Table 1 Novel antidepressant in the pipeline.

Compound	Presumed mechanism of antidepressant action	Phase	Sponsor	Characteristics
AXS-05	NMDAR antagonism	III	Axsome	AXS-05 showed rapid and durable improvement in the MADRS total score compared to placebo in one phase III DBRCT (NCT04019704). Another phase III DBRCT demonstrated its rapid antidepressant effects in the MADRS total score compared to bupropion (NCT02741791). One phase III open-label safety study has just been completed without any reported results (NCT04039022). One phase II trial is still in the recruitment stage on ClinicalTrials.gov (NCT04634669).
MIJ821 (CAD9271)	NMDAR subtype 2B negative allosteric modulation	II	Novartis	MIJ821 demonstrated greater improvements than placebo in the MADRS total score at 24 hours in a phase II DBRCT (NCT03756129). One phase II DBRCT is ongoing (NCT03756129).
Nitrous oxide	NMDAR antagonism	II	None	In a phase II crossover DBRCT, 50% nitrous oxide plus 50% oxygen was superior to that of placebo gas in the improvement of the HAMD 21 at 2 h and 24 h (NCT02139540). The results of other phase II studies examining 25% and 50% nitrous oxide have not been reported yet (NCT03283670, NCT03932825). There is one ongoing phase II DBRCT (NCT03869736).
Psilocybin	5-hydroxytryptamine 2 A agonism	II	None	One phase II waiting list–controlled trial demonstrated that the HAMD 17 scores after two psilocybin sessions in the psilocybin group were significantly lower than those in the waiting-list group (NCT03181529). In another phase II DBRCT, two administrations of psilocybin were not inferior to the treatment of escitalopram in the QIDS-SR 16 (NCT03429075). Some phase-II DBRCTs are ongoing (NCT03775200, NCT03866174, NCT03715127).
Ayahuasca	5-hydroxytryptamine 2 A agonism and Monoamine oxidase inhibition	II	None	Rapid antidepressant effects in the HAMD total score were observed in ayahuasca compared to placebo in one phase-II DBRCT (NCT02914769). No ongoing trial was registered on ClinicalTrials.gov.
Botulinum toxin A (BTA)	Positive effects of altered facial expression on emotional perception	II	None	In a phase II crossover DBRCT, there was a significant improvement in the HAMD 21 in the patients who received BTA compared with those who received placebo (NCT01392963). In another phase II DBRCT, BTA showed a significant score reduction in the MADRS compared to placebo (NCT02116361). The addition of BTA to an ongoing antidepressant also demonstrated greater efficacy in the HAMD 17 score reduction over placebo in a phase II DBRCT. In a phase IV DBRCT, BTA showed a greater response rate on the MADRS compared to placebo (NCT01556971). One clinical trial comparing two facial injection sites is ongoing (NCT03484754).
Prasterone (dehydroepiandrosterone, DHEA)	Sigma receptor agonism	II	None	In one phase II crossover DBRCT, the administration of DHEA resulted in a significant improvement in the HAMD 17 compared with placebo (NCT00001487). No ongoing trial was registered on ClinicalTrials.gov.
Casopitant (GW679769)	NK receptor antagonism	II	GlaxoSmithKline	In one phase II DBRCT, there was a significant difference in the HAMD 17 score change between casopitant and placebo (NCT00413023). Another phase II DBRCT reported that neither casopitant nor paroxetine achieved statistical separation from placebo on the HAMD 17 (NCT00102492). No active trial was registered on ClinicalTrials.gov.
Ansofaxine hydrochloride (LY03005, LPM570065)	Serotonin-norepinephrine-dopamine triple reuptake inhibition	III	Luye	Ansofaxine hydrochloride showed an antidepressant effect in the MADRS total score compared to placebo in a recent phase III DBRCT (NCT04853407). No ongoing trial was registered on ClinicalTrials.gov.

Abbreviations: DBRCT, double-blind, randomized controlled trial; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery-Asberg Depression Rating Scale; MDD major depressive disorder; NMDAR, N-methyl-D-aspartate receptor; QIDS-SR ₁₆ , 16-item Quick Inventory of Depressive Symptomatology, Self-Report; TRD, treatment-resistant depression.