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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; 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.
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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 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
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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
3.5Buspirone + 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
*
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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
Pramipexole
Placebo
ns
ns
Cusin et al, J Clin Psychiatry. 2013 Jul;74(7):e636-41.
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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 period Data derived from ClinicalTrials.gov
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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
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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 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 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
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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
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
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-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.
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Double-Blind Study of Adjunctive Ziprasidone to Escitalopram in TRD (n=139)
Papakostas et al, AmJPsychiatry2015; 172:1251–1258
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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)
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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
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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 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 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* 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
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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
Topiramate
Placebo
*
•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 [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
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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
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
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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
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]
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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 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
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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
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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
issio
n R
ate
s
%
%
%
%
%
%
%
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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.
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(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
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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