Treatment-Resistant Depression (TRD)

Transcription

1 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

2 Type Advisory Board/ Consultant Speaking/ Publishing Research Support Stock/Other Financial Options Company Disclosures (lifetime): Maurizio Fava, MD 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.; Marinus Pharmaceuticals; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Navitor Pharmaceuticals, 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; Purdue Pharma; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC ( formerly Clinical Trials Solutions, LLC); Relmada Therapeutics, Inc.; 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 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 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 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 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_ , US_ , US_ , US_ , US_ ); 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_ , US_ ). 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.

3 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?

4 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

5 Treatment Strategies for TRD Switching Dose Increase Augmentation Combination

6 Switching Treatments: For Whom? Non- Response Partial Response Marked Intolerance Switching

7 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

8 Percent of Remission in STAR*D L-2 Switch Percent HRSD-17 QIDS-SR 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):

9 Percent of Remission in STAR*D L-3 Switch 30 HRSD-17 QIDS-SR-16 Percent MRT NTP (n = 114) (n = 121) MRT NTP (n = 114) (n = 121) Fava et al. Am J Psychiatry Jul;163(7):

10 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)

11 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)

12 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 (40-60 mg/day) Fluoxetine 20 mg/day Desipramine mg/day + Fluoxetine 20 mg/day Lithium mg/day + Fava M et al. Am J Psychiatry. 1994;15(9): Fava M. J Clin Psychopharmacol Aug;22(4):

13 Double-Blind Studies of High-Dose Fluoxetine vs. Fluoxetine Augmentation with Lithium or Desipramine (n = 142) 50.00% 45.00% 40.00% 35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% Remission Rates Overall P<.05 High Dose Fluoxetine Fluox + Lithium Fluox + Desipramine Data pooled from Fava M et al. Am J Psychiatry Sep;151(9): and Fava M et al. J Clin Psychopharmacol Aug;22(4):

14 Dose Increase: Practical Approaches Gradual increasing the dose by % 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)

15 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

16 Lithium Augmentation Lithium augmentation (> 600 mg/day) of TCAs, MAOIs, and SSRIs (Bauer M, Dopfmer S. J Clin Psychopharmacol Oct;19(5): ) Disadvantages: Relatively low response rates in most recent studies (Fava M et al. J Clin Psychopharmacol Aug;22(4):379-87; Nierenberg AA et al. J Clin Psychopharmacol Feb;23(1):92-5) Risk of toxicity (Salama AA, Shafey M. Am J Psychiatry 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: ) (Bauer M, Dopfmer S. J Clin Psychopharmacol Oct;19(5): )

17 Meta-Analysis of Lithium Augmentation of Tricyclic and Second Generation Antidepressants in MDD Nelson et al, Journal of Affective Disorders 168(2014)

18 Double-Blind, Placebo-Controlled Study of Lithium Augmentation of Nortriptyline ns Lithium (n-16) Placebo (n=15) 5 0 Baseline Week 2 Week 4 Week 6 Nierenberg AA et al. J Clin Psychopharmacol Feb;23(1):92-5.

19 Thyroid Augmentation Thyroid hormone augmentation (25-50 mcg/day) (Aronson R et al. Arch Gen Psychiatry 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 Jun;32(3): ) Disadvantages: All published controlled studies concern TCAs (Aronson R et al. Arch Gen Psychiatry Sep;53(9):842-8.) and only uncontrolled studies pertain to SSRIs (Agid O. Int J Neuropsychopharmacol Mar;6(1):41-49; Iosifescu D et al. J Clin Psychiatry Aug;66(8): ) Advantage: Among the four randomized, double-blind studies, pooled effects were not significant (relative response: 1.53; 95% CI: ; p =.29) (Aronson R et al. Arch Gen Psychiatry Sep;53(9):842-8.)

20 Percent of Remission in STAR*D L-3 Augmentation 30 HRSD QIDS-SR Percent Lithium T3 (n = 69) (n = 73) Lithium T3 (n = 69) (n = 73) Nierenberg et al. Am J Psychiatry. 2006;163:

21 Percentage Reduction in MADRS Scores with Buspirone vs. Placebo Augmentation of SSRIs 40 p < 0.05 Percent p = NS Buspirone Placebo 0 All MDD patients (n = 102) MDD patients with MADRS>30 (n = 30) Appelberg BG et al. J Clin Psychiatry. 2001;62:

22 Low-Dose Combination of Buspirone (15 mg/day) and Melatonin (3 mg qhs) Is More Effective than Placebo and Buspirone Alone in MDD Buspirone + melatonin (n=67) Placebo (n=33) Buspirone (n=34) * CGI-I Scores *p<.05 combination vs placebo and buspirone alone. Fava et al. J Psychiatr Res Dec;46(12): This information includes a use that has not been approved by the US FDA.

23 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): *TRD assessed with ATRQ by site rater prior to enrollment into the prospective lead-in period Data derived from ClinicalTrials.gov

24 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]: , 2007

25 Double-Blind, Placebo-Controlled Study of Pramipexole (up to 1.5 mg bid) in Treatment Resistant Depression (n=60) 45% 40% 35% 30% 25% 20% ns ns Pramipexole Placebo 15% 10% 5% 0% Response Rates Remission Rates Cusin et al, J Clin Psychiatry Jul;74(7):e

26 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): TRD assessed with ATRQ by site rater prior to enrollment into the prospective lead-in period,

27 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 (2015) 84-94

28 Double-Blind, Placebo-Controlled Study of Quetiapine Augmentation in TRD Change in MADRS total score from randomization over time (LOCF; MITT population) Improvement LSM change from randomization Week 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 < < 0.01 < 0.05 < 0.01 QUE XR 300 mg/d + AD < < < 0.05 < 0.01 Bauer M et al. J Clin Psychiatry. 2009;70:

29 Double-Blind Study of Adjunctive Brexpiprazole to ADT in TRD Studies 227* and 228* LS mean (SE) change in MADRS total score * Study 227: LS mean (SE) change in MADRS total score * ** * ** Week * ** ** ADT + placebo (n=203) ADT + Brex 1 mg (n=211) ADT + Brex 3 mg (n=213) LS mean difference from placebo at Week 6 Brex 1 mg (95% CI: -2.73, 0.13) p= Brex 3 mg (95% CI: -3.39, -0.51); p= ** * *** *** *** *** *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 Sep;76(9): *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 Sep;76(9): *TRD assessed with ATRQ by site rater prior to enrollment into the prospective lead-in period, 29

30 Double-Blind Study of Adjunctive Ziprasidone to Escitalopram in TRD (n=139) Papakostas et al, AmJPsychiatry2015; 172:

31 A Double-Blind, Randomized, Placebo-Controlled Study of Cariprazine as Adjunctive Therapy in TRD* Durgam et al, J Clin Psychiatry Mar;77(3): *Treatment resistance assessed with the ATHF by site rater (resistance rating 3; ATHF global confidence score 3)

32 Double-Blind, Placebo-Controlled Creatine (5 gr/day) Augmentation of SSRIs in Women with MDD (n=52) Lyoo et al, Am J Psych epub

33 Double-Blind, Placebo-Controlled Trial of Adjunctive Cyclooxygenase- 2 inhibitor Celecoxib Treatment in MDD Patients Akhondzadeh et al, DEPRESSION AND ANXIETY 26: (2009)

34 Double-Blind Study of SAMe (1600 mg/d) Augmentation in SSRI-Resistant Depressed Patients Papakostas G et al; Am J Psychiatry 2010; 167:

35 Double-Blind Study of L-Methylfolate (L-MTHF) Augmentation of SSRIs in TRD - Sequential Parallel Comparison Design (SPCD) Papakostas et al, Am J Psychiatry Dec 1;169(12):

36 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

37 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

38 Double-Blind Study of Amantadine (150 mg/day) Augmentation of Imipramine in TRD Patients (n=50) Imi Alone Imi+Amant Imi Alone Imi+Amant Women Men P<.05 Rogoz Z, et al. Pharmacol Rep. 2007;59(6): Baseline Week 12

39 Double-Blind, Placebo-Controlled, Crossover Study of i.v. Ketamine in TRD (n=18) Zarate et al, Arch Gen Psychiatry. 2006;63:

40 Intravenous Ketamine in Adult Patients with Treatment- Resistant Depression: A Dose-Frequency Study* Singh et al, Am J Psychiatry Aug 1;173(8): *TRD assessed with ATRQ by SAFER rater

41 A Double-Blind, Doubly-Randomized, Placebo- Controlled Study of Intranasal Esketamine in TRD* *TRD assessed with the ATRQ Singh et al, Biol Psychiatry Sep 15;80(6):

42 Double-Blind Study of Rapastinel (GLYX-13), Modulator of the NMDA Receptor, in TRD* HDRS-17, difference from baseline * * Placebo GLYX-13 1 mg/kg 5 mg/kg 10 mg/kg 30 mg/kg Day after dosing 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:

43 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):

44 25 HAM-D Scores in Double-Blind Study of the Kainate (Glutamate) Receptor Antagonist Topiramate ( mg/day) Augmentation in TRD (n=53) * Topiramate Placebo 5 0 Baseline Week 8 p<.000 Mowla and Kardeh, Progress in Neuro-Psychopharm & Biol Psychiatry 35 (2011)

45 Adjunctive Pregabalin ( 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 Feb;33(1):95-8.

46 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):

47 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 Mean MADRS score BLOCK 1 BLOCK 2 Pla-Pla Pla-Ril Ril-Ril 4 wk 8 wk N observed cases: Week Pla-Pla Pla-Ril Ril-Ril Mathew et al, Neuropsychopharmacology May 29. doi: /npp [Epub ahead of print]

48 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

49 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,

50 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 Aug 1: doi: / [Epub ahead of print]

51 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)

52 Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine (4 mcg/kg): A Randomized, Placebo-Controlled Clinical Trial P<.05 Furey and Drevets, Arch Gen Psychiatry. 2006;63:

53 Double-Blind Study of Oral Scopolamine (1 mg/day) Augmentation on Citalopram in MDD Khajavi et al, J Clin Psychiatry 2012; 73:

54 Double-Blind, SPCD Study of ALKS 5461 (buprenorphine plus the mu antagonist Alks 33) vs. Placebo Fava et al, Am J Psychiatry May 1;173(5):

55 Double-Blind, Placebo-Controlled Study of Testosterone Gel Augmentation in 100 TRD Men Patients NS NS Pope et al, J Clin Psychopharm 2010; 30:

56 Double-Blind, Placebo-Controlled Study of Metyrapone Augmentation (500 mg BID) in TRD Patients (n=165) McAllister-Williams et al, Lancet Psychiatry 2016; 3: Eligible patients were aged years with TRD (HAMD-17 score of 18 and a MGH Treatment-Resistant Depression staging score of 2 10) and taking a singleagent or combination antidepressant treatment that included a serotonergic drug

57 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 Apr;156(4):646-9.) Estrogen: mostly anecdotal evidence (Stahl SM. J Clin Psychiatry Jun;62(6):404-5.)

58 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

59 Combination NE and 5-HT Reuptake Inhibition vs. Either Alone Remission Response without Remission Remission Rate (%) at 6 Weeks 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:

60 Double-Blind Study in 101 Non- and Partial Responders to an 8-week Fluoxetine Trial: Remission (HAM-D-17 < 8) Rates Remission Rates % % % % % ns ns ns % % Fava M. J Clin Psychopharmacol Aug;22(4):

61 Double-Blind Study of Atomoxetine Augmentation Reimherr F et al; Psychiatry Research 175 (2010) 67 73

62 Percent of Remission in STAR*D L-2 Augmentation Percent HRSD QIDS-SR BUP-SR BUS (n = 279) (n = 286) BUP-SR BUS (n = 279) (n = 286) Trivedi et al. N Engl J Med. 2006;354(12):

63 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:

64 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): doi: /jama

65 Double-Blind Study of Mirtazapine Augmentation Blier P et al; Am J Psych 2010 Mar;167(3):281-8.

66 Percent of Remission in STAR*D L-4 Percent HRSD-17 QIDS-SR TCP VEN+MRT (n = 58) (n = 51) TCP VEN+MRT (n = 58) (n = 51) McGrath et al. Am J Psychiatry. 2006;163:

67 Trazodone plus SSRIs Maes M et al; Journal of Affective Disorders 41 (1996)

68 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