In Vitro and In Vivo Neuroprotective Effects of Sarcosine.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by behavioral and psychological symptoms in addition to cognitive impairment and loss of memory. The exact pathogenesis and genetic background of AD are unclear and there remains no effective treatment option. Sarcosine, an n-methyl derivative of glycine, showed a promising therapeutic strategy for some cognitive disorders. To our knowledge, the impacts of sarcosine supplementation against AD have not yet been elucidated. Therefore, we aimed to determine the neuroprotective potential of sarcosine in in vitro and in vivo AD model. In vitro studies have demonstrated that sarcosine increased the percentage of viable cells against aluminum induced neurotoxicity. In AlCl3-induced rat model of AD, the level of antioxidant capacity was significantly decreased and expression levels of APP, BACE1, TNF-α, APH1A, and PSENEN genes were elevated compared to the control group. Additionally, histopathological examinations of the hippocampus of AlCl3-induced rat brains showed the presence of neurofibrillary tangles (NFTs). However, the administration of sarcosine produced marked improvement and protection of AD-associated pathologies induced by AlCl3 in experimental rats. Therefore, this investigation may contribute to design novel therapeutic strategies using sarcosine for the management of AD pathologies.

Millennium Nutrient N,N-Dimethylglycine (DMG) and its Effectiveness in Autism Spectrum Disorders.

Autism is a neurodevelopmental disorder belonging to the autism spectrum disorder (ASD). In ASDs, the individuals show substantial impairments in social communication, repetitive behaviours, and sensory behaviours deficits in the early stages of their life. Globally, the prevalence of autism is estimated to be less than 1%, especially in high- -income countries. In recent decades, there has been a drastic increase in the incidence of ASD, which has put ASD into the category of epidemics. Presently, two US Food and Drug Administration-approved drugs, aripiprazole and risperidone, are used to treat symptoms of agitation and irritability in autistic children. However, to date, no medication has been found to treat the core symptoms of ASD. The adverse side effects of conventional medicine and limited treatment options have led families of autistic children to turn to complementary and alternative medicine (CAM) treatments, which are perceived as relatively safe compared to conventional medicine. Recently N, N-dimethylglycine (DMG), a dietary supplement, has emerged as a useful supplement to improve the mental and physical state of children with ASD. The current review discusses ASD, the prevalence of ASD, the CAM approach, and the efficacy of CAM treatment in children with ASD. Moreover, it highlights the chemistry, pharmacological effect, and clinical studies of DMG, highlighting its potential for improving the lifestyle of children with ASD.

N,N-dimethylglycine prevents toluene-induced impairment in recognition memory and synaptic plasticity in mice.

Toluene intoxication produces deleterious effects on cognitive function, which has been associated with the inhibition of N-methyl-d-aspartate receptor (NMDAR). The present study determined whether N,N-dimethylglycine (DMG), a nutrient supplement and a partial agonist for NMDAR glycine binding site, could counteract recognition memory deficits and hippocampal synaptic dysfunction after acute toluene exposure. Male ICR mice were treated with toluene (250-750 mg/kg) for monitoring the sociability and social novelty in three-chamber test and long-term potentiation (LTP) of hippocampal synaptic transmission. Moreover, the combined effects of DMG (30-100 mg/kg) pretreatment with toluene (750 mg/kg) on three-chamber test, novel location and object recognition test and synaptic function were determined. Toluene decreased the sociability, preference for social novelty, hippocampal synaptic transmission and LTP in a dose-dependent manner. DMG pretreatment significantly reduced the toluene-induced memory impairment in social recognition, object location and object recognition and synaptic dysfunction. Furthermore, NMDAR glycine binding site antagonist, 7-chlorokynurenic acid, abolished the protective effects of DMG. These results indicate that DMG could prevent toluene-induced recognition memory deficits and synaptic dysfunction and its beneficial effects might be associated with modulation of NMDAR. These findings suggest that DMG supplementation might be an effective approach to prevent memory problems for the workers at risk of high-level toluene exposure or toluene abusers.

N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice.

Ketamine, a dissociative anesthetic, produces rapid and sustained antidepressant effects at subanesthtic doses. However, it still inevitably induces psychotomimetic side effects. N,N-dimethylglycine (DMG) is a derivative of the amino acid glycine and is used as a dietary supplement. Recently, DMG has been found acting at glycine binding site of the N-methyl-d-aspartate receptor (NMDAR). As blockade of NMDARs is one of the main mechanisms responsible for the action of ketamine on central nervous system, DMG might modulate the behavioral responses to ketamine. The present study determined the effects of DMG on the ketamine-induced psychotomimetic, anesthetic and antidepressant-like effects in mice. DMG pretreatment reversed the ketamine-induced locomotor hyperactivity and impairment in the rotarod performance, novel location and novel object recognition tests, and prepulse inhibition. In addition, DMG alone exhibited antidepressant-like effects in the forced swim test and produced additive effects when combined with ketamine. However, DMG did not affect ketamine-induced anesthesia. These results reveal that DMG could antagonize ketamine's psychotomimetic effects, yet produce additive antidepressant-like effects with ketamine, suggesting that DMG might have antipsychotic potential and be suitable as an add-on therapy to ketamine for patients with treatment-resistant depression.

Supplementation of Antipsychotic Treatment with the Amino Acid Sarcosine Influences Proton Magnetic Resonance Spectroscopy Parameters in Left Frontal White Matter in Patients with Schizophrenia.

Dysfunction of the glutamatergic system, the main stimulating system in the brain, has a major role in pathogenesis of schizophrenia. The frontal white matter (WM) is partially composed of axons from glutamatergic pyramidal neurons and glia with glutamatergic receptors. The natural amino acid sarcosine, a component of a normal diet, inhibits the glycine type 1 transporter, increasing the glycine level. Thus, it modulates glutamatergic transmission through the glutamatergic ionotropic NMDA (N-methyl-d-aspartate) receptor, which requires glycine as a co-agonist. To evaluate the concentrations of brain metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine, and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left frontal WM, Proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy was used. Twenty-five patients randomly chosen from a group of fifty with stable schizophrenia (DSM-IV-TR) and dominant negative symptoms, who were receiving antipsychotic therapy, were administered 2 g of sarcosine daily for six months. The remaining 25 patients received placebo. Assignment was double blinded. ¹H-NMR spectroscopy (1.5 T) was performed twice: before and after the intervention. NAA, Glx and mI were evaluated as Cr and Cho ratios. All patients were also assessed twice with the Positive and Negative Syndrome Scale (PANSS). Results were compared between groups and in two time points in each group. The sarcosine group demonstrated a significant decrease in WM Glx/Cr and Glx/Cho ratios compared to controls after six months of therapy. In the experimental group, the final NAA/Cr ratio significantly increased and Glx/Cr ratio significantly decreased compared to baseline values. Improvement in the PANSS scores was significant only in the sarcosine group. In patients with schizophrenia, sarcosine augmentation can reverse the negative effect of glutamatergic system overstimulation, with a simultaneous beneficial increase of NAA/Cr ratio in the WM of the left frontal lobe. Our results further support the glutamatergic hypothesis of schizophrenia.

Adding Sarcosine to Antipsychotic Treatment in Patients with Stable Schizophrenia Changes the Concentrations of Neuronal and Glial Metabolites in the Left Dorsolateral Prefrontal Cortex.

The glutamatergic system is a key point in pathogenesis of schizophrenia. Sarcosine (N-methylglycine) is an exogenous amino acid that acts as a glycine transporter inhibitor. It modulates glutamatergic transmission by increasing glycine concentration around NMDA (N-methyl-d-aspartate) receptors. In patients with schizophrenia, the function of the glutamatergic system in the prefrontal cortex is impaired, which may promote negative and cognitive symptoms. Proton nuclear magnetic resonance (¹H-NMR) spectroscopy is a non-invasive imaging method enabling the evaluation of brain metabolite concentration, which can be applied to assess pharmacologically induced changes. The aim of the study was to evaluate the influence of a six-month course of sarcosine therapy on the concentration of metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left dorso-lateral prefrontal cortex (DLPFC) in patients with stable schizophrenia. Fifty patients with schizophrenia, treated with constant antipsychotics doses, in stable clinical condition were randomly assigned to administration of sarcosine (25 patients) or placebo (25 patients) for six months. Metabolite concentrations in DLPFC were assessed with 1.5 Tesla ¹H-NMR spectroscopy. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS). The first spectroscopy revealed no differences in metabolite concentrations between groups. After six months, NAA/Cho, mI/Cr and mI/Cho ratios in the left DLPFC were significantly higher in the sarcosine than the placebo group. In the sarcosine group, NAA/Cr, NAA/Cho, mI/Cr, mI/Cho ratios also significantly increased compared to baseline values. In the placebo group, only the NAA/Cr ratio increased. The addition of sarcosine to antipsychotic therapy for six months increased markers of neurons viability (NAA) and neurogilal activity (mI) with simultaneous improvement of clinical symptoms. Sarcosine, two grams administered daily, seems to be an effective adjuvant in the pharmacotherapy of schizophrenia.

Supplementation of antipsychotic treatment with sarcosine ­ GlyT1 inhibitor ­ causes changes of glutamatergic (1)NMR spectroscopy parameters in the left hippocampus in patients with stable schizophrenia.

Glutamatergic system, the main stimulating system of the brain, plays an important role in the pathogenesis of schizophrenia. Hippocampus, a structure crucial for memory and cognitive functions and rich in glutamatergic neurons, is a natural object of interest in studies on psychoses. Sarcosine, a glycine transporter (GlyT-1) inhibitor influences the function of NMDA receptor and glutamate-dependent transmission. The aim of the study was to assess the effects of sarcosine on metabolism parameters in the left hippocampus in patients with schizophrenia. Assessments were performed using proton nuclear magnetic resonance ((1)H NMR) spectroscopy (1.5T). Fifty patients diagnosed with schizophrenia (DSM-IV-TR), with dominant negative symptoms, in stable clinical condition and stable antipsychotics doses were treated either with sarcosine (n=25) or placebo (n=25). Spectroscopic parameters were evaluated within groups and between two groups before and after 6-month intervention. All patients were also assessed with the Positive and Negative Syndrome Scale (PANSS). In the sarcosine group, after 6-month treatment, we found significant decrease in hippocampal Glx/Cr (Glx-complex of glutamate, glutamine and GABA, Cr-creatine) and Glx/Cho (Cho-choline), while N-acetylaspartate (NAA), myo-inositol (mI), Cr and Cho parameters remained stable along the study and also did not differ significantly between both groups. This is the first study showing that a pharmacological intervention in schizophrenia, particularly augmentation of the antypsychotic treatment with sarcosine, may reverse the pathological increase in glutamatergic transmission in the hippocampus. The results confirm involvement of glutamatergic system in the pathogenesis of schizophrenia and demonstrate beneficial effects of GlyT-1 inhibitor on the metabolism in the hippocampus and symptoms of schizophrenia.

Treatment for mitochondrial disorders.

BACKGROUND: Mitochondrial respiratory chain disorders are the most prevalent group of inherited neurometabolic diseases. They present with central and peripheral neurological features usually in association with other organ involvement including the eye, the heart, the liver, and kidneys, diabetes mellitus and sensorineural deafness. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and premature death. Vitamin supplements, pharmacological agents and exercise therapy have been used in isolated cases and small clinical trials, but the efficacy of these interventions is unclear. The first review was carried out in 2003, and identified six clinical trials. This major update was carried out to identify new studies and grade the original studies for potential bias in accordance with revised Cochrane Collaboration guidelines. OBJECTIVES: To determine whether there is objective evidence to support the use of current treatments for mitochondrial disease. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 July 2011), CENTRAL (2011, Issue 2, MEDLINE (1966 to July 2011), and EMBASE (January 1980 to July 2011), and contacted experts in the field. SELECTION CRITERIA: We included randomised controlled trials (including cross-over studies). Two of the authors independently selected abstracts for further detailed review. Further review was performed independently by all five authors to decide which trials fit the inclusion criteria and graded risk of bias. Participants included males and females of any age with a confirmed diagnosis of mitochondrial disease based upon muscle histochemistry, respiratory chain complex analysis of tissues or cell lines or DNA studies. Interventions included any pharmacological agent, dietary modification, nutritional supplement, exercise therapy or other treatment. The review authors excluded studies at high risk of bias in any category. The primary outcome measures included an change in muscle strength and/or endurance, or neurological clinical features. Secondary outcome measures included quality of life assessments, biochemical markers of disease and negative outcomes. DATA COLLECTION AND ANALYSIS: Two of the authors (GP and PFC) independently identified studies for further evaluation from all abstracts within the search period. For those studies identified for further review, all five authors then independently assessed which studies met the entry criteria. For the included studies, we extracted details of the number of randomised participants, treatment, study design, study category, allocation concealment and other risk of bias criteria, and participant characteristics. Analysis was based on intention-to-treat data. We planned to use meta-analysis, but this did not prove necessary. MAIN RESULTS: The authors reviewed 1335 abstracts, and from these identified 21 potentially eligible abstracts. Upon detailed review, 12 studies fulfilled the entry criteria. Of these, eight were new studies that had been published since the previous version of this review. Two studies which were included in the previous version of this review were excluded because of potential for bias. The comparability of the included studies is extremely low because of differences in the specific diseases studied, differences in the therapeutic agents used, dosage, study design, and outcomes. The methodological quality of included studies was generally high, although risk of bias was unclear in random sequence generation and allocation concealment for most studies. Otherwise, the risk of bias was low for most studies in the other categories. Serious adverse events were uncommon, except for peripheral nerve toxicity in a long-term trial of dichloroacetate (DCA) in adults.One trial studied high-dose coenzyme Q10 without clinically meaningful improvement (although there were multiple biochemical, physiologic, and neuroimaging outcomes, in 30 participants). Three trials used creatine monohydrate alone, with one reporting evidence of improved measures of muscle strength and post-exercise lactate, but the other two reported no benefit (total of 38 participants). One trial studied the effects of a combination of coenzyme Q10, creatine monohydrate, and lipoic acid and reported a statistically significant improvement in biochemical markers and peak ankle dorsiflexion strength, but overall no clinical improvement in 16 participants. Five trials studied the effects of DCA: three trials in children showed a statistically significant improvement in secondary outcome measures of mitochondrial metabolism (venous lactate in three trials, and magnetic resonance spectroscopy (MRS) in one trial; total of 63 participants). One trial of short-term DCA in adults demonstrated no clinically relevant improvement (improved venous lactate but no change in physiologic, imaging, or questionnaire findings, in eight participants). One longer-term DCA trial in adults was terminated prematurely due to peripheral nerve toxicity without clinical benefit (assessments included the GATE score, venous lactate and MRS, in 30 participants). One trial using dimethylglycine showed no significant effect (measurements of venous lactate and oxygen consumption (VO(2)) in five participants). One trial using a whey-based supplement showed statistically significant improvement in markers of free radical reducing capacity but no clinical benefit (assessments included the Short Form 36 Health Survey (SF-36) questionnaire and UK Medical Research Council (MRC) muscle strength, in 13 participants). AUTHORS' CONCLUSIONS: Despite identifying eight new trials there is currently no clear evidence supporting the use of any intervention in mitochondrial disorders. Further research is needed to establish the role of a wide range of therapeutic approaches. We suggest further research should identify novel agents to be tested in homogeneous study populations with clinically relevant primary endpoints.

Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia.

BACKGROUND: Based on the glutamatergic NMDA receptor hypofunction theory of schizophrenia, NMDA receptor modulators (NMDARMs) may have therapeutic potential in the treatment of schizophrenia. OBJECTIVE: This meta-analysis aimed to evaluate the potential of modulators of the NMDA receptor as adjunctive therapy for schizophrenia, using the results from published trials. DATA SOURCES: A primary electronic search for controlled clinical trials using NMDARMs in schizophrenia was conducted on the PubMed, Cochrane Library, EMBASE, CINAHL® and PsycINFO databases. A secondary manual search of references from primary publications was also performed. STUDY SELECTION: Inclusion criteria were the application of an established method of diagnosis, randomized case assignment, comparison of NMDARM add-on therapy with placebo, and double-blind assessment of symptoms in chronic schizophrenia using standardized rating scales. Results were based on a total sample size of 1253 cases from 29 trials that fulfilled the specified criteria. DATA EXTRACTION: Scores on rating scales or on their relevant subscales were obtained for all selected studies from published results for the minimum dataset to compute the difference between post- and pre-trial scores and their pooled standard deviation for NMDARM add-on therapy and placebo groups for negative, positive and total symptoms. RESULTS: A negative standardized mean difference (SMD) indicates therapeutic benefit in favour of NMDARM add-on therapy and all SMD results mentioned here are statistically significant. The overall effect size for NMDARMs as a group was small for negative (SMD -0.27) and medium for total (SMD -0.40) symptoms of chronic schizophrenia. Subgroup analysis revealed medium effect sizes for D-serine and N-acetyl-cysteine (NAC) for negative (SMD -0.53 and -0.45, respectively) and total (SMD -0.40 and -0.64, respectively) symptoms, and for glycine (SMD -0.66) and sarcosine (SMD -0.41) for total symptoms. As adjuvants to non-clozapine antipsychotics, additional therapeutic benefits were observed for NMDARM as a group (SMD -0.14) and glycine (SMD -0.54) for positive symptoms; D-serine (SMD -0.54), NAC (SMD -0.45) and sarcosine (SMD -0.39) for negative symptoms; and NMDARM as a group (SMD -0.38), D-serine (SMD -0.40), glycine (SMD -1.12), NAC (SMD -0.64) and sarcosine (SMD -0.53) for total symptoms. When added to clozapine, none of the drugs demonstrated therapeutic potential, while addition of glycine (SMD +0.56) worsened positive symptoms. CONCLUSIONS: Taking into consideration the number of trials and sample size in subgroup analyses, D-serine, NAC and sarcosine as adjuncts to non-clozapine antipsychotics have therapeutic benefit in the treatment of negative and total symptoms of chronic schizophrenia. While glycine improves positive and total symptoms as an adjuvant to non-clozapine antipsychotics, it worsens them when added to clozapine.

Effectiveness of nutritional supplements for reducing symptoms in autism-spectrum disorder: a case report.

OBJECTIVE: This report presents a case of a 9-year-old boy with autism that responded positively to nutritional supplements. METHODS: The supplements were dimethylglycine and a combination of a large dose of vitamin B6 (pyridoxal HCl) and magnesium. The Autism Treatment Evaluation Checklist (ATEC) was used for outcome assessment and administered by 2 of his family members both before the nutritional supplements and 5 months into the supplements, thereby referred to as pretest and post-test, respectively. Two (2) assessors independently performed evaluations. The ATEC evaluates four areas: communication, sociability, sensory/cognitive awareness, and behavior. The lower the scores are, the less severe the symptoms are. RESULTS: The ATEC evaluations by 2 independent assessors showed that the changes in total ATEC were from 63 at pretest to 33 at post-test, and from 64 at pretest to 30 at post-test, respectively. These changes represented reductions of 47.6% and 53.1%. A strong inter-rater reliability was demonstrated, with an intraclass correlation coefficient of 0.988. The school teachers also noticed improvements in various areas consistent with the ATEC evaluations. CONCLUSIONS: Although the reported findings cannot be generalized, this case report provides useful preliminary evidence to an accumulating body of literature supporting the theory and efficacies of nutritional supplements in autism-spectrum disorders.

Increased hippocampal glycine uptake and cognitive dysfunction after peripheral nerve injury.

Patients with chronic pain often have accompanying cognitive deficiency, which may reduce their quality of life and hamper efficient medical treatment. Alteration of extracellular glycine concentration may affect cognitive function and spinal pain signaling. In the present study, we assessed recognition memory by novel-object recognition and found that mice developing mechanical hypersensitivity after peripheral nerve injury exhibited impaired recognition ability for novelty, which was never observed in mice provided the selective glycine transporter 1 (GlyT1) inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS) systemically. Although systemic NFPS generated analgesia via inhibitory effects of glycine in the spinal cord, the cognitive impairment in neuropathic mice was not restored upon relief of pain alone by intrathecal injection of NFPS. Whole-cell recordings were then made from hippocampal CA1 pyramidal neurons, and the effect of exogenously applied glycine or its endogenous increase by blockade of GlyT1 with NFPS on N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents (NMDA-EPSCs) was investigated in slices prepared from neuropathic mice and mice subjected to sham treatment. In slices from neuropathic mice, NMDA-EPSCs were less potentiated by glycine, whereas they were augmented by NFPS even at lower concentrations. After treating the slices with either NFPS or the glial-selective metabolic blocker fluoroacetate, glycine potentiated NMDA-EPSCs equally in slices from neuropathic and sham-treated mice. These findings imply that chronic pain has a crucial influence on hippocampal plasticity related to cognitive function, and strongly suggest that increasing the extracellular level of glycine via blockade of GlyT1 is a potential therapeutic approach for chronic pain with memory impairment. Chronic pain crucially influences hippocampal plasticity related to cognitive function. Increasing the extracellular level of glycine via blockade of GlyT1 is a potential therapeutic approach for chronic pain with memory impairment.

Effects of sarcosine, a glycine transporter type 1 inhibitor, in two mouse seizure models.

Sarcosine, a natural amino acid found in muscles and other body tissues, is an endogenous glycine transporter type 1 inhibitor that increases the glycine concentration, resulting in an indirect potentiation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Sarcosine, similar to other NMDA receptor-activating agents, is an effective adjuvant in the treatment of schizophrenia. It is widely accepted that increased glutamatergic neurotransmission is involved in the initiation and propagation of seizures. Because sarcosine facilitates NMDA receptor function, it may affect the seizure threshold. Therefore, we examined the effects of sarcosine on the seizure threshold in two different mouse seizure models: the timed intravenous (iv) pentylenetetrazole (PTZ) infusion test and the maximal electroshock seizure threshold test. In the iv PTZ test, sarcosine did not exert a significant effect on the seizure threshold at any of the doses tested (100, 200, 400 and 800 mg/kg, ip). However, at doses of 400 and 800 mg/kg, sarcosine significantly raised the threshold for electroconvulsions (p < 0.01). The present findings indicate that sarcosine did not lower the seizure threshold. Conversely, sarcosine showed weak anticonvulsant properties by increasing the threshold current for the induction of tonic seizures. Therefore, sarcosine may be considered as a safe adjuvant treatment for schizophrenia without proconvulsant risk. In addition, the compound may serve as an interesting addition to epilepsy treatment.

Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, double-blind study.

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 x 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.

Natural approaches to epilepsy.

This article reviews research on the use of diet, nutritional supplements, and hormones in the treatment of epilepsy. Potentially beneficial dietary interventions include identifying and treating blood glucose dysregulation, identifying and avoiding allergenic foods, and avoiding suspected triggering agents such as alcohol, aspartame, and monosodium glutamate. The ketogenic diet may be considered for severe, treatment-resistant cases. The Atkins diet (very low in carbohydrates) is a less restrictive type of ketogenic diet that may be effective in some cases. Nutrients that may reduce seizure frequency include vitamin B6, magnesium, vitamin E, manganese, taurine, dimethylglycine, and omega-3 fatty acids. Administration of thiamine may improve cognitive function in patients with epilepsy. Supplementation with folic acid, vitamin B6, biotin, vitamin D, and L-carnitine may be needed to prevent or treat deficiencies resulting from the use of anticonvulsant drugs. Vitamin K1 has been recommended near the end of pregnancy for women taking anticonvulsants. Melatonin may reduce seizure frequency in some cases, and progesterone may be useful for women with cyclic exacerbations of seizures. In most cases, nutritional therapy is not a substitute for anticonvulsant medications. However, in selected cases, depending on the effectiveness of the interventions, dosage reductions or discontinuation of medications may be possible.

Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia.

BACKGROUND: Agonists at the N-methyl-D-aspartate (NMDA)-glycine site (D-serine, glycine, D-alanine and D-cycloserine) and glycine transporter-1 (GlyT-1) inhibitor (N-methylglycine, or called sarcosine) both improve the symptoms of stable chronic schizophrenia patients receiving concurrent antipsychotics. Previous studies, however, found no advantage of D-serine, glycine, or D-cycloserine added to clozapine. The present study aims to determine the effects of sarcosine adjuvant therapy for schizophrenic patients receiving clozapine treatment. METHODS: Twenty schizophrenic inpatients enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/day) which was added to their stable doses of clozapine. Measures of clinical efficacy and side-effects were determined every other week. RESULTS: Sarcosine produced no greater improvement when co-administered with clozapine than placebo plus clozapine at weeks 2, 4, and 6. Sarcosine was well tolerated and no significant side-effect was noted. CONCLUSIONS: Unlike patients treated with other antipsychotics, patients who received clozapine treatment exhibit no improvement by adding sarcosine or agonists at the NMDA-glycine site. Clozapine possesses particular efficacy, possibly related to potentiation of NMDA-mediated neurotransmission. This may contribute to the clozapine's unique clinical efficacy and refractoriness to the addition of NMDA-enhancing agents.

Treatment for mitochondrial disorders.

BACKGROUND: Mitochondrial respiratory chain disorders are the most prevalent group of inherited neurometabolic diseases. They present with central and peripheral neurological features usually in association with other organ involvement including the eye, the heart, the liver, and kidneys, diabetes mellitus and sensorineural deafness. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and premature death. Vitamin supplements, pharmacological agents and exercise therapy have been used in isolated cases and small clinical trials, but the efficacy of these interventions is unclear. OBJECTIVES: To determine whether there is objective evidence to support the use of current treatments for mitochondrial disease. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched September 2003), the Cochrane Central Register of Controlled Trials, MEDLINE (January 1966 to October 3 2003), EMBASE (January 1980 to October 3 2003) and the European Neuromuscular Centre (ENMC) clinical trials register, and contacted experts in the field. SELECTION CRITERIA: We included randomised controlled trials (including crossover studies) and quasi-randomised trials comparing pharmacological treatments, and non-pharmacological treatments (vitamins and food supplements), and physical training in individuals with mitochondrial disorders. The primary outcome measures included an improvement in muscle strength and/or endurance, or neurological clinical features. Secondary outcome measures included quality of life assessments, biochemical markers of disease and negative outcomes. DATA COLLECTION AND ANALYSIS: Details of the number of randomised patients, treatment, study design, study category, allocation concealment and patient characteristics were extracted. Analysis was based on intention to treat data. We planned to use meta-analysis, but this did not prove necessary. MAIN RESULTS: Six hundred and seventy-eight abstracts were reviewed, and six fulfilled the entry criteria. Two trials studied the effects of co-enzyme Q10 (ubiquinone), one reporting a subjective improvement and a significant increase in a global scale of muscle strength, but the other trial did not show any benefit. Two trials used creatine, with one reporting improved measures of muscle strength and post-exercise lactate, but the other reported no benefit. One trial of dichloroacetate showed an improvement in secondary outcome measures of mitochondrial metabolism, and one trial using dimethylglycine showed no significant effect. AUTHORS' CONCLUSIONS: There is currently no clear evidence supporting the use of any intervention in mitochondrial disorders. Further research is needed to establish the role of a wide range of therapeutic approaches.

Glutamate-based therapeutic approaches: inhibitors of glycine transport.

A growing body of evidence suggests that activation of the glutamatergic system, particularly N-methyl-D-aspartate (NMDA) receptor function, may be a viable approach to the treatment of schizophrenia, and potentially other cognitive disorders. The excitotoxicity associated with direct NMDA receptor agonists limits their therapeutic potential, and the glycine modulatory site of the NMDA receptor has received growing interest as a therapeutic target. One approach to enhance NMDA receptor function is to increase the availability of the necessary co-agonist glycine at this modulatory site through inhibition of glycine reuptake from the synapse via glycine transporter-1 (GlyT1). Both preclinical and clinical evidence provide support for this approach, as do recent findings demonstrating the regulation of dopaminergic neurotransmission by GlyT1 inhibition. As a result, several groups have focused on the development of novel GlyT1 inhibitors. In addition, recent electrophysiological findings and data from transgenic mouse models suggest that GlyT1 might also play a role in terminating the actions of glycine at strychnine-sensitive glycine receptors, and therefore GlyT1 antagonists also have potential for the treatment of conditions where activation of inhibitory pathways in the central nervous system might be beneficial.

Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study.

CONTEXT: Agents that enhance N-methyl-D-aspartate (NMDA) function through the glycine modulatory site (D-serine, glycine, or D-cycloserine) or through glycine transporter 1 (sarcosine) improve the symptoms of patients with stable chronic schizophrenia. OBJECTIVE: To determine whether NMDA-glycine site agonists or glycine transporter-1 inhibitors have better efficacy and whether NMDA receptor-enhancing agents have beneficial effects for acute exacerbation of schizophrenia. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Inpatient units of 2 major medical centers in Taiwan. Patients Sixty-five schizophrenic inpatients with acute exacerbation. INTERVENTIONS: Six weeks of treatment with sarcosine (2 g/d), D-serine (2 g/d), or placebo and concomitant optimal risperidone therapy. MAIN OUTCOME MEASURES: Positive and Negative Syndrome Scale (PANSS) and Scale for the Assessment of Negative Symptoms (SANS) (20 and 17 items) total scores. RESULTS: The sarcosine group revealed more reductions in PANSS total scores than the placebo (P = .04) and D-serine (P<.001) groups. Sarcosine adjunctive treatment was also superior to placebo in reducing SANS-20 (P = .007) and SANS-17 (P = .003) scores and to D-serine in decreasing SANS-20 (P = .006) and SANS-17 (P = .002) scores. The PANSS-general, PANSS-cognitive, and PANSS-depressive symptoms scores and SANS-alogia and SANS-blunted affect scores improved significantly more in sarcosine-cotreated patients than in risperidone monotherapy patients (P< or =.02 for all). Sarcosine adjunctive therapy also surpassed D-serine in terms of PANSS-general, PANSS-positive, PANSS-negative, and PANSS-depressive symptoms scores (P< or =.04 for all). D-serine and risperidone cotreatment did not differ significantly from risperidone monotherapy in all efficacy domains. CONCLUSIONS: This first short-term treatment study on NMDA receptor-enhancing agents suggests that sarcosine, superior to D-serine, can benefit not only patients with long-term stable disease but also acutely ill persons with schizophrenia. This finding indicates that a glycine transporter 1 inhibitor may be more efficacious than NMDA-glycine site agonists for adjuvant treatment of schizophrenia, at least during the acute phase. Further studies are needed.

Effectiveness of N,N-dimethylglycine in autism and pervasive developmental disorder.

N,N-dimethylglycine, a dietary supplement, has been reported to be beneficial in children with autism and pervasive developmental disorder. We examined the effectiveness of dimethylglycine in children with autism and pervasive developmental disorder in a double-blind, placebo-controlled study. Thirty-seven children between 3 and 11 years of age with a diagnosis of autism and/or pervasive developmental disorder were gender and age matched and randomly assigned to receive either placebo or dimethylglycine for 4 weeks. All children were assessed before and after treatment on two behavioral measures, the Vineland Maladaptive Behavior Domain and the Aberrant Behavior Checklist. Standardized neurologic examinations before and after treatment on 33 children showed no change. An overall improvement on all behavioral measures was observed for both the placebo and the dimethylglycine groups. However, the improvement among the children who received dimethylglycine was not statistically different from the improvement observed among the children who received the placebo. The children who participated in this study were a heterogeneous group, and their apparent responses to the dimethylglycine varied. Some children appeared to respond positively to the dimethylglycine, and there was a smaller proportion of negative changes in the dimethylglycine group, but the quantitative changes in the dimethylglycine behavioral assessments were not significantly different from what was observed among children who received placebo.