268. Targeting glutamatergic dysregulation in severe treatment-resistant obsessive-compulsive disorder: integrating serotonergic, dopaminergic, and glutamatergic therapies

Abstract

Abstract Background Obsessive-Compulsive Disorder (OCD) is a chronic and disabling psychiatric condition affecting 2–3% of the population. While selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy (CBT) remain first-line treatments, up to 40% of patients exhibit treatment-resistant OCD (TR-OCD), defined by insufficient response to at least two SSRIs at adequate doses and duration, often in combination with CBT. Recent evidence implicates glutamatergic dysregulation within cortico-striato-thalamo-cortical (CSTC) circuits as a central pathophysiological mechanism, suggesting that glutamate-modulating agents could represent a rational therapeutic strategy beyond serotonergic and dopaminergic interventions. Aims & Objectives To provide a comprehensive overview of current pharmacological strategies in severe TR-OCD, highlighting glutamatergic modulation — notably memantine — while integrating serotonergic, dopaminergic, and other emerging therapies. Method A systematic review of PubMed, Embase, and Cochrane databases from 2006 until September 2025 was conducted, including randomized controlled trials (RCTs), open-label studies, meta-analyses, and systematic reviews evaluating pharmacological interventions in adult TR-OCD. Outcomes of interest included changes in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores, response/remission rates, duration of treatment, tolerability, and safety. Results Serotonergic optimization remains foundational, with high-dose SSRIs (fluoxetine 80 mg/day, sertraline 200 mg/day, paroxetine 60 mg/day) demonstrating clinical efficacy when trials are of adequate duration (≥12 weeks). Clomipramine, a tricyclic antidepressant with potent serotonergic properties, is effective as monotherapy or combined with SSRIs under careful monitoring. Dopaminergic/antipsychotic augmentation using low-dose atypical antipsychotics — including risperidone (0.5–3 mg/day), aripiprazole (10–20 mg/day), and quetiapine (150–300 mg/day) — yields response in approximately 30–50% of SSRI nonresponders, though metabolic and neurological adverse effects necessitate vigilant monitoring. Glutamatergic modulators, particularly memantine (5–20 mg/day), have shown promising results in open-label and controlled studies, with clinically meaningful reductions in Y-BOCS scores and favorable tolerability. Additional agents under investigation include lamotrigine, N-acetylcysteine, and ketamine, targeting different aspects of glutamate neurotransmission. Overall, pharmacological management requires individualized risk–benefit assessment, particularly in polypharmacy. SSRIs and memantine are generally well tolerated, whereas antipsychotic augmentation requires careful monitoring for metabolic and extrapyramidal effects. Discussion & Conclusions TR-OCD remains a major therapeutic challenge. Targeting glutamatergic dysfunction provides a neurobiologically grounded strategy, complementing serotonergic and dopaminergic approaches. Evidence supports the use of memantine and other glutamatergic modulators as promising adjunctive options in selected patients, particularly those with severe, refractory symptoms. Nevertheless, heterogeneity in study designs, small sample sizes, and variable outcome measures limit the generalizability of findings. Future research should prioritize large-scale, multicenter RCTs, explore predictive biomarkers for response, and evaluate combination strategies with psychotherapy to optimize outcomes. Integrating glutamatergic therapy into TR-OCD treatment algorithms represents a mechanistically informed and clinically relevant frontier, offering hope for patients unresponsive to conventional pharmacotherapy.