Clinical Management of Treatment Resistant Depression

Current Guidelines and Research Updates on Management of Depression Minkyung Park, M.D. Clinical Fellow Experimental Therapeutics & Pathophysiology Branch (ETPB) National Institute of Mental Health Outline Treatment of TRD - Definition of TRD - Depression Statistics - Treatment Algorithm - Alternative Treatments - Investigative Treatments

Introduction to NIMH Studies Disclosure No personal disclosures Off-Label Use of Ketamine What is treatment resistant depression? Failure of at least two antidepressants from different pharmacological classes Of adequate dose and duration In the absence of psychosocial dysfunctionwhose primary treatment is psychotherapy and not medication. Wijeratne et al, Treatment-resistant depression: critique of current approaches, Australian and New Zealand journal of psychiatry 2008

Treatment Resistant Depression Remission Depressed Trivedi et al. (Am J Psychiatry, 2006); Rush et al. (NEJM, 2006) Depression: The Need for Improved Treatments Problems with Current Antidepressants: Low remission rates Lag of onset of antidepressant effects

Next generation antidepressant Rapid onset: Hours to days Euthymic Standard antidepressant Lag of onset: 10-14 weeks Depressed Major Depressive Episode Initiate Treatment Courtesy of Carlos Zarate Jr, MD

Lessons from STAR*D Treatment Algorithms From Tamminga CA, Depression IV. Am J Psychiatry 2003, 160:2; 237. Treatment Resistant Depression Remission Depressed Trivedi et al. (Am J Psychiatry, 2006); Rush et al. (NEJM, 2006) Augmentation Strategies for MDD Augmentation

Evidence Added $ Rating* 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 bupropion SR 300 mg

B 42 olanzapine 10 mg B 172 modafinil 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 venlafaxine XR 150 mg C 54 other atypicals C 70-158 *Thase ME. CNS Spectrums 2004;9(11):808821.(updated)

A= >1 RCTs B= 1 RCT, plus c C= Case series, anecdotal report, expert opinion D= Anecdotal reports but experts have not endorsed (Not Really) Newer Antidepressants Vortioxetine (Brintellix) Levomilnacipran (Fetzima) Vilazodone (Viibryd)

Alternative Treatments Trans magnetic Stimulation (TMS) NeuroStar TMS OReardon JP et al. Efficacy and Safety of TMS in the Acute Treatment of Major Depression: A Multisite RCT. Biol Psychiatry 2007:62:1208-16 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 rTMS vs. ECT ECT was superior to high frequency rTMS in terms of response (65% vs. 49%) and remission (53% vs. 34%) There was no difference in MMSE between rTMS and ECT in meta-analysis of 10 studies. No significant difference in almost the entire cognitive spectrum except for verbal fluency and complex figure-delayed recall. There are not enough moderate- to long-term studies looking at the cognitive

side effects of rTMS and ECT. -J. Ren Progress in Neuro-psychopharmacology and biological psychiatry 2014 STEP-BD Acute Depression Medication Trial No significant differences on transient remission, durable recovery, or emergent affective switches between groups Thase ME. STEP-BD and Bipolar Depression: What Have We Learned? Current Psychiatry Reports. 2007,9:497-503.

STEP BD Adjunctive Treatment of Bipolar TRD For those who failed mood stabilizer + antidepressant, the addition of the following drug did not significantly improve depressive symptoms From Nierenberg et al, AJP 2006;163:210-6) Lithium Light metal, the salt (lithium carbonate) has been used since 1849 for a variety of conditions

Primary treatment for mania (bipolar illness) Adjunctive treatment for unipolar depression One of only 3-4 psychiatric treatments shown to reduce risk of suicide Toxicities: Cardiac, Neuro, Renal, Thyroid, Teratogenic Depression with Psychotic Features Misdiagnosis of psychotic depression is common Delusions or hallucinations Typically mood-congruent Associated with:

Increased severity More frequent hospitalization More frequent suicide Less frequent spontaneous remission Combination pharmacotherapy needed Rothschild et al. J Clin Psychiatry. 2008 Aug;69(8):1293-6. A Double-blind Randomized Controlled Trial of Olanzapine Plus Sertraline vs Olanzapine Plus Placebo for Psychotic Depression: Study of Pharmacotherapy of Psychotic Depression (STOP-PD) (N=259) Remission rates

HAM-D change scores Meyers, B. S. et al. Arch Gen Psychiatry 2009;66:838-847. Psychotherapy for (TRD) : A systematic review Current evidence examining the effect of psychotherapy as augmentation or substitute therapy for TRD is sparse and mixed results. Psychotherapy in TRD may: Modify maladaptive cognitions and behaviors Mitigate side effects of antidepressants Patients may prefer to not take medications: help with non-adherence. Trivedi et al. J Gen Int Med 2010

American Foundation for Suicide Prevention, 2012 Geographic Variation in U.S. Suicide Rates by County Current Treatments Only FDA approved medication for suicidal behavior: clozapine for patients with schizophrenia No FDA approved medication for suicidal thoughts Lithium not FDA approved but evidence of reducing suicidal behaviors Black box warning on SSRIs may have led to decreased depression treatment in adolescents and adults Ting et al., 2012; Deisenhammer et al. J Clin Psychiatry 2009; Larkin et al. Crisis 2008; Janofsky J Am

Acad Psychiatry Law 2009; Jick et al. JAMA 2004; Diazgranados et al. J Clin Psych 2010; Lu et al., 2014 Investigative Treatments 30 HAMD Following a Single Ketamine Infusion Response: 50% decrease in HAMD 80 % Participants Responding Hamilton Depression Rating Scale (HAMD)

Rapid Antidepressant Effect of Ketamine in Unmedicated Treatment Resistant MDD (n=18) 25 20 15 10 5 * ** ** Placebo Ketamine ***

*** *** 0 70 Monoaminergic Antidepressant 71% 60 53%

50 40 35% 56% 62-65% 58% 53% 35% 30 20

13% 10 0 -60 40 80 110 230 Day Day Day Day 1 2 7 3 Minutes Zarate et al. Arch Gen Psychiatry 2006 Courtesy of Carlos Zarate Jr,

MD Time 40 80 110 230 Day Day Day Day 7 2 3 1 Minutes 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) Ketamine Placebo 35 40 35 MADRS

30 30 25 20 15 25 20 *** *** *** ****** *** *** 15

10 5 0 Replication BP study (n=15) *** *** *** *** *** ***

* 10 -60 40 80 110 230 DayDay Day Day Day Day 1 2 3 7 10 14 Minutes 0 Time Diazgranados et al. Arch Gen Psych 2010 Courtesy of Carlos Zarate Jr,

MD 5 -60 40 80 110 230 DayDay Day Day Day Day 1 2 3 7 10 14 Minutes Zarate et al. Biol Psych 2012 ***p<0.001, **p<0.01, *p<0.05 Works Across the Nation Oral, intranasal, intermuscular ketamine Repeated ketamine Other agents that work on glutamatergic

system Vagus nerve stimulation, deep brain stimulation, and rTMS Investigative Works at NIMH Currently available NIMH studies

Ketamine-alcohol AV-101 Diazoxide Brain Inflammation Study (PBR28) Neurobiology of Suicide Repeated ketamine infusion rTMS 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) Study Recruitment Inpatient and Outpatient Studies Ages 18-65, based on eligibility 44% Female 32% Minority 24 years ill 50% disabled Failed >7 antidepressants

60% failed ECT 40-50% suicide attempts (mean 2.2 attempts) Majority of subjects are local MD/DC/Virginia National Recruitment Also Healthy Controls Resource www.clinicaltrials.gov http:// www.nimh.nih.gov/labs-at-nimh/join-a-stud y/index.shtml Acknowledgement Research Subjects and their families

NIMH/ETBP Staff Extramural Collaborations Carlos Zarate R. Machado-Vieira Allison Nugent Minkyung Park Mark Niciu Marc Lener Elizabeth Ballard Jessica Ihne Jennifer Evans Rafael De Sousa Wally Duncan 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! Minkyung Park, MD [email protected] Kalene Dehaut, MSW Social Worker/Outreach Recruiter Office of the Clinical Director, NIMH [email protected] For Study Participation Questions:

1-877-MIND-NIH Vortioxetine (Brintellix) FDA approved for Major Depressive Disorder in 2013 Mechanism: SRI + NRI + 5-HT1a/5-HT1b partial agonist Dose: 5-20 mg May improve cognitive function Adverse events: nausea, vomiting, constipation Levomilnacipran (Fetzima) FDA approved for Major Depressive Disorder in 2013

Mechanism: atypical SNRI 2x greater effect on NE than 5-HT Milnacipran (Savella) FDA approved for fibromyalgia Adverse Events: nausea, vomiting, constipation, erectile dysfunction, sweating, tachycardia, palpitations Vilazodone (Viibryd) FDA approved for Major Depressive Disorder in 2011 Mechanism: SRI + 5-HT1a partial agonist Dose: 10 40 mg Possible rapid onset (due to 5-HT1a

activity) Adverse events: diarrhea, nausea, vomiting, insomnia Investigational Treatments Ketamine (NMDA Antagonists) Courtesy of Carlos Zarate Jr, Neurobiology of Suicide Protocol Identify patients in current suicidal crisis Suicide attempt or acute suicidal thoughts in last 2 weeks

Multimodal assessment to identify potential biomarkers of acute suicide risk Dimensional perspective for suicidal thoughts/behaviors Imaging, blood biomarkers, sleep, psychiatric assessment, psychosocial assessment Evaluate changes in these acute factors after ketamine infusion

Identify correlates of antisuicidal response

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