Background
Small molecules that enhance the N-methyl-D-aspartate (NMDA) neurotransmission have been shown to be beneficial as adjuvant therapy for schizophrenia. Among these compounds, sarcosine (a glycine transporter-I inhibitor), when added to an existing regimen of antipsychotic drugs, has shown its efficacy for both chronically stable and acutely ill patients. However, the efficacy of these agents as a primary antipsychotic agent has not yet been demonstrated.
Methods
Twenty acutely symptomatic drug-free patients with schizophrenia were randomly assigned under double-blind conditions to receive a 6-week trial of 2 g or 1 g of sarcosine daily.
Results
Overall, patients in the 2-g group were more likely to respond as defined by a 20% or more reduction of the Positive and Negative Syndrome Scale total score, particularly among antipsychotic-naïve patients. However, there was no significant between-group difference in the sarcosine dose × time interaction analysis. Both doses were well tolerated with minimal side effects.
Conclusions
Although patients receiving the 2-g daily dose were more likely to respond, it requires further clarification whether the effect is limited to the antipsychotic-naive population. Future placebo- or active-controlled, larger-sized studies are needed to fully assess sarcosine’s effects. (Sarcosine [N-methylglycine] Monotherapy for Schizophrenia; http://www.clinicaltrials.gov/ct/show/NCT00328276?order=1; NCT00328276)
Key Words
N-methyl-D-aspartate (NMDA) hypofunction has been implicated in its pathophysiology (
1
, 2
). The most compelling link between NMDA neurotransmission and schizophrenia concerns the mechanism of action of the psychotomimetic drug phencyclidine and the dissociative anesthetic ketamine, both being NMDA antagonists (for reviews, 2
, 3
, 4
). These NMDA antagonists cause not only psychotic symptoms but also negative symptoms and cognitive deficits (4
, 5
).Glutamate and glycine (or D-serine) serve as co-agonists at the NMDA receptor (
6
). Deutsch et al. (7
) first proposed glycinergic interventions at the strychnine-insensitive glycine binding site on the NMDA receptor complex (NMDA-glycine site) for the treatment of schizophrenia. Several studies have demonstrated the clinical benefits of treating schizophrenia with NMDA-glycine full agonists, including D-serine (8
, 9
), glycine (10
), and D-alanine (11
) or the partial agonist D-cycloserine (12
, 13
, 14
). Another approach to enhance NMDA neurotransmission is to block the reuptake of glycine through the glycine transporter-1 (GlyT-1). Sarcosine, an endogenous Gly-T1 inhibitor, has been shown to have clinical efficacy when added to conventional or atypical antipsychotic drugs (15
, 16
).It remains unclear whether NMDA enhancers alone can serve as antipsychotic drugs for schizophrenia (
12
). Preclinical data suggest that sarcosine modulation for NMDA neurotransmission can be influenced by genetic factors and environmental stress (17
). Because acute exacerbations of schizophrenia are often associated with stress, it is important to test the clinical efficacy of sarcosine during the acute phase. A recent study indicates that sarcosine rather than D-serine can augment atypical antipsychotic drugs’ benefits for acutely ill patients with schizophrenia (16
). We thus investigated the efficacy and safety of sarcosine as the sole antipsychotic agent for acute schizophrenia by comparing the effective dose of 2 g/day versus a lower dose of 1 g/day (15
).Methods and Materials
Participants
The research protocol was approved by the institutional review board. All newly hospitalized patients with schizophrenia with an acute exacerbation of their psychosis and demonstrating deterioration in self-care or social function were screened by the research psychiatrists. To be eligible for the trial, they needed to be fully capable of comprehending the trial’s purpose, procedure and treatment, risks and possible benefits, alternative treatments, and their right to refuse. Patient’s competence to consent was determined by his/her own psychiatrist. We recruited only competent subjects who gave written informed consent after they completely understood the details of the study.
Subjects, ages 18–60 years, who were physically and neurologically healthy and had normal laboratory assessments (including urine/blood routine, biochemical tests, and electrocardiograph) were eligible to enter the study. They underwent interview with the Structured Clinical Interview for DSM-IV (
18
) and had to satisfy DSM-IV criteria for schizophrenia (19
), had a minimum baseline total score of 60 on the Positive and Negative Syndrome Scale (PANSS) (20
), had no other DSM-IV Axis I diagnosis, had not taken antipsychotic drugs for at least 7 days, and had not received depot antipsychotic drugs for the preceding 3 months.Twenty Han Taiwanese schizophrenia patients were randomly assigned under double-blind conditions to receive a 6-week trial of 1 g or 2 g of sarcosine monotherapy daily. Because a substantial portion of subjects were antipsychotic-naïve, randomization was stratified by their status of antipsychotic exposure (naïve vs. non-naïve). To ensure concealment of the randomization assignment, the two doses of sarcosine were provided in coded containers containing an equal number of identical-appearing capsules. The sequence was concealed until interventions were assigned. The research pharmacist implemented random allocation. Patients, caregivers, and investigators (except the investigational pharmacist) were all masked to the assignment. Patient’s compliance and safety were closely monitored by the research psychiatrists and the nursing staff. Lorazepam was allowed for insomnia or agitation. Benztropine was allowed for extrapyramidal symptoms. No other centrally acting drugs were used. All patients took medication under the supervision of medical/nursing staff.
Assessments
All patients received evaluation at baseline and at the end of every 2-week period for 6 weeks. The primary outcome measures were the score changing rates in PANSS, Scales for the Assessment of Negative Symptoms (SANS) (
21
), and inpatient Quality of Life scales (22
). Treatment response was defined as a 20% or more reduction of the PANSS total score. Of the 21 items on the Quality of Life scale, 10 (social activity, social initiatives, social withdrawal, sense of purpose, motivation, curiosity, anhedonia, aimless inactivity, capacity for empathy, emotional interaction) were selected for the inpatient setting.Side-effect assessments included the Simpson-Angus Rating Scale (
23
) for extrapyramidal side-effects, the Abnormal Involuntary Movement Scale (AIMS) (24
), and the Barnes Akathesia Scale (25
). Systemic side effects were evaluated by means of routine physical and neurological examinations and laboratory tests and reviewed by applying the Udvalg for Kliniske Undersogelser (UKU) Side-effects Rating Scale (26
).Data Analysis
Demographic characteristics and response rates between groups were compared by Student two-sample t test (or Mann-Whitney Tests where appropriate) for continuous variables and by χ2 tests (or Fisher’s Exact tests where appropriate) for categorical variables.
We applied multiple linear regression with the generalized estimating equation (GEE) method (
27
) for the dose × time interaction analysis, which allowed controlling for baseline psychopathology. The results of GEE models were analyzed by the SAS/STAT (SAS Institute, Cary, North Carolina) “PROC GENMOD” procedure with AR (autoregressive) (1
) working correlation structure with the marginal model instead of the mixed effect model.Finally, 4 of 20 patients terminated early (see Results); they were still included in the GEE analysis although this slightly violated the “missing at random” requirement of the GEE method. Accordingly, no imputation for the incomplete data was used. All hypothesis tests were two-sided.
Results
Twenty patients entered this study. Eleven were assigned into the 2-g group and the remaining 9 into the 1-g group. Sixteen patients completed the 6-week treatment. Two patients (one from each group) dropped out after week 2 and another two (both from the 1-g group) discontinued after week 4, because of consent withdrawal due to unsatisfactory response. Among the four dropout patients (one man, three women; mean age 33 [range: 26–47]), all PANSS-total score changes were smaller than 20%.
Efficacy Between the Two Dose Groups
Patients in the two dosage groups were comparable in terms of demographic variables, age of onset, duration of illness, antipsychotic-naïve status, and ratio of paranoid versus nonparanoid subtype (Table 1). Baseline scores of all six rating scales were similar in the two groups (Table 2) (all p values > .05, two-sample t test with df = 18).
Table 1Characteristics of Patients With Schizophrenia Assigned to 2 g or 1 g of Sarcosine Treatment
| All Patients | Drug-Naive Patients | Non-Naive Patients | ||||
|---|---|---|---|---|---|---|
| 2 g | 1 g | 2 g | 1 g | 2 g | 1 g | |
| Gender (female/male) | 8/3 | 7/2 | 3/3 | 5/0 | 5/0 | 2/2 |
| Age (yr) | 34.3 (11.2) | 31.3 (10.4) | 32.0 (10.1) | 29.8 (9.0) | 37.0 (13.1) | 33.3 (13.2) |
| Age of Onset (yr) | 24.9 (11.4) | 25.0 (7.5) | 26.3 (12.2) | 27.8 (8.7) | 23.2 (11.4) | 21.5 (4.5) |
| Duration of Illness (yr) | 8.5 (8.4) | 6.4 (8.4) | 4.6 (3.6) | 1.9 (1.6) | 13.4 (10.4) | 12.1 (10.3) |
| Drug-Naïve/Non-Naïve | 6/5 | 5/4 | ||||
| Body Weight (kg) | 60.6 (11.0) | 56.2 (9.6) | 65.3 (11.9) | 52.7 (7.9) | 55.0 (7.5) | 60.6 (10.8) |
| Education (yr) | 11.5 (2.8) | 12.3 (2.3) | 11.0 (3.1) | 12.8 (2.3) | 12.0 (2.7) | 11.8 (2.6) |
| Subtype | ||||||
| Paranoid | 6 | 4 | 3 | 3 | 3 | 1 |
| Disorganized | 3 | 2 | 2 | 1 | 1 | 1 |
| Undifferentiated | 2 | 3 | 1 | 1 | 1 | 2 |
| Smoker/Non-Smoker | 1/10 | 0/9 | 1/5 | 0/5 | 0/5 | 0/4 |
SDs in parentheses.
a Between dose group differences were assessed by two-tailed Mann-Whitney test (for duration of illness), two-sample t test (df = 18, for other continuous variables), or Fisher Exact test (for gender, drug-naïve status, and ratio of paranoid vs. nonparanoid subtype), and all p values > .05.
b Onset of prodrome with behavioral or personality change.
c Smoker, smoking ≥ 10 cigarettes/day; non-smoker, smoking 0 cigarettes/day.
Table 2Clinical Measures for the 6-Week Sarcosine Treatment
| Scale | Treatment Group | Baseline | Week 2 | Week 4 | End Point | Between-Group Difference in Score Changing Rate, mean (SE) | 95% CI | Z (p) |
|---|---|---|---|---|---|---|---|---|
| Primary Outcome Measures | ||||||||
| PANSS-Total | 1 g | 101.9 (18.8) | 100.9 (18.2) | 96.1 (20.0) | 94.9 (19.7) | .22 (.16) | −.10, .54 | 1.37 (.17) |
| 2 g | 108.3 (20.8) | 95.9 (16.1) | 96.4 (19.5) | 91.2 (18.4) | ||||
| SANS | 1 g | 65.8 (26.6) | 66.7 (26.6) | 64.5 (26.2) | 63.8 (23.2) | .20 (.16) | .11, .51 | 1.26 (.21) |
| 2 g | 78.3 (27.5) | 70.3 (22.1) | 71.6 (21.7) | 66.9 (23.7) | ||||
| Quality of life | 1 g | 24.4 (8.3) | 22.4 (7.2) | 22.9 (8.4) | 24.3 (8.5) | −.11 (.09) | .28, .07 | −1.21 (.23) |
| 2 g | 16.5 (9.8) | 20.1 (8.8) | 20.4 (8.3) | 21.1 (9.3) | ||||
| Subscale Measures | ||||||||
| PANSS-positive | 1 g | 25.9 (2.2) | 25.1 (3.1) | 24.0 (4.3) | 23.6 (4.5) | .02 (.06) | .09, .14 | .41 (.68) |
| 2 g | 26.5 (4.4) | 24.2 (5.4) | 24.3 (6.1) | 22.8 (5.9) | ||||
| PANSS-negative | 1 g | 26.7 (7.6) | 26.4 (7.0) | 24.8 (7.6) | 25.1 (7.3) | .09 (.06) | .03, .21 | 1.40 (.16) |
| 2 g | 29.2 (9.2) | 25.5 (7.7) | 25.8 (7.5) | 23.7 (8.0) | ||||
| PANSS-general | 1 g | 49.3 (10.1) | 49.3 (10.6) | 47.4 (10.3) | 46.2 (10.2) | .11 (.07) | .03, .26 | 1.57 (.12) |
| 2 g | 52.5 (10.1) | 46.2 (7.9) | 46.3 (9.6) | 44.6 (8.8) |
SDs in parentheses. CI, confidence interval; PANSS, Positive and Negative Syndrome Rating Scale; 1 g, 1-g–treated patients; 2 g, 2-g–treated patients; SANS, Scale for the Assessment of Negative Symptoms.
a Dose-treatment duration (day) interaction effect between two dose groups (1 g vs. 2 g) using multiple linear regression with the generalized estimating equation method controlling for baseline psychopathology.
For comparing the rate of score change between groups, the interaction of treatment duration and sarcosine dose was examined. Overall, there was no significant effect of sarcosine dose (Table 2). However, the 2-g high-dose group was more likely to respond than the 1-g low-dose group (5 of 11 [45%] vs. 0 of 9 [0%], p = .038, Fisher Exact test). In addition, drug-naïve and non-naïve patients responded differently; all of the five responders were drug-naïve patients, whereas none of the non-naïve patients responded (p = .038, Fisher Exact test).
Adverse Effects
Both doses were well tolerated. No extrapyramidal side-effects were noted at baseline and during the study period. No patient needed benztropine. Treatment-emergent adverse events in the 2-g group included insomnia (n = 4), weight gain by 1–2 kg (n = 2), sedation (n = 1), and constipation (n = 1); the low-dose group included insomnia (n = 2), weight gain by 2 kg (n = 1), and fatigability (n = 1). These systemic side-effects were all mild and brief. They were likely coincidental observations. The routine blood cell count, chemistry, urinalysis, and electrocardiogram after sarcosine treatment remained unchanged and were all within the normal ranges (data not shown). The mean doses of lorazepam did not differ significantly between the two dose groups at each assessment during treatment with a mean range of .9–1.3 mg/day.
Discussion
In this study, there was no significant effect of sarcosine dose, although there were more patients showing a clinically significant response in the 2-g group. However, this finding was limited to those with no prior antipsychotic exposure. Owing to the small sample size, multiple confounding factors were not evaluated in this sample. Therefore, caution should be exerted in interpreting the data in this small study. It requires further clarification whether clinical response to this medication is in fact limited to the antipsychotic-naive population or patients with young age.
Future placebo- or active-controlled, larger-sized studies are needed to fully assess sarcosine’s effects. If confirmed, the findings strengthen the NMDA hypofunction hypothesis of schizophrenia (
2
, 4
, 5
) and GlyT-1 as a target for the treatment of schizophrenia (20
, 21
).Preliminary data have shown that oral glycine might have some efficacy in treating symptoms of the schizophrenia prodrome (
28
), which is consistent with our finding that most antipsychotic-naïve patients responded to 2-g/day sarcosine treatment. For NMDA neurotransmission is critical for neurodevelopment and risk factors of schizophrenia (1,2); early in the disease process, NMDA hypofunction might play a prominent role and be more amendable to the NMDA-enhancing treatment. This suggests a potential strategy of early intervention. However, it remains to be determined whether early correction of NMDA hypofunction can prevent or alter the course of illness.Sarcosine is protected by U.S. patent 6228875, 6667297, 6420351 for which GET is an inventor. All other authors reported no biomedical financial interests or potential conflicts of interest.
This work was supported by the National Science Council (Taiwan) NSC-94-2314-B-039-026, NSC-95-2314-B-006-119, NSC-95-2314-B-006-118-MY3, the National Health Research Institutes (Taiwan) NHRI-EX-96-9405PI, the National Research Program for Genomic Medicine (Taiwan) 94DOH004, the Committee on Chinese Medicine and Pharmacy, the Department of Health (Taiwan) CCMP94-RD-041, and National Cheng Kung University Project of Promoting Academic Excellence and Developing World Class Research Centers (Taiwan) (HYL). Dr. Tsai is supported in part by Los Angeles Biomedical Research Institute and an Independent Investigator Award from National Alliance of Research on Schizophrenia and Affective Disorder.
Supplementary data
References
- NMDA receptor hypofunction model of schizophrenia.J Psychiatr Res. 1999; 33: 523-533
- Glutamatergic mechanisms in schizophrenia.Annu Rev Pharmacol Toxicol. 2001; 42: 165-179
- The phencyclidine-glutamate model of schizophrenia.Clin Neuropharmacol. 1995; 18: 237-249
- Recent advances in the phencyclidine model of schizophrenia.Am J Psychiatry. 1991; 148: 1301-1308
- Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans.Arch Gen Psychiatry. 1994; 51: 199-214
- Glycine enhances NMDA-receptor mediated synaptic potentials in neocortical slices.Nature. 1989; 338: 422-424
- A “glutamatergic hypothesis” of schizophrenia: Rationale for pharmacotherapy with glycine.Clin Neuropharmacol. 1989; 12: 1-13
- D-serine added to antipsychotic for the treatment of schizophrenia.Biol Psychiatry. 1998; 44: 1081-1089
- D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia.Biol Psychiatry. 2005; 57: 577-585
- Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia.Arch Gen Psychiatry. 1999; 56: 29-36
- D-alanine added to antipsychotics for the treatment of schizophrenia.Biol Psychiatry. 2006; 59: 230-234
- Efficacy and tolerance of D-cycloserine in drug-free schizophrenic patients.Biol Psychiatry. 1996; 40: 1298-1300
- A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia.Arch Gen Psychiatry. 1999; 56: 21-27
- Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia.Am J Psychiatry. 2002; 159: 480-482
- Glycine transporter I inhibitor, N-methylglycine (sarcosine) added to antipsychotics for the treatment of schizophrenia.Biol Psychiatry. 2004; 55: 452-456
- Sarcosine (N-methylglycine) or D-serine add-on treatment for acute exacerbation of schizophrenia: A randomized, double-blind, placebo-controlled study.Arch Gen Psychiatry. 2005; 62 (1024–1196)
- Modulatory effects of d-serine and sarcosine on NMDA receptor-mediated neurotransmission are apparent after stress in the genetically inbred BALB/c mouse strain.Brain Res Bull. 2006; 31: 626-630
- Structured Clinical Interview for DSM-IV.American Psychiatric Press, Washington, DC1994
- Diagnostic and Statistical Manual of Mental Disorders.4th ed. American Psychiatric Press, Washington, DC1994
- Positive and negative syndrome scale (PANSS) manual.Schizophr Bull. 1987; 13: 261-276
- Scales for the Assessment of Negative Symptoms (SANS).University of Iowa, Iowa City1983
- The quality of life scale: An instrument for rating the schizophrenic deficit syndrome.Schizophr Bull. 1984; 10: 388-398
- Drug-induced extrapyramidal disorders.Acta Psychiatry Scand. 1970; 212: 11-19
- ECDEU Assessment Manual for Psychopharmacology.US Department of Health, Education, and Welfare, Washington, DC1976
- A rating scale for the drug-induced akathesia.Br J Psychiatry. 1989; 154: 672-676
- The UKU Side Effect Rating Scale: A new comprehensive rating scale for psychotropic drugs and cross-sectional study of side effects in neuroleptic-treated patients.Acta Psychiatr Scand. 1987; 334: 1-100
- Models for longitudinal data: A generalized estimating equation approach.Biometrics. 1988; 44: 1049-1060
- Glycine treatment of prodromal symptoms.Schizophr Res. 2006; 86 (abstract): S7
Article info
Publication history
Published online: July 23, 2007
Accepted:
April 27,
2007
Received in revised form:
April 22,
2007
Received:
October 19,
2006
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
