D-Serine

This network meta-analysis evaluated the effects of glutamatergic modulators as augmentation treatments on schizophrenia. A systematic search of PubMed, Embase, Cochrane Library, and PsycInfo for randomized controlled trials was conducted until January 2025. A random-effects network meta-analysis was performed within a frequentist framework, and the certainty of evidence was evaluated using the GRADE approach. A total of 148 randomized controlled trials and 12,339 patients were included. Among add-on glutamatergic modulators with moderate to high certainty of benefit over placebo, piracetam 2400-4800 mg/day showed the greatest improvement in total psychopathology (standardized mean differences [SMD] -0.94, 95 % confidence interval [CI] -1.47 to -0.41), benzoate 1000-2000 mg/day was most effective for positive symptoms (SMD -0.43, 95 % CI -0.71 to -0.16), memantine 5-20 mg/day ranked highest for negative symptom reduction (SMD -0.64, 95 % CI -0.85 to -0.43), and the combination of sarcosine 2000 mg/day and benzoate 1000 mg/day showed the greatest enhancement in global cognitive function (SMD 1.08, 95 % CI 0.45 to 1.71). Other agents, including d-serine 2000-4000 mg/day, evenamide 30-60 mg/day, iclepertine 10-25 mg/day, lamotrigine, luvadaxistat 50 mg/day, minocycline 100-300 mg/day, N-acetylcysteine 2000 mg/day, sarcosine 2000 mg/day, and topiramate demonstrated benefits with moderate to high certainty in one or more domains. Notably, memantine, N-acetylcysteine, and sarcosine exhibited efficacy across multiple outcome domains. The effects of some novel agents within specific dose ranges on cognitive function improvement were also observed.

Patients with Duchenne muscular dystrophy (DMD) may experience neurobehavioral and cognitive concerns, including psychiatric symptoms, due to the absence of full-length dystrophin (Dp427), frequently accompanied by deficiencies in shorter isoforms. The lack of dystrophin affects neurophysiological processes from the uterine phase, impacting neural circuitry in brain regions such as the prefrontal cortex, hippocampus, and cerebellum. This leads to reduced inhibitory GABAergic transmission and altered hippocampal glutamatergic signaling. The resulting imbalance between inhibitory and excitatory inputs contributes to the neurodevelopmental and cognitive deficits observed in DMD. Recent studies have reported correlations between serum levels of D-aspartate and D-serine, endogenous ligands of glutamatergic receptors, and conditions such as schizophrenia, spinal muscular atrophy, and aging. Furthermore, in a recent clinical study, we reported a general dysregulation of D-/L-amino acids known to modulate glutamatergic neurotransmission in the serum of DMD patients, with significant correlations between muscle wasting, motor impairment, and alterations in L-glutamate levels and the L-glutamine/L-glutamate ratio. To delve deeper into this matter, we conducted an extensive neurochemical analysis using high-pressure liquid chromatography to measure the levels of the same D-/L-amino acids across various brain regions, the spinal cord, and serum of the mdx mouse model of DMD. Our results revealed a significant reduction in prenatal D-aspartate levels and postnatal levels of specific L-amino acids in the hippocampus of dystrophic mice compared to wild type. In adult mdx mice, we also observed a near-significant decrease in hippocampal D-serine levels and a significant reduction in spinal cord D-aspartate levels. This study provides the first evidence potentially linking D-/L-amino acid dysmetabolism in the hippocampus to the described neurophysiological alterations. Although further investigations are essential to validate this hypothesis, the mechanisms proposed here offer insight into how amino acid imbalances may contribute to the DMD-associated neurological and cognitive deficits, thus supporting the rationale for developing future targeted therapeutic strategies.