Markers of glutamatergic neurotransmission and oxidative stress associated with tardive dyskinesia

Am J Psychiatry. 1998 Sep;155(9):1207-13. doi: 10.1176/ajp.155.9.1207.


Objective: Tardive dyskinesia is a movement disorder affecting 20%-40% of patients treated chronically with neuroleptic drugs. The dopamine supersensitivity hypothesis cannot account for the time course of tardive dyskinesia or for the persistence of tardive dyskinesia and the associated structural changes after neuroleptics are discontinued. The authors hypothesized that neuroleptics enhance striatal glutamatergic neurotransmission by blocking presynaptic dopamine receptors, which causes neuronal damage as a consequence of oxidative stress.

Method: CSF was obtained from 20 patients with schizophrenia, 11 of whom had tardive dyskinesia. Markers for oxidative stress, including superoxide dismutase, lipid hydroperoxide, and protein carbonyl groups, and markers for excitatory neurotransmission, including N-acetylaspartate, N-acetylaspartylglutamate, aspartate, and glutamate, were measured in the CSF specimens. Patients were also rated for tardive dyskinesia symptoms with the Abnormal Involuntary Movement Scale.

Results: Tardive dyskinesia patients had significantly higher concentrations of N-acetylaspartate, N-acetylaspartylglutamate, and aspartate in their CSF than patients without tardive dyskinesia when age and neuroleptic dose were controlled for. The significance of the higher levels of protein-oxidized products associated with tardive dyskinesia did not pass Bonferroni correction, however. Tardive dyskinesia symptoms correlated positively with markers of excitatory neurotransmission and protein carbonyl group and negatively with CSF superoxide dismutase activity.

Conclusions: These findings suggest that there are elevated levels of oxidative stress and glutamatergic neurotransmission in tardive dyskinesia, both of which may be relevant to the pathophysiology of tardive dyskinesia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Antipsychotic Agents / adverse effects
  • Aspartic Acid / analogs & derivatives
  • Aspartic Acid / cerebrospinal fluid
  • Biomarkers
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiopathology
  • Dipeptides / cerebrospinal fluid
  • Dopamine Antagonists / pharmacology
  • Dyskinesia, Drug-Induced / cerebrospinal fluid
  • Dyskinesia, Drug-Induced / etiology
  • Dyskinesia, Drug-Induced / physiopathology*
  • Female
  • Glutamates / cerebrospinal fluid
  • Glutamates / pharmacology
  • Glutamates / physiology*
  • Humans
  • Lipid Peroxides / cerebrospinal fluid
  • Male
  • Middle Aged
  • Neuropeptides / cerebrospinal fluid
  • Oxidative Stress / physiology*
  • Psychiatric Status Rating Scales / statistics & numerical data
  • Receptors, Dopamine / drug effects
  • Schizophrenia / cerebrospinal fluid
  • Schizophrenia / diagnosis
  • Schizophrenia / drug therapy
  • Superoxide Dismutase / cerebrospinal fluid
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*


  • Antipsychotic Agents
  • Biomarkers
  • Dipeptides
  • Dopamine Antagonists
  • Glutamates
  • Lipid Peroxides
  • Neuropeptides
  • Receptors, Dopamine
  • isospaglumic acid
  • Aspartic Acid
  • N-acetylaspartate
  • Superoxide Dismutase