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Leslie Citrome, MD, MPH Disclosures

Leslie Citrome, MD, MPH Disclosures. In the past 12 months, consultant: Acadia, Alkermes, Allergan, Impel, Indivior, Intra-Cellular Therapeutics, Janssen, Lundbeck, Merck, Neurocrine, Noven, Osmotica, Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva, Vanda

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Leslie Citrome, MD, MPH Disclosures

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  1. Leslie Citrome, MD, MPHDisclosures • In the past 12 months, consultant: Acadia, Alkermes, Allergan, Impel, Indivior, Intra-Cellular Therapeutics, Janssen, Lundbeck, Merck, Neurocrine, Noven, Osmotica, Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva, Vanda • In the past 12 months, speaker: Acadia, Alkermes, Allergan, Janssen, Lundbeck, Merck, Neurocrine, Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva • Stocks (small number of shares of common stock): Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased > 10 years ago • Royalties: Wiley (Editor-in-Chief, International Journal of Clinical Practice), UpToDate (reviewer), Springer Healthcare (book)

  2. Terence Ketter, MD -- DiscussantDisclosures • Dr. Ketter has received honoraria from Otsuka Pharmaceuticals; is a member of the advisory board for Alkermes; is a consultant for KLJ Associates and Neurocrine Biosciences; is a stock shareholder of Janssen Pharmaceuticals; has received grant/research support from Merck Pharmaceuticals; and has received royalties from American Psychiatric Publishing, Inc.

  3. Integrating the New and the Old: Best Practices to Assess and Measure Symptoms and How to Best Incorporate New Medication Interventions in Clinical Practice Leslie Citrome, MD, MPH Clinical Professor of Psychiatry and Behavioral Sciences New York Medical College Valhalla, NY, USA

  4. Learning Objectives • Understand how to appraise potential benefits and harms of antidepressant medication treatment using number needed to treat and number needed to harm • Understand the principles of measurement-based care

  5. Outline • Importance of treating to remission • Using rating scales • Choosing among interventions • Summary

  6. Outline • Importance of treating to remission • Using rating scales • Choosing among interventions • Summary

  7. Patients With Residual Symptoms Relapse Faster Than Patients Without Residual Symptoms Paykel ES, et al. Psychol Med. 1995;25(6):1171-1180.

  8. Concepts Related to Benefit/Risk:Effect Size - Number Needed to Treat NNT is one measure of effect size It is independent of P value and does not say anything about the likelihood of the difference between treatments being due to chance alone Helps you judge clinical significance NNT, number needed to treat. Citrome L. Acta Psychiatr Scand.2010;121(2):94-102.

  9. 76% relapse rate with residual symptoms vs. 25% relapse rate without residual symptoms How many MDD patients do you need to treat without residual symptoms vs. with residual symptoms before avoiding an additional relapse event in 15 months? NNT = 1/(.76-.25) = 1/.51 = 1.96 NNT is thus 2 Applying the Concept of NNT

  10. Outline • Importance of treating to remission • Using rating scales • Choosing among interventions • Summary

  11. MBC = the use of standardized scales to measure the outcome of psychiatric treatment Utilized in the Sequence Treatment Alternatives to Relieve Depression (STAR*D) study Recommended in the American Psychiatric Association’s Revised guidelines for the treatment of Major Depressive Disorder Measurement-based Care (MBC) in the Treatment of Depression Zimmerman M et al. Compr Psychiatry. 2012;53:117-124; Trivedi M et al. Am J Psychiatry. 2006, 163:28-40; American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. Arlington, VA: American Psychiatric Association; 2010.

  12. 120 Psychiatric outpatients with MDD Patients were randomized to treatment as usual vs MBC MBC included measuring outcome and prescribed treatment adjustments based on QIDS scores Patients treated with either NaSSA or SSRI antidepressant medication Results: Remission rate: 73.8% vs 28.8% (p < 0.001)  NNT = 3 Response rate: 86.9% vs 62.7% (p = 0.002)  NNT = 5 Number of treatment adjustments was greater in MBC condition: 44 vs 23 (p < 0.001) MBC Improves Outcomes: Beijing Study . Guo T et al. Am J Psychiatry. 2015;172(10):1004-1013.

  13. Patient Health Questionnaire-9 (PHQ-9) . Baas KD et al. J Affect Disord. 2011;129:229-235.

  14. There is an additional item: “If you checked off any problems, how difficult have these problems made it for you to do your work, take care of things at home, or get along with other people?” Patient Health Questionnaire-9 (PHQ-9) Baas KD et al. J Affect Disord. 2011;129:229-235.

  15. Scored 0 to 3 points per item (range 0 to 27) • Severity of depression: • 0−4 = minimal depression • 5−9 = mild depression • 10−14 = moderate depression • 15−19 = moderately severe depression • 20−27 = severe depression • Scale is available at: http://www.cqaimh.org/pdf/tool_phq9.pdf Kroenke K et al. J Gen Intern Med. 2001;16:606-613; The McArthur Initiative on Depression Primary Care. Available at: http://www.cqaimh.org/pdf/tool_phq9.pdf.

  16. Outline • Importance of treating to remission • Using rating scales • Choosing among interventions • Summary

  17. NNT and NNH An intervention should have a small NNT to show the benefit is large and a large NNH to show the risk of harm is small Benefits (NNT) Risks (NNH) time

  18. Indirect Comparisons Using Registration TrialsNNT for Response, NNH for D/C AE, and LHH Citrome L. J Affect Disord. 2016;196:225-233.

  19. Can We Calculate NNT and NNH for Intranasal Esketamine? Esketamine nasal spray (ESK) was approved by the FDA in March 2019 for the treatment of treatment-resistant depression in adults The Advisory Committee Briefing Document provides the data for NNT for efficacy outcomes and the NNH for discontinuation because of a common AE for study drug [intranasal ESK plus a newly initiated oral antidepressant (AD)] vs. active comparator [intranasal placebo plus a newly initiated oral AD] NNT provided in the briefing document for response (≥50% decrease from baseline on MADRS total score) and remission (MADRS scores ≤12) for the pivotal acute study (NCT02418585) and avoidance of relapse for the pivotal maintenance study (NCT02493868); NNH also provided in the briefing document for rates of discontinuation because of a common AE NNH calculated for tolerability outcomes from the Product Label (AEs, any severity)also includes data from a second study (NCT02417064) http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi.pdf; https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM630971.pdf

  20. Acute Use of Intranasal Esketamine * Pooled terms used in the product label, and thus may differ from information in the individual study reports http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi.pdf; https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM630971.pdf For intranasal ESK 56-84 mg twice weekly for 4 weeks, MADRS response with ESK plus an oral AD vs. active comparator at endpoint (69.3% vs. 52.0%) yielded a NNT value of 6, and MADRS remission at endpoint (52.5% vs. 31.0%) resulted in a NNT vs. active comparator of 5 Discontinuation rates because of a common AE (2.6% vs. 0%) yielded a NNH value of 38 LHH comparing MADRS remission vs. discontinuation because of a common AE is 38/5, or approximately 8 AEs as reported in the product label and where the NNH values vs. active comparator were <10 include dissociation* (41% vs. 9%), vertigo* (23% vs. 3%), nausea (28% vs. 9%), dizziness* (29% vs. 8%), hypoesthesia* (18% vs. 2%), sedation* (23% vs. 9%), with NNH values of 4, 5, 6, 5, 7, and 8, respectively

  21. Maintenance Use of Intranasal Esketamine http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi.pdf; https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM630971.pdf Maintenance use of ESK (dose 56-84 mg once weekly or once every other week) plus an oral AD demonstrated NNT values regarding relapse were in favor of ESK vs. active comparator, with relapse rates of 26.7% vs. 45.3% for the full stable remitters analysis set, yielding a NNT of 6; for the full stable responders analysis set, the rates were 25.8% vs. 57.6%, for a NNT of 4 Discontinuation rates because of a common AE (0.7% vs. 0%) yielded a NNH value of 152

  22. Indirect Comparisons: Acute Response * For esketamine, the discontinuation rates reflect discontinuation because of common AEs for the one identified study; from the product label data were pooled with another acute study and rates of discontinuation because of any AE were 4.6% vs. 1.4%, yielding a NNH of 31 Citrome L. Postgrad Med. 2010;122(4):39-48; Citrome L. Int J Clin Pract. 2015;69(9):978-997; Citrome L. J Affect Disord. 2016;196:225-233.

  23. Indirect Comparisons: Maintenance Durgam S, et al. Int Clin Psychopharmacol. 2018;33(6):304-311; Rosenthal JZ, et al. J Clin Psychiatry. 2013;74(2):158-166; Boulenger JP, et al. J Psychopharmacol. 2012;26(11):1408-1416; Liebowitz M, et al. Depress Anxiety. 2010;27(10):964-976; Goodwin GM, et al. J Clin Psychiatry. 2009;70(8):1128-1137; Goodwin GM, et al. Int Clin Psychopharmacol. 2013;28(1):20-28; Kamijima K, et al. Int Clin Psychopharmacol. 2006;21(1):1-9.

  24. Outline • Importance of treating to remission • Using rating scales • Choosing among interventions • Summary

  25. Summary Remission and elimination of residual symptoms in highly desirable MBC can help assess and track response and ultimately improve outcomes NNT and NNH can be helpful in appraising clinical trial results and calculating the “likelihood to help or harm”

  26. Case-based Question: Mr. G is 28-year-old man with major depressive disorder receiving escitalopram monotherapy for the past 6 weeks. His PHQ-9 score has dropped from 22 (severe) to 14 (moderate). The dose is near the top of the therapeutic range and he is 95% adherent. Mr. G is otherwise tolerating the medication well. He is not psychologically insightful and is not interested in psychotherapy of any kind. What should be the next step? Assess again using the PHQ-9 and then watchful waiting for another month while employing cognitive-behavioral therapy techniques Consider intranasal esketamine because the LHH is 8 compared to escitalopram’s LHH of 4.6 Switch to vortioxetine because the LHH is 5.1 compared to escitalopram’s LHH of 4.6 Consider augmentation with an atypical antipsychotic

  27. Questions? citrome@cnsconsultant.com or nntman@gmail.com

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