Table 2.

Study reports for randomized, double-blind, placebo-controlled trial.

Studies	Patients/ Antipsychotics	Duration	Drug	Number	Outcomes
Rezaei et al. 2013 [25]	Schizophrenia (risperidone 6 mg/day)	8 weeks	Memantine (20 mg/day)	Memantine n = 20 Placebo n = 20	Significant compared to placebo: PANSS negative subscale score (p < 0.001), PANSS total score (p < 0.001), and general psychopathology subscale score (p = 0.002). Not significant compared to placebo: PANSS positive subscale score (p = 0.759). Changes in the Hamilton Depression Rating Scale score and the Extrapyramidal Symptom Rating Scale score and frequency of adverse effects did not differ between the 2 groups.
Fakhri et al. 2016 [29]	Schizophrenia (olanzapine 15–20 mg/day)	6 weeks	Memantine (week 1: 10 mg/day; weeks 2–6: 20 mg/day)	Memantine n = 30 Placebo n = 30	Significant compared to placebo: PANSS negative subscale score (p < 0.001) and PANSS positive subscale score (p < 0.001). Females showed significantly better response than males, especially in PANSS positive subscale score. No significant changes in extrapyramidal symptoms were observed.
Mazinani et al. 2017 [30]	Schizophrenia (risperidone 4–6 mg/day)	12 weeks	Memantine (titration weeks 1–4: 5 to 20 mg/day; weeks 5–12: 20 mg/day)	Memantine n = 23 Placebo n = 23	Significant compared to placebo: PANSS negative subscale score (p = 0.003) and Mini-Mental State Examination score (p < 0.001). Not significant compared to placebo: PANSS positive subscale score (p = 0.09) and general psychopathology score (p = 0.9).
Omranifard et al. 2017 [31]	Schizophrenia (atypical antipsychotic regimen)	12 weeks	Memantine (titration weeks 1–4: 5 to 20 mg/day; weeks 5–12: 20 mg/day)	Memantine n = 30 Placebo n = 30	Significant compared to placebo: PANSS negative subscale score (p = 0.004), PANSS positive subscale score (p = 0.028), general psychopathology score (p < 0.001), depressive symptom score (p < 0.001), and total symptom severity score (p < 0.001). No serious or severe adverse effects were reported during the study.
Hassanpour et al. 2019 [32]	Schizophrenia (antipsychotic regimen)	8 weeks	Memantine (week 1: 10 mg/day; weeks 2–8: 20 mg/day)	Memantine n = 20 Placebo n = 20	Significant compared to placebo: verbal memory (p = 0.01), working memory (p = 0.007), verbal fluency letter (p = 0.002), and verbal fluency total (p = 0.013) scores of the Brief Assessment of Cognition Scale. No improvement on psychotic symptoms was observed. There was no significant difference in the Abnormal Involuntary Movement Scale and Barnes Akathisia Rating Scale scores between the 2 groups.
Schaefer et al. 2020 [35]	Acute schizophrenia with predominant positive symptoms (risperidone 2–8 mg/day)	6 weeks	Memantine (20 mg/day)	Memantine n = 5 Placebo n = 6	Significant compared to placebo: attention intensity (p = 0.005), verbal learning (p = 0.050), problem solving (p = 0.043), and flexibility (p = 0.049). Not significant compared to placebo: PANSS total score and PANSS negative subscale score
	Chronic schizophrenia with negative symptoms (risperidone 2–8 mg/day)	24 weeks	Memantine (20 mg/day)	Memantine n = 7 Placebo n = 6	Significant compared to placebo: immediate memory (p = 0.033) and PANSS total score (p = 0.026). Not significant compared to placebo: PANSS negative subscale score.
de Lucena et al. 2009 [38]	Treatment- refractory schizophrenia (mean doses of clozapine memantine: 540 mg/day; placebo: 659 mg/day)	12 weeks	Memantine (20 mg/day)	Memantine n = 10 Placebo n = 11	Significant compared to placebo: Brief Psychiatric Rating Scale total score (effect size = −2.75, p = 0.001), positive symptoms score (effect size = −1.38, p = 0.007), negative symptoms score (effect size = −3.33, p = 0.001), Clinical Global Impression score (effect size = −1.56, p = 0.001), and the Mini-Mental State Examination score (effect size = 1.32, p = 0.005). No significant changes in extrapyramidal symptoms were observed.
Veerman et al. 2016 [39]	Treatment- refractory schizophrenia (clozapine dosage was remained as much unaltered as possible)	12 weeks	Memantine (week 1: 10 mg/day; weeks 2–12: 20 mg/day)	Memantine n = 26 Placebo n = 26 (each group has 52 cases based on two cross-overs)	This study was a 26-week single-center, double-blind, placebo-controlled crossover trial. The trial consisted of two crossover, 12-week treatment phases and a placebo wash-out period of 2 weeks in the 13th and 14th week to avoid carryover effects. Significant compared to placebo: PANSS negative subscale score (effect size = 0.29, p = 0.043) and memory composite (effect size = 0.30, p = 0.032), including verbal recognition memory and paired associates learning task scores on the Cambridge Neuropsychological Test Automated Battery. Not significant compared to placebo: PANSS positive subscale score (effect size = 0.15, p = 0.299) and PANSS total score (effect size = 0.19, p = 0.174). Side effects were mild and transient.
Omranifard et al. 2015 [41]	Schizophrenia (stable-dose atypical antipsychotic)	12 weeks	Memantine (titration weeks 1–4: 5 to 20 mg/day; weeks 5–12: 20 mg/day)	Memantine n = 32 Placebo n = 32	Global Assessment of Functioning scale and quality of life scale scores increased in both groups, with significantly higher scores in the memantine add-on group than the placebo group (p < 0.001 and p < 0.001, respectively). Memantine was well tolerated with no significant side effects.

PANSS: Positive and Negative Syndrome Scale.