Levels of glutamatergic neurometabolites in patients with severe treatment-resistant schizophrenia: a proton magnetic resonance spectroscopy study

Neuropsychopharmacology. 2020 Mar;45(4):632-640. doi: 10.1038/s41386-019-0589-z. Epub 2019 Dec 16.


Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy (1H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild-to-moderate illness severity, which is not entirely reflective of what is observed in clinical practice. In this present work, we compared glutamate + glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T 1H-MRS (PRESS, TE = 35 ms). TRS criteria were defined by severe positive symptoms (i.e., ≥5 on 2 Positive and Negative Syndrome Scale (PANSS)-positive symptom items or ≥4 on 3 PANSS-positive symptom items), despite standard antipsychotic treatment. A total of 95 participants were included (29 TRS patients [PANSS = 111.2 ± 20.4], 33 non-TRS patients [PANSS = 49.8 ± 13.7], and 33 HCs). dACC Glx levels were higher in the TRS group vs. HCs (group effect: F[2,75] = 4.74, p = 0.011; TRS vs. HCs: p = 0.012). No group differences were identified in the caudate. There were no associations between Glx levels and clinical severity in either patient group. Our results are suggestive of greater heterogeneity in TRS relative to non-TRS with respect to dACC Glx levels, necessitating further research to determine biological subtypes of TRS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antipsychotic Agents / therapeutic use*
  • Cross-Sectional Studies
  • Female
  • Glutamic Acid / metabolism*
  • Humans
  • Magnetic Resonance Imaging / methods
  • Male
  • Middle Aged
  • Proton Magnetic Resonance Spectroscopy / methods*
  • Schizophrenia / diagnostic imaging*
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism*
  • Severity of Illness Index*


  • Antipsychotic Agents
  • Glutamic Acid