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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