Clinical Management of Treatment Resistant Depression 3/3/00 12:08 PM 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 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

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 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 3/3/00 12:08 PM 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 3/3/00 12:08 PM 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

Lessons from STAR*D Treatment Algorithms 3/3/00 12:08 PM 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.

Treatment Resistant Depression 3/3/00 12:08 PM 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 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. 644 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. 366 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. 2007,9:497-503.

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):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 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

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 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 2007. 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 0.058. 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 2007:62:1208-16

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

Investigational Treatments Ketamine (NMDA Antagonists) 3/3/00 12:08 PM 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

HAMD Following a Single Ketamine Infusion 3/3/00 12:08 PM 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

Rapid Antidepressant Effect of Ketamine in 3/3/00 12:08 PM 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

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

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