108] Brief episode of atypical psychosis (1) Case report; Duration: 30 days (dose not specified) Creation of psychotic symptoms None
Open in a new tab

ADHD: Attention deficit hyperactivity disorder; BLPD: Borderline personality disorder; GAD: Generalized anxiety disorder; MDD, Major depressive disorder; PTSD, post-traumatic stress disorder.

A recent study involving subjects without psychiatric illnesses found no difference between subjects receiving placebo and subjects receiving varenicline on measures of depression, anxiety, or aggression and hostility [85]. Additionally, separate case studies have found that varenicline was effective in reducing smoking in individuals with schizophrenia with no exacerbation of symptoms [86,87]. Moreover, a case series showed lack of worsening in psychosis in 13 subjects with schizophrenia successfully treated with varenicline [88]. Finally, a study by Stapleton et al. [89], has demonstrated that there is no exacerbation of symptoms of mental illness in subjects diagnosed with depression, bipolar disorder, psychosis, psychosis and depression, and eating disorders following treatment with varenicline combined with group support.

More recently, a number of pilot studies have examined the efficacy and safety of varenicline for subjects with schizophrenia (Table 2). Smith et al. [90] found that treatment with varenicline led to some cognitive improvement as measured by RBANS subscores for list learning, list recall, and language index. The same patients significantly reduced the number of cigarettes smoked as well as reduced CO expired and cotinine levels [90]. A small pilot study comparing varenicline to placebo in subjects with schizophrenia (n=4 each) found significantly increased smoking abstinence, verified by significantly lower carbon monoxide levels, in subjects in the varenicline group following 12 weeks of treatment [91]. Importantly, varenicline had no effect on psychotic, depressive, or other psychiatric symptoms [91]. Similarly, a study involving patients with schizophrenia undergoing a mandatory smoking cessation intervention showed that patients receiving varenicline had no exacerbation of depression or anxiety [92]. A larger study of 53 subjects with schizophrenia treated with varenicline and cognitive behavioral therapy (CBT) for 12 weeks found that 60.4% attained 14-day point prevalence abstinence at week 12, which was verified by significantly reduced expired CO [93]. Varenicline treatment has recently been shown to improve executive function and reduce startle reactivity, regardless of smoking status in subjects with schizophrenia [94]. Moreover, gradual titration of varenicline did not lead to increased psychosis, suicidal ideation, or depression [94]. Thus, emerging data suggests that varenicline has the potential to be safe and effective for subjects with schizophrenia. However, large-scale controlled studies are needed to provide a more accurate picture of varenicline’s efficacy and safety in subjects with schizophrenia.

The efficacy of varenicline in subjects with schizophrenia may be related to its effect on induction of dopaminergic signaling and on induction of gene expression. Dutra et al. [93] found that subjects with lower baseline scores of affective flattening were more likely to attain abstinence with varenicline and CBT. Studies have shown that affective flattening is related to dysfunction of the dopamine D2 receptor (DRD2) [95], while in a rodent model, varenicline has been shown to increase DRD2 binding in striatum [96]. Thus, the authors posit that striatal DRD2 stimulation by varenicline may be one way in which it aids smoking cessation [93].

While the recent studies cited above provide preliminary evidence that varenicline may be safe and effective for subjects with schizophrenia, concerns remain regarding possible exacerbation of psychiatric symptoms such as mania, psychosis, and suicidal ideation. Clinicians are advised to carefully discuss the pros and cons of varenicline treatment with their patients who wish to reduce or quit smoking and to closely monitor patients for any changes in behavior. Finally, a recent review has indicated an increase in suicidal ideation in subjects treated with varenicline [109].

Conclusions

Nicotine addiction remains an important health concern for subjects with schizophrenia due to the resulting increased morbidity and mortality in this population. Smoking cessation strategies in subjects with schizophrenia using nicotine replacement therapy or bupropion have been inconclusive. Due to its success in the general population, varenicline has the potential to dramatically increase smoking cessation and improve the overall health of subjects with schizophrenia. A number of case studies have demonstrated adverse psychiatric changes in healthy as well as patients diagnosed with mental illness as a result of treatment with varenicline. Other studies, however, have found no psychiatric side-effects. Careful monitoring of patients with schizophrenia receiving varenicline by clinicians is warranted. There are currently few controlled studies of varenicline to determine its safety and efficacy in subjects with schizophrenia. Further large-scale studies are required, as well as research into varenicline’s mode of action to determine if widespread use in this population is warranted.

Acknowledgments

Grant support from the National Institute on Drug Abuse (Grant # R01DA024674-01A1) to SHF is gratefully acknowledged.

Footnotes

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

References

  • 1.Fatemi SH, Folsom TD. The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull. 2009;35:528–548. doi: 10.1093/schbul/sbn187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Meltzer HY, Fatemi SH. Schizophrenia and other psychotic disorders. In: Ebert M, Loosen PT, Nurcombe B, editors. Current Diagnosis and Treatment in Psychiatry. Norwalk CT: Appleton and Lange; 2000. pp. 260–277. [Google Scholar]
  • 3.Frances RJ. Schizophrenia and substance abuse. Psych Annals. 1996;26:523–527. [Google Scholar]
  • 4.Westermeyer J. Schizophrenia and substance abuse. In: Tasman A, Riba MA, editors. Review of Psychiatry. Vol. 11. Washington DC: American Psychiatric Publishers; 1992. pp. 379–401. [Google Scholar]
  • 5.Goff DC, Henderson DC, Amico E. Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am J Psychiatry. 1992;149:1189–1194. doi: 10.1176/ajp.149.9.1189. [DOI] [PubMed] [Google Scholar]
  • 6.Hughes JR, Hatsukami DK, Mitchell JE, Dahlgren LA. Prevalence of smoking among psychiatric outpatients. Am J Psychiatry. 1986;143:993–997. doi: 10.1176/ajp.143.8.993. [DOI] [PubMed] [Google Scholar]
  • 7.Patkar AA, Gopalakrishnan R, Lunda A, Leone FT, Certa KM, et al. Relationship between tobacco smoking and positive and negative symptoms in schizophrenia. J Nerv Ment Dis. 2002;190:604–610. doi: 10.1097/00005053-200209000-00005. [DOI] [PubMed] [Google Scholar]
  • 8.Procyshyn RM, Tse G, Sin O, Flynn S. Concomitant clozapine reduces smoking in patients treated with risperidone. Eur Neuropsychoph. 2002;12:77–80. doi: 10.1016/s0924-977x(01)00130-4. [DOI] [PubMed] [Google Scholar]
  • 9.Centers for Disease Control and Prevention . Vital signs: current cigarette smoking among adults aged > or = 18 years ---United States 2009. MMWR Morb Mortal Wkly Rep. 2010;59:1135–1140. [PubMed] [Google Scholar]
  • 10.Dalack GW, Meador-Woodruff JH. Acute feasibility and safety of a smoking reduction strategy for smokers with schizophrenia. Nicotine Tob Res. 1999;1:53–57. doi: 10.1080/14622299050011151. [DOI] [PubMed] [Google Scholar]
  • 11.de Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr Res. 2005;76:135–157. doi: 10.1016/j.schres.2005.02.010. [DOI] [PubMed] [Google Scholar]
  • 12.Himelhoch S, Lehman A, Kreyenbuhl J, Daumit G, Brown C, et al. Prevalence of chronic obstructive pulmonary disease among those with serious mental illness. Am J Psychiatry. 2004;161:2317–2319. doi: 10.1176/appi.ajp.161.12.2317. [DOI] [PubMed] [Google Scholar]
  • 13.Lichtermann D, Ekelund J, Pukkala E, Tanskanen A, Lönnqvist J. Incidence of cancer among persons with schizophrenia and their relatives. Arch Gen Psychiatry. 2001;58:573–578. doi: 10.1001/archpsyc.58.6.573. [DOI] [PubMed] [Google Scholar]
  • 14.Tran E, Rouillon F, Loze JY, Casadebaig F, Philippe A, et al. Cancer mortality in patients with schizophrenia: an 11-year prospective cohort study. Cancer. 2009;115:3555–3562. doi: 10.1002/cncr.24383. [DOI] [PubMed] [Google Scholar]
  • 15.Bushe CJ, Hodgson R. Schizophrenia and cancer: in 2010 do we understand the connection? Can J Psychiatry. 2010;55:761–767. doi: 10.1177/070674371005501203. [DOI] [PubMed] [Google Scholar]
  • 16.Wang Y, He G, He L, McGrath J. Do shared mechanisms underlying cell cycle regulation and synaptic plasticity underlie the reduced incidence of cancer in schizophrenia? Schizophr Res. 2011;130:282–284. doi: 10.1016/j.schres.2011.05.009. [DOI] [PubMed] [Google Scholar]
  • 17.Dalack GW, Healy DJ, Meador-Woodruff JH. Nicotine dependence and schizophrenia: clinical phenomenon and laboratory findings. Am J Psychiatry. 1998;155:1490–1501. doi: 10.1176/ajp.155.11.1490. [DOI] [PubMed] [Google Scholar]
  • 18.Ziedonis DM, George TP. Schizophrenia and nicotine use: report of a pilot smoking cessation program and review of neurobiological and clinical issues. Schizophr Bull. 1997;23:247–254. doi: 10.1093/schbul/23.2.247. [DOI] [PubMed] [Google Scholar]
  • 19.Glynn SM, Sussman S. Why patients smoke. Hosp Community Psychiatry. 1990;41:1027–1028. doi: 10.1176/ps.41.9.1027. [DOI] [PubMed] [Google Scholar]
  • 20.Gurpegui M, Martinez-Ortega JM, Jurado D, Aguilar MC, Diaz FJ, et al. Subjective effects and the main reason for smoking in outpatients with schizophrenia: a case-control study. Comp Psychiatry. 2007;48:186–191. doi: 10.1016/j.comppsych.2006.10.002. [DOI] [PubMed] [Google Scholar]
  • 21.Adler LE, Olincy A, Waldo M, Harris JG, Griffith J, et al. Schizophrenia, sensory gating, and nicotinic receptors. Schizophr Bull. 1998;24:189–202. doi: 10.1093/oxfordjournals.schbul.a033320. [DOI] [PubMed] [Google Scholar]
  • 22.Lyon ER. A review of the effects of nicotine on schizophrenia and antipsychotic medications. Psychiatr Serv. 1999;50:1346–1350. doi: 10.1176/ps.50.10.1346. [DOI] [PubMed] [Google Scholar]
  • 23.Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008;10:1691–1715. doi: 10.1080/14622200802443569. [DOI] [PubMed] [Google Scholar]
  • 24.Ziedonis D, Williams JM, Smelson D. Serious mental illness and tobacco addiction: a model program to address this common but neglected issue. Am J Med Sci. 2003;326:223–230. doi: 10.1097/00000441-200310000-00014. [DOI] [PubMed] [Google Scholar]
  • 25.Gustafson R. Operant conditioning of activities of daily living on a psychogeriatric ward: a simple method. Psychol Rep. 1992;70:603–607. doi: 10.2466/pr0.1992.70.2.603. [DOI] [PubMed] [Google Scholar]
  • 26.Corrigall WA. Understanding brain mechanisms in nicotine reinforcement. Br J Addict. 1991;86:507–510. doi: 10.1111/j.1360-0443.1991.tb01798.x. [DOI] [PubMed] [Google Scholar]
  • 27.Imperato A, Mulas A, Di Chiara G. Nicotine preferentially stimulates dopamine release in the limbic system of freely moving rats. Eur J Pharmacol. 1986;132:337–338. doi: 10.1016/0014-2999(86)90629-1. [DOI] [PubMed] [Google Scholar]
  • 28.Mereu G, Yoon KW, Boi V, Gessa GL, Naes L, et al. Preferential stimulation of ventral tegmental area dopaminergic neurons by nicotine. Eur J Pharmacol. 1987;141:395–399. doi: 10.1016/0014-2999(87)90556-5. [DOI] [PubMed] [Google Scholar]
  • 29.Fibiger HC, Phillips AG. Reward, motivation, cognition: psychobiology of mesotelencephalic dopamine systems. In: Bloom FE, editor. Handbook of Physiology, Section I: The Nervous System, Vol 4: Intrinsic Regulatory Systems of the Brain. New York: Oxford University Press; 1986. [Google Scholar]
  • 30.Koob GF, Bloom FE. Cellular and molecular mechanisms of drug dependence. Science. 1988;242:715–723. doi: 10.1126/science.2903550. [DOI] [PubMed] [Google Scholar]
  • 31.Wise RA, Bozarth MA. Brain reward circuitry: four circuit elements “wired” in apparent series. Brain Res Bull. 1984;12:203–208. doi: 10.1016/0361-9230(84)90190-4. [DOI] [PubMed] [Google Scholar]
  • 32.Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, et al. Inhibition of monoamine oxidase B in the brains of smokers. Nature. 1996;379:733–736. doi: 10.1038/379733a0. [DOI] [PubMed] [Google Scholar]
  • 33.Carlsson A, Waters N, Carlsson ML. Neurotransmitter interactions in schizophrenia-therapeutic implications. Eur Arch Psychiatry Clin Neurosci. 1999;249:37–43. doi: 10.1007/pl00014183. [DOI] [PubMed] [Google Scholar]
  • 34.AE, Mays VK, Rigotti NA, Tisdale T, Cather C, et al. A pilot trial of bupropion added to cognitive behavioral therapy for smoking cessation in schizophrenia. Nicotine Tob Res. 2001;3:397–403. doi: 10.1080/14622200110073920. [DOI] [PubMed] [Google Scholar]
  • 35.Evins AE, Cather C, Deckersbach T, Freudenreich O, Culhane MA, et al. A double-blind placebo-controlled trial of bupropion sustained-release for smoking cessation in schizophrenia. J Clin Psychopharmacol. 2005;25:218–225. doi: 10.1097/01.jcp.0000162802.54076.18. [DOI] [PubMed] [Google Scholar]
  • 36.Fatemi SH, Stary JM, Hatsukami DK, Murphy SE. A double-blind placebo-controlled cross over trial of bupropion in smoking reduction in schizophrenia. Schizophr Res. 2005;76:353–356. doi: 10.1016/j.schres.2005.02.021. [DOI] [PubMed] [Google Scholar]
  • 37.George TP, Vessicchio JC, Termine A, Bregartner TA, Feingold A, et al. A placebo controlled trial of bupropion for smoking cessation in schizophrenia. Biol Psychiatry. 2002;52:53–61. doi: 10.1016/s0006-3223(02)01339-2. [DOI] [PubMed] [Google Scholar]
  • 38.George TP, Vessicchio JC, Sacco KA, Weinberger AH, Dudas MM, et al. A placebo-controlled trial of bupropion combined with nicotine patch for smoking cessation in schizophrenia. Biol Psychiatry. 2008;63:1092–1096. doi: 10.1016/j.biopsych.2007.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Weiner E, Ball MP, Summerfelt A, Gold J, Buchanan RW. Effects of sustained-release bupropion and supportive group therapy on cigarette consumption in patients with schizophrenia. Am J Psychiatry. 2001;158:635–637. doi: 10.1176/appi.ajp.158.4.635. [DOI] [PubMed] [Google Scholar]
  • 40.Tsoi DT, Porwal M, Webster AC. Efficacy smoking cessation and reduction in schizophrenia: a systematic review and meta-analysis. Br J Psychiatry. 2010;196:346–353. doi: 10.1192/bjp.bp.109.066019. [DOI] [PubMed] [Google Scholar]
  • 41.Levin ED, Wilson W, Rose JE, McEvoy J. Nicotine-haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacology. 1996;15:429–436. doi: 10.1016/S0893-133X(96)00018-8. [DOI] [PubMed] [Google Scholar]
  • 42.McEvoy JP, Freudenreich O, Levin ED, Rose JE. Haloperidol increases smoking in patients with schizophrenia. Psychopharmacology (Berl) 1995;119:124–126. doi: 10.1007/BF02246063. [DOI] [PubMed] [Google Scholar]
  • 43.Yang YK, Nelson L, Kamaraju L, Wilson W, McEvoy JP. Nicotine decreases bradykinesia-rigidity in haloperidol-treated patients with schizophrenia. Neuropsychopharmacology. 2002;27:684–686. doi: 10.1016/S0893-133X(02)00325-1. [DOI] [PubMed] [Google Scholar]
  • 44.de Leon J, Diaz FJ, Josiassen RC, Cooper TB, Simpson GM. Does clozapine decrease smoking? Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:757–762. doi: 10.1016/j.pnpbp.2005.04.031. [DOI] [PubMed] [Google Scholar]
  • 45.George TP, Sernyak MJ, Ziedonis DM, Woods SW. Effects of clozapine on smoking in chronic schizophrenic outpatients. J Clin Psychiatry. 1995;56:344–346. [PubMed] [Google Scholar]
  • 46.McEvoy JP, Freudenreich O, Wilson WH. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol Psychiatry. 1999;46:125–129. doi: 10.1016/s0006-3223(98)00377-1. [DOI] [PubMed] [Google Scholar]
  • 47.George TP, Ziedonis DM, Feingold A, Pepper WT, Satterburg CA, et al. Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia. Am J Psychiatry. 2000;157:1835–1842. doi: 10.1176/appi.ajp.157.11.1835. [DOI] [PubMed] [Google Scholar]
  • 48.Fowler CD, Arends MA, Kenny PJ. Subtypes of nicotinic acetylcholine receptors in nicotine reward, dependence, and withdrawal: evidence from genetically modified mice. Behav Pharmacol. 2008;19:461–484. doi: 10.1097/FBP.0b013e32830c360e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Markou A. Review: Neurobiology of nicotine dependence. Philos Trans R Soc Lond B Biol Sci. 2008;363:3159–3168. doi: 10.1098/rstb.2008.0095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Marubio LM, Gardier AM, Durier S, David D, Klink R, et al. Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors. Eur J Neurosci. 2003;17:1329–1337. doi: 10.1046/j.1460-9568.2003.02564.x. [DOI] [PubMed] [Google Scholar]
  • 51.Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, et al. Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature. 1998;39:173–177. doi: 10.1038/34413. [DOI] [PubMed] [Google Scholar]
  • 52.Tapper AR, McKinney SL, Nashmi R, Schwarz J, Deshpande P, et al. Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization. Science. 2004;306:1029–1032. doi: 10.1126/science.1099420. [DOI] [PubMed] [Google Scholar]
  • 53.Coe JW, Brooks PR, Vatelino MG, Wirtz MC, Arnold EP, et al. Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem. 2005;48:3474–3477. doi: 10.1021/jm050069n. [DOI] [PubMed] [Google Scholar]
  • 54.Aubin HJ, Bobak A, Britton JR, Oncken C, Billing CB, Jr, et al. Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised, open-label trial. Thorax. 2008;63:717–724. doi: 10.1136/thx.2007.090647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Bolliger CT, Issa JS, Posadas-Valay R, Safwat T, Abreu P, et al. Effects of varenicline in adult smokers: a multinational, 24-week, randomized, double-blind, placebo-controlled study. Clin Ther. 2011;33:465–477. doi: 10.1016/j.clinthera.2011.04.013. [DOI] [PubMed] [Google Scholar]
  • 56.Boudrez H, Gratziou C, Messig M, Metcalfe M. Effectiveness of varenicline as an aid to smoking cessation : results of an inter-European observational study. Curr Med Res Opin. 2011;27:769–775. doi: 10.1185/03007995.2011.557718. [DOI] [PubMed] [Google Scholar]
  • 57.Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA. 2006;296:47–55. doi: 10.1001/jama.296.1.47. [DOI] [PubMed] [Google Scholar]
  • 58.Grassi MC, Enea D, Ferketich AK, Lu B, Pasquariello S, et al. Effectiveness of varenicline for smoking cessation: a 1-year follow-up study. J Subst Abuse Treat. 2011;41:64–70. doi: 10.1016/j.jsat.2011.01.014. [DOI] [PubMed] [Google Scholar]
  • 59.Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006;296:56–63. doi: 10.1001/jama.296.1.56. [DOI] [PubMed] [Google Scholar]
  • 60.Niaura R, Hays JT, Jorenby DE, Leone FT, Pappas JE, et al. The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers: a randomized controlled trial. Curr Med Res Opin. 2008;24:1931–1941. doi: 10.1185/03007990802177523. [DOI] [PubMed] [Google Scholar]
  • 61.Nides M, Glover ED, Reus VI, Christen AG, Make BJ, et al. Varenicline and safety of bupropion for Versus Bupropion SR or placebo for smoking cessation: a pooled analysis. Am J Health Behav. 2008;32:664–675. doi: 10.5555/ajhb.2008.32.6.664. [DOI] [PubMed] [Google Scholar]
  • 62.Sofuoglu M, Duffey D, Mooney ME. Varenicline increases smoking abstinence at 6 months to a year compared with placebo or bupropion; nausea is the most commonly reported adverse effect. Evid Based Med. 2011;16:113–114. doi: 10.1136/ebm1200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Tonstad S, Tonnesen P, Hajek P, Williams KE, Billing CB, et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA. 2006;296:64–71. doi: 10.1001/jama.296.1.64. [DOI] [PubMed] [Google Scholar]
  • 64.West R, Baker CL, Cappelleri JC, Bushmakin AG. Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt. Psychopharmacology (Berl) 2008;197:371–377. doi: 10.1007/s00213-007-1041-3. [DOI] [PubMed] [Google Scholar]
  • 65.Tonstad S. Varenicline for smoking cessation. Expert Rev Neurother. 2007;7:121–127. doi: 10.1586/14737175.7.2.121. [DOI] [PubMed] [Google Scholar]
  • 66.Kristensen PL, Pedersen-Bjergaard U, Thorsteinsson B. Varenicline may trigger severe hypoglycaemia in Type 1 diabetes. Diabet Med. 2008;25:625–626. doi: 10.1111/j.1464-5491.2008.02419.x. [DOI] [PubMed] [Google Scholar]
  • 67.Moore TJ, Glenmullen J, Furberg CD. Thoughts and acts of aggression/ violence towards others reported in association with varenicline. Ann Pharmacother. 2010;44:1389–1394. doi: 10.1345/aph.1P172. [DOI] [PubMed] [Google Scholar]
  • 68.Food and Drug Administration. 2011 www.fda.gov/Drugs/DrugSafety/ucm264436.htm.
  • 69.Obach RS, Reed-Hagen AE, Krueger SS, Obach BJ, O’Connell TN, et al. Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro. Drug Metab Dispos. 2006;34:121–130. doi: 10.1124/dmd.105.006767. [DOI] [PubMed] [Google Scholar]
  • 70.Burstein AH, Clark DJ, O’Gorman M, Willavize SA, Brayman TG, et al. Lack of pharmacokinetic and pharmacodynamic interactions between a smoking cessation therapy, varenicline, and warfarin: an in vivo and in vitro study. J Clin Pharmacol. 2007;47:1421–1429. doi: 10.1177/0091270007307574. [DOI] [PubMed] [Google Scholar]
  • 71.Bertilsson L. Metabolism of antidepressant and neuroleptic drugs by cytochrome p450s: clinical and interethnic aspects. Clin Pharmacol Ther. 2007;82:606–609. doi: 10.1038/sj.clpt.6100358. [DOI] [PubMed] [Google Scholar]
  • 72.Bondolfi G, Morel F, Crettol S, Rachid F, Baumann P, et al. Increased clozapine plasma concentrations and side effects induced by smoking cessation in 2 CYP1A2 genotyped patients. Ther Drug Monit. 2005;27:539–543. doi: 10.1097/01.ftd.0000164609.14808.93. [DOI] [PubMed] [Google Scholar]
  • 73.Schaffer SD, Yoon S, Zadezensky I. A review of smoking cessation: potentially risky effects on prescribed medications. J Clin Nurs. 2009;18:1533–1540. doi: 10.1111/j.1365-2702.2008.02724.x. [DOI] [PubMed] [Google Scholar]
  • 74.Ahmed AI. A manic episode in a 64-year-old man: an adverse effect of varenicline. Gen Hosp Psychiatry. 2011;33:200, e9–e11. doi: 10.1016/j.genhosppsych.2010.11.005. [DOI] [PubMed] [Google Scholar]
  • 75.Francois D, Odom A, Kotbi N. A case of late-life onset mania during Varenicline assisted smoking cessation. Int J Geriatr Psychiatry. 2011;26:658–659. doi: 10.1002/gps.2615. [DOI] [PubMed] [Google Scholar]
  • 76.Freedman R. Exacerbation of schizophrenia by varenicline. Am J Psychiatry. 2007;164:1269. doi: 10.1176/appi.ajp.2007.07020326. [DOI] [PubMed] [Google Scholar]
  • 77.Hussain S, Kayne E, Guwanardane N, Petrides G. Varenicline induced mania in a 51 year old patient without history of bipolar illness. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1162–1163. doi: 10.1016/j.pnpbp.2011.02.023. [DOI] [PubMed] [Google Scholar]
  • 78.Ismail Z, Syms J, Blumberger D, George TP. Varenicline induced polydipsia and hyponatremia in a patient with schizophrenia. Schizophr Res. 2010;119:268. doi: 10.1016/j.schres.2010.01.027. [DOI] [PubMed] [Google Scholar]
  • 79.Kohen I, Kremen N. Varenicline-induced manic episode in a patient with bipolar disorder. Am J Psychiatry. 2007;164:1269–1270. doi: 10.1176/appi.ajp.2007.07010173. [DOI] [PubMed] [Google Scholar]
  • 80.MacSuibhne S, Giwa TA, McCauley MD. Varenicline (champix)-associated manic relapse in bipolar affective disorder. Ir Med J. 2010;103:286. [PubMed] [Google Scholar]
  • 81.Morstad AE, Kutscher EC, Kennedy WK, Carnahan RM. Hypomania with agitation associated with varenicline use in bipolar II disorder. Ann Pharmacother. 2008;42:288–289. doi: 10.1345/aph.1K511. [DOI] [PubMed] [Google Scholar]
  • 82.Popkin MK. Exacerbation of recurrent depression with varenicline. Am J Psychiatry. 2008;165:774. doi: 10.1176/appi.ajp.2008.07111735. [DOI] [PubMed] [Google Scholar]
  • 83.Waldo MC, Woodward L, Adler LE. Varenicline and P50 auditory gating in medicated schizophrenic patients: a pilot study. Psychiatry Res. 2010;175:179–180. doi: 10.1016/j.psychres.2009.01.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Food and Drug Administration. 2008 http://www.fda.gov/cder/drug/advisory/varenicline.htm.
  • 85.Garza D, Murphy M, Tseng L-J, Riordan HJ, Chatterjee A. A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo. Biol Psychiatry. 2011;69:1075–1082. doi: 10.1016/j.biopsych.2010.12.005. [DOI] [PubMed] [Google Scholar]
  • 86.Anghelescu I. Successful smoking cessation and improvement of negative symptoms with varenicline in a stable schizophrenia patient. J Neuropsychiatry Clin Neurosci. 2009;21:102–103. doi: 10.1176/jnp.2009.21.1.102. [DOI] [PubMed] [Google Scholar]
  • 87.Fatemi SH. Varenicline efficacy and tolerability in a subject with schizophrenia. Schizophr Res. 2008;103:328–329. doi: 10.1016/j.schres.2008.05.002. [DOI] [PubMed] [Google Scholar]
  • 88.Evins AE, Goff DC. Varenicline treatment for smokers with schizophrenia: a case series. J Clin Psychiatry. 2008;69:1016. doi: 10.4088/jcp.v69n0620a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Stapleton JA, Watson L, Spirling LI, Smith R, Milbrandt A, et al. Varenicline in the routine treatment of tobacco dependence: a pre-post comparison with nicotine replacement therapy and an evaluation in those with mental illness. Addiction. 2008;103:146–154. doi: 10.1111/j.1360-0443.2007.02083.x. [DOI] [PubMed] [Google Scholar]
  • 90.Smith RC, Lindenmayer JP, Davis JM, Cornwell J, Noth K, et al. Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder. Schizophr Res. 2009;110:149–155. doi: 10.1016/j.schres.2009.02.001. [DOI] [PubMed] [Google Scholar]
  • 91.Weiner E, Buchholz A, Coffay A, Liu F, McMahon RP, et al. Varenicline for smoking cessation in people with schizophrenia: a double blind randomized pilot study. Schizophr Res. 2011;129:94–95. doi: 10.1016/j.schres.2011.02.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Liu ME, Tsai SJ, Jeang SY, Peng SL, Wu SL, et al. Varenicline prevents affective and cognitive exacerbation during smoking abstinence in male patients with schizophrenia. Psychiatry Res. 2011;190:79–84. doi: 10.1016/j.psychres.2011.04.018. [DOI] [PubMed] [Google Scholar]
  • 93.Dutra SJ, Stoeckel LE, Carlini SV, Pizzagalli DA, Evins AE. Varenicline as a smoking cessation aide in schizophrenia: effects on smoking behavior and reward sensitivity. Psychopharmacology (Berl) 2012;219:25–34. doi: 10.1007/s00213-011-2373-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Hong LE, Thaker GK, McMahon RP, Summerfelt A, Rachbeisel J, et al. Effects of Moderate-Dose Treatment with Varenicline on Neurobiological and Cognitive Biomarkers in Smokers and Nonsmokers with Schizophrenia and Schizoaffective Disorder. Arch Gen Psychiatry. 2011;68:1195–1206. doi: 10.1001/archgenpsychiatry.2011.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Heinz A, Knable MB, Coppola R, Gorey JG, Jones DW, et al. Psychomotor slowing, negative symptoms and dopamine receptor availability—an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients. Schizophr Res. 1998;31:19–26. doi: 10.1016/s0920-9964(98)00003-6. [DOI] [PubMed] [Google Scholar]
  • 96.Crunelle CL, Miller ML, de Bruin K, van den Brink W, Booij J. Varenicline increases striatal dopamine D (2/3) receptor binding in rats. Addict Biol. 2009;14:500–502. doi: 10.1111/j.1369-1600.2009.00168.x. [DOI] [PubMed] [Google Scholar]
  • 97.McClure JB, Swan GE, Jack L, Catz SL, Zbikowski SM, et al. Mood, side-effects and smoking outcomes among persons with and without probable lifetime depression taking varenicline. J Gen Intern Med. 2009;24:563–569. doi: 10.1007/s11606-009-0926-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Philip NS, Carpenter LL, Tyrka AR, Whiteley LB, Price LH. Varenicline augmentation in depressed smokers: an 8-week, open-label study. J Clin Psychiatry. 2009;70:1026–1031. doi: 10.4088/jcp.08m04441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Tonstad S, Davies S, Flammer M, Russ C, Hughes J. Psychiatric adverse events in randomized, double-blind, placebo-controlled clinical trials of varenicline: a pooled analysis. Drug Saf. 2010;33:289–301. doi: 10.2165/11319180-000000000-00000. [DOI] [PubMed] [Google Scholar]
  • 100.Pirmoradi P, Roshan S, Nadem SS. Neuropsychiatric disturbance after initiation of varenicline in a patient with a history of alcohol abuse and major depression. Am J Health Syst Pharm. 2008;65:1624–1626. doi: 10.2146/ajhp070641. [DOI] [PubMed] [Google Scholar]
  • 101.Pumariega AJ, Nelson R, Rotenberg L. Varenicline-induced mixed mood and psychotic episode in a patient with a past history of depression. CNS Spectr. 2008;13:511–514. doi: 10.1017/s1092852900016746. [DOI] [PubMed] [Google Scholar]
  • 102.DiPaula BA, Thomas MD. Worsening psychosis induced by varenicline in a hospitalized psychiatric patient. Pharmacotherapy. 2009;29:852–857. doi: 10.1592/phco.29.7.852. [DOI] [PubMed] [Google Scholar]
  • 103.Liu ME, Tsai SJ, Yang ST. Varenicline-induced mixed mood and psychotic episode in a patient with Schizoaffective Disorder. CNS Spectr. 2009;14:346. doi: 10.1017/s1092852900022975. [DOI] [PubMed] [Google Scholar]
  • 104.Lyon G. Possible varenicline-induced paranoia and irritability in a patient with major depressive disorder, borderline personality disorder, and methamphetamine abuse in remission. J Clin Psychopharmacol. 2008;28:720–721. doi: 10.1097/JCP.0b013e31818db354. [DOI] [PubMed] [Google Scholar]
  • 105.Alhatem F, Black JE. Varenicline-induced mania in a bipolar patient. Clin Neuropharmacol. 2009;32:117–118. doi: 10.1097/WNF.0b013e31816f75bc. [DOI] [PubMed] [Google Scholar]
  • 106.Kutscher EC, Stanley M, Oehlke K. Chantix-induced mental status changes in a young healthy female. S D Med. 2009;62:193–195. [PubMed] [Google Scholar]
  • 107.Raidoo BM, Kutscher EC. Visual hallucinations associated with varenicline: a case report. J Med Case Reports. 2009;3:7560. doi: 10.1186/1752-1947-3-7560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Cinemre B, Akdag ST, Metin O, Doganavsargil O. Varenicline-induced psychosis. CNS Spectr. 2010;15:470–472. doi: 10.1017/s1092852900000407. [DOI] [PubMed] [Google Scholar]
  • 109.Moore TJ, Furberg CD, Glenmullen J, Maltsberger JT, Singh S. Suicidal behavior and depression in smoking cessation treatments. PLoS One. 2011;6:e27016. doi: 10.1371/journal.pone.0027016. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES