. 2022 Jan 26;179(6):1146–1186. doi: 10.1111/bph.15753

TABLE 2.

Summary of targets and drug candidates in Phase III studies

Target	Drug candidate (mechanism of action)	Title, aim, NCT number	Study design, endpoints (1. = primary outcome, 2. = secondary outcome measures)	Study arms N, age (years)	Current status (outcome)
NMDA receptor	Ketamine (antagonist)	Action of ketamine in treatment‐resistant depression NCT01945047	*Randomized, double‐blind, crossover assignment, 2‐step study* 1. Change in MADRS score, BDNF gene VAL/MET polymorphism 2. Plasma and salivary concentrations of cortisol, melatonin and inflammatory mediators; CGI‐S, and self‐reported depression, and suicidality in comparison with midazolam	2 arms in 2 steps Step 1: Single i.v. 0.5 mg·kg⁻¹ bolus infusion ketamine or 1 mg·kg⁻¹ midazolam over 40 min Step 2: 6 ketamine or midazolam infusions N = 46, age: 18–65	Completed (2013–2017): Cumulative and sustained antidepressant effects
Evaluation of schemes of administration of intravenous ketamine in depression NCT03742557	R andomized, initially double‐blind then open‐label, placebo‐controlled, parallel assignment study 1. Changes of HAM‐D and MADRS scores, brain glutamate and GABA concentrations (up to 12 weeks)	2 arms: Ketamine i.v. 0.5 mg·kg⁻¹ over 40 min, twice weekly for 8 weeks or placebo (saline) N = 30, age: 18–65	Recruiting (2018–2020)
Ketamine for treatment‐resistant late‐life depression NCT02556606	*Randomized, quadruple‐blind, parallel assignment study* 1. MADRS score (4‐week follow‐up) 2. Clinician‐administered dissociative state scale, cognitive test batteries, dementia screening test, general side effect rating scale, BDNF, resting‐state EEG, blood inflammatory biomarkers	4 arms: Single i.v. 0, 1, 0.25, 0.5 mg·kg⁻¹ bolus infusion ketamine or 1, 0.03 mg·kg⁻¹ midazolam over 40 min N = 46, age: >55	Active, not recruiting (2015–)
AXS‐05 (dextromethorphan + bupropion)	A study to assess the efficacy and safety of AXS‐05 in subjects with treatment‐resistant major depressive disorder NCT02741791	*Randomized, active‐controlled, double‐blind study* 1. Changes of MADRS score 2. Clinical Global Impressions‐Severity, HAM‐D	2 arms: Oral test compound or bupropion (6 weeks) N = 312, age: 18–65	Completed (2016–2020): Results are not published
Open‐label safety study of AXS‐05 in subjects with depression NCT04039022	*Open‐label, multicentre, long‐term, single group assignment study* 1. Safety (types and rates of adverse events) 2. Change in MADRS score	2 arms: Oral test compound (2 times a day) for up to 12 months N = 300, age: 18–65	Recruiting (2019–, estimated completion 2020)
Opioid receptors	Buprenorphine (partial μ receptor agonist + κ opioid receptor antagonist)	Buprenorphine for TRD (BUP‐TRD) NCT01407575	*Randomized, triple‐blind, placebo‐controlled, parallel design study* 1. Changes in MADRS score, BP, side effect rating scale, heart rate, weight 2. Brief Symptom Inventory—Anxiety Scale, Positive/Negative Affect Scale	2 arms: Buprenorphine (0.2–1.6 mg sublingual; 8 weeks) or placebo N = 13, age: >21	Completed (2011–2018): Results are not published
Combination approaches	Antidepressant + lamotrigine	Efficacy and safety of antidepressant augmentation with lamotrigine NCT00652171	*Randomized, triple‐blind, placebo‐controlled, parallel add‐on assignment pilot study* 1. MADRS score changes 2. CGI score	2 arms: Oral 200 mg·day⁻¹ lamotrigine or placebo added to the ongoing antidepressant (8 weeks) N = 34, age: 18–60	Completed (2004–2006): No differences compared with placebo; side effects: dyspepsia, nausea, rashes
	Antidepressant + olanzapine	The study of olanzapine plus fluoxetine in combination for treatment of TRD NCT00035321	*Randomized, double‐blind, active compound‐controlled, parallel assignment study* 1. MADRS score changes 2. Side effects, laboratory parameters, HAM‐A, HAM‐D, CGI and BCRS scores	3 arms: Olanzapine + fluoxetine or olanzapine or fluoxetine (8 weeks) N = 605, age: 18–65	Completed (2002–2006): Significantly greater antidepressant effect of the combination
Olanzapine augmentation therapy in treatment‐resistant depression: A double‐blind placebo‐controlled trial NCT00273624	*Randomized, quadruple‐blind, placebo‐controlled add‐on parallel assignment study, 2 steps* 1. HAM‐D score changes 2. MADRS, HAM‐D subscales, CGI	2 arms: Oral 10 mg·day⁻¹ olanzapine or placebo added to the ongoing antidepressant (2‐week treatment, responder selection, further 2‐month treatment, 2‐week follow‐up) N = 60, age: 18–65	Terminated (2006–2016)
Antidepressant + risperidone	Risperidone vs. bupropion ER augmentation of SSRIs in TRD NCT00179244	*Randomized, open‐label, comparative crossover, add‐on assignment study* 1. MADRS score changes 2. HAM‐D. BDI, HAM‐A, CGI scores	2 arms: Oral risperidone or bupropion ER added to the ongoing SSRI (6 weeks) N = 30, age: >18	Completed (2005–2015): Results are not published
A study of the effectiveness and safety of risperidone to augment SSRI therapy in patients with TRD NCT00044681	*Randomized, double‐blind, placebo‐controlled, parallel add‐on assignment study* 1. MADRS score changes 2. HAM‐D and CGI scores	2 arms: Oral risperidone (0.25, 0.5, 0, 2 mg·day⁻¹) or placebo (30 weeks) added to citalopram (20–40 mg, 36 weeks) N = 258, age: 18–85	Completed (2002–2004): Results are not published
Antidepressant + simvastatin	Simvastatin as an augmentation treatment for treatment‐resistant depression: Randomized controlled trial NCT03435744	*Randomized, double‐blind, placebo‐controlled add‐on parallel assignment study* 1. MADRS score changes	2 arms: Oral 20 mg·day⁻¹ simvastatin or placebo added to the ongoing antidepressant (3 months) N = 150, age: 18–75	Recruiting (2019–)
Antidepressant + minocycline	Minocycline as adjunctive treatment for treatment‐resistant depression NCT03947827	*Randomized, quadruple‐blind, placebo‐controlled add‐on parallel assignment study* 1. HAM‐D score changes 2. CGI, quality of life scale, GAD‐7	2 arms: Oral 100–200 mg·day⁻¹ minocycline or placebo added to the ongoing antidepressant (6 weeks) N = 100, age: 18–80	Recruiting (2020–2021): Interim report‐minocycline is well tolerated and effective in reducing depressive symptoms
Antidepressant + aripiprazole	Aripiprazole augmentation therapy in treatment‐resistant depression NCT00276978	*Open‐label pilot study* 1. HAM‐D score changes 2. HAM‐D, MADRS, CGI, BDI	Single arm: Oral 10 mg·day⁻¹ aripiprazole to concurrent antidepressant (pre–post comparison, 3 weeks) N = 20, age: 18–70	Terminated (2006–2016)

Target

Drug candidate (mechanism of action)

Title, aim, NCT number

Study design, endpoints (1. = primary outcome, 2. = secondary outcome measures)

Study arms N, age (years)

Current status (outcome)

NMDA receptor

Ketamine (antagonist)

Action of ketamine in treatment‐resistant depression

NCT01945047

Randomized, double‐blind, crossover assignment, 2‐step study

1. Change in MADRS score, BDNF gene VAL/MET polymorphism

2. Plasma and salivary concentrations of cortisol, melatonin and inflammatory mediators; CGI‐S, and self‐reported depression, and suicidality in comparison with midazolam

2 arms in 2 steps

Step 1: Single i.v. 0.5 mg·kg⁻¹ bolus infusion ketamine or 1 mg·kg⁻¹ midazolam over 40 min

Step 2: 6 ketamine or midazolam infusions

N = 46, age: 18–65

Completed (2013–2017): Cumulative and sustained antidepressant effects

Evaluation of schemes of administration of intravenous ketamine in depression

NCT03742557

R andomized, initially double‐blind then open‐label, placebo‐controlled, parallel assignment study

1. Changes of HAM‐D and MADRS scores, brain glutamate and GABA concentrations (up to 12 weeks)

2 arms: Ketamine i.v. 0.5 mg·kg⁻¹ over 40 min, twice weekly for 8 weeks or placebo (saline)

N = 30, age: 18–65

Recruiting (2018–2020)

Ketamine for treatment‐resistant late‐life depression

NCT02556606

Randomized, quadruple‐blind, parallel assignment study

1. MADRS score (4‐week follow‐up)

2. Clinician‐administered dissociative state scale, cognitive test batteries, dementia screening test, general side effect rating scale, BDNF, resting‐state EEG, blood inflammatory biomarkers

4 arms: Single i.v. 0, 1, 0.25, 0.5 mg·kg⁻¹ bolus infusion ketamine or 1, 0.03 mg·kg⁻¹ midazolam over 40 min

N = 46, age: >55

Active, not recruiting (2015–)

AXS‐05 (dextromethorphan + bupropion)

A study to assess the efficacy and safety of AXS‐05 in subjects with treatment‐resistant major depressive disorder

NCT02741791

Randomized, active‐controlled, double‐blind study

1. Changes of MADRS score

2. Clinical Global Impressions‐Severity, HAM‐D

2 arms: Oral test compound or bupropion (6 weeks)

N = 312, age: 18–65

Completed (2016–2020): Results are not published

Open‐label safety study of AXS‐05 in subjects with depression

NCT04039022

Open‐label, multicentre, long‐term, single group assignment study

1. Safety (types and rates of adverse events)

2. Change in MADRS score

2 arms: Oral test compound (2 times a day) for up to 12 months

N = 300, age: 18–65

Recruiting (2019–, estimated completion 2020)

Opioid receptors

Buprenorphine (partial μ receptor agonist + κ opioid receptor antagonist)

Buprenorphine for TRD (BUP‐TRD)

NCT01407575

Randomized, triple‐blind, placebo‐controlled, parallel design study

1. Changes in MADRS score, BP, side effect rating scale, heart rate, weight

2. Brief Symptom Inventory—Anxiety Scale, Positive/Negative Affect Scale

2 arms: Buprenorphine (0.2–1.6 mg sublingual; 8 weeks) or placebo

N = 13, age: >21

Completed (2011–2018): Results are not published

Combination approaches

Antidepressant + lamotrigine

Efficacy and safety of antidepressant augmentation with lamotrigine

NCT00652171

Randomized, triple‐blind, placebo‐controlled, parallel add‐on assignment pilot study

1. MADRS score changes

2. CGI score

2 arms: Oral 200 mg·day⁻¹ lamotrigine or placebo added to the ongoing antidepressant (8 weeks)

N = 34, age: 18–60

Completed (2004–2006): No differences compared with placebo; side effects: dyspepsia, nausea, rashes

Antidepressant + olanzapine

The study of olanzapine plus fluoxetine in combination for treatment of TRD

NCT00035321

Randomized, double‐blind, active compound‐controlled, parallel assignment study

1. MADRS score changes

2. Side effects, laboratory parameters, HAM‐A, HAM‐D, CGI and BCRS scores

3 arms: Olanzapine + fluoxetine or olanzapine or fluoxetine (8 weeks)

N = 605, age: 18–65

Completed (2002–2006): Significantly greater antidepressant effect of the combination

Olanzapine augmentation therapy in treatment‐resistant depression: A double‐blind placebo‐controlled trial

NCT00273624

Randomized, quadruple‐blind, placebo‐controlled add‐on parallel assignment study, 2 steps

1. HAM‐D score changes

2. MADRS, HAM‐D subscales, CGI

2 arms: Oral 10 mg·day⁻¹ olanzapine or placebo added to the ongoing antidepressant (2‐week treatment, responder selection, further 2‐month treatment, 2‐week follow‐up)

N = 60, age: 18–65

Terminated (2006–2016)

Antidepressant + risperidone

Risperidone vs. bupropion ER augmentation of SSRIs in TRD

NCT00179244

Randomized, open‐label, comparative crossover, add‐on assignment study

1. MADRS score changes

2. HAM‐D. BDI, HAM‐A, CGI scores

2 arms: Oral risperidone or bupropion ER added to the ongoing SSRI (6 weeks)

N = 30, age: >18

Completed (2005–2015): Results are not published

A study of the effectiveness and safety of risperidone to augment SSRI therapy in patients with TRD

NCT00044681

Randomized, double‐blind, placebo‐controlled, parallel add‐on assignment study

1. MADRS score changes

2. HAM‐D and CGI scores

2 arms: Oral risperidone (0.25, 0.5, 0, 2 mg·day⁻¹) or placebo (30 weeks) added to citalopram (20–40 mg, 36 weeks)

N = 258, age: 18–85

Completed (2002–2004): Results are not published

Antidepressant + simvastatin

Simvastatin as an augmentation treatment for treatment‐resistant depression: Randomized controlled trial

NCT03435744

Randomized, double‐blind, placebo‐controlled add‐on parallel assignment study

1. MADRS score changes

2 arms: Oral 20 mg·day⁻¹ simvastatin or placebo added to the ongoing antidepressant (3 months)

N = 150, age: 18–75

Recruiting (2019–)

Antidepressant + minocycline

Minocycline as adjunctive treatment for treatment‐resistant depression

NCT03947827

Randomized, quadruple‐blind, placebo‐controlled add‐on parallel assignment study

1. HAM‐D score changes

2. CGI, quality of life scale, GAD‐7

2 arms: Oral 100–200 mg·day⁻¹ minocycline or placebo added to the ongoing antidepressant (6 weeks)

N = 100, age: 18–80

Recruiting (2020–2021): Interim report‐minocycline is well tolerated and effective in reducing depressive symptoms

Antidepressant + aripiprazole

Aripiprazole augmentation therapy in treatment‐resistant depression

NCT00276978

Open‐label pilot study

1. HAM‐D score changes

2. HAM‐D, MADRS, CGI, BDI

Single arm: Oral 10 mg·day⁻¹ aripiprazole to concurrent antidepressant (pre–post comparison, 3 weeks)

N = 20, age: 18–70

Terminated (2006–2016)

Note: Inclusion criteria: Phase III studies available on https://clinicaltrials.gov or https://www.clinicaltrialsregister.eu/, patients with treatment‐resistant (major) depression.

Abbreviations: BCRS, Brief Cognitive Rating Scale; BDI, Beck Depression Inventory; BDNF, brain‐derived neurotrophic factor; CGI, Clinical Global Impression; CGI‐S, CGI‐Severity; GAD‐7, Generalized Anxiety Disorder 7‐item scale; HAM‐A, Hamilton Anxiety Rating Scale; HAM‐D, Hamilton Depression Rating Scale; MADRS, Montgomery–Åsberg Depression Rating Scale; VAL/MET, valine/methionine.