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(Drug information on nicotine) addiction and mental disorders may lead to the development of more targeted and effective treatment.
EpidemiologyLarge 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 (Figure) (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 ContributorsNicotine stimulates the release of several neurotransmitter systems, including dopamine(Drug information on dopamine), norepinephrine(Drug information on 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 AssessmentAn 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 in the Table.
