D-Cell Hypothesis of Schizophrenia Leading to Develop Non-D2 Receptor-Binding Antipsychotics

Abstract

Keiko Ikemoto

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for treatment of schizophrenia. The compound is trace amine-associated receptor 1 (TAAR1) full agonist and also 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), a neuroleptic acting site, of human brains, though they were scarcely found in the monkey, and D-neuron reduction in these regions by using post-mortem brains of patients with schizophrenia. The reduction of D-neurons was significant (t-test, p<0.05) in Acc of schizophrenia. I proposed “D-cell hypothesis of schizophrenia”, a link of dopamine (DA) hypothesis and neural stem cell (NSC) dysfunction hypothesis, showing NSC dysfunction-based D-neuron reduction being cellular basis of mesolimbic DA hyperactivity of schizophrenia, and predicted prospectiveness of TAAR1 ligands for treatment of schizophrenia. This hypothesis has been verified by effectiveness of a TAAR1 agonist in reducing symptoms of schizophrenia.

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