. 2021 Jun 2;5:24705470211020446. doi: 10.1177/24705470211020446

Table 1.

Phase II and III trials of glutamate/GABA-based compounds in development for the treatment of mood disorders.

NCT identifier/ trial acronym	Trial design	Condition	Expected/ actual completion date	Projected/ actual recruitment	Phase	Primary outcome measure and results if reported	Effect size (Cohen’s d unless otherwise noted; between-group)
Esketamine, Janssen Pharmaceuticals, Celon Pharma SA, and China Medical University, China**
NCT04425473 (Beijing Hospital)	Prospective, 2-arm, RCT for in patients undergoing major risk surgery	Post-operative depression	Dec 2023	564	II/III	Percentage of participants with remission (MADRS total score ≤ 10) 3 days after major surgical operation	Trial not complete.
NCT02782104* SUSTAIN-3	Open label, single group.	TRD	Dec 2022	1150	III	Long-term safety outcomes.	Trial not complete.
NCT04338321* (ESCAPE-TRD)	RCT, flexible dose study of esketamine vs. quetiapine extended release. Conducted in multiple countries.	Elderly TRD	Dec 2022	622	III	Percentage of participants with remission (MADRS total score ≤ 10).	Trial not complete.
NCT04599855	RCT, multiple fixed-dose, 3 arm study of inhaled nasal esketamine alone without additional AD.	TRD	June 2022	450	IV	Change in MADRS at 4 weeks.	Trial not complete.
NCT03185819*	4-arm RCT, fixed dose.	Suicidal MDD, ages 12-17	Feb 2022	145	II	Change from baseline in CDRS-R at 24 hours.	Trial not complete.
NCT04414943*** (Peking)	Prospective, 2-arm IV esketamine, RCT for parturients with prenatal depression.	Postpartum depression	Aug 2021	364	II	Postpartum depression prevalence at 42 days as measured by Mini-International Neuropsychiatric Interview	Trial not complete.
NCT03434041*	RCT, 2-arm plus initiation of new oral antidepressant.	TRD	Aug 2021	234	III	Change in MADRS at 4 weeks.	Trial not complete.
NCT03927378*** (Peking)	Prospective, 2-arm IV esketamine, RCT for parturients with prenatal depression.	Postpartum depression	June 2021	364	II	Postpartum depression prevalence at 42 days as measured by Mini-International Neuropsychiatric Interview	Trial not complete.
NCT03965871**	RCT, multiple dose, 4-arm study of inhaled dry powder esketamine. Conducted in Poland.	Bipolar Depression	Feb 2021	88	II	Change from baseline in MADRS total score at Day 14.	Not enough data for Cohen’s d.
NCT04303325*** (ESPOD-BI)	Prospective RCT in MDD patients undergoing breast cancer operation. Conducted in China.	Post-operative Depression	Dec 2020	36	IV	Changes of MADRS total score (baseline to postoperative 24hrs).	Not enough data for Cohen’s d.
NCT03965858**	RCT, multiple dose, 4-arm study of inhaled dry powder esketamine. Conducted in Poland.	TRD	Apr 2020	88	II	Change from baseline in MADRS total score at Day 14.	Not enough data for Cohen’s d.
NCT02918318*	RCT, multiple fixed-dose, 4-arm, study. Conducted in Japan.	TRD	Dec 2019	202	II	Change from baseline in MADRS at 4 weeks. Primary outcome was not achieved at any dose level.	0.01 (28 mg) 0.07 (58 mg) 0.02 (84 mg)
NCT03097133* ASPIRE-II	RCT, recruiting from emergency settings.	Suicidal MDD	Apr 2019	230	III	Change in MADRS at 24 hours post-dose. Positive primary outcome for reduction in depressive symptoms at 24hrs (p=0.006).²⁰	0.30 (84 mg)
NCT03039192* ASPIRE-1	RCT, recruiting from emergency settings.	Suicidal MDD	Dec 2018	226	III	Change in MADRS at 24 hours post-dose. Positive primary outcome for reduction in depressive symptoms at 24hrs (p=0.006).¹⁷	0.32 (84mg)
NCT02493868* SUSTAIN-1	Randomized withdrawal study.	TRD in remission	Feb 2018	719	III	Time to relapse in remitters (ESK+AD v. PBO+AD). Primary endpoint was met; remitters and responders who continued esketamine had a lower risk of relapse compared to those who discontinued the drug (p=0.003).¹⁵	HR= 0.49 (remission), HR = 0.3 (response)
NCT02417064* TRANSFORM-1	3-arm RCT, fixed dose study.	TRD	Feb 2018	346	III	Change in MADRS at 4 weeks (ESK+AD v. PBO+AD). Primary outcome was not met (p=0.088).¹²	0.28 (56mg) 0.22 (84mg)
NCT02418585* TRANSFORM-2	2-arm RCT, flexible dose.	TRD	Nov 2017	236	III	Change in MADRS at 4 weeks (ESK+AD v. PBO+AD). Primary endpoint was achieved (p=0.02).¹³	0.30
NCT02497287* SUSTAIN-2	Open label, single group.	TRD	Oct 2017	802	III	Long-term (up to 12-months) efficacy and safety study. Common AEs included nausea, dizziness, dissociation, and headache; 9.5% of subjects discontinued esketamine due to treatment emergent AEs. Response and remission rates at study endpoint were 76.5% and 58.2%, respectively.¹⁶	Not enough data for Cohen’s d.
NCT02422186* TRANSFORM-3	2-arm RCT, flexible dose.	TRD, elderly	Aug 2017	139	III	Change in MADRS at 4 weeks (ESK+AD v. PBO+AD). Primary outcome was not achieved (p=0.059).¹⁴	0.31
NCT02133001*	RCT, recruiting from emergency settings	Suicidal MDD	Feb 2016	68	II	Change in MADRS at 4 hours post-dose (ESK+AD v. PBO+AD). Primary outcome was achieved.⁴⁰p=0.015	0.61 (MADRS), 0.67 (MADRS-SI) at 4 hours
NCT01998958* SYNAPSE	RCT, 4-arm, dose fiding study.	TRD	Sep 2015	108	II	Change in MADRS at 1 week (placebo vs. 28mg, 56mg, and 84mg). The study achieved its primary outcome (p<0.05 for all esketamine groups compared to placebo).⁴¹	Phase 1, Phase 2: 28mg: 0.51, 0.44 56mg: 0.78, 0.60 84mg: 1.08, 1.04
NCT01640080*	RCT, multiple-dose, 3-arm study of IV esketamine. Conducted in multiple countries.	TRD	Jun 2013	30	II	Change in MADRS at 24 hours. Both doses (0.2mg/kg and 0.4mg/kg) showed significant improvement compared to placebo on secondary outcomes (HAM-D, BDI), but not the primary outcome (MADRS)⁴².	0.2mg/kg: 1.54 0.4mg/kg: 1.70
AVP-786 (Avanir/Otsuka), oral formulation
NCT02153502	2-arm RCT	TRD	Feb 2016	206	II	MADRS score at week 10; results are not publicly available. No further trials currently planned.	Not enough data for Cohen’s d.
AXS-05 (Axsome Therapeutics)
NCT04634669	Open label	TRD	May 2022	150	II	Safety outcomes: TEAEs within 12 months of AXS-05 daily dosing. Additional non-primary endpoint will measure change in MADRS.	Trial not complete
NCT04608396 (MERIT)	2-arm RCT, withdrawal study	TRD (remitted)	June 2021	50	II	Time to relapse from randomization (up to 26 weeks)	Trial not complete
NCT04039022 (COMET)	Open label	MDD, TRD	Oct 2020	876	III	Safety outcomes: types and rates of adverse events (up to 12 months). Safety profile consistent with prior trials. Of all participants, 39.7% met clinical response by Week 2 and 73.2% of patients by Week 6. Response was retained in 84.6% and 82.8% of patients at 6 and 12 months, respectively. Remission was achieved by 21.5% of patients at Week 2 and 52.5% of patients at Week 6. Remission was retained in 68.7% and 69.0% of patients at 6 and 12 months, respectively.	N/A
NCT02741791 (STRIDE-1)	2-arm RCT (active comparator: bupropion)	TRD	March 2020	312	III	Did not achieve primary endpoint (MADRS at week 6, p=0.12).²³	0.21
NCT04019704 (GEMINI)	2-arm RCT (inert placebo)	MDD	Dec 2019	327	III	Safety outcomes: types and rates of adverse events (6 weeks), and MADRS at Week 6. Primary endpoint was met.²²	0.38
NCT03595579 (ASCEND)	2-arm RCT (active comparator: bupropion)	MDD	Jan 2019	97	II	Primary outcome was safety. Change in MADRS at 6 weeks (secondary outcome) was statistically different in favor of AXS-05 (p<0.001).²¹	0.50
REL-1017 (Relmada)
NCT04688164 (RELIANCE-I)	2-arm RCT, fixed dose	MDD	Jun 2022	400	III	Change in MADRS at 4 weeks.	Trial not complete
NCT03051256	3-arm RCT (25 mg, 50mg, placebo)	TRD	Aug 2019	62	IIa	Safety and tolerability: Incidence of treatment emergent adverse events (AEs). No significant difference in AEs were found between placebo and treatment groups.²⁴	Secondary outcome (MADRS): 25mg, 50mg dose: Day 2: 0.3, 0.0 Day 4: 0.9, 0.8 Day 7: 0.8, 0.7 Day 14: 0.9, 1.0
MIJ821 (Novartis Pharmaceuticals), intravenous formulation
NCT04722666	7-arm RCT, dose finding study	MDD with suicidal intent	Dec 2023	195	II	Change from baseline in the total score of the MADRS at 24 hours (and up to 52 weeks).	Trial not complete
NCT03756129	6-arm RCT, placebo- and active- (ketamine) controlled	TRD	March 2020	72	II	MADRS score 24 hours after infusion. Results submitted, but not posted as of March 2021.	Not available
AV-101 (VistaGen), oral formulation designed for once daily dosing
NCT02484456	2-week crossover RCT	MDD	Dec 2019	22	II	Change from baseline in HAM-D. No statistically significant treatment effect was detected.²⁶p=0.71	0.261
NCT03078322 ELEVATE	2-arm RCT	MDD	Oct 2019	180	II	MADRS at 2 weeks. Primary endpoint was not achieved.³⁵	Not enough data for Cohen’s d.
Rapastinel (GLYX-13, Allergan); unless otherwise noted, rapastinel is delivered intravenously
NCT03614156	3-arm RCT, (clinically driven dosing, weekly dosing, placebo)	MDD (relapse)	July 2019	363	III	Time to first relapse during the 52 weeks. Study terminated due to business reasons.	Not enough data for Cohen’s d.
NCT03675776	3-arm RCT, (225mg, 450mg, placebo)	MDD	July 2019	50	III	Change from baseline MADRS at 6 weeks. Study terminated due to business reasons. Did not meet primary endpoint.	1.03 (225mg) 0.16 (450mg)
NCT03560518	3-arm RCT, (450mg, 900mg, placebo)	MDD	July 2019	439	III	Change from baseline MADRS at 6 weeks. Study terminated due to business reasons. Did not meet primary endpoint.	0.05 (450mg) 0.21 (900mg)
NCT03668600	Open label (flexible dose)	MDD	July 2019	230	III	Safety outcomes: Patients experiencing one or more TEAEs within 45 weeks. Study terminated due to business reasons.	Not enough data for Cohen’s d.
NCT03352453	2-arm RCT, recruiting from emergency settings	Suicidal MDD	June 2019	138	II	Change from baseline in MADRS at 1 day. (Study terminated due to business reasons.) Results were not significant	0.03
NCT02951988	3-arm, randomized withdrawal	MDD	Feb 2019	604	III	Time to first relapse during 52 weeks since randomization. Results were not significant.³¹	Not enough data for Cohen’s d.
NCT03002077	Open label, single group	MDD	Dec 2018	617	III	Safety outcomes over 52 weeks. No safety concerns identified (Clinicaltrials.gov, June 2020)	Not enough data for Cohen’s d.
NCT02943564 RAP-MD-02	3-arm, fixed-dose RCT	MDD	Dec 2018	638	III	Change from baseline in MADRS at 1 day Did not differentiate from placebo.³⁰	0.01 (225mg), 0.07 (450mg)
NCT02943577 RAP-MD-03	2-arm RCT	MDD	Nov 2018	415	III	Change from baseline in MADRS at 1 day Did not differentiate from placebo.²⁸	0.12 (450mg)
NCT02932943 RAP-MD-01	2-arm RCT	MDD	Nov 2018	457	III	Change from baseline in MADRS at 1 day Did not differentiate from placebo.²⁹	0.04 (450mg)
NCT02192099	Open label extension, single group	MDD	Nov 2018	61	II	Safety outcomes. Study Terminated.	N/A
NCT01684163	3-arm, fixed-dose RCT	MDD	Jun 2014	369	II	Change in HAM-D at 6, 12, and 16 weeks	N/A
NCT01234558	4-arm, fixed-dose RCT	MDD	Jul 2012	115	II	Change in HAM-D score at various timepoints within a 14-day period. A clear dose response relationship was observed and primary outcome measures was positive for the 5mg and 10mg doses (at days 3 and 7), but not the 1mg and 30mg doses.⁴³	5mg, 10mg dose: Day 3: 0.41, 0.36 Day 7: 0.39, 0.60
NRX-100 (single-dose IV Ketamine) followed by NRX-101 (D-cycloserine and lurasidone, NeuroRx)
NCT03395392	2-arm RCT, control arm is placebo + lurasidone	Suicidal BPD	Mar 2022	150	II/III	Change in MADRS from baseline at 6 weeks.	Trial not complete.
NCT03396068 SBP-ASIB	2-arm RCT, control arm is placebo + lurasidone	Suicidal BPD	Dec 2021	72	II/III	Change in MADRS from baseline at 6 weeks.	Trial not complete.
NCT03396601 SevereBD	2-arm RCT of NRX-100 (ketamine) v. saline	Suicidal BPD	Aug 2021	150	III	Suicidal ideation at 24 hours.	Trial not complete.
NCT03402152	Part A: NRX-101 vs. Placebo, RCT Part B: NRX-101 vs. lurasidone HCl, RCT	Bipolar MDD	Feb 2021	24	II/III	Mean change in Glx (Glutamate+Glutamine) area under the curve (AUC) measured in 15min increments over 2hrs at following experimental drug vs. comparator.	Trial not complete.
NCT02974010 STABIL-B	2-arm RCT, control arm is placebo + lurasidone	Suicidal BPD	Nov 2018	20	III	Change in MADRS from baseline at 6 weeks. Primary endpoint was achieved.⁴⁴	2.94* (resultssubmitted but not yet QC reviewed)
AGN-241751 (Allergan), oral formulation
NCT03726658	Part A: 1x/day (3mg vs. 10mg vs. placebo) RCT Part B: 2x/day (3mg vs. 25mg vs. placebo) RCT	MDD	Oct 2019	223	I/II	Part A: MADRS at 1-day post first dose Part B: MADRS at 7 days post first dose Completed, but no results posted as of March 2021.	Not available
NCT03586427	5-arm, fixed-dose RCT	MDD	Aug 2019	251	II	Change in MADRS at 1 day. Completed, but no results posted as of March 2021.	Not available
Zulresso™, Brexanolone (SAGE-547) (Sage Therapeutics) which is delivered intravenously over 60 hours
NCT03924492	Expanded Access (compassionate use)	PPD	N/A	N/A	N/A	This is an expanded access/compassionate use study intended to provide access to ZULRESSO™ (brexanolone) injection for the treatment of a limited number of eligible women with PPD during the period prior to commercial availability.	Trial not complete
NCT04273191	Open label	PPD	Aug 2021 (withdrawn)	10	IV	Change from baseline on the HAMD-17 total score and change from baseline in functional connectivity (fMRI). This study was withdrawn (Sage has decided not to proceed with this study).	N/A
NCT03665038	Open label	Adolescent PPD	Jan 2021	20	III	Percentage of participants with treatment-emergent adverse events (TEAEs). Completed, but no results posted as of March 2021.	Not available
NCT02942017	2-arm RCT	Moderate PPD	Oct 2017	108	III	Change from baseline in HAM-D at 3 days. This study met the primary endpoint (p=0.0160).³³	0.43 (90μg)
NCT02942004	2-arm RCT	Severe PPD	Oct 2017	138	III	Change from baseline in HAM-D at 60 hours. This study met the primary endpoint (p=0.0013 for the BRX60 group; p=0.0252 for the BRX90 group).³³	0.73 (60μg) 0.89 (90μg)
NCT02614547	2-arm RCT	PPD	Jul 2016	21	II	Change from baseline in HAM-D at 3 days. This trial met its primary endpoint (p=0.0075).³²	1.2
NCT02285504 547-PPD-201	Open label, single group	PPD	Jun 2015	4	II	Safety measures were primary outcomes⁴⁵.	N/A
Ganaxolone (Marinus), oral and intravenous formulations
NCT03228394 (Magnolia)	Part 1: 4-arm RCT, IV dose-finding study Part 2: 2-arm RCT of IV followed by oral medicine	PPD	May 2020	91	II	Part 1: Primary outcomes were adverse events and other safety outcomes. Part 2: No data available as of March 2021.	Not available
NCT03460756 (Amaryllis)	2-arm RCT, oral	PPD	July 2019	84	II	Primary outcome was HAM-D scores at 38 days and safety outcomes. Completed, but primary outcome is not data available as of March 2021.	Not available
NCT02900092	Open label, single group	Postmenopausal MDD	Jan 2018	10	N/A	The primary endpoint was change in depression severity (MADRS) using within-group comparison. A significant decrease was seen by Week 8 (p=.015).³⁴	N/A
Zuranolone SAGE-217 (SAGE), which is an oral formulation designed for once daily dosing
NCT04476030 CORAL	2-arm RCT (Sage-217+Sertraline vs. Placebo+Sertraline)	MDD	Dec 2021	424	III	Change from baseline in the HAM-D total score at day 15.	Trial not complete
NCT04442503SKYLARK	2-arm RCT	PPD	Dec 2021	192	III	Change from baseline in the HAM-D total score at day 15.	Trial not complete
NCT04007367, MDD-302 (REDWOOD)	2-arm RCT	MDD	Dec 2021 (suspended)	546	III	Time to relapse during the double-blind Phase (HAM-D). This trial is listed as suspended as of March 2021 (evaluating potential amendments to the study).	N/A
NCT03864614 SHORELINE	Open label, single group	MDD	Nov 2021	∼777	III	Safety and tolerability study of the initial treatment and retreatment cycles. Interim results in an SEC report state that Zuranolone was generally well-tolerated, with adverse events consistent with prior trials; 71.6% and 39.8% achieved response and remission, respectively, at day 15. Additionally, it was reported that 44.5% of participants with a positive initial response did not need an additional treatment course after up to one-year of follow-up.³⁷	Trial not complete
NCT04442490 WATERFALL	2-arm RCT	MDD	June 2021	575	III	Change from baseline in the HAM-D total score at day 15.	Trial not complete
NCT03771664, MDD-304 (RAINFOREST)	2-arm RCT	MDD	May 2020 (suspended)	102	III	Change from baseline in sleep efficiency (SE) as assessed by polysomnography (PSG). This trial is listed as suspended as of March 2021 (evaluating potential amendments to the study).	N/A
NCT03672175, MDD-301 (MOUNTAIN)	3-arm RCT	MDD	March 2020	581	III	This study did not meet its primary endpoint (p = 0.115) (change from baseline in HAM-D at Day 15).³⁶	0.04 (20mg) 0.16 (30mg)
NCT03692910, BPD-201 (ARCHWAY)	Part A: open-label Part B: 2-arm, parallel group	Bipolar depression	March 2019	35	II	Part A: Safety and tolerability of SAGE-217 as assessed by the frequency and severity of adverse events. All treatment-emergent adverse events were mild or moderate; there was a 45% response rate by Day 15. No results for Part B have been reported.	Part A: N/A Part B: Not available
NCT02978326, PPD-201 (ROBIN)	2-arm RCT	PPD	Dec 2018	153	III	The primary endpoint (change from baseline at day 14 in HAM-D) was met (p=0.0029), with a 17.8-point improvement in active v. 13.6 improvement in placebo on the HAM-D.³⁸	0.40
NCT03000530, MDD-201	Part A: open-label (N=14) Part B: 2-arm RCT (N=89)	MDD	Nov 2017	89	II	Efficacy: Primary outcome (Part B, change in HAM-D at day 15) was achieved (p<0.001).³⁵ Safety: adverse events, laboratory values, vital signs, ECG, and suicidal ideation (C-SSRS).	Part A: N/A Part B: 0.81 (30mg)
PRAX-114 (Praxis Precision Medicines), oral formulation
ACTRN12619000575134 PRAX-114-202	Randomized 3-arm fixed-dose study (no placebo arm) conducted in Australia.	MDD	Not listed	36	IIa	Safety and tolerability study. Secondary outcomes were improvement in depression outcomes. Interim results released in an SEC report showed improvements of 15 to 19 in HAM-D after 1 week of therapy across the three dose groups.³⁹	N/A

“*,” “**,” and “***” under the Esketamine section refers to the location/sponsor of the study: Janssen Pharmaceuticals*, Celon Pharma SA**, and China Medical University, China***.BPD – bipolar depression; MDD – major depressive disorder; PPD – post-partum depression.Unless otherwise noted, the data here is taken from www.clinicaltrials.gov. Compounds are grouped by purported mechanism of action and are listed in the same order they appear in Table 2 and different studies for the same compound are listed in chronological order of estimated or actual completion date. Some completed studies did not have publicly available data.