Nicotine and Schizophrenia

1. Nicotine and Schizophrenia Jill Williams, M.D.Assistant Professor of PsychiatryUMDNJ-Robert Wood Johnson Medical SchoolUMDNJ- SPH Tobacco Dependence Programjill.williams@umdnj.edu

2. “Schizophrenia”

3. 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

5. 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)

6. 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

7. 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

8. 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.

9. 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

10. CYP2A6 Metabolism of Nicotine

11. 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.

12. 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.

13. ? 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.

14. CYP2A6 Metabolism of Nicotine

15. 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.

16. 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.

17. 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

18. 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

19. 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

20. 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

21. Figure 1 Mean Nicotine 21 ng/mL 28 ng/mL p< 0.0001

22. Figure 2 Mean Cotinine 227 ng/mL 291 ng/mL p< 0.012

23. Mean 3HC: Cotinine Ratio 0.44 0.43 p=0.845

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. Portable Topography Measurement (CReSSmicro)

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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)

41. 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)

42. 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

44. 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

46. 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

47. 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

48. 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

49. 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