Project TEACH. Smoking Cessation For People With Schizophrenia. Maher Karam Hage, MD Professor, Depts. Of Behavioral Science and Psychiatry

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1 Project TEACH Smoking Cessation For People With Schizophrenia Maher Karam Hage, MD Professor, Depts. Of Behavioral Science and Psychiatry

2 Outline 1) What is behind the high comorbidity between Schizophrenia & Nicotine Dependence 2) Need for special treatment approach? 3) Any impact from smoking cessation on patients symptoms or stability?

3 Outline 1) What is behind the high comorbidity between Schizophrenia & Nicotine Dependence 2) Need for special treatment approach? 3) Any impact from smoking cessation on patients symptoms or stability?

4 Background Schizophrenia patients show poorer cognitive performance and higher rates of smoking (1,2) Smoking has been considered a potential attempt to selfmedicate and/or to partially counteract motor & cognitive side effects of certain antipsychotic medications (3,4) Cigarette smoking may reduce psychiatric symptoms and lessen antipsychotic induced extra pyramidal symptoms (4) 1) Morisano D, Bacher I, Audrain McGovern J, George TP. Mechanisms underlying the comorbidity of tobacco use in mental health and addictive disorders. Can J Psychiatry. 2009;54(6): Keefe RS, Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol. 2012(213): Winterer G. Why do patients with schizophrenia smoke? Curr Opin Psychiatry. 2010;23(2): Kumari V, Postma P. Nicotine use in schizophrenia: the self medication hypotheses. Neurosci Biobehav Rev. 2005;29(6):

5 Background (2) Patients with schizophrenia have higher rates of tobacco use 80 90% (1) while in the general population in 2014 smoking level was at 16.8% Schizophrenia patients who are smokers are thought to have better cognitive performance 1) Hughes JR, Hatsukami DK, Mitchell JE, Dahlgren LA. Prevalence of smoking among psychiatric outpatients. Am J Psychiatry. 1986;143:

6 Background (3) How about the effects of smoking in treatment resistant schizophrenia (TRS) patients? Smoker TRS patients had significantly higher scores on positive & negative syndrome scale (PANSS), & Neg. Symptoms Scale. They performed worse than nonsmokers TRS on problemsolving and other cognitive tasks (1) 1) Felice Iasevoli, Raffaele Balletta, Valentina Gilardi, Sara Giordano, and Andrea de Bartolomeis. Tobacco smoking in treatment resistant schizophrenia patients is associated with impaired cognitive functioning, more severe negative symptoms, and poorer social adjustment. Neuropsychiatr Dis Treat. 2013; 9: Published online 2013 Aug 7. doi: /NDT.S47571 PMCID: PMC

7 Shared Neurobiological Substrate A shared neurobiological substrate, ie, aberrant functioning of nicotinic cholinergic transmission, suggested to underlie both susceptibility to psychosis and vulnerability to smoking (1) Nicotine has been demonstrated to increase dopamine release in mesolimbic and mesocortical systems, (2 4) possibly underlying the cognitive enhancing properties of smoking 1) Wing VC, Wass CE, Soh DW, George TP. A review of neurobiological vulnerability factors and treatment implications for comorbid tobacco dependence in schizophrenia. Ann N Y Acad Sci. 2012;1248: ) Sesack SR, Grace AA. Cortico Basal Ganglia reward network: microcircuitry.neuropsychopharmacology. 2010;35(1): ) Livingstone PD, Srinivasan J, Kew JN, et al. alpha7 and non alpha7 nicotinic acetylcholine receptors modulate dopamine release in vitro and in vivo in the rat prefrontal cortex. Eur J Neurosci. 2009;29(3): ) George TP, Verrico CD, Picciotto MR, Roth RH. Nicotinic modulation of mesoprefrontal dopamine neurons: pharmacologic and neuroanatomic characterization. J Pharmacol Exp Ther. 2000;295(1):58 66.

8 Dopamine Pathways

9 Shared Neurobiological Substrate (2) Consistent with this view, deficits in α7 as well as in α4β2 nicotinic receptors have been associated with cognitive impairment in schizophrenia patients (1,2) Nicotine administration to schizophrenia patients has been reported to improve several cognitive tasks that are usually found to be impaired, i.e. attention & working memory (3,4) 1) Freedman R, Adams CE, Leonard S. The alpha7 nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. J Chem Neuroanat. 2000;20(3 4): ) Leonard S, Gault J, Hopkins J, et al. Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry.2002;59(12): ) Harris JG, Kongs S, Allensworth D, et al. Effects of nicotine on cognitive deficits in schizophrenia. Neuropsychopharmacology. 2004;29(7): ) Smith RC, Warner Cohen J, Matute M, et al. Effects of nicotine nasal spray on cognitive function in schizophrenia. Neuropsychopharmacology. 2006;31(3):

10 Outline 1) What is behind the high comorbidity between Schizophrenia & Nicotine Dependence 2) Need for special treatment approach? 3) Any impact from smoking cessation on patients symptoms or stability?

11 Smoking Cessation & Schizophrenia Patch or Bupropion For the patients who are unwilling or unable to quit, a smoking reduction approach may have benefits, with NRTs like the nicotine patch (1) A meta analysis suggested that bupropion is a safe medication smoking cessation with schizophrenia, although its effectiveness is inconclusive (2) 1) Dalack GW, Meador Woodruff JH. Acute feasibility and safety of a smoking reduction strategy for smokers with schizophrenia. Nicotine Tob Res Mar; 1(1):53 7 2) Tsoi DT, Porwal M, Webster AC. Efficacy smoking cessation and reduction in schizophrenia: a systematic review and meta analysis. Br J Psychiatry. 2010;196:

12 Smoking Cessation & Schizophrenia (2) Bupropion + Patch Bupropion with nicotine patch were significantly more likely to achieve continuous smoking abstinence than patch alone Importantly, the combination was well tolerated by smokers with schizophrenia and did not alter positive or negative symptoms (1) 1) George TP, Vessicchio JC, Sacco KA, Weinberger AH, Dudas MM, Allen TM, Creeden CL, Potenza MN, Feingold A, Jatlow PI. A placebocontrolled trial of bupropion combined with nicotine patch for smoking cessation in schizophrenia. Biol Psychiatry Jun 1; 63(11):1092 6

13 Smoking Cessation & Schizophrenia (3) Bupropion + CBT Bupropion with CBT were more likely to increase abstinence a week after the quit date, as well as four weeks of continuous abstinence. However, high relapse rate were found at the end of treatment Treatment with bupropion displayed a trend towards improvement in depressive & negative symptoms (1) 1) Evins AE, Cather C, Deckersbach T, Freudenreich O, Culhane MA, Olm Shipman CM, Henderson DC, Schoenfeld DA, Goff DC, Rigotti NA A double blind placebo controlled trial of bupropion sustained release for smoking cessation in schizophrenia.j Clin Psychopharmacol Jun; 25(3):218 25

14 Smoking Cessation & Schizophrenia (4) Antipsychotics Haloperidol has been shown to increase smoking (1) Atypical antipsychotics combined with a nicotine patch had an enhanced rate of smoking cessation (2) Recent study determined that clozapine had no significant effect on smoking cessation (3) 1) McEvoy JP, Freudenreich O, Levin ED, Rose JE. Haloperidol increases smoking in patients with schizophrenia. Psychopharmacology (Berl) 1995;119: ) George TP, Ziedonis DM, Feingold A, Pepper WT, Satterburg CA, Winkel J, Rounsaville BJ, Kosten TR. Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia. Am J Psychiatry Nov; 157(11): ) de Leon J, Diaz FJ, Josiassen RC, Cooper TB, Simpson GM. Does clozapine decrease smoking? Prog Neuropsychopharmacol Biol Psychiatry Jun; 29(5):

15 Smoking Cessation & Schizophrenia (5) Antipsychotics & Bupropion Tony George et. al. in (2002) showed that atypical antipsychotic medications: clozapine, risperidone, or olanzapine along with bupropion HCl did enhance smoking cessation outcomes when compared to placebo 1) George TP, Vessicchio JC, Termine A, Bregartner TA, Feingold A, et al. A placebo controlled trial of bupropion for smoking cessation in schizophrenia. Biol Psychiatry. 2002;52:53 61

16 Smoking Cessation & Schizophrenia Combination Meds, Extended Tx & H. Visits Most recent study, Aug in NTR: 34 smokers with schizophrenia randomized to either COMB EXT with Home Visits (HV), COMB EXT without HV, or Tx as usual (TAU) (1) COMB EXT: Group CBT + bupropion, nicotine patch, and nicotine lozenge, within 2 weeks and for 26 weekly visits. 1) Brody AL, Zorick T, Hubert R, Hellemann GS, Balali S, Kawasaki SS, Garcia LY, Enoki R, Abraham P, Young P, McCreary C. Combination Extended Smoking Cessation Treatment Plus Home Visits for Smokers With Schizophrenia: A Randomized Controlled Trial. Nicotine Tob Res Aug 3. pii: ntw190. [Epub ahead of print]

17 Smoking Cessation & Schizophrenia Combination Meds, Extended Tx & H. Visits HV: biweekly visits to the home, assessment of secondhand smoke (SHS) exposure and brief behavioral therapy with participants and others in the home environment. TAU consisted of group CBT plus serial single or combination medication trials as per standard care. 1) Brody AL, Zorick T, Hubert R, Hellemann GS, Balali S, Kawasaki SS, Garcia LY, Enoki R, Abraham P, Young P, McCreary C. Combination Extended Smoking Cessation Treatment Plus Home Visits for Smokers With Schizophrenia: A Randomized Controlled Trial. Nicotine Tob Res Aug 3. pii: ntw190. [Epub ahead of print]

18 Smoking Cessation & Schizophrenia Combination Meds, Extended Tx & H. Visits COMB EXT (with or without HV) had greater reductions in CPD than those treated with TAU (both ps <.01) 7 day PPA for the three groups were 45%, 20%, and 8%, respectively, which was significantly higher for COMB EXT plus HV than TAU (χ 2 (1) = 4.8, p =.03) 1) Brody AL, Zorick T, Hubert R, Hellemann GS, Balali S, Kawasaki SS, Garcia LY, Enoki R, Abraham P, Young P, McCreary C. Combination Extended Smoking Cessation Treatment Plus Home Visits for Smokers With Schizophrenia: A Randomized Controlled Trial. Nicotine Tob Res Aug 3. pii: ntw190. [Epub ahead of print]

19 Effect of Combination Extended Treatment (COMB-EXT) with or without home visits (HV) compared to treatment as usual (TAU) on measures of smoking behavior. Arthur L. Brody et al. Nicotine Tob Res 2016;ntr.ntw190 Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco This work is written by (a) US Government employee(s) and is in the public domain in the US.

20 Cognitive function in Schizophrenia & Varenicline Varenicline improved executive function and reduced startle reactivity, regardless of smoking status in subjects with schizophrenia (1) Varenicline led to some cognitive improvement for list learning, list recall, and language index (2) 1) Hong LE, Thaker GK, McMahon RP, Summerfelt A, Rachbeisel J, et al. Effects of Moderate Dose Treatment with Varenicline on Neurobiological and Cognitive Biomarkers in Smokers and Nonsmokers with Schizophrenia and Schizoaffective Disorder. Arch Gen Psychiatry. 2011;68: ) Smith RC, Lindenmayer JP, Davis JM, Cornwell J, Noth K, et al. Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder. Schizophr Res. 2009;110:

21 Smoking Cessation & Schizophrenia Varenicline In a multisite study, varenicline was well tolerated, with no evidence of exacerbation of symptoms, and was associated with significantly higher smoking cessation rates 19% versus placebo 4.7% at 12 w. (1) In a large study (53 subjects), Varenicline + CBT for 12 weeks: 60.4% attained 14 day PPA (2) 1) Williams JM, Anthenelli RM, Morris CD, et al. A randomized, double blind, placebo controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2012;73(5): ) Dutra SJ, Stoeckel LE, Carlini SV, Pizzagalli DA, Evins AE. Varenicline as a smoking cessation aide in schizophrenia: effects on smoking behavior and reward sensitivity. Psychopharmacology (Berl)2012;219:25 3

22 Smoking Cessation & Schizophrenia Varenicline Another study with varenicline in schizophrenia showed patients with lower baseline symptoms of affective flattening (more typical affect) were more likely to achieve smoking abstinence, and demonstrated larger increases in reward sensitivity during treatment (1) 1) Sunny J. Dutra, Luke E. Stoeckel, Sara V. Carlini, Diego A. Pizzagalli, A. Eden Evins. Varenicline as a Smoking Cessation Aid in Schizophrenia: Effects on Smoking Behavior and Reward Sensitivity. Psychopharmacology (Berl) Jan; 219(1): 25 34

23 Outline 1) What is behind the high comorbidity between Schizophrenia & Nicotine Dependence 2) Need for special treatment approach? 3) Any impact from smoking cessation on patients symptoms or stability?

24 Impact of Smoking Cessation on symptoms or stability? None of the published reports have found exacerbation of symptoms of psychosis or other symptoms in subjects diagnosed with schizophrenia after they quit smoking with any of the currently available medications. 1) Stapleton JA, Watson L, Spirling LI, Smith R, Milbrandt A, et al. Varenicline in the routine treatment of tobacco dependence: a pre post comparison with nicotine replacement therapy and an evaluation in those with mental illness. Addiction. 2008;103:

25 Impact of Smoking Cessation on symptoms or stability? (2) Stapleton et. al. (2008) did not find exacerbation of symptoms of mental illness in subjects diagnosed with depression, bipolar disorder, psychosis, psychosis and depression, and eating disorders following treatment with varenicline combined with group support 1) Stapleton JA, Watson L, Spirling LI, Smith R, Milbrandt A, et al. Varenicline in the routine treatment of tobacco dependence: a pre post comparison with nicotine replacement therapy and an evaluation in those with mental illness. Addiction. 2008;103:

26 Take Home Points Schizophrenia patients have a complex biology and interplay with nicotine receptors, that has an impact on manifestation of psychosis symptoms and cognitive functioning Patch and bupropion are safe but do not produce a robust abstinence when used alone In combination: Bupropion, patch and CBT would have a higher sustained abstinence in particular if extended Tx and adding Home visits

27 Take Home Points (2) Varenicline has potential for improving some of the cognitive functions in schizophrenia Varenicline significantly improves abstinence, although lower rates than general population Smoking cessation with any of the available medications do not have an impact on psych symptoms among patients with schizophrenia