Smoking and Schizophrenia
Jill Williams, M.D.Assistant Professor of Psychiatry
UMDNJ-Robert Wood Johnson Medical SchoolUMDNJ- SPH Tobacco Dependence Program
Piscataway, NJ
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
• 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