Niacin-respondent subset of schizophrenia – a therapeutic review.

Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia.

Glutamate and Possible Filtering Deficits in Schizophrenia

Measurements of glycine binding (H-glycine) in postmortem tissue of schizophrenics indicate that glycine receptors are increased in brain (e.g., in sensory cortex and premotor cortex) []. Other data show that glycine levels are increased in mesial but not lateral regions of temporal lobe in schizophrenics, (). These data are compatible with a compensatory increase in H-glycine receptors, possibly in response to reduced glutamate activity. There is, however, some evidence that neuroleptics may increase glycine levels ().

This would explain why schizophrenia symptoms often first appear during the teen years.

What Is the Role of Neurotransmitters in Schizophrenia?

The overall aim of this review was to explore the evidence in humans for the relationship between glutamate related compounds (glutamate, glutamine and Glx) and structural brain measurements in patients with schizophrenia. A review of existing literature was conducted to elucidate the role of glutamate-mediated excitotoxicity in the structural brain changes associated with schizophrenia. Unexpectedly, the search yielded only seven studies that met inclusion criteria, reflecting the paucity of literature available to effectively address this topic in humans.

For most of this century the causes of schizophrenia have been largely unknown.

In the Salk Institute study spearheaded by Salk Professor David Schubert, amyloid beta protein levels exposed to high levels of THC compounds reduced the amyloid beta protein levels as well as eliminated the inflammatory response from neuronal cells caused by the protein. The reduction of amyloid beta protein levels and inflammation allow the neurons to survive. THC-like compounds, like endocannibinoids, may be involved in protecting neuronal cells from death.

Dopamine is thought to play an important role in the development of schizophrenia.


The dopamine and glutamate theories of schizophrenia: A short review

Finally, one study measured CSF glutamate and VBR using CT in antipsychotic-free chronic schizophrenia patients (). An inverse relationship was reported between CSF glutamate and VBR, suggesting that glutamatergic cells may have degenerated over the duration of the illness as a result of toxic levels of glutamate, resulting in a lower glutamatergic measure at the time of assessment, consistent with an excitotoxic effect.

and glutamate theories of schizophrenia: ..

Overall, the studies listed in have several limitations, and as such, do not individually offer sufficient evidence to make conclusive claims about the role of glutamatergic markers in the structural alterations observed in schizophrenia. The publications by and were limited largely by the introduction of medication during the study. Antipsychotic treatment very likely confounded the relationship between markers of glutamatergic activity and volumetric losses; although patients were monitored throughout the study, it is expected that the introduction of medications influenced the serial neurochemical and structural measurements. This said, we acknowledge the practical challenges associated with performing a longitudinal study in medication-free patients. The studies conducted by and were limited by the nature of the participant population. The authors included at-risk individuals, and although useful, this sample is not necessarily generalizable to patients with schizophrenia, as many at-risk participants may not progress to the illness (); one study reported a 35% transition rate to a psychotic disorder over a 10-year follow-up (). The studies by and were limited by their targeted focus on glutamatergic levels and grey matter volume in the hippocampus. A common limitation shared among the aforementioned studies was the use of 1H-MRS, which quantifies the concentration of glutamate or glutamate-related compounds but cannot distinguish between intracellular and extracellular glutamate pools, therefore failing to precisely measure glutamate neurotransmission (). Finally, the study performed by was limited by the use of VBR, as this index of brain structure lacks sensitivity to minor neuroanatomical alterations, though this measurement was necessitated by the usage of CT. Further, the same study included participants with chronic schizophrenia; in this population, ongoing medication exposure and/or illness progression very likely confounded the relationship between glutamate levels and structural irregularities. Due to the limitations present within the reviewed studies, and the general dearth of literature exploring this topic, it remains unclear whether glutamate-mediated excitotoxicity is responsible for the structural changes observed in schizophrenia.

Glutamate and dopamine in schizophrenia: An update …

Two additional studies offer evidence that the relationship between glutamatergic markers and volumetric measures is present in the early stages of schizophrenia. In one study of participants with an ARMS, thalamic glutamate and anterior cingulate glutamine levels were associated with grey matter volume, demonstrating both positive and negative correlations depending on the brain region (). Another study, which included individuals with familial high-risk for schizophrenia, reported that Glx in both the thalamus and the caudate was negatively associated with regional brain volume, though both correlations were not significant ().