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

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

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

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

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.

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*

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.

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

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

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

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