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:

Slide 2 3/30/2016

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

Medical Impact of Tobacco

Slide 3

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, 25th 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 4

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)

Prevalence of Tobacco Smoking in Clinical Samples of People with Mental Illness and Addictive Disorders

Schi

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reni

a

Bip

olar

Dis

orde

r

Maj

or

Dep

ress

ion

Slide 5 Morisano,D.,Bacher,I.,Audrain-McGovern,J.,George,T.P.(2009).Can.J.Psychiatry.54:141-151

Mea

n Sm

okin

g Pr

eval

ence

(%)

Pani

c D

isor

der

Post

-Tra

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ic St

ress

Dis

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Alc

ohol

Dep

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Coc

aine

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epen

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oid

Dep

ende

nce

Gen

eral

U.S

. Po

pula

tion

Gen

eral

Can

adia

n Po

pula

tion

Psychiatric Disorders SUD Non-PD

0

10

20

30

40

50

60

70

80

90

Current Smoking among Adults Aged 18 or Older

Based on Serious Psychological Distress Status of Previous Month (NHIS, 1997 to 2011)

Slide 6

*DifferencebetweenesKmateandesKmatefor2011isstrategicallysignificantatthe0.5level

Perc

ent %

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 0

10

20

30

40

50

Slide 7

Tobacco Bans in Hospital Settings

Mossetal.,Am.J.Addict.2010

Disadvantages

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

LawnandPols,2005;Mossetal.,2010

Advantages

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

*PRN–KnownasmedicaKonsthataretaken“asneeded”

Key Elements of Tobacco Free CAMH

Slide 8

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

Pre-Launch N=454

Post-Launch N=356

Pre-Launch N=123

Post-Launch N=106

Staff and Patient Attitudinal Survey Results

Slide 9

Patient

Staff 10 % n  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%)

19 % n  Increase in the support of the creation of a tobacco-free policy at CAMH (48% to 67%)

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%)

Riad-Allen et al., 2016. Am. J. Addict., in press

Effects of CAMH Tobacco Free on Aggression (Code Whites)

Slide 10

Riad-Allen, L. et al. (2017). Am. J. Addict., in press

*p<0.05

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

Vulnerabilitymarkersfortobaccoaddic4oninschizophrenia

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).

BiobehaviouralVulnerabilityFactorstoTobaccoAddic4oninSchizophrenian  Biochemical(reducednAChRlevels,higherbaselinenico8nelevelsinSzversusControls)

n  Gene8c(α7nAChR,α3nAChR,COMT,DISC1,Reelin)

n  Behavioral(deficitsinreinforcement/reward)

n  Neurocogni8ve(neurophysiological/neuropsychological)

Wing, VC et al., 2012. Ann. NY Acad. Sci. 1248-89-106

Lower β2*-nAChRs in smokers with schizophrenia as compared to controls

D’Souza, DC, Esterlis, I. et al. (2012). Am. J. Psychiatry

BehavioralFactors–MecamylamineEffectsonReinforcement,Consump4onandRelapseTopography – Puff Volume

McKee et al (2009). Schizophrenia Res.

Smoking Cue-Reactivity

* *p<0.05 vs. PLO

*p<0.05 vs 10 mg/day

Fonder et al. (2005). Biol. Psychiatry

Consumption (Cigarettes/Session)

Weinberger et al (2007). Schizophrenia Res.

*p<0.05 vs. PLO

EffectsofAbs4nenceonVisuospa4alWorkingMemory(VSWM)inSmokerswithSchizophrenia

10 8 6 4 2 0 0 1 2 3 4 5 6 7 8

Abstinent Smoking

Week in Trial

Dis

tanc

e Fr

om T

arge

t (cm

)

Quit Date

SCHIZOPHRENIA

8 6 4 2 0 0

Abstinent Smoking

Week in Trial D

ista

nce

From

Tar

get (

cm)

Quit Date

CONTROLS

n=23 n=29

George, T.P. et al., (2002). Neuropsychopharmacology 26: 75-85.

1 2 3 4 5 6 7 8

Selec4veEnhancementofVSWMbyCigareJeSmokinginSchizophrenia:BlockadebyMecamylamine

* * 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.

DeficitsinFrontal-Execu4vePerformancePredictSmokingCessa4onFailureinSchizophrenia

Schizophrenia

p=0.052

Dolan, S.L., Sacco, K.A. et al., (2004). Schizophrenia Res. 70: 263-275.

Trail Making Test - Part B

020406080

100120140160

Quit Not Quit

Quit Status at Trial Endpoint

Numb

er of

Seco

nds.

Digit Span Backward

012345678

Quit Not Quit

Quit Status at Trial Endpoint

Numb

er of

Digits.

p<0.05

Moss, T.G. et al. (2009). Drug Alcohol Depend. 104: 94-99.

p<0.05

Cor4calDopamineFunc4onandSpa4alWorkingMemory

George, T.P. et al., 2003, APPI

14 12 10 8 6 4 2 0 0 0

25

50

75

100

125

CORTICAL DOPAMINE ACTIVITY SPAT

IAL

WO

RK

ING

MEM

ORY

(%)

NORMAL

SCHIZOPHRENIA STRESS

Smoking Smoking

Atypical Versus Typical Antipsychotic Drugs and Nicotine Patch for Smoking Cessation in Schizophrenia (N=45)

George, T.P. et al. (2000). Am. J. Psychiatry. 157: 1835-1842.

*p<0.05 vs. Typical

Endpoint Last Four Weeks 6-Month F/U 0

25

50

75 Atypical Typical

Smok

ing

Abs

tinen

ce R

ate

(%)

*

*

*

Combina4onofTransdermalNico4neandBupropionSRisSuperiortoPlacebo+PatchforSmokingCessa4oninSchizophrenia(N=58)

34.5

10.3

27.6

3.4

16

00

5

10

15

20

25

30

35

% S

mok

ing A

bstin

ence

..

EndpointAbstinence

ContinuousAbstinence

Six MonthAbstinence

BUPPlacebo*

*

Fisher’s Exact Test + p = 0.056 * p < 0.05 # p=0.11

George, T.P., Vessicchio, J.C. et al. (2008). Biol. Psychiatry. 63: 1092-1096.

#

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  Clozapine

n  Olanzapine

n  Haloperidol

n  Chlorpromazine

n  Caffeine

n  Not Metabolized

n  Risperidone

n  Ziprasidone

n  Aripiprazole

n  Quetiapine

n  Bupropion

n  SSRI’s DeLeon, J. (2004). Psychiatric Serv. 55: 491-493.

VareniclineandPsychiatricPopula4onsn  Severalcasereportsbothpublished(Freedman,2007;KohenandKremen,2007)andunpublished(FDAMedwatch)implica8ngvareniclineinneuropsychiatrictreatment-emergentadverseevents(TEAEs),includingsuicidality,homicidality,psychosisandmania(O’Malley,2010).

n  However,clinicalstudiescomparingPsychiatricHx+toHx-smokersinvareniclinetreatmentsuggestthattreatmentoutcomesandadverseeventsarecomparable(e.g.Stapletonetal.,2008;McClureetal.,2010).

n  Recentcontrolledstudiessupportitssafetyandefficacyinschizophrenia,,includinginabs8nence-ini8a8on(Williamsetal.,2012.J.Clin.Psychiatry;Anthenelli,RMetal.2016Lancet)andrelapse-preven8on(Evinsetal.,2014.JAMA)studies.

n  Fourstudiessuggestsitssafetyandefficacyinsmokerswithbipolardisorder(Weinbergeretal.,2008;Wuetal.,2012;Fryeetal.,2013;Chengappaetal.,2014)

VareniclineforSmokingCessa4oninPeoplewithSchizophrenia(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.

VareniclineEffectsonPosi4veandNega4veSymptomsinSmokerswithSchizophrenia

Williams, J.M. et al. (2012). J. Clin. Psychiatry.73: 654-660.

Evins,AEetal.,JAMA.311:145-154.

17-02-08 33

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.

Ouellet-Plamondon, C. et al. (2014). Curr. Addict. Rep. 1: 61-68.

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)

epetitive ranscranial agnetic timulation

r T M S

Caroline Wass, Ph.D.

Factor 1

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Factor 2

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Desire to Smoke

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Anticipation of positive effects of smoking

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Anticipation of relief from withdrawal after smoking

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Intention to Smoke

3

3.5

4

4.5

5

5.5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Factor 1

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Factor 2

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Desire to Smoke

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Anticipation of positive effects of smoking

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Anticipation of relief from withdrawal after smoking

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Factor 1

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Factor 2

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Desire to Smoke

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Anticipation of positive effects of smoking

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Anticipation of relief from withdrawal after smoking

2.5

3

3.5

4

4.5

5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

Intention to Smoke

3

3.5

4

4.5

5

5.5

Pre-rTMS Post-rTMS

TQSU

score

Active rTMS (n=4)

Sham rTMS (n=6)

rTMS reduces tobacco cravings in patients with schizophrenia

Wing, VC et al, (2012) Schizophr. Res. 139: 264-266.