Tobacco Treatment in People with Schizophrenia Tony P. George, MD, FRCPC Chief, Addictions Division, CAMH Professor and Co-Director, Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto ECHO-TEACH Talk, MD Anderson Cancer Center, February 7, 2017
Learning Objectives: n Develop an evidence-based approach to assessment and treatment for tobacco use disorder in people with schizophrenia and other serious mental illness. n Understand an approach to developing a tobacco-free mental health and addictions facility for the benefit of patients, staff and visitors 3/30/2016 Slide 2
Medical Impact of Tobacco n Tobacco use is the leading cause of preventable death in Western world (Giovino, GA, 2007) n Over 470,000 deaths per year in USA and >50,000 annual deaths in Canada attributable to tobacco addiction (George, TP, 2015. Chapter 32, Cecil Textbook of Medicine, 25 th Edition) n Significant contributor to cardiovascular, pulmonary disease and to many cancers (e.g. lung, throat) (George, 2015) n Reducing smoking leads to some health improvements (e.g. better breathing and exercise tolerance), but reductions in cardiac, pulmonary and oncological disease are only seen when quitting smoking (George, 2015) Slide 3
Mental Health Impact of Tobacco n Higher rates of smoking in mentally ill (MI) populations makes them more vulnerable to tobacco-related medical illness (Mackowick et al., 2012) n People with MI spend up to 25% of their disability income on tobacco (Ziedonis et al., 2008) n Tobacco addiction shortens the lives of people with MI by 12-13 years (Wiliams et al., 2011) n Rates of quitting smoking for MI smokers are 1/3 to 1/2 rates in the general population (Morisano et al., 2009) n Quitting smoking in MI populations leads to better psychiatric and substance use disorder outcomes, including reductions in depression and alcohol use, and less suicidal behaviours and aggression (Mackowick et al., 2012; Morozova et al., 2015) Slide 4
Prevalence of Tobacco Smoking in Clinical Samples of People with Mental Illness and Addictive Disorders 90 80 Mean Smoking Prevalence (%) 70 60 50 40 30 20 10 0 Schizophrenia Bipolar Disorder Major Depression Panic Disorder Post-Traumatic Stress Disorder Alcohol Dependence Cocaine Dependence Opioid Dependence General U.S. Population General Canadian Population Psychiatric Disorders SUD Non-PD Morisano, D., Bacher, I., Audrain-McGovern, J., George, T.P. (2009). Can. J. Psychiatry. 54: 141-151 Slide 5
Current Smoking among Adults Aged 18 or Older Based on Serious Psychological Distress Status of Previous Month (NHIS, 1997 to 2011) 50 40 Percent % 30 20 10 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 *Difference between eskmate and eskmate for 2011 is strategically significant at the 0.5 level Slide 6
Tobacco Bans in Hospital Settings Advantages Disadvantages n Great opportunity to provide motivational interventions for those not initially willing to try to quit (a teachable moment ) n Reduction in episodes of seclusion and restraint, decreased PRN* use and Length Of Stay (LOS) n The goals of a smoke-free work environment are promoted and are consistent with wellness interventions that are being implemented in most inpatient settings n Inpatients generally not interested in quitting, as this is low on their hierarchy of needs n Staff are often reluctant as it can be perceived as a distraction to treatment plans, and is a critical positive reinforcer n Lack of training of unit staff or other qualified people to conduct smoking cessation counseling n Unmotivated inpatients pose a barrier to success of those few patients wanting to quit Lawn and Pols, 2005; Moss et al., 2010 Moss et al., Am. J. Addict. 2010 *PRN Known as medicakons that are taken as needed Slide 7
Key Elements of Tobacco Free CAMH 1. No Smoking (or Vaping) at any campus site (2 main campuses + outpatient satellites) 2. No Possession of Tobacco Products on the Premises 3. Presence of Community Ambassadors, Patients and Staff who promote tobacco-free CAMH though a Wellness and Recovery Culture using a positive reinforcement approach and act as Champions for the Initiative Slide 8
Staff and Patient Attitudinal Survey Results n 10 % Staff Increase in staff confidence in having appropriate access to team / management support or training required to comply with the tobacco-free policy (12% to 22%) 7 % n Increase in awareness of how to help / where to refer a client if they want to quit (13% to 20%) Patient 19 % n Increase in the support of the creation of a tobacco-free policy at CAMH (48% to 67%) Pre-Launch N=454 Post-Launch N=356 17 % n Increase in the belief that lowering tobacco use on CAMH property is important (51% to 68%) 16 % n Increase in contributing to the success of the policy by not smoking at CAMH (56% to 72%) Pre-Launch N=123 Post-Launch N=106 Riad-Allen et al., 2016. Am. J. Addict., in press Slide 9
Effects of CAMH Tobacco Free on Aggression (Code Whites) *p<0.05 Riad-Allen, L. et al. (2017). Am. J. Addict., in press Slide 10
An approach to tobacco cessation in smokers with schizophrenia Slide 11
Quitting smoking is easy I ve done it several hundred times - Mark Twain
Case #1 n 40 year old black male with schizophrenia, never married, lives in a shelter in a major city. n Smokes 3 packs per day (illegal cigarettes), first cigarette is within 2 minutes of awakening. He also started smoking e-cigarettes ( Vapes ). n Multiple quit attempt failures since started smoking at age 14. Has tried all NRTs (gum, patch, inhaler) n Psychosis is well-managed with depot antipsychotic (Risperidone Consta), at 50 mg qmonth. Takes some oral risperidone for breakthru symptoms n Family Hx+ for CAD, Lung CA. He himself had anterior wall MI 6 months ago, after months of chest pain, took himself to local general hospital. n He doesn t really want to quit, but does not want to die from (another) MI
Question n What can we do for this man? 17-02-08 14
Vulnerability markers for tobacco addic4on in schizophrenia Wing, VC et al. (2012). Ann. NY Acad. Sci. 1249: 89-106
Reduced Smoking A Viable Target or Not? n Many smokers are simply unable to quit smoking. n Should sustained reductions in smoking been considered a goal of tobacco treatment or should reduction be a transitional goal towards eventual smoking abstinence (Hughes, 2002; George and Vessicchio, 2002; McChargue et al., 2002)? n A recent study suggests that sustained smoking reductions (50% reduction) do not reduce cancer or cardiac disease risk (Tverdall and Bjartveit, 2006).
Biobehavioural Vulnerability Factors to Tobacco Addic4on in Schizophrenia n Biochemical (reduced nachr levels, higher baseline nico8ne levels in Sz versus Controls) n Gene8c (α7 nachr, α3 nachr, COMT, DISC 1, Reelin) n Behavioral (deficits in reinforcement/reward) n Neurocogni8ve (neurophysiological/neuropsychological) Wing, VC et al., 2012. Ann. NY Acad. Sci. 1248-89-106
Lower β 2 *-nachrs in smokers with schizophrenia as compared to controls D Souza, DC, Esterlis, I. et al. (2012). Am. J. Psychiatry
Behavioral Factors Mecamylamine Effects on Reinforcement, Consump4on and Relapse Topography Puff Volume *p<0.05 vs. PLO * Consumption (Cigarettes/Session) *p<0.05 vs. PLO Smoking Cue-Reactivity *p<0.05 vs 10 mg/day McKee et al (2009). Schizophrenia Res. Weinberger et al (2007). Schizophrenia Res. Fonder et al. (2005). Biol. Psychiatry
George, T.P. et al., (2002). Neuropsychopharmacology 26: 75-85. Effects of Abs4nence on Visuospa4al Working Memory (VSWM) in Smokers with Schizophrenia Distance From Target (cm) 8 7 6 5 4 3 2 1 0 SCHIZOPHRENIA Quit Date 2 4 6 Week in Trial 8 Abstinent Smoking 10 Distance From Target (cm) 1 0 CONTROLS n=23 n=29 8 7 6 5 4 3 2 Quit Date 2 4 Week in Trial 6 Abstinent Smoking 8
Selec4ve Enhancement of VSWM by CigareJe Smoking in Schizophrenia: Blockade by Mecamylamine * * p = 0.001 vs. 5 mg/day * p < 0.001 vs. 10 mg/day p < 0.001 vs. CON Diagnosis x Dose: F=10.65, df=2,128, p<0.01 Sacco, K.A., Termine, A. et al. (2005). Arch. Gen. Psychiatry. 62: 649-659.
Deficits in Frontal-Execu4ve Performance Predict Smoking Cessa4on Failure in Schizophrenia Schizophrenia p=0.052 Number of Seconds. 160 140 120 100 80 60 40 20 0 Trail Making Test - Part B p<0.05 Quit Not Quit Digit Quit Span Status Backward at Trial Endpoint Dolan, S.L., Sacco, K.A. et al., (2004). Schizophrenia Res. 70: 263-275. Number of Digits. 8 7 6 5 4 3 2 1 0 Quit p<0.05 Quit Status at Trial Endpoint Moss, T.G. et al. (2009). Drug Alcohol Depend. 104: 94-99. Not Quit
Cor4cal Dopamine Func4on and Spa4al SPATIAL WORKING MEMORY (%) 125 100 75 50 25 0 0 2 Working Memory 4 Smoking SCHIZOPHRENIA 6 NORMAL 8 Smoking 10 CORTICAL DOPAMINE ACTIVITY STRESS 12 14 George, T.P. et al., 2003, APPI
Atypical Versus Typical Antipsychotic Drugs and Nicotine Patch for Smoking Cessation in Schizophrenia (N=45) Smoking Abstinence Rate (%) 75 50 25 0 * *p<0.05 vs. Typical * Atypical Typical Endpoint Last Four Weeks 6-Month F/U * George, T.P. et al. (2000). Am. J. Psychiatry. 157: 1835-1842.
George, T.P., Vessicchio, J.C. et al. (2008). Biol. Psychiatry. 63: 1092-1096. Combina4on of Transdermal Nico4ne and Bupropion SR is Superior to Placebo + Patch for Smoking Cessa4on in Schizophrenia (N=58) % Smoking Abstinence.. 35 30 25 20 15 10 5 0 * 34.5 10.3 Endpoint Abstinence * 27.6 3.4 Continuous Abstinence 16 0 Six Month Abstinence Fisher s Exact Test + p = 0.056 * p < 0.05 # p=0.11 # BUP Placebo
Varenicline (Champix ) n An α4β2-selective nachr partial agonist n Approved by the FDA in May, 2006 and by Health Canada in April, 2007. n In Phase III clinical trials, demonstrated superiority to both bupropion SR and placebo in continuous abstinence outcomes (Gonzalez et al., 2006, Jorenby et al., 2006) n Prevents smoking-relapse with treatment up to 24 weeks (Tonstad et al., 2006). n Dosing regimen is 0.5 mg qd x 3 days, then 0.5 mg bid x 4 days, then up to 1.0 mg bid for 12 weeks, with a label to extend treatment to 24 weeks as necessary.
Varenicline Side Effects n Main side effects are nicotine-like: Nausea (~30%), insomnia, headache and abnormal dreams. n Black Box warnings issued by FDA, Health Canada and EMEA regarding anecdotal reports of treatment-emergent suicidality, homocidality, aggression, psychosis and mania needs further study.
Cigarette Smoking, Cytochrome P450 and Psychotropic Drug Plasma Levels n Metabolized by CYP 1A2/3A4 n Not Metabolized n Clozapine n Olanzapine n Haloperidol n Chlorpromazine n Caffeine DeLeon, J. (2004). Psychiatric Serv. 55: 491-493. n Risperidone n Ziprasidone n Aripiprazole n Quetiapine n Bupropion n SSRI s
Varenicline and Psychiatric Popula4ons n Several case reports both published (Freedman, 2007; Kohen and Kremen, 2007) and unpublished (FDA Medwatch) implica8ng varenicline in neuropsychiatric treatmentemergent adverse events (TEAEs), including suicidality, homicidality, psychosis and mania (O Malley, 2010). n However, clinical studies comparing Psychiatric Hx+ to Hx- smokers in varenicline treatment suggest that treatment outcomes and adverse events are comparable (e.g. Stapleton et al., 2008; McClure et al., 2010). n Recent controlled studies support its safety and efficacy in schizophrenia,, including in abs8nence-ini8a8on (Williams et al., 2012. J. Clin. Psychiatry; Anthenelli, RM et al. 2016 Lancet) and relapse-preven8on (Evins et al., 2014. JAMA) studies. n Four studies suggests its safety and efficacy in smokers with bipolar disorder (Weinberger et al., 2008; Wu et al., 2012; Frye et al., 2013; Chengappa et al., 2014)
Varenicline for Smoking Cessa4on in People with Schizophrenia (N=127) Williams, J.M., Anthenelli, R.M., Morris, C., Tredow, J., Thompson, J.R., Yunis, C., George, T.P. (2012). J. Clin. Psychiatry. 73: 654-660.
Varenicline Effects on Posi4ve and Nega4ve Symptoms in Smokers with Schizophrenia Williams, J.M. et al. (2012). J. Clin. Psychiatry.73: 654-660.
Evins, AE et al., JAMA. 311: 145-154.
EAGLES Study Randomized Comparison of Varenicline, Bupropion SR, Nicotine Patch and Placebo for Smoking Cessation in Mentally Ill versus Non-Mentally Ill Smokers (N=8144) Anthenelli, R.M. et al. (2016). Lancet. 387: 2507-2520. 17-02-08 33
Ouellet-Plamondon, C. et al. (2014). Curr. Addict. Rep. 1: 61-68.
Caroline Wass, Ph.D. r T M S epetitive ranscranial agnetic timulation n Stimulates the cortex by trains of magnetic pulses. n Frequencies of 1 to 50Hz n rtms has recently been used to treat neuropsychiatric disorders (e.g. depression, schizophrenia, parkinson s disease)
rtms reduces tobacco cravings in patients with schizophrenia TQSU score 5 4.5 4 3.5 Factor 1 TQSU score 5 4.5 4 3.5 Factor 2 3 Active rtms (n=4) 3 Active rtms (n=4) 2.5 Pre-rTMS Sham rtms (n=6) Post-rTMS 2.5 Pre-rTMS Sham rtms (n=6) Post-rTMS 5 Desire to Smoke 5 Anticipation of r elief from withdrawal after smoking 4.5 4.5 TQSU score 4 3.5 TQSU score 4 3.5 Wing, VC et al, (2012) Schizophr. Res. 139: 264-266. 3 2.5 Pre-rTMS Active rtms (n=4) Sham rtms (n=6) Post-rTMS 3 2.5 Pre-rTMS Active rtms (n=4) Sham rtms (n=6) Post-rTMS Anticipation of positive effects of smoking Intention to Smoke 5 5.5 4.5 5 TQSU score 4 3.5 TQSU score 4.5 4 3 Active rtms (n=4) 3.5 Active rtms (n=4) 2.5 Pre-rTMS Sham rtms (n=6) Post-rTMS 3 Pre-rTMS Sham rtms (n=6) Post-rTMS