Nicotine and Schizophrenia Jill Williams, M.D. Assistant Professor of Psychiatry UMDNJ-Robert Wood Johnson Medical School UMDNJ- SPH Tobacco Dependence.

Nicotine and Schizophrenia

Jill Williams, M.D.Assistant Professor of Psychiatry

UMDNJ-Robert Wood Johnson Medical SchoolUMDNJ- 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, 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.

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

Figure 1

8155N =

SUBJECTS

smokers with schizopcontrol smokers

Nic

otin

e (

ng

/mL

)

60

50

40

30

20

10

0

-10

Mean Nicotine

21 ng/mL 28 ng/mL

p< 0.0001

Figure 2

Mean Cotinine

227 ng/mL 291 ng/mL

p< 0.012

9854N =

CASES

schizophrenic smokercontrol smokers

CO

TRAT

IO

3.0

2.5

2.0

1.5

1.0

.5

0.0

-.5

Mean 3HC: Cotinine Ratio

0.44 0.43

p=0.845

Regression

• Age, education, marital status, gender, race, employment status

• Age of onset of smoking, cigarettes per day, FTND score, years smoked, time of blood draw, and number of past quit attempts, 3HC:cotinine ratio

• Antipsychotic medication type, antipsychotic medication dose (measured in chlorpromazine equivalents)

• Diagnosis Schizophrenia or Schizoaffective Disorder

Table 5: Summary of Backward Stepwise Linear Regression Analysis for Variables Predicting Nicotine Levels (N = 128)

Variable B SE B β

Presence of Schizophrenia 6.913 1.890 .313***or Schizoaffective Disorder

Number Past Quit Attempts -.456 .247 -.158*

Note. R2 = .093, *p<.1, **p<.05, ***p<.001

Table 6 :Summary of Backward Stepwise Linear Regression Analysis for Variables Predicting Cotinine Levels (N = 148)

Variable B SE B β Presence of Schizophrenia 56.358 25.557 .177**or Schizoaffective Disorder Cigarettes Per Day 2.327 1.145 .163**

Note. R2 = .050. *p<.1, **p<.05, ***p<.001

  Smokers with schizophrenia

(n=74)  

Smokers with schizoaffective

disorder (n=26)

 p-value

Cigarettes Per Day 24.7 (12.8) 24.1 (9.9)  

CPZ equivalents

676.1 (584.4) 392.9 (253.4) 0.019

Serum Cotinine levels

309.2 (161.6) 240.0 (149.8) 0.059

Serum Nicotine levels (ng/mL)

27.1 (11.1) 27.4 (11.5) 0.903

3OH-Cotinine: Cotinine Ratio

0.4462 0.3811 0.305

Schizophrenia versus Schizoaffective Disorder

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

Authors 

Diagnoses Treatment N Outcomes

Ziedonis and George, 1997  

Schizophrenia or SchizoaffectiveDisorder

10 week MET modified group +/- 21mg patch

24 13% abstinent at 12 weeks

Addington et al., 1998  

Schizophrenia or Schizoaffective Disorder

7 week modified ALA group +/- 21mg patch

50 16% at 12 weeks

George et al., 2000

Schizophrenia or SchizoaffectiveDisorder 

21 mg/day patch and modified ALA group versus modified MET group

45 56% on atypical abstinent 22% on typicals

Weiner et al., 2001 

Schizophrenia or Schizoaffective Disorder

Bupropion 300 mg/day and modified ACS group

9 0Reduced expired CO 

Evins et al., 2001 

Schizophrenia Bupropion SR 150mg/day vs. placebo and CBT group

18 11% abstinent at 12 weeks

George et al., 2002  

Schizophrenia or Schizoaffective Disorder

Bupropion SR 300mg/day vs. placebo

32 50% abstinent in week 1

Williams et al., 2004  

Schizophrenia or SchizoaffectiveDisorder 

21mg/day patch vs. 42 mg/day patch

45 16 % abstinent at 8 weeksNo difference between patch dose groups

SELECTED STUDIES IN SCHIZOPHRENIA

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 trial42mg (double patch) vs. 21mg patch in smokers with schizophrenia/schizoaffective disorder• Patch doses decreased in an 8-week tapering

schedule • All subjects participated in 15 minute weekly

individual sessions• Self-report abstinence from smoking is verified

with weekly-expired air carbon monoxide measure (8 ppm or less considered negative).

Study Enrollment

64 outpatient smokers enrolledInterim 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 baselinedemographics smoking amountmeasures of nicotine dependencesmoking durationsymptomsdepression severity

Many (80%) of the subjects had past or present substance use disorders although most had not used substances for at least 1 year and this was not different between dose groups.

Abstinence Outcomes

The 7-day point prevalence abstinence rates at 8 weeks was 24% (n=11) in the total sample.

The rate of continuous abstinence at 8 weeks was 15.6% (n=7) in the total sample.

Abstinence rates for regular dose were not different between dose groups.

Conclusions

• 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 ResponseCraving data

1

2

3

4

5

6

7 Schizo group

Control group

Task A Task C Task D n=9 n=9 n=9

Schizophrenia slightly higher craving response to cues (mean change in craving score 3.47 vs. 2.3)

Physiological dataMean Temperature

91.3

90.089.6

89.0

89.288.9

89.188.8

88

89

89

90

90

91

91

92

92 Control group

Schizophrenia

Task A Task B Task C Task D

Mean Heart Rate

70

75

80

85

90

95

Control

Schizophrenia

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 cuesControl 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)

100

150

200

250

300

350

400

ms2

Control group

"Schizo group"

Task A Task C Task D n=4 n=4 n=4

In control group, there is a 34.6% decrease in LF from Task A-DIn alternative group, there is a 15.24% increase

Mean High Frequency (HF)

73.83

375

109103

91.83 74.8350

100

150

200

250

300

350

400

ms2

Control

"Schizo" group

Task A Task C Task D n=4 n=4 n=4

p< n.s.

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

Future Studies

• Nicotine and Cotinine levels with Smoking Topography Measures

• Bipolar Control Groups

• Nicotine Nasal Spray in Craving/ Short-Term 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 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