Transcript Nicotine and Schizophrenia

Smoking and Schizophrenia
Jill Williams, M.D.
Assistant Professor of Psychiatry
UMDNJ-Robert Wood Johnson Medical School
UMDNJ- SPH Tobacco Dependence Program
Piscataway, NJ
[email protected]
Smoking and Schizophrenia
PART I
• Clinical Epidemiology
• Review of Neurobiology
• Nicotine and Schizophrenia
PART II
• Motivational Interventions
• Pharmacological and Psychosocial
Treatment
Smoking and Schizophrenia
PART I
• ClinicalEpidemiology
• Review of Neurobiology
• Nicotine and Schizophrenia
Vocabulary
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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
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70
49
47
46
45
30
Mania
Major depression
Anxiety disorder
personality disorder
Adjustment disorder
Controls (n=411)
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
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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
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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
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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 Comorbidity
• Schizophrenia
– Hypoactivity of the Mesocortical tractmidbrain (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
60
50
Figure 1
40
30
20
10
0
-10
N =
55
81
control smokers
smokers wit h schizop
SUBJECTS
Mean Nicotine
21 ng/mL
p< 0.0001
28
ng/mL
Figure 2
Mean Cotinine
227 ng/mL
p< 0.012
291 ng/mL
3.0
2.5
2.0
1.5
1.0
COTRATIO
.5
0.0
-.5
N=
54
control smokers
98
schizophrenic smoker
CA SES
Mean 3HC: Cotinine Ratio
0.44
p=0.845
0.43
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)
SE B
β
Presence of Schizophrenia 6.913
or Schizoaffective Disorder
1.890
.313***
Number Past Quit Attempts -.456
.247
-.158*
Variable
B
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)
SE B
β
Presence of Schizophrenia 56.358
or Schizoaffective Disorder
25.557
.177**
Cigarettes Per Day
1.145
.163**
Variable
B
2.327
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
Schizophrenia versus Schizoaffective
Disorder
Smokers with
schizophrenia
(n=74)
Smokers with
schizoaffective
disorder
(n=26)
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
Cigarettes Per Day
p-value
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)
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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
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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
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Clinical evidence
Post-mortem
Psychophysiological
Genetics
Other Nicotine BenefitAuditory 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 stressed
Smoke before group
Smoke 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
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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
– Respiratory disease
2.3x
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
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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
Can’t quit
It’s all they have
It helps them
They will become
violent
Low motivation
Lack skills to quit
Enabling
Illness modulating
Ignorance and fear
Barriers to Abstinence
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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
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Fewer supports
Peers smoke
Group home smoking
Smoking within the mental health culture
Smoking as a normalizing behaviorsubstance 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-thecounter medications
Comprehensive Program
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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
Clinical Trials
Pioneering Work (Ziedonis et al., 1997)
First published trial
24 patients
NRT, behavioral treatment, individual MET
Study Population (Ziedonis)
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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
Results
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
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
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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
SELECTED STUDIES IN SCHIZOPHRENIA
Authors
Diagnoses
Treatment
N
Outcomes
Ziedonis and
George, 1997
Schizophrenia or
Schizoaffective
Disorder
10 week MET modified
group +/- 21mg patch
24
13%
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
Schizoaffective
Disorder
21 mg/day patch and
modified ALA group
versus modified MET
group
45
56% on atypical
Weiner et al.,
2001
Schizophrenia or
Schizoaffective Disorder
Bupropion 300 mg/day
and modified ACS group
9
Evins et al.,
2001
Schizophrenia
Bupropion SR
150mg/day vs. placebo
and CBT group
18
George et al.,
2002
Schizophrenia or
Schizoaffective Disorder
Bupropion SR
300mg/day vs. placebo
32
Williams et
al., 2004
Schizophrenia or
Schizoaffective
Disorder
21mg/day patch vs. 42
mg/day patch
45
abstinent at 12
weeks
abstinent
22% on typicals
0
Reduced expired CO
11% abstinent at 12
weeks
50% abstinent in week
1
16 % abstinent at 8
weeks
No difference between
patch dose groups
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 trial
42mg (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 baseline
demographics
smoking amount
measures of nicotine dependence
smoking duration
symptoms
depression 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
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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
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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
24.2
Preparation
6.1
(Steinberg 2003)
78 Smokers with Schizophrenia / Schizoaffective Dx
At least 10 cigarettes per day
Not currently in tobacco dependence treatment
Motivational Interviewing
N=32
Psychoeducation
N=34
Minimal Control
N=12
One week and one month post-intervention
follow-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.
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.
35%
32.3%
30%
One-Week
25.8%
One-Month
25%
20%
15%
11.4%
10%
5%
0%
0.0%
Motivational (N=32)
Psychoeducational
(N=34)
0.0%
0.0%
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 postintervention
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.
35
Cigarettes Per Day
30
25
20
15
10
5
0
You
Average Smoker
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
Medication
(intervention)
Management
(control)
Duration: 24
weeks
Duration: 24 weeks
Nicotine patch for
Nicotine patch for 16
16 weeks
weeks
Twenty four 50 minute
sessions
Motivational
Enhancement Therapy
Social skills training
Relapse Prevention full
Personalized Feedback
Nine 20 minute sessions
Relapse prevention lite
Medication 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 KDA14009-01)
• 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