1. TOBACCO AND SCHIZOPHRENIA
Mini Lecture 3
Module: Tobacco and Mental Health
Key References:
Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008; 10:1691–715.
Fagerstrom K, Aubin HJ. Management of smoking cessation in patients with psychiatric disorders. Curr Med Res Opin. 2009; 25:511–8.
San L, Arranz B, Martinez-Raga J. Antipsychotic drug treatment of schizophrenic patients with substance abuse disorders. Eur Addict Res. 2007; 13:230–43.

2. Objectives of the Mini Lecture
GOAL OF MINI LECTURE: Provide students with knowledge on the association between tobacco and schizophrenia.
LEARNING OBJECTIVES
Students will be able to:
Describe the burden of schizophrenia, and its association with other chronic diseases
Illustrate the biological, psychological and social factors associated with tobacco use in schizophrenia patients
Discuss how cessation can be addressed in clinical management of schizophrenia patients.
Module Description:
This mini-module will review the burden of smoking in schizophrenia patients, and provide data on the biological, psychological, and social factors associated with smoking in schizophrenia patients. Tobacco cessation should be integrated in clinical management of schizophrenia patients, and different strategies to treat tobacco addiction in schizophrenia patients will be discussed.

3. Contents Core Slides Optional Slides The Burden of Schizophrenia
Schizophrenia and Chronic Diseases
Smoking in Schizophrenia Patients
Tobacco Use and Schizophrenia
Tobacco Addiction in Schizophrenia: Treatment
Tobacco Dependence and Schizophrenia: Treatment
Tobacco Use and Schizophrenia: The Biological Factor
Smoking and Anti-psychotic Treatments
Cessation Medication in Schizophrenia Patients

4. CORE SLIDES Tobacco and Schizophrenia Mini Lecture 3
Module: Tobacco and Mental Health

5. The Burden of Schizophrenia
Schizophrenia is one of the most common psychiatric illnesses being treated. Patients can exhibit positive and negative psychotic symptoms leading to social and occupational dysfunction for at least 6 months.1
Global burden of schizophrenia:
Median incidence: 15.2 per 100,000 population
Median prevalence: 460 per 100,000 population
Median lifetime morbidity risk: 720 per 100,000 population
Median standardized mortality ratio of all causes: 2.62
Notes:
Schizophrenia is one of the most common psychiatric illnesses that require long-term care. Patients with schizophrenia can exhibit both positive (delusions, hallucinations, disorganized speech, odd behaviour) and negative symptoms (restricted emotional expression, cognitive impairments, difficulty initiating goal-directed activities).
References:
Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008; 10:1691–715.
Eaton WW, Martins SS, Nestadt G, Bienvenu OJ, Clarke D, Alexandre P. The burden of mental disorders. Epidemiol Rev. 2008; 30:1–14.
1. Ziedonis et al. 2008; 2.Eaton et al. 2008

6. Schizophrenia and Chronic Diseases
Schizophrenia patients have poorer health care, higher burden of non-communicable disease (NCD) risk factors, and more NCD premature deaths than the general population.
Schizophrenia patients have a 20% shorter life expectancy.1
Common NCD risk factors in schizophrenic: smoking, obesity and dyslipidemia, hypertension, insulin resistance, diabetes, sedentary life style, poor nutrition.2
2/3 of schizophrenia patients died of CVD vs. half of general population.1
High burden of respiratory diseases due to smoking.
Notes:
Prevalence of non-communicable disease (NCD) risk factors (i.e., smoking, obesity that leads to dyslipidemia, hypertension, insulin resistance and diabetes, sedentary life style, poor nutrition, and poor health care) were also higher in schizophrenia patients than in the general population. Therefore schizophrenia patients have 20% shorter life expectancy and higher NCD morbidity and premature death burdens. A schizophrenia patient has a double risk of CVD and a triple risk of respiratory diseases and lung cancer due to high burden of smoking compared to the general population.
Some of the antipsychotic drugs for schizophrenia treatment have adverse effects on chronic non-communicable disease risk factors; therefore, treatments given to schizophrenia patients with underlying chronic non-communicable disease should not adversely affect their risk factor patterns. This is considerably important taking into consideration that schizophrenia patients have poorer health care, less access to and consumption of medical care, and often do not comply with their medication.
References:
Hennekens CH, Hennekens AR, Hollar D, Casey DE. Schizophrenia and increased risks of cardiovascular disease. Am Heart J. 2005; 150:1115–21.
Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008; 10:1691–715.
1. Hennekens et al. 2005; 2. Ziedonis et al. 2008

7. Smoking in Schizophrenia Patients
Results from 42 studies in 18 countries showed that:
Smoking in schizophrenia patients is six times more common than in the general population (prevalence 70–85%).
More common in male patients (OR 7.2 in male vs. 3.3 in female).
50% smoked more than 25 cigarettes per day.
Schizophrenia patients typically puff more and deeper when they smoke, thus they have a higher level of nicotine and cotinine.
Quitting rate: 9% in schizophrenia patients vs % in general population.
Notes:
de Leon and Diaz1 conducted a meta-analysis to study the association between current smoking and schizophrenia in 42 epidemiological studies across 18 countries.
Reference:
de Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr Res. 2005; 76:135–57.
de Leon and Diaz 2005

8. Tobacco Use and Schizophrenia
There is a complex interaction between biological, psychological, and social factors in the association between tobacco use and schizophrenia.
Biological factors: nicotine improves sensory gating and visuospatial working memory.
Psychological factors: patients use tobacco and its perceived positive effects for self-treatment.
Social factors: cigarettes used in social exchange and as form of bonding—main barrier in promoting smoking cessation in mental health institutions.
Notes:
The association between tobacco use and schizophrenia is complex and can be caused and confounded by different biological, psychological, and social factors. Nicotine can improve deficit in auditory sensory gating and visuospatial working memory, which are impaired in schizophrenia patients. High levels of nicotine can also reduce the extrapyramidal side effects caused by antipsychotic drugs. These positive effects were perceived as beneficial by schizophrenia patients, and tobacco is therefore misused for self-treatment of neurological and psychological symptoms experienced by patients. Schizophrenia patients also share a number of social factors leading to a higher smoking rate, among which are low education, poverty, unemployment, and peer influence.
Heavy smoking in patients with schizophrenia was associated with: increased positive symptoms, decreased negative symptoms, more frequent psychiatric hospitalizations, increased substance use, increased suicide risk, fewer parkinsonian or extrapyramidal side effects, and polydipsia.
Cigarette is used as a token economy in many mental health institutions in the US and in other countries; staff and patients bond by exchanging cigarettes. Anecdotal data suggests that cigarettes are offered to patients in mental hospitals as a way to medicate them and calm them down. This can be a major barrier to the promotion of smoking cessation in mental health institutions.
See optional slides on more details on biological, psychological, and social factors.
Reference:
Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008; 10:1691–715.
Ziedonis et al. 2008

9. Tobacco Addiction in Schizophrenia: Treatment
Cessation is better achieved in patients with higher motivation to quit and a lower level of tobacco dependence.
Combination of psychosocial treatment improves chances that patients will quit.1
The polycyclic aromatic hydrocarbons (PAHs) in cigarettes affect the metabolism of antipsychotic drugs; therefore, medication has to be closely monitored during and after quitting.2
Notes:
Support for quitting is not available for schizophrenia patients who are institutionalized in mental health treatment systems. Schizophrenia patients have lower motivation to quit than the general population.
Combination of psychosocial treatment, nicotine dependence treatment medications, and social support is effective. Evidence for the effectiveness of nicotine dependence treatments is not well-established yet, and mostly comes from small uncontrolled clinical trials.
References:
Fagerstrom K, Aubin HJ. Management of smoking cessation in patients with psychiatric disorders. Curr Med Res Opin. 2009; 25:511–8.
Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008; 10:1691–715.
1. Fagerstrom and Aubin 2009; 2. Ziedonis et al. 2008

10. Tobacco Dependence and Schizophrenia Treatment1
Tobacco Dependence and Schizophrenia Treatment
Typical antipsychotic (e.g., haloperidol) increases smoking.
Atypical antipsychotic (e.g., clozapine) reduces smoking significantly in heavy smokers.1,2
Clozapine is the only atypical antipsychotic that has 5HT3 receptor antagonist activity and can improve P50 gating.
Alpha-7 nicotine receptor (α7) agonist agent (e.g., DMXB-A) improves memory, P50 response, and attention. α7-agonist is more potent and has slower decreasing response than nicotine.2
Notes:
The use of antipsychotics can affect tobacco use and dependence. Use of haloperiodol has been shown to increase smoking in schizophrenia patients. Patients who use haloperiodol may increase their smoking as a compensatory mechanism to obtain the usual nicotine reward.
San et al. conducted a review on the use of antipsychotics for treating schizophrenia patients with co-morbid substance use disorder.1 The review showed that second-generation antipsychotics, particularly clozapine, are effective for schizophrenia and comorbid substance use disorder treatment. Clozapine, an atypical antipsychotic, is 5HT3 receptor antagonist, and its binding to this receptor can improve P50 auditory sensory gating experienced by the patients. Treatment with clozapine can reduce smoking behavior, particularly in coping with the self-regulatory use of tobacco in schizophrenia patients.
References:
San L, Arranz B, Martinez-Raga J. Antipsychotic drug treatment of schizophrenic patients with substance abuse disorders. Eur Addict Res. 2007; 13:230–43.
Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008; 10:1691–715.
1. San et al. 2007; 2. Ziedonis et al. 2008

11. OPTIONAL SLIDES Tobacco and Schizophrenia Mini Lecture 3
Module: Tobacco and Mental Health

12. Tobacco Use and Schizophrenia: The Biological Factor
Nicotine improved deficit in auditory sensory gating, led to better filter of distracting stimuli and better focus of attention, and ultimately improved cognitive function.
Nicotine improved visuospatial working memory and led to better visualization of relative positions of items.
Improvement of visuospatial working memory is related to prefrontal cortical dopamine activity. Activation of the anterior cingulated and bilateral thalamus improves visuospatial working memory.
Notes:
Patients with schizophrenia experience cognitive impairment and deficits of prepulse inhibition. These are mainly related to abnormal sensorimotor gating, which leads to reduced ability to suppress the response to a second distracting auditory stimulus and to focus attention. Cigarette smoking can improve sensory gating temporarily in individuals with schizophrenia.
Schizophrenia patients also have dysregulation of the dopamine system in the prefrontal cortical, which impairs visuospatial working memory. With its effect on the dopamine system, tobacco use and nicotine can enhance visuospatial working memory. Nicotine patch can activate brain regions in the anterior cingulate and bilateral thalamus, and can improve memory.
Reference:
Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008; 10:1691–715.
Ziedonis et al., 2008

13. Smoking and Anti-psychotic Treatments
Schizophrenia patients who smoke experience less extra- pyramidal symptoms and other antipsychotic drug side-effects  misuse of nicotine as self-medication.
Polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke can induce P450 1A2 isoenzyme, and affect the metabolism of antipsychotic medications (olanzapine, clozapine, haloperidol, and fluphenazine).1
Induced P450 1A2 isoenzyme leads to lower blood levels of antipsychotic medications among smokers.
Increased antipsychotic side effects therefore should be monitored during smoking cessation treatment.2
Notes:
Polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke can interact with antipsychotic metabolism by inducing P450 1A2 isoenzyme. Activation of this isoenzyme lowers the blood level of antipsychotic medications, and therefore reduces the chance of extra pyramidal side effects caused by antipsychotic medications. The level of antipsychotic can increase when cigarette consumption is reduced, and therefore physicians providing smoking cessation intervention for schizophrenia patients should be aware of increasing side-effects during the cessation period.
Reference:
Green AI. Schizophrenia and comorbid substance use disorder: effects of antipsychotics. J Clin Psychiatry. 2005; 66 Suppl 6:21–6.
Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008; 10:1691–715.
1. Green 2005; 2.Ziedonis et al. 2008

14. Cessation Medication in Schizophrenia Patients
Combination of atypical schizophrenia treatments and nicotine dependence treatments
Buproprion: help reducing smoking and expired air CO
Nicotine patch: safe, well-tolerated, shorter long-term abstinence than expected
Nicotine nasal spray: short-term reduction in schizophrenia symptoms and impaired cognition1,2
There is very limited data about the effects of smoking cessation treatment in schizophrenic patients.
Notes:
Good support for quitting is not available for schizophrenia patients who are institutionalized in the mental health treatment system. Schizophrenia patients have lower motivation to quit than the general population. Patients should be encouraged to participate in motivational interviewing that relates smoking to their personal experiences (e.g., cost of cigarettes, medical condition caused or exacerbated by smoking). Motivational interventions for less motivated schizophrenia patients who smoked increased the success of cessation treatment and this was more effective than educational intervention or information solely.
Combinations of psychosocial treatment, nicotine dependence treatment medications, and social support are effective. Evidence for the effectiveness of nicotine dependence treatments is not well-established yet, and mostly comes from small uncontrolled clinical trials.
References:
Fagerstrom K, Aubin HJ. Management of smoking cessation in patients with psychiatric disorders. Curr Med Res Opin. 2009; 25:511–8.
Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008; 10:1691–715.
1. Fagerstrom and Aubin 2009; 2. Ziedonis et al. 2008

15. The most important health message a doctor can give to patients is to quit smoking.