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
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.,
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 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
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.,
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.
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