Smoking, nicotine dependence and psychiatric disorders

Lirio S. Covey, Ph.D.

Columbia University

New York State Psychiatric Institute

New York, NY, U.S.A.

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The long-standing view: Tobacco Use Is a Health Risk Factor

Cardiovascular disease Cancer of multiple organ sites Pulmonary Disorders Fetal/infant/childhood morbidity & mortality through second-hand smoke

The evolved view: Tobacco Use Is a More than a Risk Factor

Tobacco use, in particular, chronic use of tobacco, is a disorder in itself.

DSM-IV criteria for nicotine dependenceDSM-IV criteria for nicotine dependence

NicotineNicotine

ToleranceTolerance +Withdrawal (Anxiety, Anger, Withdrawal (Anxiety, Anger, Concentration D, Concentration D, Restlessness, Sleep Restlessness, Sleep Disturbance,Appetite Increase)Disturbance,Appetite Increase)

+

Taken in larger amounts or longer Taken in larger amounts or longer than intendedthan intended

+

Difficulty quitting or cutting downDifficulty quitting or cutting down +Much time spent to obtain the Much time spent to obtain the substancesubstance

+

Important activities given upImportant activities given up +Continued use despite harmful Continued use despite harmful consequencesconsequences

+

ATTRIBUTES OF DRUG ADDICTION: ATTRIBUTES OF DRUG ADDICTION: COMPARISON OF DRUGS OF ABUSECOMPARISON OF DRUGS OF ABUSE

HeroiHeroinn

CocainCocainee

AlcohAlcoholol

CaffeinCaffeinee

Psychoactive Psychoactive effectseffects

+ + + +

Drug-reinforced Drug-reinforced behaviorbehavior

+ + + +

Compulsive UseCompulsive Use + + + +Use despite Use despite harmful effectsharmful effects

+ + + +

Relapse after Relapse after abstinenceabstinence

+ + + -

Recurrent drug Recurrent drug cravingscravings

+ + + +

ToleranceTolerance + + + +Physical Physical dependencedependence

+ + + +

Agonist useful in Agonist useful in treating treating dependencedependence

+ - + -

ATTRIBUTES OF DRUG ADDICTION: ATTRIBUTES OF DRUG ADDICTION: COMPARISON OF DRUGS OF ABUSECOMPARISON OF DRUGS OF ABUSE

NicotinNicotinee

HeroiHeroinn

CocaiCocainene

AlcohAlcoholol

CaffeiCaffeinene

Psychoactive Psychoactive effectseffects

+ + + + +

Drug-reinforced Drug-reinforced behaviorbehavior

+ + + + +

Compulsive UseCompulsive Use + + + + +Use despite Use despite harmful effectsharmful effects

+ + + + +

Relapse after Relapse after abstinenceabstinence

+ + + + -

Recurrent drug Recurrent drug cravingscravings

+ + + + +

ToleranceTolerance + + + + +Physical Physical dependencedependence

+ + + + +

Agonist useful in Agonist useful in treating treating dependencedependence

+ + - + -

Nicotine, the main pharmacological Nicotine, the main pharmacological

ingredient in tobacco,ingredient in tobacco,

affectsaffects

functioning and structure of the brain. functioning and structure of the brain.

Nicotine has psychoactive effects

• Animals (rats, squirrel monkeys) and humans will self-administer intravenous nicotine.

• Nicotine acts on mesolimbic dopamine system, as do other drugs of abuse.

• Nicotine increases firing of neurons and release of neurotransmitters.

NICOTINNICOTINEE

DOPAMINDOPAMINEE

NOREPINEPHRINENOREPINEPHRINE

ACETYLCHOLINEACETYLCHOLINE

VASOPRESSINVASOPRESSIN

SEROTONISEROTONINN

BETA-ENDORPHINBETA-ENDORPHIN

Pleasure

Arousal

Arousal, Cognitive Enhancement

Memory Improvement

Mood Modulation

Reduction of Anxiety and Tension

Neurochemical Effects of NicotineNeurochemical Effects of Nicotine

Nicotine/Tobacco dependence is a chronic, relapsing disorder.

RELAPSE RATES from Nicotine, Heroin, Alcohol Addiction

EOT3 MOS

6 MOS12 MOS

ALCOHOL

HEROIN

NICOTINE

01020304050607080

90100

Hunt, Barnett, Branch J Clin Psychol, 1971

Nicotine/Tobacco dependence is difficult to treat.

1000 persons seeking treatment for alcohol or drug dependence treatment were asked about difficulty of quitting substances.

50% said that cigarettes would be harder to quit using then their problem substance.

Kozlowski LT, Wilkinson DA, Skinner W et al, JAMA, 1989

The “hardening hypothesis”.

As the proportion of smokers decreases, in response to negative attitudes about

smoking, the segment of the smoking population that has great difficulty

stopping smoking is increasingly made up

of smokers with psychiatric comorbidity.

Depression and Smoking in a 20-year longitudinal study of adults.

The Stirling County Study (Murphy et al, 2003, AJP)

Setting: Rural Atlantic Canada - 1952 to 1992 longitudinal data- Population N = 20,000- Demographic and psychiatric data- Prevalences comparable to national populations

Do you smoke? “A lot and some”Rates between 1952-1992

05

101520253035404550

1952 1970 1992

All Ss

Relation of Cigarette Smoking to Current Depression (O.R., 95% C.I.)

1952 1970 1992

<20/day 0.9 1.3 3.1 (1.7-.5) (0.8- 2.3) (1.8 – 5.2)

20/day 1.3 1.8 3.0 (0.8-3.2) (0.9 – 3.8) (1.7 – 5.2)

Magnitude of association increased over time.

Substantial co-morbidity between mental

illness and nicotine dependence

Multiple mental disorders are involved:

Depression (unipolar, bipolar) Anxiety disorders (generalized anxiety disorder, phobias, obsessive compulsive disorder, post traumatic stress disorder) Schizophrenia Antisocial personality disorder Conduct disorder and ADHD Alcohol dependence Drug dependence

In U.S.,

20% have a lifetime history of a mental disorder.

44% of all cigarette smoking done by persons with lifetime history of mental illness. Lasser et al, JAMA, 2000

0

5

10

15

20

25

30

35

40

45

22.5

34.8

No Mental Lifetime Past MonthIllness Mental Illness Mental Illness

41.0

Prevalence of Current SmokersU.S. National Comorbidity SurveyLasser et al, JAMA, 2000

%

Quit rates by mental illness historyLasser et al, JAMA, 2000

0

5

10

15

20

25

30

35

40

45

42.537.1

30.5

None Ever Ill Past month .

Prevalence of Current SmokingLasser, JAMA, 2000

0

510

15

2025

30

35

4045

Major Depression AlcoholDependence

Drug Dependence

No Mental Illness

%

Prevalence of Current SmokingLasser, JAMA, 2000

05

101520253035404550

GAD PTSD SimplePhobia

PanicAttacks

No MentalIllness

%

Smoking status and psychiatric lifetime diagnosis – Odds Ratios relative to never smokers (Germany)

00.5

11.5

22.5

33.5

44.5

5

Substance Use AffectiveDisorders

AnxietyDisorders

Somatoform

N=913, Lubeck, Germany John U et al, 2004, Drug Alc Dependence

P<0.001

P<0.001P<0.001 P<0.05

Prevalence of current smoking according to diagnosis: in-patient and out-patients, Paris, France

0

10

20

30

40

50

60

70

80

90

100

Poirier M, et al, 2002, Prog in Neuro-Psychopharm Biol Psychiatry

General Substance Schizophrenia Anxiety Mood Population

Odd Ratios of Nicotine Dependence and Psychiatric Disorders in the U.S.

0

2

4

6

8

10

12

14

16

DrugDependence

AlcoholDependence

MoodDisorder

AnxietyDisorder

PersonalityDisorder

Grant et al, 2004, Arch Gen Psychiatry

Major Depression

• More smokers among depressed persons• More depression among smokers• Higher nicotine dependence level• Greater difficulty in stopping • Higher frequency and intensity of withdrawal

symptoms• Higher risk of post-cessation depression

(relapse)

Schizophrenia

• High prevalence of smoking – 80-95%

• Very low rates of complete abstinence

• Smoking ameliorates symptoms

• Smoking ameliorates medication side effects

• Responsive and tolerant to NRT and bupropion

Anxiety Disorders

Generalized anxiety disorderObsessive compulsive disorderPost traumatic stress disorderPhobias

Anxiety Disorders

• Many smokers believe that smoking reduces anxiety level.

• Few studies have included sizable numbers of smokers with Anxiety Disorders.

Anxiety Disorders

• Breslau et al, 1991 – In a study of 1,200 young adults, increased

odds ratios for nicotine dependence were found for obsessive compulsive disorder, agoraphobia, and phobia.

Anxiety Disorders

• Covey et al, 1994 – In a survey of 3,000 men and women (NIMH-

ECA), Generalized Anxiety Disorder was associated with:

• Ever smoking

• Quit smoking

Anxiety Disorders

• Cinciripini et al, 1995

• Post-hoc analysis according to anxiety level at baseline.

• Lower abstinence rate among smokers with high anxiety symptoms.

Anxiety Disorders

• Dudas et al, 2005, J R Social Health

– 215 adolescents age 14-18 years– More anxiety and depressive symptoms among

smokers than non-smokers.

Anxiety Disorders

• West R, Hajek P, Am J Psychiatry 1997 – Study of 101 smokers making a quit attempt.– No increase in anxiety among those who

stopped smoking.– Decrease in anxiety from first week of

abstinence.

Anxiety and smoking:a paradoxical relationship

• Smokers say they are calmed by smoking, yet report high average levels of stress.

• Stress levels become reduced after smoking cessation.

Parrot AC, Int J Addiction, 1995

Anxiety and smoking:a paradoxical relationship

• Stress levels become reduced after smoking cessation - because the former smoker no longer suffers from the adverse mood effects of acute nicotine withdrawal.

• Acute nicotine deprivation (i.e., between cigarettes) leads to increased stress.

• Smokers then use cigarettes to reverse these withdrawal effects and "normalize" their mood.

• Dependent smokers need regular hits of nicotine just to remain feeling normal.

Parrot AC, Int J Addiction, 1995

Anxiety and smoking

“Normal mood”

Nicotinedeprivation

Withdrawal (anxiety)

Return to smoking

Returnto “normalmood”

Nicotinedeprivation

Withdrawal (anxiety)

Returntosmoking

Anxiety and smoking

“Normal mood”

Nicotinedeprivation

Withdrawal (anxiety)

Return to smoking

Returnto “normalmood”

Nicotinedeprivation

Withdrawal (anxiety)

Returntosmoking

Continuedabstinence

Return to TRUENORMAL MOOD

Attention Deficit Disorder-Hyperactivity (ADHD)

InattentionHyperactivity - ImpulsivityImpairment in at least 2 settings (e.g. school, work, home)Symptoms begin in childhood

Attention Deficit Disorder-Hyperactivity (ADHD)

• Recognized in children in early 1900s.

• In the U.S., affects 5% to 10% of children.

• Persistence in adulthood – in the 1970s.

• Persistence of 50% to 60% to adulthood.

• 2% to 4% of adults (7 million)

ADHD and Smoking

• Cigarette smoking and nicotine dependence are twice as common in adults with ADHD.– Pomerleau OF et al, 1995, J Substance Abuse

• Smoking, earlier age of smoking onset, greater amount in children with ADHD than no ADHD.– Milberger S et al, 1997, J Am Acad Child Ad Psych.

• Neuropsychological deficits improved with nicotine administration.– Potter and Newhouse, 2004, Psychopharmacol.

ADHD and Smoking

• Maternal smoking (during pregnancy) associated with hyperactivity, ADHD symptoms, ADHD.

• With adjustment for sex, family structure, socioeconomic status, maternal age, and maternal alcohol use (odds ratio 1.30; 1.08-1.58).

– Kotimaa AJ, 2003, J Am Acad Child Adol Psych.– Linnet KM, 2003, Am J Psychiatry

Alcohol Dependence

Prevalence of Current SmokingLasser, JAMA, 2000

0

510

15

2025

30

35

4045

Major Depression AlcoholDependence

Drug Dependence

No Mental Illness

%

Alcohol Dependence

• Higher rates of current smoking – 80% to 95%

• Common genetic vulnerability to nicotine and alcohol dependence suggested in twin data.

Alcohol Dependence

• Many want to quit (up to 100% in one clinical study)

– Quit rates in active drinkers lower than in nonalcoholics.

– Quit rates in recovering groups same as nonalcoholics.

Alcohol Dependence

• Kalman D, 2004 Psychol Addict Beh

– Abstinence rate related with length of alcohol abstinence.

Kalman D, 2004, Psychol Addict Beh

12 Mo

2 Mo

3-5 Mo6-11 Mo

Alcohol Dependence

• New evidence – Joseph et al, 2003

– Comparison of concurrent versus delayed smoking abstinence among alcoholics in treatment

– More relapse to alcohol with concurrent abstinence

– Warrants replication.

Drug Dependence

Prevalence of Current SmokingLasser, JAMA, 2000

0

510

15

2025

30

35

4045

Major Depression AlcoholDependence

Drug Dependence

No Mental Illness

%

Drug Dependence

• High rates of current smoking (comorbidity)– 70% in cannabis dependent– 75% in cocaine dependent– 85%-98% in methadone-maintained – Extremely high levels of nicotine dependence

• Genetic, social, environmental factors implicated.

Drug Dependence

• Claim that quitting smoking is hardest

• Strong levels of interest in quitting

1000 persons seeking treatment for alcohol or drug dependence treatment were asked about difficulty of quitting substances.

50% said that cigarettes would be harder to quit using then their problem substance.

Kozlowski LT, Wilkinson DA, Skinner W et al, JAMA, 1989

Drug Dependence:Marijuana

• Any history of cannabis use predictive of relapse to cigarette smoking.

• Current tobacco users do not respond to marijuana treatment as well as former or non-tobacco users.

Drug Dependence: Cocaine

• Among cocaine dependent persons, tobacco users smoke more cocaine and on more days than non-tobacco users.

• Tobacco use associated with route of cocaine administration (more smoking and injection of cocaine).

• Cessation of cocaine use associated with reduction in number of cigarettes used.

Drug Dependence: Opiates/Methadone

• Nicotine replacement treatments are helpful. Quit rates (32% at 12 weeks, Frosch et al, 1997) with NRT, similar to rates in non-drug dependent smokers.

• Naltrexone, an opioid antagonist, is suggested as possibly helpful smoking cessation aid for opiate dependent smokers.

Drug Dependence

• High comorbidity between nicotine dependence and drug dependence.

• Bi-directional dynamic is apparent.• Genetic, social, environmental factors

implicated.• No empirically based treatments for smokers

with drug dependence.• Desirability of concurrent treatment is unclear.

Issues in treating tobacco use among smokers with substance

use disorders• Tobacco use is not recognized as a disorder.• Presumption of low interest in quitting• Fear that tobacco withdrawal symptoms may

jeopardize sobriety (alcohol/drug dependence)• Continued use of psychoactive non-nicotine substance

reduces ability to quit tobacco• There is a paucity of evidence-based treatment

approaches• Lack of knowledge and training in smoking cessation

treatment approaches

Treatment issues for Alcohol Dependent smokers

• Bupropion (Zyban) same results as for nonalcoholic smokers

• Nicotine replacement agents• Cognitive behavioral treatment for mood

management helps alcoholic smokers with history of major depression

• 12-step program enhanced effect of standard counseling treatment

Treatments issues for drug dependent smokers

• Studies indicate high level of interest in cessation. • No reliable data is available. Few studies have been carried out.

• There is great need to develop andimplement smoking cessationinterventions for this group of smokers.

Mechanisms of Association

Mental Illness Smoking

Common Diathesis

Proposed mechanisms underlying comorbidity: 1. Causal

SMOKINGMENTALILLNESS

MENTALILLNESS SMOKING

Nicotine induces CNS alterations.

Nicotine medicates symptoms.

Proposed mechanisms underlying comorbidity: 2. Shared etiology

GENES, e.g. DRD2, DRD1

ENVIRONMENT, e.g. Childhood adversity Familial factors (relationships, modeling) Peer aggregation

Smoking “medicates” psychopathologyAuthor, yr Sample Condition

Patton, 1998 14-15 yrs Depression, anxiety

Lerman, 2001 Adults Inattention symptoms

Lerman, 1996 Adults Negative affect

Tizabi, 1999 Rats Depression (FSL rats)

Martinez-Gonzales, 2001

Rats Depression and alcohol use

Does depression influence smoking initiation? YES.

Cohort 1 (1952-1970), Stirling County study

0

1

2

3

4

5

6

7

8

Never Depressed Depressed

% Initiation

%Initiation

Does depression influence smoking initiation? YES.

Cohort 2 (1970-1992), Stirling County study

0

1

2

3

4

5

6

7

Never Depressed Depressed

%Initiation

%Initiation

Tobacco use leads to psychopathology

Author, yr Sample Diagnosis

Wu & Anthony,1999

Teens Depressive Symptoms

Goodman & Capitan, 1999

Teens Depressive Symptoms

Choi et al, 1997 Teens Depressive Symptoms

Brown et al, 1996 Teens MDD & Drug Abuse/Dependence

Breslau & Klein, 2000

Young adults Panic disorder

Johnson et al, 2000 Teens Agoraphobia,GAD

Does smoking precede depression? Stirling County study

Baseline Incidence of new status depression per 1000

Cohort 1 Smokers 4.5 1952-1970 Nonsmokers 4.6

Cohort 2 Smokers 3.8 1970-1992 Nonsmokers 3.5

The evidence suggests NO.

Shared etiology

Author, yr Sample Diagnosis/Outcome

Breslau, 1993 Young adults

MDD – ND relationship non-causal, a third factor

Kendler, 1993 Female twins

MDD - Genetic (vs familial, environmental) best model

Dierker, 2002 Probands & 1st degree relatives

Dysthymia & heavy smoking cross-aggregated in families

True, 1999 Male twins R=0.68 genetic correlation for nicotine and alcohol dependence

Which explanatory mechanism is true?

Implications

Because smoking may lead to mental illness: Prevention

Is teen-smoking a screen for psychopathology? (Smoking status a clinical tool for psychiatry) Will smoking prevention or early cessation reduce risk of mental illness ? Treatment Will cessation reduce symptoms of mental illness?

Implications

Because Mental Illness may lead to smoking, or etiology is shared:

Prevention Are psychiatric symptoms markers of risk for future nicotine dependence ? Will early treatment of mental illness prevent/reduce

nicotine dependence?Treatment Smokers with mental illness will require intensive cessation treatments, of longer duration :

- higher doses, - combination treatments (e.g. Bupr & NRT),

- longer duration (6 months vs 8-12 weeks)