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					Smoking and Schizophrenia
           Jill Williams, M.D.
     Assistant Professor of Psychiatry
 UMDNJ-Robert Wood Johnson Medical School
  UMDNJ- SPH Tobacco Dependence Program
               Piscataway, NJ
         jill.williams@umdnj.edu
  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
• 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                 Low Abuse
  – cocaine                   – caffeine
  – amphetamine               – nicotine
  – metamphetamine            – ephedrine
  – methylphenidate           – 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


                  40
Figure 1
                  30


                  20


                  10


                   0


                  -10
                    N=                    55                   81

                                    control smokers   smokers w ith schizop


                        SUBJECT S




           Mean Nicotine
                           21 ng/mL                           28         ng/mL
              p< 0.0001
Figure 2




           Mean Cotinine
                      227 ng/mL   291 ng/mL
              p< 0.012
             3.0


             2.5



             2.0


             1.5



             1.0


              .5
  COTRATIO




             0.0


             -.5
                   N=             54                   98

                            control smokers   schizophrenic sm oker


                    CASES



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
Schizophrenia versus Schizoaffective
Disorder
                         Smokers with     Smokers with
                         schizophrenia   schizoaffective   p-value
                            (n=74)          disorder
                                             (n=26)

   Cigarettes Per Day     24.7 (12.8)       24.1 (9.9)



   CPZ                  676.1 (584.4)    392.9 (253.4)     0.019
   equivalents

   Serum Cotinine       309.2 (161.6)    240.0 (149.8)     0.059
   levels


   Serum Nicotine          27.1 (11.1)     27.4 (11.5)      0.903
   levels (ng/mL)

   3OH-Cotinine:             0.4462          0.3811         0.305
   Cotinine Ratio
           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 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
• 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 motivation
 Can’t quit           Lack skills to quit
 It’s all they have   Enabling
 It helps them        Illness modulating
 They 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
             Clinical Trials
Pioneering Work (Ziedonis et al., 1997)

First published trial
  24 patients
  NRT, behavioral treatment, individual MET
        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
                    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
•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     Schizophrenia or           10 week MET modified     24   13%     abstinent at 12
George, 1997     Schizoaffective            group +/- 21mg patch
                                                                          weeks
                 Disorder

Addington et     Schizophrenia or           7 week modified ALA      50   16% at 12 weeks
al., 1998        Schizoaffective Disorder   group +/- 21mg patch


George et al.,   Schizophrenia or           21 mg/day patch and      45
2000             Schizoaffective            modified ALA group
                                                                          56% on atypical
                 Disorder                   versus modified MET           abstinent
                                            group                         22% on typicals

Weiner et al.,   Schizophrenia or           Bupropion 300 mg/day     9
2001             Schizoaffective Disorder   and modified ACS group
                                                                          0
                                                                          Reduced expired CO
Evins et al.,    Schizophrenia              Bupropion SR             18
2001                                        150mg/day vs. placebo
                                                                          11% abstinent at 12
                                            and CBT group                 weeks

George et al.,   Schizophrenia or           Bupropion SR             32
2002             Schizoaffective Disorder   300mg/day vs. placebo
                                                                          50% abstinent in week
                                                                          1

Williams et      Schizophrenia or           21mg/day patch vs. 42    45
al., 2004        Schizoaffective            mg/day patch
                                                                          16 % abstinent at 8
                 Disorder                                                 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
• 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           24.2
      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                 Psychoeducation                         Minimal Control
         N=32                                  N=34                                    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%
              25.8%                                                One-Week      One-Month

25%


20%


15%                                                   11.4%


10%


 5%
                                              0.0%                          0.0%     0.0%


 0%
        Motivational (N=32)             Psychoeducational                Control (N=12)
                                             (N=34)
    Figure 1. Percentage of participants receiving each intervention following up on
    referral to tobacco dependence treatment at one-week and one-month post-
    intervention
                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


                     30
Cigarettes Per Day




                     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
   Duration: 24           (control)
      weeks         Duration: 24 weeks
 Nicotine patch for Nicotine patch for 16
     16 weeks               weeks
Twenty four 50 minute     Nine 20 minute sessions
sessions                   Relapse prevention lite
Motivational              Medication Management
Enhancement Therapy
Social skills training
Relapse Prevention full
Personalized Feedback
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

				
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