Smoking and Schizophrenia

Jill Williams, M.D.Assistant Professor of Psychiatry

UMDNJ-Robert Wood Johnson Medical SchoolUMDNJ- SPH Tobacco Dependence Program

Piscataway, NJ

jill.williams@umdnj.edu

Smoking and Schizophrenia

PART I• Clinical Epidemiology• Review of Neurobiology• Nicotine and SchizophreniaPART II• Motivational Interventions • Pharmacological and Psychosocial

Treatment

Smoking and Schizophrenia

PART I

• Clinical Epidemiology

• Review of Neurobiology

• Nicotine and Schizophrenia

Vocabulary

• Schizophrenia

• Biology of addiction- Reward pathways

• Nicotinic receptors and receptor agonists

• Nicotine levels

• Smoking topography

• Nicotine nasal spray

• Modified behavioral therapy

“Schizophrenia”

Schizophrenia

• Affects 1% of the adult population

• Positive symptoms- delusions, paranoia, hallucinations

• Negative symptoms- amotivation, disorganization, poverty of speech

• Cognitive symptoms- disturbance of attention, working memory

Neurodevelopmental Hypothesis

• Event in fetus in second trimester

(infection, hypoxia, genetic , other)

• Agenesis of neurons in entorhinal cortex of parahippocampal gyrus and anterior cingulate gyrus

• Lack of growth in temporal lobe but also secondary effect on frontal lobe

Neurodevelopmental Hypothesis

• Clinical symptoms not seen until late adolescence

• Complete myelination of cortex not complete until second or third decade of life– DLPFC– Executive functions

Neurodevelopmental Hypothesis

• Mesolimbic tract- midbrain (VTA) to limbic

DA hyperactivity: positive symptoms

• Mesocortical tract- midbrain (VTA) to frontal and DLPFC

DA hypoactivity: negative symptoms

Schizophrenia

• High prevalence of smoking• Heavy smoking/ Highly nicotine dependent

• Nicotine produces cognitive or other benefit

• Smoking ameliorates medication side effects

• Half as successful in quit attempts as other smokers

Prevalence of Smoking

• Psychiatric outpatients (n=271); Hughes, 1986

» Smokers (%)

– Schizophrenia 88– Mania 70– Major depression 49– Anxiety disorder 47– personality disorder 46– Adjustment disorder 45– Controls (n=411) 30

Prevalence of Smoking in Schizophrenia

• Individuals with schizophrenia were 10 times more likely to have ever smoked daily than individuals in the general population

• Prevalence 55-90% replicated many countries and settings

• Two to four times higher smoking rates• Countries with cultural limitations to

smoking- use of nicotine analogs (betel nut)

International Studies

• 58% in/outpatients (42% GP; Greece)

• 41% inpatients (34% GP; Taiwan)

• 65% in/outpatients (40% GP; Scotland)

• 66% in/outpatients (34% GP; France)

• 64 % outpatients (51% GP; Spain; Herran et al., 2000)

• 38% outpatients (40% males GP; India)

Meta-analysis

• 42 studies / 20 nations

• Schizophrenia and smoking OR 5.9

• Male studies OR 7.2

• Female studies OR 3.3

• Compared to SMI controls OR 1.9

(deLeon & Diaz 2005)

Characteristics of smoking Schizophrenics

• 92 % (11 of 12 ) first episode schizophrenics smoke, no prior antipsychotic exposure

• Polydipsia associated with heavy smoking

• Higher levels of positive symptoms and decreased negative symptoms

Hypotheses

• Increased propensity to dependence

• Illness modulation effect

• Side effect reduction

• Immediate

self-medicating

effect

• Social factors

Brain Reward Systems

• Dopamine (DA) system

• Mesolimbic Dopamine system– Ventral Tegmental Area (VTA)– Nucleus Accumbens (NAc)– Projections to Medial Prefrontal Cortex

Schizophrenia and Substance Co-morbidity

• Schizophrenia– Hypoactivity of the Mesocortical tract-

midbrain (VTA) to frontal and DLPFC causes negative symptoms

• DA activation in reward pathways from drugs

• More reinforcing• Negative symptom relief

Stimulants(Gawin,Khalsa and Ellinwood, 1994)

• High Abuse

– cocaine

– amphetamine

– metamphetamine

– methylphenidate

Low Abuse

– caffeine

– nicotine

– ephedrine

– pseudoephedrine

– theophylline

– fenfluramine

Schizophrenia

• High prevalence of smoking

• Heavy smoking/ Highly nicotine dependent

• Nicotine produces cognitive or other benefit• Smoking ameliorates medication side

effects• Half as successful in quit attempts as other

smokers

Heavy Smoking

• Heavy smoking common (>25 cpd)

• Highly nicotine dependent – Fagerstrom measures of nicotine dependence in

the moderate to severe range (6-7)

• Rapid smoking (2 or more cigarettes within 10-minute periods)

• Smoking cigarettes completely to butts

Nicotine and Schizophrenia

It has been proposed that smokers with schizophrenia are more efficient smokers, who absorb more nicotine per cigarette than do smokers without this disorder.

Preliminary Evidence

• Urinary cotinine higher – 20 smokers with schizophrenia than in normal

controls who smoked the same number of cigarettes per day (Olincy et al., 1997).

– Limited by its small sample size, lack of SCID diagnoses for schizophrenia, lack of measurement of nicotine concentration and use of an enzyme-linked immunoassay technology

Cotinine

– Major nicotine metabolite

– Stable compound

– Half-life 16 hours

– Easy to measure in body fluids for 3-5 days after nicotine exposure.

– Less dependent on the time to last cigarette than is nicotine.

Nicotine and Cotinine Levels in Schizophrenia

• One objective of this study was to measure serum nicotine and cotinine levels in 100 smokers with schizophrenia and schizoaffective disorder and to compare these to control smokers without mental illness.

? Increased Nicotine and Cotinine

• Increased inhalation: Intake effect

• Reduced metabolism • In this way we can determine if higher

nicotine/cotinine levels are due to a true inhalation difference as opposed to different metabolism of nicotine between groups.

CYP2A6 Metabolism of Nicotine

3-HC: Cotinine Ratios

• Measured levels of the cotinine metabolite, 3-hydroxycotinine (3-HC).

• The ratio of 3-HC to cotinine is a marker of CYP2A6 metabolic activity and nicotine metabolism

Smokers with schizophrenia or schizoaffective disorder (N=115)• Stable on antipsychotic medications • All subjects were required to bring their own

cigarettes in for testing procedures.• Diagnosis confirmed with SCID• Smoked more than 8 cigarettes per day.• Score 24 or higher on the Folstein MMSE• Not using clonidine, bupropion, or any nicotine

products (patch, gum, inhaler, lozenge or nasal spray) • No cigars or other tobacco products.

Control Smokers (N=55)

• Healthy volunteer smokers without mental illness • SCID, Non-Patient Edition (SCID-NP) to rule out

a major psychiatric history. • No past history of any psychotic disorder, or

bipolar disorder were excluded. • No past or present use of antipsychotic medication

for any reason. • Moderate to heavy smoking control smokers were

recruited

Procedure• Usual smoking day; early afternoon • Subjects instructed to smoke one of their own

cigarettes outdoors• Two minutes later, blood draw• Baseline expired carbon monoxide reading• Analyses at Clinical Pharmacology Laboratory at

UCSF (Highly specific gas chromatography) • Nicotine, cotinine, caffeine and 3-hydroxy cotinine • Lab personnel blinded study purpose and smoker’s

identity

Figure 1

8155N =

SUBJECTS

smokers with schizopcontrol smokers

Nic

otin

e (

ng

/mL

)

60

50

40

30

20

10

0

-10

Mean Nicotine

21 ng/mL 28 ng/mL

p< 0.0001

Figure 2

Mean Cotinine

227 ng/mL 291 ng/mL

p< 0.012

9854N =

CASES

schizophrenic smokercontrol smokers

CO

TRAT

IO

3.0

2.5

2.0

1.5

1.0

.5

0.0

-.5

Mean 3HC: Cotinine Ratio

0.44 0.43

p=0.845

Regression

• Age, education, marital status, gender, race, employment status

• Age of onset of smoking, cigarettes per day, FTND score, years smoked, time of blood draw, and number of past quit attempts, 3HC:cotinine ratio

• Antipsychotic medication type, antipsychotic medication dose (measured in chlorpromazine equivalents)

• Diagnosis Schizophrenia or Schizoaffective Disorder

Table 5: Summary of Backward Stepwise Linear Regression Analysis for Variables Predicting Nicotine Levels (N = 128)

 

 

Variable B SE B β

Presence of Schizophrenia 6.913 1.890 .313***or Schizoaffective Disorder

Number Past Quit Attempts -.456 .247 -.158*

 

 

Note. R2 = .093, *p<.1, **p<.05, ***p<.001

Table 6 :Summary of Backward Stepwise Linear Regression Analysis for Variables Predicting Cotinine Levels (N = 148)

 

 

Variable B SE B β Presence of Schizophrenia 56.358 25.557 .177**or Schizoaffective Disorder Cigarettes Per Day 2.327 1.145 .163**

Note. R2 = .050. *p<.1, **p<.05, ***p<.001

 

 

Results

• Cotinine and nicotine levels of smokers with schizophrenia and schizoaffective disorder were 1.3 times higher than control smokers without major mental illness

• 3HC: Cotinine ratios were not different between groups

• Diagnosis of schizophrenia predictor of higher cotinine level

(Williams et al., in press, Schizophrenia Research)

Comparisons Between Treatment Seeking and Non-Treatment Seeking Samples

• No differences smoking variables – Mean cigarettes smoked per day, expired CO at

baseline, years smoked and age of first smoking

• No differences illness characteristics– psychiatric diagnosis, antipsychotic type (percentage on

atypical antipsychotics) or antipsychotic dose, measured in chlorpromazine (CPZ) equivalents.

• No differences between on mean cotinine or nicotine levels

  Smokers with schizophrenia

(n=74)  

Smokers with schizoaffective

disorder (n=26)

 

 p-value

Cigarettes Per Day 24.7 (12.8) 24.1 (9.9)  

CPZ equivalents

676.1 (584.4) 392.9 (253.4) 0.019

Serum Cotinine levels

309.2 (161.6) 240.0 (149.8) 0.059

Serum Nicotine levels (ng/mL)

27.1 (11.1) 27.4 (11.5) 0.903

3OH-Cotinine: Cotinine Ratio

0.4462 0.3811 0.305

Schizophrenia versus Schizoaffective Disorder

Study Strengths

• Standardized conditions for sampling nicotine

• Direct measure of nicotine• Highly specific gas chromatographic assay • Metabolic data on our subjects (3HC:Cot)• Diagnoses confirmed with SCID-IV• Controlled for confounders through

regression analyses

Medications and Nicotine/ Cotinine Levels

• Smokers with schizophrenia taking 1.7 times more medication than SA

• Is dose of antipsychotic medication an estimate of illness severity

• Illness severity a predictor of increased smoking levels

• Heavy smoking has been associated with greater illness severity in schizophrenia in clinical studies

Medications and Nicotine/ Cotinine Levels

• Heavy smoking is associated with induction of hepatic enzymes and reduction of serum levels of antipsychotics metabolized by the CYP1A2 isoenzyme

• Heavy smokers –greater hepatic induction

• Subsequent higher medication doses

Smoking topography

• 23 smokers with psychotic disorders (schizophrenia, schizoaffective disorder and psychosis not otherwise specified)

• Significantly more puffs per cigarette, • Shorter inter-puff interval, • Greater total puff duration • Suggesting greater intake of nicotine (Unpublished,

Caskey et al., 2003). • Limitations: small sample sizes and lack of blood

sampling for nicotine in all subjects

Portable Topography Measurement (CReSSmicro)

Measured Characteristics

• Puff Volume • Puff Duration • Inter-Puff Interval • Peak Flow during Puff • Time of Peak Flow • Mean Flow during Puff • Puffs per Cigarette • Time to First Puff • Time to Removal

Schizophrenia

• High prevalence of smoking• Heavy smoking/ Highly nicotine dependent

• Nicotine produces cognitive or other benefit

• Smoking ameliorates medication side effects

• Half as successful in quit attempts as other smokers

Nicotine and Cognition

• Cigarettes perhaps beneficial in performing simple, timed, repetitive, tasks

• Reaction time• Attention

– (finger tapping, visual search) (Andersson, 1975, Stevens, 1976, Gonzales & Harris, 1980, Wesnes and Warburton, 1984)

Nicotine and Cognition

• Smokers do worse on complex tasks– tasks of manipulation of short term memory (working

memory), – long term memory – comprehension

• At heavy task demands and complex problem solving, performance deficit is most pronounced

• Non-smokers outperform smokers in many tasks

Nicotinic Acetylcholine Receptors (nAChR)

• Alpha 7 receptor ligand gated Ca ion channel

• Participate in attention, memory and cognitive functions

• Evidence of involvement of clinical diagnoses of schizophrenia, Alzheimer’s disease, Parkinson’s disease, ADD, autism, Tourette’s syndrome

Nicotine and Schizophrenia

• Decreased low affinity and high affinity nAChRs

• Nicotine normalizes abnormal P50 responses• Nicotine improves smooth pursuit, decreases

saccadic eye movements• Nicotine patch improves cognitive

performance of schizophrenics on haloperidol (Levin 1996).

Nicotine and Working Memory

• Abstinent schizophrenics worse visuospatial working memory (George 2002)

• Improved verbal memory with high dose NNS (Smith 2002)

• Improved working memory with nicotine patch and increased (fMRI) activation in anterior cingulate and bilateral thalamus (Jacobsen 2004)

• Lack of improvement in verbal memory with nicotine gum/patch (Levin 1996; Harris 2004)

Neuropsychological Deficits in Schizophrenia

• Smoking Cessation Treatment Failure

• Seen schizophrenia, not controls

• VSWM and WCST deficits: less likely to quit smoking

(Dolan 2004)

Acetylcholine hypothesis of Schizophrenia

• A malfunction in interneuronal function involving Acetylcholine transmission is the core finding in schizophrenia

a7 nicotinic receptor malfunction

(R. Freedman, U of Colo)

• A deficit in cholinergic neurotransmission indistinguishable from an excess of dopaminergic transmission (Holt et al 1999)

Dopamine and Acetylcholine

• Known relationships in brain

• Clinical experience with Parkinson's disease and anti-Parkinsonian drugs

Acetylcholine hypothesis of Schizophrenia

• Clinical evidence

• Post-mortem

• Psychophysiological

• Genetics

Other Nicotine Benefit-Auditory Gating

• Auditory evoked potentials

• Normal inhibition after a stimulus

• P50 response rates 50msec after an initial stimulus

• Schizophrenics have an abnormal P50 response: failure to suppress a second stimulus

P50 Gating- Humans

• Abnormal P50 responses are normalized by cigarette smoking or high dose (6mg) nicotine gum, in schizophrenics

• P50 defect also found in non-impaired relatives of schizophrenics. Also reversed by nicotine

Saccadic Eye Movements

• Smooth pursuit eye movements• Improved smooth pursuit, decreased

saccades with smoking • Non-impaired relatives have saccades• Effects from smoking wear off after about

20 minutes

(Olincy et al, 1995)

Clinical Relevance of Abnormal P50 Finding

• ?? Distractibility• ?? Hallucinations• Patients subjective use of nicotine

Smoke when stressedSmoke before groupSmoke in response to voices

• Schizophrenics use higher doses of nicotine to activate low affinity cholinergic receptors

Genetics

• P50 a marker for schizophrenia genetics

• Linkage analyses P50 abnormality seen in family

members polymorphism on 15q14 site of a7 nicotinic receptor gene

Nicotine Receptor (a7) Agonists

• GTS-21 (DMXB-A or anabaseine)

• Rats: normalizes abnormal gating in rats

• Promising Phase I

• Less toxic than nicotine, less effects on autonomic and skeletal muscle

• Orally available and safe, few adverse effects

Nicotine vs. Tobacco

Tobacco not a pharmacological treatment Not used as a rationale to support

smoking

Risk: Benefit Ratio strongly in support of nicotine over tobacco

Financial Implications of Smoking

• Smokers with schizophrenia spent median $142.50 (range $57-319)/ month on cigarettes

• Median public assistance benefit was $596

• 27.36% of monthly income on cigarettes

(Steinberg, Williams and Ziedonis, Tobacco Control 2004)

Causes of the excess mortality of schizophrenia

• The life expectancy of patients with schizophrenia is approximately 20% shorter than that of the general population

• Smoking-related fatal disease is more prominent than in the general population(Brown et al., 2000; Br J Psychiatry)

Schizophrenia Natural Causes of Death

• Higher standardized mortality rates than the general population for

– Cardiovascular disease 2.3x– Respiratory disease 3.2x

• Both of which highly linked to smoking

Conclusions – Part I

• Smoking and schizophrenia highly linked

• Shared neurobiology

• Higher nicotine intake in schizophrenia

• Cognitive or other benefit from nicotine in schizophrenia

Smoking and Schizophrenia

PART II

• Motivational Interventions

• Pharmacological Treatment

• Psychosocial Treatment

Schizophrenia

• High prevalence of smoking

• Heavy smoking/ Highly nicotine dependent

• Nicotine produces cognitive or other benefit

• Smoking ameliorates medication side effects

• Half as successful in quit attempts as other smokers

Schizophrenia and Smoking

• Reframing our assumptions

Don’t want to quit Low motivationCan’t quit Lack skills to quitIt’s all they have EnablingIt helps them Illness modulatingThey will become Ignorance and fear

violent

Barriers to Abstinence

• Biological Factors

• Psychological Factors

• Social Factors

• Knowledge Deficit/ Cognitive Factors

• Institutional Factors

Psychological Factors

Low self-efficacy

Poor coping

Poor compliance

Low motivation

Fear of worsening symptoms

Social Factors

• Fewer supports

• Peers smoke

• Group home smoking

• Smoking within the mental health culture

• Smoking as a normalizing behavior- substance users are perceived as “friends”

Cognitive Factors

• Lack of understanding of smoking morbidity

• Impaired cognition and new learning

• Not able to use counseling from primary care and other community resources

• Poor use of self-help materials

Institutional Barriers

• Restrictive formulary

• Fear of misuse of NRT / Fear of smoking on NRT

• Psychiatrist as primary care

• Limited income, cannot afford over-the-counter medications

Comprehensive Program

• Motivational assessments and interventions• Slow pace, repetition• Alternative goals, eventual abstinence• Focused skill building, role plays• Relapse prevention skills• Strengthen self-efficacy• Psychoeducation• Support

Comprehensive Program

• Aggressive use of medications

• Modeling

• Culture of mental health settings and residences

• Psychiatrists more active in tobacco treatment

Pioneering Work (Ziedonis et al., 1997)

First published trial

24 patients

NRT, behavioral treatment, individual MET

Clinical Trials

Study Population (Ziedonis)

• Smoking onset 15 years

• Average of 27 cpd

• Baseline expired CO 27

• Fagerstrom 7

• 40% live with a smoker

• 85% had a past quit attempt longer than 24 hours

Treatment was feasible• Patients interested in participating• Patients moved from contemplation to action stage• No worsening of psychiatric disorder• 50% completed 10 week program

13% abstinent for 24 weeks

17% episodes of abstinence

Results

Clinical Trials

Addington et al, 1997

7 week Group therapy treatment (ALA based)

50 smoking schizophrenics

10 weeks NRT (40 subjects)

Results

- 42% abstinent at 7 weeks

- 16 % abstinent at 12 weeks

- 12% at 24 weeks

No change in symptoms of schizophrenia

No great difficulty in having schizophrenics use the patch

Conclusions

• It is possible for individuals with schizophrenia to stop smoking.

• Patients were more successful if they had received the nicotine patch

Schizophrenia

• High prevalence of smoking

• Heavy smoking/ Highly nicotine dependent

• Nicotine produces cognitive or other benefit

• Smoking ameliorates medication side effects

• Half as successful in quit attempts as other smokers

Smoking and Typical Antipsychotics

• Ad libitum smoking increases after initiation of haloperidol relative to a baseline rate when free of antipsychotic

• Counteract some of the adverse effects of antipsychotic drugs

• Lower rates of neuroleptic-induced Parkinsonism

Clozapine and Smoking

• Schizophrenics smoke less when treated with clozapine versus conventional antipsychotics

• Reverses P50 gating abnormality

• Preferential response and decreased smoking in treatment refractory schizophrenic smokers

Atypical Antipsychotics

• 45 schizophrenics

• ALA vs. modified treatment (MET, RP, SST, Psychoeducation)

• 10 weeks NRT

• 10 weeks group

3 weeks MET

7 weeks Psychoed, SST, RP

Atypical Antipsychotics

• Better retention in atypical group (10 vs. 7 weeks)

• Increased abstinence in patients on atypical antipsychotics (12 weeks)55.6 % (atypicals) vs. 22.2% (typicals)

16.7% vs. 7.4% at 24 weeks

Bupropion SR and Schizophrenia

8 patients, 14 week open trial

• No patients quit smoking in 14 weeks, one did in following 12 weeks

• Well tolerated- no change in anxiety or positive symptoms

• Reduced CO level(39.44 ppm vs 18.3ppm at week 14)

(Weiner 2001)

Bupropion Trial

• Bupropion and CBT (Evins et al)

• 12 weeks Bupropion 150mg QD and weekly group

• N=19• Abstinence (CO<9)• Reduction in smoking

– >50% reduction in cpd– >30% reduction in CO level

Bupropion Results

• 18 (n=19) completed 6 months study• CBT attendance was 86%• One bupropion patient abstinent at 12 weeks• None placebo group• 66% bupropion reduced smoking

11% placebo group reduced smoking

No difference in positive symptoms between groups

Summary

• Bupropion may have a role in schizophrenics

• Initial studies indicate it is safe and well tolerated

• Best dose?

Schizophrenia 2 Year Follow-up Study (Evins 2003)

• 17/18 seen at 2 year follow-up

• 75% of reducers sustained benefit at 2 years– 50% in cpd and 30% in CO

• More abstainers at 2 years than at 8 weeks– 4 (22%) versus 1(5%); all abstainers had been

reducers in initial trial

Authors 

Diagnoses Treatment N Outcomes

Ziedonis and George, 1997  

Schizophrenia or SchizoaffectiveDisorder

10 week MET modified group +/- 21mg patch

24 13% abstinent at 12 weeks

Addington et al., 1998  

Schizophrenia or Schizoaffective Disorder

7 week modified ALA group +/- 21mg patch

50 16% at 12 weeks

George et al., 2000

Schizophrenia or SchizoaffectiveDisorder 

21 mg/day patch and modified ALA group versus modified MET group

45 56% on atypical abstinent 22% on typicals

Weiner et al., 2001 

Schizophrenia or Schizoaffective Disorder

Bupropion 300 mg/day and modified ACS group

9 0Reduced expired CO 

Evins et al., 2001 

Schizophrenia Bupropion SR 150mg/day vs. placebo and CBT group

18 11% abstinent at 12 weeks

George et al., 2002  

Schizophrenia or Schizoaffective Disorder

Bupropion SR 300mg/day vs. placebo

32 50% abstinent in week 1

Williams et al., 2004  

Schizophrenia or SchizoaffectiveDisorder 

21mg/day patch vs. 42 mg/day patch

45 16 % abstinent at 8 weeksNo difference between patch dose groups

SELECTED STUDIES IN SCHIZOPHRENIA

High-Dose Nicotine Patch

• This evidence supports that currently recommended doses of nicotine replacement therapy are inadequate for many smokers

• In heavy smokers, this underdosing may be one of the reasons for the limited efficacy of transdermal nicotine

High Dose Nicotine Patch Study

• Randomized trial42mg (double patch) vs. 21mg patch in smokers with schizophrenia/schizoaffective disorder• Patch doses decreased in an 8-week tapering

schedule • All subjects participated in 15 minute weekly

individual sessions• Self-report abstinence from smoking is verified

with weekly-expired air carbon monoxide measure (8 ppm or less considered negative).

High Dose Nicotine Patch Therapy

• Heavy smokers – mean Fagerstrom 7.4– mean expired CO 23– mean cpd 26

• Smoked 20 years• About 5 prior quit attempts• Most (79%) are able to set a quit date and

make a quit attempt.

Baseline Characteristics

The two dose groups did not differ in baselinedemographics smoking amountmeasures of nicotine dependencesmoking durationsymptomsdepression severity

Many (80%) of the subjects had past or present substance use disorders although most had not used substances for at least 1 year and this was not different between dose groups.

Abstinence Outcomes

The 7-day point prevalence abstinence rates at 8 weeks was 24% (n=11) in the total sample.

The rate of continuous abstinence at 8 weeks was 15.6% (n=7) in the total sample.

Abstinence rates for regular dose were not different between dose groups.

Conclusions

• Total dose less important

• Continuous delivery less advantageous than intermittent dosing

• Peaking nicotine dose more advantageous

• Mimics a cigarette

• Intermittently high dosed nicotine

• Nicotine nasal spray

Receptor Desensitization

• Receptor desensitization important in limiting excessive receptor stimulation in the presence of agonist

• Prevents cellular excito-toxicity.

• Recovery can only occur when the agonist is removed

• P50 not corrected with nicotine patch

Alpha-7 Nicotinic Receptor Desensitization

• Alpha-7 nicotinic receptors most rapidly desensitizing of all the nicotinic receptors

• Desensitization is defined as the decrease or loss of biological response following prolonged or repeated stimulation

• Brief agonist pulses produce the fastest channel responses and fastest response decay

High and intermittently dosed nicotine

• High nicotine needed to activate the low affinity a-7 receptor

• Schizophrenics may be using nicotine in order to achieve a specific effect on a-7 receptors that is not seen in other groups of smokers.

• Schizophrenics have reduced number of nicotinic receptors

• Desensitization may have more profound effects on the system

Nicotine Nasal spray

• 1 mg droplet dosed up to 40 times/day

• Side effects- nasal irritation, rhinitis, coughing, watering eyes

• Some dependence liability

• 30-50% of abstainers using it for >6 months

Nicotine Nasal Spray

• Rapid absorption • Rapid onset of action• More immediate craving relief• Dosed intermittently • Pulsatile delivery of nicotine that more closely

mimics smoking a compared to the patch. • NNS effective in highly dependent smokers• ? More desirable for persons with schizophrenia

Nicotine Nasal Spray for Schizophrenia

• NNS: Acts as a primary reinforcer; ?greater satisfaction than slow onset products like the patch

• Smokers with schizophrenia may be more willing to use it due to this property

• Case series of 12 smokers with schizophrenia or schizoaffective disorder who had not succeeded with previous treatments for tobacco dependence

Baseline characteristics

• 6 males, 6 females• Average age 45• Smoked, on average, for 25.9 years (SD 11.1).• Mean FTND 7.8 (mod to severe dependence)• Smoked 26.7 (SD 10.1) cigarettes per day • Expired carbon monoxide (CO) of 22.3 (SD 8.0)

at the time they began treatment with the nasal spray

Nicotine Nasal Spray

• 11 tolerated the nasal spray well • Nine of 12 patients used at least 30 sprays/day 3 who are continuously abstinence still use it at

40 sprays per day, with one 10mL bottle consumed every 3 days.

• The mean length of time with nasal spray treatment for all twelve patients was 255 days (range 2-811 days) and several used it for months prior to achieving abstinence

Nicotine Nasal Spray

• Five patients (42%) were abstinent for longer than 90 days

• Four of the seven who did not quit have had substantial reductions in the amount of cigarettes smoked and expired CO (mean CO=21 before spray and mean CO= 3.5 at last visit on spray).

• Most used it at maximal doses for prolonged periods

• Increased use seems to be correlated with better outcomes

(Williams et al, Sept 2004, Psychiatric Services)

Nicotine Nasal Spray

• LIMITATIONS– Case series– Nearly all used the spray in combination with

other medications and psychosocial support.

(Adjunctive inhaler or other NRT when beyond maximum daily dose NNS)

Psychosocial Treatment Development for Smokers with

Schizophrenia

Psychosocial Treatments

• Brief Treatments– Primary care model– 5As ( Ask, Advise, Assess, Assist, Arrange)– Promoting motivation to quit (MET)

• Intensive Treatments– Tobacco treatment specialists– Behavioral health and/or addictions specialists

Motivational Levels

• Patients with schizophrenia indicate an interest in trying to cut down or quit smoking (Forchuk et al., 2002)

• Stages of Change: N=78 Precontemplation 69.7

Contemplation 24.2Preparation 6.1

(Steinberg 2003)

78 Smokers with Schizophrenia / Schizoaffective DxAt least 10 cigarettes per day

Not currently in tobacco dependence treatment

Motivational InterviewingN=32

Psychoeducation N=34

Minimal Control N=12

One week and one month post-interventionfollow-up by R.A. blind to treatment condition

Steinberg ML, Ziedonis DM, Krejci JA, Brandon TH. Motivational Interviewing With Personalized Feedback: A Brief Intervention for Motivating Smokers With Schizophrenia To Seek Treatment for Tobacco Dependence. Journal of Consulting & Clinical Psychology, in press.

25.8%

32.3%

0.0%

11.4%

0.0% 0.0%

0%

5%

10%

15%

20%

25%

30%

35%

Motivational (N=32) Psychoeducational(N=34)

Control (N=12)

Figure 1. Percentage of participants receiving each intervention following up on referral to tobacco dependence treatment at one- week and one- month post-intervention

One- Week One- Month

Steinberg ML, Ziedonis DM, Krejci JA, Brandon TH. Motivational Interviewing With Personalized Feedback: A Brief Intervention for Motivating Smokers With Schizophrenia To Seek Treatment for Tobacco Dependence. Journal of Consulting & Clinical Psychology, in press.

0

5

10

15

20

25

30

35

You Average Smoker

Cig

are

ttes

Per

Day

From the Personalized Feedback Report:How much do you smoke each day?Some people smoke so much each day that they have a cigarette in their mouth all the time. Some people are just stuck on those last few cigarettes that they don’t seem to be able to quit. Please look at the chart below to see how your smoking compares with how much other smokers smoke each day on average.

Compared with those receiving Psychoeducational or Minimal Control interventions…

– MI participants will be more likely to seek tobacco dependence treatment

Psychosocial Treatments

• Dose-response relationship between counseling intensity and success

• Provider discipline not important

• Telephone counseling, individual and group treatment are all effective

• Problem-solving or skills-training approaches helpful

Treatment of Addiction to Nicotine in Schizophrenia (TANS)

• Behavioral therapy development R01(Ziedonis PI)• TANS blends the best of tobacco dependence tx

approaches with the best from psychosocial tx of individuals with severe mental illness

• TANS is based on – Motivational Interviewing/MET– Social Skills Training– Relapse Prevention/Coping Skills Training– Nicotine patch medication– Atypical antipsychotics

TANS Treatment Overview

• Manual: handouts, different scenarios, client-centered, flexible

• Three phases: Engagement, Achieving Abstinence, Relapse Prevention

• Sessions prepare for Quit date• TANS sessions are 45 minutes• CO monitoring at every session• Nicotine patch for 20 weeks

TANS vs. Medication Management

TANS(intervention)Duration: 24

weeks

Medication Management

(control)Duration: 24 weeks

Nicotine patch for 16 weeks

Nicotine patch for 16 weeks

Twenty four 50 minute sessionsMotivational Enhancement TherapySocial skills trainingRelapse Prevention fullPersonalized Feedback

Nine 20 minute sessionsRelapse prevention liteMedication Management

Treatment Works-Future Studies

• Manualized treatments

• Nicotine and Cotinine levels

• Smoking Topography Measures

• Bipolar Control Groups

• Nicotine Nasal Spray

• Cue-exposure lab studies

Acknowledgements

• National Institute on Drug Abuse (NIDA K-DA14009-01)

• New Jersey Department of Health and Senior Services through the Comprehensive Tobacco Control Program

• Doug Ziedonis, MD, MPH, Primary Mentor • Co-Investigators: Marc Steinberg, Jonathan

Foulds, Neal Benowitz, Paul Lehrer, Maria Karavidas, Francisca Abanyie, Kunal Gandhi