3.3.3.5 The Glutamatergic Hypothesis

Glutamate receptors

• NMDA activation needs glutamate, a co-agonist (glycine or D-serine) and depolarisation to remove the magnesium block.

• Astrocytes clear glutamate and recycle it through glutamine, which limits toxicity.

NMDA hypofunction in schizophrenia

• Phencyclidine blocks the NMDA channel non-competitively. It and ketamine reproduce the positive, negative and cognitive features of schizophrenia and worsen existing psychosis.

• This broader picture supports a role for glutamate in symptoms that D2 blockade treats poorly.

• Proposed causes of hypofunction are altered subunits, reduced co-agonist, oxidative modification and altered transmitter release.

Interneurones and dopamine

• Parvalbumin-positive interneurones set pyramidal cell timing and gamma oscillations; post-mortem studies report reduced parvalbumin and glutamic acid decarboxylase 67.

• Weak excitation of these interneurones disinhibits pyramidal neurones and disorganises their output.

• Prefrontal and hippocampal glutamate regulates midbrain dopamine, so circuit disruption could cause striatal dopamine abnormalities. This may explain why D2 antagonists help positive symptoms more than cognitive deficits.

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Drug evidence

• Ketamine rapidly improves depression and suicidal ideation, possibly through interneurone disinhibition, increased AMPA activity, brain-derived neurotrophic factor and mammalian target of rapamycin signalling.

• Glycine-site and metabotropic drugs have given mixed results in schizophrenia.

Limits of the evidence

• Magnetic resonance spectroscopy measures tissue glutamate, often combined with glutamine, not synaptic release.

• Excess glutamate and receptor hypofunction can coexist in different circuits, giving apparently conflicting findings.