Comorbid Tobacco Dependence and Psychiatric Disorders

Smokers with co-morbid psychiatric and substance use disorders smoke at a much higher rate and seem to have more difficulty quitting than those in the general population. Tobacco treatment that is integrated into mental health settings may lead to greater success than non-integrated treatment. As a result, mental health care providers can play a critical role by careful assessments of smoking, employment of motivational techniques and increasing access to pharmacological and behavioral treatments.

In the United States,smoking is the leading preventable cause of disease and death and it isestimated that over 440,000 people die from smoking-related causes annually(U.S. Department of Health and Human Services, 2004). Adverse healthconsequences of smoking include lung cancer, cardiovascular disease and stroke.

Although the overall prevalence of smoking has been decreasing to 23% in2000 (Centers for Disease Control and Prevention, 2004), current smokers seemto have more difficulty quitting despite combining U.S. Food and DrugAdministration-approved pharmacological treatments (nicotine replacementtherapies, sustained-release bupropion [Zyban]) with behavioral therapies. A large proportion ofthese difficult-to-treat smokers may have comorbidpsychiatric and substance use disorders (Kalman etal., in press). Determining the usefulness of current smoking cessationtreatments can guide clinicians. Advances in our understanding of biologicalexplanations for the high rates of comorbid nicotineaddiction and mental disorders may lead to the development of more targeted andeffective treatment.


Large population-based studies in the United States report the currentrate of smoking to be approximately 22% to 28% (CDC, 2004; Grant et al., 2004; Lasser et al., 2000). Smokers with current psychiatricdisorders have significantly higher rates of smoking (41% on average), and ithas been estimated that patients with mental illness consume 44.3% of allcigarettes in the United States (Lasser etal., 2000). The highest smoking prevalences werefound for people with bipolar (68.8%), psychotic (49.4%) and substance usedisorders (49.0%) (Lasser et al.,2000).

According to the DSM-IV, nicotinedependence is determined by daily smoking (typically 10 to 40 cigarettes/day),resulting in tolerance and the presence of withdrawal symptoms after smokingcessation. While the general rate of nicotine dependence has been reported at12.8%, much higher rates have been found for smokers with psychiatric disorders(Figure) (Grant et al., 2004).

Rates of dependence in psychotic populations also appear to be high (Dalack et al., 1998; Kalman etal., in press). Smokers with comorbid psychiatric orsubstance use disorders are less likely to attempt quitting (Lasser et al., 2000) and have higher risk of developingsmoking-related illnesses (Hurt et al., 1996; Lichtermannet al., 2001).

There have been several hypotheses to explain the high rates of smokingamong people with psychiatric and substance use disorders. One hypothesis isthat genetic factors influence vulnerability to both smoking and thesedisorders (Kendler et al., 1993). Second, certainenvironmental factors (e.g., stress, poverty) are associated with increasedsmoking and the onset of symptoms of psychiatric disorders. Third, people withpsychiatric or substance use disorders use smoking as a way to self-medicateclinical symptoms, side effects of psychiatric medication or cognitive deficits(Chambers et al., 2001; Sacco et al., 2004).

Biologic and Genetic Contributors

Nicotine stimulates the release of several neurotransmitter systems,including dopamine, norepinephrine,5-hydroxytryptamine (5-HT), glutamate, γ-aminobutyricacid (GABA) and endogenous opioid peptides, and actsas an agonist on presynaptic nicotinic acetylcholinereceptors (nAChRs), which are stimulated endogenouslyby acetylcholine (Mansvelder and McGehee,2002; Picciotto, 2003). Although chronic exposure ofagonists typically produces receptor downregulation,chronic nicotine administration causes a paradoxical upregulationof nAChRs through rapid desensitization followed byreceptor inactivation (Gentry and Lukas, 2002). After a short period ofabstinence (e.g., overnight), nAChRs are resensitized and once again responsive to nicotine. Thismay explain why many smokers tend to report the first cigarette of the morningas their most satisfying.

The dopamine reward system is associated with addiction to drugs of abuse,including nicotine (Volkow et al., 2002). Nicotine isthought to be reinforced by stimulating nAChRs in theventral tegmental area of the midbrain that projectto the nucleus accumbens, an important limbic areathought to be involved in drug reinforcement and reward. Further, these neuronsproject to the prefrontal cortex, which is thought to directly influencecognitive states, such as arousal and cognitive functioning.

Nicotine administration has been shown to improve neurocognitivedeficits observed in neuropsychiatric disorders suchas schizophrenia (George et al., 2002a; Sacco et al.,2005; Smith et al., 2002), attention-deficit/hyperactivity disorder (Conners et al., 1996; Levin et al., 1996) and Alzheimer'sdisease (Newhouse et al., 1988; Potter et al., 1999).This suggests a potentially critical role for nAChRstimulation in mediating cognitive dysfunction in these specific disorders (Sacco et al., 2004). Interestingly these effects are notconsistently observed in healthy smoking controls. A series of studies haveshown that an auditory gating measure (P50) deficit associated withschizophrenia is mediated by nicotine and smoking (Adler et al., 1993; Freedmanet al., 1997; Leonard et al., 2002), and that these effects are related toactivation of one form of nAChR (α7 nAChR [CHNRA7]) and that the expression of this receptorappears to be dysregulated (Leonard et al., 2002).

Our group has found that in schizophrenia, long-term abstinence impairs visuospatial working memory (VSWM) performance (which isdependent on the prefrontal cortex), while improving performance in nonpsychiatric controls (George et al., 2002a). Enhancementof VSWM and other areas of cognitive performance may be dependent on nAChR stimulation (Sacco et al.,2005). Furthermore, patients with schizophrenia who show greater deficits inprefrontal cognitive functioning also have a harder time successfully quittingwith intervention (Dolan et al., 2004). Thus, the cognitive deficits found in neuropsychiatric disorders may be a vulnerability factorpredisposing these patients to initiate and maintain their smoking (Chambers etal., 2001).

Clinical Assessment

An assessment of smokers with psychiatric disorders should include completepsychiatric and substance use evaluations. Assessment of smoking behaviorsshould include self-report of cigarette and other tobacco use over the past 30days and surrogate measures of smoking such as expired breath carbon monoxide(CO) (levels <8 ppm are associated withabstinence) or plasma nicotine levels (levels<15 ng/mlare consistent with abstinence) (Benowitz et al.,2002).

Level of nicotine dependence can be assessed through an empiricallyvalidated measure such as the Fagerstrom Test forNicotine Dependence and the presence of nicotine withdrawal symptoms (e.g.,irritability, cravings) upon smoking abstinence. Finally, it is important todetermine the level of motivation to quit. Motivation can be measured usingscales such as the Contemplation Ladder or through direct questioning aboutinterest to quit in the next month. An approach to treatment of nicotinedependence in patients with comorbid psychiatricdisorders and substance use disorders is given in the Table.


The development of effective strategies for promoting smoking cessation inschizophrenia is of great importance given the high rates of smoking andcessation failure in this patient group. The nicotine transdermalpatch (NTP) is associated with smoking cessation rates of 27% to 42% in smokerswith schizophrenia (Addington et al., 1998; Chou etal., 2004; George et al., 2000). Further, use of the nicotine nasal spray,which produces higher plasma levels of nicotine, is associated with reductionof withdrawal and craving, and smoking cessation in smokers with schizophrenia(Williams et al., 2004).

In controlled trials, pharmacological treatment with sustained-release (SR) bupropion has been efficacious in promoting abstinence inschizophrenia. Treatment-seeking smokers have shown success (with short-termabstinence rates of 11% to 50%) with a combination of bupropionSR and cognitive-behavioral therapy (CBT) at both the 150 mg/day (Evins et al., 2001) and the 300 mg/day doses (Evins et al., 2005; George et al., 2002b). Bupropion treatment also appears to help reduce negativesymptoms.

Patients treated with atypical antipsychotic agents, especially clozapine (Clozaril), smoke less(George et al., 1995; McEvoy et al., 1999, 1995) andhave an easier time quitting (George et al., 2002b, 2000) than those treatedwith typical antipsychotic medications. However, smoking cessation can cause achange in plasma concentrations of psychotropic agents due to a decrease in theinduction of cytochrome P450 1A2. Monitoringmedication side effects may be required within the first month after quitting (Kalman et al., in press; Ziedonisand George, 1997).

Mood Disorders

Major depression.Smokers with depression have a more difficult time quitting (Glassman et al.,1988; Lasser et al., 2000; Niauraet al., 2001) and require more attempts to quit (Glassman et al., 1993, 1990)than smokers without depression. However, a past history of major depressiondoes not appear to influence tobacco treatment outcomes (Hayfordet al., 1999). Although some research has reported that smoking cessation canlead to a reemergence of depressive symptoms (Covey et al., 1997; Glassman etal., 1990), other studies have questioned this relationship (Thorsteinsson et al., 2001; Tsohet al., 2000).

Pharmacotherapies for smoking cessation have notbeen extensively evaluated in patients with current major depression. Oneopen-label trial of bupropion SR (300 mg/day)suggested that this medication was well tolerated in smokers taking selectiveserotonin reuptake inhibitor and enhanced short-term (three-month) cessationsuccess in about one-third of patients (Chengappa etal., 2001). Additional research on smokers with a history of depressionsuggested the usefulness of NTP (Thorsteinsson etal., 2001) and nicotine gum (Kinnunen et al., 1996)for short-term smoking cessation.

In addition, some antidepressant medications appear to be useful agents. Nortriptyline (Aventyl, Pamelor) (Hall et al., 1998) and bupropion(Hayford et al., 1999) have shown promise as smokingcessation aids while SSRIs do not appear to enhancesmoking abstinence (Dalack et al., 1995; Niaura et al., 2002). Behavioral therapies such as CBTshould be strongly considered, as smokers with depression are likely to failwith more minimal interventions (Brown et al., 2001). Improved cessationoutcomes with the addition of CBT have been reported for nortriptylineand nicotine gum (Hall et al., 1998, 1994).

Bipolar disorder.Glassman et al. (1993) found that patients with bipolar disorder (BD) may alsobe at risk for recurrence of depressive symptoms during smoking cessation. Noempirically based treatments have been published for smokers with BD. Our groupis currently conducting a double-blind, placebo-controlled trial of bupropion SR for the treatment of nicotine dependence insmokers with BD.

Anxiety Disorders

Cinciripini and colleagues (1995) found thatsmokers with high levels of trait anxiety taking buspirone(BuSpar) versus placebo were more likely to beabstinent at trial end point but not at follow-up. Aplacebo-controlled study of bupropion SR for smokerswith posttraumatic stress disorder reported that bupropionwas well tolerated and resulted in higher rates of smoking cessation (60%), ascompared to placebo (20%) (Hertzberg et al., 2001).Interestingly, a study by McFall and colleagues(2005) found that smokers who received tobacco treatment integrated with theirpsychiatric care were five times more likely than smokers who received separatetreatment to report abstinence from smoking nine months after the study.

Substance Use Disorders

Concurrent use of alcohol and/or other drugs is a negative predictor ofoutcomes during smoking cessation treatment (Hughes, 1996), and long-term quitrates of smokers in early recovery from substance use disorders (SUDs) are low-approximately 12% (Kalman,1998; Sussman, 2002). However, a past history ofalcoholism does not influence tobacco treatment outcome (Hayfordet al., 1999).

Conditioned effects of substance use with smoking may be an important factorinfluencing both the high rates of comorbidity andtreatment failure, as these behaviors are often concurrent. Studies of pharmacotherapies in substance abusers are few, but thereis some evidence for the utility of nicotine replacement and behavioralapproaches (e.g., contingency management) (Burling et al., 1996; Shoptaw et al., 1996). Controlled studies using bupropion SR in smokers with SUDsare in progress.

There is controversy regarding the timing of smoking cessation treatmentwith substance abusers. Some studies have suggested that concurrent treatmentfor smoking and other drugs is not associated with increased use of alcohol orother drugs (Burling et al., 2001; Kalman et al.,2004, 2001). However, one large, well-controlled study has reported thatdrinking outcomes may be worse for patients who go through concurrent alcoholand nicotine treatment, suggesting that smoking cessation should be delayeduntil after alcohol treatment has been completed (Joseph et al., 2004).


Many studies have shown that the likelihood of smoking cessation is lowerfor smokers with comorbid psychiatric and substanceuse disorders, but that with optimized treatment, reasonable success rates arepossible. Furthermore, there are important medical and psychiatric reasons toimprove smoking cessation in these populations.

As our understanding increases about biological associations between comorbid nicotine addiction and psychiatric disorders, itis clear that biological predispositions associated with the disorders may needto be a focus of treatment. Mental health providers can play a critical role insmoking cessation efforts by identifying smokers; using motivational techniquesto encourage quitting; and increasing accessibility to tobacco treatments. Thismay be most easily achieved in treatment settings that integrate nicotinedependence and mental health treatment (McFall etal., 2005).




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