Dysregulation of glutamatergic neurotransmission has been widely postulated as being involved in the etiology of schizophrenia. In the etiology of schizophrenia I have been stressing the dysregulation tricarboxylic acid (TCA) cycle via dysregulation of aconitase and the 2-oxoglutarate dehydrogenase complex stemming from shortages of coenzyme A.
The TCA cycle produces 2-oxouglutarate. .L-glutamate can be synthesized from 2-oxoglutarate. With dysregulation of the TCA cycle there can be a disruption in the synthesis of L-glutamate which would adversely affect glutamatergic neurotransmission whereby symptoms of schizophrenia could develop. .
Increasing glutamatergic neurotransmission alone via glutamate receptor agonists, however, does not solve the problem. The TCA cycle is still dysregulated.
There is strong focus on NMDA glutamate receptors in research on schizophrenia. Dysregulation of the TCA cycle, however, would dysregulate glutamatergic neurotransmission generally and also dysregulate GABA neurotransmission as GABA is synthesized from L-glutamate . D-serine which is an NMDA receptor agonist has failed in phase II trials where d-serine was being tested for effectiveness against symptoms of schizophrenia though a deuterated (i.e patenable) form of D-serine could still be effective for hair loss.
I hold that only addressing NMDA receptors will always fail in terms of the treatment of schizophrenia. Dysregulation of glutamatergic neurotransmission plays a key role in the etiology of schizophrenia, however, to address dysregulations of glutamatergic neurotransmission in schizophrenia dysregulation of the TCA cycle must be first addressed.