This document discusses the clinical management of treatment resistant depression. It begins with an overview of the NIH Clinical Center model of care provided by clinical research nurses. It then discusses statistics on depression and defines treatment resistant depression. The remainder of the document outlines current treatment algorithms and both standard and investigational treatments for treatment resistant depression, including ketamine infusion studies that have shown rapid antidepressant effects.

1. 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

2. 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

3. 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

4. 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.

5. 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

6. 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

7. 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)

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

9. 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

10. 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

11. Lessons from STAR*D
Treatment Algorithms

12. Treatment Resistant Depression
Trivedi et al. (Am J Psychiatry, 2006); Rush et al. (NEJM, 2006)

13. 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.

14. Augmentation Strategies
Augmentation Evidence
Rating*
Added $
Monthly
lithium 900 mg (to TCA) A 2
T3 25 ug (to TCA) A 3
mirtazapine 15 mg A/B 18
buspirone 40 mg B 4
Wellbutrin SR 300 mg B 42
Zyprexa 10 mg B 172
Provigil 200 mg B/C 110
nortriptyline 100 mg C 2
pindolol 10 mg C 2
lithium 900 mg (to SSRI) C 2
T3 25 ug (to SSRI) C 3
Effexor XR 150 mg C 54
other atypicals C 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

15. 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

16. 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

17. 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)

18. Investigational Treatments
Ketamine (NMDA Antagonists)
Courtesy of Carlos Zarate Jr, MD

19. 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
Placebo
Ketamine
-60 80 230
110
40 Day
1
Day
3
Day
2
Day
7
Time
*
** **
*********
0
10
20
30
40
50
60
70
80
80 230
110
40 Day
3
Day
2
Day
7
8
Weeks
13%
71%
53%
58%
56%
35%
53%
62-65%
35%
Response: 50% decrease in HAMD
HAMD Following a Single
Ketamine Infusion
Hamilton
Depression
Rating
Scale
(HAMD)
%
Participants
Responding
Monoaminergic
Antidepressant
Day
1
***p<0.001, **p<0.01, *p<0.05
Minutes
Minutes
Courtesy of Carlos Zarate Jr, MD

20. 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
40
MADRS
-60 80 230
110
40 Day
1
Day
3
Day
2
Day
7
Day
10
Day
14
0
5
10
15
20
25
30
35
40
******
******
***
***
*
-60 80 230
110
40 Day
1
Day
3
Day
2
Day
7
Day
10
Day
14
****** ***
********* ***
Time
Ketamine
Placebo
***p<0.001, **p<0.01, *p<0.05
Minutes
Minutes
Courtesy of Carlos Zarate Jr, MD

21. Acknowledgement
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
Research Subjects and their families

22. Thank You!
Rosemary Payne, MSN
rosemary.payne@nih.gov
Lawrence Park, MD
lawrence.park@nih.gov
Kalene Dehaut, MSW
Social Worker/Outreach Recruiter
Office of the Clinical Director, NIMH
kalene.dehaut@nih.gov