www.mghcme.org

Maurizio Fava, MD

Director, Division of Clinical Research of the MGH Research Institute Executive Vice Chair, MGH Department of Psychiatry

Executive Director, MGH Clinical Trials Network and Institute (CTNI)

Associate Dean for Clinical and Translational Research Slater Family Professor of Psychiatry, Harvard Medical School

Treatment-Resistant Depression (TRD)

www.mghcme.org

Disclosures (lifetime): Maurizio Fava, MD

Type Company

Advisory Board/ Consultant

Abbott Laboratories; Acadia; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; Biogen; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; Indivior; i3 Innovus/Ingenis; Intracellular; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG;Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Osmotica; Otsuka Pharmaceuticals; Pamlab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite® LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; PPD; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC ( formerly Clinical Trials Solutions, LLC); Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Shenox Pharmaceuticals; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Taisho Pharmaceutical; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc.; VistaGen

Speaking/ Publishing

Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource,Corp.; Wyeth-Ayerst Laboratories

Research Support Abbott Laboratories; Acadia Pharmaceuticals; Alkermes, Inc.; American Cyanamid;Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; AXSOME Therapeutics; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Cerecor; Clintara, LLC; Covance; Covidien; Eli Lilly and Company;EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; FORUM Pharmaceuticals; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante; Methylation Sciences Inc; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM);National Coordinating Center for Integrated Medicine (NiiCM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; NeuroRx; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC;PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Takeda Pharmaceuticals;Tal Medical; VistaGen); Wyeth-Ayerst Laboratories

Stock/Other Financial Options

Stock/Other Financial Options: Compellis Pharmaceuticals, PsyBrain, Inc. Royalty/patent, other income:Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven.

www.mghcme.org

First Steps in the Evaluation of TRD Patients

• Diagnostic reassessment

– Is the patient unipolar or bipolar?

– What are the psychiatric and medical comorbidities?

• Were the previous trials adequate in dose and duration?

• Are the blood levels of the antidepressant in a therapeutic range?

• What are the possible contributing factors?

www.mghcme.org

Contributing Factors to TRD

• Misdiagnosis (e.g., bipolar disorder)

• Psychiatric comorbidity (e.g., substance abuse, OCD, PTSD)

• Medical comorbidity (e.g., hypothyroidism)

• Psychotic features

• Pharmacokinetic factors

− Concomitant use of metabolic inducers

− Rapid/fast metabolizers

www.mghcme.org

Treatment Strategies for TRD

• Switching

• Dose Increase

• Augmentation

• Combination

www.mghcme.org

Switching Treatments: For Whom?

Switching

Non-

Response

Marked

Intolerance

Partial

Response

www.mghcme.org

Switches: Rationales

• Switch within Class:

– There may be some differences across agents within the same class in pharmacological properties in vitro or in vivo (e.g., relatively greater uptake inhibition of other neurotransmitters such as norepinephrine or dopamine)

• Switch to a Different Class:

– To obtain a different neurochemical effect (e.g., from a relatively serotonergic agent to a relatively noradrenergic agent)

– A specific depressive subtype may be more responsive to one antidepressant class than another

www.mghcme.org

Percent of Remission in STAR*D L-2 Switch

Rush et al. N Engl J Med. 2006;354(12):1231-42.

21.3

17.6

24.8 25.5 26.6 25.0

0

10

20

30

BUP-SR

(n = 239)

SER

(n = 238)

VEN-XR

(n = 250)

Perc

ent

HRSD-17 QIDS-SR-16

BUP-SR

(n = 239)

SER

(n = 238)

VEN-XR

(n = 250)

www.mghcme.org

(n = 114) (n = 121)

Fava et al. Am J Psychiatry. 2006 Jul;163(7):1161-72.

Percent of Remission in STAR*D L-3 Switch

12.3

19.8

8.0

12.4

0

10

20

30

MRT NTP

Perc

ent

HRSD-17 QIDS-SR-16

(n = 114) (n = 121) MRT NTP

www.mghcme.org

Switching: Practical Approaches

• Gradual tapering the first agent while starting the new one

– Side effects of the new drug may be intensified by the concurrent presence of the first agent

– “Start low and go slow” with the new agent

– Consider possible drug-drug interactions

• Abrupt replacement with within class-switches

• Wash-outs are necessary with MAOIs (either when you start them or when you stop them)

www.mghcme.org

Dose Increase

• Definition:

− The use of doses higher than those considered standard for a given antidepressant

• Rationale:

− To increase the chance of obtaining adequate blood levels in rapid metabolizers

− To obtain a different neurochemical effect (e.g., going from a relatively selective serotonergic effect at lower doses to a dual-action effect at higher doses)

www.mghcme.org

Double-Blind Study of High-Dose Fluoxetine vs. Lithium or Desipramine: Augmentation of Fluoxetine in Partial & Non-Responders to Fluoxetine

Fava M et al. Am J Psychiatry. 1994;15(9):1372-1374. Fava M. J Clin Psychopharmacol. 2002 Aug;22(4):379-387.

Trial Design

High-dose fluoxetine

(40-60 mg/day)

Fluoxetine 20 mg/day

+

Desipramine 25-50 mg/day

Fluoxetine 20 mg/day

+

Lithium 300-600 mg/day

MDD patients

resistant to 8 weeks

of fluoxetine 20 mg/day

www.mghcme.org

Double-Blind Studies of High-Dose Fluoxetine vs. Fluoxetine Augmentation with Lithium or Desipramine (n = 142)

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%

30.00%

35.00%

40.00%

45.00%

50.00%

Remission Rates

High Dose Fluoxetine

Fluox + Lithium

Fluox + Desipramine

Data pooled from Fava M et al. Am J Psychiatry. 1994 Sep;151(9):1372-4 and Fava M et al. J Clin Psychopharmacol. 2002 Aug;22(4):379-87.

Overall P<.05

www.mghcme.org

Dose Increase: Practical Approaches

• Gradual increasing the dose by 50-100%

• Wait at least 4 weeks before deciding whether this strategy helps

• If no side effects are present, consider increasing the dose further

• Blood levels may be informative (even with SSRIs or other newer antidepressants)

www.mghcme.org

Augmentation

• Definition: the use of a psychotropic agent (without per se an indication for depression) to enhance the effect of an antidepressant

• Rationale:

– To obtain a different neurochemical effect by adding an agent affecting different neurotransmitter systems

– To broaden the therapeutic effect (e.g., by adding an anti-anxiety agent to an antidepressant)

– To combine agents with different mechanisms of action and/or indications

www.mghcme.org

Lithium Augmentation

• Lithium augmentation (> 600 mg/day) of TCAs, MAOIs, and SSRIs (Bauer M, Dopfmer S. J Clin Psychopharmacol. 1999

Oct;19(5):427-34.)

• Disadvantages: − Relatively low response rates in most recent studies

(Fava M et al. J Clin Psychopharmacol. 2002 Aug;22(4):379-87; Nierenberg AA et al. J Clin Psychopharmacol. 2003 Feb;23(1):92-5)

− Risk of toxicity (Salama AA, Shafey M. Am J Psychiatry. 1989 Feb;146(2):278.)

− Need for blood monitoring

• Advantage: The pooled odds ratio (from 9 studies) of response during lithium augmentation compared with placebo is 3.31 (95% confidence interval: 1.46-7.53) (Bauer

M, Dopfmer S. J Clin Psychopharmacol. 1999 Oct;19(5):427-34.)

www.mghcme.org

Meta-Analysis of Lithium Augmentation of Tricyclic and Second Generation Antidepressants in MDD

Nelson et al, Journal of Affective Disorders 168(2014)269–275

www.mghcme.org

Double-Blind, Placebo-Controlled Study of Lithium Augmentation of Nortriptyline

0

5

10

15

20

25

Baseline Week 2 Week 4 Week 6

Lithium (n-16)

Placebo (n=15)

Nierenberg AA et al. J Clin Psychopharmacol. 2003 Feb;23(1):92-5.

ns

www.mghcme.org

Thyroid Augmentation

• Thyroid hormone augmentation (25-50 mcg/day) (Aronson R et al. Arch Gen Psychiatry. 1996 Sep;53(9):842-8.)

• L-triiodothyronine (T3) has been used in preference and has been thought to be superior to thyroxine (T4) (Joffe RT, Singer W. Psychiatry Res. 1990 Jun;32(3):241-51.)

• Disadvantages: – All published controlled studies concern TCAs (Aronson R

et al. Arch Gen Psychiatry. 1996 Sep;53(9):842-8.) and only uncontrolled studies pertain to SSRIs (Agid O. Int J Neuropsychopharmacol. 2003 Mar;6(1):41-49; Iosifescu D et al. J Clin Psychiatry. 2005 Aug;66(8):1038-42)

• Advantage: Among the four randomized, double-blind studies, pooled effects were not significant (relative response: 1.53; 95% CI: 0.70-3.35; p = .29) (Aronson R et al. Arch Gen Psychiatry. 1996 Sep;53(9):842-8.)

www.mghcme.org

(n = 69) (n = 73)

Nierenberg et al. Am J Psychiatry. 2006;163:1519-1530.

Percent of Remission in STAR*D L-3 Augmentation

15.9

24.7

13.2

24.7

0

10

20

30

Lithium T3

Perc

ent

HRSD-17 QIDS-SR-16

(n = 69) (n = 73) Lithium T3

www.mghcme.org

Percentage Reduction in MADRS Scores with Buspirone vs. Placebo Augmentation of SSRIs

p = NS

p < 0.05

Appelberg BG et al. J Clin Psychiatry. 2001;62:448-452.

0

5

10

15

20

25

30

35

40

All MDD patients

(n = 102)

MDD patients with

MADRS>30 (n = 30)

Buspirone

Placebo

Perc

ent

www.mghcme.org

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5Buspirone + melatonin (n=67) Placebo (n=33) Buspirone (n=34)

*p<.05 combination vs placebo and buspirone alone. Fava et al. J Psychiatr Res. 2012 Dec;46(12):1553-63. This information includes a use that has not been approved by the US FDA.

CG

I-I S

core

s Low-Dose Combination of Buspirone (15 mg/day) and Melatonin (3 mg

qhs) Is More Effective than Placebo and Buspirone Alone in MDD

*

www.mghcme.org

Double-Blind, Placebo-Controlled Study of Pramipexole (up to 1.5 mg bid) in Treatment Resistant Depression (n=60)

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Response Rates Remission Rates

Pramipexole

Placebo

ns

ns

Cusin et al, J Clin Psychiatry. 2013 Jul;74(7):e636-41.

www.mghcme.org

Lisdexamfetamine Dimesylate Augmentation for MDD with Inadequate Response to Antidepressant Monotherapy: Results from 2 phase 3 Studies*

Richards et al, Journal of Affective Disorders 206(2016): 151–160 *TRD assessed with ATRQ by site rater prior to enrollment into the prospective lead-in period Data derived from ClinicalTrials.gov

www.mghcme.org

Double-Blind, Placebo-Controlled Studies of Lisdexamfetamine Dimesylate in TRD*

0

1

2

3

4

5

6

7

8

NCT00905424 NCT01435759

SPD489 20-70 mg

Placebo

SPD489 20-50 mg

SPD489 10mg

SPD489 30mg

SPD489 50mg

SPD489 70mg

*TRD assessed with ATRQ by site rater prior to enrollment into the prospective lead-in period

Data derived from ClinicalTrials.gov

www.mghcme.org

Pooled Analysis of Studies on Modafinil (200 mg/day) Augmentation in SSRI Partial Responders with MDD and Persistent Fatigue and

Sleepiness (n=348)

Fava et al, Annals of Clinical Psychiatry, 19[3]:153–159, 2007

www.mghcme.org

Three Double-Blind Studies of Adjunctive Aripiprazole to ADT in TRD - Two Pooled Studies and a Single Study*

Two pooled studies: Thase et al, Prim Care Comp J Clin Psych. 2008;10(6):440-7. TRD assessed with ATRQ by site rater prior to enrollment into the prospective lead-in period,

www.mghcme.org

Aripiprazole Augmentation versus Antidepressant Switching for Patients with TRD: A 6-week, Randomized, Rater-blinded,

Prospective Study (n=101)

Han et al, Journal of Psychiatric Research 66-67 (2015) 84-94

www.mghcme.org

Double-Blind, Placebo-Controlled Study of Quetiapine Augmentation in TRD

Bauer M et al. J Clin Psychiatry. 2009;70:540-549.

Change in MADRS total score from randomization over time

(LOCF; MITT population)

LSM

change

from

random

izati

on

-25

-20

-15

-10

-5

0

1 2 4 6

PBO + AD (n = 160) QUE XR 150 mg/d + AD (n = 166) QUE XR 300 mg/d + AD (n = 161)

p value active treatment vs. placebo + antidepressant:

QUE XR 150 mg/d + AD < 0.001 < 0.01 < 0.05 < 0.01

QUE XR 300 mg/d + AD < 0.001 < 0.001 < 0.05 < 0.01

Week

Impro

vem

ent

-12

-10

-8

-6

-4

-2

0

0 1 2 3 4 5 6

LS

me

an

(S

E)

ch

an

ge

in

MA

DR

S t

ota

l

sco

re

Week

Study 227: LS mean (SE) change in MADRS total score

ADT + placebo (n=203)

ADT + Brex 1 mg (n=211)

ADT + Brex 3 mg (n=213)

Double-Blind Study of Adjunctive Brexpiprazole to ADT in TRD – Studies 227* and 228*

*p<0.05, **p<0.01 vs placebo

MMRM analysis; MADRS baseline: ADT + placebo 26.5, ADT + Brex 1 mg 26.9, ADT + Brex 3 mg 26.5

Study 227 CSR – Thase et al, J Clin Psychiatry. 2015 Sep;76(9):1232-40 *TRD assessed with ATRQ by site rater prior to enrollment into the prospective lead-in period, 30

*

*

* ** *

** ** **

LS mean difference from placebo at Week 6 Brex 1 mg -1.30 (95% CI: -2.73, 0.13) p=0.0737 Brex 3 mg -1.95 (95% CI: -3.39, -0.51); p=0.0079

*

**

*** *** *** ***

*p<0.05, **p<0.01, ***p<0.001 vs placebo MMRM analysis; MADRS baseline: ADT + placebo 27.3, ADT + Brex 26.9 Study 228 CSR - Thase et al. J Clin Psychiatry. 2015 Sep;76(9):1224-31.

www.mghcme.org

Double-Blind Study of Adjunctive Ziprasidone to Escitalopram in TRD (n=139)

Papakostas et al, AmJPsychiatry2015; 172:1251–1258

www.mghcme.org

A Double-Blind, Randomized, Placebo-Controlled

Study of Cariprazine as Adjunctive Therapy in TRD*

Durgam et al, J Clin Psychiatry. 2016 Mar;77(3):371-8. *Treatment resistance assessed with the ATHF by site rater (resistance rating ≥3; ATHF global confidence score ≥3)

www.mghcme.org

A Double-Blind, Randomized, Placebo-Controlled Study of Cariprazine as Adjunctive Therapy in TRD*

A post hoc band-pass filter analysis was used to identify sites with unusually high or low placebo responses (mean placebo improvement of ≥3 or ≤10 points in

MADRS total score) and exclude those sites from the analyses;

Fava et al, ACNP Annual Meeting, 2014

www.mghcme.org

Double-Blind, Placebo-Controlled Creatine (5 gr/day) Augmentation of SSRIs in Women with MDD (n=52)

Lyoo et al, Am J Psych epub

www.mghcme.org

Double-Blind, Placebo-Controlled Trial of Adjunctive Cyclooxygenase-2 inhibitor Celecoxib Treatment in MDD Patients

Akhondzadeh et al, DEPRESSION AND ANXIETY 26:607–611 (2009)

www.mghcme.org

Double-Blind Study of SAMe (1600 mg/d) Augmentation in SSRI-Resistant Depressed Patients

Papakostas G et al; Am J Psychiatry 2010; 167:942–948

www.mghcme.org

Double-Blind Study of L-Methylfolate (L-MTHF) Augmentation of SSRIs in TRD - Sequential Parallel Comparison Design (SPCD)

Papakostas et al, Am J Psychiatry. 2012 Dec 1;169(12):1267-74.

www.mghcme.org

Omega-3 Fatty Acid (1.2 gr/day) Augmentation of Citalopram Treatment for Patients With Major Depressive Disorder (n=42)

Gertsik et al, J Clin Psychopharmacol 2012;32: 61-64

www.mghcme.org

Double-Blind Study of Amantadine (150 mg/day) Augmentation of Imipramine in TRD Patients (n=50)

0

5

10

15

20

25

30

35

40

Imi Alone Imi+Amant Imi Alone Imi+Amant

Baseline

Week 12

Women Men

P<.05

Rogoz Z, et al. Pharmacol Rep. 2007;59(6):778-784.

www.mghcme.org

Double-Blind, Placebo-Controlled, Crossover Study of i.v. Ketamine in TRD (n=18)

Zarate et al, Arch Gen Psychiatry. 2006;63:856-864

www.mghcme.org

Intravenous Ketamine in Adult Patients with Treatment-Resistant Depression: A Dose-Frequency Study*

Singh et al, ASCP Annual Meeting, 2014 *TRD assessed with ATRQ by SAFER rater

www.mghcme.org

A Double-Blind, Doubly-Randomized, Placebo-Controlled Study of Intranasal Esketamine in TRD*

*TRD assessed with the ATRQ Singh et al, 2015 ASCP Annual Meeting

www.mghcme.org

Double-Blind Study of GLYX-13, Modulator of the NMDA Receptor, in TRD* GLYX-13 Significantly Reduced HDRS-17 Scores

0 7 14

-15

-10

-5

0Placebo

1 mg/kg

5 mg/kg

10 mg/kg

Day after dosing

HD

RS

-17,

diff

eren

ce

fro

m b

asel

ine

GLYX-13

30 mg/kg

1 3

IV infusion (1-14 minutes depending upon mass of subject) resulted in 45% placebo response on Day 1. A single dose of GLYX-13 at 1 and 30 mg/kg did not significantly reduce HDRS-17 score over the period of Day 1 to Day 7 or Day 14 whereas single doses of 5 or 10 mg/kg reduced HDRS-17 score over the period from Day 1 to Day 7 (P<0.05 ANCOVA). Baseline HDRS-17 scores were 26.1 + 3.70, 25.2 + 3.02, 25.1 + 2.50,and 25.5 + 3.83 (mean + SD) and N=25, 20, 17, 21, and 33 for GLYX-13 1, 5, 10, or 30 mg/kg or placebo, respectively.

*

*

Baseline HDRS-17 was 26 (n=33), 26 (n=25), 25 (n=20), 25 (n=17), 25 (n=21) for Placebo and GLYX-13, 1, 5, 10, and 30 mg/kg, respectively. *TRD assessed with ATRQ by site rater Preskorn et al, Journal of Psychiatric Practice 2015 Vol. 21, No. 2: 140-149

www.mghcme.org

Double-Blind, Placebo-Controlled Study of Adjunctive Basimglurant, Negative Allosteric Modulator of the mGlu5

Receptor, in TRD*

*Treatment History Assessed with the ATRQ converted to an electronic form and administered on a computer

www.mghcme.org

HAM-D Scores in Double-Blind Study of the Kainate (Glutamate) Receptor Antagonist Topiramate (100-200 mg/day)

Augmentation in TRD (n=53)

0

5

10

15

20

25

Baseline Week 8

Topiramate

Placebo

*

•p<.000 Mowla and Kardeh, Progress in Neuro-Psychopharm & Biol Psychiatry 35 (2011) 970–973

www.mghcme.org

Pooled Analyses of Studies of Pregabalin in GAD Patients with Depression: HAM-D-17 Changes [pregabalin increases the activity of

the neuronal glutamate transporter type 3 (EAAT3)]

0

2

4

6

8

10

12

14

16

18

20

Pregabalin 300-450 mg/day Placebo

Baseline

Endpoint

P<0.05 vs. placebo

Stein DJ et al, European Neuropsychopharmacology (2008) 18, 422–430

www.mghcme.org

Adjunctive Pregabalin (75-300 mg/day) in Partial Responders With Major Depressive Disorder and Residual Anxiety

Vitali et al, J Clin Psychopharmacol. 2013 Feb;33(1):95-8.

Pregabalin increases the activity of the neuronal glutamate transporter type 3 (EAAT3)

www.mghcme.org

Double-Blind Study of the Glutamate Release Inhibitor Lamotrigine (up to 400 mg/day) Augmentation of Paroxetine in TRD Patients

(n=96)

Barbee et al, J Clin Psychiatry 2011; 72(10):1405-1412

www.mghcme.org

Double-Blind, SPCD Study of Riluzole Augmentation in TRD

0 1 2 3 4 5 6 7 8

Me

an

MA

DR

S s

co

re

Week

Pla-Pla

Pla-Ril

Ril-Ril

BLOCK 1 BLOCK 2

N observed cases:

Pla-Pla 40 40 36 37 37 36 37 35 37

Pla-Ril 39 39 37 36 36 35 33 32 34

Ril-Ril 25 25 25 23 23 23 21 23 23

4 wk 8 wk

MADRS Scores Over 8 Week Study Period

Mathew et al, ASCP Meeting, 2015

www.mghcme.org

Double-Bind Study in MDD Patients of Monotherapy with Memantine (5-20 mg/day), a Non-Competitive Glutamate NMDA Receptor Antagonist with Greater

Potency for NMDA Receptors Containing the NR2C than for NR2A Subunit-Containing Receptors

Zarate et al, Am J Psychiatry. 2006 Jan;163(1):153-5.

www.mghcme.org

Open-Label Study of Minocycline (150 mg/day) as Adjunctive Therapy for Patients with Unipolar Psychotic Depression (n=25)

Miyaoka et al, Progress in Neuro-Psychopharmacology & Biological Psychiatry 37 (2012) 222–226

www.mghcme.org

Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine (4 mcg/Kg): A Randomized, Placebo-Controlled Clinical Trial

Furey and Drevets, Arch Gen Psychiatry. 2006;63:1121-1129

P<.05

www.mghcme.org

Double-Blind Study of Oral Scopolamine (1 mg/day) Augmentation on Citalopram in MDD

Khajavi et al, J Clin Psychiatry 2012; 73:1428-1433

www.mghcme.org

Double-Blind Study of D-Cycloserine (1 gr/day) Augmentation in Treatment Resistant Depression (n=26)

Heresco-Levy et al, International Journal of Neuropsychopharmacology (2013), 16, 501–506.

www.mghcme.org

Changes in Symptoms of Depression Questionnaire Scores with NS-189, a Neurogenic Compound, in MDD

p=0.02d=0.90

Study Day

-20 0 20 40 60 80 100

Sym

ptom

s of

Dep

ress

ion

Que

stio

nnai

re

2.0

2.2

2.4

2.6

2.8

3.0

3.2

3.4

3.6

3.8

Placebo

NS-189

NS-189 1x per day

NS-189 2x per day

NS-189 3x per day

p=0.03d=1.10

Day 28 Day 84

Fava et al, Mol Psychiatry. 2015 Dec 8. doi: 10.1038/mp.2015.178. [Epub ahead of print]

www.mghcme.org

Double-Blind, SPCD Study of ALKS 5461 (buprenorphine plus the mu antagonist Alks 33) vs. Placebo

Fava et al, Am J Psychiatry. 2016 May 1;173(5):499-508.

www.mghcme.org

Double-Blind, Placebo-Controlled Study of Testosterone Gel Augmentation in 100 TRD Men Patients

NS

NS

Pope et al, J Clin Psychopharm 2010; 30: 126-134

www.mghcme.org

Double-Blind, Placebo-Controlled Study of Metyrapone Augmentation (500 mg BID) in TRD Patients (n=165)

McAllister-Williams et al, Lancet Psychiatry 2016; 3: 117–27 Eligible patients were aged 18–65 years with TRD (HAMD-17 score of ≥18 and a MGH Treatment-Resistant Depression staging score of 2–10) and taking a single-agent or combination antidepressant treatment that included a serotonergic drug

www.mghcme.org

Other Augmentation Strategies

• Inositol (up to 12 g/day) - recent double-blind study failed to support its use (Nemets B et al. J Neural Transm. 1999;106(7-8):795-8.)

• DHEA (up to 90 mg/day) – small, positive double-blind study (Wolkowitz OM et al. Am J Psychiatry. 1999 Apr;156(4):646-9.)

• Estrogen: mostly anecdotal evidence (Stahl SM. J Clin Psychiatry. 2001

Jun;62(6):404-5.)

www.mghcme.org

Combination

• Definition: The concomitant use of two antidepressants to enhance their therapeutic effect

• Rationale:

− To obtain a different neurochemical effect by combining antidepressants affecting different neurotransmitter systems

− To combine antidepressants with different mechanisms of action

www.mghcme.org

Nelson JC et al. Biol Psychiatry. 2004;55:296-300.

Combination NE and 5-HT Reuptake Inhibition vs. Either Alone

(n = 12) (n = 14) (n = 13)

Remission Rate (%)

at 6 Weeks

* p < 0.05 for combination vs. desipramine or fluoxetine alone

0

10

20

30

40

50

60

70

Desipramine Fluoxetine Combination

Remission Response without Remission

www.mghcme.org

Double-Blind Study in 101 Non- and Partial Responders to an 8-week Fluoxetine Trial: Remission (HAM-D-17 < 8) Rates

ns

ns

ns

Fava M. J Clin Psychopharmacol. 2002 Aug;22(4):379-387.

Rem

issio

n R

ate

s

%

%

%

%

%

%

%

www.mghcme.org

Double-Blind Study of Atomoxetine Augmentation

Reimherr F et al; Psychiatry Research 175 (2010) 67–73

www.mghcme.org

Percent of Remission in STAR*D L-2 Augmentation

(n = 279) (n = 286)

Trivedi et al. N Engl J Med. 2006;354(12):1243-52.

29.7 30.1

39.0

32.9

0

10

20

30

40

50

BUP-SR BUS

Perc

ent

HRSD-17 QIDS-SR-16

(n = 279) (n = 286) BUP-SR BUS

www.mghcme.org

Double-Blind Study of Mirtazapine Augmentation

Blier P et al; Am J Psych 2010 Mar;167(3):281-8.

www.mghcme.org

(n = 58) (n = 51)

McGrath et al. Am J Psychiatry. 2006;163:1531-1541.

Percent of Remission in STAR*D L-4

6.9

13.7 13.8 15.7

0

10

20

TCP VEN+MRT

Perc

ent

HRSD-17 QIDS-SR-16

(n = 58) (n = 51) TCP VEN+MRT

www.mghcme.org

Trazodone plus SSRIs

Maes M et al; Journal of Affective Disorders 41 (1996) 201-210

www.mghcme.org

Conclusions

• Treatment resistance is common in MDD

• Many strategies may be effective approaches for partial and non-responders to antidepressant treatment

• The potential loss of partial benefit from the failed trial may reduce the feasibility of switching strategies

• The presence of significant side effects from the antidepressant itself may reduce the acceptability of dose increase, augmentation and combination strategies