Comorbid Tobacco Dependence and Psychiatric Disorders

Comorbid Tobacco Dependence and Psychiatric Disorders

By Andrea H. Weinberger, Ph.D., M.A., Kristi A. Sacco, Psy.D., M.A., and Tony P. George, M.D.

(January, 2006) -- In the United States, smoking is the leading preventable cause of disease and death and it is estimated that over 440,000 people die from smoking-related causes annually (U.S. Department of Health and Human Services, 2004). Adverse health consequences of smoking include lung cancer, cardiovascular disease and stroke.

Although the overall prevalence of smoking has been decreasing to 23% in 2000 (Centers for Disease Control and Prevention, 2004), current smokers seem to have more difficulty quitting despite combining U.S. Food and Drug Administration-approved pharmacological treatments (nicotine replacement therapies, sustained-release bupropion [Zyban]) with behavioral therapies. A large proportion of these difficult-to-treat smokers may have comorbid psychiatric and substance use disorders (Kalman et al., in press). Determining the usefulness of current smoking cessation treatments can guide clinicians. Advances in our understanding of biological explanations for the high rates of comorbid nicotine addiction and mental disorders may lead to the development of more targeted and effective treatment.

Epidemiology

Large population-based studies in the United States report the current rate of smoking to be approximately 22% to 28% (CDC, 2004; Grant et al., 2004; Lasser et al., 2000). Smokers with current psychiatric disorders have significantly higher rates of smoking (41% on average), and it has been estimated that patients with mental illness consume 44.3% of all cigarettes in the United States (Lasser et al., 2000). The highest smoking prevalences were found for people with bipolar (68.8%), psychotic (49.4%) and substance use disorders (49.0%) (Lasser et al., 2000).

According to the DSM-IV, nicotine dependence is determined by daily smoking (typically 10 to 40 cigarettes/day), resulting in tolerance and the presence of withdrawal symptoms after smoking cessation. While the general rate of nicotine dependence has been reported at 12.8%, much higher rates have been found for smokers with psychiatric disorders (Grant et al., 2004).

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

There have been several hypotheses to explain the high rates of smoking among people with psychiatric and substance use disorders. One hypothesis is that genetic factors influence vulnerability to both smoking and these disorders (Kendler et al., 1993). Second, certain environmental factors (e.g., stress, poverty) are associated with increased smoking and the onset of symptoms of psychiatric disorders. Third, people with psychiatric or substance use disorders use smoking as a way to self-medicate clinical 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-aminobutyric acid (GABA) and endogenous opioid peptides, and acts as an agonist on presynaptic nicotinic acetylcholine receptors (nAChRs), which are stimulated endogenously by acetylcholine (Mansvelder and McGehee, 2002; Picciotto, 2003). Although chronic exposure of agonists typically produces receptor downregulation, chronic nicotine administration causes a paradoxical upregulation of nAChRs through rapid desensitization followed by receptor inactivation (Gentry and Lukas, 2002). After a short period of abstinence (e.g., overnight), nAChRs are resensitized and once again responsive to nicotine. This may explain why many smokers tend to report the first cigarette of the morning as their most satisfying.

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

Nicotine administration has been shown to improve neurocognitive deficits observed in neuropsychiatric disorders such as 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's disease (Newhouse et al., 1988; Potter et al., 1999). This suggests a potentially critical role for nAChR stimulation in mediating cognitive dysfunction in these specific disorders (Sacco et al., 2004). Interestingly these effects are not consistently observed in healthy smoking controls. A series of studies have shown that an auditory gating measure (P50) deficit associated with schizophrenia is mediated by nicotine and smoking (Adler et al., 1993; Freedman et al., 1997; Leonard et al., 2002), and that these effects are related to activation of one form of nAChR (α7 nAChR [CHNRA7]) and that the expression of this receptor appears to be dysregulated (Leonard et al., 2002).

Our group has found that in schizophrenia, long-term abstinence impairs visuospatial working memory (VSWM) performance (which is dependent on the prefrontal cortex), while improving performance in nonpsychiatric controls (George et al., 2002a). Enhancement of 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 in prefrontal cognitive functioning also have a harder time successfully quitting with intervention (Dolan et al., 2004). Thus, the cognitive deficits found in neuropsychiatric disorders may be a vulnerability factor predisposing these patients to initiate and maintain their smoking (Chambers et al., 2001).

Clinical Assessment

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

Level of nicotine dependence can be assessed through an empirically validated measure such as the Fagerstrom Test for Nicotine Dependence and the presence of nicotine withdrawal symptoms (e.g., irritability, cravings) upon smoking abstinence. Finally, it is important to determine the level of motivation to quit. Motivation can be measured using scales such as the Contemplation Ladder or through direct questioning about interest to quit in the next month. An approach to treatment of nicotine dependence in patients with comorbid psychiatric disorders and substance use disorders is given.

Schizophrenia

The development of effective strategies for promoting smoking cessation in schizophrenia is of great importance given the high rates of smoking and cessation failure in this patient group. The nicotine transdermal patch (NTP) is associated with smoking cessation rates of 27% to 42% in smokers with schizophrenia (Addington et al., 1998; Chou et al., 2004; George et al., 2000). Further, use of the nicotine nasal spray, which produces higher plasma levels of nicotine, is associated with reduction of 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 in schizophrenia. Treatment-seeking smokers have shown success (with short-term abstinence rates of 11% to 50%) with a combination of bupropion SR 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 negative symptoms.

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

Mood Disorders

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

Pharmacotherapies for smoking cessation have not been extensively evaluated in patients with current major depression. One open-label trial of bupropion SR (300 mg/day) suggested that this medication was well tolerated in smokers taking selective serotonin reuptake inhibitor and enhanced short-term (three-month) cessation success in about one-third of patients (Chengappa et al., 2001). Additional research on smokers with a history of depression suggested the usefulness of NTP (Thorsteinsson et al., 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 smoking cessation aids while SSRIs do not appear to enhance smoking abstinence (Dalack et al., 1995; Niaura et al., 2002). Behavioral therapies such as CBT should be strongly considered, as smokers with depression are likely to fail with more minimal interventions (Brown et al., 2001). Improved cessation outcomes with the addition of CBT have been reported for nortriptyline and nicotine gum (Hall et al., 1998, 1994).

Bipolar disorder. Glassman et al. (1993) found that patients with bipolar disorder (BD) may also be at risk for recurrence of depressive symptoms during smoking cessation. No empirically based treatments have been published for smokers with BD. Our group is currently conducting a double-blind, placebo-controlled trial of bupropion SR for the treatment of nicotine dependence in smokers with BD.

Anxiety Disorders

Cinciripini and colleagues (1995) found that smokers with high levels of trait anxiety taking buspirone (BuSpar) versus placebo were more likely to be abstinent at trial end point but not at follow-up. A placebo-controlled study of bupropion SR for smokers with posttraumatic stress disorder reported that bupropion was well tolerated and resulted in higher rates of smoking cessation (60%), as compared to placebo (20%) (Hertzberg et al., 2001). Interestingly, a study by McFall and colleagues (2005) found that smokers who received tobacco treatment integrated with their psychiatric care were five times more likely than smokers who received separate treatment 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 of outcomes during smoking cessation treatment (Hughes, 1996), and long-term quit rates of smokers in early recovery from substance use disorders (SUDs) are low-approximately 12% (Kalman, 1998; Sussman, 2002). However, a past history of alcoholism does not influence tobacco treatment outcome (Hayford et al., 1999).

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

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

Conclusions

Many studies have shown that the likelihood of smoking cessation is lower for smokers with comorbid psychiatric and substance use disorders, but that with optimized treatment, reasonable success rates are possible. Furthermore, there are important medical and psychiatric reasons to improve smoking cessation in these populations.

As our understanding increases about biological associations between comorbid nicotine addiction and psychiatric disorders, it is clear that biological predispositions associated with the disorders may need to be a focus of treatment. Mental health providers can play a critical role in smoking cessation efforts by identifying smokers; using motivational techniques to encourage quitting; and increasing accessibility to tobacco treatments. This may be most easily achieved in treatment settings that integrate nicotine dependence and mental health treatment (McFall et al., 2005).

Dr. Weinberger is postdoctoral fellow in the division of substance abuse, department of psychiatry, Yale University School of Medicine.

Dr. Sacco is associate research scientist in the division of substance abuse, department of psychiatry, Yale University School of Medicine.

Dr. George is associate professor, division of substance abuse, department of psychiatry, Yale University School of Medicine, and director, Program for Research in Smokers with Mental Illness, Connecticut Mental Health Center, New Haven.

See references

Last updated: 1/06

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