Schizophrenia: glutamate and brain structure

The glutamate hypothesis

Glutamate is the brain's main excitatory neurotransmitter. The hypothesis says schizophrenia involves underactivity (hypofunction) of NMDA glutamate receptors.

Evidence

• Javitt and Zukin (1991): PCP and ketamine, which block NMDA receptors, produce schizophrenia-like symptoms in healthy volunteers, including negative symptoms and cognitive deficits, which the dopamine hypothesis struggles to explain.
• Ketamine can produce dopamine abnormalities like those in schizophrenia, suggesting NMDA problems may disrupt the regulation of dopamine.
• Demjaha et al. (2014) reported that some patients who do not respond to antipsychotics have raised glutamate with normal dopamine function.

Brain structure

Neuroimaging (9.1.9) has found structural differences on average.

• Johnstone et al. (1976) used CT scans of long-stay (institutionalised) patients with chronic schizophrenia and found enlarged ventricles (fluid-filled spaces) compared with controls; larger ventricles went with greater cognitive impairment.
• Criticism: most patients were taking antipsychotics, which may affect the brain; later studies of unmedicated patients still found some average differences, but not in everyone with the diagnosis.

Evaluation

• Glutamate explains negative and cognitive symptoms better than dopamine alone, but glutamate-based drugs have failed in large trials so far, and the evidence relies partly on drug models.
• Brain structure evidence is objective (scans) but correlational: differences could be a cause, an effect of illness, or an effect of medication.
• Both are reductionist, but combine with dopamine and genes into a fuller biological account (9.3.4).

Worked example

Why does ketamine research support the glutamate hypothesis more than the dopamine hypothesis?

1. Ketamine blocks NMDA glutamate receptors.
2. In healthy volunteers it produces negative symptoms and cognitive deficits as well as positive symptoms.
3. Amphetamine (a dopamine drug) mainly produces positive symptoms, so glutamate hypofunction explains the full range of symptoms better.

Answer: Blocking glutamate receptors reproduces negative and cognitive symptoms, which dopamine models do not.

Check yourself

1. The glutamate hypothesis suggests schizophrenia involves
   • overactivity of D2 receptors only
   • underactivity of NMDA receptors
   • too much serotonin
   • too little cortisol
   Show answer

   underactivity of NMDA receptors. NMDA hypofunction.

2. Which drug, when given to healthy volunteers, produces negative symptoms and cognitive deficits?
   • Amphetamine
   • Fluoxetine
   • Chlorpromazine
   • Ketamine
   Show answer

   Ketamine. Ketamine blocks NMDA receptors.

3. What did Johnstone et al. (1976) find using CT scans?
   • Smaller ventricles in patients
   • Enlarged ventricles in patients with schizophrenia
   • No differences at all
   • Excess dopamine in the blood
   Show answer

   Enlarged ventricles in patients with schizophrenia. Ventricles were larger on average in patients.

4. Why can Johnstone et al. (1976) not show that enlarged ventricles cause schizophrenia?
   • CT scans cannot show ventricles
   • There was no control group
   • The patients had long illnesses and medication, which could have affected the brain
   • The patients were all children
   Show answer

   The patients had long illnesses and medication, which could have affected the brain. The patients were long-stay chronic patients, mostly medicated, so brain differences could be effects of illness or treatment.

5. Explain why brain structure findings cannot show that brain differences cause schizophrenia.
   Show answer

   The findings are correlational, so enlarged ventricles could be a result of the illness or of antipsychotic medication rather than its cause.. Correlation, plus medication as a confounding variable.

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Sources

• Pearson Edexcel International Advanced Subsidiary/Advanced Level in Psychology specification (issue January 2026)
• Pearson IAL Psychology component guide: WPS04 (Issue 2, November 2024)
• Psychiatric Times: Glutamate and schizophrenia, theory and treatment implications
• Johnstone, Crow, Frith, Husband and Kreel (1976), Cerebral ventricular size and cognitive impairment in chronic schizophrenia, The Lancet
• Howes and Kapur (2009), The dopamine hypothesis of schizophrenia: version III, the final common pathway, Schizophrenia Bulletin

Last updated 8 November 2026. Spotted a mistake? Tell us.