Nicotine and Schizophrenia

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Nicotine and Schizophrenia

• Jill Williams, M.D.Assistant Professor of
  PsychiatryUMDNJ-Robert Wood Johnson Medical
  SchoolUMDNJ- SPH Tobacco Dependence
  Programjill.williams_at_umdnj.edu

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Schizophrenia
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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

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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)

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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

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Heavy Smoking

• Heavy smoking common (gt25 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

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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.

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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

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CYP2A6 Metabolism of Nicotine
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Cotinine

• 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.

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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.

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? 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.

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CYP2A6 Metabolism of Nicotine
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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
  
• Our second objective was to compare the 3-HC to
  cotinine ratios in schizophrenia, to examine the
  possibility of differences in the rate of
  nicotine metabolism between these groups.

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Smokers with schizophrenia or schizoaffective
disorder (N115)

• 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.

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Smokers with Schizophrenia

• 2 Samples
• Baseline assessment for High Dose Patch Study
  (n65)
• Sample of Non-treatment seeking smokers (n50)
• Schizophrenia and Schizoaffective Disorder

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Control Smokers (N55)

• 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

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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 smokers
  identity

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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

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Figure 1
Mean Nicotine 21 ng/mL 28
ng/mL plt 0.0001
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Figure 2
Mean Cotinine 227 ng/mL 291
ng/mL plt 0.012
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Mean 3HC Cotinine Ratio 0.44
0.43 p0.845
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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, 3HCcotinine ratio
• Antipsychotic medication type, antipsychotic
  medication dose (measured in chlorpromazine
  equivalents)
• Diagnosis Schizophrenia or Schizoaffective
  Disorder

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Table 5 Summary of Backward Stepwise Linear
Regression Analysis for Variables Predicting
Nicotine Levels (N 128)
 
 
Variable B SE B ß Presence of
Schizophrenia 6.913 1.890 .313 or
Schizoaffective Disorder Number Past Quit
Attempts -.456 .247 -.158
 
 
Note. R2 .093, plt.1, plt.05, plt.001
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Table 6 Summary of Backward Stepwise Linear
Regression Analysis for Variables Predicting
Cotinine Levels (N 148)
 
 
Variable B SE B ß   Presence of
Schizophrenia 56.358 25.557 .177 or
Schizoaffective Disorder   Cigarettes Per
Day 2.327 1.145 .163 Note. R2 .050.
plt.1, plt.05, plt.001
 
 
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Schizophrenia versus Schizoaffective Disorder
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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

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Study Strengths

• Standardized conditions for sampling nicotine
• Direct measure of nicotine
• Highly specific gas chromatographic assay
• Metabolic data on our subjects (3HCCot)
• Diagnoses confirmed with SCID-IV
• Controlled for confounders through regression
  analyses

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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

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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

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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

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Portable Topography Measurement (CReSSmicro)
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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

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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

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Neurobiology of Smoking and Schizophrenia

• Reduced up-regulation of high-affinity nicotinic
  receptors
• Decreased low affinity and high affinity nAChRs
• Abnormal P50 responses are normalized by
  cigarette smoking in schizophrenics
• Improved smooth pursuit, decreased saccades with
  smoking
• Improved cognition, attention

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Nicotine Benefits

• Nicotine seems to play an important role in
  symptom modulation and attentional processes in
  schizophrenia
• P50/ Auditory evoked potentials
• Failure to suppress a second stimulus
• Saccadic eye movements
• Visuospatial working memory

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P50 Gating- Humans

• Abnormal P50 responses are normalized by
  cigarette smoking in schizophrenics
• Short-lived, requires 3 cigarettes and may be
  gone within 10 minutes after smoking (Adler
  1993).
• P50 defect also found in non-impaired relatives
  of schizophrenics. Also reversed by nicotine
  (gum)
• Not observed with nicotine patch

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P50 Implications

• Clinically linked to auditory hallucinations and
  filtering out other distracting noises
• Linked to decreased hippocampus size in
  schizophrenics
• Linked to reduction in ?7 nicotinic receptors on
  GABA-B inhibitory interneurons

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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)

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Acetylcholine hypothesis

• A deficit in cholinergic neurotransmission may be
  similar in its effects and potentially
  indistinguishable from an excess of dopaminergic
  transmission in the striatum
• (Holt et al 1999)

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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

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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

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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

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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

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Reduced Side Effects

• Higher levels of positive symptoms and decreased
  negative symptoms
• Ad libitum smoking increases after initiation of
  haloperidol
• Schizophrenics who smoke -lower rates of
  neuroleptic-induced Parkinsonism (Menza, 1991)
• Smoke less on clozapine
• 92 (11 of 12 ) first episode schizophrenics
  smoke, no prior antipsychotic exposure

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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

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SELECTED STUDIES IN SCHIZOPHRENIA
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Motivation to Quit

• Patients with schizophrenia indicate an interest
  in trying to cut down or quit smoking
• Respond to motivational interventions (Steinberg)

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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

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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).

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Study Enrollment

• 64 outpatient smokers enrolled
• Interim data analysis on first 55 subjects.
• - 6 did not complete assessments and dropped out
  of the study without setting a quit date.
• -4 did not put on the nicotine patch even one
  time and are also excluded
• 45 subjects who received the patch and are
  defined as our intent to treat group.

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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.

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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.

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Abstinence Outcomes

• The 7-day point prevalence abstinence rates at 8
  weeks was 24 (n11) in the total sample.
• The rate of continuous abstinence at 8 weeks was
  15.6 (n7) in the total sample.
• Abstinence rates for regular dose were not
  different between dose groups.

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Conclusions

• These findings are similar to reports from other
  studies of schizophrenics treated with nicotine
  patch
• Failure to detect differences in abstinence rates
  between high dose (42mg) and regular dose
  nicotine patch

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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

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Nicotine Nasal spray

• 1 mg droplet dosed up to 30 times/day
• Side effects- nasal irritation, rhinitis,
  coughing, watering eyes
• Some dependence liability
• 30-50 of abstainers using it for gt6 months

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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

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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

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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

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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

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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 CO21
  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)

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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)

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Psychosocial Treatment Development for Smokers
with Schizophrenia

• NIDA Behavioral Therapy Development R01
• Doug Ziedonis, PI

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Treatment of Addiction to Nicotine in
Schizophrenia (TANS)

• 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, specific tobacco dependence tx
  (NRT) and specific tx for schizophrenia (atypical
  antipsychotics)
• TANS can be delivered in either individual or
  group formats

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TANS Treatment Overview

• Manual handouts, mandatory and optional
  sessions, different scenarios, client-centered,
  flexible
• Three phases Engagement, Achieving Abstinence,
  Relapse Prevention
• TANS sessions are 45 minutes, 20 sessions in 26
  weeks
• Control treatment sessions are 20 minutes, 9
  sessions in 26 weeks
• CO monitoring at every session
• NRT (TANS)21 mg patch for 16 weeks starting week
  5
• and 14 mg patch for 4 weeks for controls
  it starts at
• week 3 with 21 mg for 12 weeks and 14 mg for
  4 weeks

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Important Topics

• Initial assessment
• Breaking smoking links
• Preparing for quit date
• Withdrawal
• Understanding cravings
• Introduction to role plays
• Cigarette refusal skills
• Asking for help
• Relapse prevention

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Craving and Schizophrenia

• Brain abnormalities in dopaminergic systems in
  schizophrenia may enhance drug craving and reward
  mechanisms.
• Addiction as a symptom of schizophrenia (Chambers
  RA, 2001, Biol Psychiatry)
• High craving for cocaine during early recovery
  and more cue-elicited craving than
  non-psychiatric controls (Carol et al, 2001
  Smelson et al, 2002)

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Cue-Exposure Methods

• Human lab methodology
• Prime patients with drug cues and then measure
  the effects in a controlled environment
• Videotapes, scripted imagery of imagined smoking
  as well as in-vivo tests involving manual
  handling of cigarettes and paraphenalia, and
  simulated smoking.

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Craving Measures

• Subjective
• Elusive Craving concept
• Urge, Want, Desire
• Objective/ Physiologic
• Increased arousal on measures of skin conductance
  (?) , skin temperature (?), heart rate (?) and
  respiration

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Craving pilot study

• 10 with schizophrenia/ schizoaffective disorder
• 10 smoking controls without major mental illness
• Baseline assessments demographic information,
  smoking history, expired CO and nicotine
  dependence.

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Cue-exposure methods

• Cue-session
• 90 minutes after last cigarette
• Videotaped cues
• Live and imagery cues
• A nicotine craving visual analogue scale and
  physiological measurements to assess nicotine
  craving
• Psycho-physiological lab of Paul Lehrer, PhD

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Subjective Craving Response
Schizophrenia slightly higher craving response to
cues (mean change in craving score 3.47 vs. 2.3)
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Physiological data

• Multivariate analysis revealed significant
  changes across tasks for both
• groups (plt.05) while trends were noted for
  shifts between tasks
• These shifts are thought not be independent of
  task manipulation
• Smokers with schizophrenia appear stressed at
  baseline and
• throughout procedures (Increased arousal) and
  a blunted response to cues
• Control smokers show a craving response to cues
  (decrease in skin temperature)
• Abnormal physiologic measures in schizophrenia
  an illness or
• antipsychotic medication effect?

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Schizophrenia lower LF at baseline linked to
poorer health/ similar to HRV Controls higher HF
at baseline correlates to increased
parasympathetic activity (relaxed) Smokers with
schizophrenia blunted responses higher levels of
baseline stress and arousal
plt n.s.
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Future Studies

• Nicotine and Cotinine levels with Smoking
  Topography Measures
• Bipolar Control Groups
• Nicotine Nasal Spray in Craving/ Short-Term
  Abstinence Lab Study

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Bipolar Disorder

• Heavy smoking linked to psychosis in bipolar
  affective disorder
• Virtually no studies examining the role of
  smoking in bipolar disorder.
• Some genetic linkage to the ?-7 nicotinic
  receptor locus on chromosome 15
• Similarities in medication profiles allows for
  analyses across diagnoses

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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