1. Clinical Management of Treatment Resistant Depression
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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 Treatment of TRD
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
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
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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. Depression: The Need for Improved Treatments
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Depression: The Need for Improved Treatments
Depression: Adverse Effects
Problems with Current Antidepressants:
Disruption to personal,
family, and social life
Occupational impairment
Risk of suicidal behavior
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
Major Depressive Episode
Initiate Treatment
Courtesy of Carlos Zarate Jr, MD

11. Lessons from STAR*D Treatment Algorithms
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Lessons from STAR*D Treatment Algorithms
The NIMH-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study was conducted to determine the effectiveness of different treatments for people with major depression who have not responded to initial treatment with an antidepressant. This is the largest and longest study ever conducted to evaluate depression treatment. This page provides information about the study.
From Tamminga CA, Depression IV. Am J Psychiatry 2003, 160:2; 237.
Major depressive disorder is a common, costly, and
disabling condition affecting 4.9%–17.9% of the population in
a lifetime. From 20%–30% of affected persons suffer a
chronic, relapsing course. Many medications and several
time-limited psychotherapies have shown established efficacy
in randomized controlled trials. Among outpatients with
major depressive disorder treated for the first time, about 50%
will have a response (i.e., exhibit a clinically significant symptom
reduction). However, of these “responders,” only 50%–
70% will achieve symptom remission, which, since remission
is associated with the best day-to-day functioning and best
prognosis, is the goal of treatment.
For those cases of depression not remitting with the first
treatment, little controlled trial evidence is available by which
to select the next treatment. It is believed that a switch to a
new, second treatment may result in a 50% response rate,
with lower response rates expected with the third or fourth
treatment step. Psychiatry faces the challenge of recommending
the next best treatment steps, or series of steps, for depressed
persons not experiencing a remission with the first or
subsequent treatments. Therapeutic strategies may include
switching (i.e., stopping one treatment and starting another)
or augmenting/combining (i.e., adding a second treatment to
the first).
STAR*D (Sequenced Treatment Alternatives to Relieve
Depression) is a multisite, prospective, sequentially randomized
controlled trial of outpatients with nonpsychotic major
depressive disorder that is using randomization to compare
various switching or augmenting strategies (as shown in the
Figure) either commonly used or that are based on pharmacologic
reasoning. The study includes self-declared patients
seeking treatment at either primary or specialty care
practices.
Patients, as in practice, may select among the strategies.
For instance, a patient may choose to only accept augmentation
or only switching. However, all participants are randomly
assigned to the specific treatments within the strategies that
they find acceptable. This so-called equipoise stratified randomized
design mimics clinical practice, so that results
should have high practical relevance.

12. Treatment Resistant Depression
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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
4,360 participants across 22 clinical centers
Aims: Provide relevant clinical information to the practitioners, besides conventional industry sponsored RCTs
Differences: enrolled a large nationally representative sample, allow typical co-morbidities (e.g. substance abuse), follow prescribed standard of care practice (allowing concurrent medications administration)
Other goals: to collect longitudinal data describing the treated course of bipolar (over 2 y follow up)
Conduce a series of focused RCTs on under-researched topics important to clinical management of bipolar, particularly bipolar depression
Studies done in combination with already prescribed mood stabilization treatment.
Focused studies
Study 1: Largest of the RCTs, examined the effectiveness of antidepressants bupropion and paroxetine as acute phase therapies for bipolar depression in pts taking mood stabilizers.
these 2 AD’s were picked as they were commonly used, and felt to be least associated with switching.
Study 2: Investigated adjunctive focused psychotherapy in pts taking mood stabilizers (and +/- concomitant antidepressants)
Study 3: Examined 2 alternate pharmocotherapies for antidepressant resistant bipolar depression (lamotrigine (novel anticonvulsant), risperidone (atypical antipsychotic), inositol (sugar derivative with modulatory effect on intracellular signaling—neuronal signaling )
All randomized, only #1 was masked and placebo controlled. #2 and #3 were “open label”
Will look at study 1 on next slide.
Briefly, study 2 examined intensive psychosocial interventions with less intense psychoeducation (3 session).
CBT: cognitive behavioral therapy: psychoeducation (including strategies for detecting and dealing with warning signs of impending relapse), behavioral activation (ie. Activity scheduling and graded task assignments), problem solving, and cognitive restructuring ((ie. Socratic questioning and recognition of automatic negative thoughts and beliefs, and exploration of more positive or balanced alternative interpretations).
IPSRT: individual interpersonal and social rhythms therapy: targeted irregular sleep/wake schedules and inconsistencies in daily routines using the social rhythm metric instrument and identification of key interpersonal problem areas (ie. Role disputes, role transitions, unresolved grief, interpersonal deficits). Monitoring and recording of daily activities. Aim to maximize consistency in daily routine and promote mood stability.
FFT: family focused therapy: regular participation of at least 1 famil member: psychoeducation, stress management, interpersonal communication.
Results: intensive psychotherapies significantly higher recovery rates at 1 y (64 v. 52%)
Significantly faster time to recovery (median 169 v. 279 days)
1.6x more likely to be in remission during any study month.
No interaction: psychotherapy X pharmacotherapy (antidepressants)
Trend toward FFT being the most effective.
Study 3. AD resistant bipolar depression (paroxetine, bupropion or other reuptake inhibitors)
66 ss randomized to 16 w adjunctive tx with lamotrigine, inositol or risperidone
Inositol, a simple six-carbon sugar, forms the basis of a number of important intracellular signaling molecules, and thought to treat BP given inositol depletion hypothesis.
Equipoise stratified randomization: all 3 or 2 or 3.
Recovery: ltg 24% v. ino 17% v. risp 5%, non signficant trend
Ltg favored on CGI and GAF scores
Take home: overall generally poor response rates.
Study 4. longitudinal study of recovered. Original plan was to compare vpa and lithium, alone and in combination….closed due to poor enrollment
Naturalistic study with 2 y follow up of 2000 pts.
858 ss followed recovered and had at least 1 y follow up: 22.4% MDE, 6.4% manic/hypomanic/mixed episode recurrence.
Highest recurrence for those with >20 lifetime episodes.
Increased risk of manic/hypomanic/mixed recurrent for rapid cycling w/in past year, bipolar I, current subst abuse, number of lifetime manic episodes, residual manic sxs, number of depressive episodes in past year.
Increased risk of depression for lifetime hx of eating disorder, comorbid anxiety disorder, number of lifetime MDE, residual manic sxs, residual depressive sxs.
Take home: presence of residual mood elevation sxs largest independent predictor of risk of recurrence of depressed or mood elevation episodes…therefore clinicians need to treat to remission and monitor closely.
Inclusion: bipolar disorder I, II, NOS, or cyclothymia
patients were assigned a “STEP-BD-certified” psychiatrist. These psychiatrists received 20 hours of training on best practice procedures for how to treat patients with bipolar disorder. These “best practices” were written by a committee of bipolar disorder experts, who identified nine different clinical decision points corresponding to nine common clinical situations in the treatment of bipolar patients. At each decision point, there is a defined Standard Care Pathway with a “menu of reasonable choices
The researchers found that slightly more than half (58%) of this group of patients achieved recovery, defined as having only two symptoms of the disorder for a period of at least 8 weeks, during the 2-year follow-up period. In addition, almost half of the recovery group had a recurrence during the up to 2 years of follow-up, and the majority (70%) of recurrences were characterized by a return to a depressive state.
According to the researchers, these results indicate that in spite of modern, evidence-based treatment, bipolar disorder remains a highly recurrent, predominantly depressive illness.
VPA was associated with PCOS (menstrual irregularities, hirsutism, acne, male-pattern hair loss, elevated testosterone).
4360 pts2689 (62%) experienced a MDE were eligible for and consented to RCT participation.
Randomized to: paroxetine (93 ss), bupropion (86), placebo (187)
Discontinuation rate in both groups was 34%, no difference. 12% antidep group dropped out due to intolerable SFX, 9% of placebo group
Significant non adherence of mood stabilizer: 25% antidep, 29% placebo
No significant difference on transient remission (<8w), or durable recovery (>8w), or TEAS-treatment emergent affective switches
Transient remission: in the 15% range
Durable recovery: 24% active v. 27% placebo
TEAS: 10% active v. 11% placebo (for pts with previous antidep switch, 14% antidep v. 25% placebo, p= 0.10)
Take home: Study supports mood stabilizer alone (no antidepressant augmentation) as first line strategy for BP depression.
AD’s ineffective, though no increase in switching compared with placebo.
From: Thase ME. STEP-BD and Bipolar Depression: What Have We Learned? Current Psychiatry Reports ,9:

14. Augmentation Strategies
Evidence Rating*
Added $ Monthly
lithium 900 mg (to TCA) A 2
T3 25 ug (to TCA) 3
mirtazapine 15 mg
A/B 18
buspirone 40 mg B 4
Wellbutrin SR 300 mg 42
Zyprexa 10 mg
172
Provigil 200 mg
B/C
110
nortriptyline 100 mg C
pindolol 10 mg
lithium 900 mg (to SSRI)
T3 25 ug (to SSRI)
Effexor XR 150 mg 54
other atypicals
70-158
*Thase ME. CNS Spectrums 2004;9(11): (updated)
A= >1 RCTs
B= 1 RCT, plus c
C= Case series, anecdotal report, expert opinion
D= Anecdotal reports but experts have not endorsed
Nevertheless, when we do resort to augmentation, what is the evidence for efficacy and what are the comparative costs? I have included all augmentations rated at least C by Thase. I have here the VA costs – you can extrapolate to what they would be in the other situations from the tables I showed previously. Out of pocket for Olanzapine in retail pharmacy is $355. Provigil (modafinil) is $267. Obviously there are side effect issues that would govern choice and how to weigh these would have to be individualized to the patient depending on their likely susceptibilies and preferences

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
Examining the data supporting rTMS also raises further questions which underscore the difficulty of obtaining firm evidence for the efficacy of somatic treatments, and I would argue, bring into question, the validity of a pure physicalist perspective.
The results upon which FDA clearance was based was published by John OReardon in The pivotal trial was a randomized, double-blind, sham-controlled trial lasting six weeks and included 325 patients, 155 of whom were randomly assigned to receive active rTMS treatments. The remaining 146 patients were randomly assigned to go through a “sham TMS” treatment: the device had inactive, nonmagnetic treatment coils.
The change in the total score on the Montgomery-Asberg Depression Rating Scale (MADRS) was defined as the a priori primary outcome measure. Nine secondary outcomes were also measured, including the Hamilton Depression Rating Scale for Depression (HamD).
Primary endpoint (MADRS at 4 wks) non-significant (p=0.057)
*Effect size 0.39 (active v. sham)
1.7 points on MADRS (very small)
At four weeks the difference between the two groups had a p-value of 0.057, and at six weeks the p-value was Thus, Study 101 was judged a failed trial—it did not support the hypothesis favoring the efficacy of rTMS.
O’Reardon JP et al. Efficacy and Safety of TMS in the Acute Treatment of Major Depression: A Multisite RCT. Biol Psychiatry 2007:62:

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)
Symbyax for acute TRD
Brintellix (2013)
Frtzima (2013)
Viibryd (2011)
Risperidone, ziprasidone manic/mixed episodes
Asenapine 2009: sz, manic/mixed BP I

18. Investigational Treatments Ketamine (NMDA Antagonists)
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Investigational Treatments Ketamine (NMDA Antagonists)
Ketamine
Non-competitive NMDA receptor antagonist
FDA approved for use as anesthesia
AZD6765:
Low-trapping NMDA channel blocker
No dissociative side effects
Only weak antidepressant effects
Ketamine produces rapid antidepressant effects in MDD and BP depression
Ketamine produces rapid antisuicidal effects
Low-trapping NMDA antagonist has rapid antidepressant effect and no psychotomimetic side effects
Courtesy of Carlos Zarate Jr, MD

19. HAMD Following a Single Ketamine Infusion
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Rapid Antidepressant Effect of Ketamine in Unmedicated Treatment Resistant MDD (n=18)
HAMD Following a Single Ketamine Infusion
Response: 50% decrease in HAMD
Monoaminergic
Antidepressant
71%
62-65%
56%
58%
53%
53%
% Participants Responding
Hamilton Depression Rating Scale (HAMD) *
35%
35% ** **
***
***
***
13%
-60 40 80
110
230
Day 1
Day 2
Day 3
Day 7 40 80
110
230
Day 1
Day 2
Day 3
Day 7 8
Weeks
Minutes
Minutes
Time
***p<0.001, **p<0.01, *p<0.05
Zarate et al. Arch Gen Psychiatry 2006
Courtesy of Carlos Zarate Jr, MD

20. Rapid Antidepressant Effect of Ketamine in
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Rapid Antidepressant Effect of Ketamine in
Treatment Resistant Bipolar (BP) Depression
First BP Study of Ketamine (n=18)
Replication BP study (n=15)
Ketamine
Placebo
MADRS *
***
***
***
***
***
***
***
***
***
***
***
***
***
-60 40 80
110
230
Day 1
Day 2
Day 3
Day 7
Day 10
Day 14
-60 40 80
110
230
Day 1
Day 2
Day 3
Day 7
Day 10
Day 14
Minutes
Time
Minutes
Diazgranados et al. Arch Gen Psych 2010
Zarate et al. Biol Psych 2012
Courtesy of Carlos Zarate Jr, MD
***p<0.001, **p<0.01, *p<0.05

21. Research Subjects and their families
Acknowledgement
Research Subjects and their families
NIMH/ETBP Staff
Extramural Collaborations
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
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

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