YaleCME. 5th Annual Yale Psychopharmacology Master Class: Focus on Depression. October 9, Yale School of Medicine Department of Psychiatry

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1 Yale School of Medicine Department of Psychiatry 5th Annual Yale Psychopharmacology Master Class: Focus on Depression October 9, 2015 YaleCME CONTINUING MEDICAL EDUCATION

2 5 th Annual Yale Psychopharmacology Master Class: Focus on Depression October 9, 2015 LEARNING OBJECTIVES This course will enable participants to: Participants who attend this conference will be able to: Assess the efficacy and safety of currently available pharmacological treatments Assess the role of various treatment options in challenging situations, specifically bipolar depression and late-life depression Evaluate evidence-based treatment algorithms and rating scales Identify future developments in psychopharmacology and clinical trial options Describe state of the art data on the role of current psychotropic medications and medical devices in the treatment of serious mood disorders Apply rational prescribing practices in keeping with guidelines released by the American Psychiatric Association and large scale real-world clinical outcome studies Identify future developments in psychopharmacology which may impact practice State the role of various psychopharmacological, brain stimulation and psychosocial treatments in challenging situations ACCREDITATION STATEMENT The Yale School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. DESIGNATION STATEMENT The Yale School of Medicine designates this live activity for a maximum of 6.0 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

3 Schedule 7:30am 8:30am 8:45am 9:45am 10:00am 10:45am 11:30am 12:15pm 1:30pm 2:15pm 3:00pm 3:15pm 4:00pm Registration and Continental Breakfast Welcome and Introductions Gerard Sanacora MD, PhD New Developments in Treating Treatment Resistant Major Depression: Are they Ready for Prime Time? Gerard Sanacora MD, PhD Refreshment Break Evaluating the Relative Efficacy and Safety of Currently Available Medications for TRD Michael E. Thase MD Treatment Resistant Depression: Definition, Subtypes and Clinical Implications Michael E. Thase MD Breakout Sessions Lunch Kappa Opioid Antagonism as a Potential Therapy for Anhedonia: The FAST-MAS Trial Andrew D. Krystal MD Interaction of Alcohol Abuse and Mood Disorders Ismene L. Petrakis MD Refreshment Break Nicotine and Mood Disorder Interactions (smoking and mood disorders) Stephanie S. O'Malley PhD Closing Remarks & Adjourn Gerard Sanacora MD, PhD

4 Faculty COURSE DIRECTOR Gerard Sanacora MD, PhD Professor of Psychiatry Yale School of Medicine Director, Yale Depression Research Program FACULTY Andrew D. Krystal MD Psychiatrist Department of Psychiatry Division of Brain Stimulation and Neurophysiology Duke University School of Medicine Stephanie S. O'Malley PhD Professor of Psychiatry Director, Division of Substance Abuse Research in Psychiatry Deputy Chair, Clinical Research, Yale School of Medicine Ismene L. Petrakis MD Professor of Psychiatry Chief of Psychiatry, VA Connecticut Healthcare System Yale School of Medicine Michael E. Thase MD Professor of Psychiatry Perelman School of Medicine, University of Pennsylvania Physician 1, Philadelphia VA Medical Center

5 5 th Annual Yale Psychopharmacology Master Class: Focus on Depression October 9, 2015 DISCLOSURE SUMMARY It is the policy of Yale University School of Medicine, through its Center for Continuing Medical Education, to ensure balance, independence, objectivity, and scientific rigor in all its educational programs. All faculty participating in this symposium are required to disclose to the program audience (orally or with slide): any relevant financial relationship(s) they (or spouse/partner) have with a commercial interest that benefits the individual in any financial amount that has occurred within the past 12 months; and the opportunity to affect the content of CME about the products or services of the commercial interest. The Center for Continuing Medical Education will ensure that any conflicts of interest are resolved before the educational activity occurs. The following indicates participants responses to disclosure policy: Name Nothing to Disclose Speaker (and/or spouse/partner) has significant corporate relationship(s) with: Role of service/financial relationship Andrew D. Krystal MD Not available at the time of printing Stephanie S. O Malley PhD Abbott, Eli Lilly, Pfizer, Ethypharma Alkermes Pfizer Hazelden Betty Ford ASCP Work group Advisory Board Clinical Trial Scientific Panel Foundation Ismene L. Petrakis MD Alkermes Consultant Gerard Sanacora MD Not available at the time of printing Michael Thase MD Not available at time of printing After review by the Course Director, it has been determined there are no conflicts of interest.

6 5 th Annual Yale Psychopharmacology Master Class: Focus on Depression October 9, 2015 This activity did not receive any educational grant funding.

7 HOW TO ACCESS THE ONLINE COURSE SYLLABUS Using your smart phone, tablet, or laptop: 1. Open your preferred web browser (safari, chrome, internet explorer) 2. Log onto the Yale CME Website 3. Click on Conference Schedule which is located at the top of the screen. 4. Find today s conference 5 th Annual Yale Psychopharmacology Master Class: Focus on Depression and open the link by clicking on the title. 5. Click on View Syllabus located under the conference title. QUICK ACCESS from your tablet or smart phone using the following QR code: This QR Code will bring you directly to the conference page, proceed with step 5 above. *You will be able to access the syllabus after the conference inside your Yale CME profile. Questions please see the Yale CME representative at the registration desk. THANK YOU!

8 HOW TO OBTAIN YOUR CME CERTIFICATE In order to obtain your certificate you must complete an online posttest and evaluation. You will receive an from Yale CME within 3-5 business days post-conference, with the instructions below: 1. A link to login to your profile will be provided in the 2. Login using your address and password 3. Click on My live conferences 4. A list of your registered conferences will appear. Enter the eligible credits for the conference you wish to print your certificate 5. Click Save 6. Click Start to complete the post-test; click Submit 7. Upon completion of the post test, click Start to complete the evaluation; click Submit evaluation 8. Click Print to print your certificate Questions please contact Yale CME at or cme@yale.edu

9 The views of the speakers do not necessarily reflect the views of the Yale School of Medicine ~~~~~~~~~~~~~~~~~~~~~ Recording of this session by attendees is strictly prohibited

10 New Developments in the Approach to Treatment Resistant Mood Disorders: Are They Ready for Prime Time? Gerard Sanacora, M.D., Ph.D. Professor Yale University School of Medicine Department of Psychiatry Director, Yale Depression Research Program Scientific Director, Yale-New Haven Hospital Interventional Psychiatry Service Faculty Disclosure Consulting fees: AstraZeneca, Avanier Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly & Co., Hoffman La-Roche, Merck, Navigen, Naurex, Noven Pharmaceuticals, Servier Pharmaceuticals, Takeda, Teva and Vistagen Therapeutics over the last 24 months. Research contracts: AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Johnson & Johnson (Janssen), Hoffman La-Roche, Merck & Co., Naurex and Servier over the last 24 months. Free medication was provided to Dr. Sanacora for an NIH sponsored study by Sanofi-Aventis. In addition Dr.Sanacora holds shares in BioHaven Pharmaceuticals Holding Company and is a co-inventor on a US patent (#8,778,979) held by Yale University * Greater than $10, in income.

11 Death Rates* for Coronary Heart Disease, United States, Actual Rate and Expected Rates if Rise had Continued or Reached a Plateau *Age-adjusted. National Institutes of Health. National Heart, Lung, and Blood Institute. Accessed September 1, Outline of Discussion Topics 1. The need for novel therapeutic strategies in the treatment of Mood Disorders 2. New Approaches to the development of novel therapeutic approaches 3. Novel Therapeutics in development 4. How to consider the use of novel therapeutics when treating/counseling a patient

12 Suicide in the United States Suicide accounted for 36,891 deaths in 2009 Heart disease Malignant Neoplasms Chronic resp. disease Cerebrovascular Unintentional injury Alzheimer s disease Diabetes mellitus Influenza & Pneumonia Nephritis Suicide Septicemia Liver disease Hypertension Parkinson s disease Homicide Pneumonitis Benign neoplasms Aortic aneurysm HIV Viral hepatitis 0 100, , , , ,000 Number of Deaths Suicide is the 10th leading cause of death among persons aged 10 years, United States, ,000 Rate per 100,000 Population Males Both Sexes Females Trends in suicide rates have remained relatively stable from in persons aged 10 years, by sex, United States Centers for Disease Control and Prevention. Accessed September 1, ADT = antidepressant treatment; CT = cognitive therapy; STAR*D = Sequenced Treatment Alternatives to Relieve Depression; SR = sustained release; XR = extended release. Zisook S, et al. J Clin Psychiatry. 2008;69(7):

13 The monoaminergic hypothesis of mood disorders has dominated the field for nearly a half of century Schildkraut JJ, et al. Science. 1967;156(3771): The need for a next generation of medications was emphasized by the large scale practical trials like CATIE, STAR*D, and STEP-BD, each of which revealed very modest effects with optimized use of the current generation of medications. The next generation of medications may be built on an understanding of pathophysiology rather than the me-too approach that has characterized the past four decades of drug development. CATIE = Clinical Antipsychotic Trials of Intervention Effectiveness; STEP-BD = Systematic Treatment Enhancement Program. Brady LS, et al. Neuropsychopharmacology. 2012;37(1):

14 Transformataive Change Discovery of DNA Structure in 1953 Diagnostic and Statistical Manual of Mental Disorders was published in 1952 Approaches to Drug Discovery for Depression Monteggia LM, et al. Nature. 2014;515(7526):

15 Research Domain Criteria (RDoC) Aims to reframe mental health from research to treatment, cuts across traditional diagnostic categories to identify relationships among observable behavior, neurobiological measures, and patient self-reports. Facts and Myths about RDoC October 13, 2015, 1:30 2:30 PM EDT Register for the Webinar Understanding Brain Structure and Function

16 Neurocircuitry of Depression Created by Sanacora from multiple references including Drevets et al. Brain Struct Funct 213, (2008). Phillips et al. Am J Psychiatry Feb 1;172(2):124-38, and Pizzagalli. Annu Rev Clin Psychol The Brain Reward Circuitry in Mood Disorders Russo SJ, et al. Nat Rev Neurosci. 2013;14(9):

17 Understanding the Mechanisms of Reward Muschamp JW, et al. Cold Spring Harb Perspect Med. 2013;3(2):a Developing Novel Treatment Approaches Rorick-Kehn LM, et al. Neuropharmacology. 2014;77:

18 NIH FAST: Fast-Fail Trials NIMH is supporting the Fast-Fail Trials (FAST) initiative through three (3) NIMH Contracts awarded in September 2012 (period of performance from September 24, 2012 through September 23, 2015), to provide a rapid way to test new or repurposed compounds for their potential as psychiatric medications. The aim is not only to quickly identify compounds that merit more extensive testing, but to identify targets in the brain for the development of additional candidate compounds. FAST will aim at answering the following questions: Does the compound engage a target in the brain, for example, does it interact with a specific receptor in brain cells or alter signaling in the brain by a specific neurotransmitter? Does it measurably alter a feature of brain function; for example change the results of a test of memory, cognition, or attention? Developing Novel Treatment Approaches Official Title: A Phase 1 Study of Kappa and Mu Opioid Receptor Occupancy Associated With Repeated Dosing of LY

19 Opioid Modulation in Major Depressive Disorder Efficacy of BUP/SAM therapy in MDD. Displayed are mean decreases from baseline in HAM-D17 (left) and MADRS (right) total scores after 7 days of therapy. P-values are from Exact Wilcoxon tests and are based on observed data Ehrich et al. Neuropsychopharmacology (2015) 40, Developing Novel Treatment Approaches ALKS-5461 is a combination of both buprenorphine (suboxone) and samidorphan

20 mglur5 in the Nucleus Accumbens is Critical for Promoting Resilience to Chronic Stress Shin S, et al. Nat Neurosci. 2015;18(7): Glutamatergic Drugs and Other Rapid Acting Antidepressant Agents

21 12/11/14 Special K, a Hallucinogen, Raises Hopes and Concerns as a Treatment for Depression - NYTimes.com / nyti.ms/ 1D6E78e BUSINESS DAY Special K, a Hallucinogen, Raises Hopes and Concerns as a Treatment for Depression By ANDREW POLLACK DEC. 9, 2014 It is either the most exciting new treatment for depression in years or it is a hallucinogenic club drug that is wrongly being dispensed to desperate patients in a growing number of clinics around the country. It is called ketamine or Special K, in street parlance. While it has been used as an anesthetic for decades, small studies at prestigious medical centers like Yale, Mount Sinai and the National Institute of Mental Health suggest it can relieve depression in many people who are not helped by widely used conventional antidepressants like Prozac or Lexapro. And the depression seems to melt away within hours, rather than the weeks typically required for a conventional antidepressant. But some psychiatrists say the drug has not been studied enough to be ready for use outside of clinical trials, and they are alarmed that clinics are springing up to offer ketamine treatments, charging hundreds of dollars for sessions that must be repeated many times. We don t know what the long-term side effects of this are, said Dr. Anthony J. Rothschild, a professor of psychiatry at the University of Massachusetts Medical School. Pharmaceutical companies hope to solve the problem by developing drugs that work like ketamine but without the side effects, which are often described as out-of-body experiences. On Tuesday, at a medical conference in Phoenix, a privately held 1/5

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23 Why has ketamine gained such interest in the lay media? Patients Having at Least 50% Improvement in Depression (%) There is a Clear Unmet Need for Medications with a Faster Onset of Action Time to Response with Citalopram, STAR*D Trial >13 Weeks of Treatment STAR*D = Sequenced Treatment Alternatives to Relieve Depression. Trivedi MH, et al. Am J Psychiatry. 2006;163(1):28-40.

24 What is the history behind the discovery of rapid-acting antidepressant drugs? Our brightest blazes of gladness are commonly kindled by unexpected sparks. Samuel Johnson, The Idler; Poems Antidepressant Effects of Glutamatergic Drugs 100% 75% n=25 DCS treatment n=18 n=14 It is difficult to explain why psychiatric benefits should have occurred almost immediately following drug administration 50% All Responses 25% Excluding Temporary Response 0% Depression insomnia Anorexia (Crane, Compr Psychiatry 1961)

25 Antidepressant Actions of Ketamine Mean HDRS/ Depression severity Ketamine Treatment (0.5 mg/kg Single Infusion) Placebo Treatment Time (Min) Time (Hour) Ketamine treatment was a 0.5 mg/kg single infusion. HDRS = Hamilton Depression Rating Scale for depression. Berman R, et al. Biol Psychiatry. 2000;47: Antidepressant Actions of Ketamine Proportion With 50% Change in Score from Baseline (HDRS) Placebo Ketamine Proportion in Remission (HDRS Score 7) Time (Min) Time (Day) Time (Min) Time (Day) Proportion of responders (50% improvement on 21-item HDRS) to ketamine and placebo treatment from minute 40 to day 7 post-infusion (n=18) Zarate CA, et al. Arch Gen Psychiatry. 2006;63:

26 Scopus document search using search terms ketamine and major depression search terms End of 2014 All studies with depressive episodes are positive so far aan het Rot et al. Biol Psychiatry 2012

27 From: Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression The APA Council of Research Task Force on Novel Biomarkers and Treatments American Journal of Psychiatry, 2015; 172: a The A) top plot shows results one day after initiation of ketamine (heterogeneity: χ2=4.27, df=4, p=0.51, I2=0%). The B) bottom plot shows results one week after initiation of ketamine (heterogeneity: χ2=1.14, df=5, p=0.95, I2=0%). Date of download: 10/07/2015 Copyright American Psychiatric Association. All rights reserved.

28 Current data provide compelling evidence that the antidepressant effects of ketamine infusion are both rapid and robust, albeit transient. Yet, this enthusiasm should be tempered with the realization that ketamine s clinical trial data, although positive, remain limited and demonstrate only a transient benefit. From: Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression The APA Council of Research Task Force on Novel Biomarkers and Treatments American Journal of Psychiatry Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults Cochrane Database Syst Rev Sep 29;9: To draw more robust conclusions, further RCTs (with adequate blinding) are needed to explore different modes of administration of ketamine and to study different methods of sustaining antidepressant response, such as repeated administrations.

29 Addressing the Limitations of the Ketamine Studies to Date? 1. Ineffective study drug blinding 2. Optimal dosing has not been determined (dose, route, or frequency) 3. Unknown duration of effect 4. Longer-term effectiveness and safety of the treatment approach is unclear 5. Moderators of response are unknown Subtype, genetic, or endophenotypic differences in response Drug-drug interactions (regarding both safety and efficacy) 6. Mediators of response (mechanism of action) are unknown Proximal effects Downstream effects Are ketamine s antidepressant effects largely due to functional unblinding?

30 Rapid Antidepressant Actions of Ketamine Compared to Midazolam Response rates to Ketamine 3 days 60% 7 days 46% Midazolam 3 days 21.5% 7 days 17.5% Murrough JW, et al. Am J Psychiatry. 2013;170(10): At what dose should the ketamine be delivered for the treatment of depression?

31 Subanesthetic Doses of Ketamine Increase while Anesthetic Doses of Ketamine Decrease or Have No Effect on Extracellular Levels of Glutamate in the Prefrontal Cortex * = significant differences from saline-treated groups as determined by Kruskal Wallis ANOVA (n = 6 for 30 mg/kg; n = 7 for 20 mg/kg; n = 7 for 10 mg/kg groups). * = significant differences as compared with saline-treated group (n = 6 for 50 mg/kg; n = 5 for 200 mg/kg). Moghaddam B, et al. J Neurosci. 1997;17(8): Dose Dependence of Ketamine Effects FST Phosphorylation **P <.01, ANOVA. FST = forced swim test. Li N, et al. Science. 2010;329(5994): Chowdhury GM, et al. Biol Psychiatry. 2012;71(11): Chowdhury, Behar

32 Is there a Dose-Response Relationship in Humans? A service of the U.S. National Institutes of Health Trial record 1 of 1 for: NCT Previous Study Return to List Next Study Double--Blind, Placebo--Controlled Trial of Ketamine Therapy in Treatment--Resistant Depression (TRD) This study is not yet open for participant recruitment. (see Contacts and Locations) Verified May 2014 by Massachusetts General Hospital Sponsor: Massachusetts General Hospital Collaborators: National Institute of Mental Health (NIMH) Baylor College of Medicine Mount Sinai School of Medicine Stanford University University of Texas Yale University ClinicalTrials.gov Identifier: NCT First received: August 8, 2013 Last updated: May 29, 2014 Last verified: May 2014 History of Changes New NIMH funded multisite study examining various doses [.1,.2,.5, and 1 mg/kg IV over 40 mins] (NCT ) YDRP number for referrals Can the Effect Be Improved if Repeated? Will a Slower infusion work? 10 depressed patients were treated with 2X/week infusions of ketamine.5 mg/kg administered over 100 min until either remission was achieved or 4 infusions were given 80% of the completers responded to ketamine infusions. 3 of these 8 patients responded after only 1 infusion, while the other 5 responders needed 2 infusions Relapse (rise of MADRS score >9). Of the 5 patients who remitted in the acute phase, 2 sustained the remitted state during 4 weeks of follow-up Rasmussen KG, et al. J Psychopharmacol. 2013;27(5):

33 Is There a Cumulative Effect of Treatment? Response and Remission to Serial Intravenous Subanesthetic Ketamine in TRD 14 participants enrolled. 11 of 12 participants (91.6%) who completed all 6 infusions achieved response criterion, 8 (66.6%) remitted. After the 1st infusion, only 3 and 1 out of 12 responded and remitted, respectively. 4 achieved response and 6 remitted after 3 infusions. 5 out of 11 participants remained in response throughout the 4 weeks of follow-up. The mean time for 6 participants who relapsed was 16 days. Ketamine IV (.5 mg/kg) was administered over a 12-day period during on a Monday Wednesday Friday schedule, corresponding to study days 1, 3, 5, 8, 10, and 12. Depression severity was measured MADRS at baseline, and then 40, 100, and 160 min after infusion was started. Response was defined as 50% improvement from baseline score in MADRS. Remission was defined as MADRS score 9. TRD = treatment-resistant depression. Shiroma PR, et al. J Affect Disord. 2014;155: Is There a Cumulative Effect of Treatment? How Many Treatments Should Be Given? How Frequently Should it Be Dosed? Singh J, et al. A Double-Blind, Randomized, Placebo-Controlled, Parallel Group, Dose Frequency Study of Intravenous Ketamine in Patients with Treatment-Resistant Depression. Presented at: Society of Biological Psychiatry 69th Annual Scientific Meeting; May 8-10, 2014; New York, NY.

34 Is There a Cumulative Effect of Treatment? How Many Treatments Should Be Given? How Frequently Should it Be Dosed? Longer-Term Antidepressant Effects of Randomized Saline Controlled Repeated Ketamine Infusions; 2X/ vs 3X/ Week Dosing Ketamine 69% Responders 38% Remitters Ketamine 55% Responders 23% Remitters Singh J, et al. A Double-Blind, Randomized, Placebo-Controlled, Parallel Group, Dose Frequency Study of Intravenous Ketamine in Patients with Treatment-Resistant Depression. Presented at: Society of Biological Psychiatry 69th Annual Scientific Meeting; May 8-10, 2014; New York, NY. Can adjunctive CBT be useful in preventing Ketamine Relapse? (Sam Wilkinson, Detre Award) J ECT 2006

35 By what route should the ketamine be delivered for the treatment of depression? Intranasal Ketamine in Major Depressive Disorder Change in depression severity in patients with treatment-resistant depression after intranasal administration of ketamine or placebo. Change in Montgomery-Åsberg Depression Rating Scale (MADRS) depression severity 24 hours after administration was th... Lapidus et al. Biol Psychiatry Dec 15;76(12):970-6

36 11/6/14 A Study to Evaluate the Safety and Efficacy of Intranasal Esketamine in Treatment-resistant Depression - Full Text View - ClinicalTrials.gov A service of the U.S. National Institutes of Health A Study to Evaluate the Safety and Efficacy of Intranasal Esketamine in Treatment--resistant Depression (SYNAPSE) This study is currently recruiting participants. (see Contacts and Locations) Verified October 2014 by Janssen Research & Development, LLC Sponsor: Janssen Research & Development, LLC Information provided by (Responsible Party): Janssen Research & Development, LLC ClinicalTrials.gov Identifier: NCT First received: November 25, 2013 Last updated: October 9, 2014 Last verified: October 2014 History of Changes Full Text View Tabular View No Study Results Posted Disclaimer How to Read a Study Record Purpose The purpose of this study is to assess the efficacy and dose response of intranasal esketamine (Panel A: 28 mg, 56 mg, and 84 mg and Panel B: 14 mg and 56 mg) compared with placebo in improving depressive symptoms in participants with treatment--resistant depression (TRD). Condition Intervention Phase Treatment Resistant Depressive Disorder Drug: Esketamine 14 mg Drug: Esketamine 28 mg Drug: Esketamine 56 mg Drug: Esketamine 84 mg Drug: Placebo Phase 2 Ketamine use in the treatment of Suicidal Ideation

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38 The purpose of this study is to evaluate the efficacy of intranasal esketamine 84 milligram (mg) compared with intranasal placebo along with standard care treatment, in reducing the symptoms of major depressive disorder (MDD), including the risk for suicide as assessed by the Investigator, in participants who will be assessed to be at imminent risk for suicide. Is it Safe to Dose Repeatedly? Potential Structural Changes with Chronic Ketamine Exposure Liao Y, et al. Biol Psychiatry. 2011;69(1): We have demonstrated a reduction in frontal gray matter volume in patients after chronic ketamine use. The link between frontal gray matter attenuation and the duration of ketamine use and cumulative doses of ketamine perhaps suggests a dose-dependent effect of long-term use of the drug. Our results have important connotations for the clinical picture that is likely to emerge with the growing recreational use of ketamine. the results showed that the lesions in the brains of ketamine addicts were located in many regions which appeared 2-4 years after ketamine addiction. Cortical atrophy was usually evident in the frontal, parietal or occipital cortices of addicts. Such study confirmed that many brain regions in the human were susceptible to chronic ketamine injury and presented a diffuse effect of ketamine on the brain which might differ from other central nervous system (CNS) drugs Wang C, et al. Front Neuroanat. 2013;7:23.

39 Is it Safe to Dose Repeatedly? Possible Cognitive Effects of Chronic Ketamine Abuse These findings imply that heavy use of ketamine is harmful to aspects of both cognitive function and psychological wellbeing. Morgan CJ, et al. Addiction. 2010;105(1): Frequent ketamine use is associated with impairments in working memory, episodic memory and aspects of executive function as well as reduced psychological wellbeing. Recreational ketamine use does not appear to be associated with distinct cognitive impairments although increased levels of delusional and dissociative symptoms were observed. As no performance decrements were observed in the ex-ketamine users, it is possible that the cognitive impairments observed in the frequent ketamine group are reversible upon cessation of ketamine use, although delusional symptoms persist. Morgan CJ, et al. Addiction. 2009;104(1): Is it Safe to Dose Repeatedly? Short-Term Effects of Repeated Ketamine on Neurocognition among TRD Participants Our findings suggest a potential baseline neurocognitive predictor of ketamine response and the apparently lack of short-term neurocognitive impairment after completion of six ketamine infusions in TRD. *P <.05. Mean z-score of neurocognitve tasks at baseline and at follow-up visits post-ketamine treatment among participants with TRD. Attention: Identification Task (IDN). Working Memory: One Back Task (ONB); Two Back Task (TWOB); Groton Maze Learning Test (GML). Visual Memory: Continuous Paired Associate Learning Task (CPAL); One Card Learning Task (OCL); Groton Maze Learning Test Delayed Recall (GMR). Verbal Memory: International Shopping List Task (ISL); International Shopping List Task: Delayed Recall (ISRL). Speed of Processing: Groton Maze Chase Test (GMCT); Detection Task (DET). Set shifting: Set-Shifting Task (SETS). Shiroma PR, et al. Int J Neuropsychopharmacol. 2014;[Epub ahead of print].

40 Is it Safe to Dose Repeatedly? Individual and Group Changes in Memory Performance from Baseline to Day 21 The results suggest that ketamine does not cause memory deficits when given on up to six occasions. Confidence in this conclusion is enhanced by the fact that the two measures of autobiographical memory function and a measure of episodic memory function concur, as does an assessment of subjective memory. Diamond PR, et al. J Psychopharmacol. 2014;28(6): Moderators of the Antidepressant Effect? Diagnostic Genetic Drug Interactions Demographic and Psychosocial factors

41 Other Potential Mechanisms Monoaminergic Effects Yamamoto et al. Neuropsychopharmacology (2013) 38, ; Fukumoto et al. Psychopharmacology (Berl) Jun;231(11): Opioid Effects Anti-Inflammatory Effects Dale et al. Anesthesia & Analgesia, (2012) 115(4): Balancing the Potential Benefits with the Current Knowledge and Potential Risks of Ketamine Treatment Small Sample Sizes Shortage of Long-Term Data Substance Abuse Liability

42 Practical Take-Aways 1. Advances in basic neuroscience research are changing the way we conceptualize mood disorders and are beginning to provide new targets for future treatment development. 2. There are new approaches being taken (NIMH sponsored RAPID, FAST, RDoC programs) to the diagnosis and treatment of mental disorders based on the advances in the behavioral neuroscience. 3. Clinical trials are viable and potentially very valuable treatment options for patients. 4. The off label use of medications in the treatment of TRD is possible, but should be be done with caution and forethought. Yale Depression Research Program (YDRP) Donna Fasula Jane Wanyiri Beth Cooper Lisa Roach Sam Wilkinson Gretchen Hermes Yale New-Haven Psychiatric Hospital; Interventional Psychiatric Services (IPS) Robert Ostroff Sam Wilkinson Dan Moore Michael Vollmar

43 Treatment Resistant Depression: Key Concepts Michael E. Thase, M.D. University of Pennsylvania School of Medicine Philadelphia Veterans Affairs Medical Center University of Pittsburgh Medical Center Treatment Resistant Depression: Overview Only about 50% of patients respond to first-line therapy & only about 33% remit 1,2 Less than half of patients who do not respond to the first antidepressant therapy won t respond to second agent 1 Even after multiple interventions, approximately 25% of patients remain depressed, and the likelihood of response to antidepressants decreases with the number of failed treatment trials 3 Nonresponse represents a failure of both specific and nonspecific elements of therapy 1 AHCPR 2 Fava et al Rush et al. 2006

44 Medical Payments for TRD vs Non-TRD Depressed Patients Employee Population, 1998 Cost Annual Average Payments Per Person $15,000 $12,000 $9,000 $6,000 $3,000 $0 Depression Nonpsychotic Mental Disorders Other Non-Mental Health Diagnosis $4,043 $6,665 $14,990 Average Beneficiary TRD-unlikely TRD-likely Corey-Lisle et al Patient History of Response The words resistance, refractory, and intractable are often used interchangeably and can lead to confusion regarding the patient s past treatment history For a more precise description, patients can be staged according to the number and classes of antidepressants that have failed to produce a response Another factor to consider is whether the treatment failures occurred in separate episodes or during the same episode Thase & Rush 1995

45 Defining TRD: A Work In Progress No universally accepted criteria currently exist to diagnose patients as treatment resistant Most current definitions of TRD include the concept of multiple failures to respond to adequate treatment trials An emerging definition of TRD is failure to respond to adequate trials of 2 different antidepressants Two key elements of an adequate treatment trial are: Adequate dose Adequate duration of treatment Proper identification requires ruling out other comorbid conditions and assessing factors associated with poorer outcomes Longitudinal Goals of Treatment Adapted from: Kupfer DJ. J Clin Psychiatry. 1991;52: AHCPR. Depression in Primary Care Volume 2: Treatment of Major Depression; Publication Streja DA, et al. Am J Manag Care. 1999;5: Russell JM, et al. Am J Manag Care. 1999;5: Melfi CA, et al. Arch Gen Psychiatry. 1998;55: Lin EH, et al. Med Care. 1995;33: Rush AJ, et al. Psychiatr Ann. 1995;25:

46 For Milder Depressions, Nonspecific Factors Outweigh Medication Effects ADM = antidepressant medication; HDRS = Hamilton Rating Scale for Depression. Fournier JC, et al. JAMA. 2010;303(1): True Drug Responders Only Account for About 1/3 rd of Responders Escitalopram: n = 676 PBO: n = 681 Benefitters 40 Non-benefitters 40 Benefitters Non-benefitters Patients (%) 20 Patients (%) MADRS score at Week MADRS score at Week 8 MADRS scores improved by 15.9 points in patients with a true treatment effect NNT for escitalopram is 5 (19.5%) MADRS = Montgomery-Åsberg Depression Rating Scale; NNT = number needed to treat. Thase ME, et al. Br J Psychiatry. 2011;199(6):

47 Many Antidepressant Responders Have Persistent Residual Symptoms STAR*D Study (N=2,876) 67% Remission ~33% Mild symptoms ~28% Moderate symptoms ~23% Severe symptoms ~12% Very severe symptoms ~4% Percent Depressive Symptoms (QID-SR Score) After Up to 12 Weeks Antidepressant Treatment STAR*D = Sequenced Treatment Alternatives to Relieve Depression Trivedi MH et al. (2006), Am J Psychiatry 163(1):28-40 Even Adequate Responders with High Residual Symptom Levels Are at Increased Relapse Risk Cumulative Probability of Relapse domains 1 domain 2 domains 3 domains 4 domains 5 domains Overall 40% relapse rate QIDS IVR Relapse Time (Weeks) Sleep disturbance Sad mood Appetite/weight Concentration Outlook Suicidal ideation Involvement Energy/fatigue Psychomotor Increasing number of symptom domains leads to increased risk of relapse (x 2 [5]= , P=0.0033) Nierenberg AA et al. Psychol Med. 2010;40(1):41 50.

48 Consequences of inadequate response societal costs Association of treatment response with healthcare resource utilisation and employment 1 Mean (SD) treatment response, % Responders Partial responders Non-responders Variable (n=1,852) (n=1,868) (n=2,268) Emergency department use <0.01 Hospitalisation <0.01 Employed <0.01 Activity impairment 32.9 (29.3) 47.7 (29.0) 61.1 (27.9) <0.01 Greater healthcare costs and resource utilisation, including emergency and inpatient services 1,2 General medical healthcare costs for MDD increased with increasing lines of therapies 3,4 Inadequate response is also detrimental to work productivity 2 a Calculated using Χ 2 test and analysis of variance, as appropriate p a 1. Knoth et al. Am J Manag Care 2010;16(8):e188 e196; 2. Mauskopf et al. Depress Anxiety 2009;26(1):83 97; 3. Russell et al. J Clin Psychiatry 2004;65(3): ; 4. Birnbaum et al. Pharmacoeconomics 2009;27(6): Consequences of inadequate response in MDD Reduced quality of life 1 Residual cognitive symptoms 2 Reduced functioning 1 Increased suicidality 3 Reduced well-being 4 Quality of life 1 Functional status 1 Well-being 4 Mean change from baseline in Q-LES-Q score Mean change from baseline in SAS-SR score Mean change from baseline in utility weights Remission Partial response Non-response Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; SAS-SR=Social Adjustment Scale Self-Report 1. Miller et al. J Clin Psychiatry 1998;59(11): ; 2. McClintock et al. J Clin Psychopharmacol 2011;31(2): ; 3. Courtet et al. Eur Neuropsychopharmacol 2014;24(10): ; 4. Sapin et al. Health Qual Life Outcomes 2004;2:20 12

49 Consequences of inadequate response: Family and caregivers Inadequately treated depression can be frustrating for a patient s family and caregivers Caregiver burden can affect the caregiver s workplace performance 1 Children of parents with depression are more likely to have behavioural problems at school 1 Spouses of depressed patients experience high levels of anxiety, depression, and marital maladjustment 2 1. National Alliance on Mental Illness (NAMI), Policymakers Toolkit. Available from: Policymakers_Toolkit&Template=/ContentManagement/ContentDisplay.cfm&ContentID= Accessed June 2015; 2. Spangenberg & Theron. J Psychol 1999;133(3): Antidepressant Nonresponse is Multi-determined Diagnosis Drug selection Dosage/adherence Duration of therapy Disabilities/complexity/comorbidities

50 Major Depressive Episodes More Likely to be Treatment Resistant Severe Persistent With Anxious Features With Psychotic Features Bipolar I, Bipolar II, and? Mixed Features Highly comordid (not DSM5 term) Factors Associated with Treatment Resistance in MDD P=0.009 P=0.018 P=0.003 P=0.019 P=0.001 P=0.049 P=0.009 P=0.008 P<0.001 P<0.001 P<0.001 Odds Ratio Souery D et al. J Clin Psychiatry. 2007:68(7);

51 Greater Depressive Illness Burden Requires More Treatment Steps Feature Step 1 (n=3671) Step 2 (n=1439) Step 3 (n=390) Step 4 (n=123) Illness duration (yrs) Current MDE 2 yrs 24.8% 27.0% 27.4% 30.3% #MDEs Prior suicide attempt 16.9% 17.8% 19.0% 20.3% >4 Axis I conditions 11.2% 13.1% 17.7% 17.0% GMC burden Rush AJ, et al. Am J Psychiatry. 2006;163: Number of Comorbid Axis I Disorders Associated with Remission (HAMD 17 ) Odds 1.5 Ratio >4 Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006

52 Number of Concurrent GMCs Associated with Lower QIDS-SR 16 Remission Rates (N = 2876) 1.5 (p =< ) Relative to GMC = 0 Odds Ratio Trivedi et al., Am J Psychiatry, 163(1):28-40, >4 Drug metabolism can influence efficacy Venlafaxine-treated MDD patients were classified as extensive metabolizers (EMs) or partial metabolizers (PMs) 1* Response and remission rates in MDD patients were greater in EMs vs PMs: 1 HRSD17 response c MADRS response c HRSD17 remission d MADRS remission e In PMs, desvenlafaxine could be a better option than venlafaxine More broadly, it is important to recognize that apparently similar individuals can respond very differently to any given treatment *Based on plasma ratios of venlafaxine to its primary metabolite, desvenlafaxine. a p<0.02 (EM vs PM); b p<0.001 (EM vs placebo); c response defined as 50% decreased from baseline score; d HDRS17 remission defined as total score 7; e MADRS remission defined as total score 12. HDRS, 17-item Hamilton Rating Scale for Depression; MADRS, Montgomery-Asberg Depression Rating Scale. 1. Lobello et al. J Clin Psychiatry 2010;71:

53 Personalised treatment polygenic risk score Prediction of percentage improvement and remission in STAR*D from PRSs constructed from a meta-analysis of GENDEP and MARS Remission Change on depression scale % ** * * * * * * * * p-value threshold for SNP inclusion in PRS *p<0.05, **p<0.01 for PRS as predictor of STAR*D variance Remission (defined in individual studies): logistic (pseudo R 2 ) regression; percentage change: linear (R 2 ) regression; PRS=polygenic risk score 2,256 patients, 1.2 million SNPs, but a very low PRS GENDEP, MARS, and STAR*D Investigators. Am J Psychiatry 2013;170(2): What Constitutes an Adequate Trial of an Antidepressant? Longer (duration) is generally better (>4 weeks at a full therapeutic dose) Whenever possible, the dose should be increased above the minimum Intolerance does not equal nonresponse Residual symptoms (nonremission) do not equal nonresponse

54 Two-thirds of STAR*D Responders did so by Week % N = 2876 Response = 50% QIDS-SR Percent >13 Weeks Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006 A Simple System for Staging Antidepressant Resistance Stage I: failure of an adequate trial of one class of major antidepressant Stage II: failure of adequate trials of two distinctly different classes of antidepressants Stage III: stage II plus failure of a third class of antidepressant, including a TCA Stage IV: stage III plus failure of an adequate trial of MAOI Stage V: stage IV plus failure of an adequate course of ECT Adapted from Thase ME, Rush AJ. J Clin Psychiatry. 1997;58(Suppl 13):23-29.

55 Decrement in Remission Rates After Two Trials in STAR*D Supports a Minimum Definition of TRD Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial Adult outpatients with nonpsychotic major depressive disorder received one to four successive acute treatment steps Remission defined as a score of 5 on the Quick Inventory of Depressive Symptomatology Self Report (QIDS SR 16 ) Patients not achieving remission, or being unable to tolerate a treatment step were encouraged to move to the next step Step Number QIDS SR 16 remission rate (%) Step1: Citalopram (N= 3671) Step 2: Four switch treatments: (citalopram stopped; new treatment initiated with sustained release bupropion, cognitive therapy, sertraline, or extended release venlafaxine); three augmentation treatments: (citalopram plus bupropion, buspirone, or cognitive therapy) (N= 1439) Rush et al.,am J Psychiatry 2006; 163: Step 3: Two switch treatments: (mirtazapine or nortriptyline); two augmentation strategies: (lithium or T3). (Sustained release bupropion, or extended release venlafaxine; only for patients who received cognitive therapy alone or combined with citalopram in Step 2) (N=390) Step 4: Tranylcypromine or extended release venlafaxine plus mirtazapine; (two switch treatments (mirtazapine or nortriptyline) or two augmentation strategies (lithium or T3); only for patients who received cognitive therapy alone or combined with citalopram in Step 2) (N=123) Relapse Rates Similarly Showed a Linear Decrement in Benefit Across Levels Cumulative Probability Step 2 Steps 3 Steps 4 Steps (N = 1085) (N = 383) (N = 35) (N = 15) p < Months in Follow-Up Relapse = QIDS-IVR 16 >11

56 Other TRD Classification Systems MGH Treatment History Form: grades adequacy of trial and includes adjunctive therapy strategies EMEA (official description accepted by European regulatory authority): two adequate trials with medications from distinctly different classes Maudsley Staging System: rates treatment, severity, and chronicity dimensions Establishing the Characteristics of Historical Treatment Failures with Antidepressant(s) Several instruments available Antidepressant Treatment History Form (ATHF) Harvard Antidepressant Treatment History (HATH) Massachusetts General Hospital Antidepressant Treatment Questionnaire (ATRQ) Key information items Duration Dose Efficacy Non-pharmacological treatment

57 Antidepressant Treatment History Form (ATHF) 0 No treatment or no drugs with known psychotropic actions 1 Any drug <4 weeks or less than minimum adequate daily dose For ECT 1 3 ECT sessions For psychotic MDD plus chlorpromazine equivalent <400 or <3 weeks 2 Any drug 4 weeks at less than minimum adequate daily dose For ECT 4 6 ECT sessions For psychotic MDD always when chlorpromazine equivalent <400 or <3 weeks or when monotherapy with antipsychotic (chlorpromazine equivalent 400 and 3 weeks) 3 Any drug 4 weeks at minimum adequate daily dose For ECT 7 9 unilateral ECT sessions For psychotic MDD plus chlorpromazine equivalent 400 and 3 weeks 4 Any drug 4 weeks at higher than minimum adequate daily dose, or any drug at level 3 augmented with lithium 2 weeks For ECT unilateral/7 9 bilateral ECT sessions For psychotic MDD plus chlorpromazine equivalent 400 and 3 weeks 5 Any drug at level 4 augmented with lithium 2 weeks For ECT 13 unilateral/ 10 bilateral ECT sessions For psychotic MDD plus chlorpromazine equivalent 400 and 3 weeks Sackeim et al., The impact of medication resistance and continuation pharmacotherapy on relapse following response to electroconvulsive therapy in major depression. J. Clin. Psychopharmacol. 1990, 10 (2), Oquendo et al., Inadequacy of antidepressant treatment for patients with major depression who are at risk for suicidal behavior. Am. J. Psychiatry 1999, 156 (2), Current FDA Perspective Inadequate response is lack of remission and can be determined prospectively or retrospectively Treatment Resistant Depression requires nonresponse to at least two trials, with one being prospective Add-on therapies are called adjuncts

58 Current European Regulatory Perspective Different Treatment Modalities Based on Degree of Improvement on Initial Treatment(s) Initial treatment(s) for MDD Response Inadequate response TRD Continue treatment Add-on Switch to monotherapy Is the dichotomy between inadequate response and Treatment Resistant Depression clinically meaningful, and is it supported by data? Is it Necessary to Prospectively Demonstrate Failure to Antidepressant Treatment? Efficacy of adjunct drug vs. placebo in combination/augmentation trials for antidepressant partial responders and non responders with MDD Response Remission Iovieno & Papakostas, J Clin Psychiatry 73:5, May 2012 Patients suitable for TRD studies can be identified by capturing historical data using validated prior response measures, and current symptom severity measures, without the requirement for a prospective run in period.

59 Other Potential Advantages of Prospective Lead-in Reduces attrition rates Permits greater opportunity to detect fraudulent or nonadherent patients Allows for establishing a more stable/reliable baseline Permits strategies to shield randomization STAR*D Level 2 Results Do Not Support Regulatory Perspective Remission Rate (%) Venlafaxine XR Bupropion SR Sertraline Remission Rate (%) CIT+Bupropion SR CIT+Buspirone Monotherapy 0 Combination Rush AJ et al. N Engl J Med. 2006;354(12):1231 Trivedi MH et al. N Engl J Med. 2006;354(12):1243

60 Re-analysis of Adjunctive Aripiprazole Studies Likewise Fails to Support Regulatory Perspective Pooled data from three randomized, double-blind, placebo-controlled studies assessing the efficacy of adjunctive aripiprazole to antidepressant treatment (ADT) in patients with major depressive disorder. In a post-hoc analysis ADT minimal responders were defined as those with a less than 25% reduction in MADRS total score during an 8-week prospective phase; ADT partial responders exhibited a 25 49% reduction in MADRS total score. Nelson et al., International Clinical Psychopharmacology 2012, 27: Psychosocial Matrix of Nonresponse Ongoing stress/distress marital discord lack of social support limited resources Maladaptive interpersonal style antecedent (personality disorder) consequence Demoralization Nonadherence

61 Psychotherapeutic Issues in Refractory Depression Reestablishing morale Increased activity Coping behaviors Noncompliance Focused, specific goals Mobilization of resources Rehabilitation issues Avoid blaming the victim Conclusions Depression is one of the world s greatest public health problems and nonresponse to standard medications represents the greatest unmet need in therapeutics Definitions of treatment resistant depression are arbitrary and there is room for innovation Until better ways of matching treatments and patients are identified, careful assessment & iterative, sequential trials are best approach

62 Strategies for Treatment Resistant Depression: Comparative Efficacy Michael E. Thase, M.D. University of Pennsylvania School of Medicine Philadelphia Veterans Affairs Medical Center University of Pittsburgh Medical Center Disclosure Within the past 3 years, Dr. Thase has been a consultant to Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Forest Laboratories (PGx), Janssen Pharmaceutica, Lundbeck, Merck (Organon & Schering- Plough), Mylan (Dey), Neuronetics, Novartis, Otsuka, Pfizer, Rexahn, Shire US, Sunovion, Takeda, Teva, and Transcept. He has received honoraria for talks from AstraZeneca, Bristol- Myers Squibb, Eli Lilly and Company, Lundbeck, Merck, Mylan, Otsuka, and Pfizer. He has received research funding from AstraZeneca, Eli Lilly and Company, Forest, GlaxoSmithKline, NeoSync, Otsuka, and Pfizer, as well as the National Institute of Mental Health and the Agency for Healthcare Research and Quality. His wife is an employee of Peloton Advantage, which does business with Pfizer.

63 A Simple System for Staging Antidepressant Resistance Stage I: failure of an adequate trial of one class of major antidepressant Stage II: failure of adequate trials of two distinctly different classes of antidepressants Stage III: stage II plus failure of a third class of antidepressant, including a TCA Stage IV: stage III plus failure of an adequate trial of MAOI Stage V: stage IV plus failure of an adequate course of ECT Adapted from Thase ME, Rush AJ. J Clin Psychiatry. 1997;58(Suppl 13): Should we switch or use adjunctive strategies? Parsimony favors switching Adjunctive therapies often easier to implement (i.e., avoids washout and cross-titration) STAR*D disappointingly did not answer this question aside from demonstrating that adjunctive strategies preferred for partial responders and switching preferred for nonresponders

64 STAR-D Remission Rates Across All 4 Levels Level weeks Level 2 2, weeks Level 3 4,5 Remission Definition: HAMD weeks Level 4 6 % Remission 14 weeks Low Treatment Resistance High Mono, single medication regimen; Augm, combination medication treatment. 1 Trivedi MH et al. Am J Psychiatry. 2006;163(1):28 40; 2 Trivedi MH et al. N Engl J Med. 2006;354(12): ; 3 Rush AJ et al. N Engl J Med. 2006;354(12): ; 4 Nierenberg AA et al. Am J Psychiatry. 2006;163(9): ; 5 Fava M et al. Am J Psychiatry. 2006;163(7): ; 6 McGrath PJ et al. Am J Psychiatry. 2006;163(9): The Case for Switching Antidepressants Clinically necessary when first drug is poorly tolerated Second drug selection is iterative, guided by outcome with first Can pick medications with distinctly different MoAs Efficacy of second antidepressant clearly established

65 Should We Switch Within- or Across Classes? Across-class switch was the standard until the mid-1990s Subsequent study results muddied the water A second within-class trial with an SSRI or SNRI is now an accepted option No consensus on a third within-class trial Remission rates in patients with treatmentresistant depression after switching drugs (%) 80 p value vs venlafaxine group (Fisher s exact test) Remission rate p< p = p = p = p = p = Venlafaxine group Conventional antidepressants group Fluoxetine group Paroxetine group Citalopram group Sertraline group Mirtazapine group Remission: HAM-D total score 7 Subjects: 3,097 outpatients at least 18 years old with a diagnosis of major depressive disorder based on DSM-IV classification who had a HAM-D 17 total score 17 and who showed inadequate response or intolerance to treatment with a conventional antidepressant (e.g., fluoxetine, paroxetine, sertraline, or citalopram) for at least 4 weeks. Method: An open-label study. Patients were randomly assigned to orally receive venlafaxine or a conventional antidepressant for 24 weeks. Patients in the venlafaxine group received venlafaxine sustained-release capsules at doses of 75 to 225mg/day, and those in conventional antidepressant group received fluoxetine, paroxetine, or citalopram at doses of 20 to 60mg, sertraline at doses of 50 to 200mg/day, or mirtazapine at doses of 15 to 45mg/day. Safety: 483 adverse events occurred in 274 (15.0%) patients in the venlafaxine group. The number of AEs in the conventional antidepressant group was 472 in 266 paents (15.9%). 8 Baldomero, E. B. et al.:depress Anxiety 22 (2):68, 2005

66 STAR*D Level 2 Results Remission Rate (%) Venlafaxine XR Bupropion SR Sertraline Remission Rate (%) CIT+Bupropion SR CIT+Buspirone Monotherapy 0 Combination Rush AJ et al. N Engl J Med. 2006;354(12):1231 Trivedi MH et al. N Engl J Med. 2006;354(12):1243 Remission and response rates for venlafaxine vs SSRI following nonresponse to SSRI response Remission rate Baldomero et al. Poirier and Boyer Rush et al. Total Response rate Baldomero et al. Poirier and Boyer Rush et al. Total Risk difference (fixed) 95% CI Favors SSRI Favors venlafaxine Risk difference (fixed) 95% CI Favors SSRI Favors venlafaxine Subjects and methods: Literature searches were performed to obtain randomized comparative studies that investigate antidepressant switching strategies in patients with major depressive disorder and insufficient response to SSRIs. Subsequently, in a meta-analysis, remission and response rates were compared using obtained data. The dosage of venlafaxine was 75 to 375mg/day in 3 studies included in the analysis. Ruhé, H.G. et al.:j Clin Psychiatry 67 (12): 1836, 2006

67 CYP2D6 Status and Response to Venlafaxine: Pooled Analysis of RCTs Lobello K, et al. J Clin Psychiatry. 2010;71(11): The Case for Adjunctive Therapy Builds on partial success of first therapy Avoiding washout is a pragmatic benefit for patients When effective, benefits may be rapid Can choose rx to target specific sx

68 Adjunctive Strategies: 2015 Lithium & other mood stabilizers Thyroid hormones Modafinil and psychostimulants Buspirone and BZs Methylfolate (Deplin) 2nd generation antipsychotics (SGAs) Adjunctive Therapy with Lithium Salts More than 60 published studies, but rarely used in the US in 2015 Definitely effective(meta-analytic p<10-6 ) Usual blood level:.4-.8 meq/l Rapid response is rare, so allow 6 weeks for response May be both an adjunct and a primary antidepressant Thase ME, Rush AJ. In: Psychopharmacology: The Fourth Generation of Progress, FE Bloom, DJ Kupfer (Eds.), New York, NY, Raven Press, 1995, pp Crossley and Bauer, J Clin Psychiatry, 2009

69 Placebo Controlled Lithium Augmentation Studies Review: Lithium augmentation Comparison: 01 Lithium augmentation studies Outcome: 01 Response rates Study or sub-category Review: Lithium augmentation Comparison: 01 Treatment Lithium augmentation studies Control OR (fixed) Weight Outcome: 01 Response n/n rates n/n 95% CI % OR (fixed) 95% CI Bauman /10 Control 2/14 n/n (fixed) % CI 9.00 [1.27, 63.89] Study Treatment OR (fixed) Weight OR or sub-category n/n 95% CI % Browne /7 2/ [0.35, 25.87] Heninger /8 0/7 2/14 [1.27, ] [1.00, ] Bauman / Browne / Joffe /17 2/10 3/16 0/7 [0.35, 25.87] [1.00, ] 4.88 [1.01, 23.57] Heninger / Kantor /4 0/3/16 [1.01, ] 3.00 [0.09, ] Joffe / Katona /29 8/32 0/3 [0.09, ] 3.21 [1.09, 9.48] Kantor / Katona / Nierenberg /18 8/32 3/17 3/17 [1.09, 9.48] [0.08, ] 0.58 [0.08, 4.01] Nierenberg / Schoepf /14 0/13 [1.35, ] [1.35, ] Schoepf / Stein /16 4/18 [0.08, ] 0.50 [0.08, 3.19] Stein / Zusky / Zusky /8 2/8 2/8 [0.21, 15.41] [0.21, 15.41] Total (95% CI) 131 Total (95% CI) Total events: 53 (Treatment), (Control) Test for heterogeneity: Chi² = 11.90, df = 9 Total events: 53 (Treatment), Test for 24 overall (Control) effect: Z = 4.06 (P < ) [1.80, 5.37] [1.80, 5.37] (P = 0.22), I² = 24.4% Test for heterogeneity: Chi² = 11.90, df = 9 (P = 0.22), I² = 24.4% Test for overall effect: Z = 4.06 (P < ) Favors control Favors treatment Favors control Favors treatment Meta-analysis of 10 augmentation studies. Overall pooled rates of response: lithium 53/131 or 40.5% vs 24/138 or 17.4%. Crossley and Bauer, J Clin Psychiatry, 2009 Augmentation with Other Mood Stabilizers Lamotrigine now most widely used; efficacy unproven for all but lithium Quelching effect for divalproex and carbamazepine for patients with PTSD? Coverage of subtle bipolar or mixed syndromes Relief of secondary symptoms such as pain

70 Adjunctive Thyroid Hormone 11 published studies T 3 preferred over T µg/day of T 3 Safe and easy, but inconsistent efficacy for patients with normal thyroid functions Significantly easier to implement than lithium in STAR*D Treatment of choice for patients with elevated TSH levels? Meta-Analysis of RCTs of Adjunctive Thyroid Therapy All 8 Trials, N=298 OR=2.09 (95% CI ), P= Controlled Trials, N=75 OR= 1.53 (95% CI ), P=.29 Response Rate (% ) T3 Placebo Response Rate (%) T3 Placebo 0 0 Aronson et al. Arch Gen Psychiatry 1996;53:

71 Adjunctive Therapy With Lithium or Thyroid Hormone: Results of STAR*D Level 3 Comparison Nierenberg AA, et al. Am J Psychiatry. 2006;163(9): Potential Pharmacogenetic Relationship with Response to Adjunctive T3? There are functional polymorphisms in the genes that code for the enzymes that convert T4 to T3 (deiodinases) In a relatively large study of thyroid (T3) acceleration of sertraline response, patients with the DIO1-C785T polymorphism (i.e., lower conversion activity) were more responsive to T3 (Cooper-Kazaz et al., 2009)

72 Is the benefit of Adjunctive T3 Limited to Women? Effect Size as a Function of Sample Gender Ratio (6 Studies, n=125) Standardized Effect Size % Percent Female in Sample r=.76, p=.041 Altshuler et al (2001) Am J Psychiatry Adjunctive Therapy with Modafinil, Armodafinil, and Other Stimulants Modafinil and armodafinil (indirectly) dopaminergic agonists with limited abuse potential Though proven to relieve sleepiness and fatigue, effects on other depressive symptoms less certain in MDD Inconsistent evidence in RCTs of TRD and bipolar depression

73 Effect of Adjunctive Lisdexamphetamine on Executive Function in MDD Self-Report Informant Report BRIEF-A Self- Report GEC T Score LS Mean (95% CI) Change from Baseline Informant Report GEC T Score LS Mean (95% CI) Change from Baseline LDX augmentation is not FDA approved for MDD. *P <.05. P <.01. P <.001 BRIEF-A = Behavior Rating Inventory of Executive Function-Adult Version; GEC = Global Executive Composite; LS = least square; EOS = end of study; LDX = lisdexamfetamine. Madhoo M, et al. Neuropsychopharmacology Other Dopaminergic Options Pramipexole - dopamine agonist approved for PD - some evidence of efficacy in small studies Classic psychostimulants - subjective benefits for drive, energy, and concentration - four contemporary placebo-controlled trials with SSRI nonresponders have yielded mixed results

74 Buspirone Augmentation Popularity has waned despite good overall showing in STAR*D Reasonably safe (10 mg - 40 mg/day), but unproven efficacy Secondary effects anxiety relief? (failed in STAR*D) reversal of sexual side effects Other Reasonable Options for Anxious Depression? Adjunctive benzodiazepines effective but concerns about dependence and tolerance Adjunctive second generation antipsychotics effective, but concerns about longer term safety MAOIs?

75 Rationale for Adjunctive L- Methylfolate L-methylfolate, not folate, is the necessary cofactor for synthesis of monoamines About 2/3rds of the population have a polymorphism of the C677T MTHFR gene that slows synthesis of L-methylfolate As a medical food, Deplin 15 mg/day is safe, generally well-tolerated and much less expensive than branded SGAs Efficacy data starting to emerge From: l-methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parallel-Sequential Trials American Journal of Psychiatry FIGURE 1. Pooled Response Rates in Two Trials of -Methylfolate (MTHF) Compared With Placebo as an Adjunct to SSRIs in Patients With SSRI-Resistant Depressionª a Response was defined as a reduction of 50% in Hamilton Depression Rating Scale score during treatment or a final score of 7. Significant difference between groups in trial 2 (p=0.04). The pooled analysis was conducted as described in Fava et al.. Date of download: 08/27/2015 Copyright American Psychiatric Association. All rights reserved.

76 Combining Antidepressants: Advanced Practice or Fad? Once considered indicative of bad practice, combining antidepressants is now commonly done for TRD Bupropion & mirtazapine now preferred No antidepressant has FDA approval for this use and only one (mirtazapine) has the support of two positive studies Most newer combos safe; caveats Concurrent Combined Antidepressants: Contrasting Results of Two RCTs Percentage of patients Blier et al Rush et al FLU (n=28) FLU + MIRT (n=26) ESC + PBO (n=224) BUP + ESC (n=221) VEN + MIRT (n=25) BUP + MIRT (n=25) 80 VEN + MIRT (n=220) * 54 * Percentage of patients Responders Remitters 0 Responders Remitters Responders Remitters *p<0.05; FLU=fluoxetine; MIRT=mirtazapine; VEN=venlafaxine; BUP=bupropion; ESC=escitalopram 12 Week acute phase 1. Blier, et al. Am J Psychiatry. 2010;167(3): ; 2. Rush, et al. Am J Psychiatry. 2011;168(7): Months continuation phase

77 Antipsychotic Augmentation SGAs now widely used Efficacy likely across the class Not delimited to psychotic depression or bipolar depression Important differences in side effects among drugs Atypical antipsychotics as adjunctive therapy for MDD Adjunctive efficacy has been demonstrated for four SGAs: risperidone (not FDA approved) olanzapine (in combination with fluoxetine) aripiprazole quetiapine XR brexpiprazole

78 Meta-Analysis of Response Rates in Double-Blind, Placebo-Controlled, Atypical Augmentation Trials Odds Ratios of Response Rates With Atypicals and Placebo Trials Nested by Drug Olanzapine trials Shelton 2001 Shelton II 2005 Corya 2006 Thase 2007 Thase II 2007 Risperidone trials Mahmoud 2007 Keitner 2009 Reeves 2008 Quetiapine trials Khullar 2006 Mattingly 2006 McIntyre 2006 Earley 2007 El-Khalili 2008 Aripiprazole studies Berman 2007 Marcus 2008 Berman 2008 Test for overall effect: OR (Fixed) 95% CI Subtotal Subtotal Subtotal Subtotal 1.39 (1.05, 1.84); Z=2.30, P= (1.18, 2.82); Z=2.71, P= (1.24, 2.09); Z=3.56, P= (1.58, 2.72); Z=5.28, P= (1.46, 1.95); Z=7.00, P< Favors Control Favors Treatment Nelson JC, Papakostas GI; AJP, 2009 Updated Systematic Review and Meta- Analysis of Adjunctive SGAs Pooled Response, Remission, and Adverse-Event Rates 100 % Patients Atypical Placebo Response Remission Adverse Event Discontinuations Nelson JC, Papakostas GI; AJP, 2009

79 Olanzapine Augmentation to Fluoxetine in Treatment-Resistant Depression MADRS Mean From Baseline Efficacy (Improvement in MADRS) * Mean in Weight (kg) Adverse Events (Weight Increase) FLX *P<.001 vs FLX and OLZ. Thase ME et al. J Clin Psychiatry. 2007;68: OLZ OFC Studies of Newer SGAs Brexpiprazole recently approved Lurasidone efficacy shown in bipolar depression and MDD with mixed features Studies of cariprazine ongoing

80 Adjunctive Brexpiprazole: Efficacy on Depressive Symptoms (MADRS) Studies 227 and 228: Primary endpoint mean change in MADRS total score LS mean (SE) change MADRS total score ** * ** * ** * *** ** *** *** *** *** *** ** *** *** LS mean difference from placebo at Week 6 Brex 1 mg: -2.02, p= Brex 2 mg: -2.35, p= Brex 3 mg: -2.54, p= *p<0.05, **p<0.01, ***p<0.001 versus placebo; MMRM analysis; efficacy per final protocol population; pooled placebo group MADRS baseline: ADT + placebo 26.9, ADT + Brex 1 mg 26.9, ADT + Brex 2 mg 26.9, ADT + Brex 3 mg 26.5 Source: Thase et al. JCP 2015a&b 37 Adjunctive SGA Therapy: Key Issues & Questions Is efficacy sustained? Cost effectiveness vs other options? Ultimate risks of TD and metabolic complications Syndromal indications & possible differences for symptomatic efficacy and metabolic side effects

81 Treatment Strategy of Choice for Stage III TRD: Monoamine Oxidase Inhibitors 30%-60% response rates in TCA era More effective in: atypical depression (Columbia) anergic depression (Pittsburgh) bipolar depression Poor showing for tranylcypromine in STAR*D? role of seligiline patch Treatment Strategy of Choice for Stage IV TRD: Electroconvulsive Therapy Most effective treatment available Two options: bilateral or ultrahigh energy RUL Treatment of choice for delusional and melancholic cases of TRD Less effective in TRD than in uncomplicated depression (i.e., 50%-60% vs 90%) Majority of TRD cases will relapse within 1 year of successful ECT

82 High Risk of Relapse Following Successful ECT of TRD Probability of Remaining Well (%) Inadequate Pre-ECT Pharmacotherapy Adequate Pre-ECT Pharmacotherapy Weeks at Risk Sackeim HA, et al. J Clin Psychopharmacol. 1990;10: Prevention of Relapse Following ECT: Efficacy of Lithium + Nortriptyline Sackeim HA, et al. JAMA. 2001;285(10):

83 Other Neuromodulation Strategies Transcranial Magnetic Stimulation (rtms) Vagus Nerve Stimulation Deep Brain Stimulation Repetitive Transcranial Magnetic Stimulation (rtms): Summary Better tolerated and safer than ECT Definite therapeutic effects (nonpsychotic MDD and less advanced cases of TRD); efficacy confirmed by recent NIMH-funded multi-center trial Dose/response/duration characteristics still not well developed Labor-intensive and until coverage issues addressed - expensive Perhaps delimited to patients who are too mild for or who refuse or can t tolerate ECT

84 Recent Clinical Studies Replicate Antidepressant Effects of TMS Improved study designs Larger samples More treatment sessions Optimized stimulation parameters Recent meta-analysis from Five sham-controlled studies N=274 patients Effect size = 0.76 Pivotal trial effect size = 0.83 for ATHF 1 group Gross et al (Acta Psych Scand, 2007) Uncommon Treatment Strategies Chronotherapies (sleep deprivation, phototherapy) Other nutriceuticals (e.g., SAM-e) Opiates Experimental pharmacotherapies (e.g., ketamine infusion)

85 Efficacy of a Combination Opiate Medication (ALKS 5461) in Major Depressive Disorder BUP= buprenorphine SAM= samidorphan (μ-opioid receptor antagonist) Ehrich, et al. Neuropsychopharmacology. AOP 14 January Efficacy of BUP/SAM therapy in MDD. Displayed are mean decreases from baselne in HAM-D17 (left) and MADRS (right) total scores after 7 days of therapy. P-values are from Exact Wilcoxon tests and are based on observed data. Psychotherapeutic Issues in Refractory Depression Reestablishing morale Increased activity Coping behaviors Noncompliance Focused, specific goals Mobilization of resources Rehabilitation issues Avoid blaming the victim

86 Conclusions Focus first on assessment and staging Logical choices are available for careful, sequential trials When in doubt, try again New developments every year Ample room for improvement Requires an ongoing systematic nationwide approach

87 Kappa Opioid Antagonism as a Potential Therapy for Anhedonia: The FAST MAS Trial Andrew D. Krystal, MD, MS Professor of Psychiatry and Behavioral Sciences Duke University School of Medicine Financial Relationships Consultant/Advisory Board: Astra Zeneca, Attentiv, Bioexcel, Eisai, Jazz, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Pernix, Sunovion Grant Funding: Brainsway, Neosync, NIH, Novartis, Janssen, Sunovion, Teva

88 Overview Preclinical Data Indicating Promise of KOR Antagonism for Improving Anhedonia FAST MAS FAST MAS Phase 2a LY Double Blind, Placebo Controlled, Randomized Clinical Trial Preclinical Data on Promise of κ Opioid Receptor (KOR) Antagonism There is an extensive set of pre clinical studies suggesting that KOR antagonists are likely to have therapeutic effects in those with mood and anxiety spectrum disorders. Includes studies indicating role of kappa opiate system in mediating both anxiety and depression symptoms Includes studies suggesting that KOR antagonists have effects on animal models of both major depression and anxiety.

89 Preclinical Data on Promise of KOR Antagonism: Stress Evidence that kappa opiate system is critical for mediating the adverse effects of stress. Stress leads to anxiety by CRF1 receptor activation of dynorphins in basolateral amygdala which bind to KOR. Place aversion and social avoidance occurring with repeated stress is mediated via dynorphin activation in ventral striatum, an effect which can be mimicked by KOR agonists and blocked by KOR antagonists. KOR antagonists also block stress related impairment in elevated plus maze spontaneous exploration. Bruchas et al., PLoS One Dec 31;4(12):e8528; Land et al., J Neurosci Jan 9;28(2): Peters et al., Eur J Pharmacol Jul 1;661(1 3):27 34; Schindler et al.,. J Neurosci Dec 5;32(49): Preclinical Data on Promise of KOR Antagonism: Anxiolytic Like Effects Prodynorphin knockouts (prodynorphin is the precursor protein for dynorphins) and KOR antagonists have been found to have anxiolyticlike effects in the novelty induced hypophagia test, the defensive burying tests, the elevated plus maze test, fear potentiated startle test, open field test, and light dark test. Wittmann et al., Neuropsychopharmacology Feb;34(3):775 85; Knoll et al.,. Biol Psychiatry Sep 1;70(5): Carr and Lucki. Psychopharmacology (Berl) Jun;210(2):

90 Preclinical Data on Promise of KOR Antagonism: Antidepressant Like Effects Dynorphin mediates dysphoric aspects of stress via KOR binding; this is prevented by knocking out dynorphin or administering a KOR antagonist Depression like behaviors caused by stress are mediated by kappa opiate receptors and mimicked by KOR agonists. KOR antagonist treated mice and KOR knockout mice show a reduction of stress induced depression like behavior. Stress triggers KOR activation of dorsal raphe neurons which project to nucleus accumbens and decrease dopamine release thereby diminishing reward and increasing drug seeking KOR antagonists or knocking out the prodynorphin gene leads to antidepressant like effects (reduced immobility in the forced swim test and reduced learned helplessness) KOR agonists have depressogenic effects in conjunction with decreasing nucleus accumbens dopamine release Shirayama et al., J Neurochem Sep;90(5): Reindl et al., Pharmacology. 2008;81(3): Todtenkopf et al., Psychopharmacology (Berl) Apr;172(4): Carlezon et al., J Pharmacol Exp Ther Jan;316(1): McLaughlin et al., J Neurosci Jul 2;23(13): Mague et al., J Pharmacol Exp Ther Apr;305(1): Chartoff et al., Mol Pharmacol Mar;75(3): Chartoff et al., Neuropharmacology Jan;62(1): Land et al., J Neurosci Jan 9;28(2):407 14; McLaughlin et al., Neuropsychopharmacology Jun;31(6):1241 8; Knoll and Carlezon. Brain Res Feb 16;1314:56 73; Lemos et al., J Neurosci Sep 5;32(36): Preclinical Data on Promise of KOR Antagonism: Anhedonia KOR stimulation inhibits dopamine release in striatum and caudate) and induces a negative mood state. KOR agonists decrease phasic dopamine release in the nucleus accumbens and increase intracranial selfstimulation (a model of anhedonia), whereas KOR antagonists have the opposite effect. KOR agonists block cocaine s anti anhedonic effect on intracranial self stimulation and block the reinforcing rewarding effects on drugs of abuse, whereas, giving a KOR antagonist prior to cocaine withdrawal prevented anhedonic like intracranial self stimulation responses Bruijnzeel. Brain Res Rev Dec 11;62(1): Carlezon et al., J Pharmacol Exp Ther Jan;316(1): Chartoff et al., Neuropharmacology Jan;62(1): Ebner et al., Psychopharmacology (Berl) Jun;210(2): Maisonneuve et al., Neurosci Lett Nov 7;181(1 2): Muschamp et al., J Neurosci Feb 23;31(8): Tomasiewicz et al.,. Biol Psychiatry Dec 1;64(11): Wee and Koob. Psychopharmacology (Berl) Jun;210(2):

91 Human Data on Promise of KOR Antagonism: Depression Open label study; N=6 failed antidepressant meds and ECT were found to improve with buprenorphine (a KOR antagonist and partial mu agonist) Double blind, placebo controlled, N=32 with treatmentresistant depression treated with buprenorphine plus mu receptor antagonist, samidorphan (simulated kappa opiate receptor antagonist). Following 7 days of treatment a 1:1 ratio of BUP and SAM exhibited statistically significant improvement vs placebo in HAM D17 total score (p=0.032) and nearly significant improvement in Montgomery Åsberg Depression Rating Scale (MADRS) total score (p=0.054). Overall, BUP/SAM therapy was well tolerated. Nyhuis et al., J Clin Psychopharmacol Oct;28(5): Ehrich et al., Neuropsychopharmacology Dec 18. [Epub ahead of print] Summary of Data on Promise of KOR Antagonism Together, the available data provide a compelling indication that KOR antagonists are likely to have therapeutic effects in patients with mood and anxiety spectrum disorders. These data point to the adverse effects of stress and particularly anhedonia as therapeutic targets of interest with these agents. We are pursuing studies of a KOR antagonist in NIMH FAST MAS

92 NIMH Fast Fail Trial Networks for Evaluating New Experimental Medicines Established networks for carrying out early phase trials of molecules engaging promising new targets embodying principles just discussed Unique NIMH/private/academic partnership Meant to: Provide a path for promising compounds currently not being developed Establish a new standard for early phase drug development that will improve the cost/benefit of CNS drug development and rekindle pharma interest Improve our understanding of mechanisms of psychopathology, treatments for psychiatric disorders, and optimal trial methodologies Awarded Grants in 3 Areas: Mood and Anxiety Spectrum Disorders (FAST MAS) Grant Awarded to DCRI (PI: A Krystal) Psychotic Spectrum Disorders (FAST PS) Grant Awarded to Columbia (PI: J Lieberman) Autism Spectrum Disorders (FAST AS) Grant Awarded to UCLA (PI: J McCracken) FAST MAS Team FAST MAS Trial Management and Administration: Duke Clinical Research Institute (DCRI) FAST MAS Administrative Team: PI A Krystal; Signal Detection R Keefe; MRI Allen Song; QEEG A Krystal; PET E Morris (Yale) A Shekhar (U. Indiana); Statistics S C Chow FAST MAS Research Sites Duke University: PI H Lisanby Yale University: PI G Sanacora; E Morris Mt. Sinai University: PI W Goodman CoI D Iosifescu Case Western University: PI J Calabrese Baylor University: PI S Matthew Indiana University: PI A Goddard; J Nurnburger; A Shekhar

93 Goal of FAST MAS: Address Problems with Early Phase Trials Key problems in psychiatric treatment development: I. Do not test specific a priori hypothesis; test general hypothesis that the drug is effective Go to Phase III without establishing POC: Fail to test the specific hypothesis that engaging the target of interest has the intended effect on neurocircuitry or neurophysiologic process of interest All I care about is if it works and if it works I don t care how» Makes outcomes vulnerable to non specific effects and bias» Greatly diminishes likelihood of replication II. Often employ dose not established to engage the target of interest May not be achieving the intended effect on target Leaves problematic uncertainty after the study about whether dose was high enough or too high Goal of FAST MAS: Address Problems with Early Phase Trials Key problems: III. Phase 2a studies, critical gate to most expensive phase of development, are frequently underpowered, mini phase 3 trials Use Clinical Endpoints: too variable to test potential with sufficient power at limited cost DSM Problems:» Limited biomarker potential because of weak correspondence of DSM and neurobiology;» Many diagnoses have unacceptable test retest reliability» Diagnoses may not have a unique pathophysiology (e.g. MDD 5/9 dx criteria) Vulnerability to bias;» Basing Go/No Go decision on getting significance on clinical endpoint (e.g. HAM D) in such a study is extremely risky Provides precarious basis for drug development; contributes to excruciatingly expensive failures to replicate Phase 2 finding in Phase 3

94 Quick Win/Fast Fail Given that the vast majority of drug candidates are destined to fail can we find a way to have them fail faster and less expensively? Requires a redistribution of R&D investments from the later stages of development to earlier phase studies Design Phase I and Phase IIa studies so that at the end of Phase IIa you have a definitive indication of a target s potential; Allow go no go decision Employ The Experimental Therapeutics Paradigm Adopt RDOC dimensional diagnostic framework as means of applying neuroscience advances Study dose established to robustly engage target in Phase 1 Carry out studies to test specific POC hypothesis that engaging the target has anticipated effect on brain circuitry Employ Biomarkers in Phase 2a to evaluate if effect on brain circuitry has occurred» Closer than clinical endpoints to pathophysiology and therapeutic mechanisms; thereby decrease variability and increase power» Diminishes vulnerability to bias» Potential to allow smaller/cheaper early phase studies Paul et al., Nature Reviews Key Steps in Implementing this Approach To Implement the FAST Approach We Had to Identify: Target of importance to the field Molecule which engages that target that is available Dose of the molecule to study that robustly engages the target Must have means to measure target engagement Appropriate RDoC construct(s) Outcome measures Includes reliable measure of effect on brain circuitry Patient population to study and how to select for that population Number of subjects to include in the trial

95 FAST MAS KOR Antagonist Study Chose to test the effects of Kappa Opioid Receptor (KOR) Antagonism on reward circuitry It is a target of interest to the field which has been minimally tested It has promising pre clinical and preliminary human data Availability of PET ligand to establish receptor occupancy Means (fmri) to test the hypothesis that engaging the target (blocking KORs) achieves a desired effect reward brain circuitry There is a molecule available which engages this target which is available CERC 501 is a high affinity, selective kappa opioid receptor antagonist Favorable pharmacologic and adverse effects profiles support its use Toxicology, SAD, MAD completed Dose which robustly engages target already established with single dose PET Choice of RDoC Construct(s): Anhedonia Chosen because pre clinical data strongly suggest that pharmacologically engaging the kappa opioid receptor (via antagonism) should measurably affect reward related brain circuitry so as to improve reward related function. The inability to experience pleasure is a core symptom of major depression but also cuts across traditional DSM diagnosis (anxiety disorders and schizophrenia) Treadway et al., 2009; Pizzagalli et al., 2005, 2009; Joiner et al., Psych Res. 2003; Snaith et al., BJP,1995

96 FAST MAS KOR Antagonist Study Design Phase 2a POC Study 8 week, double blind, parallel group, placebocontrolled, 2 arm study of CERC 501 vs Placebo; N=90 Evaluating effects on reward circuitry Evaluating a dosage of CERC 501 which robustly engages the KOR based on prior PET study Phase 2a Study Primary Outcome Stress Triggers Dynorphin Release Which Inhibits VTA and NA Via KOR POC Hypothesis: KOR Antagonism Increases VTA Activation in Anticipation of Reward Figure from Koob et al., Neuropharmacology. 2014

97 Phase 2a Study Primary Outcome Primary Measure of engaging circuitry related to hedonic experience/response for establishing POC: Ventral striatal activation in anticipation of rewards in monetary incentive delay (MID) task fmri MDD patients have decreased ventral striatal activation to anticipated reward with MID vs healthy controls Ventral striatal activation to anticipated reward with MID is negatively correlated with anhedonia scale score Study powered to detect effect size of 0.5 Capacity to estimate effect size on primary outcome limited by very few treatment studies carried out with MID fmri If we don t engage the circuitry it would not make sense to move forward even if there is a therapeutic effect on a clinical or selfreport endpoint; This would be a setup for a failed phase III trial. Wacker et al., 2009; Pizzagalli et al., 2004, 2009; Stoy et al., 2012; Ossewaarde et al., 2011; Treadway et al., 2009; Pizzagalli et al., 2005, 2009; Joiner et al., Psych Res. 2003; Snaith et al., BJP,1995 Phase 2a Study Outcomes: Represent Multiple Domains of Reward Function Key Secondary Behavioral intermediate phenotype assessment (more closely linked to neural circuitry than clinical outcome but also linked to clinical outcome) Probabilistic Reward Task assesses capacity to learn based on reward Clinical Outcome: Measured with validated clinical scale demonstrated to be sensitive to treatment effects in depressed patients treated with SSRI/SNRI Snaith Hamilton Pleasure Scale (SHAPS) Exploratory Additional circuit measure QEEG measure of cingulate activity Additional Reward Related Behavioral Measure Effort Expenditure for Rewards Task assesses the degree to which one is motivated by reward as demonstrated by effort Additional Reward Related Self report scale Temporal Experience of Pleasure Scale (TEPS) HAM D, HAM A Wacker et al., 2009; Pizzagalli et al., 2004, 2009; Stoy et al., 2012; Ossewaarde et al., 2011; Treadway et al., 2009; Pizzagalli et al., 2005, 2009; Joiner et al., Psych Res. 2003; Snaith et al., BJP,1995

98 Novel Choice of Subject Population Diagnostic mix of subjects: Entry Criteria: DSM diagnosis of a mood and anxiety spectrum disorder One third must meet anxiety disorder criteria and not MDD Otherwise concern is that we d have a population only with MDD and not have the opportunity to assess reward effects cross diagnostically consistent with RDOC FDA approval only possible if you can show that improvement of the RDOC endpoint does not represent improvement of one of the symptoms of a disorder» Either have to show that:» 1) Treatment improves anhedonia but NOT depression scale (HAM D or MADRS)» 2) Treatment improves anhedonia in patients cross diagnostically Anhedonia (Snaith Hamilton > 20) Circuit measure work insufficient to allow screening This would ultimately be the goal. Summary/Conclusions FAST MAS Phase 2a Trial is a Landmark Study with Novel Methodology intended to: Improve our understanding of mechanisms of anhedonia Establish methods for studying treatments for anhedonia and RDoC outcomes in general Pave the way for future early phase drug development work which is more cost effective Contribute to increasing investment of industry in neuroscience drug development Ultimately foster the development of new, effective treatments for people with mental illness

99 Many People to Credit NIMH Team Mi Hillefors, Jill Heemskerk, Steve Zalcman, Kristina McLinden, Bruce Cuthbert, Ashley Kennedy, Adam Haim, Bill Potter Consultant Group Steve Hyman, Steve Paul, Diego Pizzagalli, Eric Wong, Mauricio Tohen, Carlos Zarate, Tom Laughren FAST MAS Team: Sanjay Matthew, Gerard Sanacora, Wayne Goodman, Dan Iosifescu, S. Holly Lisanby, Anantha Shekhar, John Nurnberger, Evan Morris, Joe Calabrese, Richard Keefe, Allen Song, Michael Pencina, Shein Chung Chow Maurizio Fava and RAPID Team Eli Lilly Cerecor

100 Ismene Petrakis, M.D. Professor of Psychiatry, Yale University, School of Medicine Chief, Psychiatry, VA Connecticut Healthcare System Provided consultation for Alkermes Company and Recovery Centers of America Disclaimer: this presentation will discuss off-label uses of medications for indications not approved by the FDA.

101 Fermented drinks date back thousands of years Beverages made from honey, dates, cereals, grapes and other fruits Sumerian and Egyptian texts mention medicinal wine Dionysis, God of Wine Ancient Greeks had a God of Wine US since its founding, alcohol played important role, safer to drink than water. In wine there is wisdom, in beer there is Freedom, in water there is bacteria. Benjamin Franklin

102 Among adults in US (>18) 86.8% have sampled alcohol in their lifetime; 70.7% have used alcohol in past year; 56.4% have used alcohol in the past month NIAAA, 2013 We were not a hugging people. In terms of emotional comfort it was our belief that no amount of physical contact could match the healing powers of a well made cocktail. David Sedaris, Naked

103 Standard Drinks o Way to compare drinks based on alcohol content o For example: one beer, one glass of wine= 1 standard drink o Mixed drinks probably a bit higher Guidelines suggest: o Per week: <14 drinks for men; < 7 drinks for women o On any single day: < 4 drinks for men; < 3 drinks for women DSM-IV Alcohol Abuse, Alcohol Dependence DSM-V: integrates the two DSM IV disorders into a single disorder called alcohol use disorder, or AUD, with mild, moderate, and severe sub-classifications.

104 o Consuming more alcohol or other substance than originally planned o Worrying about stopping or consistently failed efforts to control one s use o Spending a large amount of time using drugs/alcohol o Use of the substance results in failure to fulfill major role obligations o Craving the substance (alcohol or drug) o Continuing the use of a substance despite health problems o Continuing the use of a substance despite its having negative effects in relationships with others o Repeated use of the substance in a dangerous situation (for example, when having to operate heavy machinery, when driving a car) o Giving up or reducing activities in a person s life because of the drug/alcohol use o Tolerance o Withdrawal Mild (2-3 symptoms): Moderate (4-5); Severe (>6) (Expired) Wikipedia: In common and historic usage, alcoholism refers to any condition that results in the continued consumption of alcoholic beverages despite the health problems and negative social consequences it causes.

105 Community Samples show high rates of co-morbidity NESARC o Most have independent mood and SA disorder o 20% /20% o 12 month, and lifetime association of AUD in those w/mdd o NLAES o Among those w/ MDD, 32% met criteria for AUD Clinical Samples o 25-75% % of those seeking treatment for AUD have some depression o STAR*D trial, 25% met criteria for SA disorder National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), 2004 National Longitudinal Alcohol Epidemiologic Survey (NLAES), 1995 Economic Burden: $223.5 billion health care costs (most due to binge drinking) 88,000 deaths attributable to alcoholrelated causes (3 rd most preventable cause of death) Family (10% of children) Social (missed work)

106 Difficulty in making accurate diagnosis Course of each, complicated by presence of other disorder o More frequent episodes of depression o Depression can lead to relapse Higher risk of suicide (As high as 66%) Depression AUD Common Etiology

107 Substance abuse precedes Psychiatric Disorders Substance abusers are in dangerous situations, more likely to experience traumatic events Chronic SA leads to higher levels of arousal, sensitization of neurobiological stress, therefore vulnerability Psychiatric disorder precedes Substance Abuse: Self Medication Hypothesis Use substances to treat symptoms of depression, anxiety or psychosis Use substances to treat side effects of medications to treat psychiatric disorders

108 But it is my conviction now that alcohol played a perverse trick on me when we said farewell to each other: although, as everyone should know, it is a major depressant, it had never truly depressed me during my drinking career, acting instead as a shield against anxiety. Suddenly vanished, the great ally which for so long had kept my demons at bay was no longer there to prevent those demons from beginning to swarm through the subconscious, and I was emotionally naked, vulnerable as I had never been before. Doubtless, depression had hovered near me for years, waiting to swoop down. Now I was in the first stage premonitory, like a flicker of sheet lightning barely perceived of depression s black tempest. William Styron, Darkness Visible

109 Compartmentalized Treatment Settings Misdiagnosis ounder-reporting of symptoms olack of Recognition of Underlying Disorder Problems with engagement oactive psychiatric symptoms olack of Insight Assess level of care needed Use of Motivational Interviewing (MI) techniques Treatment o Initiate Office Based Treatment Brief Physician Advice Office based treatment OR o Referral to specialty SA treatment setting

110 HOW DO WE TREAT EXCESSIVE ALCOHOL USE IN PATIENTS WITH PSYCHIATRY CO-MORBIDITY? We use the tools we already have Our tools or Psychopharmacology Psychotherapy Alcohol use disorder + heavy drinking Desire to decrease drinking Patient preference (psychosocial treatment vs medication) No medical contraindication

111 Strategy #1: use medications used to treat alcohol use disorders o Are they safe/effective in MDD? Strategy #2: use medications used to treat depression o Are they safe/effective in comorbid AUD? Strategy #3: combination #1 + #2 Disulfiram (Antabuse R ) in use for over 50 years Naltrexone (Revia R ) FDA Approved in 1994 Acamprosate (Campral R ) FDA Approved in 2004 Naltrexone depot (Vivitrol R ) FDA Approved in 2006

112 Medications approved by FDA to treat Alcoholism Disulfiram (Antabuse R ) Naltrexone (Revia R ) Acamprosate (Campral R ) Naltrexone (Vivitrol R ) Oral opioid antagonist Numerous studies showing efficacy, understanding mechanism of action Oral formulation o Inexpensive, modest efficacy Long-acting, IM naltrexone o Vivitrol R (every 28 day medication) Improve compliance, well tolerated, effective

113 Oral Dose 50mg/day Prior to initiation, check LFT s Most common side effects: nausea, headache, dizziness, insomnia, vomiting, anxiety and somnolence. Compatible with psychosocial treatment Cannot be prescribed in those who are using opioids Mechanism: Naltrexone Attenuates Stimulant and Enhances Sedative Effects of Ethanol in Healthy Subjects (n=19) Biphasic Alcohol Effects Scale Stimulant Rising Blood Alcohol Level Falling Blood Alcohol Level Sedative Rising Blood Alcohol Level Falling Blood Alcohol Level Placebo Naltrexone Swift et al. AJP 1994

114 Long-acting naltrexone o Vivitrol R Q28 day medication 380mg or 190mg Improve compliance, well tolerated, effective Garbutt et al., 2005

115 53 clinical trials with Naltrexone >9,000 participants o ORAL: o No return to drinking o No return to heavy drinking o IM: o Reduction in heavy drinking *Jonas et al, 2014 JAMA Family history o FHP better response to NLTX (Krishnan-Sarin et al., 2007) Genetic predictors of response to treatment o COMBINE STUDY: Mu-opioid receptor OPRM1 Asp40 allele predicts naltrexone treatment response (Anton et al., 2008) Genetic moderators in response to pharmacotherapy (Ray et al., 2007) o Laboratory study o G allele of A118G: NLTX blunts effect of ethanol in laboratory

116 Limitations o Small effect size o Not clear for which patients is it most effective o Cannot be used in those who need opioids for pain management o Not widely accepted <2% of VA patients prescribed NLTX in VA Nationally (Petrakis, 2003) 3% of VA Patients in 2007 (Harris et al, 2010) Survey of Physicians Psychiatrists showed low usage, even among Addiction Psychiatrists (Thomas et al, 2003) Logistic Regression Analysis Results Naltrexone Utilization* (n=194,001) Adjusted Statistics Odds Ratio Z Predisposing Factors Age Female African-American Hispanic Drug Abuse Major Depression Dysthymia Anxiety Disorder PTSD Schizophrenia Personality Disorder Bipolar Disorder Organic Brain Syndrome Psychiatric Hospitalization 1-21 days >21 days p < < <.0001 <.0001 < <.0001 <.0001 *Within the group of patients with an alcohol related diagnosis Petrakis I, Leslie D, Rosenheck R. (2003) Use of Naltrexone in the Treatment of Alcoholism Nationally in the Department of Veterans Affairs. Alcoholism: Clinical & Experimental Research 27 (11): \ N=99,456 Odds P Ratio Any mental health inpatient hospitalization 5.62 <.0001 Any psychiatric outpatient visit 4.90 <.0001 Any substance abuse outpatient visit 6.47 <.0001 Adjustment disorder Depression Other psychiatric diagnoses 1.70 <.0001 Received depot naltrexone among those who had any naltrexone N=3,180 Odds P Ratio Any mental health inpatient hospitalization 3.47 <.0001 Any psychiatric outpatient visit Any substance abuse outpatient visit Adjustment disorder Marienfeld C, Iheanacho T, Issa M, Rosenheck RA. Long-acting injectable depot naltrexone use in the Veterans Health Administration: A national study. Submitted

117 Safe? Yes [Several studies testing its use in depressed AUD subjects (Saloum et al., 1998; Petrakis et al., 2003; Pettinati et al., 2010) Effective? Yes (Pettinati et al, 2010) Can combine with antidepressant therapy? Yes (Pettinati et al, 2010) Other: Does treatment with naltrexone cause or exacerbate mood disorder- NO Synthetic derivative of homotaurine (analogue of GABA) Most studies conducted in Europe, more recently tested in USA? dose-response effect May effect GABA or glutamate system

118 Dose recommended mg day in divided doses (333mg, 2 tabs tid) Recommended for post-detoxification Most common side effects: abdominal pain, diarrhea, sexual side effects, confusion Compatible with psychosocial counseling Pros: o Safe (not metabolized thru liver) o Acamprosate may improve abstinence rates o Restore NMDA function o Help with sleep/anxiety? Cons: o Two large US Trials: o COMBINE: Acamprosate disappointing o Only other large US trial also primarily negative

119 27 clinical trials with Acamprosate >7,000 participants o No return to any drinking No difference between acamprosate and naltrexone *Jonas et al, 2014 JAMA Safe? Yes Effective? Yes [Acamprosate effect similar in depressed patients as in non-depressed patients (Lejoyeux & Lehert, 2011).] Can combine with antidepressant therapy? Yes Other: Motivation, compliance lower in depressed patients

120 Mechanism of Action o Inhibits aldehhyde dehydrogenase o Alcohol-disulfiram reaction: flushing, palpitations, SOB, nausea and HA. Disulfiram o Research called efficacy into question o Efficacy linked to compliance (Fuller et al., 1986) Mechanism of Action Ethanol ADH Acetaldehyde ALDH Disulfiram Acetate ADH alcohol dehydrogenase ALDH aldehyde dehydrogenase

121 Dose 250mg per day o May increase to 500 mg Check LFT s prior to initiation Must be abstinent for 48 + hours Most common side effects: GI disturbance, headache, metallic taste in mouth, peripheral neuropathy Educate on potential for alcohol-disulfiram reaction Limitations: o Acceptability (both patient and clinician) o Compliance, compliance, compliance. Questions: o Enhancing motivation o Use in special populations (dually diagnosed, cocaine dependent) Other mechanism of action o Dopamine b-hydroxylase inhibitor o May be mechanism that can lead to precipitation of psychosis, other (more positive) effects

122 Safe? Yes (Petrakis et al., 2007) Effective? Not tested Can combine with antidepressant therapy? Yes (Petrakis et al, 2007) Other: Other actions include dopamine - hydroxylase inhibitor Most promising new medication Anti-epileptic, has effects on GABA Two substantial trials: o 12-week trial conducted (Johnson et al., 2003) o Second multi-site study (Johnson et al., 2007) Escalating doses 25mg-300mg Outcomes suggest, compared to placebo o Fewer drinking days, drinks per drinking days o Decrease craving o Can initiate while still drinking? o?better than naltrexone and acamprosate, but more SE s

123 Johnson et al., 2003 Safe? Maybe [May augment SSRI (Mowla and Kardeh, 2011), but also linked to depression (Celano et al, 2011)] Effective? Not tested Can combine with antidepressant therapy? Yes Other: Prominent cognitive side effects are problematic in general, may be of particular concern in depression

124 Some promising studies Early studies, mostly small n One promising study (Mason et al., 2014) o 12-week trial conducted o 900 mg vs mg vs PLA Outcomes suggest, compared to placebo o Higher abstinence rates o Well tolerated Mason BJ, Quello S, Goodell V. Shadan F, Kyle M, Begovic A. (2014) Gabapentin Treatment for Alcohol Dependence A Randomized Clinical Trial JAMA Intern Med, 174(1):70-77.

125 Safe? Maybe [adjunct treatment for bipolar disorder and depression (reviewed in Pichler et al, 2015); also possible link to depressive symptoms] Effective? Not tested Can combine with antidepressant therapy? Yes* Other: Gabapentin reported to have abuse potential; SE includes somnolence First Line: o Naltrexone (po or IM) o Acamprosate Second Line: o Disulfiram Consider: o Topiramate Other o Gabapentin

126 First-line antidepressant treatment Selective serotonin reuptake inhibitors (SSRIs) * Tricyclic antidepressants (TCAs)* Dopamine agonists (DAs) Serotonin norepinephrine reuptake inhibitors (SNRIs) Norepinephrine reuptake inhibitors (NRIs) Use of Antidepressants in Individuals with SA Disorders (Nunes and Levin, 2004)* From: Treatment of Depression in Patients With Alcohol or Other Drug Dependence: A Meta-analysis JAMA. 2004;291(15): doi: /jama Figure Legend: Effect sizes are Cohen d, error bars represent the 95% confidence intervals (CIs). Studies are stratified into groups with low (<25%) vs high (>25%) categories of placebo response, measured as the percentage decrease in the Hamilton Depression Scale between baseline and end-of-study in the placebo group. Copyright 2015 American Medical Association. All rights reserved.

127 Use of Antidepressants in Individuals with SA Disorders (Nunes and Levin, 2004)* From: Treatment of Depression in Patients With Alcohol or Other Drug Dependence: A Meta-analysis JAMA. 2004;291(15): doi: /jama Figure Legend: Effect sizes are Cohen d on outcomes reflecting quantity of substance use (mainly by self-report). Error bars represent the 95% confidence intervals(cis). Studies are stratified into 2 groups based on the size of the effect of medication on depression outcome (Cohen d for the Hamilton Depression Scale)effect size lower than 0.50 (low); and effect size greater than 0.50 (high).the study by Roy did not have the data necessary for analysis for this figure. Copyright 2015 American Medical Association. All rights reserved. Tricyclic Antidepressants Conflicting results Desipramine (Mason et al, 1996) o 77 participants with MDD +AUD o Decrease in depressive symptoms o Decrease in drinking Imipramine (McGrath et al., 1996) 69 participants with MDD + AUD Imipramine associated with greater decrease in depression No effect on drinking

128 SSRI s alcohol preference in laboratory animals SSRI s tested in heavy drinkers (include citalopram, fluoxetine, zimeledine, viqualine), small in alcohol consumption. Some studies showed early benefit of SSRI s, not sustained throughout treatment Meta-analysis found no sustained effect of SSRI in those without psychiatric comorbidity (Torrens at al, 2005). Unidimensional typology: Winokur (1971) Primary and Secondary Alcoholics Onset of psychiatric symptoms Mutidimensional typology: Cluster analysis: o Babor, Type A and Type B Cloninger, Type I and Type II Type I: onset after 25, no criminality, ability to abstain for periods Low in novelty seeking, high in harm avoidance Type II: onset before 25, recurrent severe medical consequences, male only High novelty seeking, low harm avoidance

129 Likely a differential effect depending on classification of alcoholism (Kranzler et al, 2011.) Setraline (200mg) vs. placebo Planned analysis based on subtype and genotype (sertonin transporter gene) Moderating effect of genotype dependent on age of onset LOA (Late onset, low vulnerability)-drink less on SSRI EOA (early onset, high vulnerability)-drink more on SSRI Anti-dipsotropic + Antidepressant Medication

130 Well designed study o 12-week trial conducted o 170 participants o 4 groups (S 200mg, S + NLT 100mg, NLX 100mg, PLA) Outcomes suggest, compared to placebo o Higher abstinence rates o Well tolerated Pettinati HM et al, 2010

131 Depression outcomes Pettinati HM et al, 2010 Medications A very small piece of a bigger picture

132 Cognitive Behavioral Therapies: o Developed for both AUD and MDD Successfully combined with Motivational Interviewing (Riper et al, 2014) Ongoing research studies: o Interpersonal Psychotherapy (The Meadow Project) for women o ME +CBT for adolescents o Supportive text messaging

133 Key ingredient is connectedness opeer group ofamily Access to substances/drugs Time management Money management Voluntary worldwide fellowship Started in 1935 Program of total abstinence Cooperation with other organizations Attendance at AA associated with good clinical outcomes

134 Many different types of meetings AA for dually addicted individuals o Double Trouble Other support groups oregionally determined Ex: Rational Recovery, SMART Recovery, Women for Sobriety, Moderation Management, Accelerated Recovery Family involvement shown to improve outcomes in every domain Families can get assistance from support groups as well http.// http.//

135 Do remember to evaluate for comorbid SA disorders Consider using augmentation strategy with medications to treat alcohol dependence o Naltrexone o Acamprosate o Disulfiram can be used safely o Other options: Topiramate, gabapentin Combination with antidepressant therapy is likely best

136 Forget to provide integrated treatment/coordinate treatment Forget that when using medications, there are special considerations o eg. Some medications have been associated with worsening depression (topiramate) Forget that there s room for improvement For more information http.// Johnson, BA, Pettinati HM et al, American Journal of Psychiatry, 2013; 170:23-30

137 References National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), 2004 National Longitudinal Alcohol Epidemiologic Survey (NLAES), 1995 Swift RM, et al. Am J Psychiatry, 1994;151(10): Johnson BA et al, Lancet, 2003;361: Garbutt JC, et al. JAMA, 2005;293(13): Jones DE, et al. JAMA, 2014;311(18): Krishnan-Sarin K et al, Biol Psychiatry, 2007;63:694-7 Anton RF et al, Arch Gen Psychiatry, 2008;65(2): Ray LA et al, Arch Gen Psychiatry, 2007;64(9): Petrakis IL et al, Alcohol Clin Exp Res, 2003;27(11): Harris AHS et al, Psychiatric Services, 2010;61(4):392-8 Pettinati HM et al, Am J Psychiatry, 2010;167: Lejoyeuz M & Lehert P, Alcohol & Alcoholism, 2011;46(1):61-7 Petrakis IL et al, J Clin Psychopharmocol, 2007;27(2):160-5 Mowla & Kardeh, Prog Neuropsychopharmacol Biol Psychiatry, 2011;35(4):970-3 Celano et al, Dialogues Clin Neurosci, 2011; 13(4): Mason BJ et al, JAMA Intern Med, 2014;174(1):70-77 Nunes EV & Levin FR. JAMA, 2004;291(15):

138 Nicotine and Mood Disorders Interactions and Treatment Implications Stephanie S. O Malley Professor of Psychiatry Yale University School of Medicine Disclosure Member, American Society of Clinical Psychopharmacology workgroup, the Alcohol Clinical Trial Initiative, sponsored by Abbott Laboratories, Eli Lilly & Company, Pfizer, Ethypharma; Medication supplies, Pfizer Advisory Board, Alkermes Clinical Trial Contract, Eli Lilly Scientific Panel of Advisors, Hazelden Betty Ford Foundation. Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

139 Overview Interrelationships between Nicotine and Depression Interventions for Smoking Cessation Behavioral Support Pharmacological Treatments 44% 44% Consume almost half of all cigarettes smoked in the U.S. Lasser et al 2000, Grant et al 2004 Have 2 4 times higher smoking rates CDC 2013, Morisano et al 2009 Have lifespans years shorter than the general population Parks et al 2006, Goff et al 2005 Have lower cessation rates 4 Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

140 18% 40 61% 40 61% of depressed individuals vs. 18% of general population Smoke High smoking prevalence among depressed individuals Morisano, % 15% Current MDD 15% 15% of current smokers vs. 6.7% of general population 39% 16 CES D Depression highly prevalent among smokers Goodwin et al, 2014 Anda et al, % of current smokers vs. 15% of never smokers 5 Cholingergic hypothesis of depression Janowsky 1972 Depressive symptoms increase with acetylcholinesterase inhibitors (e.g., physostigmine) Nicotine has demonstrated antidepressant properties in depressed nonsmokers and depressed smokers Classical antidepressants (TCAs, SSRIs, bupropion) act as noncompetitive antagonists of nachr. Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

141 Nicotine upregulates 2 *-nachrs Nicotine increases the number of total 2* -nachrs. This was initially described in animal studies after chronic nicotine exposure (Kassiou et al., 2001, Marks et al., 1992). Confirmed postmortem (Breese et al., 1997; Court et al., 1998) and in vivo (Staley et al, 2006) in human tobacco smokers. Nicotine itself acts a chaperone and leads to increased receptors on the cell membrane (Srinivasan et al., 2011). The changes in receptor density may be involved in tobacco smoking dependence. nachr receptor availablity is lower in MDD vs controls (nonsmokers) All Controls (1, 3) vs. All Depressed (2, 4) Results Effect Num DF Den DF F Value Pr > F Group Region <.0001 Group*Region Saricicek et al., Am J Psychiatr, 2012, 169: Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

142 In vivo imaging of the beta 2 containing nachr Control Control Nonsmoker (Male; 41yo) 41yo) Acute Depressed Nonsmoker (Male; 39yo) V T nachr receptor availability, while still low, is higher in remitted depression versus acute depression beta-2*nachr V(T)/f(p) using [I-123]5IA Acute Depressed Recovered Depressed Acute Depressed (2) vs. Recovered Depressed (4) Results Effect Num DF Den DF F Value Pr > F Group Region <.0001 Group*Region Saricicek et al., Am J Psychiatr, 2012, 169: Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

143 β 2 -nachr availability correlates with # euthymic months in rmdd beta-2 nachr availability Frontal Cortex* R 2 = 0.16 r= 0.4; p= Number of euthymic months beta-2 nachr availability Thalamus R 2 = r=0.04; P= Number of euthymic months beta-2 nachr availability Parietal Cortex* R 2 = 0.25 r= 0.5; p= Number of euthymic months beta-2 nachr availability Striatum R 2 = r=0.8; P= Number of euthymic months β 2 *-nachr availability is lower in bipolar depressed but not euthymic subjects Hannestad et al., Biological Psychiatry, 2013 Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

144 Summary The cholinergic system is implicated in depression and smoking Evidence of greater cholinergic activity and less receptor availability in depression Of note, classical antidepressants have nicotinic antagonist effects, that are likely to upregulate nicotinic receptors Treatments for smoking cessation in this population also target this system SMOKING CESSATION INTERVENTIONS Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

145 Interest in Quitting The Depression and Bipolar Support Alliance (DBSA) found: 74.6% of current smokers expressed a desire to quit smoking 64.7% had tried to quit smoking in the last year Depression and Bipolar Support Alliance, Online Survey. (2008). Funded by the Smoking Cessation Leadership Center. Draft report. The CHALLENGES of QUITTING People smoke in many different situations: When drinking coffee While driving in the car When bored While stressed While at a bar After meals During breaks at work While on the telephone When spending time with family or friends who use tobacco While drinking alcohol or using drugs Quitting requires coping changing how a person thinks and what they do in these situations Quitting requires motivation thinking about a more positive life outlook and other meaningful reasons to quit Clinicians can address these issues Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

146 TOBACCO QUITLINES Tobacco cessation counseling, provided at no cost via telephone to all Americans Staffed by trained specialists Up to 4 6 personalized sessions (varies by state) Up to 30% success rate for patients who complete sessions RESEARCH on TOBACCO & DEPRESSION Most of the research has been conducted with people with a history of MDD, in free-standing smoking clinics Greater tobacco abstinence with increased psychological support (Hall et al., 1994; Brown et al., 2001) Individuals with recurrent MDD may be especially helped by CBT mood management approaches Individuals with a history of MDD may have more difficulty quitting and more severe withdrawal symptoms than those without MDD Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

147 MENTAL HEALTH OUTCOMES: DEPRESSED SMOKERS TREATED for TOBACCO Among depressed patients who quit smoking: No increase in suicidality Quit: 0% vs Smoking: 1-4% No increase in psych hospitalization Quit: 0-1% vs. Smoking: 2-3% Comparable improvement in % of days with emotional problems No difference in use of marijuana, stimulants or opiates Less alcohol use among those who quit smoking Prochaska et al., 2008, Am J Public Health FDA-APPROVED MEDICATIONS for CESSATION Nicotine polacrilex gum Nicorette (OTC) Generic nicotine gum (OTC) Nicotine lozenge Nicorette Lozenge (OTC) Nicorette Mini Lozenge (OTC) Generic nicotine lozenge (OTC) Nicotine transdermal patch NicoDerm CQ (OTC) Generic nicotine patches (OTC, Rx) Nicotine nasal spray Nicotrol NS (Rx) Nicotine inhaler Nicotrol (Rx) Bupropion SR (Zyban) Varenicline (Chantix) Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

148 Bupropion SR (Zyban, generic Non-nicotine medication Antidepressant Weak inhibitor of dopamine reuptake Partial agonist at nicotinic receptors 150mg daily for 3 days followed by 150 mg 2x per day at least 8 hours between doses Doubles quit rates Bupropion SR Has been associated with lower weight gain following cessation May be efficacious in individuals with history of depression and can be combined with SSRI s Contraindications: Hx seizure or seizure risk, heavy etoh use or sudden disruption of etoh MAO inhibitor within 14d Eating disorders Side effects: anxiety, insomnia, dizzy, dry mouth, nausea. Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

149 Nicotine Replacement Therapy Replaces 30 50% of the nicotine from a cigarette Reduces physical withdrawal from nicotine Reduces the immediate, reinforcing effects of nicotine that is rapidly absorbed via tobacco smoke PLASMA NICOTINE CONCENTRATIONS for NICOTINE-CONTAINING PRODUCTS Cigarette Cigarette Nasal spray Plasma nicotine (mcg/l) Inhaler Lozenge (2mg) Gum (2mg) Patch 0 1/0/ /10/ /20/1900 1/30/1900 2/9/ /19/ /29/ Time (minutes) Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

150 Nicotine Patch Dosage based on cigarettes per day/smokeless tobacco cans or pouches per week Single patch worn for 24 hours; removed at night if sleep disturbance Placed on clean, dry, hairless skin above the waist and below the neck. Applied to new area each day. Nicotine Lozenge and Gum Dosage based on time to first use upon waking (within 30 minutes 4 mg) Use every 1 2 hours, minimum of 9 pieces Coach patients on how to use Have them try it with supervision Explain how they work and the distinction between chewing gum and mints Proper storage and disposal to keep away from children Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

151 Instructions Place lozenge in mouth and allow to slowly dissolve Do not chew or swallow lozenges Once in a while, move the lozenge The FDA has concluded that there are no significant safety concerns about combining nicotine replacement therapy with other nicotine containing products, including cigarettes use of products beyond 12 weeks potential for abuse or dependence US Department of Health and Human Services, US Food and Drug Administration: Modifications to labeling of nicotine replacement therapy products for over-the-counter human use. Fed Register 2013;78: Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

152 Combination Nicotine Replacement Therapy Improves outcomes for most patients Combination NRT Long-acting formulation (patch) Produces relatively constant levels of nicotine PLUS Short-acting formulation (gum, lozenge, inhaler, nasal spray) Allows for acute dose titration as needed for withdrawal symptoms Pretreatment with Nicotine Patches for 1 week prior to the quit date increases success Alter the plan if ---- Symptoms of nicotine overdose Severe nausea, vomiting, dizziness, weakness and rapid heart beat Irregular heart beat or palpitations Patch rash or swelling that does not go away in 4 days Gum/Lozenge mouth problems or persistent indigestion. Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

153 PreQuit Counseling Help identify their reasons for quitting Identify smoking patterns chart out when and where they smoke their cigarettes Educate smoker about changing patterns What cigarettes could they give up? What locations could they make smoke free (or have already made smoke free)? Could they delay the first cigarette of the day? Practice Quit Attempt Goal: practice coping with withdrawal How bad do they think it ll be? How have they coped in the past and how will them cope now? 4 D s: Drink, Delay, Distract, Deep breathing NRT 8 hours Debrief in anticipation of future quit attempt Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

154 Efficacy of Combination vs. Single NRT (Fiore et al. 2003) VARENICLINE Chantix (Pfizer) Nonnicotine cessation aid Partial nicotinic receptor agonist Oral formulation Copyright The Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.