list of investigational antidepressants list of investigational antidepressants this is a list of investigational antidepressants, or antidepressants that are currently under development for clinical use in the treatment of mood disorders but are not yet approved. chemical/generic names are listed first, with developmental code names, synonyms, and brand names in parentheses. all drugs listed are specifically under development for major depressive disorder (mdd) and/or treatment-resistant depression (trd) unless noted otherwise. other forms of depression may include bipolar depression and postpartum depression. glutamatergics nmda receptor modulators 4-chlorokynurenine (av-101) – nmda receptor glycine site antagonist apimostinel (gate-202, nrx-1074) – nmda receptor modulator arketamine (pcn-101, hr-071603) – unknown mechanism of action, indirect ampa receptor activator esketamine (esketamine dpi, falkieri, pg061) – non-competitive nmda receptor antagonist – approved for trd, specifically under development for bipolar depression and "depressive disorders" esmethadone (dextromethadone; rel-1017) – nmda receptor antagonist open channel blocker ketamine (pmi-100, pmi-150, r-107, shx-001, sls-002; tur-002) – non-competitive nmda receptor antagonist mij-821 – nmda receptor subunit 2b (nr2b) negative allosteric modulator rislenemdaz (cerc-301, mk-0657) – nmda receptor nr2b antagonist ampa receptor modulators tak-653 (nbi-1065845) – ampa receptor positive allosteric modulator monoaminergics monoamine reuptake inhibitors opc-64005 – serotonin–norepinephrine–dopamine reuptake inhibitor (sndri) pdc-1421 (bli-1005) – norepinephrine reuptake inhibitor (nri) toludesvenlafaxine (ansofaxine; ly03005, lpm570065) – sndri monoamine reuptake inhibitors and receptor modulators hypidone (yl-0919) – sri, 5-ht1a receptor partial agonist, and 5-ht6 receptor agonist tgba01ad (fkb01md) – serotonin reuptake inhibitor (sri), 5-ht1a and 5-ht1d receptor agonist, and 5-ht2 receptor antagonist vortioxetine (trintellix) – sri, 5-ht1a receptor agonist, 5-ht1b receptor partial agonist, 5-ht1d, 5-ht3, and 5-ht7 receptor antagonist – approved for mdd, under development for bipolar depression monoamine releasing agents lisdexamfetamine (elvanse, ldx, nrp-104, s-877489, shp-489, spd-489, tyvense, venvanse, vyvanse) – norepinephrine–dopamine releasing agent (ndra) midomafetamine (mdma; ecstasy) – serotonin–norepinephrine–dopamine releasing agent (sndra) monoamine receptor modulators aramisulpride/esamisulpride (85:15 ratio) (sep-4199) – 5-ht7 receptor antagonist (aramisulpride) and d2 and d3 receptor antagonist (esamisulpride) – specifically under development for the treatment of bipolar depression gepirone (tgfk07ad; travivo) – 5-ht1a receptor partial agonist pramipexole (ctc-501, ctc-413) – d2, d3, and d4 receptor agonist psilocybin – 5-ht2a receptor agonist atypical antipsychotics brilaroxazine (rp-5063, rp-5000) – aa – specifically under development for the treatment of mdd cariprazine (reagila, vraylar) – aa – approved for bipolar depression, under development for mdd lumateperone (iti-007) – aa – specifically under development for the treatment of mdd and bipolar depression lurasidone (latuda) – aa – specifically under development for the treatment of mdd pimavanserin (nuplazid; acp-103; bvf-048) – 5-ht2a receptor antagonist – specifically under development for the treatment of mdd others ademetionine (same; msi-190, msi-195, strada) – cofactor in monoamine neurotransmitter biosynthesis – specifically under development in the united states and europe for the adjunctive treatment of mdd gabaergics and neurosteroids gabaa receptor positive modulators zuranolone (sage-217) – gabaa receptor positive allosteric modulator – specifically under development for the treatment of mdd and postpartum depression others 3β-methoxypregnenolone (map-4343) – selective microtubule-associated protein 2 (map2) stimulant itruvone (ph-10) – vomeropherine (precise mechanism of action unknown/undisclosed) opioidergics κ-opioid receptor antagonists aticaprant (jnj-67953964, cerc-501, ly-2456302) – selective κ-opioid receptor antagonist btrx-335140 (btrx-140) – selective k-opioid receptor antagonist buprenorphine/samidorphan (alks-5461) – κ-opioid receptor antagonist and μ-opioid receptor antagonist cvl-354 – selective κ-opioid receptor antagonist nociceptin receptor antagonists btrx-246040 (ly-2940094) – nociceptin receptor antagonist cholinergics muscarinic acetylcholine receptor modulators scopolamine (dpi-386) – muscarinic acetylcholine receptor antagonist others onabotulinumtoxina (botulinum toxin a, botox) – acetylcholine release inhibitor – specifically under development for the treatment of mdd in women as a local injection to paralyze facial muscles orexin receptor antagonists jnj-61393215 (jnj-3215; orexin-1) – ox1 receptor antagonist seltorexant (min-202, jnj-42847922, jnj-922) – ox2 receptor antagonist others bi-1358894 – trpc4 and trpc5 inhibitor crisdesalazine (aad-2004) – mpges-1 inhibitor erteberel – selective erβ receptor agonist jnj-54175446 – p2rx7 purinoceptor antagonist nsi-189 – hippocampal neurotrophic agent (precise mechanism of action unknown) nv-5138 – sestrin2 modulator and consequent mammalian target of rapamycin complex 1 (mtorc1) activator sng-12 – undefined mechanism of action ts-121 – vasopressin 1b receptor antagonist wip-df17 – undefined mechanism of action xen1101 - kcnq2/3 channel opener mixed tramadol (ets6103; viotra) – μ-opioid receptor agonist, serotonin–norepinephrine reuptake inhibitor (snri) and possible serotonin releasing agent (sra), 5-ht2c receptor antagonist, and other actions combinations carbidopa/oxitriptan (evx-101) – serotonin precursor and aromatic l-amino acid decarboxylase inhibitor cycloserine/lurasidone (nrx-101; cyclurad) – nmda receptor glycine site partial agonist and aa combination – specifically under development for the treatment of bipolar depression deudextromethorphan/quinidine (avp-786, ctp-786) – σ1 receptor agonist, sri, uncompetitive nmda receptor antagonist, and other actions not under development the following notable drugs are of investigational interest as potential antidepressants but are not formally under clinical development for approval at this time: hydroxynorketamine ((2r,6r)-hnk) – metabolite of ketamine which may be involved in ketamine's antidepressant-like effects in mice mesembrine is an alkaloid present in sceletium tortuosum (kanna). it has been shown to act as a serotonin reuptake inhibitor. minocycline – microglia inhibitor and other actions; a 2018 systematic review and meta-analysis reported that the overall antidepressant effect size of minocycline compared to placebo was -0.78 (95% ci: -0.4 to -1.33, p=0.005), indicative of a large and statistically significant antidepressant effect nitrous oxide – nmda receptor antagonist and other actions r13 – an orally active prodrug of tropoflavin with improved pharmacokinetics tropoflavin (7,8-dihydroxyflavone; 7,8-dhf) – trkb agonist