2. 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
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)

3. Terence Ketter, MD -- Discussant Disclosures
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.

4. 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

5. 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

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

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

8. Patients With Residual Symptoms Relapse Faster Than Patients Without Residual Symptoms
Subjects were psychiatric in-patients or outpatients aged satisfying the Research Diagnostic Criteria (RDC) for definite primary unipolar major depression. Patients were followed every 3 months to remission and thereafter. Remission was defined as at least 2 consecutive months, retrospectively rated, with symptoms below the threshold for definite RDC major depression. Subsequent relapse was defined as at least 1 month with return of symptoms, retrospectively rated, sufficiently severe to satisfy RDC criteria for definite major depression.
Residual symptoms reaching 8 or more on the Hamilton Depression Scale 17-item total were present in 32% (19) of the 60 who remitted below major depression by 15 months. The pattern was of typical depressive symptoms. Residual symptoms were very strong predictors of subsequent early relapse, which occurred in 76% (13/17) of those with residual symptoms and 25% (10/40) of those without.
Paykel ES, et al. Psychol Med. 1995;25(6):

9. 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):

10. Applying the Concept of NNT
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/( ) = 1/.51 = 1.96
NNT is thus 2

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

12. Measurement-based Care (MBC) in the Treatment of Depression
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
Zimmerman M et al. Compr Psychiatry. 2012;53: ; 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.

13. MBC Improves Outcomes: Beijing Study
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)
Abstract
OBJECTIVE:
The authors compared measurement-based care with standard treatment in major depression.
METHODS:
Outpatients with moderate to severe major depression were consecutively randomized to 24 weeks of either measurement-based care (guideline- and rating scale-based decisions; N=61), or standard treatment (clinicians' choice decisions; N=59). Pharmacotherapy was restricted to paroxetine (20-60 mg/day) or mirtazapine (15-45 mg/day) in both groups. Depressive symptoms were measured with the Hamilton Depression Rating Scale (HAM-D) and the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR). Time to response (a decrease of at least 50% in HAM-D score) and remission (a HAM-D score of 7 or less) were the primary endpoints. Outcomes were evaluated by raters blind to study protocol and treatment.
RESULTS:
Significantly more patients in the measurement-based care group than in the standard treatment group achieved response (86.9% compared with 62.7%) and remission (73.8% compared with 28.8%). Similarly, time to response and remission were significantly shorter with measurement-based care (for response, 5.6 weeks compared with 11.6 weeks, and for remission, 10.2 weeks compared with 19.2 weeks). HAM-D scores decreased significantly in both groups, but the reduction was significantly larger for the measurement-based care group (-17.8 compared with -13.6). The measurement-based care group had significantly more treatment adjustments (44 compared with 23) and higher antidepressant dosages from week 2 to week 24. Rates of study discontinuation, adverse effects, and concomitant medications did not differ between groups.
CONCLUSIONS:
The results demonstrate the feasibility and effectiveness of measurement-based care for outpatients with moderate to severe major depression, suggesting that this approach can be incorporated in the clinical care of patients with major depression. .
Guo T et al. Am J Psychiatry. 2015;172(10):

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

15. Patient Health Questionnaire-9 (PHQ-9)
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?”
Baas KD et al. J Affect Disord. 2011;129:

16. 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:
Kroenke K et al. J Gen Intern Med. 2001;16: ;
The McArthur Initiative on Depression Primary Care. Available at:

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

18. NNT and NNH Benefits (NNT) Risks (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

19. Indirect Comparisons Using Registration Trials NNT for Response, NNH for D/C AE, and LHH
Abstract
BACKGROUND:
Vortioxetine is approved for the treatment of major depressive disorder and differs from other antidepressants in terms of its pharmacodynamic profile. Given the limited number of head-to-head studies comparing vortioxetine with other antidepressants, indirect comparisons using effect sizes observed in other trials can be helpful to discern potential differences in clinical outcomes.
METHODS:
Data sources were the clinical trial reports for the pivotal short-term double-blind trials for vortioxetine and from publicly available sources for the pivotal short-term double-blind trials for two commonly used generic serotonin specific reuptake inhibitor antidepressants (sertraline, escitalopram), two commonly used generic serotonin-norepinephrine reuptake inhibitor antidepressants (venlafaxine, duloxetine), and two recently introduced branded antidepressants (vilazodone, levomilnacipran). Response was the efficacy outcome of interest, defined as a≥50% reduction from baseline on the Montgomery-Asberg Depression Rating Scale or Hamilton Depression Rating Scale. The tolerability outcome of interest was discontinuation because of an adverse event. Number needed to treat (NNT) and number needed to harm (NNH) for these outcomes vs. placebo were calculated, as well as likelihood to be helped or harmed (LHH) to contrast efficacy vs. tolerability.
RESULTS:
The analysis included 8 studies for duloxetine, 3 studies for escitalopram, 5 studies for levomilnacipran, 1 study for sertraline, 4 studies for venlafaxine, 2 studies for vilazodone, and 11 studies for vortioxetine. NNTs for response vs. placebo were 6 (95% CI 5-8), 7 (5-11), 10 (8-16), 6 (4-13), 6 (5-9), 8 (6-16), and 9 (7-11), respectively. NNHs for discontinuation because of an adverse event vs. placebo were 25 (17-51), 31 (19-92), 19 (14-27), 7 (5-12), 8 (7-11), 27 (15-104), and 43 (28-91), respectively. LHH values contrasting response vs. discontinuation because of an adverse event were 4.3, 4.6, 1.8, 1.2, 1.4, 3.3, and 5.1 respectively.
LIMITATIONS:
Subjects were all participants in carefully designed and executed clinical trials and may not necessarily reflect patients in clinical settings who may have complex psychiatric and non-psychiatric comorbidities. The measured outcomes come from different studies and thus comparisons are indirect.
CONCLUSIONS:
Vortioxetine demonstrates similar efficacy to that observed for duloxetine, escitalopram, levomilnacipran, sertraline, venlafaxine, and vilazodone, however overall tolerability as measured by discontinuation because of an adverse event differs. Vortioxetine is 5.1 times more likely to be associated with response than discontinuation because of an adverse event when compared to placebo.
Citrome L. J Affect Disord. 2016;196:

20. 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 (NCT ) and avoidance of relapse for the pivotal maintenance study (NCT ); 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 (NCT )

21. Acute Use of Intranasal Esketamine
For intranasal ESK 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
* Pooled terms used in the product label, and thus may differ from information in the individual study reports

22. Maintenance Use of Intranasal Esketamine
Maintenance use of ESK (dose 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

23. Indirect Comparisons: Acute Response
Agent
Response (≥50% decrease in rating scale) vs. placebo
Discontinuation because of an AE*
LHH for response vs. discontinuation because of an AE
Rates
NNT
NNH
Esketamine (pivotal study)
69.3% vs. 52.0% 6
2.6% vs. 0% 38
6.3
Olanzapine-fluoxetine
40.3% vs. 27.8% 8
11.6% vs. 2.6% 12
1.5
Adjunctive aripiprazole
37.4% vs. 22.5% 7
3.8% vs. 1.5% 43
6.1
Adjunctive quetiapine XR
56.0% vs. 46.3% 11
12.1% vs. 2.3%
1.0
Adjunctive brexpiprazole
25.2% vs. 15.6%
2.6% vs. 0.7% 53
4.8
Duloxetine
51.5% vs. 34.1%
8.5% vs. 4.4% 25
4.3
Escitalopram
53.1% vs. 38.1%
5.2% vs. 1.9% 31
4.6
Levomilnacipran
44.8% vs. 34.6% 10
8.8% vs. 3.3% 19
1.8
Sertraline
51.7% vs. 32.7%
17.4% vs. 2.0%
1.2
Venlafaxine
48.3% vs. 30.6%
17.1% vs. 4.3%
1.4
Vilazodone
40.7% vs. 28.3%
7.0% vs. 3.1% 27
3.3
Vortioxetine
48.9% vs. 37.0% 9
6.3% vs. 3.9%
5.1
* 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): ; Citrome L. J Affect Disord. 2016;196:

24. Indirect Comparisons: Maintenance
Agent
Observed relapse/recurrence rates vs. placebo
NNT vs. placebo
Esketamine
26.7% vs. 45.3% 6
Vilazodone
20 mg/d: 11.4% vs. 12.6%;
40 mg/d: 13.4% vs. 12.6%
20 mg/d: 84
40 mg/d: -125
Desvenlafaxine
13.6% vs. 28.3% 7
Vortioxetine
15.0% vs. 30.0%
Quetiapine
14.2% vs. 34.4% 5
Agomelatine
20.6% vs. 41.4%
Sertraline
8.5% vs. 19.5% 10
Durgam S, et al. Int Clin Psychopharmacol. 2018;33(6): ; Rosenthal JZ, et al. J Clin Psychiatry. 2013;74(2): ; Boulenger JP, et al. J Psychopharmacol. 2012;26(11): ; Liebowitz M, et al. Depress Anxiety. 2010;27(10): ; Goodwin GM, et al. J Clin Psychiatry. 2009;70(8): ; Goodwin GM, et al. Int Clin Psychopharmacol. 2013;28(1):20-28; Kamijima K, et al. Int Clin Psychopharmacol. 2006;21(1):1-9.

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

26. 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”

27. 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

28. 
Questions? or