Nicotine dependence through tobacco use is a serious public health problem in the United States. Cessation rates have slowed in recent years, and in some populations such as adolescents, women, and the mentally ill, rates have increased and/or remained very high. These subsets of smokers are of particular interest to the addiction psychiatrist given the high rates of treatment failure. Dr. George provided an overview of the biology of nicotine addiction with a focus on basic mechanisms that underlie pharmaco-logical treatments. Dr. Oncken discussed the epidemiological evidence suggesting that smoking rates are declining less rapidly in women compared to men. Studies of patients with schizophrenia show that 74-92% smoke cigarettes regularly compared to 24.7% of the general population. Dr. Evins addressed treatment strategies for this population. Dr. Hughes presented assessment and treatment issues for tobacco dependence in patients with alcoholism and other substance abuse disorders.

Symposium Chairs: Thomas R. Kosten, MD and Tony P. George, MD, Yale University, New Haven, CT

The National Institute on Drug Abuse (NIDA) has recently reported that the prevalence of adult cigarette smokers is high but has stabilized between 20-25% with the highest rates being in the South and the Midwest. The fact that the rates have stabilized may represent those who have more difficulty quitting smoking, specifically the high risk groups including women, alcohol and drug users, and psychiatric patients.

Nicotine has rewarding and reinforcing properties. I will discuss the basic mechanisms of nicotine addiction. The nucleus accumbens (n.a.) was depicted by Time magazine (12/11/00) as the drug users’ "sweet spot." Nicotine causes an increase in the nucleus accumbens affecting reward and reinforcement by stimulation of various forms of nicotinic receptors. Nicotine mimics the action of neurotransmitter acetylcholine at this receptor. Nicotinic receptor subunits, which make up various pharmacologically-distinct forms of nicotinic receptors can be divided into three families:

1. muscle subunits
2. neuronal subunits
3. a -bungarotoxin-sensitive subunits

Subunits in #2 and possibly #3 contribute to the process of nicotine reinforcement and reward. Nicotine causes an increase in the activity of the neurons on which they are located, which is associated with dopamine (and other neurotransmitter) release. Nicotine’s actions on the mesolimbic dopamine system are thought to be the final common pathway in mediating most drugs of abuse’s influence on reward and reinforcement. Nicotine mimics the actions of acetylcholine, the endogenous neurotransmitter to the brain and ultimately causes an ion channel opening and an influx of ions into the neuron. Ultimately there is a depolarization of the neuron on which nicotine receptors sit. The actions of nicotine, however, are short-lived (milliseconds) since nicotinic receptors rapidly desensitize.

The neurotransmitters implicated in nicotine addiction are:

• Dopamine (DA)
• Norepinephrine (NE)
• Serotonin (5-HT)
• g -aminobutyric acid (GABA)
• Glutamate (Glu)
• Endogenous Opioid Peptides (EOPS)
• Corticotrophin Releasing Factor(CRF)

Nicotine likely works on integrated brain systems to exert its psychopharmacological effects. When a person is smoking, nicotine gets to their brain in five seconds and activates neurotransmission in pathways containing nicotineic receptors. In the act of smoking, aerosolized nicotine goes straight from the lungs to the brain. Thus,

smoking nicotine is a highly effective way to get nicotine to the brain; nicotine replacement doesn’t get nicotine to the brain as rapidly as smoking a cigarette.

Dani and Heinemann (1996)¹ present a hypothetical cycle for perpetuating nicotine use. The increased number of nAChRs and the subsequent pathology of nicotinic cholinergic function are hypothesized to develop after chronic use of nicotine.

This is why smokers often say that the most satisfying cigarette of the day is the first one—it causes the maximum amount of neurotransmitter release.

Using an animal model, nicotine was administered to rats/mice. The dose effects of nicotine on cognitive function at a modest dose (0.2 mg per kilogram) resulted in an increase in cognitive performance; yet, when the dose was increased, performance declined.² This is consistent with smokers’ reports they titrate their cigarette smoking to a very particular level. They maintain constant blood levels in this way.

There are established (FDA-approved) pharmacotherapies for treating nicotine dependence:

• Over-the-counter (gum and patch) or prescription (spray and inhaler) nicotine replacement therapy:
• Sustained-release bupropion (Zyban®) which works best in combination with behavioral therapies.

Novel biological treatments for tobacco addiction include:

• Nicotine vaccine
• Nicotinic receptor agonists and antagonists
• Serotonin Selective Reuptake Inhibitors (SSRIs)
• Tricyclic antidepressants such as nortriptyline
• GABA and Glutamatergic agents
• Monoamine Oxidase Inhibitors (for both A and B subtypes)
• Opioid antagonists such as Naltrexone
• CRF antagonists
• For co-morbid psychiatric disorders, the newer antidepressant agents and atypical antipsychotic drugs

Cigarette smoking reduces MAO A and B activity; non-smokers have higher levels of binding.^3,4 Smokers have much less binding and are similar to treatment with selegiline (Deprenyl). Some component of tobacco smoke, which is not nicotine, causes the reduction of MAO activity.

A recent study⁵ compared the effect of selegiline vs. placebo on smoking abstinence rates. This was an eight-week trial with 40 subjects; selegiline caused a significant elevation of quit rates. Almost 50% quit. After six months, there was a big attrition back to smoking. There appeared to be a drug to placebo difference, although not at significant levels.

There is evidence that nicotinic receptor stimulation is therapeutic in the following neuropsychiatric disorders:

• Schizophrenia
• Major Depression
• Tourette’s Syndrome
• Attention Deficit/Hyperactivity Disorder
• Parkinson’s Disease
• Alzheimer’s Disease
• Panic Disorder/PTSD
• Alcohol and Cocaine Addiction

Average prevalence rates of tobacco use in patients with schizophrenia⁶ are between 70-75%. In recent studies with schizophrenics,⁷ nicotine had beneficial effects on cognitive function. When they quit smoking, cognitive deficits increased. Furthermore, the newer antipsychotic drugs (atypical agents) like olanzapine, risperidone, and clozapine, which have reduced medication side effects and improve some aspects of cognitive dysfunction in schizophrenics, may facilitate smoking cessation in these patients with both nicotine patch⁸ and bupropion.⁹

In summary, we know that nicotine has discrete receptor sites and actions in the brain, which may explain the addictive properties of tobacco. A better understanding of nicotine’s biology may lead to improved treatments for nicotine addiction and possibly better preventive approaches. Nicotinic agents may have therapeutic roles in a variety of CNS and other nicotine-responsive disorders.

References:

1. Dani J., Heinemann S. Molecular and cellular aspects of nicotine abuse. Neuron. 1996; 16:905-908.
2. George TP, Verrico CD, Roth RH. Effects of repeated nicotine pre-treatment on mesoprefontal dopaminergic and behavioral responses to acute footshock stress. Brain Research. 1998; 801:36-49.
3. Fowler JS, Volkow ND, Wang G-J, et al. Inhibition of monoamine oxidase B in the brains of smokers. Nature. 1996a;379:733-736.
4. Fowler JS, Volkow ND, Wang G-J, et al. Brain monoamine oxidase A: inhibition by cigarette smoke. Proc Natl Acad Sci USA. 1996b;93:14065-14069.
5. George TP, Vessicchio JC, Termine A, Jatlow PI, Kosten TR, O'Malley SS. A preliminary trial of selegiline hydrochloride versus placebo for smoking cessation. Biol Psychiatry. 2002d. submitted.
6. George TP, Vessicchio JC, Nicotine addiction and schizophrenia. Psychiatric Times. 2001b;18(2):39-42.
7. George TP, Vessicchio JC, Termine A, Sahady DM, Head CA, Pepper WT, Kosten TR, Wexler BE. Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology. 2002a;26(1):75-85.
8. George TP, Zeidonis DM, Feingold A, Pepper WT, Satterburg CA, Winkel J, Rounsaville BJ, Kosten TR. Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia. Am J Psychiatry. 2000a;57(11):835-1842.
9. George TP, Vessicchio JC, Termine A., Bregartner TA, Rounsaville BJ, Kosten TR. A placebo-controlled study of bupropion for smoking cessation in schizophrenia. Biol Psychiatry. 2002b. In press.

Funded in part by: NIDA grants K12- DA- 00167, R01- DA-13672 and R01- DA- 14039 to T.P.G.; and The Yale TTURC (CENTURY; P50- DA- 13334.)

The rates of smoking among women are declining less rapidly compared to men. Women may be at added risk for some of the deleterious effects of smoking including lung cancer, pregnancy-related problems and cervical cancers, impaired fertility and early menopause. Although nicotine addiction treatment is similar for men and women, there may be some unique barriers for smoking cessation in women.

Review of data showing that women appear to be less successful at smoking cessation compared to men is discussed, including some reasons why women may be less successful. This session includes a discussion of the practical implications for smoking treatment in clinical practice. There is evidence that there are gender differences in smoking. Specifically, the quit ratio (former/ever) is higher in men vs. women (52% vs. 47%)¹. In examining birth cohorts, smoking prevalence curves within comparable birth cohorts show less quitting for women² and one large community randomized intervention trial shows that women have lower rates of quitting³. Trends in quitting in the United States between 1955 and 1994 show a decline in men from 60% to 30% with much less rapid declines in women.

There are some unique barriers that may impact smoking treatment in women such as hormonal changes (menstrual cycle, pregnancy-related, post-partum, menopausal period); depression and weight control.

Smoking withdrawal symptoms are similar to menstrual symptoms. Perkins⁴ found that the menstrual cycle might influence cessation. Women quitting during the luteal phase (2^nd half of the cycle) reported significantly greater tobacco withdrawal and depressive symptoms than those quitting in the follicular phase (1^st half of cycle). The implications for clinical practice are that it may be reasonable for patients to pick a quit date in the follicular versus luteal phase. There are no randomized trials actually showing this would improve cessation rates but it may alleviate discomfort. The nicotine patch may lessen severe symptomatology in the late luteal phase⁵.

The incidence of depression and anxiety in women is twice that of men and can greatly affect smoking cessation efforts. In addition, persons with a history of depression may be less likely to quit smoking and they also may be at greater risk for depression after smoking cessation. Glassman⁶ conducted a trial of sertraline for smoking cessation in persons with major depressive disorder (65% women). Among abstainers, more had a major depressive disorder episode than among those who continued to smoke.

In a study of postmenopausal women to evaluate the effects of behavioral counseling, patients were given four two-hour counseling sessions and a nicotine or placebo patch for smoking cessation. At 12 weeks of abstinence, depression was not significant but medication was significant. Preliminary study results indicate that postmenopausal women with a history of depression may especially benefit from a behavioral intervention program and nicotine replacement for smoking cessation. Bupropion or nortriptyline could also be considered for treatment for persons with a history of depression who are attempting smoking cessation.

Smoking cessation leads to an average 10-pound weight gain. Women with weight concerns related to smoking cessation do poorly in treatment studies of smoking cessation.⁷ Cognitive behavioral therapy to reduce weight concerns improved cessation better than standard counseling alone or using concurrent weight control measures.⁸ Exercise may significantly enhance cessation and reduce weight gain.⁹ Bupropion SR or nicotine gum may delay weight gain.¹⁰

Other issues to consider in planning smoking treatment for women include their motivation to quit and the potential for late relapse that may contribute to less successful outcomes in women. Stress, negative affect, and environmental cues may especially play a role in smoking maintenance in women.¹¹ Some studies suggest that women, compared to men, are less sensitive to the discriminative effects of nicotine.¹²

It is clear that women are at risk for health-related problems of smoking. Hormonal changes, depressive symptomatology, and weight concerns may need to be addressed in women considering treatment. More research is needed to better identify gender differences in smoking cessation.

1. Center for Disease Control and Prevention. Surveillance for selected tobacco-use behaviors-United States. 1900-94. Morbidity and Mortality Weekly Report. 1994;43:1-43.
2. Escobedo LG, Peddicord, JP. Smoking prevalence in US birth cohorts: The influence of gender and education. Am J Public Health. 1996;86:231-36.
3. Bjornson W, Rand C, Connett JE, Lindgren P, Nides M, Pope F, Buist S, Hoppe-Ryan C, O’Hara P. Gender differences in smoking cessation after 3 years in the lung health study. Am J Public Health. 1995;85:223-30.
4. Perkins KA, Levine M, Marcus M, Shiffman S, D’Amico D, Miller A, Keins A, Ashcom J, Broge M. Tobacco withdrawal in women and menstrual cycle phase. J Consult Clin Psychol. 2000;68:176-180.
5. Allen SS, Hatsukami D, Christianson D, Brown S. Effects of transdermal nicotine on craving, withdrawal and premenstrual symptomatology in short-term smoking abstinence during different phases of the menstrual cycle. Nicotine and Tobacco Research. 2000;2:231-241.
6. Glassman AH, Covey LS, Stetner F, Rivelli S. Smoking cessation and the course of major depression: a follow-up study. Lancet. 2001;357:1929-32.
7. French SA, Jeffrey RW. Weight concerns and smoking: a literature review. Ann Behav Med. 1995;17:234-44.
8. Perkins KA, Marcus M, Levine M, Damico D, Miller A, Broge M, Ashcom J, Shiffman S. Cognitive-behavioral therapy to reduce weight concerns improves smoking cessation outcomes in weight-concerned women. J Consult Clin Psychol. 2001;69:604-13.
9. Marcus BH, Albrecht AE, King TK, Parisi AF, Pinto BM, Roberts M, Niaura RS, Abrams DB. The efficacy of exercise as an aid for smoking cessation in women: A randomized controlled trial. Arch Intern Med. 1999;159:12229-34.
10. Fiore MC, Bailey WC, Cohen SJ, Dorfman SF, Goldstein MG, Gritz ER. Treating tobacco use and dependence. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. June 2000.
11. Benowitz NL, Hatsukami D. Gender differences in the pharmacology of nicotine addiction. Addict Biol. 1998;3:383-404.
12. Perkins, KA. Nicotine discrimination in men and women. Pharmacology Biochemistry & Behavior. 1999;2:295-99.

This session will address treatments that address both nicotine addiction and psychiatric symptoms in patients with schizophrenia. Anywhere from 74-92% of patients with schizophrenia smoke cigarettes, compared with less than 25% of the general adult population in the United States. Neuronal nicotinic receptors have been implicated in the pathophysiology of schizophrenia because of high rates of smoking, abnormalities in expression and function of nicotinic receptors, and linkage between auditory p50 deficits and the region of chromosome 15 coding the alfa 7 nicotinic receptor subunit in patients with schizophrenia. Presynaptic nicotine binding stimulates glutamate, dopamine, norepinephrine
and serotonin release. Therefore it is likely that treatments used to facilitate smoking cessation in patients with schizophrenia may need to substitute for nicotine. At the least, treatments for smoking cessation in schizophrenia must be evaluated on the basis of both smoking and clinical outcomes.

In our pilot trial of bupropion 150 mg per day vs. placebo added to a 12 session group CBT program we found that bupropion added to CBT was more effective for smoking cessation and was associated with greater stability of psychiatric symptoms. The bupropion group had significantly fewer psychotic symptoms, depreressive symptoms and negative symptoms than the placebo group. at 6 months 10 percent of the bupropion group was abstinent. At 6 months, the bupropion group had a 40% reduction in expired air CO. At 2 years, the group as a whole had a 22% quit rate and a 45% reduction rate.

We are now evaluating bupropion 300 mg per day vs placebo and in a separate study are evaluating NRT plus bupropion vs. NRT alone added to CBT for smoking cessation in schizophrenia. These studies have extensive cognitive batteries as well to measure acute and chronic effects of smoking cessation on measures of attention and memory.

The goals of future studies should include:
1. Identification of treatment most effective for smoking cessation in schizophrenia
2. Investigation of the effect of long-term tobacco abstinence on cognitive function and clinical symptoms
3. Development of nicotinic agonists if chronic nicotine use is found to be beneficial for clinical symptoms or cognitive function.

Treating Nicotine Dependence in Current and Recovering Alcohol/Drug Abusers

The prevalence of smoking in male alcoholics decreased from approximately 90% in 1965 to 75% in 2000. In nonalcoholic males, it decreased from 60% to 24%. If this trend is projected out to 2020-2030, most smokers will have alcohol/drug abuse or psychiatric comorbidity.

The importance of treating nicotine dependence in alcoholics is illustrated in a study that showed that more recovering alcoholics die of tobacco-related illness than alcohol-related illness. A common reason for not addressing nicotine dependence is the belief that smoking cessation threatens sobriety. In recent studies, 10% of recovering alcoholics say it does (90% say it doesn’t), 16% say craving is increased (84% say it isn’t), and 18% relapse to alcohol/drug use during tobacco abstinence (82% do not).

Several lines of evidence indicate smokers with a history of alcoholism are more nicotine dependent than smokers without this history. Interestingly, most data shows no difference in the ability of recovering alcoholics and non-alcoholics to quit on a given attempt. The probable reason recovering alcoholics don’t have more trouble quitting despite increased nicotine dependence is because they have learned from their recovery from alcoholism. They have taken those skills, either through self-recovery or through recovery in a program, and they are able to apply them to their more severe nicotine dependence. These two skills offset each other.

Despite an ability to quit, over a lifetime only about 20% of recovering alcoholics quit smoking compared to 50% of nonalcoholic smokers. This suggests recovering alcoholics try less often to quit than non-alcoholics do. This suggests that it is important to encourage recovering alcoholics to quit smoking. Recommending cessation is also important because when the physician doesn’t ask about smoking, patients think: "the physician is less than thorough" or "the physician doesn’t think I can quit smoking."

Nicotine replacement, Bupropion and behavior therapy aid in cessation in smokers. They work to a similar degree in smokers with a history of alcoholism. Brief advice works with smokers, but it is unknown if this works to a similar degree in smokers with a history of alcoholism. It is also not known whether Nicotine Anonymous or naltrexone benefit smokers. About 25% of people want to both stop drinking and smoking at the same time and the data suggest this should be pursued in such smoker using proven treatments. Naltrexone might be helpful as it may help both problems—but no one has yet done this type of trial.

It is very important to tell patients the rationale for no smoking policies in inpatient units. Tell them the rationale: second hand smoke is a carcinogen, and you don’t want ex-smokers to go back to smoking.

This is especially critical when managing an adolescent program. Alcohol and nicotine withdrawal have several common symptoms and sometimes irritability, etc. from nicotine withdrawal can be mistaken for irritability from alcohol withdrawal. Use of nicotine products in this setting may result in less need to use of diazepam.

In conclusion,

• many smokers are alcohol dependent;
• many recovering alcoholics are interested in quitting smoking;
• as many alcoholics die from smoking as from alcohol;
• recovering alcoholics are more nicotine-dependent;
• smoking cessation needs to be kept on the active problem list;
• provide motivation every few months to stop smoking;
• let the smoker decide the timing;
• go with proven therapies: gum, patch, inhaler, bupropion, behavior therapy and social support; and
• monitor weekly to prevent remission of alcohol/drug problem.

References:

1. Hughes JR. Treating smokers with current or past alcohol dependence. Am J Health Behav. 1996;20(5): 286-290.
2. Hurt RD, Offord KP, Croghan IT, Gomez-Dahl L., Kottke TE, Mores RM, Melton III J. Mortality following inpatient current or past alcohol dependence: Addictions treatment; role of tobacco use in a community-based cohort. JAMA. 1996;275 (14):1097-1102.