Treatment-Resistant Depression (TRD) 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

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?

Non- Partial Marked Response Response Intolerance

Switching

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

HRSD-17 QIDS-SR-16

30 26.6 24.8 25.5 25.0 21.3

20 17.6 Percent 10

0 BUP-SR SER VEN-XR BUP-SR SER VEN-XR (n = 239) (n = 238) (n = 250) (n = 239) (n = 238) (n = 250)

Rush et al. N Engl J Med. 2006;354(12):1231-42. www.mghcme.org Percent of Remission in STAR*D L-3 Switch

30 HRSD-17 QIDS-SR-16

19.8 20 12.3 12.4 Percent 10 8.0

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

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

Trial Design

MDD patients resistant to 8 weeks of fluoxetine 20 mg/day

High-dose fluoxetine Fluoxetine 20 mg/day Fluoxetine 20 mg/day (40-60 mg/day) + + Desipramine 25-50 mg/day Lithium 300-600 mg/day

Fava M et al. Am J Psychiatry. 1994;15(9):1372-1374. Fava M. J Clin Psychopharmacol. 2002 Aug;22(4):379-387. www.mghcme.org Double-Blind Studies of High-Dose Fluoxetine vs. Fluoxetine Augmentation with Lithium or Desipramine (n = 142)

50.00% Overall P<.05 45.00% 40.00% 35.00% 30.00% High Dose Fluoxetine 25.00% Fluox + Lithium 20.00% Fluox + Desipramine 15.00% 10.00% 5.00% 0.00% Remission Rates 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. 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

15 ns Lithium (n-16) Placebo (n=15) 10

0 Baseline Week 2 Week 4 Week 6

Nierenberg AA et al. J Clin Psychopharmacol. 2003 Feb;23(1):92-5. 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 Percent of Remission in STAR*D L-3 Augmentation

HRSD-17 QIDS-SR-16 30 24.7 24.7

20 15.9 13.2 Percent 10

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

Nierenberg et al. Am J Psychiatry. 2006;163:1519-1530. www.mghcme.org Percentage Reduction in MADRS Scores with Buspirone vs. Placebo Augmentation of SSRIs

40 p < 0.05

35 p = NS Buspirone 30 Placebo 25

Percent 15

0 All MDD patients MDD patients with (n = 102) MADRS>30 (n = 30)

Appelberg BG et al. J Clin Psychiatry. 2001;62:448-452. www.mghcme.org Low-Dose Combination of Buspirone (15 mg/day) and Melatonin (3 mg qhs), Stimulating Hippocampal Neurogenesis, in MDD 3.5 Buspirone + melatonin (n=67) Placebo (n=33) Buspirone (n=34) 3.0 2.5 * 2.0

1.5

I Scores I -

CGI 1.0 0.5 0.0

*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. www.mghcme.org Targeting Neurogenesis: The Neurogenesis-Promoting Agent NSI-189 for the Treatment of MDD

3.8 p=0.02 p=0.03 3.6 d=0.90 d=1.10

3.4

3.2

3.0

2.8

2.6 Placebo 2.4 NS-189 NS-189 1x per day NS-189 2x per day 2.2 Symptoms of Questionnaire Depression NS-189 3x per day

2.0 -20 0 20 40 60 80 100 Study Day Fava et al, Mol Psychiatry. 2016 Oct;21(10):1483-4. 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 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 Double-Blind, Placebo-Controlled Study of Pramipexole (up to 1.5 mg bid) in Treatment Resistant Depression (n=60)

45%

40%

35% ns 30% ns 25% Pramipexole 20% Placebo 15%

10%

0% Response Rates Remission Rates

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

Change in MADRS total score from randomization over time (LOCF; MITT population) 0 PBO + AD (n = 160) QUE XR 150 mg/d + AD (n = 166) -5 QUE XR 300 mg/d + AD (n = 161)

-10

-15 Improvement

-20 LSM change change LSM

-25

from randomization from 1 2 4 6 Week 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

Bauer M et al. J Clin Psychiatry. 2009;70:540-549. www.mghcme.org Double-Blind Study of Adjunctive Brexpiprazole to ADT in TRD – Studies 227* and 228*

Study 227: LS mean (SE) change in MADRS total score 0 ADT + placebo (n=203) -2 ADT + Brex 1 mg (n=211) ADT + Brex 3 mg (n=213) -4 * LS mean difference ** -6 from placebo at Week 6 score * ** * Brex 1 mg * -8 * -1.30 (95% CI: -2.73, 0.13) ** ** p=0.0737 *** -10 ** *** Brex 3 mg

LS mean LS (SE) changein MADRS total *** *** -12 -1.95 (95% CI: -3.39, -0.51); 0 1 2 3 4 5 6 p=0.0079 Week

*p<0.05, **p<0.01 vs placebo *p<0.05, **p<0.01, ***p<0.001 vs placebo MMRM analysis; MADRS baseline: ADT + placebo 26.5, ADT + Brex 1 mg MMRM analysis; MADRS baseline: ADT + placebo 27.3, ADT + 26.9, ADT + Brex 3 mg 26.5 Brex 26.9 Study 228 CSR - Thase et al. J Clin Psychiatry. 2015 Study 227 CSR – Thase et al, J Clin Psychiatry. 2015 Sep;76(9):1232-40 Sep;76(9):1224-31.

*TRD assessed with ATRQ by site rater prior to enrollment into the prospective lead-in period, 30 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 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 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]

www.mghcme.org Palmitoylethanolamide (600 mg bid), with Anti-Inflammatory and Endocannabinoid Effects, as Adjunctive Therapy in MDD (n=58)

Ghazizadeh-Hashemi et al, Journal of Affective Disorders 232 (2018) 127–133 www.mghcme.org Double-Blind Study of the Anti-Viral Amantadine (150 mg/day) Augmentation of Imipramine in TRD Patients (n=50)

40 P<.05 35 30 25 20 Baseline Week 12 15 10 5 0 Imi Alone Imi+Amant Imi Alone Imi+Amant Women Men Rogoz Z, et al. Pharmacol Rep. 2007;59(6):778-784.

www.mghcme.org Double-Blind, Placebo-Controlled Study of SAGE-217, a Next Generation Positive Allosteric Modulator of GABA, in MDD

70% Day 14 Remission Rates: P=0.0005

60%

50%

40%

30%

20%

10%

0% Remission Rates Sage-217 Placebo http://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-reports-positive-top-line-results-phase-2 www.mghcme.org Double-Blind, Placebo-Controlled, Crossover Study of i.v. Ketamine, a Selective NMDA Receptor Antagonist, 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, Am J Psychiatry. 2016 Aug 1;173(8):816-26.

*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, Biol Psychiatry. 2016 Sep 15;80(6):424-31. www.mghcme.org Double-Blind Study of Rapastinel (GLYX-13), Modulator of GLYX-13 Significantlythe NMDA Receptor, Reduced in TRD* HDRS-17 Scores

0 Placebo GLYX-13 1 mg/kg 5 mg/kg -5 10 mg/kg 30 mg/kg

-10

from baseline from *

HDRS-17, HDRS-17, difference -15 *

0 1 3 7 14 Day after dosing Baseline HDRS-17 was 26 (n=33), 26 (n=25), 25 (n=20), 25 (n=17), 25 (n=21) for IV infusion (1-14 minutesPlacebo depending and GLYX-13, 1, upon 5, 10, and mass 30 mg/kg, of respectively. subject) resulted in 45% placebo response on *TRD assessed with ATRQ by site rater Day 1. A single dose of GLYXPreskorn- et13 al, Journalat 1 ofand Psychiatric 30 Practicemg/kg 2015 didVol. 21, not No. 2: significantly 140-149 www.mghcme.org 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. 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 Quiroz et al, JAMA Psychiatry. 2016;73(7):675-684.

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)

15 * Topiramate Placebo 10

0 Baseline Week 8

•p<.000 Mowla and Kardeh, Progress in Neuro-Psychopharm & Biol Psychiatry 35 (2011) 970–973 www.mghcme.org 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. www.mghcme.org Citicoline or CDP-Choline (100 mg BID), Increases EAAT2 Expression, a Glutamate Transporter, Combination Therapy for Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

Roohi-Azizi et al, Clin Neuropharm 2017;40: 1–5 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 (100 mg/day) (Inhibitor of the Release of Glutamic Acid and a Noncompetitive Antagonist of N- methyl-D-aspartate (NMDA) Receptors) Augmentation in TRD MADRS Scores Over 8 Week Study Period

BLOCK 1 BLOCK 2

Pla-Pla

Pla-Ril

Ril-Ril Mean MADRS score MADRS Mean

4 wk 8 wk 0 1 2 3 4 5 6 7 8 N observed cases: Week 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

Mathew et al, Neuropsychopharmacology. 2017 May 29. doi: 10.1038/npp.2017.106. [Epub ahead of print] www.mghcme.org Effect of Memantine (20 mg/day), a Low-affinity Voltage-dependent Uncompetitive Antagonist at Glutamatergic NMDA Receptors, 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 www.mghcme.org 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. www.mghcme.org Dextromethorphan/Quinidine (45/10 mg/day) (Dextromethorphan being 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 www.mghcme.org Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine (4 mcg/Kg), Which Increases mTORC1 Signaling: A Randomized, Placebo-Controlled Clinical Trial

P<.05

Furey and Drevets, Arch Gen Psychiatry. 2006;63:1121-1129 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, 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 Pooled Analysis of the FORWARD-4 and FORWARD-5 SPCD Studies of ALKS 5461

Ehrich et al, SOBP Meeting, 2017 www.mghcme.org Double-Blind, Crossover Trial (n=29) of a Single-Dose Psilocybin (0.3 mg/kg) or Niacin, Both in Conjunction with Psychotherapy, in Patients with Cancer-Related Anxiety and Depression

Ross et al, Journal of Psychopharmacology 2016, Vol. 30(12) 1165–1180 www.mghcme.org Rapid Antidepressant Effects of the Psychedelic Ayahuasca in TRD: a Randomized Placebo-Controlled Trial (n=29)

Palhano-Fontes et al, Psychological Medicine 1–9. https:// doi.org/10.1017/S0033291718001356 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 Combination NE and 5-HT Reuptake Inhibition vs. Either Alone

Remission 70 Response without Remission 60

Remission 50 Rate (%) 40

at 6 Weeks 30

0 Desipramine Fluoxetine Combination (n = 12) (n = 14) (n = 13)

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

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

Remission Remission Rates %

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

HRSD-17 QIDS-SR-16 50 39.0 40 32.9 29.7 30.1 30

Percent 20

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

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

www.mghcme.org Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial

P<.05 vs Switch and vs Bupropion Augment

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

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 Percent of Remission in STAR*D L-4

20 HRSD-17 QIDS-SR-16 15.7 13.7 13.8

6.9 Percent

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

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