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Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor

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PSY12-0872 Revision date: 2013/3/17; Text word count: 3818

A Randomized, Double-Blind, Placebo-Controlled Add-on Treatment of

Benzoate, a D-Amino Acid Oxidase Inhibitor, for Schizophrenia

Hsien-Yuan Lane, MD, PhD, Ching-Hua Lin, MD, PhD, Michael F. Green, PhD,

Gerhard Hellemann, PhD, Chih-Chia Huang, MD, PhD, Po-Wei Chen, MD,

Rene Tun, MD, Yue-Cung Chang, PhD, Guochuan E. Tsai, MD, PhD

From the Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan (Drs Lane, Huang); the Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (Drs Lane, Huang); Department of Adult Psychiatry, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan (Dr Lin); Department of Psychiatry, Taichung Chin-Ho Hospital, Taichung, Taiwan (Dr Chen), Department of Mathematics, Tamkang University, Taipei, Taiwan (Dr Chang), Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, California (Drs Tun, Tsai), Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, California. (Drs Green, Hellemann), VA Greater Los Angeles Healthcare System, Los Angeles, California (Dr Green).

Correspondence: Guochuan E. Tsai, M.D., Ph.D., Department of Psychiatry, Harbor-UCLA Medical Center, 1000 W. Carson Street, Torrance, CA 90509, U.S.A. (e-Mail: etsai@labiomed.org), 310-781-1401 (office), 310-781-1093 (fax).

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Abstract

Context— People with schizophrenia experience positive symptoms, negative symptoms, and cognitive impairments. In addition to dopaminergic hyperactivity, hypofunction of N-methyl-D-aspartate receptor (NMDAR) plays 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, including coagonists, glycine, serine, D-alanine, as well as glycine transporter I inhibitor, sarcosine and bitopertin, revealed beneficial, but limited, efficacy for positive and negative symptoms as well as cognition. Another method to enhance NMDA function is to raise the levels of D-amino acids (DAA) by blocking their metabolism. Sodium benzoate is a DAA oxidase (DAAO) inhibitor.

Objective—To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia.

Design—A randomized, double-blind, placebo-controlled trial. Setting—Two major medical centers in Taiwan.

Patients—Fifty-two patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer.

Interventions—Six weeks of add-on treatment of 1-g/d sodium benzoate or placebo. Main outcome measure: Positive and Negative Syndrome Scale (PANSS) total score.

Methods—Clinical efficacy and side-effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment.

Results—Benzoate produced an 21% improvement in PANSS total score and large effect sizes (1.16-1.69) in PANSS total and subscales, Scales for the Assessment of Negative symptoms, Global Assessment of Function, Quality of Life, Clinical Global Impression, and improvement in the neurocognition subtests as recommended by the NIMH Initiative Measurement of Treatment Research to Improve Cognition in Schizophrenia (MATRICS), including the domains of processing speed and visual learning. Benzoate was well tolerated without significant side-effects.

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Conclusions—Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for DAAO inhibition as a novel approach for new drug development for schizophrenia.

The trial was registered with the number of NCT 00960219

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Introduction

Schizophrenia is a devastating mental disorder of high morbidity and mortality. A substantial portion of patients with schizophrenia suffer from deteriorating function and lifelong illness.1 Clinical manifestation of schizophrenia consists of several domains including positive symptoms, negative symptoms, and cognitive deficits.2 The latter two have been considered as the main outcome predictors for schizophrenia.3 Unfortunately, the pharmacological therapy for negative symptom and cognitive dysfunction remains elusive. There are a considerable percentage of patients resistant or only partially responsive to available antipsychotic medications.4 Health threatening side-effects further limit their clinical use.5 There is a great need to develop new therapies with better outcome and safer side-effect profiles.

Effective treatment for schizophrenia should be based upon its neurobiological basis. However, the discovery of antipsychotic medications had been serendipitous so far. In addition to the dopaminergic system, hypofunction of N-methyl-D-aspartate subtype ionotropic glutamate receptor (NMDAR) may play a role in the pathophysiology of schizophrenia.6-9 NMDAR is critically involved in neurocognition and neurotoxicity. Plenty of studies suggest that glutamatergic system is involved in the aberrant neurotransmission of schizophrenia.7 NMDAR antagonists, such as ketamine and phencyclidine, induce a psychotic state which resembles schizophrenia more closely than dopamine agonists,6 as they cause not only positive symptoms but also negative symptoms and cognitive deficits associated with schizophrenia.

Although NMDAR antagonism accounts well for the phenomenology of schizophrenia, a critical challenge is whether it can be a pharmacotherapeutic basis for developing new treatment. Glycine was the first agonist applied to enhance NMDA function in schizophrenia.10 To date, several trials on adjuvant NMDA-enhancing agents, including the coagonists (such as glycine, D-serine, D-alanine) (see ref.11 for a review) and glycine transporter I inhibitors, sarcosine and bitopertin, revealed beneficial, but limited, efficacy on clinical symptoms.12-16 A meta-analysis of the studies revealed modest effect sizes for domains of clinical symptoms.11 The result of eight hundred subjects from 26

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studies showed that the NMDA-enhancing agents are significantly effective in most schizophrenic symptom domains, including depressive (effect size = 0.40), negative (0.38), positive symptom (0.26), and general psychopathology (0.26) symptoms. However, these small-sized studies11, 12-16 had virtually no or limited17 data on cognition. In addition, the CONSIST study18 was substantially larger in the sample size and had the design relevant for interpreting negative symptoms and cognition effects of glycine and D-cycloserine. The results were unequivocally negative.

D-serine is more potent than glycine as the neurotransmitter for the coagonist site of the NMDAR.17, 19-22 D-amino acid oxidase (DAAO), a flavoenzyme of peroxisomes existing in CNS, is responsible for degrading D-serine and D-alanine.23-25 Another alternative to enhance NMDA function is to inhibit DAAO activity and raises levels of D-amino acids. More than 30 studies demonstrated the association of DAAO and DAAO activator (G72) with schizophrenia.26, 27 The expression and activity of DAAO are increased in patients with schizophrenia.28, 29 DAAO+/- mice exhibit elevated D-serine levels and enhanced NMDA receptor function in vivo.30-32

DAAO inhibitors have been contemplated as new therapeutics for schizophrenia,33 but unsuccessful so far.34 A review34 concluded “collectively, the limited experience with a small number of structurally diverse inhibitors indicates that extensive inhibition of peripheral and central DAAO has a limited effect on brain or extracellular D-serine concentration,” “(animal) behavioral effects of DAAO inhibitors are fairly modest and inconsistent.” Therefore, instead of sole use of DAAO inhibitor or D-serine, coadministration of DAAO inhibitors and D-serine was recommended.33, 35, 36

The litmus test for DAAO inhibition therapy is a clinical trial in schizophrenia patients.37 Benzoate is a DAAO inhibitor readily available to test this novel therapeutic approach.38 Benzoic acid was discovered in the 16th century by the dry distillation of gum benzoin, first described by Nostradamus. Benzoic acid occurs naturally free and bound as benzoic acid esters in many plants and animals and is a natural constituent of many kinds of food, including milk products.39 Benzoic acid and its salts are GRAS (generally recognized as safe) food preservatives,40 widely used in manufacturing fruit

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jelly, buffer, soy-bean sauce, processed meat, etc.

To test the hypothesis that DAAO inhibition is a useful therapeutic approach for the treatment of schizophrenia, we examined the efficacy for clinical symptoms and safety of add-on treatment of sodium benzoate in patients with chronically stable schizophrenia. Due to the critical role of the NMDA system in cognition, we also hypothesized that neurocognition can be improved by DAAO inhibition.

Methods

Subjects

Patients with schizophrenia were recruited from the Department of psychiatry, China Medical University Hospital (Taichung, Taiwan) and Kaohsiung Municipal Kai-Syuan Psychiatric Hospital (Kaohsiung, Taiwan). The research protocol was approved by the Institutional Review Boards (IRB), and all patients provided written informed consent after complete description of the study.

Han Chinese patients were enrolled into this study if they: (1) were physically healthy and had all laboratory assessments (including urine/blood routine, biochemical tests, and electrocardiograph) within normal limits, (2) aged 18–65 year, (3) satisfied DSM-IV criteria for schizophrenia confirmed by the Structured Clinical Interview for DSM-IV (SCID),41, 42 (4) remained symptomatic but without clinically significant fluctuation and the antipsychotic doses were unchanged for at least 3 months and will be maintained during the period of the 6-week trial in this study, (5) had a minimum baseline total score of 60 on PANSS,43 and (6) agreed to participate in the study and provide informed consent. Exclusion criteria included DSM-IV diagnosis of mental retardation, substance (including alcohol) abuse or dependence; history of epilepsy, head trauma or CNS diseases; pregnancy or lactation; inability to follow protocol. The clinical characteristics were similar to the other study16 in chronically stable population.

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Sodium benzoate is a food preservative approved by World Health Organization, USA, European Union, and Taiwan, and is also approved for treatment of urea cycle enzymopathies. An earlier open-label, pilot dose-finding trial was performed by dosing sodium benzoate between 250 and 1000 mg/day. Three out of five patients received 1000-mg/day benzoate, and their PANSS-total scores decreased from 78 to 58, 80 to 59, and 84 to 60, respectively. The other two patients received lower dosages and did not improve. None of the five patients had evident side effects. We decided to apply 1000-mg/day in the double-blind trial.

In this 6-week, doubled-blind study, patients were randomized in a cluster of 6 subjects through a computer-generated randomization table to receive active treatment or placebo in a 1:1 ratio. Study medications were given twice daily. To ensure randomization was blind, medication was provided in coded containers with identical-appearing capsules of placebo or sodium benzoate. Patient’s compliance and safety were closely monitored by the research psychiatrists and the nursing staff.

Clinical Assessments

Clinical assessments were conducted biweekly, and cognitive function was measured at baseline and at endpoint. Primary outcome measure was total score of PANSS.43 Secondary outcome measures included PANSS subscales, Scale for the Assessment of Negative Symptoms-20 items (SANS),44 Global Assessment of Function (GAF),42 Quality of Life Scale (QOL),15, 45 Clinical Global Impression (CGI),46 Hamilton Depression Rating Scale-17 items (HDRS),47 and cognitive function (see below).

Measurements of Cognitive Function

Cognitive function was assessed using a battery of tests that were the same as, or the analogues of (due to lack of Chinese versions of some tests), the tests included in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB).48 This study was started before a commercial version of the MCCB was available in

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Chinese and can be considered similar to the Chinese MCCB. The battery assesses 7 domains: (1) speed of processing, consisting of 3 tests: Category Fluency, Trail Marking A, and WAIS-III Digit Symbol-Coding; (2) sustained attention by Continuous Performance Test;49 (3) working memory, verbal (backward digit span)50 and nonverbal (WMS-III, spatial span)51; (4) verbal learning and memory (WMS-III, word listing); (5) visual learning and memory (WMS-III, visual reproduction); (6) reasoning and problem solving (WISC-III, Maze)52, and (7) social cognition, measured by the Managing Emotions Branch of the Mayer–Salovey–Caruso Emotional Intelligence Test Version 2.0 (MSCEIT V2.0).53 The Chinese-version of the MSCEIT tasks were translated and back-translated from English to Mandarin Chinese with satisfactory reliability and validity54 and applicability.55, 56 One of the developers of the MCCB, Dr Green (a co-author), reviewed the tests utilized in this study. Each domain and composite score was standardized to a T score (mean of 50 and a standard deviation of 10) using the data from all of the study subjects at baseline.

The MCCB allows for the calculation of a general composite score (that includes all 7 domains) as well as a neurocognitive composite (that includes the 6 neurocognitive domains without social cognition). This latter score is considered to be preferable if a drug is thought to have effects that are limited to non-social domains. Because we did not have a clear expectation, we considered both the general composite and the neurocognitive composite in the analyses.

Measurements of Side Effects

Side effect assessments included Simpson-Angus Rating Scale for extra-pyramidal side-effects,57 Abnormal Involuntary Movement Scale (AIMS) for dyskinesia, and Barnes Akathisia Scale. System side effects were examined biweekly by routine physical and neurological examinations and the Udvalg for Kliniske Undersogelser (UKU) Side-effects Rating Scale.58 Routing laboratory tests, including CBC, biochemistry, urine analysis and EKG were done at screening, baseline and endpoint.

Data Analysis

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used to compare differences of nominal variables. Independent sample t-test or Mann Whitney U test was used to compare clinical characteristics in two treatment groups. Because there were repeated assessments, mean changes in clinical assessment (PANSS, SANS, CGI, GAF, QOL, HDRS) were assessed using the mixed-model repeated measure (MMRM) methods with treatment, week and treatment-week interaction as fixed effects and intercept as the only random effect; baseline value as the covariance. An autoregressive AR(1) covariance matrix was fit to the within-patient repeated measures. The MMRM analyses were performed using the SAS PROC Mixed procedure. Therapeutic effect size (Cohen's d) was used to determine the magnitude of improvement resulting from benzoate add-on treatment compared with placebo. This was calculated using the MMRM analysis model as the least squares mean (LSM) difference between benzoate and placebo divided by estimated pooled standard deviation obtained from the standard error × square root of the number of group subjects. To compare effects of add-on benzoate treatment on two major types of drugs, haloperidol and risperidone (Table 1), post-hoc MMRM analyses were used with drug-treatment-week interaction term to determine the difference.

For assessing the general cognitive ability of the patients, a general composite score (that includes all 7 domains) as well as a neurocognitive composite (that includes the 6 neurocognitive domains without social cognition) were calculated by standardizing the sum of T scores.59 MMRM, adjusted with age, gender, education, treatment and visit, was utilized to analyze the between-group difference.

For checking effects of improvements of positive and negative domains on improvement of negative symptoms and on cognitive function, multiple regression analyses were applied.

All p values were based on two-tailed tests with a significance level of 0.05.

Results

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Fifty-two patients were eligible and randomized (27 placebo; 25 benzoate) (Figure 1). Baseline demographics are summarized in Table 1. The mean age of the 52 patients was 37.3 ± 8.8 (SD) years, the mean age at illness onset was 22.9 ± 6.1 years, the mean number of hospitalization was 3.2 ± 3.0, the mean education duration was 10.8 ± 2.2 years, and mean body weight was 66.4 ± 12.1 kg. There was no significant difference between the two treatment groups in terms of gender, age, age at illness onset, number of hospitalization, education level, body weight, and the antipsychotic equivalent dose60 which the subjects had been stabilized on (P > 0.05).

PANSS

The mean ± SD scores of the two groups of patients are shown in Table 2. At week 0 (baseline), there were no significant differences between the two groups in PANSS total score (t = 0.82, P = 0.42), positive subscale score (t = 0.17, P = 0.87), negative subscale score (t = 0.84, P = 0.40), and general psychopathology subscale score (t = 0.80, P = 0.43).

After treatment, benzoate produced greater improvement in total, positive, PANSS-negative, and PANSS-general psychopathology than placebo therapy (all P values < 0.001; effect sizes (ES) = 1.16-1.69) (Table 2). In addition, MMRM analyses for the measurements at the endpoint and for the patients who completed the 6 weeks of treatment both showed that benzoate surpassed placebo in all outcome measures of Table 2 (not shown). Supplemental Table 1 compares percentage of patients who improved to various degrees in terms of PANSS-total score at each visit in the two treatment groups.

Post-hoc MMRM analyses revealed that add-on benzoate treatment was effective on two major types of drugs, risperidone and haloperidol. Among risperidone-treated patients, benzoate treatment was significantly better than placebo in scores of PANSS-total (score reduction from 81.5 to 71.0 for benzoate group, from 83.9 to 79.4 for placebo group, P = 0.0002), positive, PANSS-negative, but not PANSS-general (not shown). Among haloperidol-treated patients, benzoate treatment was also significantly better than placebo in scores of PANSS-total (score reduction from

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89.6 to 69.3 for benzoate group, from 88.8 to 78.7 for placebo group, P = 0.0014), PANSS-positive, PANSS-negative, and PANSS-general (not shown).

SANS, GAF, QOL, CGI, and HDRS

The mean ± SD scores of the assessments other than PANSS are shown in Table 3. At week 0 (baseline), there were no significant differences between the two groups in SANS total score (t = 1.13, P = 0.26), GAF score (t = 0.36, P = 0.72), QOL score (t = 0.42, P = 0.68), CGI score (t = 0.42, P = 0.68), and HDRS score (t = 0.57, P = 0.57).

After treatment, benzoate produced greater improvement in SANS, GAF, QOL, CGI, and HDRS than placebo therapy (all P values < 0.001; ES = 0.74-1.56) (Table 3). In addition, MMRM analyses for the measurements in the endpoint and for the completers both showed that benzoate surpassed placebo in all the outcome measures of Table 3 (not shown).

Post-hoc MMRM analyses revealed that add-on benzoate treatment was effective on two major types of drugs, risperidone and haloperidol. Among risperidone-treated patients, benzoate treatment was significantly better than placebo in scores of SANS, GAF, QOL, CGI, but not HDRS (not shown). Among haloperidol-treated patients, benzoate treatment was also significantly better than placebo in scores of SANS, GAF, QOL, and HDRS, but not CGI (not shown).

For checking the effect of improvement in positive symptoms on improvement in negative symptoms, regression analysis which showed that score changes in PANSS-positive had marginal effect on score change in SANS after benzoate treatment (B = 0.40, SE = 0.71, t = 1.99, P = 0.059).

Cognitive Battery

After 6-weeks treatment, the between-group difference in the overall neurocognitive composite was significant after treatment (P = 0.035, ES = 0.67 ), but the overall composite score was not significant (Table 4). The benzoate group was better in speed of processing (P = 0.026, ES = 0.65) and visual

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learning and memory (P = 0.019, ES= 0.70).

To explore the effect of improvement in positive and negative symptoms on improvement in neurocognition after benzoate treatment, multiple regression analysis showed that score changes in PANSS-positive (B = 0.20, SE = 0.67, t = 0.30, P = 0.77) and SANS (B = 0.27, SE = 0.20, t = 1.40, P = 0.18) had no significant effect on change of neurocognitive composite scores.

Side Effects

All the two treatment groups had minimal EPS at the beginning of the study. The baseline score of Simpson-Angus Rating Scale was 1.0 ± 2.0 in the placebo group and 1.3 ± 2.3 in the benzoate group, the AIMS score was 0.9 ± 2.0 in the placebo group and 1.0 ± 2.2 in the benzoate group, and the Barnes Akathesia Scale score was 0.0 ± 0.3 in the placebo group and 0.1 ± 0.3 in the benzoate group, respectively. There were no significant differences between the two groups in Simpson-Angus (P = 0.59), AIMS (P = 0.85) and Barnes Akathesia score (P = 0.58).

At endpoint, the severity of EPS remained minimal and did not have significant differences between the groups. The mean of Simpson-Angus score at endpoint was 0.9 ± 1.8 in the placebo group and 1.3 ± 2.2 in benzoate group (P = 0.64), AIMS score was 0.5 ± 1.5 in the placebo group and 0. 5 ± 1.6 in the benzoate group (P = 0.98), and Barnes Akathesia score was 0.0 ± 0.2 in the placebo group and 0.0 ± 0.2 in the benzoate group (P = 0.54).

Treatment-emergent adverse events other than EPS in the placebo group included weight gain (N = 2), insomnia (N = 1), tremor (N = 1), constipation (N = 1), fatigue (N = 1), and salivation (N = 1); the benzoate group included weight gain (N = 1), insomnia (N = 2) and tachycardia (N = 1). These systemic side effects were all mild and brief, not warranting medical treatment. They were likely coincidental observations.

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and were all within the normal ranges (data not shown). No dropout was due to side-effects.

Discussion

The present study demonstrated that sodium benzoate, a DAAO inhibitor, can improve a wide variety of symptom domains of schizophrenia. After6 weeks of benzoate treatment, PANSS-total scores decreased by a mean of 21%. This decrement would be less than clinically significant for patients with acute exacerbation.61 However, it is beneficial for the patients with high level of symptoms who

had been stabilized with antipsychotics for 3 months or longer in this study; as reflected by the improvement of CGI severity scores from 4.6 to 3.5. The effect sizes observed (Tables 2, 3) are larger than other trials of NMDA-enhancing agents, mostly < 0.4.11 The large effect sizes could be

due to the good CNS bioavailability of benzoate (vs. the other small polar amino acids and DAAO inhibitors tested before) to raise the DAA pool by the inhibition of DAAO. It is encouraging that benzoate treatment improves those who are still highly symptomatic despite treatment with antipsychotics. It remains to be determined whether the treatment is good for the whole spectrum of symptom severity.

In addition to clinical symptoms, neurocognition was improved. NMDAR regulates synaptic plasticity, memory, and cognition. Attenuation of NMDAR-mediated neurotransmission can result in loss of neuronal plasticity and cognitive deficits. Hypo-NMDA function induced by NMDA receptor antagonists is neurotoxic, likely accounting for deterioration and brain atrophy.62 NMDA-enhancing agents are supposed to work as not only antipsychotics but also cognitive enhancers in schizophrenia patients.8 Consistently, NMDA-enhancing agents can benefit cognitive function in animal models of schizophrenia.63 In the current study, benzoate treatment improved neurocognition in general and specifically in processing speed and visual memory (Table 4). The improvement was neither large in terms of effect size nor comprehensive across domains, particularly if adjustment for multiple comparisons were conducted. Longer duration and/or higher dose of treatment may facilitate and

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solidify the gain of function more substantially.

Deficits in cognitive functions have been considered as core symptoms and outcome predictors of schizophrenia, more than hallucinations or delusions.3, 45 Nevertheless, preserving and even enhancing cognitive functioning have recently been recognized as a critical therapeutic goal because the cognitive effects of typical and atypical antipsychotics are negligible at best.48 The current study is the first double-blind one which showed potential efficacy of an NMDA-enhancing agent in MATRICS-like battery, also lending support to a recent open-label trial64 which showed that 4 weeks of adjunctive treatment with high-dose D-serine improved MATRICS scores. There currently is no cognition enhancer approved for schizophrenia. Our findings in neurocognition do point to a novel approach to reach the goal of improving cognition.

Benzoate improved symptom domains and neurocognition globally in the present study. For considering the issue of pseudospecificity65,66 and to explore whether the improvement in neurocognitive function was secondary to improvement in other domains,67 multiple regression analysis showed that improvement in the positive and negative symptoms contributed little to the improvement of neurocognition. We did not study the influence of extrapyramidal side effect because there was no change of the extrapyramidal side effect by the benzoate treatment. Neither were the depressive symptoms assessed due to the low level of HAMD scores (Table 3). Nonetheless, any add-on therapy that beats placebo may be related to counteracting adverse effects of antipsychotic drugs. Future study with a prospective design and a larger sample size is needed to clarify this issue. 67

Given the fact that D2 receptor antagonism is the prominent pharmacological property shared by typical and most atypical antipsychotic medications, whether there is an interaction between D2-dopamine receptor antagonism and facilitation of endogenous NMDA receptor-mediated neurotransmission68 that contributes to the therapeutic effect in schizophrenia, deserves further neurophysiologcal and pharmacodynamic studies.68 In addition, sodium benzoate also has

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anti-inflammatory activity and up-regulates a neuroprotective protein, DJ-1 (PARK7), in astrocytes and neurons.69 Nevertheless, it is unclear how these mechanisms may contribute to a therapeutic effect in a short-term trial.

The toxicology of benzoate administration had been studied extensively with good safety margin.39 Benzoic acid and its salts are known and used as food preservatives represented by the E-numbers E210-213. Concentration as a preservative is limited by the FDA in the U.S. to 0.1% by weight. WHO suggest a provisional tolerable intake of 5 mg/kg/day.39 Sodium benzoate is also an active ingredient of Ammonul, which is a therapy for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle. The recommended maintenance dose of sodium benzoate is 5.5 g (i.v.)/m2/24 hours for patients with body weight > 20 kg (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020645s008lbl.pdf). For a person with 65 kg and 170 cm, the body surface area is 1.75 m2 and the daily dose of 9.625 g is much higher than the dose, 1 g per day, used in the current study.

Several concerns were raised regarding the safety issue of benzoate. Benzoic acid and its salts may react with ascorbic acid to form benzene, a known carcinogen. However, FDA did not confirm the presence of benzene in their survey of beverage, of which both benzoate and ascorbic acid existed (http://www.fda.gov/Food/FoodborneIllnessContaminants/ChemicalContaminants/ucm055131.htm). Nevertheless, we advise that benzoate and high content ascorbic acid should not be taken at the same time. In addition, it was suggested that when certain artificial colors are paired with benzoate, hyperactive behaviors may result.70 However, combination formulations were tested; it is unclear whether benzoate or the artificial colors is the culprit.71 In the adult population, we did not observe hyperactivity or other side effects which raise safety concern in the short-term study.

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and neurocognition. DAAO inhibition, as exampled by benzoate treatment, represents a novel therapeutic target to develop new pharmacotherapy for the clinical efficacy and improvement of life functioning in schizophrenia given it shows preliminary findings of addressing both the symptom domains and neurocognition. Further larger-sized, proof-of-principle studies are necessary to substantiate the validity of this novel therapeutic approach.

Acknowledgements

This work was supported in part by the National Science Council, Taiwan (NSC-97-2314-B-039-006-MY3, NSC-99-2314-B-280-001-MY3, NSC-99-2811-B-039-005, and NSC-100-2627-B-039-001, NSC-101-2314-B-039-030-MY3, and NSC-101-2627-B-039-001), National Health Research Institutes, Taiwan (NHRI-EX-101-9904NI), Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004), and China Medical University Hospital, Taiwan (CMU 101-AWARD-13, DMR-99-153 and DMR-99-117). The statistical analysis was done by Y-C Chang. Dr. Lane who is independent of any

commercial funder had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Role of sponsors

The sponsors were not involved in the "design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript."

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Figure legend

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Table 1. Demographic, Clinical and Antipsychotic Characteristics of the Patients Assigned to Placebo or Sodium Benzoate Treatment

Treatment Groups Placebo (n = 27) Benzoate (n = 25) p Value Demographics Gender, female, n (%) 12 (44.4) 14 (56.0) 0.58 a

Age, year, mean (SD) 36.3 (7.9) 38.4 (9.7) 0.39 b

Age at illness onset, year, mean (SD) 23.4 (6.2) 22.2 (6.0) 0.40 c No. of hospitalizations, mean (SD) 3.1 (2.8) 3.3 (3.2) 0.91c

Education, year, mean (SD) 10.5 (2.0) 11.1 (2.3) 0.32 b

Body weight, kg, mean (SD) 64.4 (12.4) 68.6 (11.7) 0.21 b

No. of patients using typical vs. atypical antipsychotics 13:14 14:11 0.59 a Amisulpride Chlorpromazine Flupenthixol Haloperidol Quetiapine Risperidone Sulpiride Ziprasidone Zotepine 1 1 2 9 2 7 1 0 4 2 4 0 9 1 6 1 1 1 0.58 a

Chlorpromazine equivalent dose, mg/day d 561.3 (308.0) 587.5 (449.3) 0.50 c a Fisher's Exact test; b independent t-test; c Mann-Whitney U test

d Among the 52 patients, 27 received concurrent typical antipsychotics and the other 25 received concurrent atypical antipsychotics. Of the 27 using typical agents, 13 were randomized to the placebo

group and their mean chlorpromazine equivalent dose (Gardner et al. 2010) was 660.0  409.9

mg/day; the other 14 were allocated to the benzoate group and their mean chlorpromazine equivalent

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equivalency (Mann-Whitney U test, P=0.90).

Of the other 25 who received concurrent atypical antipsychotics, 14 were randomized to the placebo

group and their mean olanzapine equivalent dose (Gardner et al. 2010) was 15.7  4.2 mg/day; the

other 11 received benzoate treatment and their mean olanzapine equivalent dose was 13.5  4.9

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Table 2. Clinical Measures of Positive and Negative Syndrome Scale (PANSS) over the Six-week Treatment *

Scale Treatment Group Baseline Mean ± SD Week 2 Mean ± SD Week 4 Mean ± SD Week 6 Mean ± SD Difference in Score Changing Rate vs. Placebo, Mean ± SE

t Value P Value Effect Size

(Cohen’s d) Total Placebo 87.3 ± 8.6 (N=27) 84.3 ± 10.3 (N=27) 83.1 ± 9.6 (N=24) 81.4 ± 10.0 (N=23) -2.1 ± 0.3 -7.60 <0.001 1.53 Benzoate 90.3 ± 16.3 (N=25) 82.4 ± 13.9 (N=25) 76.5 ± 12.8 (N=25) 71.7 ± 14.3 (N=24) Subscale Positive Placebo 20.4 ± 4.4 20.0 ± 4.7 19.5 ± 4.2 18.8 ± 4.1 -0.6 ± 0.1 -7.40 <0.001 1.69 Benzoate 20.6 ± 3.6 18.4 ± 3.4 17.0 ± 3.3 15.3 ± 3.4 Negative Placebo 24.8 ± 3.6 23.9 ±3.9 23.4 ± 3.4 23.1 ± 3.6 -0.6 ± 0.1 -6.20 <0.001 1.19 Benzoate 26.1 ± 6.9 24.0 ± 6.1 22.1 ± 5.6 20.8 ± 6.0 General psychopathology Placebo 42.2 ± 4.7 40.4 ± 5.3 40.3 ± 5.2 39.6 ± 5.7 -0.9 ± 0.2 -5.69 <0.001 1.16 Benzoate 43.6 ± 8.2 40.0 ± 7.0 37.4 ± 6.5 35.7 ± 7.2

* Mixed-model repeated measure (MMRM) methods with treatment, week and treatment-week interaction as fixed effects and intercept as random effect; baseline value as the covariance. An autoregressive AR(1) covariance matrix was fit to the within-patient repeated measures. P values were based on two-tailed tests. Degree of freedom for all

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Table 3. Clinical Measures of SANS, CGI, GAF, QOL and HDRS over the Six-week Treatment *

Scale Treatment Group BaselineMean ± SD Week 2Mean ± SD Week 4Mean ± SD Week 6Mean ± SD Difference in Score Changing Rate vs.

Placebo, Mean ± SE t Value P Value Effect Size(Cohen’s d) SANS Placebo 55.0 ± 13.1 (N=27) 52.6 ± 12.8 (27) 52.0 ± 12.4 (24) 51.3 ± 12.4 (23) -2.0 ± 0.2 -8.01 <0.001 1.56 Benzoate 59.2 ± 14.2 (N=25) 52.5 ± 13.9 (25) 46.7 ± 13.4 (25) 42.5 ± 14.6 (24) GAF Placebo 41.4 ± 7.8 42.5 ± 7.9 43.5 ± 7.9 45.2 ± 8.3 1.1 ±0.2 6.07 <0.001 1.20 Benzoate 40.6 ± 8.6 44.4 ± 8.4 48.0 ± 8.4 51.5 ± 8.7 QOL Placebo 16.4 ± 7.4 18.2 ± 7.5 19.5 ± 7.2 20.8 ± 6.8 1.1±0.2 6.88 <0.001 1.50 Benzoate 15.4 ±10.0 19.6 ± 9.8 23.3 ± 9.2 26.8 ±10.9 CGI Placebo 4.5 ± 0.8 4.4 ± 0.8 4.4 ± 0.8 4.3 ± 0.8 -0.1± 0.02 -4.90 <0.001 1.21 Benzoate 4.6 ± 0.6 4.1 ± 0.8 3.6 ± 0.7 3.5 ± 0.7 HDRS Placebo 6.3 ± 4.0 5.7 ± 3.8 5.6 ± 4.2 5.2 ± 3.5 -0.3 ± 0.1 -3.55 <0.001 0.74 Benzoate 7.1 ± 5.4 5.3 ± 4.7 4.4 ± 3.8 3.8 ± 3.1

Abbreviations : SANS, Scale for the Assessment of Negative Symptoms-20 items; GAF, Global Assessment of Function; QOL, Quality of Life Scale; CGI, Clinical Global Impression - severity of illness; HDRS, Hamilton Depression Rating Scale-17 items.

* Mixed-model repeated measure (MMRM) methods with treatment, week and treatment-week interaction as fixed effects and intercept as random effect; baseline value as the covariance. An autoregressive AR(1) covariance matrix was fit to the within-patient repeated measures. P values were based on two-tailed tests. Degree of freedom for all

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Table 4. Cognitive Measures with 7 domains recommended by Measurement and Treatment Research to Improve Cognition in Schizophrenia

(MATRICS) Committee over the Six-week Treatment *

Cognitive Domain Treatment Group (N) Baseline Mean (SD) Endpoint Mean (SD) Least Squares Mean Change (SE) [Benzoate-placebo]

t Value P Valuea,b Effect Size

(Cohen’s d) Speed of processing Placebo (25) 49.3 (9.2) 50.0 (8.1)

3.2 (1.4) 2.30 0.026 0.65

Benzoate (22) 50.8 (11.0) 54.7 (13.9) Attention / Vigilance Placebo (26) 50.2 (10.5) 50.2 (10.2)

2.3 (2.5) 0.93 0.36 0.27

Benzoate (23) 49.8 (9.6) 52.1 (7.9) Working memory Placebo (23) 47.2 (7.1) 47.6 (7.9)

0.2 (1.9) 0.12 0.91 0.036

Benzoate (22) 53.0 (11.8) 53.7 (12.5) Verbal learning and memory Placebo (26) 49.2 (9.1) 54.1 (9.4)

3.4 (2.5) 1.37 0.18 0.39

Benzoate (23) 51.0 (11.1) 59.4 (12.4) Visual learning and memory Placebo (25) 49.0 (8.0) 52.9 (10.3)

6.3 (2.6) 2.44 0.019 0.70

Benzoate (23) 51.1 (11.9) 61.2 (14.2) Reasoning and problem solving Placebo (26) 50.2 (9.9) 55.4 (8.5)

1.0 (2.3) 0.43 0.67 0.12

Benzoate (23) 49.8 (10.4) 56.1 (8.0) Social cognition Placebo (20) 46.9 (6.5) 50.0 (9.6)

-0.1 (3.8) -0.02 0.98 <0.01

Benzoate (19) 53.3 (12.0) 56.2 (11.3) Global composite score † Placebo (17) 47.4 (8.6) 50.9 (8.6)

2.9 (1.9) 1.49 0.15 0.51

Benzoate (17) 52.6 (10.9) 59.0 (12.3) Neurocognitive composite ‡ Placebo (22) 48.9 (9.6) 52.8 (9.6)

3.7 (1.7) 2.19 0.035 0.67

Benzoate (20) 51.3 (10.5) 58.9 (12.8)

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†For assessing the global composite, an overall composite T score that included all 7 domains was calculated by standardizing the sum of T scores.

‡For assessing the neurocognitive ability, an overall composite T score that included all 6 neurocognitive domains, excluding social cognition, was calculated by standardizing the sum of T scores.

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數據

Table 1. Demographic, Clinical and Antipsychotic Characteristics of the Patients Assigned to  Placebo or Sodium Benzoate Treatment
Table 2. Clinical Measures of Positive and Negative Syndrome Scale (PANSS) over the Six-week Treatment *
Table 3. Clinical Measures of SANS, CGI, GAF, QOL and HDRS over the Six-week Treatment *
Table 4. Cognitive Measures with 7 domains recommended by Measurement and Treatment Research to Improve Cognition in Schizophrenia  (MATRICS) Committee over the Six-week Treatment *

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