Table 1.

Placebo-controlled, randomized, double-blind clinical trials of glutamate-modulating drugs as monotherapy or augmentation of the existing psychotropic regimen in OCD.

Study & Drug		Duration & Dose		Adjunctive/ Monotherapy		Subjects		Treatment Resistance at Baseline		Endpoint Results on Efficacy	Side Effects		Effect on Primary Outcome: (Yes/no)
Riluzole
Grant et al., 2014		12 weeks Final dose: 100 mg/day		Adjunctive Initial treatment: SRI		60 pediatric OCD patients (17 with comorbid ASD)		Yes		No significant differences in change of CY-BOCS, CGAS, CGI-I and CGI-S scores between the placebo and riluzole groups at the end of the trial	Mainly well tolerated 1 pancreatitis case 5 transaminases elevation cases		CY-BOCS score change: no CGI-I score change: no CGI-S score change: no CGAS score change: no
Pittenger et al., 2015		12 weeks + 2 weeks lead-on placebo Final dose: 100 mg/day		Adjunctive Initial treatment: SRI		38 adult OCD patients (27 outpatients and 11 inpatients)		Yes		No significant difference in Y-BOCS scores change between the placebo and riluzole groups at the end of the trial Among OCD outpatients only significantly more achieved at least partial treatment response with adjunctive riluzole.	Well tolerated		Y-BOCS score change: no
Emamzadehfard et al., 2016		10 weeks Final dose: 100 mg/day		Adjunctive Initial treatment: fluvoxamine		50 adult OCD patients				Significant greater reduction of Y-BOCS total and compulsions scores between the placebo and riluzole groups at the end of the trial	Well tolerated		Y-BOCS score change: yes
Memantine
Ghaleiha et al., 2013		8 weeks Final dose: 20 mg/day		Adjunctive Initial treatment: fluvoxamine		42 adult OCD patients		No		Greater reduction of Y-BOCS scores in the memantine group at the end of the trial (p = 0.006)	Well tolerated		Y-BOCS score change: yes
Haghighi et al., 2013		12 weeks Dose: 5-10 mg/day		Adjunctive Initial treatment: SRI		40 adult OCD patients		No		Greater reduction of Y-BOCS scores in the memantine group at the end of the trial (p = 0.005)	Well tolerated		Not predefined Y-BOCS score change: yes
Ketamine
Rodriguez et al., 2013		Ketamine & saline i.v. infused at least 1 week apart in random order Dose: 0.5 mg/kg		Monotherapy		15 adult OCD patients (2 with mild or moderate comorbid depression)		Part of the sample		Greater reduction in Y-BOCS scores for subjects receiving ketamine as first infusion at 7 days post infusion (p < 0.01) Obsession symptoms severity (OCD-VAS score) with ketamine significantly lower at mid-infusion, 230 min and 7 days post infusion compared to the saline group	Mild increase in blood pressure and pulse Dissociation, psychotic and manic symptoms, time perception distortion, dizziness, nausea, vomiting, headache		Not predefined Y-BOCS score change: yes for ketamine as first infusion OCD-VAS score change: yes
Glycine
Greenberg et al., 2009		12 weeks Final dose: 60 g/day		Adjunctive Initial treatment: stable psycho- pharmacological or psychotherapeutic treatment		24 adult OCD patients		Not specified		Reduction of Y-BOCS scores in the glycine compared to the placebo group at the endpoint showed a trend towards significance (p = 0.053)	High drop-out rate related to glycine’s unpleasant taste and nausea		Y-BOCS score change: no (strong trend towards significance)
Study & Drug		Duration & Dose		Adjunctive/ Monotherapy		Subjects		Treatment Resistance at Baseline		Endpoint Results on Efficacy	Side Effects		Effect on Primary Outcome: (Yes/no)
Topiramate
Mowla et al., 2010		12 weeks Dose: 100-200 mg/day		Adjunctive Initial treatment: existing treatment regimen		49 adult OCD patients		Yes		Y-BOCS score mean decrease 32.0% in the topiramate group vs. 2.4% in the placebo group (p < 0.05)			Y-BOCS score change: yes
Berlin et al., 2011		12 weeks Dose: 50-400 mg/day		Adjunctive Initial treatment: SSRI		36 adult OCD patients		Yes		No significant treatment effect of topiramate on total Y-BOCS scores (p = 0.11) or obsessions subscores (p = 0.99) Significant treatment effect of topiramate on Y-BOCS compulsions subscores (p = 0.014).	Due to adverse effects 28% discontinuation and 39% dose reduction in the topiramate group Weight loss, influenza-like symptoms, taste perversion, paresthesia, memory difficulty		Y-BOCS total score change: no Y-BOCS obsessions subscore change: no Y-BOCS compulsions subscore change: yes
Afshar et al., 2014		12 weeks Dose range: 100-200 mg/day		Adjunctive Initial treatment: SRI		38 adult OCD patients		Yes		No significant difference in Y-BOCS scores between the topiramate and placebo group at the end of the study (p = 0.058) Y-BOCS scores were significantly lower in the topiramate vs. the placebo group at weeks 4 (p = 0.01) and 8 (p = 0.01) of the trial.	2 patients dropped out due to adverse effects. Paresthesia, cognitive problems, weight loss, micturation frequency, renal stone, decreased appetite		Y-BOCS score change at the end of the trial: no (strong trend towards significance) Treatment response: no (strong trend)
Lamotrigine
Bruno et al., 2012		16 weeks Final dose: 100 mg/day		Adjunctive Initial treatment: SRI		40 (final sample 33) adult OCD patients		Yes		Lamotrigine was associated with greater reduction of Y-BOCS (p < 0.0001) and HDRS scores (p < 0.0001) at endpoint. Lamotrigine was associated with lower CGI-S scores at the end of the trial (p < 0.0001).	Well tolerated Sedation, fatigue, headache, skin rash		Y-BOCS score change: yes CGI-S score difference: yes HDRS score change: yes
Khalkhali et al., 2016		12 weeks Final dose: 100 mg/day		Adjunctive Initial treatment: SRI		53 adult OCD patients		Yes		Lamotrigine was associated with greater reduction of the total Y-BOCS score (p = 0.007), as well as the obsessions (p = 0.01) and compulsions subscales (p = 0.005).	Well tolerated Headache, skin rash		Y-BOCS score change: yes
N-acetylcysteine
Afshar et al., 2012		12 weeks Dose: up to 2.4 g/day		Adjunctive Initial treatment: SRI		48 adult OCD patients		Yes		Greater reduction of Y-BOCS scores in the NAC compared to the placebo group at the end of the trial (p = 0.003) Significantly more patients in the NAC compared to the placebo group were responders (p = 0.013).	Well tolerated Nausea, vomiting, diarrhea		Y-BOCS change: yes Treatment response rate: yes
Study & Drug	Duration & Dose		Adjunctive/ Monotherapy		Subjects		Treatment Resistance at Baseline		Endpoint Results on Efficacy			Side Effects		Effect on Primary Outcome: (Yes/no)
N-acetylcysteine
Sarris et al., 2015	16 weeks Dose: 3 g/day		Monotherapy or adjunctive Initial treatment: existing stable treatment regimen or monotherapy		44 adult OCD patients		Not specified		No significant difference in Y-BOCS scores changes between the NAC and placebo group at the end of the study			Well tolerated Heartburn		Y-BOCS change: no
Paydary et al., 2016	10 weeks Dose: 2 g/d		Adjunctive Initial treatment: fluvoxamine		44 adult OCD patients				Greater reduction of Y- BOCS total scores (p = 0.012) and obsessions subscale (p = 0.011) in the NAC compared to the placebo group at the end of the trial			Well tolerated		Y-BOCS change: yes
Costa et al., 2017	16 weeks Dose: 3 g/d		Adjunctive Initial treatment: SRI		40 adult OCD patients		Yes		No significant difference in Y-BOCS scores changes between the NAC and placebo group at the end of the study Some benefit in reducing anxiety symptoms in the NAC group			Well tolerated Abdominal pain		Y-BOCS change: no
Minocycline
Esalatmanesh et al., 2016	10 weeks Dose: 200 mg/d		Adjunctive Initial treatment: fluvoxamine		102 adult OCD patients		No		Greater reduction of Y-BOCS total scores (p = 0.003), the obsession subscale (p = 0.001) and greater response rate in the minocycline group at the end of the trial			Well tolerated		Y-BOCS change: yes

Abbreviations: ADIS = Anxiety Disorders Interview Schedule, ASD = autism spectrum disorder, CBT = cognitive behavioural therapy, CSR = clinical severity rating, CY-BOCS = Children's Yale-Brown Obsessive Compulsive Scale, CGAS = Children's Global Assessment Scale, CGI-I = Clinical Global Impression – Improvement, CGI-S = Clinical Global Impression - Severity, GOCS = Global Obsessive-Compulsive Scale, HDRS = Hamilton Rating Scale for Depression, NAC = N-acetylcysteine, OCD-VAS = OCD visual analog scale, SSRI = selective serotonin reuptake inhibitor, SUDS = Subjective Units of Distress Scale, Y-BOCS = Yale-Brown Obsessive Compulsive Scale.