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Augmentation with glutamatergic modulators for schizophrenia: A network meta-analysis.

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Glutamatergic modulators show promise as add-on treatments for schizophrenia. Piracetam, benzoate, and memantine effectively target specific symptoms, while combinations enhance cognitive function.

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Area of Science:

  • Neuroscience and Psychiatry
  • Pharmacology

Background:

  • Schizophrenia is a complex psychiatric disorder with persistent symptoms despite standard treatments.
  • Glutamatergic dysfunction is implicated in the pathophysiology of schizophrenia.
  • Novel augmentation strategies targeting the glutamatergic system are under investigation.

Purpose of the Study:

  • To systematically evaluate the efficacy of glutamatergic modulators as add-on treatments for schizophrenia using network meta-analysis.
  • To compare the effectiveness of various glutamatergic agents across different symptom domains and cognitive function.

Main Methods:

  • A comprehensive systematic search of major biomedical databases (PubMed, Embase, Cochrane Library, PsycInfo) was conducted up to January 2025.
  • A random-effects network meta-analysis was performed using a frequentist approach.
  • The certainty of evidence for treatment effects was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach.

Main Results:

  • 148 randomized controlled trials involving 12,339 patients were included in the analysis.
  • Piracetam (2400-4800 mg/day) demonstrated significant improvement in total psychopathology (SMD -0.94).
  • Benzoate (1000-2000 mg/day) was most effective for positive symptoms (SMD -0.43), and memantine (5-20 mg/day) for negative symptoms (SMD -0.64).
  • A combination of sarcosine (2000 mg/day) and benzoate (1000 mg/day) showed the greatest cognitive enhancement (SMD 1.08).
  • Memantine, N-acetylcysteine, and sarcosine showed benefits across multiple symptom domains.
  • Several other agents, including d-serine, evenamide, and N-acetylcysteine, demonstrated efficacy with moderate to high certainty.

Conclusions:

  • Glutamatergic modulators represent a promising class of augmentation therapies for schizophrenia, offering benefits across various symptom dimensions.
  • Specific agents like piracetam, benzoate, and memantine show targeted efficacy for total, positive, and negative symptoms, respectively.
  • Combinations of glutamatergic agents and individual agents like memantine, N-acetylcysteine, and sarcosine hold potential for improving cognitive function and addressing multiple aspects of schizophrenia.
  • Further research into novel agents and optimal dosing strategies is warranted to refine glutamatergic augmentation therapies.