sodium-benzoate and Schizophrenia

The role of sodium benzoate, an NMDA receptor enhancer, in schizophrenia has been evaluated in a few clinical trials, but results are contradictory and inconclusive. The present meta-analysis has evaluated the efficacy and safety of add-on sodium benzoate for the treatment of schizophrenia.. After performing a literature search on MEDLINE/PubMed, Scopus, Cochrane databases and International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from four relevant articles. PRISMA guidelines were followed in the selection, analysis, and reporting of findings. The random-effect model was used to estimate effect size. Quality assessment was done using the risk of bias assessment tool, and sensitivity analysis was done in case of high heterogeneity.. Add-on sodium benzoate can improve positive symptoms of schizophrenia significantly (MD: -1.87; 95%CI: -3.25 to -0.48; p = 0.008) but had no significant favourable effect on negative symptoms (p = 0.84), general psychopathology (p = 0.49), and total PANSS score (p = 0.19) over the control. There was no significant improvement in GAF (p = 0.43), CGI (p = 0.58), cognitive function (p = 0.46) and quality of life (p = 0.73). Extrapyramidal symptoms were significantly higher (MD: 0.39; 95% CI:0.19-0.60; p = 0.0002) in the sodium benzoate group in comparison to the control group; however, there was no significant difference in respect to other adverse events.. Sodium benzoate can improve the positive symptoms of schizophrenia without any beneficial effect on other symptomatology, cognition, quality of life and functioning. Further studies are needed to evaluate long-term efficacy, safety and use in specific subgroups of patients.

Topics: Amino Acids; Humans; Oxidoreductases; Quality of Life; Schizophrenia; Sodium Benzoate

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.

Topics: Animals; Antipsychotic Agents; D-Amino-Acid Oxidase; Dopamine Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Molecular Targeted Therapy; Receptors, Cholinergic; Receptors, G-Protein-Coupled; Schizophrenia; Sodium Benzoate

Clozapine has been regarded as the last-line antipsychotic agent for patients with refractory schizophrenia. However, many patients remain unresponsive to clozapine, referred to as "clozapineresistant", "ultra-treatment-resistant", or remain in incurable state. There has been no convincing evidence for augmentation on clozapine so far. Novel treatments including numerous N-methyl-Daspartate (NMDA) receptor (NMDAR) enhancers, such as glycine, D-serine, D-cycloserine, and Nmethylglycine (sarcosine) failed in clinical trials. Earlier, the inhibition of D-amino acid oxidase (DAAO) that may metabolize D-amino acids and activate NMDAR has been reported to be beneficial for patients with schizophrenia receiving antipsychotics except for clozapine. A recent randomized, double-blind, placebo-controlled clinical trial found that add-on sodium benzoate, a DAAO inhibitor, improved the clinical symptoms in patients with clozapine- resistant schizophrenia, possibly through DAAO inhibition (and thereby NMDAR activation) and antioxidation as well; additionally, sodium benzoate showed no obvious side effects, indicating that the treatment is safe at doses up to 2 g per day for 6 weeks. More studies are warranted to elucidate the mechanisms of sodium benzoate for the treatment of schizophrenia and the etiology of this severe brain disease. If the finding can be reconfirmed, this approach may bring new hope for the treatment of the most refractory schizophrenia. This review summarizes the current status of clinical trials and related mechanisms for treatmentresistant, especially, clozapine-resistant schizophrenia. The importance of understanding the molecular circuit switches is also highlighted which can restore brain function in patients with schizophrenia. Future directions in developing better treatments for the most difficult to cure schizophrenia are also discussed.

Topics: Antioxidants; Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Sodium Benzoate

There is evidence that sodium benzoate (BZ) may be an effective adjunctive treatment for schizophrenia. The clinical efficacy of BZ has been investigated in chronic schizophrenia; however, the efficacy of this agent has not been studied in individuals with early psychosis.. To examine the clinical efficacy of the adjunctive use of BZ for symptoms in people with early psychosis.. Using a placebo-controlled double-masked parallel-group design, this randomized clinical trial was conducted from August 2015 to July 2018. Participants aged between 15 and 45 years experiencing early psychosis were enrolled from 5 major clinical sites in Queensland, Australia. Data analysis was conducted from October 2018 to February 2020.. Participants were randomized 1:1 (50 participants in each group) to receive 500 mg of sodium benzoate twice daily or placebo for 12 weeks.. The primary efficacy outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks. The key secondary efficacy measures were (1) the Clinical Global Impression score, (2) the Hamilton Depression Rating Scale for depression, (3) functioning as assessed by the clinician-rated Global Assessment of Function, and (4) the Assessment of Quality of Life Scale. The PANSS subscale scores and impact on selected amino acid concentrations were also assessed.. The study comprised 100 participants with a mean (SD) age of 21.4 (4.1) years, of whom 73 (73%) were male individuals. The mean (SD) baseline PANSS score was 75.3 (15.4). We found no improvement in total PANSS score in the BZ group compared with the placebo group. The end result of least-squares mean difference (SE) for total PANSS was -1.2 (2.4) (P = .63). There were no differences in any subscales of the PANSS, any secondary measures, nor any amino acid concentrations. The dose of BZ was well tolerated without any clinically significant treatment-emergent adverse event differences between BZ and placebo groups.. In this randomized clinical trial, there was no evidence that adjunctive use of 500 mg of BZ twice daily is an effective treatment for individuals with early psychosis.. anzctr.org.au Identifier: ACTRN12615000187549.

Topics: Adolescent; Adult; Antifungal Agents; Australia; Case-Control Studies; Drug Therapy, Combination; Female; Humans; Male; Placebos; Psychiatric Status Rating Scales; Psychotic Disorders; Quality of Life; Schizophrenia; Sodium Benzoate; Treatment Outcome; Young Adult

Clozapine is the last-line antipsychotic agent for refractory schizophrenia. To date, there is no convincing evidence for augmentation on clozapine. Activation of N-methyl-D-aspartate receptors, including inhibition of D-amino acid oxidase that may metabolize D-amino acids, has been reported to be beneficial for patients receiving antipsychotics other than clozapine. This study aimed to examine the efficacy and safety of a D-amino acid oxidase inhibitor, sodium benzoate, for schizophrenia patients who had poor response to clozapine.. We conducted a randomized, double-blind, placebo-controlled trial. Sixty schizophrenia inpatients that had been stabilized with clozapine were allocated into three groups for 6 weeks' add-on treatment of 1 g/day sodium benzoate, 2 g/day sodium benzoate, or placebo. The primary outcome measures were Positive and Negative Syndrome Scale (PANSS) total score, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, and Global Assessment of Functioning. Side effects and cognitive functions were also measured.. Both doses of sodium benzoate produced better improvement than placebo in the Scale for the Assessment of Negative Symptoms. The 2 g/day sodium benzoate also produced better improvement than placebo in PANSS-total score, PANSS-positive score, and Quality of Life Scale. Sodium benzoate was well tolerated without evident side effects. The changes of catalase, an antioxidant, were different among the three groups and correlated with the improvement of PANSS-total score and PANSS-positive score in the sodium benzoate group.. Sodium benzoate adjuvant therapy improved symptomatology of patients with clozapine-resistant schizophrenia. Further studies are warranted to elucidate the optimal dose and treatment duration as well as the mechanisms of sodium benzoate for clozapine-resistant schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition; D-Amino-Acid Oxidase; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Linear Models; Male; Middle Aged; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Sodium Benzoate; Taiwan; Treatment Outcome

In addition to dopaminergic hyperactivity, hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel treatment approach. To date, several trials on adjuvant NMDA-enhancing agents have revealed beneficial, but limited, efficacy for positive and negative symptoms and cognition. Another method to enhance NMDA function is to raise the levels of d-amino acids by blocking their metabolism. Sodium benzoate is a d-amino acid oxidase inhibitor.. To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia.. A randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer.. Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo.. The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment.. Benzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms-20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects.. Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for d-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Cognition Disorders; D-Amino-Acid Oxidase; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Food Preservatives; Humans; Male; Middle Aged; Neuropsychological Tests; Placebos; Psychiatric Status Rating Scales; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Sodium Benzoate; Treatment Outcome; Young Adult

Schizophrenia is a persistent psychotic disorder often accompanied by severe disability and premature mortality. New pharmacological treatments are urgently needed. Sodium benzoate, a common food preservative holds potential to be an effective, accessible treatment for schizophrenia, though the optimal dosing and mechanism of action of the compound requires further investigation.. Individuals with persistent treatment-refractory schizophrenia (n=52) will be recruited. Patients will be randomised in a 1:1:1:1 ratio to receive treatment of one of three active doses (1000, 2000 or 4000 mg daily) of sodium benzoate or placebo for 6 weeks duration. The primary outcome measurement is change in the Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measurements are PANSS subscales, Global Assessment of Function (GAF), Clinical Global Impression (CGI) and Patient Global Impression (PGI-I). Change in concentrations of peripheral amino acids (D-alanine, L-alanine, D-serine, L-serine, glycine and glutamate), plasma sodium benzoate, plasma catalase, 3-nitrotyrosine, malondialdehyde and high-sensitivity C-reactive protein (hs-CRP) will be determined as tertiary measures.. This trial seeks to build upon previous research indicating potential efficacy of sodium benzoate for reduction of symptoms in individuals with treatment-refractory schizophrenia. The trial aims to improve the understanding of the mechanism of action of the compound.. Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621000327886 . Registered on 23 March 2021.

Topics: Antipsychotic Agents; Australia; Double-Blind Method; Humans; Schizophrenia; Schizophrenia, Treatment-Resistant; Sodium Benzoate; Treatment Outcome

Cognitive decline and psychosis have been hypothesized to be mediated by N-methyl-d-aspartate receptor (NMDAR) hypofunction. Consistent with this hypothesis, chronic treatment with d-alanine, a coagonist at the glycine site of the NMDAR, leads to an improvement of positive and cognitive symptoms in schizophrenic patients. d-alanine is oxidized by d-amino acid oxidase (DAAO); thus, an inhibitor of DAAO would be expected to enhance d-alanine levels and likewise lead to desirable clinical outcomes. Sodium benzoate, on the basis of d-amino acid inhibition, was observed to display beneficial clinical effects in schizophrenic and Alzheimer's patients. However, in the clinical pilot studies using sodium benzoate, d-amino acids were not quantified to verify that sodium benzoate's efficacy was mediated through DAAO inhibition. In this study, d-alanine content was monitored in cerebral spinal fluid (CSF) of dogs treated with daily injections of d-alanine (30 mg/kg) alone and in combination with sodium benzoate (30 mg/kg) for seven consecutive days. We reasoned that the cerebral spinal fluid d-alanine quantity is reflective of the brain d-alanine levels and it would increase as a consequence of DAAO inhibition with sodium benzoate. We found that d-alanine treatment lead to maximal concentration of 7.51 μM CSF d-alanine level; however, coadministration of sodium benzoate and d-alanine did not change CSF d-alanine level beyond that of d-alanine treatment alone. As a consequence, we conclude that clinical efficacy associated with chronic administration of sodium benzoate in schizophrenic and Alzheimer's patients is likely not mediated through inhibition of DAAO.

Topics: Alanine; Alzheimer Disease; Animals; Benzoic Acid; Cognitive Dysfunction; D-Amino-Acid Oxidase; Dogs; Humans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Sodium Benzoate; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Double-Blind Method; Glutamic Acid; Humans; Oxidoreductases; Schizophrenia; Sodium Benzoate

Topics: Antipsychotic Agents; Cognition Disorders; D-Amino-Acid Oxidase; Female; Food Preservatives; Humans; Male; Schizophrenia; Sodium Benzoate

Topics: Antipsychotic Agents; Cognition Disorders; D-Amino-Acid Oxidase; Female; Food Preservatives; Humans; Male; Schizophrenia; Sodium Benzoate