Wikipedia

List of investigational antidepressants

This is a list of investigational antidepressants, or drugs that are currently under development for clinical use in the treatment of depression but are not yet approved. Specific indications include major depressive disorder, treatment-resistant depression, bipolar depression, and postpartum depression, among others.

Chemical/generic names are listed first, with developmental code names, synonyms, and brand names in parentheses.

This list was last comprehensively updated in August 2024. It is likely to become outdated with time.

Under development

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Preregistration

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  • Buprenorphine/samidorphan (ALKS-5461) – μ-opioid receptor partial agonist, κ-opioid receptor antagonist, δ-opioid receptor antagonist, and μ-opioid receptor antagonist combination – New Drug Application (NDA) rejected in 2019 [1][1]

Phase 3

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  • Aticaprant (AVTX-501; CERC-501; JNJ-3964; JNJ-67953964; LY-2456302) – κ-opioid receptor antagonist [2]
  • Cycloserine/lurasidone (Cyclurad; NRX-101) – ionotropic glutamate NMDA receptor glycine site partial agonist and atypical antipsychotic (non-selective monoamine receptor modulator) combination [3]
  • Esmethadone (dextromethadone; REL-1017) – ionotropic glutamate NMDA receptor antagonist and other actions [4]
  • Ketamine (HTX-100; NRX-100) – ionotropic glutamate NMDA receptor antagonist [5]
  • Navacaprant (BTRX-140; BTRX-335140; CYM-53093; NMRA-140; NMRA-335140) – κ-opioid receptor antagonist [6]
  • Pimavanserin (ACP-103; BVF-048; Nuplazid) – serotonin 5-HT2A receptor antagonist or inverse agonist [7]
  • Psilocybin (COMP-360) – non-selective serotonin receptor agonist and psychedelic hallucinogen [8]
  • Seltorexant (JNJ-42847922; JNJ-7922; MIN-202) – orexin OX2 receptor antagonist [9]
  • SEP-4199 (non-racemic amisulpride; aramisulpride/esamisulpride [85:15 ratio]) – atypical antipsychotic (dopamine D2 and D3 receptor antagonist and serotonin 5-HT2B and 5-HT7 receptor antagonist) [10]
  • SNG-12 (Synapsinae) – glycine transporter 1 (GlyT1) inhibitor [11]
  • Solriamfetol (Sunosi; JZP-110; SKLN05; ARL-N05; YKP-10A; R-228060; ADX-N05) – norepinephrine and dopamine reuptake inhibitor and trace amine-associated receptor 1 (TAAR1) agonist [12][13][2]
  • Ulotaront (SEP-363856; SEP-856) – serotonin 5-HT1A receptor agonist and trace amine-associated receptor 1 (TAAR1) agonist [14]

Phase 2/3

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  • PRAX-114 – extrasynaptic GABAA receptor-preferring positive allosteric modulator and neurosteroid [15]

Phase 2

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  • 4-Chlorokynurenine (4-CL-KYN; AV-101) – ionotropic glutamate NMDA receptor glycine site antagonist and kynurenine modulator [16]
  • Ademetionine (MSI-190; MSI-195; S-Adenosyl-L-Methionine; Sam-E; SAMe; Strada) – cofactor in monoamine neurotransmitter biosynthesis [17]
  • ALTO-100 (NSI-189) – unknown mechanism of action (neurogenesis stimulant and brain-derived neurotrophic factor (BDNF) modulator) [18] [19]
  • ALTO-203 – histamine H3 receptor agonist [20]
  • ANC-501 (TS-1211; TS-121) – vasopressin V1b receptor antagonist [21]
  • Apimostinel (AGN-241660; GATE-202; NRX-1074) – ionotropic glutamate NMDA receptor glycine site partial agonist [22]
  • Arketamine ((R)-ketamine; PCN-101) – ionotropic glutamate NMDA receptor antagonist [23]
  • Azetukalner (1OP-2198; Encukalner; VRX-621698; XEN-1101; XPF-008) – KCNQ potassium channel agonist [24]
  • BHV-7000 (BPN-25203; KB-3061) – KCNQ2 potassium channel stimulant [25]
  • BI-1358894 – transient receptor potential cation TRPC4 and TRPC5 channel inhibitor [26]
  • Centanafadine (CTN; EB-1020) – serotonin, norepinephrine, and dopamine reuptake inhibitor [27]
  • Deudextromethorphan/quinidine (AVP-786; CTP-786; d-DM/Q; d6-DM/Q; deuterated dextromethorphan/ultra-low-dose quinidine) – sigma σ1 receptor agonist, serotonin reuptake inhibitor, ionotropic glutamate NMDA receptor antagonist, other actions, and CYP2D6 inhibitor combination [28]
  • Esketamine (CLE-100) – ionotropic glutamate NMDA receptor antagonist [29]
  • FKB-01MD (FKB01MD; TGBA-01AD; TGBA01AD) – serotonin reuptake inhibitor, serotonin 5-HT1A receptor agonist, serotonin 5-HT1D receptor modulator, and serotonin 5-HT2 receptor agonist [30]
  • GM-1020 – ionotropic glutamate NMDA receptor antagonist [31][3]
  • Itruvone (PH-10; PH-10A; PH10-NS) – chemoreceptor cell stimulant, vomeropherine, and neurosteroid [32]
  • JNJ-54175446 (JNJ-5446) – purinergic P2X7 receptor antagonist [33]
  • JNJ-55308942 – purinergic P2X7 receptor antagonist [34]
  • JNJ-61393215 – orexin OX1 receptor antagonist [35]
  • Ketamine (extended-release; R-107; R107) – ionotropic glutamate NMDA receptor antagonist [36]
  • Ketamine (intranasal; Ereska; PMI-100; PMI-150; SLS-002; TUR-002) – ionotropic glutamate NMDA receptor antagonist [37]
  • Ketamine (prolonged-release oral; KET-01) – ionotropic glutamate NMDA receptor antagonist [38]
  • Liafensine (BMS-820836; DB-104) – serotonin, norepinephrine, and dopamine reuptake inhibitor [39]
  • Lisdexamfetamine (Vyvanse) – norepinephrine and dopamine releasing agent [40]
  • Lysergic acid diethylamide (LSD; MB-22001) – non-selective serotonin receptor agonist and psychedelic hallucinogen [41]
  • Mebufotenin (5-MeO-DMT; 5-Methoxy-N,N-Dimethyltryptamine; BPL-002; BPL-003) – non-selective serotonin receptor agonist and psychedelic hallucinogen [42]
  • Mifepristone (Mifeprex; RU-38486; RU-486) – progesterone receptor antagonist, glucocorticoid receptor antagonist, and androgen receptor antagonist [43]
  • MK-1942 – undefined mechanism of action [44]
  • N,N-Dimethyltryptamine (DMT; BMND-01; BMND-02; BMND-03) – non-selective serotonin receptor agonist and psychedelic hallucinogen [45]
  • NBI-1070770 – NR2B subunit-containing ionotropic glutamate NMDA receptor negative allosteric modulator [46]
  • NORA-520 (brexanolone prodrug) – GABAA receptor positive allosteric modulator and neurosteroid [47]
  • Onabotulinum toxin A (BoNTA; Botox; Botulinum toxin A injectable; GSK-1358820; OnabotA X; onabotulinumtoxinA X; Vistabel; Vistabex) – acetylcholine release inhibitor and neuromuscular blocking agent [48]
  • Onfasprodil (CAD-9271; MIJ-821; MIJ821) – NR2B subunit-containing ionotropic glutamate NMDA receptor negative allosteric modulator [49]
  • OPC-64005 – serotonin, norepinephrine, and dopamine reuptake inhibitor [50]
  • Osavampator (TAK-653; NBI-1065845; NBI-845) – ionotropic glutamate AMPA receptor positive allosteric modulator [51]
  • OSU-6162 (PNU-9639; PNU-96391; PNU-96391A) – serotonin 5-HT2A receptor partial agonist (non-hallucinogenic), dopamine D2 receptor partial agonist, so-called "monoaminergic stabilizer", and sigma σ1 receptor ligand [52][4][5][6][7][8][9]
  • PDC-1421 (ABV-1504; ABV-1505; ABV-1601; BLI-1005) – norepinephrine reuptake inhibitor [53]
  • Pegipanermin (DN-TNF; INB-03; LIVNate; Quellor; XENP-1595; XENP-345; XPro-1595; XPro595; XPro) – tumor necrosis factor α (TNFα) inhibitor [54]
  • Pramipexole (CTC-413; CTC-501) – dopamine D2, D3, and D4 receptor agonist [55]
  • Pregnenolone methyl ether (3β-methoxypregnenolone; MAP-4343) – microtubule-associated protein (MAP) stimulant and tubulin polymerization promoter [56]
  • Ralmitaront (RG-7906; RO-6889450) – trace amine-associated receptor 1 (TAAR1) agonist [57]
  • RE-104 – serotonin 5-HT2A receptor agonist [58]
  • Rislenemdaz (AVTX-301; CERC-301; MK-0657) – NR2B subunit-containing ionotropic glutamate NMDA receptor negative allosteric modulator [59]
  • Ropanicant (SUVN-911) – α4β2 nicotinic acetylcholine receptor antagonist [60]
  • SP-624 – sirtuin 6 (SIRT6) stimulant [61]
  • SPN-820 (NV-5138; SPN-821) – sestrin2 modulator and mammalian target of rapamycin complex 1 (mTORC1) stimulant [62]
  • Tildacerfont (SPR-001; LY-2371712) – corticotropin releasing factor receptor 1 (CRF1) antagonist [63]
  • Tramadol (controlled-release; ETS-6103; ETX-6103; Viotra) – μ-opioid receptor agonist, serotonin and norepinephrine reuptake inhibitor, serotonin 5-HT2C receptor antagonist, and other actions [64]
  • TS-161 – metabotropic glutamate mGlu2 and mGlu3 receptor antagonist [65]
  • UE-2343 (Xanamem) – 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor (glucocorticoid synthesis inhibitor)[66]
  • Zelquistinel (AGN-241751; GATE-251) – ionotropic glutamate NMDA receptor partial positive allosteric modulator [67]

Phase 1/2

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  • CYB-003 (deuterated psilocybin analogue) – serotonin 5-HT2A receptor agonist [68]
  • PT-00114 (PT100114) – corticotropin releasing hormone (CRH) inhibitor [69]

Phase 1

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  • ABX-002 (LL-340001 prodrug) – thyroid hormone receptor β (TRβ) agonist [70][10]
  • Agomelatine (ALTO-300; agomelatine 25 mg formulation) – serotonin 5-HT2C receptor antagonist and melatonin MT1 and MT2 receptor agonist [71][11]
  • BI-1569912 – NR2B subunit-containing ionotropic glutamate NMDA receptor negative allosteric modulator [72]
  • BRII-296 (extended-release injectable aqueous suspension formulation of brexanolone) – GABAA receptor positive allosteric modulator and neurosteroid [73][12]
  • Brilaroxazine (RP-5000; RP-5063) – atypical antipsychotic (non-selective monoamine receptor modulator) [74]
  • Carbidopa/oxitriptan (EVX-101) – serotonin precursor (5-hydroxytryptophan; 5-HTP) and aromatic L-amino acid decarboxylase (AAAD) inhibitor combination [75]
  • Crisdesalazine (AAD-2004) – microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitor [76]
  • CVL-354 – κ-opioid receptor antagonist [77]
  • DGX-001 – gut–brain axis modulator [78][13]
  • DSP-3456 – metabotropic glutamate mGlu2 and mGlu3 receptor negative allosteric modulator [79]
  • Ebselen (DR-3305; Harmokisane; PZ-51; SPI-1005; SPI-3005) – multiple mechanisms of action [80]
  • KAR-2618 (GFB-887) – transient receptor potential cation TRPC4 and TRPC5 channel inhibitor [81]
  • PIPE-307 – muscarinic acetylcholine M1 receptor antagonist [82]
  • SAL-0114 – undefined mechanism of action [83]
  • Scopolamine (DPI-385-CVS; DPI-386; DPI-386 Nasal Gel; DPI-386-SG; DPI-386-SS; DPI-387; DPI-521-CG; DPI-550-TBI; INSCOP spray) – non-selective muscarinic acetylcholine receptor antagonist [84]
  • Traneurocin (Biocovax; Biomedivir; Dexaneurosone; NA-831; NA-81; Nanomedivir; Neurosivir; Traneurocine) – synaptic ionotropic glutamate AMPA receptor positive allosteric modulator and neurogenesis stimulant [85]
  • VLS-01 (N,N-dimethyltryptamine; DMT) – non-selective serotonin receptor agonist and psychedelic hallucinogen [86]
  • XW-10508 (oral esketamine conjugate prodrug) – ionotropic glutamate NMDA receptor antagonist [87]

Preclinical

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  • ACD-856 – tropomyosin receptor kinase A (TrkA) and B (TrkB) positive allosteric modulator [88]
  • ALTO-202 – NR2B subunit-containing ionotropic glutamate NMDA receptor antagonist [89]
  • Brexpiprazole (long-acting injectable; MTD-211) – atypical antipsychotic (non-selective monoamine receptor modulator) [90]
  • CB-03 (CB-04; CB-003; CB03-154) – KCNQ2 and KCNQ2 potassium channel stimulant [91]
  • CRHR1 antagonist therapeutic (HMNC Brain Health) – corticotropin releasing factor receptor 1 (CRF1) antagonist [92]
  • Duloxetine (oral suspension) – serotonin and norepinephrine reuptake inhibitor [93]
  • ENX-104 – dopamine D2 and D3 receptor antagonist [94]
  • Etifoxine deuterated (GRX-917) – GABAA receptor positive allosteric modulator and translocator protein (TSPO; peripheral benzodiazepine receptor) agonist (neurosteroidogenesis stimulant) [95]
  • GABA positive allosteric modulator (CS Bay Therapeutics) – GABAA receptor positive allosteric modulator [96]
  • INV-88 – macrophage migration inhibitory factor (MIF) inhibitor [97]
  • ITI-333 – serotonin 5-HT2A receptor partial agonist, μ-opioid receptor biased partial agonist, α1A-adrenergic receptor antagonist, and dopamine D1 receptor antagonist [98]
  • Ketamine (depot; ALA-3000) – ionotropic glutamate NMDA receptor antagonist [99]
  • Lithium cocrystal (AL-001; LiProSal; lithium salicylate L-proline ionic cocrystal) – unknown mechanism of action and mood stabilizer (improved formulation of lithium) [100]
  • LPH-5 – selective serotonin 5-HT2A receptor partial agonist and psychedelic hallucinogen [101][14][15]
  • LPCN-1154 (LPCN1154; oral brexanolone) – GABAA receptor positive allosteric modulator and neurosteroid [102][16]
  • Lucid-PSYCH (Lucid-201) – undefined mechanism of action and psychedelic hallucinogen [103]
  • Mebufotenin (5-MeO-DMT; 5-methoxy-N,N-dimethyltryptamine; LSR-1019) – non-selective serotonin receptor agonist and psychedelic hallucinogen [104]
  • Midomafetamine (microneedle transdermal patch; 3,4-methylenedioxymethamphetamine; MDMA) – serotonin, norepinephrine, and dopamine releasing agent and weak serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonist [105]
  • Nezavist – GABAA receptor positive allosteric modulator [106]
  • NLX-101 (F-15599) – serotonin 5-HT1A receptor full agonist [107]
  • PSIL-001 (DMT analogue) – serotonin 5-HT1 receptor modulator [108]
  • PSIL-002 (DMT analogue) – serotonin 5-HT1 receptor modulator [109]
  • Psylo-4001 – serotonin 5-HT2A receptor modulator and psychedelic hallucinogen [110]
  • SYT-510 – endocannabinoid reuptake inhibitor [111]
  • TF-0066 – undefined mechanism of action [112]

Research

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  • BHV-5000 – low-trapping ionotropic glutamate NMDA receptor antagonist [113]
  • NP-10679 – NR2B subunit-containing ionotropic glutamate NMDA receptor negative allosteric modulator [114]
  • Psilocybin (MYCO-001; MYCO-003) – non-selective serotonin receptor agonist and psychedelic hallucinogen [115]
  • Small molecule therapeutic - Rugen Therapeutics – undefined mechanism of action [116]

Phase unknown

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  • Amuxetine – serotonin, norepinephrine, and dopamine reuptake inhibitor [117][17]
  • EDG-005 – undefined mechanism of action [118]
  • EDG-006 – undefined mechanism of action [119]
  • Iloperidone (Fanapt; Fanaptum; Fiapta; HP-873; ILO-522; VYV-683; Zomaril) – atypical antipsychotic (non-selective monoamine receptor modulator) [120]
  • INV-407 – undefined mechanism of action [121]
  • Ketamine (intravenous/oral; Braxia) – ionotropic glutamate NMDA receptor antagonist [122]
  • SK-2110 (buprenorphine implant) – μ-opioid receptor partial agonist, κ-opioid receptor antagonist, and δ-opioid receptor antagonist – under development in China [123][18]
  • Venlafaxine (controlled-release) – serotonin and norepinephrine reuptake inhibitor [124]

Not under development

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Development suspended

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  • BVF-045 (bupropion/undisclosed serotonin reuptake inhibitor) – norepinephrine and dopamine reuptake inhibitor, nicotinic acetylcholine receptor negative allosteric modulator, and serotonin reuptake inhibitor combination [125] [126] [127]
  • Dexmedetomidine (BXCL-501; Igalmi; KalmPen) – α2-adrenergic receptor agonist [128]
  • ETX-155 – GABAA receptor positive allosteric modulator [129]
  • Ganaxolone (CCD-1042; Ztalmy) – GABAA receptor positive allosteric modulator and neurosteroid [130]

No development reported

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  • AAG-561 – corticotropin releasing hormone (CRH) inhibitor [131]
  • Adinazolam (Deracyn; U-41123; U-41123F) – GABAA receptor positive allosteric modulator and benzodiazepine [132]
  • Amitifadine (DOV-21947; EB-1010) – serotonin, norepinephrine, and dopamine reuptake inhibitor [133]
  • AN-788 (NSD-788) – serotonin and dopamine reuptake inhibitor [134]
  • ANAVEX 1-41 (blarcamesine analogue) – sigma σ1 receptor agonist, muscarinic acetylcholine receptor modulator, and sodium and chloride channel modulator [135]
  • Aripiprazole (transdermal; AQS-1301) – atypical antipsychotic (non-selective monoamine receptor modulator) [136]
  • Arketamine (HR-071603; (R)-ketamine nasal spray) – ionotropic glutamate NMDA receptor antagonist [137]
  • AZD-8108 – ionotropic glutamate NMDA receptor antagonist [138]
  • BCI-632 – metabotropic glutamate mGlu2 and mGlu3 receptor antagonist [139]
  • BCI-838 – metabotropic glutamate mGlu2 and mGlu3 receptor antagonist [140]
  • BMS-866949 (CSTI-500) – serotonin, norepinephrine, and dopamine reuptake inhibitor [141]
  • BNC-210 (IW-2143) – α7 nicotinic acetylcholine receptor negative allosteric modulator [142]
  • Bryostatin 1 (MW-904) – protein kinase C (PKC) stimulant [143]
  • BTRX-246040 (LY-2940094) – nociceptin receptor antagonist [144]
  • Bupropion/naltrexone (Contrave) – norepinephrine and dopamine reuptake inhibitor, nicotinic acetylcholine receptor negative allosteric modulator, and μ-opioid receptor antagonist combination [145]
  • Cericlamine (JO-1017) – serotonin reuptake inhibitor [146]
  • Citalopram/pipamperone (PipCit; PNB-01) – serotonin reuptake inhibitor and typical antipsychotic combination [147]
  • Depression therapy - Genopia Biomedical – undefined mechanism of action [148]
  • (R)-Desmethylsibutramine ((+)-desmethylsibutramine; or (R)-desmethylsibutramine/(+)-didesmethylsibutramine) – serotonin, norepinephrine, and dopamine reuptake inhibitor [149]
  • Dipraglurant (ADX-48621; mGluR5-NAM) – metabotropic glutamate mGlu5 receptor negative allosteric modulator [150]
  • Erteberel (LY-500307; SERBA-1) – estrogen receptor β (ERβ) agonist [151]
  • Esketamine (esketamine DPI; Falkieri; PG061; S-ketamine) – ionotropic glutamate NMDA receptor antagonist [152]
  • Eszopiclone (Lunesta) – GABAA receptor positive allosteric modulator and Z-drug [153]
  • EVT-101 (ENS-101) – NR2B subunit-containing ionotropic glutamate NMDA receptor negative allosteric modulator [154]
  • Fananserin (RP-62203) – serotonin 5-HT2A receptor antagonist and dopamine D4 receptor antagonist [155]
  • Fibroblast growth factor 1 (FGF-1) – fibroblast growth factor receptor (FGFR) agonist [156]
  • Filorexant (MK-6096) – orexin OX1 and OX2 receptor antagonist [157]
  • GEA-857 (alaproclate analogue) – potassium conductance putative blocker [158]
  • GSK-588045 – serotonin 5-HT1A, 5-HT1B, and 5-HT1D receptor antagonist [159]
  • GSK-1360707 – serotonin, norepinephrine, and dopamine reuptake inhibitor [160]
  • HS-10353 – GABAA receptor positive allosteric modulator [161][19]
  • Hypidone – serotonin reuptake inhibitor and serotonin 5-HT1A and 5-HT6 receptor agonist [162]
  • Igmesine (CI-1019; JO-1784) – sigma σ1 receptor agonist [163]
  • Imiloxan (RS-21361) – α2-adrenergic receptor antagonist [164]
  • IN-ASTR-001 – undefined mechanism of action [165]
  • Ketamine (transdermal patch; SHX-001) – ionotropic glutamate NMDA receptor antagonist [166]
  • Ketamine (sublingual; ketamine wafer; SLS-003; Wafermine) – ionotropic glutamate NMDA receptor antagonist [167]
  • KFM-19 – adenosine A1 receptor antagonist [168]
  • LSM-6 (3-hydroxy-N-dimethylphenethylamine) – undefined mechanism of action (adrenergic and serotonergic agent; constituent of Limacia scanden Lour.) [169][20]
  • Lumateperone deuterated (ITI-1284) – atypical antipsychotic (non-selective monoamine receptor modulator) [170]
  • Midomafetamine (3,4-methylenedioxymethamphetamine; MDMA; ecstasy) – serotonin, norepinephrine, and dopamine releasing agent and weak serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonist [171]
  • Mitizodone (HEC-113995) – serotonin reuptake inhibitor and serotonin receptor agonist [172]
  • Nivacortol (nivazole; NEBO-174; novozola) – glucocorticoid receptor antagonist [173]
  • Omiloxetine – serotonin reuptake inhibitor [174]
  • Oxitriptan (5-hydroxytryptophan; 5-HTP; EVX-301) – serotonin precursor [175]
  • Pseudohypericin – undefined mechanism of action (constituent of St John's wort) [176]
  • Psilocybin (CYB-001; INT0052/2020) – non-selective serotonin receptor agonist and psychedelic hallucinogen [177]
  • Psilocybin (biosynthetic psilocybin; PB-1818) – non-selective serotonin receptor agonist and psychedelic hallucinogen [178]
  • QRX-002 – ionotropic glutamate NMDA receptor antagonist [179]
  • RG-7351 – trace amine-associated receptor 1 (TAAR1) agonist [180]
  • Riluzole (sublingual; BHV-0223; Nurtec) – complex mechanism of action or glutamatergic modulator [181]
  • Risperidone (Risperdal) – atypical antipsychotic (non-selective monoamine receptor modulator) [182]
  • SAR-102779 (SAR-10279) – neurokinin NK2 receptor antagonist [183]
  • SD-254 (deuterated venlafaxine) – serotonin and norepinephrine reuptake inhibitor [184]
  • SEP-378614 – undefined mechanism of action [185]
  • SNA-1 – undefined mechanism of action [186]
  • SPL-801-B ((2R,6R)-hydroxynorketamine; 6-HNK) – non-hallucinogenic ketamine derivative/metabolite [187]
  • TrkB receptor antagonist (Celon Pharma) – tropomyosin-related kinase B (TrkB) receptor antagonist [188]
  • YDP-2225 – undefined mechanism of action [189]

Development discontinued

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  • ABT-436 – vasopressin V1b receptor antagonist [190]
  • Adatanserin (WAY-SEB-324; WY-50324; SEB-324) – serotonin 5-HT1A receptor partial agonist and serotonin 5-HT2A and 5-HT2C receptor antagonist [191]
  • ADX-71149 (JNJ-1813; JNJ-40411813; JNJ-mGluR2-PAM) – metabotropic glutamate mGlu2 receptor modulator [192]
  • Amesergide (LY-237733) – serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor antagonist, α2-adrenergic receptor antagonist, and other actions [193]
  • Amibegron (SR-58611; SR-58611A) – β3-adrenergic receptor agonist [194]
  • Aprepitant (MK-869) – neurokinin NK1 receptor antagonist[21][22][23]
  • ARA-014418 (AR-A014418; GSK-3β Inhibitor VIII) – glycogen synthase kinase GSK-3β inhibitor [195]
  • Armodafinil (CEP-10953; Nuvigil; (R)-modafinil) – atypical dopamine reuptake inhibitor [196]
  • Atipamezole (antisedan; MPV-1248) – α2-adrenergic receptor antagonist [197]
  • Atomoxetine (LY-139603; Strattera; Tomoxetine) – norepinephrine reuptake inhibitor [198]
  • AZD-2066 – metabotropic glutamate mGlu5 receptor antagonist [199]
  • AZD-2327 – δ-opioid receptor agonist [200]
  • AZD-8129 (AR-A000002; AR-A2XX; AR-A2) – serotonin 5-HT1B receptor antagonist [201]
  • Basimglurant (NOE-101; RG-7090; RO-4917523) – metabotropic glutamate mGlu5 receptor antagonist [202]
  • Befloxatone (MD-370503) – monoamine oxidase MAO-A reversible inhibitor [203]
  • BMS-181101 (BMY-42569) – serotonin reuptake inhibitor and serotonin 5-HT1A and 5-HT1D receptor agonist [204]
  • Buspirone (transdermal; BuSpar Patch) – serotonin 5-HT1A receptor partial agonist [205]
  • Casopitant (GW-679769; GW679769) – neurokinin NK1 receptor antagonist[24]
  • Centpropazine – serotonin reuptake inhibitor [206]
  • Cibinetide (ARA-290) – erythropoietin receptor (EpoR) agonist [207]
  • Citalopram (controlled-release) – serotonin reuptake inhibitor [208]
  • Clavulanic acid (RX-10100; Serdaxin; Zoraxel) – β-lactamase inhibitor and unknown mechanism of action (dopamine and serotonin release enhancer, possibly via Munc18-1 and Rab4 interactions, also glutamate transporter GLT1 expression enhancer) [209][25]
  • Clovoxamine (DU-23811) – serotonin and norepinephrine reuptake inhibitor [210]
  • Coluracetam (BCI-540; MKC-231) – ionotropic glutamate AMPA receptor positive allosteric modulator, choline uptake and acetylcholine synthesis enhancer, and racetam [211][26][27][28]
  • CP-316311 – corticotropin releasing hormone (CRH) inhibitor [212]
  • Crinecerfont (NBI-74788; SSR-125543; SSR-125543A) – corticotropin releasing factor receptor 1 (CRF1) antagonist [213]
  • CRL-41789 – undefined mechanism of action [214]
  • Cutamesine (AGY-94806; Msc-1; SA-4503) – sigma σ1 receptor agonist [215]
  • CX157 (KP157; TriRima; Tyrima) – monoamine oxidase MAO-A reversible inhibitor[29]
  • Dapoxetine (LY-210448; Priligy) – serotonin reuptake inhibitor [216]
  • Dasotraline (DSP-225289; SEP-225289; SEP-0225289; SEP-289) – serotonin, norepinephrine, and dopamine reuptake inhibitor [217]
  • DDP-225 – norepinephrine reuptake inhibitor and serotonin 5-HT3 receptor antagonist [218]
  • Decoglurant – metabotropic glutamate mGlu2 and mGlu3 receptor antagonist [219]
  • Delequamine (RS-15385; RS-15385197) – α2-adrenergic receptor antagonist [220]
  • Delucemine (NPS-1506) – ionotropic glutamate NMDA receptor polyamine site antagonist and serotonin reuptake inhibitor [221]
  • Dexmecamylamine (AT-5214; NIH-11008; S-mecamylamine; TC-5214) – α3β4 and α4β2 nicotinic acetylcholine receptor negative allosteric modulator [222]
  • Dexnafenodone (LU-43706) – serotonin and norepinephrine reuptake inhibitor [223]
  • DMP-695 – corticotropin releasing hormone (CRH) inhibitor [224]
  • DOV-216303 – serotonin, norepinephrine, and dopamine reuptake inhibitor [225]
  • DPC-368 – undefined mechanism of action [226]
  • DSP-1200 – serotonin 5-HT2A receptor antagonist, dopamine D2 receptor antagonist, and α2A-adrenergic receptor antagonist [227]
  • Edivoxetine (EDP-125; LY-2216684) – norepinephrine reuptake inhbitor [228]
  • Elzasonan (CP-448187) – serotonin 5-HT1B and 5-HT1D receptor antagonist[30]
  • Emapunil (AC-5216; XBD-173) – translocator protein (TSPO; peripheral benzodiazepine receptor) agonist (neurosteroidogenesis stimulant) [229]
  • Emicerfont (GW-876008; GW-876008X) – corticotropin releasing factor receptor 1 (CRF1) antagonist [230]
  • Eplivanserin (Ciltyri; Sliwens; SR-46349; SR-46349B; SR-46615A) – serotonin 5-HT2A receptor antagonist [231]
  • Eptapirone (F-11440) – serotonin 5-HT1A receptor full agonist [232]
  • Esreboxetine ((S,S)-Reboxetine; AXS-14; PNU-165442G) – norepinephrine reuptake inhibitor [233]
  • Esuprone (LU-43839) – monoamine oxidase MAO-A reversible inhibitor [234]
  • Ethyl eicosapentaenoic acid (Ethyl-EPA) – omega-3 fatty acid [235]
  • Farampator (CX-691; ORG-24448) – ionotropic glutamate AMPA receptor positive allosteric modulator [236]
  • Fasoracetam (AEVI-001; LAM-105; MDGN-001; NFC-1; NS-105) – unknown mechanism of action (metabotropic glutamate receptor modulator) and racetam [237][31][26]
  • FCE-25876 – serotonin reuptake inhibitor [238]
  • Flerobuterol – β-adrenergic receptor agonist [239]
  • Flesinoxan (DU-29373) – serotonin 5-HT1A receptor agonist [240]
  • Flibanserin (Addyi; BIMT-17; Girosa) – serotonin 5-HT1A receptor agonist, serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor antagonist, and dopamine D4 receptor antagonist [241]
  • (R)-Fluoxetine – serotonin reuptake inhibitor [242]
  • Fluparoxan (GR-50360; GR-50360A) – α2-adrenergic receptor antagonist [243]
  • Gaboxadol (LU-02030; LU-2-030; MK-0928; OV-101; THIP) – GABAA receptor agonist [244]
  • Girisopam (EGIS-5810; GYKI-51189) – GABAA receptor positive allosteric modulator and benzodiazepine [245]
  • GYKI-52895 – dopamine reuptake inhibitor [246]
  • Haloperidol (CLR-3001) – typical antipsychotic (non-selective monoamine receptor modulator; low-dose withdrawal therapy) [247][32]
  • HT-2157 (SNAP-37889) – galanin GAL3 receptor antagonist [248]
  • ICI-170809 (ZM-170809) – serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor antagonist [249]
  • Idazoxan – α2-adrenergic receptor antagonist [250]
  • Ipsapirone (BAY-Q-7821; TVX-Q-7821) – serotonin 5-HT1A receptor partial agonist [251]
  • IRFI-165 – adenosine A1 receptor antagonist [252]
  • Istradefylline (KW-6002; Nourianz; Nouriast) – adenosine A2 receptor antagonist [253]
  • JNJ-18038683 – serotonin 5-HT7 receptor antagonist [254]
  • JNJ-19567470 (CRA-5626; R-317573) – corticotropin releasing factor receptor 1 (CRF1) antagonist [255]
  • JNJ-26489112 – unknown mechanism of action (topiramate successor) [256]
  • JNJ-39393406 – α7 nicotinic acetylcholine receptor positive allosteric modulator [257]
  • Lanicemine (AZD-6765) – low-trapping ionotropic glutamate NMDA receptor antagonist [258]
  • LB-100 (LB-1) – protein phosphatase 2A (PP2A) inhibitor [259]
  • Levoprotiline (CGP-12103; CGP-12103A; CGS-12103; R(–)-oxaprotiline; R(–)-hydroxymaprotiline) – histamine H1 receptor antagonist, other actions, and tetracyclic antidepressant [260][33]
  • Lithium – unknown mechanism of action and mood stabilizer [261]
  • Litoxetine (IXA-001; SL-810385) – serotonin reuptake inhibitor and weak serotonin 5-HT3 receptor antagonist [262]
  • Losmapimod (FTX-1821; GS-856553; GSK-856553; GW-856553; GW-856553X) – p38-α/β mitogen-activated protein kinase (MAPK) inhibitor and double homeobox 4 (DUX4) inhibitor [263]
  • LU-AA34893 (LU-AA-34893) – serotonin receptor modulator [264]
  • LU-AA39959 (LU-AA-39959) – ion channel modulator [265]
  • Lubazodone (SM-50C; YM-35992; YM-992) – serotonin reuptake inhibitor and serotonin 5-HT2A receptor antagonist [266]
  • Masitinib (AB-07105; AB-1010; Alsitek; Masican; Masipro; Masiviera) – tyrosine kinase inhibitor and other actions [267]
  • Mecamylamine (Inversine; Tridmac) – nicotinic acetylcholine receptor negative allosteric modulator [268]
  • MIN-117 (WF-516) – serotonin and dopamine reuptake inhibitor, serotonin 5-HT1A and 5-HT7 receptor antagonist, and α1-adrenergic receptor antagonist [269]
  • ML-105 – undefined mechanism of action [270]
  • Naloxone/tianeptine (TNX-601; TNX-601-CR; TNX-601-ER) – μ-opioid receptor agonist, serotonin reuptake enhancer, tricyclic antidepressant, and μ-opioid receptor antagonist combination [271]
  • Naluzotan (PRX-00023) – serotonin 5-HT1A receptor partial agonist and sigma σ1 receptor antagonist [272]
  • NB-415 – vasopressin V1b receptor antagonist [273]
  • Neboglamine (nebostinel; CR-2249; XY-2401) – ionotropic glutamate NMDA receptor glycine site positive allosteric modulator [274]
  • Nefiracetam (BRN 6848330; CCRIS 6729; DM 9384; DMPPA; DN-9384; DZL-221; HL-0812; HPI-001; Motiva; Translon) – unknown mechanism of action (voltage-gated calcium channel potentiator, α4β2 nicotinic acetylcholine receptor potentiator, ionotropic glutamate NMDA receptor potentiator (possible glycine site partial positive allosteric modulator), ionotropic glutamate AMPA receptor potentiator, and GABAA receptor agonist) and racetam [275][34][35][36][37][26]
  • Nemifitide (INN-00835) – unknown mechanism of action [276]
  • NS-2359 (GSK-372475) – serotonin, norepinephrine, and dopamine reuptake inhibitor [277]
  • NS-2389 (GW-650250; GW-650250A) – serotonin, norepinephrine, and dopamine reuptake inhibitor [278]
  • ORM-10921 – α2C-adrenergic receptor antagonist [279]
  • Orvepitant (GW-823296; GW-823296X; GW823296) – neurokinin NK1 receptor antagonist [280][38]
  • Osanetant (ACER-801; SR-142801; SR-142806) – neurokinin NK3 receptor antagonist [281]
  • Pexacerfont (BMS-562086) – corticotropin releasing factor receptor 1 (CRF1) antagonist [282]
  • PF-04455242 – κ-opioid receptor antagonist [283]
  • PT-150 (ORG-34517; SCH-900636) – glucocorticoid receptor antagonist and androgen receptor antagonist [284]
  • Radafaxine (GW-353162; (2S,3S)-hydroxybupropion) – norepinephrine and dopamine reuptake inhibitor [285]
  • Ramelteon (Rozerem; TAK-375) – melatonin MT1 and MT2 receptor agonist [286]
  • Rapastinel (BV-102; GLYX-13; TPPT-amide) – ionotropic glutamate NMDA receptor glycine site partial agonist [287]
  • RG-7166 – serotonin, norepinephrine, and dopamine reuptake inhibitor [288]
  • Ritanserin (R-55667) – serotonin 5-HT2A and 5-HT2C receptor antagonist [289]
  • Robalzotan (AZD-7371; NAD-299) – serotonin 5-HT1A receptor antagonist
  • Rolipram (ME-3167; ZK-62711) – phosphodiesterase 4 (PDE4) inhibitor [290]
  • Sabcomeline (BCI-224; CEB-242; Memric; SB-202026) – muscarinic acetylcholine M1 receptor agonist [291]
  • Saredutant (SR-48968) – neurokinin NK2 receptor antagonist[39][40]
  • SB-236057 – serotonin 5-HT1B receptor inverse agonist [292]
  • SB-245570 – serotonin 5-HT1B receptor antagonist [293]
  • Sibutramine (Aoquqing; BTS-54524; Ectiva; KES-524; Meridia; Reductase; Reductil; Reduxade; Sibutral) – serotonin, norepinephrine, and dopamine reuptake inhibitor [294]
  • Siramesine (LU-28179) – sigma σ2 receptor agonist [295]
  • Sirukumab (CNTO-136; Plivensia) – interleukin 6 (IL-6) inhibitor [296]
  • SKL-10406 (SKL-DEP) – serotonin, norepinephrine, and dopamine reuptake inhibitor [297]
  • SKL-PSY (FZ-016) – serotonin 5-HT1A receptor agonist [298]
  • Sodium phenylbutyrate (slow-release; LU-901; Lunaphen) – histone deacetylase (HDAC) inhibitor [299]
  • SSR-149415 (SR-149415) – vasopressin V1b receptor antagonist [300]
  • SSR-241586 – neurokinin NK2 and NK3 receptor antagonist [301]
  • Tandospirone (metanopirone; Sediel; SM-3997) – serotonin 5-HT1A receptor partial agonist and α2-adrenergic receptor antagonist [302]
  • Tasimelteon (BMS-214778; Hetlioz; VEC-162) – melatonin MT1 and MT2 receptor agonist [303]
  • Tedatioxetine (LU-AA24530) – serotonin, norepinephrine, and dopamine reuptake inhibitor, serotonin 5-HT2A, 5-HT2C, and 5-HT3 receptor antagonist, and α1A-adrenergic receptor antagonist [304]
  • Tianeptine (JNJ-39823277; TPI-1062) – μ-opioid receptor agonist, serotonin reuptake enhancer, and tricyclic antidepressant [305]
  • TS-111 – undefined mechanism of action [306]
  • Tulrampator (CX-1632; S-47445) – ionotropic glutamate AMPA receptor positive allosteric modulator [307]
  • Vanoxerine (boxeprazine; GBR-12909) – atypical dopamine reuptake inhibitor [308]
  • Verucerfont (GSK-561679; NBI-77860) – corticotropin releasing factor receptor 1 (CRF1) antagonist [309]
  • Vestipitant (GW-597599; GW-597599B) – neurokinin NK1 receptor antagonist [310][24]
  • Viloxazine (Qelbree) – norepinephrine reuptake inhibitor [311]
  • VN-2222 – serotonin reuptake inhibitor and serotonin 5-HT1A receptor partial agonist [312]
  • VUFB-17649 – serotonin reuptake inhibitor [313]
  • VUFB-18285 – serotonin reuptake inhibitor [314]
  • ZD-4974 – neurokinin NK1 receptor antagonist [315]
  • Zelatriazin (TAK-041; NBI-1065846; NBI-846) – G protein-coupled receptor 139 (GPR139) agonist [316]
  • Ziprasidone (Geodon) – atypical antipsychotic (non-selective monoamine receptor modulator) [317]

Preregistration submission withdrawal

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  • Aripiprazole/sertraline (ASC-01) – atypical antipsychotic (non-selective monoamine receptor modulator) and serotonin reuptake inhibitor combination [318]

Formal development never or not yet started

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  • Mevidalen (LY-3154207; D1 PAM) – dopamine D1 receptor positive allosteric modulator – under development for Lewy body disease [319][41]

Clinically used drugs

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Main article: List of antidepressants

Approved drugs

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  • Agomelatine (Valdoxan) – serotonin 5-HT2C receptor antagonist and melatonin MT1 and MT2 receptor agonist [320]
  • Amineptine (Survector, Maneon) – norepinephrine and dopamine reuptake inhibitor – withdrawn[42]
  • Amisulpride (Solian) – atypical antipsychotic (dopamine D2 and D3 receptor antagonist and serotonin 5-HT2B and 5-HT7 receptor antagonist) [321]
  • Amitriptyline (Elavil) – tricyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[40]
  • Amoxapine (Asendin) – tetracyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[40][42]
  • Aripiprazole (Abilify) – atypical antipsychotic (non-selective monoamine receptor modulator) [322]
  • Brexanolone (allopregnanolone; SAGE-547; SGE-102; Zulresso) – GABAA receptor positive allosteric modulator and neurosteroid – approved for postpartum depression[323]
  • Brexpiprazole (Rexulti) – atypical antipsychotic (non-selective monoamine receptor modulator) [324]
  • Bupropion (Wellbutrin) – norepinephrine and dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator [325]
  • Bupropion/dextromethorphan (Auvelity) – sigma σ1 receptor agonist, serotonin reuptake inhibitor, norepinephrine and dopamine reuptake inhibitor, nicotinic acetylcholine receptor negative allosteric modulator, ionotropic glutamate NMDA receptor antagonist, other actions, and CYP2D6 inhibitor combination [326]
  • Butriptyline (Evadyne) – tricyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator) – discontinued[42]
  • Cariprazine (Vraylar) – atypical antipsychotic (non-selective monoamine receptor modulator) [327]
  • Citalopram (Celexa) – serotonin reuptake inhibitor [328]
  • Desipramine (Norpramin) – tricyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[40]
  • Desvenlafaxine (Pristiq) – serotonin and norepinephrine reuptake inhibitor [329] [330]
  • Desvenlafaxine (extended-release; Khedezla) – serotonin and norepinephrine reuptake inhibitor – withdrawn [331]
  • Desvenlafaxine (extended-release; WIP-DF17) – serotonin and norepinephrine reuptake inhibitor – registered in South Korea [332][43][44]
  • Dosulepin (dothiepin; Prothiaden) – tricyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[42]
  • Doxepin (Sinequan) – tricyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[40]
  • Duloxetine (Cymbalta; Drizalma Sprinkle) – serotonin and norepinephrine reuptake inhibitor [333] [334]
  • Escitalopram (Lexapro) – serotonin reuptake inhibitor [335]
  • Esketamine (Spravato) – ionotropic glutamate NMDA receptor antagonist [336]
  • Fluoxetine (Prozac; Sarafem) – serotonin reuptake inhibitor [337] [338]
  • Fluvoxamine (Luvox) – serotonin reuptake inhibitor[40]
  • Gepirone (Exxua) – serotonin 5-HT1A receptor partial agonist and α2-adrenergic receptor antagonist [339]
  • Hypericum extract (LI-160; St John's wort) – undefined mechanism of action [340]
  • Imipramine (Tofranil) – tricyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[40]
  • Iproniazid (Marsilid) – monoamine oxidase MAO-A and MAO-B irreversible inhibitor – withdrawn[45]
  • Isocarboxazid (Marplan) – monoamine oxidase MAO-A and MAO-B irreversible inhibitor[40][45]
  • Levomilnacipran (Fetzima) – serotonin and norepinephrine reuptake inhibitor [341]
  • Levosulpiride (L-sulpiride; Levobren; Levopraid; Levosulpride; RV-12309; Sulpepta) – dopamine D2 and D3 receptor antagonist and serotonin 5-HT4 receptor agonist [342]
  • Lofepramine (Lomont) – tricyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[42]
  • Lumateperone (Caplyta) – atypical antipsychotic (non-selective monoamine receptor modulator) [343]
  • Lurasidone (Latuda) – atypical antipsychotic (non-selective monoamine receptor modulator) [344]
  • Maprotiline (Ludiomil) – tetracyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[42]
  • Mianserin (Tolvon) – tetracyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[42]
  • Milnacipran (Dalcipran; Ixel; Savella) – serotonin and norepinephrine reuptake inhibitor [345]
  • Mirtazapine (Remeron) – α2-adrenergic receptor antagonist, serotonin 5-HT2A, 5-HT2C, and 5-HT3 receptor antagonist, H1 receptor inverse agonist, and tetracyclic antidepressant [346]
  • Moclobemide (Aurorix; Manerix) – monoamine oxidase MAO-A reversible inhibitor [347][45]
  • Nefazodone (BMY-13754; Dutonin; MJ-13754; MS-13754; Nefadar; Serzone) – serotonin 5-HT1A receptor ligand, serotonin 5-HT2A and 5-HT2C receptor antagonist, α1- and α2-adrenergic receptor antagonist, weak serotonin, norepinephrine, and dopamine reuptake inhibitor, and other actions – mostly withdrawn [348]
  • Nomifensine (Merital; Alival) – norepinephrine and dopamine reuptake inhibitor – withdrawn[42]
  • Nortriptyline (Aventyl) – tricyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[40]
  • Olanzapine (Zyprexa) – atypical antipsychotic (non-selective monoamine receptor modulator) [349]
  • Olanzapine/fluoxetine (OFC; Symbyax; ZypZac) – atypical antipsychotic (non-selective monoamine receptor modulator) and serotonin reuptake inhibitor combination [350]
  • Opipramol (Ensidon; G-33040; Insidon; Nisidana) – sigma σ1 and σ2 receptor agonist, serotonin 5-HT2A receptor antagonist, dopamine D2 receptor antagonist, α1-adrenergic receptor antagonist, histamine H1 receptor antagonist, other actions, and tricyclic antidepressant [351]
  • Paroxetine (Paxil; Seroxat) – serotonin reuptake inhibitor [352] [353]
  • Phenelzine (Nardil) – monoamine oxidase MAO-A and MAO-B irreversible inhibitor[40][45]
  • Protriptyline (Vivactil) – tricyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[42]
  • Quetiapine (Seroquel) – atypical antipsychotic (non-selective monoamine receptor modulator) [354]
  • Reboxetine (Edronax) – norepinephrine reuptake inhibitor [355]
  • Selegiline (Emsam) – monoamine oxidase MAO-B irreversible inhibitor, catecholaminergic activity enhancer, and weak norepineprhine releasing agent (via metabolites) [356]
  • Sertraline (Zoloft; Lustral) – serotonin reuptake inhibitor [357]
  • Setiptiline (Tecipul; Tesolon) – serotonin receptor antagonist, α2-adrenergic receptor antagonist, norepinephrine reuptake inhibitor, and tetracyclic antidepressant [358]
  • Tianeptine (Coaxil; Stablon; Tatinol) – μ-opioid receptor agonist, serotonin reuptake enhancer, and tricyclic antidepressant [359]
  • Toludesvenlafaxine (ansofaxine; 4-methylbenzoate desvenlafaxine; desvenlafaxine prodrug; LPM-570065; LY-03005; Ruoxinlin) – serotonin, norepinephrine, and dopamine reuptake inhibitor [360]
  • Tranylcypromine (Parnate) – monoamine oxidase MAO-A and MAO-B irreversible inhibitor[40][45]
  • Trazodone (Oleptro; Trittico) – serotonin 5-HT1A receptor partial agonist, serotonin 5-HT2A and 5-HT2C receptor antagonist, α1- and α2-adrenergic receptor antagonist, weak serotonin reuptake inhibitor, and other actions [361]
  • Trimipramine (Surmontil) – tricyclic antidepressant (non-selective monoamine reuptake inhibitor and/or receptor modulator)[40]
  • Venlafaxine (Effexor) – serotonin and norepinephrine reuptake inhibitor [362]
  • Vilazodone (Viibryd) – serotonin reuptake inhibitor and serotonin 5-HT1A receptor agonist [363]
  • Viloxazine (Vivalan) – norepinephrine reuptake inhibitor[42]
  • Vortioxetine (Trintellix) – serotonin reuptake inhibitor, serotonin 5-HT1A and 5-HT1B receptor agonist, and serotonin 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist [364]
  • Zimelidine (Zelmid) – serotonin reuptake inhibitor – withdrawn[42]
  • Zuranolone (BIIB-125; S-812217; SAGE-217; SGE-797; Zurzuvae) – GABAA receptor positive allosteric modulator and neurosteroid – approved for postpartum depression[365]

See also

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References

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  1. ^ Taylor NP (4 February 2019). "FDA rejects Alkermes' depression drug ALKS 5461". Fierce Biotech. Retrieved 8 August 2024.
  2. ^ Abad VC, Guilleminault C (December 2018). "Solriamfetol for the treatment of daytime sleepiness in obstructive sleep apnea". Expert Rev Respir Med. 12 (12): 1007–1019. doi:10.1080/17476348.2018.1541742. PMID 30365900. Solriamfetol hydrochloride, previously known as JZP-110, SKLN05, ARL-N05, YKP-10A, R-228060, ADX-N05, was initially developed by the SK Group as YKP-10A, a drug to treat depression. SK Group licensed rights outside of 11 countries in Asia to Aerial BioPharma in 2011. [...]
  3. ^ Klein AK, Austin EW, Cunningham MJ, Dvorak D, Gatti S, Hulls SK, Kiss L, Kruegel AC, Marek GJ, Papp M, Sporn J, Hughes ZA (May 2024). "GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents". Neuropsychopharmacology. 49 (6): 905–914. doi:10.1038/s41386-023-01783-1. PMC 11039472. PMID 38177696.
  4. ^ Canal CE, Morgan D (2012). "Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model". Drug Test Anal. 4 (7–8): 556–576. doi:10.1002/dta.1333. PMC 3722587. PMID 22517680. Regardless, a more parsimonious explanation is that certain 5-HT2 receptor-activating compounds, such as DOI and psilocin, cause specific conformations of 5-HT2 receptors that lead to LSD-like psychedelic effects.[94,232] Moreover, although the 5-HT2 agonists mCPP, lorcaserin, and quipazine, are often considered 'non-hallucinogenic', they actually do produce perceptual, cognitive, and emotional changes that may be considered 'hallucinogenic'.[15,233,234] These effects, however, are generally not considered LSD-like. Finally, it is noteworthy that novel, partial 5-HT2A/D2 receptor agonists also attenuate the DOI-elicited HTR.[235,236]
  5. ^ Mirchandani-Duque M, Choucri M, Hernández-Mondragón JC, Crespo-Ramírez M, Pérez-Olives C, Ferraro L, Franco R, Pérez de la Mora M, Fuxe K, Borroto-Escuela DO (April 2024). "Membrane Heteroreceptor Complexes as Second-Order Protein Modulators: A Novel Integrative Mechanism through Allosteric Receptor-Receptor Interactions". Membranes (Basel). 14 (5): 96. doi:10.3390/membranes14050096. PMC 11122807. PMID 38786931. This concept is also supported by experiments on OSU-6162, a selective Sigma 1R ligand in low doses [176]. This Sigma1R ligand produced in the nucleus accumbens shell substantial increases in the density of the D2R–Sigma1R and A2AR–D2R heterocomplexes, supporting the existence of A2AR–D2R–Sigma1R trimeric complexes in which the Sigma1R agonist can strongly enhance the antagonistic allosteric A2AR–D2R interaction. This mechanism may mediate the enhanced antagonistic A2AR–D2R interaction, causing marked inhibition of cocaine reward, leading to cocaine addiction.
  6. ^ Carlsson ML, Burstein ES, Kloberg A, Hansson S, Schedwin A, Nilsson M, Rung JP, Carlsson A (November 2011). "I. In vivo evidence for partial agonist effects of (-)-OSU6162 and (+)-OSU6162 on 5-HT2A serotonin receptors". J Neural Transm (Vienna). 118 (11): 1511–1522. doi:10.1007/s00702-011-0704-8. PMID 21874578.
  7. ^ Burstein ES, Carlsson ML, Owens M, Ma JN, Schiffer HH, Carlsson A, Hacksell U (November 2011). "II. In vitro evidence that (-)-OSU6162 and (+)-OSU6162 produce their behavioral effects through 5-HT2A serotonin and D2 dopamine receptors". J Neural Transm (Vienna). 118 (11): 1523–1533. doi:10.1007/s00702-011-0701-y. PMID 21866391.
  8. ^ Sahlholm K, Århem P, Fuxe K, Marcellino D (January 2013). "The dopamine stabilizers ACR16 and (-)-OSU6162 display nanomolar affinities at the σ-1 receptor". Mol Psychiatry. 18 (1): 12–14. doi:10.1038/mp.2012.3. PMID 22349783.
  9. ^ Borroto-Escuela DO, Romero-Fernandez W, Wydra K, Zhou Z, Suder A, Filip M, Fuxe K (February 2020). "OSU-6162, a Sigma1R Ligand in Low Doses, Can Further Increase the Effects of Cocaine Self-Administration on Accumbal D2R Heteroreceptor Complexes". Neurotox Res. 37 (2): 433–444. doi:10.1007/s12640-019-00134-7. PMC 6989596. PMID 31782100.
  10. ^ Wang K, Chen F, Wang J, Liu H (2024). "Drug discovery targeting thyroid hormone receptor β (THRβ) for the treatment of liver diseases and other medical indications". Acta Pharmaceutica Sinica B. doi:10.1016/j.apsb.2024.07.025.
  11. ^ "ALTO-300". Carilion Clinic. Retrieved 2024-08-09. ALTO-300 is a 25 mg formulation of the atypical antidepressant agomelatine, which targets the melatonin and serotonin signaling systems and has been shown to modulate mood and circadian rhythms. This medication is approved for the treatment of depression in several countries outside of the United States.
  12. ^ Carlini SV, Osborne LM, Deligiannidis KM (December 2023). "Current pharmacotherapy approaches and novel GABAergic antidepressant development in postpartum depression". Dialogues Clin Neurosci. 25 (1): 92–100. doi:10.1080/19585969.2023.2262464. PMC 10557560. PMID 37796239. BRII-296 is an extended-release injectable aqueous suspension formulation of brexanolone. Phase 1 trials in 116 subjects testing 6 dose regimens are complete with the sponsor reporting that a single intramuscular injection of 600 mg achieved dose linearity, early drug absorption, and gradual and extended-release profiles without the need for dose titration or tapering, however results have not been published (Brii Biosciences Limited 2023b).
  13. ^ "Viage Therapeutics". Viage Therapeutics. 20 July 2023. Retrieved 9 August 2024. DGX-001, Viage's clinical drug candidate, represents a first-in-class oral drug candidate targeting the gut-brain axis. The proposed mechanism of action of DGX-001 is to modulate the vagus nerve through specific receptor interactions on enteroendocrine cells in the gut, resulting in a regulation of brain cell activity.
  14. ^ M Ro Rsted E, Jensen AA, Smits G, Frydenvang K, Kristensen JL (May 2024). "Discovery and Structure-Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists". J Med Chem. 67 (9): 7224–7244. doi:10.1021/acs.jmedchem.4c00082. PMC 11089506. PMID 38648420.
  15. ^ Jensen AA, Cecchi CR, Hibicke M, Bach AH, Kaadt E, Märcher-Rørsted E, Nichols CD, Elfving B, Kristensen JL (22 April 2024), The selective 5-HT 2A receptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents, doi:10.1101/2024.04.19.590212
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  18. ^ "8741810.PDF" (PDF). Retrieved 7 August 2024. [SK2110 - Buprenorphine implant for the treatment of major depressive disorder SK2110 is an implant of buprenorphine hydrochloride for patients with major depression and refractory depression who cannot be relieved by taking at least two drugs. Buprenorphine hydrochloride was developed by Indivior and is a KOR1 antagonist and MOR1 agonist. Currently, the highest development stage of the drug is approval for marketing, which is used to treat opioid dependence, chronic pain, pain and substance-related disorders. The company changes the route of administration to prepare an implant, which can reduce the frequency of administration, improve the bioavailability of the drug, improve patient compliance, and maintain a stable blood drug concentration, thereby reducing adverse drug reactions. At the same time, the implanted administration method can also play a role in avoiding drug abuse. At present, the project is conducting laboratory preparation small-scale trial prescription process exploration and preliminary pharmacodynamic studies. SK2110 can take effect quickly and quickly relieve patients' depressive symptoms. It is expected to submit an IND application to my country's drug regulatory authorities in 2024.]
  19. ^ Shen Q, Li M, Li Y, Zhang R, Lin H, Yang F, Wu Q, Pan C, Yu X, Yuan D, Chen Q, Chen H, Wang Z (2023). "Safety, pharmacokinetics, and pharmacodynamics of HS-10353 in healthy adults and patients with major depressive disorder: a phase 1 study". Neuroscience Applied. 2: 102911. doi:10.1016/j.nsa.2023.102911.
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  28. ^ Zarate CA, Machado-Vieira R (March 2017). "Ketamine: translating mechanistic discoveries into the next generation of glutamate modulators for mood disorders". Mol Psychiatry. 22 (3): 324–327. doi:10.1038/mp.2016.249. PMC 5641407. PMID 28070122. Because AMPA appeared critical to ketamine's antidepressant effects, researchers reasoned that AMPA positive modulators—also known as AMPAkines—could positively influence mood. Previous studies evaluating AMPAkines in mood disorders achieved mixed results, potentially due to low bioavailability and toxicity profile.20 To overcome the issue of low bioavailability, other AMPAkines were recently developed and tested in initial Phase 1 and 2 studies, particularly coluracetam (BCI-540)21 and ORG-26576.22 Both agents showed preliminary therapeutic effects in major depressive disorder when tested in small samples.23,24
  29. ^ Borbély É, Simon M, Fuchs E, Wiborg O, Czéh B, Helyes Z (March 2022). "Novel drug developmental strategies for treatment-resistant depression". Br J Pharmacol. 179 (6): 1146–1186. doi:10.1111/bph.15753. PMC 9303797. PMID 34822719.
  30. ^ Dale E, Pehrson AL, Jeyarajah T, Li Y, Leiser SC, Smagin G, Olsen CK, Sanchez C (April 2016). "Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function". CNS Spectr. 21 (2): 143–161. doi:10.1017/S1092852915000425. PMC 4825106. PMID 26346726. The 5-HT1B/1D receptor antagonist elzasonan (CP-448187) was recently under development for the treatment of MDD and was tested in several phase-2 clinical trials, but its development program was also discontinued.140
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  32. ^ Kennedy SH, Giacobbe P, Placenza F, Hudson CJ, Seeman P, Seeman MV (September 2014). "Depression treatment by withdrawal of short-term low-dose antipsychotic, a proof-of-concept randomized double-blind study". J Affect Disord. 166: 139–143. doi:10.1016/j.jad.2014.04.014. PMID 25012422.
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  35. ^ Yoshii M, Watabe S, Murashima YL, Nukada T, Shiotani T, Nishizaki T (2001). "Neuronal Ca 2+ Channels and Nicotinic ACh Receptors as Functional Targets of the Nootropic Nefiracetam". Psychogeriatrics. 1 (1): 39–49. doi:10.1111/j.1479-8301.2001.tb00071.x. ISSN 1346-3500.
  36. ^ Gualtieri F, Manetti D, Romanelli MN, Ghelardini C (2002). "Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs". Curr Pharm Des. 8 (2): 125–38. doi:10.2174/1381612023396582. PMID 11812254. In general, piracetam-like nootropics show no affinity for the most important central receptors (Ki > 10 μM). A modest affinity for muscarinic receptors is shown by aniracetam (Ki = 4.4 μM [58]) and nebracetam (Ki = 6.3 μM [61]). Nefiracetam is the only one showing affinity in the nanomolar range (Ki = 8.5 nM on the GABAA receptor [58]). [...] Nefiracetam (chart (1)) is awaiting approval. It presents a variety of pharmacological actions as it is reported to activate the cholinergic, GABAergic and other monaminergic systems and to modulate N-type calcium channels [78-81].
  37. ^ Gouliaev AH, Senning A (May 1994). "Piracetam and other structurally related nootropics". Brain Res Brain Res Rev. 19 (2): 180–222. doi:10.1016/0165-0173(94)90011-6. PMID 8061686. As mentioned above, no commonly accepted mechanism for the racetam nootropics has yet been established, They do not seem to act on any well characterised receptor site with the exception of nefiracetam which has high affinity for GABA, receptors (see Table 1). [...] Receptor: GABAA. Receptor ligand: [3H]muscimolA. Compound: nefiracetam. IC50: 8.5 nMB. Refs.: 222. [...] From Table 1 it is, however, evident that the piracetam-like nootropics do not exhibit high affinity for any of the receptor types tested so far (except for nefiracetam, which shows some activity at GABAA receptors)
  38. ^ Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, Gomeni R, Lawson E, Lopez M, Millns H, Rabiner EA, Trist D, Trower M, Zamuner S, Krishnan R, Fava M (May 2013). "Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies". J Psychopharmacol. 27 (5): 424–434. doi:10.1177/0269881113480990. PMID 23539641.
  39. ^ Quartara L, Altamura M, Evangelista S, Maggi CA (December 2009). "Tachykinin receptor antagonists in clinical trials". Expert Opin Investig Drugs. 18 (12): 1843–1864. doi:10.1517/13543780903379530. PMID 19938899.
  40. ^ a b c d e f g h i j k l Namiot ED, Smirnovová D, Sokolov AV, Chubarev VN, Tarasov VV, Schiöth HB (July 2024). "Depression clinical trials worldwide: a systematic analysis of the ICTRP and comparison with ClinicalTrials.gov". Transl Psychiatry. 14 (1): 315. doi:10.1038/s41398-024-03031-6. PMC 11291508. PMID 39085220.
  41. ^ Svensson KA, Hao J, Bruns RF (2019). "Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders". Neuropsychotherapeutics. Adv Pharmacol. Vol. 86. pp. 273–305. doi:10.1016/bs.apha.2019.06.001. ISBN 978-0-12-816668-0. PMID 31378255. The close structural analog of DETQ, LY3154207, is currently in phase 2 testing for Lewy Body dementias, including patients with Parkinson's disease.
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