Treatment of Tobacco and Cocaine Use Disordersmedia-ns.mghcpd.org.s3.amazonaws.com... · A. Eden...

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A. Eden Evins, MD, MPH Director, Center for Addiction Medicine

Massachusetts General Hospital Associate Professor of Psychiatry

Harvard Medical School

Treatment of Tobacco and Cocaine Use Disorders

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A. Eden Evins, MD, MPH

My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose: Research Support (to institution): Forum Pharmaceuticals, Pfizer Inc. Advisory Board: Reckitt Benckizer

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• Nearly 68 million smokers in the US

• 3 million tobacco-related deaths annually worldwide-- 440,000 in the US

• 19% of Americans currently smoke

• 25% of Americans are former smokers

• 54% of those with SMI smoke

• Numbers of smokers are INCREASING

• 100 million people died in the last century from smoking related causes Anticipated that 1 billion smokers worldwide will die from smoking related causes in this century – WHO

Public Health Burden of Tobacco

Dependence

MD-4

Potential public health impact of improved,

integrated addiction treatment in a chronic care

model

• Opioid overdoses killed more than 29,000 people

in 2014, more than any prior year.

• Over 88,000 alcohol related deaths per year and

increasing.

• Over 430,000 tobacco related deaths per year and

not decreasing.

• Approx. 18,000 illicit drug overdose deaths

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Smoking Kills

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Quitting Helps

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Illustration of the effects of a 3-fold difference in annual death rates on mortality at ages 35-79 *

78%

47%

Adapted from the One Million Women Study

Pirie, Peto, et al., Lancet 2013

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THE MILLION WOMEN STUDY

Pirie, Lancet, 2013

Quitting by age 50 cuts mortality in half

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50 Years after the first Surgeon General’s report of an association between smoking and cancer, adult smoking has declined 55% in the general US population. Smoking prevalence among adults with SMI in the US today is 53%.

This is higher than in the US general population in 1964.

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• In those with one or more lifetime hospitalizations for schizophrenia, bipolar disorder, or MDD,

• HALF died from to 1 of 19 diseases identified by CDC as causally linked to tobacco use

Smoking-Related Mortality in Those with

Psychiatric Disorders

Callaghan, 2014

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• Death

• MI

• Stroke

• Progression of atherosclerosis

• Bronchitis

• Diabetes Morbidity

• Cancer Risk

• Progression of COPD

Quitting Reduces

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• 26 studies

• Change in psychiatric symptoms was compared between continuing smokers and successful quitters

• Depression, anxiety, stress and quality of life improved among those who quit smoking significantly compared to those who continued smoking.

• It did not matter whether one had a pre-existing psychiatric diagnosis or not!!!

• Effect sizes comparable to those observed for antidepressant medications!!!

META-ANALYSIS CONFIRMS: SMOKING CESSATION IMPROVES

PSYCHIATRIC SYMPTOMS, QUALITY OF LIFE

Taylor et al. BMJ 2014

Smoking Cessation

Is Associated

with Improved Psychiatric Symptoms

Taylor et al., BMJ, 2014

Evins, MGH CAM

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•Acetylcholine stimulates nicotinic cholinergic receptors on dopaminergic and glutamatergic neurons in hippocampus prefrontal cortical areas as well as nucleus accumbens and other reward areas

•Nicotine stimulates a4b2, a7 and other nAChRs in brain

•Therapies target Nicotinic Receptors: NRT, Varenicline

•Or downstream targets such as dopaminergic targets: Bupropion, agents specific for subtypes of dopaminergic receptors under development

•Glutamatergic agents under development

•Exception: Nicotine stimulation upregulates receptor expression, especially high-affinity a4b2 receptors

Addiction to Nicotine:

Mechanism and Therapeutic Targets

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Cessation Works: Pharmacotherapy + Behavioral Therapy Doubles to

Triples Abstinence Rates

Cahill et al., JAMA 2014

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Cessation Works: Pharmacotherapy + Behavioral Therapy Doubles to Triples Abstinence Rates

First Line Tx: 1a. Varenicline, Dual NRT,

1b. Bupropion, Single NRT

1c. Varenicline + NRT (single study)

Cahill et al., JAMA, 2014

Varenicline & Dual NRT superior to bupropion & single NRT

Cahill et al., JAMA, 2014

Varenicline + NRT more effective than placebo + varenicline

Koegelenberg et al., JAMA, 2014

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For tobacco dependence: average of 5 attempts at abstinence before long-term abstinence achieved

Treatments double to triple abstinence rates and are Underutilized!

With Sustained Treatment Efforts, Addictive Disorders for which Treatments are Available are Good Prognosis Disorders

Addiction Treatment Works: Expect and Treat Relapses

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Repeat Cessation Attempts Are Effective

Gonzales, Clin Pharmacol Ther, 2014

Varenicline, 12-week trial, was associated with significantly higher quit rates than placebo in those who had failed one or more prior varenicline trials.

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Consider Maintenance Treatment: Point Prevalence Abstinence During One Year Maintenance Treatment

***

**

Evins, Cather, et al., JAMA. 2014

247 enrolled, 203 started open treatment, 87 (43%) attained abstinence at week 12 and were randomized to 40 weeks maintenance therapy

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Maintenance Treatment Extends Continuous

Abstinence Even More in Those with SMI

Evins, et al., under review, Evins, et al., 2014, JAMA; Tonstad, et al., 2006 JAMA

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• Pharmacotherapy + Behavioral Tx Doubles to Triples Quit Rates over placebo and are Universally Recommended in those without psychiatric illness and increases success rates over 5-fold in those with SMI

• Pharmacotherapy – First line:

• 1a. varenicline, dual NRT (short- + long-acting NRT)

• 1b. Bupropion, single NRT – Second line: nortriptyline

• Behavioral Treatment – Brief advice, individ/group tx, set a quit date, use “quit lines”

– Web, phone, in person, printed materials

– Example: http://www.trytostop.org/ Mass

• Multiple quit attempts are usual and

should be expected.

Treatment for Nicotine Dependence

http://www.trytostop.org/

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• Advise all your patients who smoke to quit

• Review health risks of tobacco use

• Educate about effective available treatments, choose and prescribe a pharmacotherapy

• Emphasize past successes, even if small, and encourage repeat attempts

• Set a quit date

• Refer for peer group support and or Quit Line

• Refer for or perform behavioral relapse prevention – CBT

• Brief advice to quit smoking has a significant impact on abstinence rates at 6 months

– Brief advice alone decreases fatal coronary artery disease, lung cancer, and total mortality

Give Brief Physician Advice to Quit

Lancaster and Stead, 2005a

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• Treatment guidelines recommend physician advice to quit at every visit, and physician recommendation for cessation plan for all smokers.

• But physicians document smoking status at 70% of visits; counsel to quit at 30% of visits; prescribe medications at <1% of visits

• No improvement since 1990

• Psychiatrists rarely offer counseling to quit smoking. In one study, only 12.4% of smoking patients were advised to quit.

Treatment is effective in the long run and is underprescribed!

Effective Treatments: Underutilized!

Himloch and Daumit, 2003; Thorndike, 2001.

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• Selective, partial a4 b2 and full a7 NAChR agonist

• FDA approved 2006 as an aid for smoking cessation

• Reduces nicotine withdrawal symptoms

– Stimulates NAChRs

• Reduces nicotine-induced dopamine release and reward

– Blocks binding of nicotine at NAChRs

• Superior efficacy vs placebo (and bupropion and NRT)

• Well tolerated from a psychiatric standpoint in all controlled studies to date as well as all large epidemiologic studies.

Varenicline (Chantix)

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Case Reports: Irritability, Impulsive Behavior, Depressed Mood, Suicidal Behavior

NOT seen in controlled trials to date in smokers with or without co-morbid psychiatric illness

Varenicline : Safety

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Observational Studies of Varenicline & NPS

Study Sample Outcome Adj. HR*

Meyer 2013 Addiction 35,800 US MHS 2006-2007

NPS hospital. (prim diag) 30 days

NPS hospital. (any diag) 30 days

NPS outpt visits

1.14 (0.56, 2.34)

0.79 (0.50, 1.24)

0.71 (0.60, 0.84)

Thomas 2013 BMJ

112,805 UK NHS 2006-2011

Fatal/nonfatal self-harm 90 days

Initiated antidepressant 90 days

0.88 (0.52, 1.49)

0.75 (0.65, 0.87)

Kotz 2015 Lancet Resp Med

158,209 UK NHS 2007-2012

Depression

Fatal/nonfatal self-harm 6 mo

0.65 (0.61, 0.68)

0.60 (0.48, 0.76)

Cunningham 2016 Addiction

15,255 US VA 2006-2007


NPS outpt visit in 30 days

0.15 – 2.00 all NS

Signif for Schiz only 1.27 (1.07, 1.51)

+5 visits per 100 yrs tx

Molero 2015 BMJ

69,757 Sweden (self-controlled) 2006-2009

Hospital or outpt specialist psychoses, mood, or anxiety

Fatal/nonfatal self-harm

1.18 (1.05, 1.31) (Specific to mood or

anxiety tx in Psych-HX)

1.00 (0.72, 1.37)

Pasternak 2013 Addiction

77,726 Denmark 2007-2010

NPS ER visit or hosp. in 30 days (vs. bupropion)

0.85 (0.55, 1.30)

*All analyses used statistical adjustment to control for confounds, effect is a hazard ratio

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NPS outpt visits

1.14 (0.56, 2.34)

0.79 (0.50, 1.24)

0.71 (0.60, 0.84)

Thomas 2013 BMJ

112,805 UK NHS 2006-2011



0.88 (0.52, 1.49)

0.75 (0.65, 0.87)


158,209 UK NHS 2007-2012

Depression


0.65 (0.61, 0.68)

0.60 (0.48, 0.76)


15,255 US VA 2006-2007



0.15 – 2.00 all NS



Molero 2015 BMJ






1.00 (0.72, 1.37)


77,726 Denmark 2007-2010


0.85 (0.55, 1.30)

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NPS outpt visits

1.14 (0.56, 2.34)

0.79 (0.50, 1.24)

0.71 (0.60, 0.84)

Thomas 2013 BMJ

112,805 UK NHS 2006-2011



0.88 (0.52, 1.49)

0.75 (0.65, 0.87)


158,209 UK NHS 2007-2012

Depression


0.65 (0.61, 0.68)

0.60 (0.48, 0.76)


15,255 US VA 2006-2007



0.15 – 2.00 all NS



Molero 2015 BMJ






1.00 (0.72, 1.37)


77,726 Denmark 2007-2010


0.85 (0.55, 1.30)

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NPS outpt visits

1.14 (0.56, 2.34)

0.79 (0.50, 1.24)

0.71 (0.60, 0.84)

Thomas 2013 BMJ

112,805 UK NHS 2006-2011



0.88 (0.52, 1.49)

0.75 (0.65, 0.87)


158,209 UK NHS 2007-2012

Depression


0.65 (0.61, 0.68)

0.60 (0.48, 0.76)


15,255 US VA 2006-2007



0.15 – 2.00 all NS



Molero 2015 BMJ






1.00 (0.72, 1.37)


77,726 Denmark 2007-2010


0.85 (0.55, 1.30)

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NPS outpt visits

1.14 (0.56, 2.34)

0.79 (0.50, 1.24)

0.71 (0.60, 0.84)

Thomas 2013 BMJ

112,805 UK NHS 2006-2011



0.88 (0.52, 1.49)

0.75 (0.65, 0.87)


158,209 UK NHS 2007-2012

Depression


0.65 (0.61, 0.68)

0.60 (0.48, 0.76)


15,255 US VA 2006-2007



0.15 – 2.00 all NS



Molero 2015 BMJ






1.00 (0.72, 1.37)


77,726 Denmark 2007-2010


0.85 (0.55, 1.30)

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NPS outpt visits

1.14 (0.56, 2.34)

0.79 (0.50, 1.24)

0.71 (0.60, 0.84)

Thomas 2013 BMJ

112,805 UK NHS 2006-2011



0.88 (0.52, 1.49)

0.75 (0.65, 0.87)


158,209 UK NHS 2007-2012

Depression


0.65 (0.61, 0.68)

0.60 (0.48, 0.76)


15,255 US VA 2006-2007



0.15 – 2.00 all NS



Molero 2015 BMJ






1.00 (0.72, 1.37)


77,726 Denmark 2007-2010


0.85 (0.55, 1.30)

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NPS outpt visits

1.14 (0.56, 2.34)

0.79 (0.50, 1.24)

0.71 (0.60, 0.84)

Thomas 2013 BMJ

112,805 UK NHS 2006-2011



0.88 (0.52, 1.49)

0.75 (0.65, 0.87)


158,209 UK NHS 2007-2012

Depression


0.65 (0.61, 0.68)

0.60 (0.48, 0.76)


15,255 US VA 2006-2007



0.15 – 2.00 all NS



Molero 2015 BMJ






1.00 (0.72, 1.37)


77,726 Denmark 2007-2010


0.85 (0.55, 1.30)

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NPS outpt visits

1.14 (0.56, 2.34)

0.79 (0.50, 1.24)

0.71 (0.60, 0.84)

Thomas 2013 BMJ

112,805 UK NHS 2006-2011



0.88 (0.52, 1.49)

0.75 (0.65, 0.87)


158,209 UK NHS 2007-2012

Depression


0.65 (0.61, 0.68)

0.60 (0.48, 0.76)


15,255 US VA 2006-2007



0.15 – 2.00 all NS



Molero 2015 BMJ






1.00 (0.72, 1.37)


77,726 Denmark 2007-2010


0.85 (0.55, 1.30)

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NPS outpt visits

1.14 (0.56, 2.34)

0.79 (0.50, 1.24)

0.71 (0.60, 0.84)

Thomas 2013 BMJ

112,805 UK NHS 2006-2011



0.88 (0.52, 1.49)

0.75 (0.65, 0.87)


158,209 UK NHS 2007-2012

Depression


0.65 (0.61, 0.68)

0.60 (0.48, 0.76)


15,255 US VA 2006-2007



0.15 – 2.00 all NS



Molero 2015 BMJ






1.00 (0.72, 1.37)


77,726 Denmark 2007-2010


0.85 (0.55, 1.30)

www.mghcme.org







NPS outpt visits

1.14 (0.56, 2.34)

0.79 (0.50, 1.24)

0.71 (0.60, 0.84)

Thomas 2013 BMJ

112,805 UK NHS 2006-2011



0.88 (0.52, 1.49)

0.75 (0.65, 0.87)


158,209 UK NHS 2007-2012

Depression


0.65 (0.61, 0.68)

0.60 (0.48, 0.76)


15,255 US VA 2006-2007



0.15 – 2.00 all NS



Molero 2015 BMJ






1.00 (0.72, 1.37)


77,726 Denmark 2007-2010


0.85 (0.55, 1.30)

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Fatal/Non-Fatal Self-Harm

Endpoint Author

Varenicline

# Events/ Sample Size

Comparator

# Events/ Sample Size

Hazard Ratio

95% CI

Lower Limit

Upper Limit

Suicide attempt Cunningham 0 / 11,774 0 / 23,548 NA NA NA

Suicide Thomas 2 / 30,352 6 / 78,407 NA NA NA

Fatal Or Non Fatal Self Harm

Thomas 19 / 30,352 69 / 78,407 0.88 0.52 1.49

Kotz 119 / 51,450 540 / 106,759 0.56 0.46 0.68

Molero 657 / 69,757 NA 1.00 0.72 1.37

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Summary: Observational Studies

Multiple outcomes assessed and most not significant

Fatal and nonfatal self-harm events are rare

No evidence of an increased risk for the most severe NPS events in varenicline users

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Pooled Analysis of ALL Psychiatric Adverse Effects in 17 RCT’s of Varenicline

Varenicline increased incidence of nausea but not psychiatric adverse events while increasing abstinence rates by 124% vs placebo and 22% vs. bupropion

Having a psychiatric illness increased the risk for psychiatric adverse events in smokers trying to quit and did so equally in those assigned to varenicline and placebo

In a large observational study in 35,800 outpatients trying to quit smoking, there were fewer psychiatric adverse events in those prescribed varenicline than those prescribed NRT

Results replicated now in multiple studies in different practice populations: DoD, VA, UK NHS

Varenicline Safety in 17 Randomized

Controlled Trials:

Gibbons and Mann 2013; Tonstad et al., 2010; Kotz et al., 2015

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EAGLES: Study Design

• Design: Prospective, randomized, double-blind, 24-week trial

• Treatments: varenicline, bupropion, NRT patch, placebo – Triple dummy design – All subjects received smoking cessation counseling

• Duration: 12 weeks treatment; 12 weeks non-treatment follow-up

• Target Sample Size: 8000 randomized subjects – 2000 per treatment (1000 with and 1000 without psychiatric

disorder)

• Primary comparisons: varenicline vs. placebo and bupropion vs. placebo

Author: Larry Samuels Reference: A3051123 Study protocol

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EAGLES: Primary Objectives

• Assess risk of clinically significant neuropsychiatric (NPS) adverse events (AEs) in subjects using varenicline, bupropion, nicotine replacement therapy (NRT), or placebo

• Determine whether subjects with prior history of psychiatric disorders are at greater risk for development of clinically significant NPS AEs compared to subjects without such history while using varenicline or bupropion as aids to smoking cessation

Author: Larry Samuels Reference: A3051123 Study protocol

AE=Adverse Event

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EAGLES: Study Diagram

BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Study

Contacts

(Week)

Varenicline

Bupropion

Nicotine Patch (NRT)

Placebo

Screening

Visit

Baseline

Randomization

Vertical ticks represent subject clinic visits

BID=Twice Daily; BL=Baseline; QD=Once Daily

Treatment Phase Non-Treatment Follow-Up

Target Quit

Date

Begin dosing: varenicline (0.5 mg QD)

Begin 0.5 mg BID Day 4

Begin 1 mg BID Day 8

Begin dosing: bupropion (150 mg QD)


Begin 21 mg QD (7 weeks) 14 mg QD

7 mg QD

Author: Larry Samuels Reference: CSR

Primary Safety Endpoint

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BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Study

Contacts

(Week)

Varenicline

Bupropion


Placebo

Screening

Visit

Baseline

Randomization




Target Quit

Date







7 mg QD



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BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Study

Contacts

(Week)

Varenicline

Bupropion


Placebo

Screening

Visit

Baseline

Randomization




Target Quit

Date







7 mg QD



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Study Population

• Included: Smokers age 18 to 75 years; average ≥10 cigarettes/day

• Excluded: Subjects with imminent suicidal risk or those engaging in self-injurious behaviors

• Psychiatric diagnosis confirmed by Structured Clinical Interview for DSM-IV Disorders (SCID) administered by trained mental health professionals

Author: Larry Samuels Reference: Study A3051123 protocol

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Study Population


• Non-Psychiatric cohort: No current or past psychiatric diagnosis • Psychiatric cohort: One or more clinically stable, current or past

diagnosis

Mood Disorders Major depressive disorder (MDD), bipolar I, bipolar II

Anxiety Disorders Panic disorder with or without agoraphobia, post-traumatic stress disorder, obsessive-compulsive disorder, social phobia, generalized anxiety disorder

Psychotic Disorders Schizophrenia, schizoaffective disorder

Personality Disorders Limited to past history of borderline personality disorder

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Development of Composite NPS Safety Endpoint

• Broad range of NPS AEs reported in the postmarketing experience for varenicline and reflected in the label

• A composite of NPS events provides for increased sensitivity of the endpoint

• Included only moderate to severe NPS events to increase specificity and minimize inclusion of less clinically significant events and events associated with nicotine withdrawal

Author: Larry Samuels Source:

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Primary Safety Endpoint Designed to Capture Serious NPS AEs

Primary Safety Endpoint: Percent of subjects reporting one or more of the following during treatment and up to 30 days after last dose:

Anxiety

Depression

Feeling abnormal

Hostility

Agitation

Aggression

Delusions

Hallucinations

Homicidal ideation

Mania

Panic

Paranoia

Psychosis

Suicidal ideation

Suicidal behavior

Suicide*

Classified as Moderate

or Severe

Classified as Severe

Severity assessment

Moderate = interferes to some extent with subject’s usual function

Severe = interferes significantly with subject’s usual function * Includes completed suicide and depression suicidal


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Study Size

• In agreement with FDA, EAGLES was sized to attain an adequate level of precision in the estimation of the risk difference in the NPS composite endpoint

• An Independent Data Monitoring Committee reviewed un-blinded safety data every 4 months to monitor safety and at 50% and 75% of available data to ensure that the target sample size was correct

• For an attributable risk difference corresponding to an increase on a relative risk scale of 75% in the incidence of the primary safety endpoint vs. placebo

Cohort N Width of 95% CI

Non-Psychiatric 4000 ±1.9%

Psychiatric 4000 ±2.6%

Overall Study 8000 ±1.6%

CI=Confidence Interval

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Key Secondary Safety Endpoints

• Percentage of subjects with severe NPS AEs in the primary composite endpoint by cohort

• Analyses of the individual components of the primary endpoint

• Psychiatric rating scales

– Columbia - Suicide Severity Rating Scale (C-SSRS)

– Hospital Anxiety and Depression Scale (HADS)

– Clinical Global Impression of Improvement (CGI-I)

Author: Larry Samuels Reference: Study A3051123 Protocol

Author: Larry Samuels Reference: Study A3051123 Protocol

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Subject Disposition

Screened=11,186 Number (%) of Subjects

Varenicline Placebo NRT Bupropion Total

Non-Psychiatric Cohort

All randomized (ITT), n 1005 1009 1013 1001 4028

All treated (safety), n 990 999 1006 989 3984

Completed study, n (%) 787 (79.5) 787 (78.8) 767 (76.2) 783 (79.2)

Did not complete study, n 203 212 239 206

Psychiatric Cohort





ITT=Intent-To-Treat population (efficacy analysis). All Treated population (safety analysis): received at least one dose of study drug

Author: Thomas McRae Source:

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Subject Disposition

Screened=11,186 Number (%) of Subjects

Varenicline Placebo NRT Bupropion Total






Psychiatric Cohort





ITT=Intent-To-Treat population (efficacy analysis). All Treated population (safety analysis): received at least one dose of study drug


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Baseline Characteristics

Non-Psychiatric Cohort N=3984

Psychiatric Cohort N=4074

Demographic Characteristics

Male, % 50.2 38.0

Age, years 46.0 47.1

Smoking Characteristics

FTNDa score, mean 5.5 6.0

Duration of smoking, years 28.1 28.6

Suicidality (Measured by C-SSRS)

Lifetime suicide ideation, % 4.8 33.8

Lifetime suicide behavior, % 0.7 12.6

Hospital Anxiety and Depression Scale (HADS)

Anxiety, mean 2.7 5.2

Depression, mean 1.5 3.2

a. Fagerstrom Test for Nicotine Dependence


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Male, % 50.2 38.0













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Male, % 50.2 38.0













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Baseline Characteristics: Psychiatric Cohort


%

Primary Diagnosis (SCID)

Mood disorders 70.7

Anxiety disorders 19.2

Psychotic disorders 9.5

Personality disorder 0.6

Psychotropic Medication Use at Baseline

Received psychotropic medication at enrollment 49.0

Antidepressants 33.8

Anxiolytics, hypnotics and other sedatives 15.3

Antipsychotics 16.0

Mood stabilizers 2.0


Author: Larry Samuels Reference:

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Baseline Characteristics: Psychiatric Cohort


%

Primary Diagnosis (SCID)

Mood disorders 70.7

Anxiety disorders 19.2

Psychotic disorders 9.5

Personality disorder 0.6

Psychotropic Medication Use at Baseline

Received psychotropic medication at enrollment 49.0

Antidepressants 33.8

Anxiolytics, hypnotics and other sedatives 15.3

Antipsychotics 16.0

Mood stabilizers 2.0


Author: Larry Samuels Reference:

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Perspectives on Smoking Cessation

• Challenging to disentangle NPS AEs without placebo control – Tobacco withdrawal symptoms and signs – Potential drug-related adverse event – Emergence or recurrence of psychiatric symptoms – Another medication’s side effect – Stress of quitting smoking

• EAGLES results shed light on this diagnostic dilemma • Unintended consequences of the Boxed Warning

– Contributes to misattribution of symptoms and “a rush to judgment”

– Another hurdle for those already facing many barriers

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Primary Neuropsychiatric AE Composite Endpoint: Observed incidence

4.0

1.3

6.5

4.5

2.2

6.7

3.9

2.5

5.3

3.7

2.4

4.9

0

1

2

3

4

5

6

7

8

9

10

OverallN=8058

Non-Psychiatric N=3984

PsychiatricN=4074

Ob

se

rve

d I

nc

ide

nc

e o

f E

ve

nt,

%

Varenicline Bupropion NRT Placebo

Author: Cristina Russ Source: Pfizer BD Table 10 QC: Chetna Bhattacharyya

n 80 90 79 74 13 22 25 24 67 68 54 50 N 2016 2006 2022 2014 990 989 1006 999 1026 1017 1016 1015

Treatment + 30 days; Anthenelli RM, Benowitz NL, West R, St. Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE. Effects of varenicline and bupropion in smokers with and without psychiatric disorders. Lancet. 2016 Apr 22

• Similar across treatment arms for overall study population • Non-psychiatric< psychiatric, regardless of treatment • Difference in varenicline vs. placebo may differ by cohort

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Primary NPS Endpoint: Risk Difference vs. Placebo - Overall Study Population

Treatment Comparisons Risk Difference

(95% CI)

Varenicline vs. placebo 0.16 (-0.99, 1.30)

Bupropion vs. placebo 0.85 (-0.35, 2.05)

NRT vs. placebo 0.12 (-1.04, 1.28)

-5 -4 -3 -2 -1 0 1 2 3 4 5

Risk Difference (95% CI)

Author: Cristina Russ Source: Pfizer BD Table 11 And Figure 2 QC: Chetna Bhattacharyya

Anthenelli RM, Benowitz NL, West R, St. Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE. Effects of varenicline and bupropion in smokers with and without psychiatric disorders. Lancet. 2016 Apr 22

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Primary NPS Endpoint: Risk Differences vs. Placebo Non-Psychiatric and Psychiatric Cohort



Varenicline vs. placebo -1.28 (-2.40, -0.15)

Bupropion vs. placebo -0.08 (-1.37, 1.21)

NRT vs. placebo -0.21 (-1.54, 1.12)



Varenicline vs. placebo 1.59 (-0.42, 3.59)

Bupropion vs. placebo 1.78 (-0.24, 3.81)

NRT vs. placebo 0.37 (-1.53, 2.26)

-5 -4 -3 -2 -1 0 1 2 3 4 5


Small numerical decrease in the non-psychiatric cohort and small numerical

increase (95% CI includes 0) in the psychiatric cohort for varenicline vs. placebo

Author: Cristina Russ Source: Pfizer BD Table 11 QC: Chetna Bhattacharyya

www.mghcme.org

67

14

68

14

54

14

50

13

0

10

20

30

40

50

60

70

80

Total Severe Adverse Events

Nu

mb

er

of

Su

bje

cts

wit

h E

ve

nts


Author: Cristina Russ Source: Pfizer BD Table 14 QC: Marianna Bruno

NPS Primary Endpoint – Subjects with Any Event and with Severe Events - Psychiatric Cohort

Treatment + 30 days

www.mghcme.org

67

26

68

21

54

19

50

23

0

10

20

30

40

50

60

70

80

Total Combined

Nu

mb

er

of

Su

bje

cts

wit

h E

ve

nts


Author: Cristina Russ Source: Pfizer BD Table 14 QC: Marianna Bruno

NPS Primary Endpoint – Subjects with Severe, Serious Adverse Events or Events Leading to Treatment Discontinuation - Psychiatric Cohort

Severe Events and/or Serious Adverse Events and/or

Events Leading to Treatment Discontinuation

Treatment + 30 days

www.mghcme.org

NPS Primary Endpoint: Frequency of Components Non-Psychiatric Cohort

0

5

10

15

20

25

30

Nu

mb

er

of

su

bje

cts

wit

h a

dve

rse

eve

nts

in

a c

ert

ain

co

mp

on

en

t


Author: Cristina Russ QC: Kevin Booth Source: Pfizer BD Table 12

Treatment + 30 days

www.mghcme.org

NPS Primary Endpoint: Frequency of Components Psychiatric Cohort

0

5

10

15

20

25

30

Nu

mb

er

of

su

bje

cts

wit

h a

dve

rse

eve

nts

in

a c

ert

ain

co

mp

on

en

t


Author: Cristina Russ QC: Kevin Booth Source: Pfizer BD Table 13

Treatment + 30 days

www.mghcme.org

Columbia Suicide Severity Rating Scale (C-SSRS)


N=3984 Psychiatric Cohort

N=4074

Varenicline n (%)

Bupropion n (%)

NRT n (%)

Placebo n (%)

Varenicline n (%)

Bupropion n (%)

NRT n (%)

Placebo n (%)

During Treatment + 30 Days

Assessed, n 988 983 996 995 1017 1012 1006 1006

Suicidal behavior 0 1 (0.1) 1 (0.1) 1 (0.1)a 1 (0) 1 (0.1) 0 2 (0.2)

Suicidal ideation (without behavior)

9 (0.9) 4 (0.4) 4 (0.4) 7 (0.7) 29 (2.9) 16 (1.7) 23 (2.4) 26 (2.8)

a. Completed suicide

Author: Cristina Russ QC: Sarah Dubrava Source: SCSa3050686a Subject on NRT 10571010 cut wrist - excluded vs programatic table – verbatim husband May 25; last dose March 9 Non psych behavior NRT – 10161040 – cut left wrist Pb – 11441029 completed suicide Bp 11101153 gun in mouth – was added with new algorithm Psych Var – 10091085 hallucination – jumping in front of bus Bup – 10881338 – gas from lighter Pb – 12081087 – overdose in endpoint Pb – 10071005 – overdose with study drug, not in endpoint

www.mghcme.org




N=4074

Varenicline n (%)

Bupropion n (%)

NRT n (%)

Placebo n (%)

Varenicline n (%)

Bupropion n (%)

NRT n (%)

Placebo n (%)


Assessed, n 988 983 996 995 1017 1012 1006 1006



9 (0.9) 4 (0.4) 4 (0.4) 7 (0.7) 29 (2.9) 16 (1.7) 23 (2.4) 26 (2.8)



www.mghcme.org




N=4074

Varenicline n (%)

Bupropion n (%)

NRT n (%)

Placebo n (%)

Varenicline n (%)

Bupropion n (%)

NRT n (%)

Placebo n (%)


Assessed, n 988 983 996 995 1017 1012 1006 1006



9 (0.9) 4 (0.4) 4 (0.4) 7 (0.7) 29 (2.9) 16 (1.7) 23 (2.4) 26 (2.8)

with intent and or plan

0 1 0 0 0 0 1 2



www.mghcme.org



N=4074

Varenicline n (%)

Bupropion n (%)

NRT n (%)

Placebo n (%)

Varenicline n (%)

Bupropion n (%)

NRT n (%)

Placebo n (%)


Assessed, n 988 983 996 995 1017 1012 1006 1006



9 (0.9) 4 (0.4) 4 (0.4) 7 (0.7) 29 (2.9) 16 (1.7) 23 (2.3) 26 (2.8)

Suicidal ideation and/or behavior

9 (0.9) 5 (0.5) 5 (0.5) 8 (0.8) 30 (2.9) 17 (1.7) 23 (2.3) 28 (2.8)




www.mghcme.org

Hospital Anxiety and Depression Scale (HADS): Anxiety Worsening of Category of Severity vs. Baselinea

5.3

2.1

7.3

3.1

7.5

3.2

7.3

2.7

0

10

20

Any worsening of category Increase from below 11 to ≥11

Su

bje

cts

, %

14.1

8.1

17.9

9.2

15.8

8.3

15.7

8.8

0

10

20


Su

bje

cts

, %

Author: Cristina Russ QC: David Lawrence Source: SCSa3050673c Please confirm manual calculations


Psychiatric Cohort

a. At any time during treatment + 30 days


Scores 0-7: Normal 8-10: Suggestive 11- 21: Probable

www.mghcme.org

Hospital Anxiety and Depression Scale (HADS): Depression

Worsening of Category of Severity vs. Baselinea

6.3

1.4

5.3

1.5

4.4

1.4

5.6

1.6

0

10

20


Su

bje

cts

, %

15.7

7.2

15.6

7

17.3

7.6

15.9

6.5

0

10

20


Su

bje

cts

, %

Author: Cristina Russ QC: David Lawrence Source: SCSa3050673c




Psychiatric Cohort

Scores 0-7: Normal 8-10: Suggestive 11- 21: Probable

www.mghcme.org

Clinical Global Impression of Improvement (CGI-I) Worsening vs. Baselinea

7.5

1.3 0.1

7

1.1 0

7

0.8 0.1

7.5

1.3 0

0

5

10

15

20

Minimally Worse Much Worse Very Much Worse

Su

bje

cts

, %


Author: Cristina Russ QC: Kevin Booth Source: SCSa3050672c


Psychiatric Cohort

14.5

3.4

0.2

16

2.6 0.3

15.9

2.3 0

14

3

0.3 0

5

10

15

20

Minimally Worse Much Worse Very Much Worse

Su

bje

cts

, %


www.mghcme.org

Efficacy: Continuous Abstinence Rates (ITT) Non-Psychiatric Cohort

38.0

26.1 26.4

13.7

0

5

10

15

20

25

30

35

40

Weeks 9–12

Co

nti

nu

ou

s A

bs

tin

en

ce

Ra

te, %

Varenicline (N=1005)

Bupropion (N=1001)

NRT (N=1013)

Placebo (N=1009)

Author: Cristina Russ QC: Larry Samuels Source: Pfizer BD Table 28 and Figure 9

Odds Ratios CAR Weeks 9-12 Main Efficacy Measure

OR (95% CI)

Varenicline vs. placebo 4.00 (3.20, 5.00)

Varenicline vs. NRT 1.74 (1.43, 2.10)

Varenicline vs. bupropion 1.77 (1.46, 2.14)

www.mghcme.org

Efficacy: Continuous Abstinence Rates (ITT) Non-Psychiatric Cohort

38.0

25.5 26.1

18.8

26.4

18.5

13.7

10.5

0

5

10

15

20

25

30

35

40

Weeks 9–12 Weeks 9–24

Co

nti

nu

ou

s A

bs

tin

en

ce

Ra

te, %


Bupropion (N=1001)

NRT (N=1013)

Placebo (N=1009)



OR (95% CI)




Odds Ratios CAR Weeks 9-24

OR (95% CI)




Anthenelli RM, Benowitz NL, West R, St. Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE. Effects of varenicline and bupropion in smokers with and without psychiatric disorders. Lancet. 2016.

www.mghcme.org

Efficacy: Continuous Abstinence Rates (ITT) Psychiatric Cohort

29.2

18.3 19.3

13.7

20.4

13 11.4

8.3

0

5

10

15

20

25

30

35

40

Weeks 9–12 Weeks 9–24

Co

nti

nu

ou

s A

bs

tin

en

ce

Ra

te,

%


Bupropion (N=1033)

NRT (N=1025)

Placebo (N=1026)



OR (95% CI)




Odds Ratios CAR Weeks 9-24

OR (95% CI)




Anthenelli RM, Benowitz NL, West R, St. Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE. Effects of varenicline and bupropion in smokers with and without psychiatric disorders. Lancet. 2016.

www.mghcme.org

EAGLES Conclusions

• Results did no show an increased risk of NPS AEs in the composite primary endpoint in the overall study population for varenicline or bupropion vs. placebo or vs. NRT patch

• In all treatment arms, including placebo, incidence of the primary NPS endpoint was higher in the psychiatric vs non-psychiatric cohort

• Risk differences for varenicline vs. placebo – Non-psychiatric cohort: AE Rate No Effect for Treatments than Placebo – Psychiatric cohort: No Effect of Treatment

» Did not reach statistical significance (95% CIs include 0) » Were not driven by events that were severe, or serious adverse events,

or led to treatment discontinuation, or resulted in harm to self or others

• Sensitivity analysis of expanded endpoint consistent with primary analysis

• Psychiatric scales (C-SSRS, HADs, and CGI-I) did not show an increased neuropsychiatric risk for varenicline vs. placebo or vs. NRT

• In both cohorts: Varenicline > Bupropion and single NRT > placebo

Author: Cristina Russ QC: Larry Samuels

www.mghcme.org

EAGLES is a Landmark Study of Clinical and Public Health Importance

• The EAGLES trial is the first:

– To compare safety and efficacy of all 3 FDA approved smoking cessation therapies in large samples of patients with and without a history of psychiatric disorder

– To allow for comparison of safety and efficacy of smoking cessation aids in smokers with different mental illnesses

M

D

-

7

6

www.mghcme.org

EAGLES is a Landmark Study of Clinical and Public Health Importance

• Study population is representative of patients seen in primary care and in community mental health settings

• Psychiatric Cohort – Stable but symptomatic,

– Half on psychotropic medication at baseline

– Half with major depressive disorder had recurrent depression

– One third had a second psychiatric diagnosis / comorbidity

– One fourth had a prior substance use disorder

– One eighth had made a prior suicide attempt

www.mghcme.org

EAGLES is a Confirmatory Trial for Efficacy

• Efficacy conclusions replicate and extend findings from smaller trials and meta-analyses in those with and without mental illness

• The efficacy data are clear

Varenicline > bupropion and nicotine patch > placebo

• Agreement with overall, growing body of evidence, raising confidence in the findings

www.mghcme.org

EAGLES Quantifies NPS Risk Across Treatment and Cohort

• Greater risk of NPS AE’s in Psych group versus Non-Psych group, independent of treatment – ~2% NPS AE rate in smokers without mental illness

– ~5-7% NPS AE rate in smokers with mental illness

• NPS AE rates in smokers during a cessation attempt are not different by treatment

• No pattern of NPS AE’s – No pattern in the most worrisome NPS AE’s

– No psychiatric subgroup appears to be at increased risk


www.mghcme.org

38.0

26.1 26.4

13.7

0

5

10

15

20

25

30

35

40

Co

nti

nu

ou

s A

bs

tin

en

ce

Ra

te, %

Varenicline (N=2037) Bupropion (N=2034)

NRT (N=2038) Placebo (N=2035)

1.3 2.2 2.5 2.4

0

5

10

15

Ob

se

rve

d I

nc

ide

nc

e o

f E

ve

nt,

%

EAGLES Allows Comparison of Neuropsychiatric Safety and Efficacy in Those without Psychiatric Illness


Primary NPS Composite

Safety Endpoint

CARs Week 9-12

www.mghcme.org

EAGLES Allows Comparison of Neuropsychiatric Safety and Efficacy in Those with Psychiatric Illness

a

Adapted from Evins, et al., Society for Research on Nicotine and Tobacco 2016; Chicago

a. One additional participant (NRT group/mood subcohort) who reported suicide ideation was identified after clinical database lock and was not

included in the analysis

6.3 5.7 6.8 6.3 8.0 6.4 5.1 4.6 5.5 6.3 5.7 4.6

05

101520253035

Psychotic Disorder Anxiety Disorder Mood Disorder

Ob

se

rve

d R

ate

o

f N

PS

Eve

nts

, %


23.2 27.0

30.4

11.2 13.9

21.7

13.1

21.9 21.2

4.1 8.0

13.2

0

5

10

15

20

25

30

35

Psychotic Disorder Anxiety Disorder Mood Disorder

Ob

se

rve

d

CA

Rs

, %

Primary NPS Composite Safety Endpoints by Treatment for Those with

Primary Psychotic, Anxiety and Mood Disorders

CARs Week 9-12 by Treatment and Psychiatric Diagnosis

www.mghcme.org

Neuropsychiatric Adverse Event Rate During Smoking Cessation is Independent of Treatment

• NPS AEs are seen in trials regardless of treatment

• Clinicians who prescribe a treatment and observe a NPS AE likely attribute this AE to the treatment.

• This happened in our large maintenance treatment trial of varenicline, in trials of bupropion, and in clinical practice.

Evins, et al., JAMA 2014; Evins, et al., J Clin Psychopharm 2007

www.mghcme.org

Why Might There be Significant NPS AEs Among Smokers, Independent of Treatment

(and Abstinence)?

• Smoking is an addiction; like all drug addictions, there are: – Well documented brain changes

– Increased neuropsychiatric events, e.g. suicide

– Suicide risk reduced in smokers who quit

• People with psychiatric illness are more likely to smoke

• Attempts to quit smoking are not risk free, with or without pharmacologic support and independent of abstinence – Well replicated in smokers with history of depression

Volkow et al., Am. J. Psych, 1999; Fehr et al., Am J Psych 2008; Li, et al., J Psych Res 2012; Berlin et al., NTR 2011;

Brown 1996; Tsoh, et al., Am J Psych 2000; Torres, et al., Psychol Med 2010; Evins, et al., JAMA 2014

www.mghcme.org

Implication of EAGLES: Offer Treatment to All Smokers, Including Those with Stable Mental Illness

• EAGLES trial shows NPS safety and efficacy of smoking cessation treatments for smokers with mental illness, a group that is:

– More likely to smoke, to smoke heavily, and be dependent

– Less likely to quit without a cessation aid

– More likely to relapse after discontinuation of cessation aids

– Likely to benefit from maintenance treatment

– Less likely to receive advice to quit from a medical provider

– Less likely to receive cessation aid

• Smokers with mental illness are less likely to receive a pharmacotherapeutic cessation aid from a medical provider

– This contributes to the 25 year mortality gap in those with mental illness, secondary to diseases causally related to tobacco smoking

www.mghcme.org

Risk/Benefit Considerations for Varenicline

• Physicians overestimate the risk of NPS AEs with varenicline

• Physicians underestimate the benefit of varenicline on improving quit rates

• It is imperative we find ways to increase use of the most effective smoking cessation treatment for our patients who try time and again to quit smoking

www.mghcme.org

• Dosing: 0.5 and 1.0 mg tabs

– 0.5 mg/d x 3 d

– 0.5 mg bid x 4 d

– 1.0 mg bid x 11 weeks

– Additional 12 weeks Tx recommended in those who achieve abstinence

– 12-month safety data published: well tolerated

• Renal excretion

• No significant drug-drug interactions or effect on cytochrome enzymes

• Nausea-common, headache, insomnia/dreams

Varenicline (Chantix)

www.mghcme.org

• Antidepressant acting via dopaminergic & noradrenergic mechanism; also a competitive NAChR inhibitor

• First-line (1b) treatment

• Doubles odds of long-term abstinence

• Independent of depressive symptoms

• 40-44% abstinence at end of treatment

• Approx 50% relapse at 12 months

Bupropion SR

Hurt et al. NEJM. 1996; Cox et al, 2004; USPHS, 2004; Hughes et al, 2005.

www.mghcme.org

• Treatment with Varenicline (n=696) and Bupropion (n=671) Significantly Improved Self Rated Quality of Life Over Placebo (n=685) at 12, 24, and 52 Weeks

• Significant positive association between smoking cessation and self rating of vitality, self-control, anxiety, and overall mental health profile

• Replication of several studies demonstrating reduced self report of anxiety after smoking cessation…

Varenicline and Bupropion Improved Health Related Quality of Life

Hays et al., 2010

www.mghcme.org

• First-line (Dual NRT 1a, single NRT 1b)

• Doubles odds of abstinence over placebo

• Helpful with or without counseling

• All forms appear equally effective overall

• In heavy smokers, there is a dose-response curve with gum favoring higher dose (4 mg)

• Dose: 20-30 mg/day; may be a benefit to increased doses of NRT and to combinations of NRT forms

– Long acting: transdermal patch

– Short acting: gum, inhaler, nasal spray

– Proper use of gum is critical

– Combination use is most common

Nicotine Replacement Therapy (NRT)

Silagy et al, 2005.

www.mghcme.org

May improve abstinence rates

For smokers who have relapsed after treatment with single agent, consider maintenance treatment or combination treatment:

• NRT: long acting (patch) + short acting (gum, inhaler or nasal spray ) + CBT

• Bupropion 150 mg bid + NRT + CBT

• Varenicline + NRT

Combination Pharmacotherapy for Nicotine Dependence

www.mghcme.org

• Current guidelines recommend behavioral tx + pharmacotherapy – Motivational enhancement

– Relapse prevention

– Partner support

• Guidelines are based on several large meta-analyses of controlled trials

• Telephone counseling provides a modest benefit in quit rates vs minimal intervention – www.trytostop.org or 1-800-TRY-TO-STOP

• Physical exercise can decrease cravings and attenuate weight gain

Behavioral Interventions

USPHS, 2000; Stead et al, 2003.

www.mghcme.org

• Peaks in 4 days

• Lasts for several weeks

• Can be severe, not life threatening

– Anxiety

– Awakening during sleep

– Depression

– Difficulty concentrating

– Impatience

– Irritability/anger

– Restlessness

– Decreased heart rate

– Weight gain

Withdrawal Syndrome:

Nicotine

www.mghcme.org

• Smoking speeds hepatic metabolism of many medications

• Serum concentrations of medications that are stable in smokers may rise following abstinence

• CYP 1A1, 1A2, and 2E1

– Abstinence associated with 30-42% reduction in 1A2 activity over the first 1-3 days of abstinence

– Therapeutic drug monitoring and 10% dose reduction has been recommended

• Take care when prescribing bupropion to those on clozapine because of additive seizure risk

Tobacco Abstinence: Effects on Metabolism

Seppala NH, et al.,1999. Desai HD, et al., 2001. Faber & Fuhr, 2004.

www.mghcme.org

• Give physician advice to quit smoking

• Develop a “quit day” plan, teach coping skills, build in self-rewards, and provide written cues to reinforce abstinence

• Treat with combined behavioral treatment and pharmacotherapy

• Long-term NRT or non nicotine treatment may be warranted, both to sustain abstinence and to improve symptoms

Summary – Nicotine Dependence

Evins AE and MGH Center for Addiction Medicine.

www.mghcme.org

• Major epidemic since 1980

• Availability of cheap, high-potency drug

• New forms: freebase/crack

• 30 million in US have used cocaine

• < 20% become regular users

• 17% risk of dependence (NCS)

• Increasing incidence of lacing with Levamisole

– Up to 80% of samples

– 3-13% risk of agranulocytosis with sustained exposure

Cocaine Dependence

www.mghcme.org

• Dopamine stimulation of neurons in nucleus accumbens normally limited by dopamine reuptake

• Cocaine blocks dopamine reuptake

• Assoc. with excessive dopamine stimulation in reward system of brain - “HIGH”

• Also assoc. with depletion of dopamine in the nerve terminals of the dopaminergic neurons involved - “LOW”

• Compensatory down-regulation of post-synaptic dopamine receptors

• Protracted syndrome of refractoriness to reward

Pharmacology of Cocaine Dependence

www.mghcme.org

• Binge symptoms:

– Intense euphoria

– Increased anxiety, dysphoria, tremor, hyperactivity

– Long-lasting craving

– Paranoid ideations, delusions

– Panic attacks, depression, mania

• Withdrawal:

– Onset: <24 hrs, peak: 2-4 days

– Duration: 7-10 days

– Protracted depression, craving: 1-3 months

Cocaine Use Patterns

www.mghcme.org

• Acute cocaine intoxication:

– Onset: seconds

– Duration: 30-60 min

– Dysphoria: within hours

– Recovery: < 48 hrs

– OD requires life support, airway

• Cocaine delusional disorder

– Diazepam for agitation

– Antipsychotics for delusions

• Hospitalize if suicidal or delusional

Treating Cocaine Intoxication

www.mghcme.org

• Pharmacotherapy not required in mild withdrawal states

• For severe cocaine withdrawal: • Amantadine – indirect dopamine agonist, increases dopamine levels

• Propranolol – B-adrenergic blocker reduces anxiety / severe adrenergic symptoms - 1 mg IV q min, up to 8 min

• Seizures: IV diazepam

Treating Cocaine Withdrawal

www.mghcme.org

Relapse prevention: Pharmacotherapy

• Disulfiram effective in 3 trials

• Inhibits DA-beta hydroxylase

• Reduced craving & relapse

• Baclofen – GABA-B agonist: 20 mg tid

• Topiramate increases GABA & inhibits glutamate: 25 mg po qd, slowly increase to 200 mg qd (Kampman, 2004)

• Modafinil enhances glutamate levels: 200-400 mg po qd

• However, Overall:

• Disulfiram: evidence not supportive

• Topiramate, other anticonvulsants: evidence not supportive

• Anticonvulsants: evidence not supportive

• Antipsychotics: evidence not supportive

Treating Cocaine Dependence

www.mghcme.org

Relapse prevention: Psychotherapy

– Contingency Management

– Manual-guided CBT

– 12-step facilitation

– Individual plus group therapy

– Behavioral reinforcement:

• Urine testing with contingencies

• Restrict access to money & friends

– High-intensity support to disrupt binge cycles


www.mghcme.org

As with any substance use disorder, treat anxiety and depressive symptoms in those suspected of having an independent mood or anxiety disorder, especially if these symptoms appear to be interfering with attainment of abstinence

Co-morbid depression: – SSRIs – effective if depressed

– “May” also reduce cocaine use

– Avoid TCAs, may be associated with cardiac arrhythmia when combined with cocaine

Co-morbid bipolar disorder: No adequate med trials – Consider combination therapy if rapid cycling


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