Glutamatergic Medications Show Promise in Improving OCD Symptoms

Glutamatergic medications show promise in improving symptoms of obsessive-compulsive and related disorders, including obsessive-compulsive disorder (OCD), a recent study found.1

“Our findings, albeit with low certainty, indicate that these medications are associated with significant improvement in OCRD symptoms,” wrote investigators, led by David R. A. Coelho, MD, MPH, from Harvard T.H. Chan School of Public Health. “When restricting to OCD trials, our evidence suggests, with moderate certainty, that these medications are associated with significantly reduced Y-BOCS scores.”

Many neuropsychiatric conditions are characterized by obsessive-compulsive symptoms—OCD, body dysmorphic disorder, skin-picking disorder, trichotillomania, and hoarding disorder. Obsessive-compulsive and related disorders affect approximately 2% to 3% of the US population and impair daily functioning. Standard treatment options, such as selective serotonin reuptake inhibitors (SSRIs), clomipramine, and cognitive behavioral therapy, often do not work, with approximately 60% of patients not adequately responding to SSRIs as monotherapy.

Evidence has shown glutamatergic dysfunction, often in cortico-striatal-thalamo-cortical circuits, is in the pathophysiology of these obsessive-compulsive disorders.2 Glutamatergic medications have shown promise as adjunctive treatments, particularly N-acetylcysteine (NAC) and memantine for OCD.3

Previous meta-analyses studied glutamatergic medications only in OCD or focused solely on the medications of NAC or memantine. Studies did not broadly assess glutamatergic medications among several obsessive-compulsive and related disorders or include subgroup analyses to take into consideration clinical characteristics.

Thus, investigators conducted a systematic review and meta-analysis of 27 trials involving 1369 individuals to evaluate the effectiveness of glutamatergic medications in improving symptoms across a diverse range of obsessive-compulsive and related disorders. The studies included were double-blind, placebo-controlled, randomized clinical trials from Iran (n = 15), the US (n = 8), Australia (n = 2), Brazil (n = 1), and Italy (n = 1), leveraged from PubMed, Embase, PsychINFO, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials.

The sample had a mean age of 31.5 years and 65.6% females. 23 studies included adults, and 4 included children and adolescents. OCD was examined in 23 studies, the most out of all the disorders, and trichotillomania and skin-picking disorder were examined in 2 studies each. Treatments assessed included NAC (n = 10), memantine (n = 4), lamotrigine and riluzole (n = 3), topiramate (n = 2), amantadine (n = 1), glycine (n = 1), l-carnosine (n = 1), minocycline (n = 1), and pregabalin (n = 1).

The trials reported minimal or no adverse effects, and among those who did, the adverse effects were generally mild to moderate. Common adverse events among patients taking NAC included vomiting, diarrhea, stomach and abdominal pain, and heartburn.

The meta-analysis evaluating glutamatergic medications for obsessive-compulsive and related disorders had a large effect size (Cohen d, -0.80; 95% confidence interval [CI],-1.13 to -0.47; P < .001) when comparing the intervention group (n = 688) with the control group (n = 681). Subgroup analyses demonstrated no significant differences in the effect size of glutamatergic medications on symptoms of obsessive-compulsive related disorders by type of disorder, population, refractoriness, augmentation strategy, risk of bias, and type of glutamatergic medication. A sensitivity analysis that excluded a single study and univariate meta-regression analyses that controlled for mean age, mean years of living with the obsessive-compulsive-related disorder, or weeks of treatment did not significantly alter the overall effect size.

The meta-analysis that solely evaluated glutamatergic medications for OCD symptoms found a statistically significant mean reduction in Y-BOCS scores (mean difference, -4.17; 95% CI< -5.82 to -2.52; P < .001) when comparing the intervention group (n – 592) with the control group (n = 590). The subgroup analysis, sensitivity analysis, and univariate meta-regression analyses found no significant differences in the medication’s effectiveness.

“Further subgroup analyses for OCRDs and OCD did not reveal statistically significant differences, indicating no variation by type of OCRD, population, refractoriness of OCRD or OCD, augmentation strategy, risk of bias, or type of glutamatergic medication,” investigators wrote. “Future research with larger sample sizes should focus on dose-dependent effects, additional OCRD subtypes, and novel glutamatergic treatments to enhance our understanding and treatment strategies.”

References

1. Coelho DRA, Yang C, Suriaga A, et al. Glutamatergic Medications for Obsessive-Compulsive and Related Disorders: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025;8(1):e2452963. doi:10.1001/jamanetworkopen.2024.52963
2. Burguière E, Monteiro P, Mallet L, Feng G, Graybiel AM. Striatal circuits, habits, and implications for obsessive-compulsive disorder. Curr Opin Neurobiol. 2015 Feb;30:59-65. doi: 10.1016/j.conb.2014.08.008. Epub 2014 Sep 19. PMID: 25241072; PMCID: PMC4293232.
3. Pittenger C. Glutamate modulators in the treatment of obsessive-compulsive disorder. Psychiatr Ann. 2015 Jun;45(6):308-315. doi: 10.3928/00485713-20150602-06. PMID: 26236057; PMCID: PMC4517847.