www.mghcme.org

Maurizio Fava, MD

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

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

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

Treatment-Resistant Depression (TRD)

Disclosures (lifetime): Maurizio Fava, MDType CompanyAdvisory Board/Consultant

Abbott Laboratories; Acadia; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; AuspexPharmaceuticals; 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.; Marinus Pharmaceuticals; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Navitor Pharmaceuticals, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neuronetics, Inc.; NextWavePharmaceuticals; 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; Purdue Pharma; PuretechVentures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC ( formerly Clinical Trials Solutions, LLC); Relmada Therapeutics, Inc.; RexahnPharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; ShenoxPharmaceuticals; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; SupernusPharmaceuticals, Inc.; Synthelabo; Taisho Pharmaceuticals; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex; Teva Pharmaceuticals; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Usona Institute,Inc.; Vanda Pharmaceuticals, Inc.; Versant Venture Management, LLC; 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; Primedia; 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.; Marinus Pharmaceuticals; 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; Otsuka Pharmaceutical Development, Inc.; 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; Taisho Pharmaceuticals; Takeda Pharmaceuticals; Tal Medical; VistaGen; Wyeth-Ayerst Laboratories

Stock/Other Financial Options

Equity Holdings: Compellis; PsyBrain, Inc.Royalty/patent, other income: Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven. Patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691).Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd.

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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?

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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

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Treatment Strategies for TRD

• Switching

• Dose Increase

• Augmentation

• Combination

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Switching Treatments: For Whom?

Switching

Non-Response

MarkedIntolerance

PartialResponse

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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

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Percent of Remission in STAR*D L-2 Switch

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

21.317.6

24.8 25.526.6

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)

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(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

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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)

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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)

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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

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Double-Blind Studies of High-Dose Fluoxetine vs. FluoxetineAugmentation 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 FluoxetineFluox + LithiumFluox + Desipramine

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

Overall P

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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)

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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

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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.)

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

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

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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

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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.)

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(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

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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 withMADRS>30 (n = 30)

BuspironePlacebo

Perc

ent

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0.0

0.5

1.0

1.5

2.0

2.5

3.0

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

*p

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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 periodData derived from ClinicalTrials.gov

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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

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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

PramipexolePlacebo

ns

ns

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

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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,

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

Prospective Study (n=101)

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

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Double-Blind, Placebo-Controlled Study of QuetiapineAugmentation 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

cha

nge

from

ran

dom

izat

ion

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

Week

Impr

ovem

ent

-12

-10

-8

-6

-4

-2

0

0 1 2 3 4 5 6

LS m

ean

(SE)

cha

nge

in M

ADR

S to

tal

scor

e

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

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

Papakostas et al, AmJPsychiatry2015; 172:1251–1258

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A Double-Blind, Randomized, Placebo-ControlledStudy 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)

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

Lyoo et al, Am J Psychepub

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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)

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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

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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.

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

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

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Citicoline (100 mg BID) Combination Therapy for Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

Roohi-Azizi et al, Clin Neuropharm 2017;40: 1–5

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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

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

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

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

Singh et al, Am J Psychiatry. 2016 Aug 1;173(8):816-26.

*TRD assessed with ATRQ by SAFER rater

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

*TRD assessed with the ATRQSingh et al, Biol Psychiatry. 2016 Sep 15;80(6):424-31.

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Double-Blind Study of Rapastinel (GLYX-13), Modulator of the NMDA Receptor, in TRD*

0 7 14

-15

-10

-5

0 Placebo

1 mg/kg 5 mg/kg10 mg/kg

Day after dosing

HDRS

-17,

differ

ence

from

base

line

GLYX-13

30 mg/kg

1 3

*

*

Baseline HDRS-17 was 26 (n=33), 26 (n=25), 25 (n=20), 25 (n=17), 25 (n=21) forPlacebo 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

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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 computerQuiroz et al, JAMA Psychiatry. 2016;73(7):675-684.

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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

TopiramatePlacebo

*

•p

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Adjunctive Pregabalin (75-300 mg/day) (pregabalin increases the activity of the neuronal glutamate transporter type 3 (EAAT3)) in Partial

Responders With Major Depressive Disorder and Residual Anxiety

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

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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

Chart1

MADRS DiffMADRS Diff

HDRS DiffHDRS Diff

CGI-S DiffCGI-S Diff

NS

NS

NS

Lamotrigine

Placebo

9.31

9.37

7.52

7.04

1.04

1.17

Sheet1

LamotriginePlacebo

MADRS Diff9.319.37

HDRS Diff7.527.04

CGI-S Diff1.041.17

To resize chart data range, drag lower right corner of range.

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Double-Blind, SPCD Study of Riluzole (100 mg/day) (Inhibitor of the Release of Glutamic Acid and a Noncompetitive Antagonist of N-

methyl-D-aspartate (NMDA) Receptors) Augmentation in TRD

0 1 2 3 4 5 6 7 8

Mea

n M

ADR

S sc

ore

Week

Pla-Pla

Pla-Ril

Ril-Ril

BLOCK 1 BLOCK 2

N observed cases:Pla-Pla 40 40 36 37 37 36 37 35 37Pla-Ril 39 39 37 36 36 35 33 32 34Ril-Ril 25 25 25 23 23 23 21 23 23

4 wk 8 wk

MADRS Scores Over 8 Week Study Period

Mathew et al, Neuropsychopharmacology. 2017 May 29. doi: 10.1038/npp.2017.106. [Epub ahead of print]

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Effect of Memantine (20 mg/day) Combination Therapy on Symptoms in Patients with Moderate-to-Severe Depressive Disorder:

Randomized, Double-Blind, Placebo-Controlled Study

Amidfar et al, Journal of Clinical Pharmacy and Therapeutics, 2017, 42, 44–50

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Double-Blind Study of D-Cycloserine (1 gr/day) (a Partial Agonist at the Glycine Recognition Site of the Glutamatergic NMDA Receptor)

Augmentation in Treatment Resistant Depression (n=26)

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

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Minocycline (200 mg/day) (an Anti-Inflammatory and Neuroprotective Agent) as an Adjunct for Treatment-Resistant

Depressive Symptoms: A Pilot, Randomized Placebo-Controlled Trial

Husain et al, J Psychopharmacol. 2017 Aug 1:269881117724352. doi: 10.1177/0269881117724352. [Epub ahead of print]

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Dextromethorphan/Quinidine (45/10 mg/day) (Dextromethorphan is an NMDA receptor Antagonist) Pharmacotherapy in Patients

with TRD: A Proof of Concept, Open Clinical Trial

Murrough et al, Journal of Affective Disorders 218 (2017) 277–283

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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

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

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

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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.

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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

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

McAllister-Williams et al, Lancet Psychiatry 2016; 3: 117–27Eligible 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

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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.)

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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.orgNelson 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

RemissionResponse without Remission

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

nsns

ns

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

Rem

issi

on R

ates

%

%

%

%

%

%

%

Chart1

All SubjectsAll SubjectsAll Subjects

Non-RespondersNon-RespondersNon-Responders

Partial RespondersPartial RespondersPartial Responders

High-Dose Fluox

Fluox & DMI

Fluox & Lithium

42.4

29.4

23.5

35.3

26.3

12.5

50

33.3

33.3

Sheet1

All SubjectsNon-RespondersPartial Responders

High-Dose Fluox42.435.350

Fluox & DMI29.426.333.3

Fluox & Lithium23.512.533.3

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Double-Blind Study of AtomoxetineAugmentation

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

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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

39.032.9

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

Open-Label, Randomized Trial of Aripiprazole Versus Bupropion Augmentation in Patients With Major Depressive Disorder Unresponsive to Selective Serotonin Reuptake Inhibitors

Cheon et al, J Clin Psychopharmacol 2017;37: 193–199

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Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant

Treatment: The VAST-D Randomized Clinical Trial

Mohamed et al, JAMA. 2017;318(2):132-145. doi:10.1001/jama.2017.8036

P

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 13.815.7

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

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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

Treatment-Resistant �Depression (TRD)Disclosures (lifetime): Maurizio Fava, MDFirst Steps in the Evaluation of TRD PatientsContributing Factors to TRDTreatment Strategies for TRDSwitching Treatments: For Whom?Switches: RationalesPercent of Remission in STAR*D L-2 SwitchPercent of Remission in STAR*D L-3 SwitchSwitching: Practical ApproachesDose IncreaseDouble-Blind Study of High-Dose Fluoxetine vs. Lithium or Desipramine: �Augmentation of Fluoxetine in Partial & Non-Responders to Fluoxetine Double-Blind Studies of High-Dose Fluoxetine vs. Fluoxetine Augmentation with Lithium or Desipramine (n = 142)Dose Increase: Practical ApproachesAugmentationLithium AugmentationMeta-Analysis of Lithium Augmentation of�Tricyclic and Second Generation Antidepressants in MDDDouble-Blind, Placebo-Controlled Study of Lithium Augmentation of NortriptylineThyroid AugmentationPercent of Remission in STAR*D L-3 AugmentationPercentage Reduction in MADRS Scores with Buspirone vs. Placebo Augmentation of SSRIsLow-Dose Combination of Buspirone (15 mg/day) and Melatonin (3 mg qhs) Is More Effective than Placebo and Buspirone Alone in MDDLisdexamfetamine Dimesylate Augmentation for MDD with Inadequate Response to Antidepressant Monotherapy: Results from 2 phase 3 Studies*Pooled Analysis of Studies on Modafinil (200 mg/day) Augmentation in SSRI Partial Responders with MDD and Persistent Fatigue and Sleepiness (n=348)Double-Blind, Placebo-Controlled Study of Pramipexole (up to 1.5 mg bid) in Treatment Resistant Depression (n=60)Three Double-Blind Studies of Adjunctive Aripiprazole to ADT in TRD - Two Pooled Studies and a Single Study*Aripiprazole Augmentation versus Antidepressant Switching for�Patients with TRD: A 6-week, Randomized, Rater-blinded, Prospective Study (n=101)Double-Blind, Placebo-Controlled Study of Quetiapine Augmentation in TRDDouble-Blind Study of Adjunctive Brexpiprazole to ADT in TRD – Studies 227* and 228*Double-Blind Study of Adjunctive Ziprasidone to Escitalopram in TRD (n=139)A Double‑Blind, Randomized, Placebo‑Controlled Study of Cariprazine as Adjunctive Therapy in TRD*Double-Blind, Placebo-Controlled Creatine (5 gr/day) Augmentation of SSRIs in Women with MDD (n=52)Double-Blind, Placebo-Controlled Trial of Adjunctive Cyclooxygenase-2 inhibitor Celecoxib Treatment in MDD PatientsDouble-Blind Study of SAMe (1600 mg/d) Augmentation in SSRI-Resistant Depressed PatientsDouble-Blind Study of L-Methylfolate (L-MTHF) Augmentation of SSRIs in TRD - Sequential Parallel Comparison Design (SPCD)Omega-3 Fatty Acid (1.2 gr/day) Augmentation of Citalopram Treatment for Patients With Major Depressive Disorder (n=42)Citicoline (100 mg BID) Combination Therapy for Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled TrialDouble-Blind Study of Amantadine (150 mg/day)�Augmentation of Imipramine in TRD Patients (n=50)Double-Blind, Placebo-Controlled, Crossover Study of i.v. Ketamine in TRD (n=18)Intravenous Ketamine in Adult Patients with Treatment-Resistant Depression: A Dose-Frequency Study*A Double-Blind, Doubly-Randomized, Placebo-Controlled Study of Intranasal Esketamine in TRD*Double-Blind Study of Rapastinel (GLYX-13), Modulator of the NMDA Receptor, in TRD*Double-Blind, Placebo-Controlled Study of Adjunctive Basimglurant, Negative Allosteric Modulator of the mGlu5 Receptor, in TRD*HAM-D Scores in Double-Blind Study of the Kainate (Glutamate) Receptor Antagonist Topiramate (100-200 mg/day) Augmentation in TRD (n=53)Adjunctive Pregabalin (75-300 mg/day) (pregabalin increases the activity of the neuronal glutamate transporter type 3 (EAAT3)) in Partial Responders With Major Depressive Disorder and Residual AnxietyDouble-Blind Study of the Glutamate Release Inhibitor Lamotrigine (up to 400 mg/day) Augmentation of Paroxetine in TRD Patients (n=96)Double-Blind, SPCD Study of Riluzole (100 mg/day) (Inhibitor of the Release of Glutamic Acid and a Noncompetitive Antagonist of N-methyl-D-aspartate (NMDA) Receptors) Augmentation in TRD Effect of Memantine (20 mg/day) Combination Therapy on Symptoms in Patients with Moderate-to-Severe Depressive Disorder: Randomized, Double-Blind, Placebo-Controlled StudyDouble-Blind Study of D-Cycloserine (1 gr/day) (a Partial Agonist at the Glycine Recognition Site of the Glutamatergic NMDA Receptor) Augmentation in Treatment Resistant Depression (n=26)Minocycline (200 mg/day) (an Anti-Inflammatory and Neuroprotective Agent) as an Adjunct for Treatment-Resistant�Depressive Symptoms: A Pilot, Randomized Placebo-Controlled TrialDextromethorphan/Quinidine (45/10 mg/day) (Dextromethorphan is an NMDA receptor Antagonist) Pharmacotherapy in Patients with TRD: A Proof of Concept, Open Clinical TrialAntidepressant Efficacy of the Antimuscarinic Drug Scopolamine (4 mcg/Kg): A Randomized, Placebo-Controlled Clinical TrialDouble-Blind Study of Oral Scopolamine �(1 mg/day) Augmentation on Citalopram in MDDDouble-Blind, SPCD Study of ALKS 5461 (buprenorphine plus the mu antagonist Alks 33) vs. PlaceboDouble-Blind, Placebo-Controlled Study of Testosterone Gel Augmentation in 100 TRD Men PatientsDouble-Blind, Placebo-Controlled Study of Metyrapone Augmentation (500 mg BID) in TRD Patients (n=165)Other Augmentation StrategiesCombinationCombination NE and 5-HT Reuptake Inhibition �vs. Either AloneDouble-Blind Study in 101 Non- and Partial Responders to an 8-week Fluoxetine Trial: Remission (HAM-D-17 < 8) Rates Double-Blind Study of Atomoxetine AugmentationPercent of Remission in STAR*D L-2 AugmentationOpen-Label, Randomized Trial of Aripiprazole Versus Bupropion Augmentation in Patients With Major Depressive Disorder Unresponsive to Selective Serotonin Reuptake InhibitorsEffect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical TrialDouble-Blind Study of Mirtazapine AugmentationPercent of Remission in STAR*D L-4Trazodone plus SSRIsConclusions