A Systematic Review and Meta-Analysis of Glutamatergic Medications for Obsessive-Compulsive and Related Disorders (OCRDs)

Academic Context

Obsessive-Compulsive and Related Disorders (OCRDs) represent a group of neuropsychiatric conditions characterized by excessive, persistent obsessions or compulsions. These disorders include Obsessive-Compulsive Disorder (OCD), Body Dysmorphic Disorder (BDD), Excoriation Disorder (skin-picking), Trichotillomania (hair-pulling), and Hoarding Disorder, among others, and significantly impair sufferers’ daily life functioning. While standard treatments, such as Selective Serotonin Reuptake Inhibitors (SSRIs), clomipramine, and Cognitive Behavioral Therapy (CBT), are effective for many patients, approximately 60% of individuals fail to respond adequately to SSRIs as a monotherapy, indicating the need for novel therapeutic strategies.

In recent years, the role of the glutamatergic system in the pathophysiology of OCRDs has drawn increased attention. Studies suggest that glutamatergic dysfunction, particularly in cortico-striatal-thalamo-cortical circuits, may contribute to these conditions. Consequently, glutamatergic medications, which can modulate glutamate neurotransmission, such as N-Acetylcysteine (NAC) and memantine, have emerged as promising treatment options.

Study Origin

This study was authored by David R. A. Coelho, Chen Yang, Armiel Suriaga, Justen Manasa, Paul A. Bain, Willians Fernando Vieira, Stefania Papatheodorou, and Joshua D. Salvi and published in JAMA Network Open on January 2, 2025. The authors represent renowned institutions such as the Harvard T.H. Chan School of Public Health, the University of São Paulo, and Massachusetts General Hospital.

Objective of the Study

The study aimed to assess the efficacy of glutamatergic medications, either as monotherapy or as SSRIs augmentation, in improving OCRD symptoms through a systematic review and meta-analysis of double-blind, placebo-controlled randomized clinical trials (RCTs).

Methods

Data Sourcing and Screening

The research team conducted electronic searches in PubMed, Embase, PsycINFO, Web of Science, and the Cochrane Central Register of Controlled Trials on October 16, 2024, without applying date restrictions. Two researchers independently screened literature, using inclusion criteria of double-blind RCTs comparing glutamatergic medications to placebo in OCRD patients. Excluded were non-English publications, study protocols, trials involving psychological therapy augmentation, and studies lacking retrievable outcome data.

Data Extraction and Synthesis

The meta-analysis utilized a random-effects model. Subgroup analyses were conducted by OCRD type, population characteristics, treatment refractoriness, augmentation approach, bias risk, and glutamatergic medication type. Sensitivity analyses employed a leave-one-out method.

Primary Outcome Measures

OCRD symptom improvement was assessed using Standardized Mean Difference (Cohen’s d), while symptom improvement specific to OCD was measured using Mean Differences in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores.

Results

Study Inclusion and Characteristics

Twenty-seven RCTs involving 1,369 patients (mean age: 31.5 years; 65.6% female) were included. Among these, 23 trials focused on OCD, 2 on trichotillomania, and 2 on excoriation disorder. Most studies (¹⁷⁄₂₇) were rated as low risk of bias.

OCRD Symptom Improvement

Glutamatergic medications showed a large pooled effect size in improving OCRD symptoms (Cohen d = -0.80; 95% CI: -1.13 to -0.47), albeit with low certainty of evidence. Subgroup analyses revealed no significant differences by OCRD type, population, refractoriness, augmentation strategies, bias risk, or medication type.

OCD Symptom Improvement

For OCD-specific trials (23 studies), glutamatergic medications significantly reduced Y-BOCS scores (Mean Difference = -4.17, 95% CI: -5.82 to -2.52) with moderate certainty of evidence. Subgroup analyses indicated no significant differences across variables such as population characteristics or treatment strategies.

Discussion and Conclusions

Key Findings

This study’s findings suggest that glutamatergic medications may provide significant symptomatic relief for OCRDs, especially OCD. However, due to high heterogeneity and potential publication bias, results should be interpreted cautiously.

1. Mechanisms of Action: Insights into the modulation of synaptic plasticity and neuronal excitability suggest a potential therapeutic role for glutamatergic medications. For example, NAC may reduce oxidative stress by elevating glutathione and modulating the glutamate system, while memantine inhibits excessive corticostriatal glutamate transmission.
2. Consistency Across Subgroups: Subgroup analyses revealed no significant variations, supporting the robustness of the overall findings.

Contribution to Existing Literature

This systematic review expands on prior analyses, which largely focused on specific OCRDs or individual glutamatergic medications such as NAC or memantine. By examining a broader range of disorders and conducting subgroup analyses, this study provides more comprehensive insights.

Limitations

• Small sample sizes in some trials and subgroups.
• Exclusion of non-English studies and gray literature.
• Lack of analysis by dosage effects due to inconsistent reporting.
• Limited representation of disorders like BDD and hoarding disorder.
• The absence of promising drugs such as ketamine and troriluzole due to inclusion criteria.

Conclusion

Glutamatergic medications demonstrate promise for treating OCRDs, particularly OCD. Future research should aim for larger trials, extended assessments of dose-dependent effects, and exploration of novel medications to enrich therapeutic strategies.

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This systematic review underscores the potential of glutamatergic drugs as effective interventions for OCRDs. Further research will deepen understanding and foster improved treatment methodologies, ultimately benefiting patients who fail to respond to conventional therapies.