Genetic Evidence for a Novel Glutamatergic Augmentation in Treatment-Resistant OCD: CREB1 as a Key Driver of Impaired Plasticity

Background. A large proportion of people with obsessive–compulsive disorder (OCD) – roughly 40–60 % even after carefully optimised treatment – do not improve enough with selective serotonin re-uptake inhibitors (SSRIs). Small naturalistic series have suggested that the Cheung Glutamatergic Regimen (CGR), an inexpensive oral combination of dextromethorphan, fluoxetine and piracetam, can ease symptoms quickly. Because CGR acts on synaptic plasticity rather than pure serotonin tone, we asked whether common genetic risk for OCD is concentrated in the same plasticity pathway.Methods. Summary statistics from the 2025 OCD genome-wide association study (23 493 cases and 1 114 613 controls of European ancestry, 23andMe data excluded) were analysed with MAGMA v1.10. Single-nucleotide polymorphisms (SNPs) were mapped, with a 10 kb margin, to 22 genes chosen a priori: NMDA and AMPA receptor subunits, metabolic targets, and six downstream plasticity genes. Two custom sets were evaluated – a "pro-plasticity" group (BDNF, NTRK2, MTOR, AKT1, CREB1, ARC) and an "anti-plasticity" single-gene set (PTEN). The lead SNP was annotated for expression and splicing effects through Open Targets Genetics.Results. Among the 22 candidates, CREB1 stood out (Z = 2.857; p = 0.00214), passing Bonferroni correction for the panel. BDNF (p = 0.058) and PTEN (p = 0.078) showed suggestive but non-significant signals, whereas all NMDA/AMPA receptor genes and metabolic loci (CYP2D6, SIGMAR1) were clearly null (p > 0.10). The top variant, rs7591784 (p = 1.17 × 10⁻⁷), alters CREB1 transcript usage in multiple tissues. Set-based enrichment for the six pro-plasticity genes was not significant (β = 0.167; p = 0.321), reflecting the fact that most of the signal lay in CREB1 alone.Conclusion. Common OCD risk is disproportionately centred on CREB1, a transcription factor that drives long-term synaptic change, rather than on the glutamate receptors that lie upstream. This genetic pattern lends biological weight to the reported clinical benefit of CGR: by delivering a rapid, AMPA-mediated calcium surge, the regimen may compensate for genetically weakened CREB1 activity and sidestep the comparatively weak serotonergic cascade of SSRIs. Prospective trials that stratify patients by CREB1 risk status are warranted, and transcriptional plasticity emerges as an appealing target for new treatments in refractory OCD.