Glutamatergic Medications for Obsessive-Compulsive and Related Disorders: A Systematic Review and Meta-Analysis

Overview

Journal JAMA Netw Open

Publisher American Medical Association

Specialty General Medicine

Date 2025 Jan 2

PMID 39745698

Authors

David R A Coelho

Chen Yang

Armiel Suriaga

Justen Manasa

Paul A Bain

Willians Fernando Vieira

Stefania Papatheodorou

Joshua D Salvi

Affiliations

Soon will be listed here.

Abstract

Importance: Obsessive-compulsive and related disorders (OCRDs) encompass various neuropsychiatric conditions that cause significant distress and impair daily functioning. Although standard treatments are often effective, approximately 60% of patients may not respond adequately, underscoring the need for novel therapeutic approaches.

Objective: To evaluate improvement in OCRD symptoms associated with glutamatergic medications as monotherapy or as augmentation to selective serotonin reuptake inhibitors, with a focus on double-blind, placebo-controlled randomized clinical trials (RCTs).

Data Sources: Electronic searches were conducted in PubMed, Embase, PsycINFO, Web of Science, and Cochrane Central Register of Controlled Trials on October 16, 2024, without date limits.

Study Selection: Two investigators independently screened records to identify double-blind RCTs comparing glutamatergic medications with placebo for patients with OCRDs regardless of age, sex, gender, or refractoriness. Abstracts, study protocols, non-English studies, and trials involving augmentation to psychotherapy were excluded.

Data Extraction And Synthesis: Data were extracted and synthesized using random-effects meta-analyses. Subgroup analysis was conducted based on type of OCRD, population, refractoriness of OCRD, augmentation strategy, risk of bias, and type of glutamatergic medication. Sensitivity analysis was performed using a leave-one-out approach.

Main Outcomes And Measures: Improvement in OCRD symptoms was measured by standardized mean difference (Cohen d). Improvement in obsessive-compulsive disorder (OCD) symptoms was measured by mean difference (reduction in Yale-Brown Obsessive Compulsive Scale [Y-BOCS] scores).

Results: A total of 27 RCTs (1369 participants; mean [SD] age, 31.5 [7.8] years; 65.6% female) were included. Glutamatergic medications showed a large effect size in improving OCRD symptoms (Cohen d = -0.80 [95% CI, -1.13 to -0.47]; low certainty of evidence). In the 23 OCD-specific RCTs, glutamatergic medications demonstrated a significant mean reduction in Y-BOCS scores (mean difference, -4.17 [95% CI, -5.82 to -2.52]; moderate certainty of evidence).

Conclusions And Relevance: These findings indicate that glutamatergic medications may be effective in treating OCRDs, particularly OCD. However, high heterogeneity and potential publication bias necessitate cautious interpretation. Further research with larger sample sizes is needed to explore dose-dependent effects, additional OCRD subtypes, and other promising glutamatergic medications.

References

Sarris J, Oliver G, Camfield D, Dean O, Dowling N, Smith D . N-Acetyl Cysteine (NAC) in the Treatment of Obsessive-Compulsive Disorder: A 16-Week, Double-Blind, Randomised, Placebo-Controlled Study. CNS Drugs. 2015; 29(9):801-9. DOI: 10.1007/s40263-015-0272-9. View

Laoutidis Z, Lekka G, Kioulos K . Glutamatergic Agents as Add-On Medication for the Treatment of Obsessive-Compulsive Disorder: A Systematic Review and Meta-Analysis. J Clin Psychiatry. 2016; 77(12):e1576-e1583. DOI: 10.4088/JCP.15r10164. View

Kariuki-Nyuthe C, Gomez-Mancilla B, Stein D . Obsessive compulsive disorder and the glutamatergic system. Curr Opin Psychiatry. 2013; 27(1):32-7. DOI: 10.1097/YCO.0000000000000017. View

Naderi S, Faghih H, Aqamolaei A, Mortazavi S, Mortezaei A, Sahebolzamani E . Amantadine as adjuvant therapy in the treatment of moderate to severe obsessive-compulsive disorder: A double-blind randomized trial with placebo control. Psychiatry Clin Neurosci. 2018; 73(4):169-174. DOI: 10.1111/pcn.12803. View

Bloch M, Panza K, Grant J, Pittenger C, Leckman J . N-Acetylcysteine in the treatment of pediatric trichotillomania: a randomized, double-blind, placebo-controlled add-on trial. J Am Acad Child Adolesc Psychiatry. 2013; 52(3):231-40. PMC: 3745012. DOI: 10.1016/j.jaac.2012.12.020. View

Egger M, Davey Smith G, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315(7109):629-34. PMC: 2127453. DOI: 10.1136/bmj.315.7109.629. View

Welter M, Burbaud P, Fernandez-Vidal S, Bardinet E, Coste J, Piallat B . Basal ganglia dysfunction in OCD: subthalamic neuronal activity correlates with symptoms severity and predicts high-frequency stimulation efficacy. Transl Psychiatry. 2012; 1:e5. PMC: 3309476. DOI: 10.1038/tp.2011.5. View

Grant J, Chamberlain S, Redden S, Leppink E, Odlaug B, Kim S . N-Acetylcysteine in the Treatment of Excoriation Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2016; 73(5):490-6. DOI: 10.1001/jamapsychiatry.2016.0060. View

Koran L, Abujaoude E, Large M, Serpe R . The prevalence of body dysmorphic disorder in the United States adult population. CNS Spectr. 2008; 13(4):316-22. DOI: 10.1017/s1092852900016436. View

10.

Raghu G, Berk M, Campochiaro P, Jaeschke H, Marenzi G, Richeldi L . The Multifaceted Therapeutic Role of N-Acetylcysteine (NAC) in Disorders Characterized by Oxidative Stress. Curr Neuropharmacol. 2020; 19(8):1202-1224. PMC: 8719286. DOI: 10.2174/1570159X19666201230144109. View

11.

Paydary K, Akamaloo A, Ahmadipour A, Pishgar F, Emamzadehfard S, Akhondzadeh S . N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther. 2016; 41(2):214-9. DOI: 10.1111/jcpt.12370. View

12.

Greenberg W, Benedict M, Doerfer J, Perrin M, Panek L, Cleveland W . Adjunctive glycine in the treatment of obsessive-compulsive disorder in adults. J Psychiatr Res. 2008; 43(6):664-70. DOI: 10.1016/j.jpsychires.2008.10.007. View

13.

Grant J, Odlaug B, Kim S . N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2009; 66(7):756-63. DOI: 10.1001/archgenpsychiatry.2009.60. View

14.

DellOsso B, Altamura A, Mundo E, Marazziti D, Hollander E . Diagnosis and treatment of obsessive-compulsive disorder and related disorders. Int J Clin Pract. 2007; 61(1):98-104. DOI: 10.1111/j.1742-1241.2006.01167.x. View

15.

Fontenelle L, Mendlowicz M, Versiani M . The descriptive epidemiology of obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30(3):327-37. DOI: 10.1016/j.pnpbp.2005.11.001. View

16.

Vlcek P, Polak J, Brunovsky M, Horacek J . Role of Glutamatergic System in Obsessive-Compulsive Disorder with Possible Therapeutic Implications. Pharmacopsychiatry. 2017; 51(6):229-242. DOI: 10.1055/s-0043-118665. View

17.

Esalatmanesh S, Abrishami Z, Zeinoddini A, Rahiminejad F, Sadeghi M, Najarzadegan M . Minocycline combination therapy with fluvoxamine in moderate-to-severe obsessive-compulsive disorder: A placebo-controlled, double-blind, randomized trial. Psychiatry Clin Neurosci. 2016; 70(11):517-526. DOI: 10.1111/pcn.12430. View

18.

Costa D, Diniz J, Requena G, Joaquim M, Pittenger C, Bloch M . Randomized, Double-Blind, Placebo-Controlled Trial of N-Acetylcysteine Augmentation for Treatment-Resistant Obsessive-Compulsive Disorder. J Clin Psychiatry. 2017; 78(7):e766-e773. DOI: 10.4088/JCP.16m11101. View

19.

Wu K, Hanna G, Rosenberg D, Arnold P . The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder. Pharmacol Biochem Behav. 2011; 100(4):726-35. PMC: 3437220. DOI: 10.1016/j.pbb.2011.10.007. View

20.

Maia T, Cooney R, Peterson B . The neural bases of obsessive-compulsive disorder in children and adults. Dev Psychopathol. 2008; 20(4):1251-83. PMC: 3079445. DOI: 10.1017/S0954579408000606. View