1. Causes of Schizophrenia:
Glutamate and the Glutamate Hypothesis
Erik Messamore, MD, PhD
Associate Professor of Psychiatry, Northeast Ohio Medical University
Medical Director, Best Practices for Schizophrenia Treatment (BeST) Center
Option 1

2. The Schizophrenias. Beyond Dopamine
Known…
Dopamine hypothesis has dominated thought about schizophrenia cause
All FDA-recognized treatments are dopamine receptor antagonists
But…
DA receptor antagonism does not relieve all symptoms of schizophrenia
DA receptor antagonists are ineffective for a portion of patients with schizophrenia
Clozapine is the most effective schizophrenia treatment, yet is the weakest dopamine receptor antagonist
Therefore…
Need to address other possible contributing factors, and treatments other than dopamine receptor antagonism

3. Glutamate The most important of the amino acid neurotransmitters
Other major amino acid neurotransmitters include:
aspartate (excitatory)
glycine (inhibitory)
GABA (inhibitory)
Glutamate is the most abundant neurotransmitter in the brain
> 50% of synapses are glutamate synapses

4. Evidence for Glutamate Dysfunction in Schizophrenia
NMDA receptor antagonists produce psychotic symptoms (that more closely resemble many features of schizophrenia, incl. cognitive and negative sx)
NMDA receptor antagonists reproduce electrophysiological abnormalities observed in patients with schizophrenia
NMDA receptor antibody encephalitis can present as a schizophrenia-identical syndrome
Genome-wide association studies in schizophrenia consistently implicate genes related to the NMDA receptor
Decreased expression of NMDA receptor genes in post-mortem brain
Numerous imaging studies showing abnormal levels of glutamate in vivo with schizophrenia
Psychotogenic NMDA receptor antagonists include:
Phencyclidine (PCP)
Ketamine

5. Reduced NMDA Receptor Binding in Medication-Free Schizophrenia
Pilowsky, L. S., Bressan, R. A., Stone, J. M., Erlandsson, K., Mulligan, R. S., Krystal, J. H., & Ell, P. J. (2006). First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Molecular Psychiatry, 11(2), 118–119.

6. Receptors for Glutamate
Two receptor families
1. Metabotropic receptor family
glutamate signal at these receptors changes phospholipase C activity or cAMP levels
→ slower-acting changes in excitability, gene expression
mGluR 1/5
mGluR 2/3
mGluR 4/6/7/8
2. Ionotropic receptor family
these are glutamate-activated ion channels (Ca and/or Na)
→ rapid changes in cell membrane potential → cell signaling, LTP, apoptosis
quisqualate receptor,
kainate receptor,
N-methyl-D-aspartate (NMDA) receptor*

7. Proposed Role for NMDA Receptor Hypofunction in Psychosis
Tsutsui, K., Kanbayashi, T., Takaki, M., Omori, Y., Imai, Y., Nishino, S., … Shimizu, T. (2017). N-Methyl-D-aspartate receptor antibody could be a cause of catatonic symptoms in psychiatric patients: case reports and methods for detection. Neuropsychiatric Disease and Treatment, 13, 339–345.

8. NMDA Receptor Hypofunction is Associated with Increased Glutamate Levels
Elevated levels of glutamate, especially if accompanied by increased synaptic release, may account for aberrant synaptic pruning or neurotoxicity

9. Glutamate-Modifying Medications
The following have shown benefit as adjunctive agents in the treatment of schizophrenia:
NMDA Receptor Co-Agonists
May augment glutamate signaling in the setting of hypofunctional NMDA receptor
Glycine
d-Serine
d-Cycloserine
Glycine Transport Inhibitors
Elevate synaptic glycine levels, thus indirectly augmenting glutamate signal at the NMDA receptor
- Sarcosine

10. Glutamate-Modifying Medications
Medications that block glutamate release or partially block NMDA receptor, yet have shown benefit in the treatment of schizophrenia
Memantine
Minocycline
Lamotrigine
Topiramate

11. Summary
Biomarkers of abnormal glutamate signaling are abundant in schizophrenia
NMDA receptor hypoactivity is a hypothesis to account for psychosis - as well as negative and cognitive symptoms of schizophrenia
Elevated glutamate levels are also present in schizophrenia, may account for excessive pruning or neurotoxicity
Drugs that augment NMDA receptor function show early signs of efficacy
Drugs that limit glutamate signal and/or limit glutamate release also show efficacy