2023 NEI Synapse: Novel Receptor Science in Schizophrenia
March 30, 2023   

2023 NEI Synapse Session Highlight

New Approaches: Novel Receptor Science in Schizophrenia
Presented by Stephen M. Stahl, MD, PhD, DSc (Hon.) and Andrew J. Cutler, MD

Thursday, March 30, 2023

The 2023 NEI Synapse opened up with an insightful presentation by NEI's founder Dr. Stephen Stahl and Chief Medical Officer of NEI, Dr. Andrew Cutler, titled “ New Approaches: Novel Receptor Science in Schizophrenia.” As the title suggests, this presentation covered new knowledge of the neurobiological mechanisms that contribute to the symptoms of schizophrenia along with new pharmacotherapies that are either now available or in clinical trials. To begin, Dr. Stahl reviewed the classical dopamine theory of schizophrenia, which included the idea that a hyperactive mesolimbic dopamine pathway leads to positive symptoms of psychosis and a hypoactive mesocortical dopamine pathway leads to negative symptoms of psychosis. He expanded on this theory by discussing the role of serotonin and its function as a modifier for these dopaminergic pathways. Specifically, increased serotonergic signaling to these dopaminergic pathways contributes to both the positive and negative symptoms of schizophrenia. New medications are now in clinical trials that act as either serotonin 5HT-2A receptor antagonists or inverse agonists to modify these dopaminergic signals and aid in the symptoms of schizophrenia.

In addition to discussing the serotonergic and dopaminergic effects on schizophrenia, Dr. Stahl and Dr. Cutler discussed the glutamate theory of schizophrenia and how new medications target cholinergic circuits to modify glutamatergic signaling to reduce psychotic symptoms. These new procholinergic drugs help to alleviate psychotic symptoms by binding to postsynaptic M1 receptors located on GABA interneurons in the frontal cortex to affect the mesocortical pathway, or to presynaptic M4 receptors of cholinergic projections that modulate the mesolimbic pathway. In the case of M1 agonists, activation of M1 receptors increases the activity of GABA interneurons in the frontal cortex, which send inhibitory signals to overactive glutamatergic inputs to mesocortical dopaminergic pathways. The increase in inhibitory signals helps to dampen the overactive glutamatergic signals and increase dopamine release in the frontal cortex. In contrast, the M4 agonist acts at presynaptic cholinergic projections to mesolimbic dopamine pathways to decrease dopaminergic activity.

Finally, Dr. Stahl and Dr. Cutler discussed the new findings surrounding the role of trace amine-associated receptor 1 (TAAR1). Amines are formed in trace concentrations from the amino acid tyrosine and tryptophan when either tyrosine hydroxylase or trytophan hydroxlyase are omitted. These trace amines bind to intracellular TAAR1 receptors to bias G-protein coupled receptor mechanisms of dopamine and serotonin receptors to the inhibitory pathway. In the case of presynaptic TAAR1 receptor modulation, this results in a decrease in the neurotransmitter available to be loaded into presynaptic vesicles. Overall, this fascinating presentation by Dr. Stahl highlights the new thinking surrounding the treatment and understanding of psychosis.

Dr. Stephen Stahl, MD, PhD, DSc & Dr. Andrew Cutler, MD. New Approaches: Novel Receptor Science in Schizophrenia. Presented March 31 at 2023 NEI Synapse, Nashville, TN.

To Learn More: The recording of this presentation, as well as all of the other presentation from the 2023 NEI Synapse, will be available as Encore Presentations for NEI Members.


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