Treating Smoking Dependence in Depressed Alcoholics Nassima Ait-Daoud, M.D.; Wendy J. Lynch, Ph.D.; J. Kim Penberthy, Ph.D.; Alison B. Breland, Ph.D.; Gabrielle R. Marzani-Nissen, M.D.; and Bankole A. Johnson, D.Sc., M.D., Ph.D. Alcoholism and nicotine dependence share many neurobiological underpinnings; the presence of one drug can cause a person to crave the other. Depressive illness can complicate comorbid alcohol and nicotine dependence by exacerbating the negative affect encountered during attempts to abstain from one or both drugs. Given the morbidity and mortality associated with cigarette smoking, it is imperative to identify treatments to promote smoking cessation and address comorbid psychiatric conditions contemporaneously. Pharmacotherapeutic options demonstrating varying degrees of efficacy and promise in preclinical and clinical studies include nicotine replacement therapy (NRT), selective serotonin reuptake inhibitors (SSRIs), bupropion, varenicline, tricyclic antidepressants, and bupropion plus NRT. Topiramate has shown potential for promoting smoking cessation in alcoholics, although its safety in depressed patients has not been fully explored. The efficacy of medications for treating nicotine dependence is generally enhanced by the inclusion of behavioral interventions such as cognitive behavioral therapy. When group cohesion and social support are stressed, success rates increase among depressed smokers undergoing smoking cessation treatment. Additional treatment strategies targeting dually dependent individuals with comorbid psychiatric disorders, including special populations such as women and adolescents, await further investigation. KEY WORDS: Alcohol and tobacco; alcoholism; cigarette smoking; nicotine dependence; emotional and psychiatric depression; comorbidity; agents for alcohol and other drug (AOD) concurrent mental disorders; cessation of AOD use (AODU); smoking cessation treatment; serotonin receptors; serotonin reuptake inhibitors; pharmacotherapy; bupropion; varenicline; topiramate; tricyclic antidepressant; nicotine replacement therapy; psychotherapy; cognitive behavioral therapy igarette smoking is the leading consequences of comorbid1 substance NASSIMA AIT-DAOUD, M.D., is an cause of preventable morbidity abuse and can complicate the course of assistant professor; WENDY J. LYNCH, and mortality in the United psychiatric disorders. C PH.D., is an assistant professor; J. KIM States (McGinnis and Foege 1993). People who are dependent on either PENBERTHY, PH.D., is an assistant Fifty to 90 percent of people with men- alcohol or nicotine often are at increased professor; ALISON B. BRELAND, PH.D., risk for the other comorbid disorder. tal illness or addiction also are nicotine was an assistant professor; GABRIELLE R. Smokers have two to three times greater dependent (Williams and Ziedonis MARZANI-NISSEN, M.D., is an assistant risk for alcohol dependence than non- 2004). Compared with the general professor; and BANKOLE A. JOHNSON, smokers (Breslau 1995), and about population, alcohol-dependent or other D.SC., M.D., PH.D., is an alumni 80 percent of alcoholics also are depen- mentally ill smokers have increased professor and chairman, all in the dent on nicotine (Hughes 1996). physical health consequences and Department of Psychiatry and Indeed, recent research has suggested a mortality rates (Williams and Ziedonis Neurobehavioral Sciences, University neurobiological link between nicotine 2004). Further, co-occurrence of sub- of Virginia, Charlottesville, Virginia. stance abuse and depression is associ­ and alcohol dependence. For instance, alcohol and nicotine share a common ated with greater impairment and ALISON B. BRELAND, PH.D., currently is neurobiological substrate involving the worse treatment outcomes than either an adjunct instructor in the Department disorder alone (Brown et al. 2000). 1For a definition of this and other technical terms used in of Psychology, Virginia Commonwealth Therefore, smoking exacerbates the this article, please see the glossary, p. 220. University, Richmond, Virginia. Vol. 29, No. 3, 2006 213 cortico-mesolimbic dopamine system, response to the discomfort associated would be expected to be more difficult which is critical for expressing the posi­ with the urge to drink or to enhance to treat. This article will review some of tive reinforcing effects of these drugs their mood (Rohsenow et al. 1997). the treatments available to help patients (Hemby et al. 1997; Wise 1996). Some practitioners might be reluc­ with comorbid alcohol and nicotine Preclinical studies also show that neu­ tant to treat nicotine dependence in dependence and depression, discuss the rochemical interactions between alco­ mental health settings if they think that limitations of these treatments, and hol and nicotine can augment the rein­ it would depress mood and increase introduce some of the new treatment forcing effects of the combination anxiety among patients trying to over­ approaches that might lessen the chal­ (Soderpalm et al. 2000) and that the come other addictions or mental illness. lenge of treating this population. presence of one drug can trigger drug- Nevertheless, despite the belief that seeking behavior for the other (Lê et al. smoking cessation can trigger alcohol 2003). relapse among people dependent on Basic Research Tobacco and alcohol seem to trigger both drugs, contemporary studies show similar central opioid peptide responses; that smoking cessation treatment does An understanding of the neurochemi­ therefore, both substances often are not cause abstinent alcoholics to relapse cal mechanisms underlying the addic­ used as self-medication for comorbid (Hughes and Callas 2003). Indeed, treat­ tive properties of alcohol and nicotine affective disorder (Abrams et al. 1992; ment that promotes smoking cessation is critical for the development of Hertling et al. 2005; Pomerleau and among smokers within an alcohol- potential pharmacotherapies. As with Pomerleau 1987). Thus, Currie and dependent population might decrease other drugs of abuse, the reinforcing colleagues (2001) have suggested that the likelihood of relapse to drinking. effects of both alcohol and nicotine people with a combined history of The clinical approach toward treat­ appear to be mediated, at least in part, alcohol dependence and major depres­ ing people with comorbid nicotine and by dopaminergic projections in the sion are at high risk of using smoking alcohol dependence becomes more cortico-mesolimbic system (Johnson as a means of mood enhancement. complicated among patients who also 2004; Koob 2003; Samson and Harris Craving for alcohol or nicotine is posi­ have a depressive illness. Such individu­ 1992). Alcohol, both directly and indi­ tively correlated with depression and als might smoke or drink to relieve rectly, can increase excitatory cellular anxiety, and alcohol-dependent patients negative affective mood states such as activation of dopaminergic cell bodies often experience the urge to smoke in depression and anxiety and therefore in the ventral tegmental area (VTA). This, in turn, leads to the facilitation of dopamine release in the nucleus accum­ bens (Brodie et al. 1999; Johnson 2005; Ortiz et al. 1995). The primary Locus coeruleus action by which alcohol increases dopamine in the nucleus accumbens appears to be via its effects on gamma­ aminobutyric acid (GABA) neurons in the VTA (for a review, see Johnson 2004). Recent evidence, however, demonstrates that alcohol also can exert its reinforc­ ing and dopamine-enhancing effects through activation of nicotinic acetyl­ choline receptors. In laboratory rats, chronic treatment with nicotine increases the reinforcing and dopamine- enhancing effects of alcohol, and these effects are blocked by the nicotinic receptor antagonist mecamylamine (for a review, see Larsson and Engel 2004). Nucleus Raphe These results suggest that nicotinic accumbens nuclei acetylcholine receptors in the VTA Ventral Pons might serve as a common substrate for tegmental alcohol–nicotine interactions. area Serotonin appears to play a critical role in mediating the reinforcing effects of alcohol and nicotine, and it has been Parts of the brain involved in alcohol/nicotine dependence and psychiatric disorders. implicated in the pathophysiology of various neuropsychiatric disorders, 214 Alcohol Research & Health Smoking Dependence and Depressed Alcoholics including depression. Both alcohol and of SSRIs in treating alcohol dependence history of depression was comparable nicotine stimulate the serotonergic system. has depended on clinical subtype. to the effect observed among smokers Long-term use of alcohol and nicotine Among patients who develop problem with no history of depression or alco­ can, however, produce a hypo-seroton­ drinking early in life, have a strong holism (Hayford et al. 1999). However, ergic state that might trigger or worsen family history of alcoholism, and fre­ because smokers with current depression a depression. For instance, both chronic quently exhibit impulsive behaviors and alcoholism (i.e., within the past alcohol and nicotine administrations (i.e., early-onset or type B alcoholics), year) were excluded from the study, dose-dependently reduce the synthesis SSRIs worsen drinking outcomes these findings might be of limited sig­ of tryptophan hydroxylase (the rate- (Kranzler et al. 1996). In contrast, nificance. Unfortunately, bupropion limiting enzyme for serotonin synthesis) SSRIs improve drinking outcomes has not been found to be effective for