Download Nicotine and Schizophrenia

Nicotine and Schizophrenia
Jill Williams, M.D.
Assistant Professor of Psychiatry
UMDNJ-Robert Wood Johnson Medical School
UMDNJ- SPH Tobacco Dependence Program
[email protected]
“Schizophrenia”
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 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)
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
CYP2A6 Metabolism of Nicotine
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.
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, 3hydroxycotinine (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.
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.
Smokers with Schizophrenia
• 2 Samples
• Baseline assessment for High Dose Patch
Study (n=65)
• Sample of Non-treatment seeking smokers
(n=50)
• Schizophrenia and Schizoaffective Disorder
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
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
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
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
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
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
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
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
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
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
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)
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)
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
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
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
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
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
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
Motivation to Quit
• Patients with schizophrenia indicate an
interest in trying to cut down or quit
smoking
• Respond to motivational interventions
(Steinberg)
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).
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.
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
• 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
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
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 >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
NIDA Behavioral Therapy Development R01
Doug Ziedonis, PI
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
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
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
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)
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.
Craving Measures
• Subjective
• Elusive Craving concept
– Urge, Want, Desire
• Objective/ Physiologic
• Increased arousal on measures of skin
conductance () , skin temperature (),
heart rate () and respiration
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.
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
Subjective Craving Response
Craving data
7
6
Schizo group
Control group
5
4
3
2
1
Task A
n=9
Task C
n=9
Task D
n=9
Schizophrenia slightly higher craving response to
cues (mean change in craving score 3.47 vs. 2.3)
Physiological data
Mean Heart Rate
Mean Temperature
Control
92
92
Control group
91.3
90
91
90.0
85
89.6
90
90
89
Schizophrenia
Schizophrenia
91
89
95
89.0
89.2
88.9
89.1
88.8
88
Task A
Task B
Task C
Task D
80
75
70
Task A
Task B
Task C
Task D
Multivariate analysis revealed significant changes across tasks for both
groups (p<.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?
Mean Low Frequency(LF)
Mean High Frequency (HF)
400
Control group
"Schizo group"
350
350
"Schizo" group
375
300
250
ms2
ms2
300
200
250
200
150
150
100
Control
400
Task A
n=4
Task C
Task D
n=4
n=4
In control group, there is a 34.6% decrease in LF from Task A-D
In alternative group, there is a 15.24% increase
103
109
100
73.83
50
91.83
74.83
Task A
Task C
Task D
n=4
n=4
n=4
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
p< n.s.
Future Studies
• Nicotine and Cotinine levels with Smoking
Topography Measures
• Bipolar Control Groups
• Nicotine Nasal Spray in Craving/ ShortTerm Abstinence Lab Study
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
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