Depressive disorder

Summary

Depressive disorder (MONDO:0002050) is a disease (an umbrella term covering 7 Mondo subtypes) with 5 cohort genes (44 GWAS associations across 66 studies) and 4,995 clinical trials. Top therapeutic interventions include venlafaxine, citalopram, and fluoxetine.

At a glance

• Umbrella term: 7 Mondo subtypes
• Cohort genes: 5
• GWAS associations: 44
• ClinVar variants: 8
• Clinical trials: 4,995

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	depressive disorder
Mondo ID	MONDO:0002050
MeSH	D003866
DOID	DOID:1596
ICD-10-CM	F32
NCIT	C2982
SNOMED CT	35489007
UMLS	C0011581
MedGen	4229
Is cancer (heuristic)	no

Also known as: depression · melancholia · melancholias · syndrome, depressive · syndromes, depressive

Data availability: 8 ClinVar variants · 44 GWAS associations (66 studies) · 1 GenCC gene-disease record · 95 cell lines.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › mental disorder › mood disorder › depressive disorder

Related subtypes (4): dysthymic disorder, atypical depressive disorder, cyclothymic disorder, bipolar disorder

Subtypes (7): seasonal affective disorder, major depressive disorder, melancholia, postpartum depression, bipolar depression, neurotic depression, mixed anxiety and depressive disorder

Genetics & variants

GWAS landscape

44 GWAS associations across 66 studies. Top hits map to 25 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
chr11:113377488	1e-19		C	0.04
chr7:2074122	3e-17		A	0.05
chr6:152254115	7e-13		A	0.03
rs12140625	7e-13	RN7SKP19 - LINC01360	A	0.03
rs11157241	8e-13	LRFN5-DT	T	0.03
chr14:42143231	1e-12		A	0.03
rs11763750	1e-12	MAD1L1	G	0.04
rs4936272	1e-12	DRD2	T	0.03
rs531450121	2e-12	PLA2G2C	C	1.95
chr3:49236439	3e-12		T	0.03
chr2:233667744	1e-11		A	0.03
chr9:140258802	2e-11		G	0.05
rs553807001	2e-11	FAM177A1	C	2.97
rs570665128	3e-11	SWAP70	G	2.31
rs9586	4e-11	KLHDC8B	C	0.03
rs1075046	4e-09	CDH12	G	0.31
rs4786119	6e-09	RBFOX1	C	0.38
rs1853229	2e-08	PTPRD	T	0.9
rs138801403	3e-08	CBR3-AS1	A	0.84
rs56289435	4e-08	PLPPR5-AS1, PLPPR5	C	0.2
rs57729223	7e-08	NTRK3-AS1 - MRPL46	?	3.6
rs117741236	7e-08	TGM5	G	1.01
rs11130245	4e-07	GNAT1 - SLC38A3	?
rs78063755	1e-06	CDH4	?	2.3
rs2297754	3e-06	FMO5	?	6.37
rs2597874	3e-06	RPL36AP23 - LINC02945	?	2.09
rs75155690	3e-06	BUB3	?	5.87
rs9356570	3e-06	TCP10L2 - HPAT5	?	0.25
rs9268145	3e-06	TSBP1, TSBP1-AS1	?	2.95
rs41376753	5e-06	OR2F2 - OR2F1	?	1.72

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90476511	Verma A	2024	180,565	243,442	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480750	Verma A	2024	62,513	50,894	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90476922	Verma A	2024	31,025	284,643	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90078637	Backman JD	2021	29,907	14,440	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90082623	Backman JD	2021	29,907	14,440	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90077761	Backman JD	2021	27,241	304,513	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90081747	Backman JD	2021	27,241	304,513	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90078271	Backman JD	2021	26,963	396,723	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90082257	Backman JD	2021	26,963	396,723	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90078286	Backman JD	2021	26,143	345,589	Exome sequencing and analysis of 454,787 UK Biobank participants.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	4
Tier 3: regulatory	1
Tier 4: intronic/intergenic	32

MAF distribution

Bucket	Variants
common (>=0.05)	29
low_freq (0.01-0.05)	3
rare (<0.01)	3
unknown	2

Functional consequences

Consequence	Count
intron_variant	20
unknown	7
intergenic_variant	5
3_prime_UTR_variant	3
regulatory_region_variant	1
splice_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
chr11:113377488				0.365			1e-19	Tier 4: intronic/intergenic
chr7:2074122				0.198			3e-17	Tier 4: intronic/intergenic
chr6:152254115				0.332			7e-13	Tier 4: intronic/intergenic
rs12140625	1	73200544	A>G,T	0.464	intergenic_variant	RN7SKP19 - LINC01360	7e-13	Tier 4: intronic/intergenic
rs11157241	14	41582568	T>C	0.422	intron_variant	LRFN5-DT	8e-13	Tier 4: intronic/intergenic
chr14:42143231				0.477			1e-12	Tier 4: intronic/intergenic
rs11763750	7	2040479	G>A	0.166	intron_variant	MAD1L1	1e-12	Tier 4: intronic/intergenic
rs4936272	11	113448185	T>C	0.487	intron_variant	DRD2	1e-12	Tier 4: intronic/intergenic
rs531450121	1	20163479	C>G,T	0.001	3_prime_UTR_variant	PLA2G2C	2e-12	Tier 2: splice/UTR
chr3:49236439				0.281			3e-12	Tier 4: intronic/intergenic
chr2:233667744				0.408			1e-11	Tier 4: intronic/intergenic
chr9:140258802				0.119			2e-11	Tier 4: intronic/intergenic
rs553807001	14	35057344	C>T	0	intron_variant	FAM177A1	2e-11	Tier 4: intronic/intergenic
rs570665128	11	9749274	G>A,T	0	intron_variant	SWAP70	3e-11	Tier 4: intronic/intergenic
rs9586	3	49176204	C>G,T	0.247	3_prime_UTR_variant	KLHDC8B	4e-11	Tier 2: splice/UTR
rs1075046	5	22852875	C>A,G,T	0.454	intron_variant	CDH12	4e-09	Tier 4: intronic/intergenic
rs4786119	16	6753435	T>A,C	0.385	intron_variant	RBFOX1	6e-09	Tier 4: intronic/intergenic
rs1853229	9	10503904	C>T	0.021	intron_variant	PTPRD	2e-08	Tier 4: intronic/intergenic
rs138801403	21	36149648	G>A	0.012	intron_variant	CBR3-AS1	3e-08	Tier 4: intronic/intergenic
rs56289435	1	99226692	CACACAA>C,CACACAAACACAA	0.498	intron_variant	PLPPR5-AS1, PLPPR5	4e-08	Tier 4: intronic/intergenic
rs57729223	15	88271981	C>T	0.05	intergenic_variant	NTRK3-AS1 - MRPL46	7e-08	Tier 4: intronic/intergenic
rs117741236	15	43263196	A>G	0.023	intron_variant	TGM5	7e-08	Tier 4: intronic/intergenic
rs11130245	3	50200714	T>A	0.05	intergenic_variant	GNAT1 - SLC38A3	4e-07	Tier 4: intronic/intergenic
rs78063755	20	61460980	C>T	0.05	intron_variant	CDH4	1e-06	Tier 4: intronic/intergenic
rs2297754	1	147213525	T>C		intron_variant	FMO5	3e-06	Tier 4: intronic/intergenic
rs2597874	4	111615513	C>A,G,T	0.05	intron_variant	RPL36AP23 - LINC02945	3e-06	Tier 4: intronic/intergenic
rs75155690	10	123161005	C>T		intron_variant	BUB3	3e-06	Tier 4: intronic/intergenic
rs9356570	6	167218800	T>A,C,G	0.05	regulatory_region_variant	TCP10L2 - HPAT5	3e-06	Tier 3: regulatory
rs9268145	6	32289507	T>G	0.05	intron_variant	TSBP1, TSBP1-AS1	3e-06	Tier 4: intronic/intergenic
rs41376753	7	143939387	C>G,T	0.05	intergenic_variant	OR2F2 - OR2F1	5e-06	Tier 4: intronic/intergenic

ClinVar germline variants

8 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 2 pathogenic, 1 conflicting classifications of pathogenicity, 1 affects, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267861	46;XX;t(2;11)(q11.2;p13)dn		Pathogenic	criteria provided, single submitter
812745	NM_000435.3(NOTCH3):c.634T>C (p.Cys212Arg)	NOTCH3	Pathogenic	no assertion criteria provided
426106	NM_021830.5(TWNK):c.1121G>A (p.Arg374Gln)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812744	NM_000435.3(NOTCH3):c.1136G>C (p.Cys379Ser)	NOTCH3	Likely pathogenic	criteria provided, single submitter
127974	NM_005591.4(MRE11):c.1727G>A (p.Arg576Gln)	MRE11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
267829	46;XX;t(5;10)(p13.3;q21.1)dn		Uncertain significance	criteria provided, single submitter
481777	NM_005591.4(MRE11):c.229G>A (p.Glu77Lys)	MRE11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1292053	NM_018245.3(OGDHL):c.2174A>T (p.Asn725Ile)	OGDHL	Affects	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
APAF1	Limited	Autosomal dominant	depressive disorder

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TWNK	Orphanet:1186	Infantile-onset spinocerebellar ataxia
TWNK	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
TWNK	Orphanet:363534	Mitochondrial DNA depletion syndrome, hepatocerebrorenal form
TWNK	Orphanet:642945	Perrault syndrome type 1
TWNK	Orphanet:642976	Perrault syndrome type 2
TWNK	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
MRE11	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
MRE11	Orphanet:240760	Nijmegen breakage syndrome-like disorder
MRE11	Orphanet:251347	Ataxia-telangiectasia-like disorder
NOTCH3	Orphanet:136	Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy
NOTCH3	Orphanet:2591	Infantile myofibromatosis
NOTCH3	Orphanet:2789	Lateral meningocele syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APAF1	HGNC:576	ENSG00000120868	O14727	Apoptotic protease-activating factor 1	gencc
TWNK	HGNC:1160	ENSG00000107815	Q96RR1	Twinkle mtDNA helicase	clinvar
OGDHL	HGNC:25590	ENSG00000197444	Q9ULD0	2-oxoglutarate dehydrogenase-like, mitochondrial	clinvar
MRE11	HGNC:7230	ENSG00000020922	P49959	Double-strand break repair protein MRE11	clinvar
NOTCH3	HGNC:7883	ENSG00000074181	Q9UM47	Neurogenic locus notch homolog protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APAF1	Apoptotic protease-activating factor 1	Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis.
TWNK	Twinkle mtDNA helicase	Mitochondrial helicase involved in mtDNA replication and repair.
OGDHL	2-oxoglutarate dehydrogenase-like, mitochondrial	2-oxoglutarate dehydrogenase (E1-like) component of the 2-oxoglutarate dehydrogenase multienzyme complex (OGDHC) which mediates the decarboxylation of alpha-ketoglutarate in the tricarboxylic acid cycle.
MRE11	Double-strand break repair protein MRE11	Core component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
NOTCH3	Neurogenic locus notch homolog protein 3	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.4

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	2	6.9×	0.088
Enzyme (other)	2	4.8×	0.088
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APAF1	Scaffold/PPI	no		CARD, WD40_rpt, NB-ARC
TWNK	Enzyme (other)	yes	3.6.4.12	DNA_helicase_DnaB-like_C, Twinkle-like, P-loop_NTPase
OGDHL	Enzyme (other)	yes	1.2.1.105	DH_E1, Transketolase-like_Pyr-bd, 2oxoglutarate_DH_E1
MRE11	Other/Unknown	no		Mre11, Calcineurin-like_PHP, Mre11_DNA-bd
NOTCH3	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
gastrocnemius	1
male germ line stem cell (sensu Vertebrata) in testis	1
tendon of biceps brachii	1
adult mammalian kidney	1
right hemisphere of cerebellum	1
right lobe of liver	1
calcaneal tendon	1
oocyte	1
secondary oocyte	1
popliteal artery	1
right coronary artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APAF1	254	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
TWNK	211	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, gastrocnemius
OGDHL	186	broad	marker	adult mammalian kidney, right lobe of liver, right hemisphere of cerebellum
MRE11	254	ubiquitous	marker	calcaneal tendon, oocyte, secondary oocyte
NOTCH3	273	ubiquitous	marker	popliteal artery, tibial artery, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APAF1	5,147
NOTCH3	4,403
MRE11	3,932
OGDHL	2,138
TWNK	1,390

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APAF1	O14727	14
MRE11	P49959	10
NOTCH3	Q9UM47	6
TWNK	Q96RR1	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OGDHL	Q9ULD0	90.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 75. Enrichment computed across 5 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective LFNG causes SCDO3	1	571.0×	0.017	NOTCH3
Activation of caspases through apoptosome-mediated cleavage	1	475.8×	0.017	APAF1
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	475.8×	0.017	NOTCH3
Sensing of DNA Double Strand Breaks	1	475.8×	0.017	MRE11
SMAC (DIABLO) binds to IAPs	1	407.9×	0.017	APAF1
SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes	1	407.9×	0.017	APAF1
SMAC, XIAP-regulated apoptotic response	1	407.9×	0.017	APAF1
Formation of apoptosome	1	356.9×	0.017	APAF1
Noncanonical activation of NOTCH3	1	356.9×	0.017	NOTCH3
Cytochrome c-mediated apoptotic response	1	317.2×	0.017	APAF1
Strand-asynchronous mitochondrial DNA replication	1	285.5×	0.017	TWNK
STING mediated induction of host immune responses	1	259.6×	0.017	MRE11
Regulation of the apoptosome activity	1	259.6×	0.017	APAF1
TP53 Regulates Transcription of Caspase Activators and Caspases	1	237.9×	0.017	APAF1
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	237.9×	0.017	MRE11
Apoptotic factor-mediated response	1	219.6×	0.017	APAF1
HDR through MMEJ (alt-NHEJ)	1	219.6×	0.017	MRE11
IRF3-mediated induction of type I IFN	1	203.9×	0.017	MRE11
Diseases of DNA Double-Strand Break Repair	1	203.9×	0.017	MRE11
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	203.9×	0.017	MRE11
Transcriptional Regulation by TP53	2	31.0×	0.017	APAF1, MRE11
Pre-NOTCH Processing in Golgi	1	158.6×	0.021	NOTCH3
Resolution of D-Loop Structures	1	158.6×	0.021	MRE11
Diseases of DNA repair	1	142.8×	0.021	MRE11
TP53 Regulates Transcription of Cell Death Genes	1	135.9×	0.021	APAF1
DNA Double Strand Break Response	1	119.0×	0.021	MRE11
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	119.0×	0.021	NOTCH3
Impaired BRCA2 binding to PALB2	1	114.2×	0.021	MRE11
NOTCH3 Intracellular Domain Regulates Transcription	1	109.8×	0.021	NOTCH3
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	105.7×	0.021	MRE11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
forebrain development	2	140.4×	0.005	APAF1, NOTCH3
response to G1 DNA damage checkpoint signaling	1	3370.4×	0.006	APAF1
mitochondrial double-strand break repair via homologous recombination	1	3370.4×	0.006	MRE11
regulation of mitotic recombination	1	1685.2×	0.007	MRE11
regulation of apoptotic DNA fragmentation	1	1685.2×	0.007	APAF1
glomerular capillary formation	1	1123.5×	0.009	NOTCH3
telomeric 3’ overhang formation	1	842.6×	0.011	MRE11
mitochondrial transcription	1	481.5×	0.012	TWNK
meiotic DNA double-strand break formation	1	481.5×	0.012	MRE11
neuroblast differentiation	1	421.3×	0.012	NOTCH3
DNA strand resection involved in replication fork processing	1	421.3×	0.012	MRE11
negative regulation of double-strand break repair via nonhomologous end joining	1	421.3×	0.012	MRE11
R-loop processing	1	337.0×	0.013	MRE11
DNA double-strand break processing	1	306.4×	0.013	MRE11
mitochondrial DNA replication	1	306.4×	0.013	TWNK
protein hexamerization	1	280.9×	0.013	TWNK
homologous recombination	1	280.9×	0.013	MRE11
cardiac muscle cell apoptotic process	1	240.7×	0.015	APAF1
2-oxoglutarate metabolic process	1	187.2×	0.017	OGDHL
mitotic intra-S DNA damage checkpoint signaling	1	187.2×	0.017	MRE11
mitotic G2/M transition checkpoint	1	160.5×	0.018	MRE11
neuron fate commitment	1	160.5×	0.018	NOTCH3
sister chromatid cohesion	1	153.2×	0.018	MRE11
telomere maintenance via telomerase	1	146.5×	0.018	MRE11
artery morphogenesis	1	134.8×	0.019	NOTCH3
homologous chromosome pairing at meiosis	1	120.4×	0.019	MRE11
positive regulation of apoptotic signaling pathway	1	116.2×	0.019	APAF1
DNA-templated DNA replication	1	112.3×	0.019	TWNK
reciprocal meiotic recombination	1	112.3×	0.019	MRE11
tricarboxylic acid cycle	1	102.1×	0.020	OGDHL

Therapeutics

Drugs indicated for this disease

54 approved, 111 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Agomelatine	Approved (phase 4)
Amineptine	Approved (phase 4)
Amitriptyline	Approved (phase 4)
Amoxapine	Approved (phase 4)
Aripiprazole	Approved (phase 4)
Betaine	Approved (phase 4)
Brexanolone	Approved (phase 4)
Bupropion	Approved (phase 4)
Butriptyline	Approved (phase 4)
Citalopram	Approved (phase 4)
Clomipramine	Approved (phase 4)
Desipramine	Approved (phase 4)
Desvenlafaxine	Approved (phase 4)
Dibenzepin	Approved (phase 4)
Dothiepin	Approved (phase 4)
Doxepin	Approved (phase 4)
Escitalopram	Approved (phase 4)
Esketamine	Approved (phase 4)
Fluvoxamine	Approved (phase 4)
Folic Acid	Approved (phase 4)
Imipramine	Approved (phase 4)
Iprindole	Approved (phase 4)
Iproniazid	Approved (phase 4)
Lamotrigine	Approved (phase 4)
Levomilnacipran	Approved (phase 4)
Lithium Carbonate	Approved (phase 4)
Lofepramine	Approved (phase 4)
Maprotiline	Approved (phase 4)
Medifoxamine	Approved (phase 4)
Mianserin	Approved (phase 4)
Milnacipran	Approved (phase 4)
Minaprine	Approved (phase 4)
Mirtazapine	Approved (phase 4)
Moclobemide	Approved (phase 4)
Nefazodone	Approved (phase 4)
Nialamide	Approved (phase 4)
Nomifensine	Approved (phase 4)
Nortriptyline	Approved (phase 4)
Oxitriptan	Approved (phase 4)
Paroxetine	Approved (phase 4)
Phenelzine	Approved (phase 4)
Protriptyline	Approved (phase 4)
Reboxetine	Approved (phase 4)
Sertraline	Approved (phase 4)
Sodium Citrate	Approved (phase 4)
Toloxatone	Approved (phase 4)
Tranylcypromine	Approved (phase 4)
Trazodone	Approved (phase 4)
Trimipramine	Approved (phase 4)
Tryptophan	Approved (phase 4)
Venlafaxine	Approved (phase 4)
Vilazodone	Approved (phase 4)
Zimeldine	Approved (phase 4)
Zuranolone	Approved (phase 4)
Acamprosate	Phase 3 (in late-stage trials)
Alprazolam	Phase 3 (in late-stage trials)
Amibegron	Phase 3 (in late-stage trials)
Amisulpride	Phase 3 (in late-stage trials)
Amlodipine	Phase 3 (in late-stage trials)
Armodafinil	Phase 3 (in late-stage trials)
Benperidol	Phase 3 (in late-stage trials)
Bifeprunox	Phase 3 (in late-stage trials)
Biperiden	Phase 3 (in late-stage trials)
Brexpiprazole	Phase 3 (in late-stage trials)
Bromazepam	Phase 3 (in late-stage trials)
Bromperidol	Phase 3 (in late-stage trials)
Brotizolam	Phase 3 (in late-stage trials)
Buprenorphine	Phase 3 (in late-stage trials)
Buspirone	Phase 3 (in late-stage trials)
Carbamazepine	Phase 3 (in late-stage trials)
Cariprazine	Phase 3 (in late-stage trials)
Celecoxib	Phase 3 (in late-stage trials)
Chloral Hydrate	Phase 3 (in late-stage trials)
Chlorprothixene	Phase 3 (in late-stage trials)
Clobazam	Phase 3 (in late-stage trials)
Clomethiazole	Phase 3 (in late-stage trials)
Clonazepam	Phase 3 (in late-stage trials)
Clozapine	Phase 3 (in late-stage trials)
Corn Oil	Phase 3 (in late-stage trials)
Dexmecamylamine	Phase 3 (in late-stage trials)
Diazepam	Phase 3 (in late-stage trials)
Diphenhydramine	Phase 3 (in late-stage trials)
Doconexent	Phase 3 (in late-stage trials)
Donepezil	Phase 3 (in late-stage trials)
Duloxetine	Phase 3 (in late-stage trials)
Fish Oil	Phase 3 (in late-stage trials)
Fluoxetine	Phase 3 (in late-stage trials)
Flupentixol	Phase 3 (in late-stage trials)
Fluphenazine Enanthate	Phase 3 (in late-stage trials)
Flurazepam	Phase 3 (in late-stage trials)
Fluspirilene	Phase 3 (in late-stage trials)
Gabapentin	Phase 3 (in late-stage trials)
Galantamine	Phase 3 (in late-stage trials)
Haloperidol	Phase 3 (in late-stage trials)
Hydroxyzine	Phase 3 (in late-stage trials)
Icosapent	Phase 3 (in late-stage trials)
Indiplon	Phase 3 (in late-stage trials)
Ketamine	Phase 3 (in late-stage trials)
Lacosamide	Phase 3 (in late-stage trials)
Levetiracetam	Phase 3 (in late-stage trials)
Levomepromazine	Phase 3 (in late-stage trials)
Liothyronine	Phase 3 (in late-stage trials)
Lisdexamfetamine	Phase 3 (in late-stage trials)
Lorazepam	Phase 3 (in late-stage trials)
Lormetazepam	Phase 3 (in late-stage trials)
Lurasidone	Phase 3 (in late-stage trials)
Melatonin	Phase 3 (in late-stage trials)
Melitracen	Phase 3 (in late-stage trials)
Melperone	Phase 3 (in late-stage trials)
Memantine	Phase 3 (in late-stage trials)
Methylphenidate	Phase 3 (in late-stage trials)
Metyrapone	Phase 3 (in late-stage trials)
Midazolam	Phase 3 (in late-stage trials)
Mifepristone	Phase 3 (in late-stage trials)
Minocycline	Phase 3 (in late-stage trials)
Naltrexone	Phase 3 (in late-stage trials)
Nicergoline	Phase 3 (in late-stage trials)
Nitrazepam	Phase 3 (in late-stage trials)
OMEGA-3 FATTY ACIDS	Phase 3 (in late-stage trials)
Olanzapine	Phase 3 (in late-stage trials)
Opipramol	Phase 3 (in late-stage trials)
Oxazepam	Phase 3 (in late-stage trials)
Oxcarbazepine	Phase 3 (in late-stage trials)
PEGINTERFERON ALFA-2A	Phase 3 (in late-stage trials)
Paliperidone	Phase 3 (in late-stage trials)
Perazine	Phase 3 (in late-stage trials)
Perphenazine	Phase 3 (in late-stage trials)
Phenobarbital	Phase 3 (in late-stage trials)
Phenytoin	Phase 3 (in late-stage trials)
Pimozide	Phase 3 (in late-stage trials)
Pipamperone	Phase 3 (in late-stage trials)
Piracetam	Phase 3 (in late-stage trials)
Pramipexole	Phase 3 (in late-stage trials)
Pregabalin	Phase 3 (in late-stage trials)
Promethazine	Phase 3 (in late-stage trials)
Prothipendyl	Phase 3 (in late-stage trials)
Psilocybin	Phase 3 (in late-stage trials)
Pyrimethamine	Phase 3 (in late-stage trials)
Pyritinol	Phase 3 (in late-stage trials)
Quetiapine	Phase 3 (in late-stage trials)
Ramelteon	Phase 3 (in late-stage trials)
Ribavirin	Phase 3 (in late-stage trials)
Risperidone	Phase 3 (in late-stage trials)
Rivastigmine	Phase 3 (in late-stage trials)
Saredutant	Phase 3 (in late-stage trials)
Selegiline	Phase 3 (in late-stage trials)
Sertindole	Phase 3 (in late-stage trials)
Silybin A	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
St. John’S Wort	Phase 3 (in late-stage trials)
Sulpiride	Phase 3 (in late-stage trials)
Temazepam	Phase 3 (in late-stage trials)
Thioridazine	Phase 3 (in late-stage trials)
Tianeptine	Phase 3 (in late-stage trials)
Tiapride	Phase 3 (in late-stage trials)
Topiramate	Phase 3 (in late-stage trials)
Triazolam	Phase 3 (in late-stage trials)
Valproic Acid	Phase 3 (in late-stage trials)
Vitamin E	Phase 3 (in late-stage trials)
Vortioxetine	Phase 3 (in late-stage trials)
Zaleplon	Phase 3 (in late-stage trials)
Ziprasidone	Phase 3 (in late-stage trials)
Zolpidem	Phase 3 (in late-stage trials)
Zopiclone	Phase 3 (in late-stage trials)
Zuclopenthixol	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): AV-101, Ademetionine, Ascorbic Acid, Aspirin, Atorvastatin, Cannabinol, Cholecalciferol, Crinecerfont, Cyanocobalamin, Dapagliflozin, Drospirenone, Estradiol, Ethinyl Estradiol, Ezogabine, Gepirone, Guanfacine, Modafinil, Niacin, Niacinamide, Nicotine, Nitroprusside, OMEGA-3-ACID ETHYL ESTERS, Onabotulinumtoxina, Oxytocin, Pentoxifylline, Pindolol, Prasterone, Progesterone, Quinidine, Riluzole, Rosuvastatin, Scopolamine, Sirolimus, Sulforaphane, Ubidecarenone, Ulipristal Acetate, Viloxazine, Volinanserin.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 3

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
APAF1	THONZONIUM BROMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APAF1	6	4
NOTCH3	1	2
TWNK	0	0
OGDHL	0	0
MRE11	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
THONZONIUM BROMIDE	4	APAF1
CEFIXIME	4	APAF1
DOXORUBICIN HYDROCHLORIDE	4	APAF1
METHYLENE BLUE ANHYDROUS	4	APAF1
BENZETHONIUM CHLORIDE	2	APAF1
VAREGACESTAT	2	NOTCH3
CALANOLIDE A	1	APAF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MRE11	36	Binding:36
APAF1	10	Functional:8, Binding:2
NOTCH3	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TWNK	3.6.4.12	DNA helicase
OGDHL	1.2.1.105	2-oxoglutarate dehydrogenase system

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

7 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
THONZONIUM BROMIDE	4	APAF1
CEFIXIME	4	APAF1
DOXORUBICIN HYDROCHLORIDE	4	APAF1
METHYLENE BLUE ANHYDROUS	4	APAF1
BENZETHONIUM CHLORIDE	2	APAF1
VAREGACESTAT	2	NOTCH3
CALANOLIDE A	1	APAF1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	APAF1
B	Phased (≥1) drug, not yet approved	1	NOTCH3
C	Druggable family + PDB, no drug	1	TWNK
D	Druggable family + AlphaFold only, no drug	1	OGDHL
E	Difficult family or no structure, no drug	1	MRE11

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TWNK	0	—
OGDHL	0	—
MRE11	36	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4,995.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	287
PHASE2	279
PHASE3	196
PHASE1	167
PHASE2/PHASE3	59
PHASE1/PHASE2	57
EARLY_PHASE1	46
Not specified	9

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02752542	PHASE4	RECRUITING	Personalized Indications for CBT and Antidepressants in Treating Depression
NCT03480061	PHASE4	ACTIVE_NOT_RECRUITING	Dexmedetomidine to Reduce the Incidence of POCD After Open Cardiac Surgery
NCT04245748	PHASE4	RECRUITING	Determining Optimal Treatment Sequences in Anxious Depression (DOTS-AD)
NCT04303325	PHASE4	RECRUITING	Effect of Esketamine on Postoperative Depression、Gut Microbiota、Bispectral Index Data of Depression Patients Undergoing Breast Cancer Operation (ESPOD-BI)
NCT04400266	PHASE4	RECRUITING	Buspirone and Melatonin for Depression Following Traumatic Brain Injury
NCT05282277	PHASE4	RECRUITING	Examining the Effects of Estradiol on Neural and Molecular Response to Reward
NCT05599126	PHASE4	RECRUITING	A Study of Mianserin in Combination With SSRIs in Depression With Sleep Problems
NCT05655754	PHASE4	RECRUITING	Comparison of Esketamine/Propofol and Methohexital Anesthesia for ECT
NCT05768126	PHASE4	RECRUITING	Prediction of ECT Treatment Response and Reduction of Cognitive Side-effects Using EEG and Rivastigmine
NCT05976347	PHASE4	RECRUITING	Identifying and Treating Depression in the Orthopaedic Trauma Population
NCT06004115	PHASE4	RECRUITING	Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression
NCT06075771	PHASE4	RECRUITING	Dopaminergic Therapy for Anhedonia - 2
NCT06317636	PHASE4	ACTIVE_NOT_RECRUITING	Propofol-Enhanced Assessment of Ketamine for Chronic Pain and Depression
NCT06417437	PHASE4	RECRUITING	Non-invasive BCI and Application Verification for Depressed People
NCT06433635	PHASE4	ACTIVE_NOT_RECRUITING	Sequential Multiple Assignment Randomized Trial for Bipolar Depression
NCT06580041	PHASE4	ENROLLING_BY_INVITATION	Precision Care for Major Depressive Disorder
NCT06707012	PHASE4	RECRUITING	Efficacy of Metformin as an Adjunct to Standard Antidepressant Therapy in Treating Depression Among Obese Patients
NCT06903819	PHASE4	RECRUITING	Ketamine for Pain, Opioid Use, and Mental Health in Orthopedic Trauma Patients
NCT07110831	PHASE4	NOT_YET_RECRUITING	Disposition Kinetics of Dolutegravir Among People Living With HIV With Major Depression in Nigeria
NCT07182890	PHASE4	RECRUITING	Efficacy of Clostridium Butyricum in Alleviating Anxiety and Depression in Patients With Functional Dyspepsia
NCT07187492	PHASE4	RECRUITING	Efficacy of Bacillus Coagulans in Alleviating Anxiety and Depression in Patients With Functional Dyspepsia
NCT07432815	PHASE4	RECRUITING	Treatment of Psoriasis With Depression and/or Anxiety With Methotrexate vs Combined Methotrexate and Antidepressant
NCT00000378	PHASE4	COMPLETED	Antidepressant Treatment of Melancholia in Late Life
NCT00004554	PHASE4	COMPLETED	Sertraline for Alcohol Dependence and Depression
NCT00006180	PHASE4	COMPLETED	Bone Loss in Premenopausal Women With Depression
NCT00006204	PHASE4	COMPLETED	Drug Treatment for Depressed Alcoholics (Naltrexone/Fluoxetine)
NCT00009191	PHASE4	COMPLETED	The Depression in Alzheimer’s Disease Study (DIADS)
NCT00018759	PHASE4	COMPLETED	Treatment Effects on Platelet Calcium in Hypertensive and Depressed Patients
NCT00018824	PHASE4	COMPLETED	Treating Alcohol Use In Older Adults With Depression
NCT00021528	PHASE4	COMPLETED	Sequenced Treatment Alternatives to Relieve Depression (STAR*D)
NCT00029172	PHASE4	COMPLETED	Treatment for Post-Stroke Depression
NCT00030147	PHASE4	COMPLETED	Raloxifene and Rimostil for Perimenopause-Related Depression
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00044616	PHASE4	COMPLETED	Relapse Prevention for Bipolar Type-II Disorder
NCT00045916	PHASE4	COMPLETED	Optimizing Electroconvulsive Therapy for Depression
NCT00047671	PHASE4	COMPLETED	Ethnic Variations in Antidepressant Response
NCT00055328	PHASE4	COMPLETED	Treatment for Depression in the Primary Care Setting
NCT00057551	PHASE4	COMPLETED	Research Evaluating the Value of Augmenting Medication With Psychotherapy
NCT00057577	PHASE4	COMPLETED	Prevention of Recurrence in Depression With Drugs and CT
NCT00067912	PHASE4	COMPLETED	Duloxetine vs. Active Comparator for the Treatment of Depression

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
VENLAFAXINE	4	75
CITALOPRAM	4	74
FLUOXETINE	4	69
SERTRALINE	4	37
ESCITALOPRAM	4	33
BUPROPION	4	31
PAROXETINE	4	28
DULOXETINE	4	22
NALTREXONE	4	18
CARBIDOPA ANHYDROUS	4	15
CARIPRAZINE	4	15
FLUVOXAMINE	4	15
KETAMINE	4	15
DESVENLAFAXINE	4	12
ZIPRASIDONE	4	12
MIRTAZAPINE	4	10
VORTIOXETINE	4	9
NORTRIPTYLINE	4	8
PRAMIPEXOLE	4	8
BREXPIPRAZOLE	4	6
DONEPEZIL	4	6
LEVODOPA	4	6
DESIPRAMINE	4	5
LAMOTRIGINE	4	5
MEMANTINE	4	5
ARMODAFINIL	4	4
BUSPIRONE	4	4
LITHIUM CARBONATE	4	4
LORAZEPAM	4	4
NITROUS OXIDE	4	4