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Treatment-refractory schizophrenia

disease
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Also known as refractory schizophreniaTRS

Summary

Treatment-refractory schizophrenia (MONDO:0005414) is a disease with 4 cohort genes (3 GWAS associations across 4 studies) and 11 clinical trials.

At a glance

  • Cohort genes: 4
  • GWAS associations: 3
  • Clinical trials: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical nametreatment-refractory schizophrenia
Mondo IDMONDO:0005414
EFOEFO:0004609
UMLSC3544321
MedGen1786789
Is cancer (heuristic)no

Also known as: refractory schizophrenia · treatment-refractory schizophrenia · TRS

Data availability: 3 GWAS associations (4 studies).

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › cognitive disorder › psychotic disorder › schizophrenia › treatment-refractory schizophrenia

Related subtypes (17): paranoid schizophrenia, schizophrenia 1, schizophrenia 3, schizophrenia 5, schizophrenia 7, schizophrenia 8, schizophrenia 2, schizophrenia 10, schizophrenia 11, schizophrenia 12, schizophrenia 15, schizophrenia 16, chromosome 2p16.3 deletion syndrome, early-onset schizophrenia, schizophrenia 19, schizophrenia 17, childhood-onset schizophrenia

Genetics & variants

GWAS landscape

3 GWAS associations across 4 studies. Top hits map to 2 distinct genes (as reported by GWAS).

Top associations by p-value

rsIDp-valueGeneRisk alleleOdds ratio
rs112654612e-07SLAMF1 - SETP9C1.45
rs2305292e-07NFKB1T1.45
rs22374576e-07GRB10T1.74

Top studies (by case count)

StudyLead authorYearCasesControlsTitle
GCST90102461Pardinas AF202210,50124,542Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia.
GCST90102463Pardinas AF202210,5010Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia.
GCST001458Liou YJ20125220Genome-wide association study of treatment refractory schizophrenia in Han Chinese.
GCST002604Li J2014790A genetic locus in 7p12.2 associated with treatment resistant schizophrenia.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

TierVariants
Tier 1: coding0
Tier 2: splice/UTR0
Tier 3: regulatory0
Tier 4: intronic/intergenic3

MAF distribution

BucketVariants
common (>=0.05)3
low_freq (0.01-0.05)0
rare (<0.01)0
unknown0

Functional consequences

ConsequenceCount
intron_variant3

Top variants

rsIDChrPosAllelesMAFConsequenceGenep-valueTier
rs112654611160660353T>A,C,G0.41intron_variantSLAMF1 - SETP92e-07Tier 4: intronic/intergenic
rs2305294102536261T>A,C,G0.47intron_variantNFKB12e-07Tier 4: intronic/intergenic
rs2237457750658447C>A,G,T0.36intron_variantGRB106e-07Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
DDCOrphanet:35708Aromatic L-amino acid decarboxylase deficiency
GRB10Orphanet:96182Silver-Russell syndrome due to maternal uniparental disomy of chromosome 7
NFKB1Orphanet:696874NFKB1-related immune dysregulation

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

SubsetGenes
gwas_only4

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
SLAMF1HGNC:10903ENSG00000117090Q13291Signaling lymphocytic activation moleculegwas
DDCHGNC:2719ENSG00000132437P20711Aromatic-L-amino-acid decarboxylasegwas
GRB10HGNC:4564ENSG00000106070Q13322Growth factor receptor-bound protein 10gwas
NFKB1HGNC:7794ENSG00000109320P19838Nuclear factor NF-kappa-B p105 subunitgwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
SLAMF1Signaling lymphocytic activation moleculeSelf-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family.
DDCAromatic-L-amino-acid decarboxylaseCatalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine and L-5-hydroxytryptophan to serotonin.
GRB10Growth factor receptor-bound protein 10Adapter protein which modulates coupling of a number of cell surface receptor kinases with specific signaling pathways.
NFKB1Nuclear factor NF-kappa-B p105 subunitNF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as infl…

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.5

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.

FamilyGenesFoldFDR
Antibody/Immunoglobulin17.3×0.392
Scaffold/PPI14.3×0.392
Enzyme (other)13.0×0.392
Transcription factor12.1×0.403

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
SLAMF1Antibody/ImmunoglobulinyesIg-like_dom, Sig_lymph_act_molc_N, Ig-like_fold
DDCEnzyme (other)yes4.1.1.28PyrdxlP-dep_de-COase, Aromatic_deC, PyrdxlP-dep_Trfase_major
GRB10Scaffold/PPInoRA_dom, SH2, PH_domain
NFKB1Transcription factornoNFkB/Dor, Death_dom, Ankyrin_rpt

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)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)4
unknown0

Top tissues across cohort

TissueCohort genes
granulocyte1
lymph node1
thymus1
adult organism1
ileal mucosa1
jejunal mucosa1
body of pancreas1
substantia nigra pars compacta1
visceral pleura1
calcaneal tendon1
cartilage tissue1
endometrium epithelium1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
SLAMF1159broadmarkerthymus, lymph node, granulocyte
DDC177tissue_specificmarkerjejunal mucosa, ileal mucosa, adult organism
GRB10292ubiquitousmarkerbody of pancreas, substantia nigra pars compacta, visceral pleura
NFKB1252ubiquitousmarkerendometrium epithelium, cartilage tissue, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
NFKB110,484
DDC2,649
SLAMF12,298
GRB102,284

Structural data

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

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
NFKB1P1983815
DDCP207118
SLAMF1Q132916
GRB10Q133222

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
Catecholamine biosynthesis1951.7×0.011DDC
Serotonin and melatonin biosynthesis1761.3×0.011DDC
IRS activation1761.3×0.011GRB10
CLEC7A/inflammasome pathway1634.4×0.011NFKB1
DEx/H-box helicases activate type I IFN and inflammatory cytokines production1543.8×0.011NFKB1
IkBA variant leads to EDA-ID1543.8×0.011NFKB1
Regulation of NFE2L2 gene expression1475.8×0.011NFKB1
Interleukin-1 processing1423.0×0.011NFKB1
Regulated proteolysis of p75NTR1346.1×0.011NFKB1
Signal attenuation1346.1×0.011GRB10
NF-kB is activated and signals survival1292.8×0.011NFKB1
MAP3K8 (TPL2)-dependent MAPK1/3 activation1237.9×0.011NFKB1
Response of EIF2AK1 (HRI) to heme deficiency1237.9×0.011GRB10
RIP-mediated NFkB activation via ZBP11223.9×0.011NFKB1
Insulin receptor signalling cascade1223.9×0.011GRB10
The NLRP3 inflammasome1223.9×0.011NFKB1
CD209 (DC-SIGN) signaling1173.0×0.013NFKB1
TRAF6 mediated NF-kB activation1152.3×0.014NFKB1
Purinergic signaling in leishmaniasis infection1141.0×0.014NFKB1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells1119.0×0.016NFKB1
FLT3 Signaling1115.3×0.016GRB10
TAK1-dependent IKK and NF-kappa-B activation1100.2×0.017NFKB1
SARS-CoV-1 activates/modulates innate immune responses190.6×0.018NFKB1
Transcriptional Regulation by VENTX188.5×0.018NFKB1
RET signaling186.5×0.018GRB10
Signaling by SCF-KIT182.8×0.018GRB10
Activation of NF-kappaB in B cells165.6×0.021NFKB1
Activation of STAT3 by cadherin engagement154.4×0.024NFKB1
PKMTs methylate histone lysines153.6×0.024NFKB1
FCERI mediated NF-kB activation152.1×0.024NFKB1

GO biological processes 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.

GO termCohort genesFoldFDRSample cohort genes
negative regulation of interleukin-12 production2526.6×4e-04SLAMF1, NFKB1
regulation of vesicle fusion12106.5×0.007SLAMF1
negative regulation of CD40 signaling pathway12106.5×0.007SLAMF1
myeloid dendritic cell activation involved in immune response11404.3×0.007SLAMF1
vascular associated smooth muscle cell migration11404.3×0.007GRB10
positive regulation of miRNA metabolic process11404.3×0.007NFKB1
catecholamine metabolic process11053.2×0.007DDC
negative regulation of vitamin D biosynthetic process11053.2×0.007NFKB1
serotonin biosynthetic process11053.2×0.007DDC
positive regulation of hyaluronan biosynthetic process11053.2×0.007NFKB1
natural killer cell proliferation1842.6×0.007SLAMF1
cellular response to dsRNA1842.6×0.007NFKB1
carboxylic acid metabolic process1702.2×0.007DDC
mammary gland involution1702.2×0.007NFKB1
negative regulation of T cell cytokine production1601.9×0.007SLAMF1
cellular response to interleukin-171601.9×0.007NFKB1
leukocyte chemotaxis involved in inflammatory response1526.6×0.007SLAMF1
negative regulation of glycogen biosynthetic process1526.6×0.007GRB10
cellular response to nicotine1526.6×0.007NFKB1
positive regulation of dendritic cell chemotaxis1526.6×0.007SLAMF1
positive regulation of T-helper 1 cell cytokine production1526.6×0.007SLAMF1
gene expression239.9×0.007DDC, GRB10
dopamine biosynthetic process1468.1×0.007DDC
antibacterial innate immune response1383.0×0.009NFKB1
positive regulation of lipid storage1351.1×0.009NFKB1
negative regulation of D-glucose import across plasma membrane1300.9×0.010GRB10
positive regulation of vascular endothelial growth factor receptor signaling pathway1263.3×0.011GRB10
cellular response to interleukin-61247.8×0.011NFKB1
cellular response to angiotensin1234.1×0.011NFKB1
natural killer cell differentiation1221.7×0.011SLAMF1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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.

SymbolExample approved molecule
NFKB1INDOPROFEN

Top cohort targets by molecule count

SymbolMoleculesMax phase
NFKB11524
SLAMF100
DDC00
GRB1000

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
INDOPROFEN4NFKB1
VAMOROLONE4NFKB1
BORTEZOMIB4NFKB1
DEXAMETHASONE4NFKB1
SULFASALAZINE4NFKB1
LEVOSALBUTAMOL4NFKB1
CLOTRIMAZOLE4NFKB1
GLIPIZIDE4NFKB1
SALMETEROL XINAFOATE4NFKB1
PHENELZINE4NFKB1
SULFAPHENAZOLE4NFKB1
AMOXAPINE4NFKB1
PROPANTHELINE4NFKB1
DECAMETHONIUM4NFKB1
NICARDIPINE HYDROCHLORIDE4NFKB1
PHENTOLAMINE MESYLATE4NFKB1
PHENYLEPHRINE4NFKB1
CARISOPRODOL4NFKB1
AZELAIC ACID4NFKB1
CARBETAPENTANE CITRATE4NFKB1
NIALAMIDE4NFKB1
EPINEPHRINE BITARTRATE4NFKB1
NILUTAMIDE4NFKB1
BUDESONIDE4NFKB1
ESTRONE4NFKB1
METHAPYRILENE4NFKB1
PIMOZIDE4NFKB1
TRIAMCINOLONE4NFKB1
BISOPROLOL FUMARATE4NFKB1
AZACITIDINE4NFKB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

SymbolAssaysType breakdown
NFKB1256Binding:249, Functional:7
GRB109Binding:9
DDC8Functional:6, Binding:2

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
DDC4.1.1.28aromatic-L-amino-acid decarboxylase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

SymbolChEMBL assays
NFKB1256

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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.

CompoundMax phaseCohort target (bioactivity)
INDOPROFEN4NFKB1
VAMOROLONE4NFKB1
BORTEZOMIB4NFKB1
DEXAMETHASONE4NFKB1
SULFASALAZINE4NFKB1
LEVOSALBUTAMOL4NFKB1
CLOTRIMAZOLE4NFKB1
GLIPIZIDE4NFKB1
SALMETEROL XINAFOATE4NFKB1
PHENELZINE4NFKB1
SULFAPHENAZOLE4NFKB1
AMOXAPINE4NFKB1
PROPANTHELINE4NFKB1
DECAMETHONIUM4NFKB1
NICARDIPINE HYDROCHLORIDE4NFKB1
PHENTOLAMINE MESYLATE4NFKB1
PHENYLEPHRINE4NFKB1
CARISOPRODOL4NFKB1
AZELAIC ACID4NFKB1
CARBETAPENTANE CITRATE4NFKB1
NIALAMIDE4NFKB1
EPINEPHRINE BITARTRATE4NFKB1
NILUTAMIDE4NFKB1
BUDESONIDE4NFKB1
ESTRONE4NFKB1
METHAPYRILENE4NFKB1
PIMOZIDE4NFKB1
TRIAMCINOLONE4NFKB1
BISOPROLOL FUMARATE4NFKB1
AZACITIDINE4NFKB1

Druggability pyramid

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

TierDefinitionGenesSymbols
AApproved (phase 4 drug)1NFKB1
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug2SLAMF1, DDC
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug1GRB10

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
SLAMF10—
DDC8—
GRB109—

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

PhaseTrials
Not specified9
PHASE41
PHASE2/PHASE31

Top trials by phase / activity

NCTPhaseStatusTitle
NCT02049021PHASE4UNKNOWNElectroconvulsive Therapy (ECT) in Patients With Super Refractory Schizophrenia
NCT03094429PHASE2/PHASE3RECRUITINGAn Adaptive Phase II/III, Two-Part, Double-Blind, Randomized, Placebo-controlled, Dose-Finding, Multi-center Study of the Safety and Efficacy of NaBen®, as an Add-on Therapy With Clozapine, for Residual Symptoms of Refractory Schizophrenia in Adults
NCT06257056Not specifiedRECRUITINGDeep Brain Stimulation for Psychosis
NCT06749444Not specifiedRECRUITINGCognitive Behavioral Therapy for Sleep and Circadian Disturbances (CBT-I) in Treatment-Resistant Schizophrenia
NCT07369401Not specifiedNOT_YET_RECRUITINGDeep Brain Stimulation of the Nucleus Accumbens and Anterior Limb of the Internal Capsule in the Treatment of Refractory Schizophrenia
NCT01386918Not specifiedCOMPLETEDRepetitive Transcranial Magnetic Stimulation for Refractory Auditory Hallucinations in Schizophrenia
NCT01879956Not specifiedUNKNOWNOccupational Therapy in the Rehabilitation of Executive Functions in Patients With Schizophrenia
NCT01948999Not specifiedTERMINATEDElectroconvulsive Therapy for Treatment Refractory Schizophrenia - A Randomized, Double-blinded, Sham-controlled Study
NCT02377505Not specifiedCOMPLETEDDeep Brain Stimulation in Treatment Resistant Schizophrenia
NCT04302636Not specifiedUNKNOWNThe Synergistic Effect of Hypoglycemic Index Diet on Refractory Schizophrenia
NCT04352569Not specifiedUNKNOWNEfficacy of tDCS in the Treatment of Resistant Auditory Hallucinations in Schizophrenia

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

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This page pulls from 68 datasets indexed by BioBTree:

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