Glutamate is an amino acid neurotransmitter and the main excitatory transmitter in the central nervous system. Glutamate receptors can be classified into two major categories, ionotropic and metabotropic receptors. The ionotropic glutamate receptors includes the N-methyl-D-aspartic acid (NMDA) receptor and has been investigated in respect to its possible involvement in schizophrenia. The glutamate hypothesis postulates that the activity of the NMDA receptor is compromised in schizophrenia.



The concept of a hypofunction of the glutamate transmitter system was proposed as a causal mechanism in schizophrenia. A study showed that patients with schizophrenia had low levels of glutamate in the cerebrospinal fluid. This theory was not successful because these findings could not be achieved in subsequent studies.

However, the glutamate hypofunction hypothesis has recently been formulated based on the findings that NMDA non-competitive receptor antagonists such as phencyclidine (PCP; angel dust) and ketamine can induce psychotic symptoms in healthy individuals and can significantly exacerbate pre-existing symptoms in patients with schizophrenia. The range of symptoms produced includes positive, negative and cognitive symptoms, in particular affecting memory. Therefore, since NMDA is a glutamate receptor and NMDA antagonists induce sympotoms of schizophrenia, it has been postulated that schizophrenia is due to an underactivity of the glutamatergic system. It has also been hypothesised that an abnormal glutamate function, particularly a hypofunction of NMDA, may explain the cognitive deficit that is increasingly recognised as a central feature of schizophrenia, responsible in part for the negative symptoms of the disorder. 

The glutamate system influences many other neuronal networks, including the dopaminergic system. A reduction in NMDA function has been seen to cause a lack of inhibition of mesolimbic dopamine neurones. This subsequently increases the release of mesolimbic dopamine and hence the production of positive symptoms.

One possibility is therefore that excess dopamine receptor activation is mainly responsible for positive symptoms, which is secondary to a primary deficiency of NMDA- receptor activation which is responsible for the negative symptoms.

This theory has been further supported by the glutamate co-agonist, glycine. Glycine has been shown to produce antipsychotic effects and seems to consistently improve cognition and reduce persistent negative symptoms in patients with schizophrenia.