Clozapine is currently the “gold standard” for treatment-resistant schizophrenia. However, many patients have persistent psychotic symptoms despite treatment with clozapine, and evidence for augmentation strategies in clozapine non-responders remains scarce.1 The mechanism(s) of action of clozapine remain unclear but may involve modulation of N-methyl-D-aspartate (NMDA) glutamate receptors. Several clinical trials have found that NMDA-enhancing agents, including glycine, D-cycloserine, D-serine, and sarcosine, may improve psychopathology in some patients with schizophrenia, although the evidence in clozapine-resistant patients is not convincing.1
Inhibition of the enzyme D-amino acid oxidase (DAAO) represents a new mechanism for enhancing NMDA signaling. Sodium benzoate, a commonly used food preservative, is a DAAO inhibitor with good CNS bioavailability. A previous study found that 1 g/day of adjunctive sodium benzoate was associated with improvements in clinical and cognitive symptoms in patients with chronic schizophrenia, although its effect on clozapine-resistant schizophrenia remains unknown.2
Lin and colleagues3 investigated 2 doses of adjunctive sodium benzoate in patients with clozapine-resistant schizophrenia. Inpatients were recruited from 4 major psychiatric centers in Taiwan. Inclusion criteria were: age 18-65 and a DSM-IV diagnosis of schizophrenia. Participants were physically healthy with normal laboratory studies, had failed at least 2 antipsychotic trails prior to clozapine, and had been receiving clozapine for >12 weeks without a satisfactory response (defined as a baseline Positive and Negative Syndrome Scale [PANSS] score >70 and Scale for the Assessment of Negative Symptoms [SANS] score >40). Exclusion criteria were a DSM-IV diagnosis of schizoaffective disorder or mood disorder; mental retardation; substance use disorder; history of epilepsy, head trauma, or CNS disease; or pregnancy or lactation.
Subjects were randomized in a double-blind fashion to receive 6 weeks of adjunctive sodium benzoate (1g or 2g/day) or placebo in a 1:1:1 ratio. Efficacy and safety were evaluated at baseline and at weeks 2, 4, and 6. The primary outcome measures were PANSS total score, SANS, Quality of Life Scale (QOLS), and Global Assessment of Functioning (GAF) scores. Secondary outcome measures were PANSS subscales, the Hamilton Depression Rating Scale, and cognitive function. Changes in outcome measures were analyzed using a multiple linear regression model.
Eighty-three inpatients were screened, and 60 patients were randomized. A total of 59 subjects completed the 6-week trial. The mean subject age was 45; 68% were male; and the mean clozapine dose was 260 mg/day.
After 6 weeks of treatment, both dosages of sodium benzoate were associated with significant improvements in SANS scores compared to placebo (effect sizes of 0.72 and 0.65 for 1g and 2g/day, respectively). Sodium benzoate 2g/day was also associated with a significant improvement in PANSS total and positive scores and QOLS compared to placebo (effect sizes of 0.8 for each). There were no differences in GAF scores between subject groups. For other secondary outcomes, including depression and cognition, there were also no differences between subject groups.
There were no changes in extrapyramidal symptoms, routine laboratory studies, or ECG parameters with adjunctive sodium benzoate treatment. One patient in the sodium benzoate 2g/day group reported having difficulty concentrating, and 1 patient in the placebo group reported palpitations.
The bottom line
To the authors’ knowledge, this is the first study to demonstrate benefits of an NMDA enhancer in patients with clozapine-resistant schizophrenia. Sodium benzoate at both 1g and 2g/day was more effective than placebo in improving negative symptoms, and this medication had a favorable safety profile. Sodium benzoate 2g/d also improved total psychopathology and quality of life scores.
The authors noted the relatively small sample size and short trial duration as potential study limitations and call for additional studies of both doses of sodium benzoate in longer trials. They concluded that DAAO inhibitors may represent a novel treatment approach for patients with clozapine-resistant schizophrenia.
Dr. Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, GA, and Schizophrenia Section Editor and Editorial Board Member for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.
1. Sommer IE, Begemann MJ, Temmerman A, et al. Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull. 2012;38:1003-1011.
2. Lane HY, Lin CH, Green MJ, et al. Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry. 2013;70:1267-1275.
3. Lin C-H, Lin C-H, Chang Y-C, et al. Sodium benzoate, a D-amino acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry. 2017; doi:10.1016/j.biopsych.2017.12.006.