Table 1 Controlled clinical trials reporting Glutamatergic drugs in OCD

1

Afshar et al., 2012

Patients with refractory OCD(n = 38)

1- control group (n = 24)

2- experimental group (n = 24)

1- Control group: placebo, identical pills

2- Experimental group: initial dosage of 600 mg/d of NAC, which doubled weekly to a maximum dose of 2400 mg/d

• Serotonin reuptake inhibitor treatment continued throughout the study with the same dose as the preintervention phase

• 12 wks follow up

➢ Y-BOCS: Mean difference 95%CI; − 5.14 [− 6.87, − 3.41]

➢ Adverse effects: no unusual or serious adverse event was observed. The adverse events reported during trial were only gastrointestinal.

Eight patients in the NAC group reported nausea/vomiting of mild to moderate intensity compared with 2 patients in the placebo group.

Mild diarrhea was reported by 4 patients in the NAC group but none of the patients in the placebo group

2

Arabzadeh et al., 2017

Those with a diagnosis of moderate to severe OCD defined by a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of ≥ 21 (Goodman, Price, Rasmussen, et al., 1989) were included(n = 50)

1- control group (n = 25)

2- experimental group (n = 25)

Hepatectomy and radio-chemotherapy were front-line therapies

1- Control group: Fluvoxamine (200 mg) + placebo

2- Experimental group: Fluvoxamine (200 mg daily) + L-carnosine 500 mg twice per day

• Follow up after 10 wks

➢ Y-BOCS: Mean difference 95%CI; − 3.00 [− 4.70, − 1.30] P value:0.01

➢ Adverse effects: Headache 6 Dry mouth 6 Nausea 3 Constipation 6 Sweating Frequency of side effects was not different between the two groups.

3

Costa et al., 2017

Patients with OCD (n = 40)

1- control group (n = 22)

2- experimental group (n = 18)

1- Control group: SRI + Placebo

2- Experimental group: SRI + N-Acetyl Cysteine

• 16 wks follow up

• During the first week, patients started the trial with either NAC 1200 mg (one 600-mg capsule twice a day) or an equivalent number of placebo capsules. In the second week, the dosage was increased to 4 capsules per day (NAC 2400 mg [2 capsules twice a day] or an equivalent number of placebo capsules). Finally, on the third week, the target dose of 5 capsules per day was reached (NAC 3000 mg [2 capsules in the morning and 3 in the evening] or an equivalent number of placebo capsules) and sustained for the remainder of the study.

➢ Overall survival in 8 years* (HR; 95%CI; P value): 0.69 (0.41–1.15); P = 0.1545

➢ Recurrence-free survival in 5 years* (HR; 95%CI; P value): 0.31 (0.09–1.07); P = 0.0639

➢ Toxicity grade 3–4: none was reported

4

Emamzadehfard et al. 2016

Patients with OCD (n = 54)

1- control group (n = 27)

2- experimental group (n = 27)

according to the DSMIV-TR and a Yale–Brown Obsessive Compulsive Scale (Y-BOCS) score of ≥21

1. Control group: fluvoxamine 200 mg/day + placebo

2. Experimental group: fluvoxamine 200 mg/day + riluzole 50 mg BD 10 wks follow up

➢ Y-BOCS: Mean difference 95%CI; − 3.56 [− 6.89, − 0.23] p value:0.04 Adverse effects: Experimental group: Drowsiness, 6 (24%) Constipation, 5 (20%) 5 (20%) Dizziness, 4 (16%)Abdominal pain, n (%) 5 (20%) 4(16%) Increased appetite, n (%) 4 (16%) 5 (20%) Decreased appetite, n (%) 3 (12%) 4 (16%) Nausea, n (%) 6 (24%) 5 (20%) Headache, n (%) 4 (16%) 4 (16%) Dry mouth, n (%) 3 (12%) 3 (12%) Cough, 4 (16%) Diarrhea, 6 (24%) 4 (16%) Increase in liver-function tests (4%) 0

5

Esalatmanesh et al., 2016

Patients with OCD Y-BOCS > 21 (n = 132)

1- control group (n = 66)

2- experimental group (n = 66)

• Almost half of the patients had hepatitis B

• Hepatectomy or TACE were frontline therapies

1- Control group: Fluvoxamine 200 mg/day + placebo (identical, same shaped capsule)

2- Experimental group: Fluvoxamine 200 mg/day + Minocycline 100 mg twice daily 10 wks follow up

➢ Y-BOCS: Mean difference 95%CI; −3.21 [− 0.84– − 5.58] p value:0.008

➢ Adverse effects: No difference between to gropus

6

Farnia et al., 2018

Patients with OCD (n = 99)

1- control group (n = 33)

2- experimental group 1 (n = 33)

3- experimental group 2 (n = 33)

1. Control group: Fluoxetine 40 mg/day + placebo (identical pills)

2. Experimental group 1: Fluoxetine 40 mg/day + gabapentin 300 mg/day

3. Experimental group 2: Fluoxetine 40 mg/day + memantine 10 mg/day

• From baseline to the end of the fourth week, daily dosage of fluoxetine was 20 mg; from the beginning of the fifth week to the end of the eighth week, daily dosage of fluoxetine was 40 mg.

• From baseline to the end of the fourth week, daily dosage of gabapentin was 100 mg; fromthe beginning ofthe fifthweek to theend of the eighth week, daily dosage of gabapentin was 300 mg

• memantine was given daily at 5 mg in the morning/evening for the four first weeks of the study, and then increased to 10 mg daily for weeks five to eight. Likewise, placebos were given daily in the morning/evening

➢ memantine vs. placebo:

Mean difference 95% CI: - 1.12 [− 0.916, −  3.1622] P-value:0.2

➢ Gabapentin vs. placebo

Mean difference 95% CI: - 2.550[− 0.7895, −  4.3105] P-value:0.0061

➢ Adverse effects: More rash was seen in memantine group than control group Sleepiness was reported in gabapentin group

7

Ghaleiha et al., 2013

Patients with OCD (n = 42)

• control group (n = 21)

• experimental group (n = 21)

1- Control group: fluvoxamine 200 mg/day + placebo (with the same shape and taste as memantine)

2- Experimental group: fluvoxamine 200 mg/day + memantine 20 mg/day

• All patients received fluvoxamine100mg/ day for the first four weeks of the trial followed by 200 mg/day for the rest of the study

• 8 wks follow up

• Y-BOCS: has not reported the mean of score after the trial. Just reports remission rate

• Adverse effects in control group: Drowsiness (26%) Headache (21%) Constipation (31%) Dizziness (21%) Fatigue (16%) Nausea (21%) Decreased appetite (26%) Itching (10%) Nervousness (21%) Rash (5%) in experimental group: Drowsiness (21%) Headache (16%) Constipation (31%) Dizziness 3 (16%) Fatigue (16%) Nausea (26%) Decreased appetite (21%) Itching (16%)Nervousness (21%) Rash (10%)

8

Greenberg et al., 2009

Patients with OCD (n = 24)

• control group (n = 12)

• experimental group (n = 12)

1. Control group: placebo fluid (dextrose, fructose, fine granular citric acid, orange flavoring and ProSweetTM flavor enhancer)

2. Experimental group: glycine powder 30 g dissolved in water or juice, twice daily

• The experimental intervention was adjunctive to participants’ continuing psychotropic and psychotherapeutic regimens, which were managed by their treatment providers in the community.

• 12 wks follow up

➢ Y-BOCS: Mean difference 95%CI; −5.30 [− 11.56, 0.96];p value: 0.1650

➢ Adverse effects: constipation 1; nausea or disagreeable taste 8 out of 16 dropped patients

9

Haghighi et al., 2013

Patients with OCD (n = 40)

• control group (n = 20)

• experimental group (n = 20)

1- Control group: placebo (identical pill)

2- Experimental group: memantine (5–10 mg/day)

• All patients use medication 1 week prior to the beginning of the study (and continued throughout the study) of an SSRI (e.g., escitalopram, 10 mg/day; citalopram, 30–50 mg/day) or clomipramine (100–175 mg/day) at therapeutic dosages for at least 12 consecutive weeks

• 12 wks follow up

➢ Y-BOCS: Mean difference 95%CI; −3.21 [− 0.84– − 5.58] p value:0.008

➢ Adverse effects: light-headedness and vertigo 5% (similar to placebo group)

10

Modarresi et al., 2018

Patients with OCD (n = 32)

• control group (n = 16)

• experimental group (n = 16)

1- Control group: placebo (identical pills)

2- Experimental group: memantine 10 mg/day

• Patients continue their SRI therapy during the study

• 12 wks follow up

➢ Y-BOCS: Mean difference 95%CI; −13.53 [− 15.59, − 11.47] p value< 0.001

➢ Adverse effects: Headache 13.3%Constipation6.6% Nausea 6.6% Dizziness 13.3% Decreased appetite 6.6%

11

Mowla et al., 2019

Patients with OCD (n = 56)

• control group (n = 28)

• experimental group (n = 28)

• the patients in this study had failed to respond to at least 12 weeks of treatment with an adequate and stable dose of sertraline, as reflected by a baseline Yale–Brown Obsessive Compulsive Scale (YBOCS) of 18 or greater before enrollment in our trial

1- Control group:sertraline + placebo (identical pills

2- Experimental group: Sertraline + pregabalin (75 mg/day initialy, increase 75 mg weekly

• The sertraline dosage had been tittered up until patient’s intolerance.

• No pregabalin dose escalation was administered in the case of patient’s intolerance or clinical response.

➢ Y-BOCS: Mean difference 95%CI; −8.82 [− 11.17, − 6.47] p value< 0.001

➢ Adverse effects: Dizziness 4%, drowsiness 18%, headache 4%

12

Naderi et al., 2019

Patients with OCD (n = 106)

• control group (n = 53)

• experimental group (n = 53)

• The patients were not allowed to have received any psychotropic medications during the last 6 weeks or to have participated in psychotropic sessions

• met the DSM-5 diagnostic criteria for moderate to severe OCD and had a Yale–Brown Obsessive Compulsive Scale (Y-BOCS) score of > 21

1- Control group: fluvoxamine (100 mg twice a day) + placebo

2- Experimental group: fluvoxamine (100 mg twice a day) + amantadine (100 mg daily)

• All patients received 100 mg/day fluvoxamine for 28 days, which was followed by 200 mg/day for the rest of the trial, regardless of their treatment groups

➢ Y-BOCS: Mean difference 95%CI; − 2.31 [− 4.58, − 0.04] p value:0.047 Adverse effects: Abdominal pain (5.8%) Decreased appetite (3.9%) Increased appetite (3.9%) Insomnia (1.9%) Headache (3.9%) Nervousness (1.9%) Tremor (1.9%) Constipation (3.9%)

13

Paydari et al., 2016

Patients with OCD (n = 46)

• control group (n = 23)

• experimental group (n = 23)

• (DSM-IV TR) criteria of moderate-to-severe OCD and scored ≥21 in Y-BOCS

1- Control group: fluvoxamine (200 mg daily) + placebo (identical pills)

2- Experimental group: fluvoxamine (200 mg daily) + NAC (2000 mg daily)

• The NAC initial dosage was 1000 mg/day (500 mg two times a day) for the first week, followed by 2000 mg/day (1000 mg bid) for the subsequent 9 weeks

• 10 wks follow up

➢ Y-BOCS: Mean difference 95%CI; − 2.04 [− 4.97, − 0.88] p value:0.16

➢ Adverse effects: Drowsiness, 18% Constipation 23% Dizziness 27% Vomiting27% Nausea27% Headache18% Dry mouth14% Increased blood Pressure14% Diarrhoea18%

14

Pittenger et al., 2015

Patients with OCD (n = 38)

1- control group (n = 18)

2- experimental group (n = 20)

• treatment with an SSRI or clomipramine at a stable effective dose for 8 weeks (by patient report) is an item in inclusion criteria

1- Control group: Placebo

2- Experimental group: riluzole 50 mg bid

• all subjects began with a 2-week single-blind placebo lead-in phase, followed by 12 weeks of double-blind riluzole or placebo. In posttrial debriefing, no subjects expressed awareness of this initial placebo lead-in phase. Any subjects experiencing a greater than 25% improvement in the Y-BOCS over this 2-week placebo lead-in phase were excluded from randomization.

• 12 wks follow up

• Low-dose stable neuroleptic augmentation and benzodiazepine use were permitted

• Ongoing psychotherapy of 12 weeks duration was permitted

➢ Y-BOCS: Mean difference 95%CI: − 4.5[− 6.5074, − 2.4926] p value:0.002

➢ Adverse effects: Nausea: < 10% in experimental group

15

Rodriguez 2013

Patients with OCD (n = 38)

1. control group (n = 18)

2. experimental group (n = 20)

• Patients on average were off all psychotropic medications for 2.9 years

1. Control group: Placebo (saline infusion)

2. Experimental group: Ketamine infusion(0.5 mg/kg)

• Cross-over study

• One week duration

• Include only the first period of study, because of significant carryover effect

➢ Y-BOCS: Mean difference 95%CI − 5.46 [− 13.15, 2.22] p value: 0.1868

➢ Adverse effects:

° During infusion: Dissociation: 93% unusual content of thought:87% elevated mood: 7%

° Post-infusion:dizziness 20% nausea: 13% headache 13%

° All side effects were resolved after 110 min of infusion

16

Rutrick et al., 2017

Patients with OCD (n = 50)

1. control group (n = 24)

2. experimental group (n = 26)

• All patients had used SRI for 12wks before baseline and had insufficient response (Y-BOCS score > 16)

1. Control group: Placebo

2. Experimental group: Magovlurant 200 mg BiD

• 19 wks follow up. First 4 wks for dose titration and last 3 wks for taper of mavoglurant

• During the study patients remained on their SSRI treatment

• Patients who were receiving cognitive behavioral therapy (CBT) as a part of their standard care continued to receive this therapy for the duration of the study.

➢ Y-BOCS: Mean difference 95%CI 1.80 [−4.30, 7.90] p value: 0.5658

➢ Adverse effects [placebo(%) vs experimental(%)]: Headache 8 (33.3) 10 (38.5) Insomnia 2 (8.3) 6 (23.1) Dizziness 2 (8.3) 5 (19.2) Nasopharyngitis 4 (16.7) 2 (7.7) Abdominal pain upper 1 (4.2) 2 (7.7) Abnormal dreams 1 (4.2) 2 (7.7) AST increased 1 (4.2) 2 (7.7) Depression 2 (8.3) 1 (3.8) Fatigue 1 (4.2) 2 (7.7) Vertigo 1 (4.2) 2 (7.7)

17

Sarris et al., 2015

Patients with OCD (n = 50)

1. control group (n = 24)

2. experimental group (n = 26)

• patients were on either no treatment or a stable treatment regimen for a minimum of four weeks of current treatment and a minimum of 12 weeks if this is their first OCD treatment

1. Control group: Same shaped cellulose capsule

2. Experimental group: NAC 3000 mg/day

• 16 wks follow up

• NAC was titrated, 1000 mg/day in week 1, 2000 mg/day in week 2

➢ Y-BOCS: Mean difference 95%CI; − 2.04 -0.59 [− 6.31, 5.13] p value: 0.8425

➢ Adverse effects: heartburn 20%