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)

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Disclosures (lifetime): Maurizio Fava, MD Type Company Advisory Board/ Consultant

Abbott Laboratories; 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.; 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; i3 Innovus/Ingenis; 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; 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; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc.

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 Abbot Laboratories; Alkermes, Inc.; American Cyanamid;Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company;EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; 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 Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; 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; 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); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven. 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

Marked Intolerance

Partial Response

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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.

21.3 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)

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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. 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 FluoxetineFluox + LithiumFluox + 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

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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 of Tricyclic 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 with MADRS>30 (n = 30)

Buspirone Placebo

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<.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.

CGI-I

Sco

res

Low-Dose Combination of Buspirone (15 mg/day) and Melatonin (3 mg qhs) Is More Effective than Placebo and Buspirone Alone in MDD

*

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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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Placebo-Controlled Study of Lisdexamfetamine Dimesylate Augmentation of SSRIs in MDD

Trivedi et al, J Clin Psychiatry. 2013 Aug;74(8):802-9

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Double-Blind, Placebo-Controlled Studies of SPD489 (Lisdexamfetamine Dimesylate) in TRD*

*TRD assessed with ATRQ by site rater prior to enrollment into the prospective lead-in period Data 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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Three Double-Blind Studies of Adjunctive Aripiprazole to ADT in MDD - 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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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

cha

nge

fr

om r

ando

miz

atio

n

-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

Impr

ovem

ent

Double-Blind Study of Adjunctive Brexpiprazole to ADT in MDD – Study 228*

*p<0.05, **p<0.01, ***p<0.001 vs placebo MMRM analysis; MADRS baseline: ADT + placebo 27.3, ADT + Brex 26.9

Thase et al. J Clin Psychiatry. 2015 Sep;76(9):1224-31. Study 228 CSR (ST tables) TRD assessed with ATRQ by site rater prior to enrollment into the prospective lead-in period

*

**

*** ***

*** ***

LS mean difference from placebo at Week 6 -3.21 (95% CI: -4.87, -1.54) p=0.0002

Double-Blind Study of Adjunctive Brexpiprazole to ADT in MDD – Study 227*

*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

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

Fava et al, ACNP Annual Meeting, 2014 *Treatment resistance assessed with the ATHF by site rater (resistance rating ≥3; ATHF global confidence score ≥3)

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

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

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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 Psych epub

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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 - 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 Citalopram Treatment for Patients With Major Depressive Disorder (n=42)

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

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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<.05

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

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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, ASCP Annual Meeting, 2014 *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 ATRQ Singh et al, 2015 ASCP Annual Meeting

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Double-Blind Study of 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) 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

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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 computer

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

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

the neuronal glutamate transporter type 3 (EAAT3)]

02468

101214161820

Pregabalin 300-450 mg/day Placebo

BaselineEndpoint

P<0.05 vs. placebo

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

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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)

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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

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Double-Blind, SPCD Study of Riluzole 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 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

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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.

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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

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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<.05

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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 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.

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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

PlaceboNS-189NS-189 1x per dayNS-189 2x per dayNS-189 3x per day

p=0.03d=1.10

Day 28 Day 84

Fava et al, Molecular Psychiatry (in press)

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

Fava et al, submitted for publication

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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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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.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

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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

ns ns

ns

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

Rem

issi

on R

ates

%

%

%

%

%

%

%

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Double-Blind Study of Atomoxetine Augmentation

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

39.0 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

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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