Clinical Management of Treatment Resistant Depression

Rosemary Payne, M.S.N.Senior Supervisory Nurse Manager

Clinical CenterNational 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 TRDLawrence 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 TeamMission• 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

Clinical Practice

Care Coordination

and Continuity

Contribution to the Science

Human Subjects

Protection

Study Management

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

Euthymic

Depressed

Next generation antidepressant

Lag of onset:10-14 weeks

Rapid onset: Hours/day

• Disruption to personal, family, and social life• Occupational impairment• Risk of suicidal behavior

Depression: Adverse Effects Problems with Current Antidepressants:

• Low remission rates• Questionable efficacy in bipolar

depression• Lag of onset of antidepressant effects

Standard antidepressant(Monoaminergic)

Major Depressive Episode

Initiate Treatment

Depression: The Need for Improved Treatments

Courtesy of Carlos Zarate Jr, MD

Lessons from STAR*DTreatment Algorithms

Treatment Resistant Depression

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

STEP-BDStudy 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 StrategiesAugmentation Evidence

Rating*Added $ Monthly

lithium 900 mg (to TCA) A 2T3 25 ug (to TCA) A 3mirtazapine 15 mg A/B 18buspirone 40 mg B 4Wellbutrin SR 300 mg B 42Zyprexa 10 mg B 172Provigil 200 mg B/C 110nortriptyline 100 mg C 2pindolol 10 mg C 2lithium 900 mg (to SSRI) C 2T3 25 ug (to SSRI) C 3Effexor XR 150 mg C 54other atypicals C 70-158

*Thase ME. CNS Spectrums 2004;9(11):808-821.(updated)

A= >1 RCTsB= 1 RCT, plus cC= Case series, anecdotal report, expert opinionD= 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 TreatmentsKetamine (NMDA Antagonists)

Courtesy of Carlos Zarate Jr, MD

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

Zarate et al. Arch Gen Psychiatry 2006

0

5

10

15

20

25

30

PlaceboKetamine

-60 80 23011040 Day1

Day3

Day2

Day7

Time

*

** ********

***

0

10

20

30

40

50

60

70

80

80 23011040 Day3

Day2

Day7

8Weeks

13%

71%

53%58%56%

35%

53%

62-65%

35%

Response: 50% decrease in HAMDHAMD Following a Single Ketamine Infusion

Ham

ilto

n D

epre

ssio

n R

atin

g S

cale

(H

AM

D)

% P

arti

cip

ants

Res

po

nd

ing Monoaminergic

Antidepressant

Day1

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

MinutesMinutes

Courtesy of Carlos Zarate Jr, MD

Rapid Antidepressant Effect of Ketamine in Treatment Resistant Bipolar (BP) Depression

Diazgranados et al. Arch Gen Psych 2010 Zarate et al. Biol Psych 2012

Replication BP study (n=15)First BP Study of Ketamine (n=18)

0

5

10

15

20

25

30

35

MA

DR

S

-60 80 23011040 Day1

Day3

Day2

Day7

Day10

Day14 0

5

10

15

20

25

30

35

40

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

****

-60 80 23011040 Day1

Day3

Day2

Day7

Day10

Day14

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

Time

KetaminePlacebo

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

MinutesMinutes

Courtesy of Carlos Zarate Jr, MD

Acknowledgement

NIMH/ETBP StaffCarlos ZarateR. Machado-VieiraAllison NugentMaura FureyMin ParkMark NiciuErica RichardsJenny Vande VoortTyler ArdElizabeth BallardWally DuncanNiall LallyImmaculata UkohRezvan AmeliNancy BrutscheIntramural Research Program, NIMHOffice of the Clinical Director, NIMH7SE, OP4, 7SW, NCF staffMEG/MRI/MRS/PET/SSCC Cores

Extramural CollaborationsTodd Gould, Robert Schwartz (MD Psych Rsrch)Vistagen TherapeuticsRima 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

Research Subjects and their families

Thank You!

Rosemary Payne, MSNrosemary.payne@nih.gov

Lawrence Park, MDlawrence.park@nih.gov

Kalene Dehaut, MSWSocial Worker/Outreach Recruiter

Office of the Clinical Director, NIMH

kalene.dehaut@nih.gov