1. 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

2. Outline Treatment of TRD - Definition of TRD - Depression Statistics - Treatment Algorithm - Alternative Treatments - Investigative Treatments Introduction to NIMH Studies

3. Disclosure No personal disclosures Off-Label Use of Ketamine

4. 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 dysfunction- whose 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

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

6. Euthymic Depressed Next generation antidepressant Lag of onset: 10-14 weeks Rapid onset: Hours to days Standard antidepressant Major Depressive Episode Initiate Treatment Depression: The Need for Improved Treatments Courtesy of Carlos Zarate Jr, MD Low remission rates Lag of onset of antidepressant effects Problems with Current Antidepressants:

7. Lessons from STAR*D Treatment Algorithms From Tamminga CA, Depression IV. Am J Psychiatry 2003, 160:2; 237.

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

9. Augmentation Strategies for MDD AugmentationEvidence Rating* Added $ Monthly lithium 900 mg (to TCA)A2 T3 25 ug (to TCA)A3 mirtazapine 15 mgA/B18 buspirone 40 mgB4 bupropion SR 300 mgB42 olanzapine 10 mgB172 modafinil 200 mgB/C110 nortriptyline 100 mgC2 pindolol 10 mgC2 lithium 900 mg (to SSRI)C2 T3 25 ug (to SSRI)C3 venlafaxine XR 150 mgC54 other atypicalsC70-158 *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

10. (Not Really) Newer Antidepressants Vortioxetine (Brintellix) Levomilnacipran (Fetzima) Vilazodone (Viibryd)

11. Alternative Treatments

12. Trans magnetic Stimulation (TMS)

13. 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

14. 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

15. 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

16. 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.

17. 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)

18. 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

19. 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.

20. Meyers, B. S. et al. Arch Gen Psychiatry 2009;66:838-847. 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

21. 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

22. American Foundation for Suicide Prevention, 2012

23. Geographic Variation in U.S. Suicide Rates by County

24. 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

25. Investigative Treatments

26. Rapid Antidepressant Effect of Ketamine in Unmedicated Treatment Resistant MDD (n=18) Zarate et al. Arch Gen Psychiatry 2006 -60 80230110 40 Day 1 Day 3 Day 2 Day 7 Time * ** *** 80230110 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 Courtesy of Carlos Zarate Jr, MD

27. Rapid Antidepressant Effect of Ketamine in Treatment Resistant Bipolar (BP) Depression Diazgranados et al. Arch Gen Psych 2010Zarate et al. Biol Psych 2012 Replication BP study (n=15)First BP Study of Ketamine (n=18) MADRS -6080 230 11040 Day 1 Day 3 Day 2 Day 7 Day 10 Day 14 *** * -6080 230 11040 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 Courtesy of Carlos Zarate Jr, MD

28. 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

29. Investigative Works at NIMH

30. Currently available NIMH studies Ketamine-alcohol AV-101 Diazoxide Brain Inflammation Study (PBR28) Neurobiology of Suicide Repeated ketamine infusion rTMS

31. 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)

32. 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

33. Resource www.clinicaltrials.gov http://www.nimh.nih.gov/labs-at-nimh/join-a- study/index.shtml http://www.nimh.nih.gov/labs-at-nimh/join-a- study/index.shtml

34. Acknowledgement NIMH/ETBP Staff 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 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

35. Thank You! Minkyung Park, MD minkyung.park@nih.gov Kalene Dehaut, MSW Social Worker/Outreach Recruiter Office of the Clinical Director, NIMH kalene.dehaut@nih.gov For Study Participation Questions: 1-877-MIND-NIH

36. 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

37. 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

38. 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

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

40. 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 Neurobiology of Suicide Protocol