Clinical Management of Treatment Resistant Depression Rosemary Payne, M.S.N.

Senior Supervisory Nurse Manager Clinical Center National Institute of Health Lawrence Park, M.D.

Medical Director Experimental Therapeutics & Pathophysiology Branch (ETPB) National Institute of Mental Health

Outline

• • – – – – NIH-CC Model of Care Rosemary Payne, MSN Mission Dimensions of Practice Nursing Demographics Research Participation – – – – – Treatment of TRD Lawrence Park, MD Depression Statistics TRD Treatment Algorithm Alternative Treatments Investigative Treatments

• • •

NIH-CC – Clinical Research Nurse (CRN) Model of Care

Clinical Nursing Research Leadership – Sr. Supervisory Nurse – Nurse Manager – Team Leader – Clinical Manager Clinical Research Team – Protocol Coordinator – Primary Nurse – Associate Nurse Clinical Research Support – Clinical Research Nurse – per diem – Patient Care Technician – Behavioral Health Technician – Research Support Assistant – Unit Clerk

Mission/Vision of NIH-CC-CRN Team

• • • Mission Provided clinical care for patients participating in clinical research studies conducted by investigators within the Intramural Research Program at the National Institutes of Health. As integral research team members, we provide support for the design, coordination, implementation and dissemination of clinical research by NIH investigators, with a focus on patient safety, continuity of care and informed participation. We are also committed to supporting the NIH effort to train the next generation of clinical researchers and provide national leadership for the clinical research enterprise.

• • • Vision The Clinical Center leads the Nation in developing a specialty practice model for Clinical Research Nursing.

This model will define the roles and contributions of nurses who practice within the clinical research enterprise, as they provide care to research participants and support accurate, reliable and ethical study implementation. We will also develop and disseminate practice documents, standards and management tools for implementing clinical research nursing across a wide continuum of practice settings.

The Art/Science of Clinical Research Nursing

Dimensions of Practice

Study Management Human Subjects Protection Contribution to the Science Clinical Practice Care Coordination and Continuity

Clinical Research Nurse Demographics

• • • • Education Preparation – Inpatient – 70% Bachelor of Science or higher – Outpatient – 88% Bachelor of Science or higher Years of Clinical Research Nurse Experience – Inpatient – 7 to 30 years – Outpatient – 5 to 35 years Multi-cultural and inclusionary Specialty and advance practice

Research Participant

• • • • Individualized research and nursing plan of care.

Interdisciplinary team approach to research, stabilization and reintegration.

Collaboration and/or referral to community providers and supports.

Structured community outings and access to other ancillary support services (social workers, recreational/rehabilitation therapists, nutritionists, pharmacists and chaplains)

Research Subject Demographics

• • • • Local – Maryland/DC/Virginia National geography Ages 18-65, based on eligibility Multicultural and diverse

Acknowledgements

• • • • • • • John Gallin, MD – Clinical Center Director Clare Hastings, PhD, Chief Nursing Officer Barbara Jordan, PhD, Service Chief – NBHP Rosemary Payne, MSN, Sr. Supervisory Nurse Manager Victoria Liberty, BSN, Clinical Manager Roger Brenholtz, MSN, Clinical Manager Brenda Justement, MSN, Clinical Manager

Depression: The Need for Improved Treatments Depression: Adverse Effects

•

Disruption to personal,

•

family, and social life Occupational

•

impairment Risk of suicidal behavior Problems with Current Antidepressants:

• • • Low remission rates Questionable efficacy in bipolar depression Lag of onset of antidepressant effects

Next generation antidepressant Rapid onset: Hours/day Euthymic Lag of onset: 10-14 weeks Standard antidepressant (Monoaminergic) Depressed Initiate Treatment Major Depressive Episode

Courtesy of Carlos Zarate Jr, MD

Lessons from STAR*D Treatment Algorithms

Treatment Resistant Depression

Trivedi et al. (Am J Psychiatry, 2006); Rush et al. (NEJM, 2006)

STEP-BD Study 1. Acute Phase BP Depression

• • • • Discontinuation rate – 34% both groups Remission transient ~15% both group Durable recovery (8w) – 24% active – 27% placebo TEAS rate (switching) – 10% active – 11% placebo

From: Thase ME. STEP-BD and Bipolar Depression: What Have We Learned? Current Psychiatry Reports. 2007,9:497-503.

Augmentation Strategies

Augmentation lithium 900 mg (to TCA) T3 25 ug (to TCA) mirtazapine 15 mg buspirone 40 mg Wellbutrin SR 300 mg Zyprexa 10 mg Provigil 200 mg nortriptyline 100 mg pindolol 10 mg lithium 900 mg (to SSRI) T3 25 ug (to SSRI) Effexor XR 150 mg other atypicals Evidence Rating* A A A/B B B B B/C C C C C C C Added $ Monthly 2 3 18 4 42 172 110 2 2 2 3 54 70-158 *Thase ME. CNS Spectrums 2004;9(11):808 821.(updated) A= >1 RCTs B= 1 RCT, plus c C= Case series, anecdotal report, expert opinion D= Anecdotal reports but experts have not endorsed

Electroconvulsive Therapy (ECT)

• • • • • • Oldest, most effective treatment for depression Mechanism of action unknown Seizure a necessary component of treatment General anesthesia required Confusion/memory loss potential side effects Relapse a major issue

NeuroStar TMS

O’Reardon JP et al. Efficacy and Safety of TMS in the Acute Treatment of Major Depression: A Multisite RCT. Biol Psychiatry 2007:62:1208-16

Other Pharmacological Strategies

• • New Antidepressants – Vortioxetine – Levomilnacipran – Vilazodone Atypical Antipsychotic Augmentation – Olanzapine (UP, with fluoxetine) – Quetiapine (UP adjunctive) – Aripiprazole (UP adjunctive) – Lurasidone (BP monotherapy/adjunctive)

Investigational Treatments Ketamine (NMDA Antagonists)

Courtesy of Carlos Zarate Jr, MD

Rapid Antidepressant Effect of Ketamine in Unmedicated Treatment Resistant MDD (n=18) 30

HAMD Following a Single Ketamine Infusion

80

Response: 50% decrease in HAMD

25 20 70 60

53% 56% 71% 58% 53% Monoaminergic Antidepressant 62-65%

50 15

*

40

35% 35%

10 5

** ** Placebo Ketamine ****** ***

30 20 10

13%

0 0 -60 40 80 110 Minutes 230 Day Day 1 2 Day 3 Day 7 Time

Zarate et al. Arch Gen Psychiatry 2006

40 Courtesy of Carlos Zarate Jr, MD 80 110 230 Minutes Day 1 Day 2 Day 3 Day 7 8 Weeks

***p<0.001, **p<0.01, *p<0.05

Rapid Antidepressant Effect of Ketamine in Treatment Resistant Bipolar (BP) Depression First BP Study of Ketamine (n=18) Replication BP study (n=15)

15 10 5 0 40 35 30 25 20

Ketamine Placebo

40 35 30

****** *** ****** *** ***

25 20

****** *** *** *** *** *

15 10 Minutes 5 -60 40 80 110 230 Day Day 1 2 Day 3 Day 7 Day 10 Day 14 0 Time -60 40 80 110 230 Day 1 Day 2 Day 3 Day 7 Day 10 Day 14 Minutes

Diazgranados et al. Arch Gen Psych 2010

Courtesy of Carlos Zarate Jr, MD

Zarate et al. Biol Psych 2012 ***p<0.001, **p<0.01, *p<0.05

Acknowledgement

Research Subjects and their families NIMH/ETBP Staff

Carlos Zarate R. Machado-Vieira Allison Nugent Maura Furey Min Park Mark Niciu Erica Richards Jenny Vande Voort Tyler Ard Elizabeth Ballard Wally Duncan Niall Lally Immaculata Ukoh Rezvan Ameli Nancy Brutsche Intramural Research Program, NIMH Office of the Clinical Director, NIMH 7SE, OP4, 7SW, NCF staff MEG/MRI/MRS/PET/SSCC Cores

Extramural Collaborations

Todd Gould, Robert Schwartz (MD Psych Rsrch) Vistagen Therapeutics Rima Kaddurah-Daouk (Duke University) Gustavo Turecki (McGill University) Per Svenningsson (Karolinska Institutet) Paul Greengard (Rockefeller University) Brian Roth (University of North Carolina) Michael Perlis,Philip Gehrman,David Dinges (UPenn) RAPID Fast-Fail Trials

Thank You!

Rosemary Payne, MSN [email protected]

Lawrence Park, MD [email protected]

Kalene Dehaut, MSW Social Worker/Outreach Recruiter Office of the Clinical Director, NIMH [email protected]