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Nicotine Dependence in the Mental Health Population

Nicotine Dependence in the Mental Health Population. Overview. Neurobiology of addiction Nicotine addiction Nicotine withdrawal Smoking and psychiatric disorders: overview Specific disorders Depression Suicide Schizophrenia Generalized anxiety disorder (GAD) Panic disorder.

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Nicotine Dependence in the Mental Health Population

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  1. Nicotine Dependence in the Mental Health Population

  2. Overview • Neurobiology of addiction • Nicotine addiction • Nicotine withdrawal • Smoking and psychiatric disorders: overview • Specific disorders • Depression • Suicide • Schizophrenia • Generalized anxiety disorder (GAD) • Panic disorder

  3. Neurobiology of Addiction

  4. Begins with social drug taking and acute reinforcement Pattern of escalating compulsive use Dependence Stages of Addiction Acute Reinforcement/Social Drug Taking GeneticVariables Environmental Factors Stress Conditioning Effects Escalating/Compulsive Use Relapse Dependence Withdrawal Protracted Withdrawal Recovery? Le Moal et al. Eur Neuropsychopharmacol. 2007;17:377-393.

  5. PreoccupationAnticipation Preoccupation with obtainingPersistent physical or psychological problems Taken inlarger amountsthan intended WithdrawalNegative Affect Persistent desire BingeIntoxication Tolerance withdrawal Social, occupational, or recreational activities compromised Spiraling Distress Addiction Spiraling Cycle of Addiction (DSM-IV) • The 3 major components of the addiction cycle are preoccupation–anticipation, binge–intoxication, and withdrawal–negative affect • The cycle is conceptualized as a spiral that increases in amplitude with repeated experience, ultimately resulting in the pathologic addictive state Koob. Eur Neuropsychopharmacol. 2003;13:442-452.

  6. Neurocircuits That Underlie Addiction Drug-Seeking Behavior Motor Cortex Prefrontal CortexAnterior CingulatePrelimbic CortexOrbitofrontal Cortex Drug and CueReinstatement:“Craving” Thalamus BasolateralAmygdala Behavioral Output:“Compulsivity” Pallidum Central Nucleusof Amygdala Bed Nucleus ofStria Terminalis ENK DA Drug-AssociatedReinforcement:“Reward” and “Stress” Nucleus Accumbens (nAcc) ENK DA CRF CRF ENK NE NE DA -END Pontine Nuclei Arcuate VTA NE=norepinephrine, ENK=enkephalin, CRF=corticotropin-releasing factor, DA=dopamine, -END=-endorphin.Le Moal et al. Eur Neuropsychopharmacol. 2007;17:377-393.

  7. Relapse occurs in response to stimulation by compulsive drive circuits and deficits in inhibitory restraint Neurobiologic Basis for Relapse Compulsive Drive Circuits Inhibitory ControlDeficits • Priming • Drug cues • Obsessive thoughts (craving) • Stress • Impulsivity (automaticity) • Decision making Adinoff. Harv Rev Psychiatry. 2004;12:305-320.

  8. Summary: Neurobiology of Addiction • Addiction is a multistep process • Multiple neurocircuits are involved in the craving, reward, stress, and compulsivity associated with addiction • Relapse occurs in response to stimulation by compulsive drive circuits and deficits in inhibitory restraint

  9. Nicotine Dependence • Action of nicotine in the central nervous system • Neurobiologic and physiologic effects of tobacco dependence

  10. 3 or more of the following symptoms within a 1-year time span: Tolerance to nicotine with decreased effect and increasing dose to obtain same effect Withdrawal symptoms with cessation Persistent desire to smoke despite efforts to decrease intake Extensive time spent smoking or purchasing tobacco Postponing work, social, or recreational events in order to smoke Continuing to smoke despite health hazards Nicotine Dependence: DSM-IV-TR Criteria N CH3 N Nicotine American Psychiatric Association. Diagnostic and Statistical Manual of Mental DisordersFourth Edition Text Revision. Washington, DC: American Psychiatric Association; 2000; http://www.intox.org/databank/documents/supplem/supp/sup2.htm. Accessed October 19, 2007.

  11. Nicotine binds preferentially to nicotinic acetylcholinergic receptors (nAchRs) in the central nervous system When nicotine binds to the nAChR, the receptor complex undergoes a conformational change, allowing the channel gate to open, permitting the passage of cations, resulting in signal transmission H2N HOOC Neuronal Nicotine Acetylcholine Receptor Ligand binding site NH2 COOH H2N COOH M1 Extracellular M2 B A M3 Cytoplasmic M4 PresynapticnAChRs PostsynapticnAChRs C PreterminalnAChRs Laviolette et al. Nat Rev Neurosci. 2004;5:55-65.

  12. The 42 nicotinic receptor in the VTA mediates the effects of nicotine in the central nervous system After nicotine binds to the 42 nicotinic receptor in the VTA, it results in a release of dopamine in the nAcc, which is believed to be linked to reward b2 b2 a4 a4 b2 4b2 Nicotinic receptor NIC nAcc Nicotine - Ventraltegmental area(VTA) Dopamine - Mechanism of Action of Nicotine in the Central Nervous System nAcc= Nucleus Accumbens. Adapted from Picciotto et al. Nicotine Tob Res. 1999;1:S121-S125.

  13. D D D D – β2 subunit containing nAChR - Nicotine - Dopamine D Nicotine Stimulates Dopamine Release • Nicotine activates 42 nicotinic receptors in the VTA, resulting in dopamine release at the nAcc. This may result in the short-term reward/satisfaction associated with cigarette smoking Reward D Axon VTA nAcc nAcc= Nucleus Accumbens; VTA= Ventral Tegmental Area. Adapted from Picciotto et al. Nicotine Tob Res. 1999;1:S121-S125.

  14. Role of Dopamine in Nicotine Addiction NH2 • Rewarding effects of nicotine are dependent on mesolimbic dopamine-mediated transmission • In nicotine-dependent patients, the drive for continued drug use results from the need for heightened dopamine concentrations OH OH Dopamine Adinoff. Harv Rev Psychiatry. 2004;12:305-320. http://www.biopsychiatry.com/dopamine/dopamine.jpg. Accessed May 1, 2007.

  15. D D D D D D D D D – β2 subunit containing nAChR - Nicotine - Dopamine D Chronic Nicotine Exposure: Up-Regulation of Nicotine Receptors • With chronic exposure, nicotine stimulates 42 nicotinic receptor activation and desensitization, followed by 42 nicotinic receptor up-regulation and an increase in the number of 42 nicotinic receptors Reward D Axon VTA nAcc Adapted from Picciotto et al. Nicotine Tob Res. 1999;1:S121-S125; Corringer et al. J Phys Paris. 2006;99:162-171.

  16. Dopamine Nicotine The Cycle of Nicotine Addiction • Nicotine binding causes an increase in release of dopamine • Dopamine gives feelings of pleasure and calm • The dopamine decrease between cigarettes leads to withdrawal symptoms of irritability and stress • The smoker craves nicotine to restore pleasure and calmness • Smokers generally titrate their smoking to achieve maximal stimulation and avoid symptoms of withdrawal and craving Jarvis. BMJ. 2004;328:277-279; Picciotto et al. Nicotine Tob Res. 1999;1:S121-S125.

  17. Role of Environmental Stimuli in Nicotine Dependence • Environmental/social stimuli associated with smoking play a role in reinforcing nicotine dependence • Nonnicotine stimuli are important in both motivating and maintaining smoking behavior • Role of environmental vs pharmacologic stimuli in nicotine dependence varies between men and women Direct pharmacologic effects of nicotine are necessary but not sufficient to explain tobacco dependence; these effects must take into account the environmental/social context in which the behavior occurs Caggiula et al. Physiol Behav. 2002;77:683-687.

  18. Summary: Nicotine Dependence • Nicotine dependence is a well-defined addictive disorder • Nicotine’s effects on the 42 receptors in the Ventral Tegmental Area (VTA) results in • Acute dopamine release and short-term reward • Chronic receptor activation, desensitization, and up-regulation • The dopaminergically mediated physical and psychological rewards of smoking reinforce repeat behavior • Environmental/social stimuli associated with smoking play a role in reinforcing nicotine dependence

  19. Nicotine Withdrawal

  20. ‘‘Why do people smoke . . . to relax; for the taste; to fill the time; something to do with my hands. . . . But, for the most part, people continue to smoke because they find it too uncomfortable to quit’’Philip Morris, 1984 Philip Morris. Internal presentation. 1984, 20th March; Kenny et al. Pharmacol Biochem Behav. 2001;70:531-549.

  21. Nicotine Withdrawal • Nicotine withdrawal syndrome consists of both somatic and affective symptomatology Withdrawal Syndrome Irritability, frustration, or anger Insomnia/sleep disturbance Anxiety (may increase or decrease with quitting) Increased appetite or weight gain Dysphoric or depressed mood Restlessness or impatience Difficulty concentrating American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision. Washington, DC: American Psychiatric Association; 2000.

  22. 1 2 3 4 5 6 7 8 9 10 Select Withdrawal Symptoms Over Time Nicotine Gum Placebo Mean Adjusted Withdrawal Score Impatience Irritability/Anger 1.5 1.0 0.5 0.0 Postcessation Weeks Postcessation Weeks Mean Adjusted Withdrawal Score Anxiety/Tension Excessive Hunger Postcessation Weeks Postcessation Weeks N = 40. Mean adjusted withdrawal scores are from an analysis of covariance with baseline cigarettes per day and baseline scores on the items shown as covariates. Gross et al. Psychopharmacology. 1989;98:334-341.

  23. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Nicotine Withdrawal: Severity • Smokers experiencing severe withdrawal have the most pronounced symptoms of depression Withdrawal Symptoms Mild Moderate Severe Endorsement Probabilitya Restlessness Headaches Craving Nicotine Irritability Nervousness Hands Shaking Feeling Drowsy Upset Stomach Depressed Mood Increased Appetite Heart Slowed Down Trouble Sleeping Poor Concentration aClasses of withdrawal syndrome are defined by groups of respondents who endorsed similar combinations of symptoms. Estimates of prevalence for different classes of withdrawal were obtained along with expected frequencies of endorsement for each symptom of withdrawal by type. Madden et al. Addiction. 1997;92(7):889-902.

  24. Severity of Withdrawal and Psychiatric Disorders • Smokers with a history of psychiatric disorders have a higher likelihood of experiencing severe withdrawal Odds Ratio (95% CI)a Major Depression Alcohol Dependence Conduct Disorder Agoraphobia SocialPhobia aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons.Madden. Addiction. 1997;92(7): 889-902.

  25. Summary: Nicotine Withdrawal • Nicotine withdrawal syndrome consists of both somatic and affective symptomatology • Smokers experiencing severe withdrawal have the most pronounced symptoms of depression • Smokers with a history of psychiatric disorders have a higher likelihood of experiencing severe withdrawal

  26. Smoking and Psychiatric Disorders: Overview

  27. Prevalence of Smoking in the Psychiatric Population P<.001 P<.001 Lifetime Smoking Rates (%) Lasser et al. JAMA. 2000;284(20):2606-2610.

  28. Increased Cigarette Consumption in Smokers With Psychiatric Disorders Cigarettes/Day Lasser et al. JAMA. 2000;284(20):2606-2610.

  29. Underdiagnosis of “Nicotine Dependence” in the Psychiatric Setting Mental Health Records Documented (%) Peterson et al. Am J Addict. 2003;12:192-197.

  30. Smoking: Risk Factor for Psychiatric Disorders • Estimated effects of preexisting daily smoking varies across disorders Odds Ratio (95% CI)a,b,c Major Depression Dysthymia Panic Disorder Agoraphobia GAD=generalized anxiety disorder. These models predict the subsequent onset of specific disorders in all daily smokers, without controlling for other psychiatric disorders that preceded the onset of daily smoking and without taking into account the proximity and intensity of smoking.aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons. bFrom a series of 10 survival models for first onset of specific disorders associated with prior daily smoking as time dependent, adjusted for race, sex, age, education, and same-year onset. cP.05. Breslau et al. Psychol Med. 2004;34:323-333.

  31. Psychiatric Disorders in Dependent and Nondependent Smokers • The associations of psychiatric disorders with tobacco dependence are stronger than with nondependent smoking Odds Ratio (95% CI)a b b aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons; sex adjusted. bAdjusted for other substance dependencies.Breslau. Behav Genet. 1995;25(2):95-101.

  32. Psychiatric Disorders: Odds of Progression to Nicotine Dependence Odds Ratio (95% CI)a Major Depressionb PanicDisorder Agoraphobiab GADc aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons. Preexisting disorder is defined as first onset at least 1 year before onset of daily smoking. bP<.05.cGAD= Generalized Anxiety Disorder Breslau et al. Biol Psychiatry. 2004;55:69-76.

  33. Psychiatry and Smoking Illicit Drug Use • Psychiatric patients who smoke have P=.0000 % • Higher incidence of illicit drug use Noncompliant With Treatment P=.0000 • Poorer treatment compliance % P=.000 • Lower Global Assessment Functioning (GAF) score GAF Score 50 Montoya et al. Am J Addict. 2005;14(5):441-454.

  34. Nicotine Addiction: Social and Psychological Factors • Smoking • Accepted part of the culture in many psychiatric treatment facilities • Shared social activity • Barrier to achieving relationships, employment, and housing for psychiatric patients Williams et al. Addict Behav. 2004;29:1067-1083; Reuters UK. http://uk.reuters.com/article/personalFinanceNews/idUKNOA82640920070629. Accessed September 25, 2007.

  35. Smoking and Psychiatric Symptomatology • In patients with schizophrenia, smoking may be associated with improvements in specific symptoms and cognitive measures Compton et al. Harv Rev Psychiatry. 2006;14(4):212-222; Depressed Man_PRinc_SF8575_Reference. http://db2.photoresearchers.com/search/SF8575. Accessed September 28, 2007.

  36. Summary: Smoking and Psychiatric Disorders • Smoking is highly prevalent in the psychiatric population • Nicotine-dependent smokers in the mental health population • Smoke greater quantities • Frequently are underdiagnosed • Have a higher incidence of illicit drug use, poorer treatment compliance, and lower GAF scores • May derive symptomatic relief from their psychiatric disorders as a result of smoking • Estimated effects of preexisting daily smoking varies across disorders • Active psychiatric disorders may predict an increased risk of smokers’ progression to nicotine dependence • Numerous social and psychological factors play a role in the perpetuation of nicotine dependence in the mentally ill

  37. Smoking and Depression

  38. Prevalence of Depression • In the United Kingdom, 56% of patients with depression are regular smokers, which is more than double the prevalence rate (26%) in the general population Depressed Patients General Population Nonsmokers Current Smokers Farrell et al. Int Rev Psychiatry. 2003;15:43-49; Mackay et al. The Tobacco Atlas. 2nd ed. 2006.

  39. Risk of Depression in Adolescent Smokers • In nondepressed adolescents, current cigarette smoking was the strongest predictor of developing high depressiveb symptoms Odds Ratio (95% CI)a aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons.bThose scoring above the cutpoints for the modified Centers for Epidemiologic Studies-Depression Scale (CES-D) were considered to have high depressive symptomatology. Goodman et al. Pediatrics. 2000;106(4):748-755.

  40. Smoking Affects Psychomotor Performance Pre Post Depressed Smokers Control Smokers 400 400 380 380 360 360 340 340 Mean Reaction Time (ms)a Mean Reaction Time (ms)a 320 320 300 300 280 280 260 260 0 1 2 3 0 1 2 3 Cigarette Cigarette aMean reaction time was measured using a computer-based simple reaction time task. Malpass et al. Psychopharmacology. 2007;190:363-372.

  41. Quitting and Depression • Smokers with a history of depression are less likely to quit • Even minimal levels of depression can affect abstinence after an attempt to quit POMS Depression 0 1.0 0.9 POMS Depression 1 0.8 0.7 0.6 0.5 Cumulative Proportion Surviving 0.4 0.3 P<.01 0.2 0.1 0.0 0 5 10 15 20 25 30 Days to First Cigarette POMS=Profile of Mood State is a 65-item measure designed to assess a patient’s current mood state. Niaura et al. Psychol Addict Behav. 2001;15:13-17.

  42. Summary: Smoking and Depression • Smoking is highly prevalent in patients who have depression • Patients with depression may smoke to ameliorate their depressive symptoms • Depressed smokers are less likely to successfully quit smoking

  43. Smoking and Suicide

  44. Increased Rate of Suicide in Smokers • There is a strong association between heavy smoking and high suicide rate Annual Suicide Rate per 100,000 by Cigarettes Smoked/Day Never Smokers Ex-smokers 1-14 15-24 25 Cigarettes/Day Current Smokers Men Doll et al. BMJ. 1994;309:901-911.

  45. Smoking and Suicide: Increased Risk P<.001 Relative Risk(95% CI)a 1-14 (n=1333) 15 (n=2241) Never Smokers Ex-smokers Cigarettes/DayCurrent Smokers aRelative risk was defined as the suicide incidence rate among those with a history of smoking divided by the rate among nonsmokers. Adjusted for time period, age, alcohol intake, and marital status. Miller et al. Am J Public Health. 2000;90:768-773.

  46. Increased Risk of Suicidal Behavior • Tobacco use is associated with an increased risk in suicidal behavior among adolescents and adults, independent of other substance use, depressive symptoms, and prior suicidal ideation P<.05 Odds Ratio (95% CI)a aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed person. Adjusted for history of major depression, alcohol, and drug use disorders.Breslau et al. Arch Gen Psychiatry. 2005;62:328-334.

  47. Smoking and Suicide: Violent vsNonviolent Deaths • Smoking is associated with an increased risk of both violentand nonviolent suicide Nonsmokers Light/moderate smokers P<.01 Heavy Smokers P<.01 P=.05 Relative Risk (95% CI)a P=.03 Violent Suicides Nonviolent Suicides aThe probability of an event (developing a disease) occurring in exposed people compared with the probability of the event in nonexposed people.Tanskanen et al. Acta Psychiatr Scand. 2000;101:243-245.

  48. Inverse relationship between the quantity of cigarettes smoked and CSF 5-HIAA (index of serotonin function) (P.003) Reduced CSF 5-HIAA concentration is independently associated with History of a higher lethality in suicide attempts Severity of lifetime aggression 120 100 80 60 40 20 0 Suicidal Behavior and Serotonin CSF 5-HIAA (pmol/mL) 0 1-20 21-39 40 Cigarettes/DayCurrent Smokers CSF 5-HIAA=cerebrospinal fluid 5-hydroxyindoleacetic acid. Malone et al. Am J Psychiatry. 2003;160:773-779; Placidi et al. Biol Psychiatry. 2001;50:783-791.

  49. Adolescent Psychiatric Inpatients: Smoking and Suicide Regular Daily Smoking Odds Ratio (95% CI)a None Ambivalent/Mild Attempts Obvious/Life-Threatening Attempts aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons.Mäkikyrö et al. J Adolesc Health. 2004;34:250-253.

  50. Nicotine Dependence: Increased Suicide Risk • Harris et al performed a statistical overview of the medical literature to estimate the suicide risk associated with common mental disorders • A standardized mortality ratio (SMR)a was calculated for each disorder • Nicotine dependence had a significantly raised SMR, 244 (207-286) • There appears to be a distinct association between smoking and suicide aSMR is an indirect method of adjusting a rate. It is defined as the number of observed deaths (in the cohort) divided by the number of expected deaths. The expected number of deaths in the reference population by age group is applied to the number of persons in each age group in the study population to obtain the expected number of deaths in this population.Harris et al. Br J Psychiatry. 1997;170:205-228; CNN.com. http://archives.cnn.com/2000/HEALTH/children/10/03/teen.smoking.ap. Accessed September 25, 2007.

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