The Serotonin Hypothesis of Schizophrenia

THE SEROTONIN HYPOTHESIS OF SCHIZOPHRENIA

The discovery that indole hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists led to the search for endogenous hallucinogens in the urine, blood, and brains of patients with schizophrenia. This proved fruitless, but the identification of many 5-HT-receptor subtypes led to the piv-otal discovery that 5-HT_2A-receptor and possibly 5-HT_2C stimula-tion was the basis for the hallucinatory effects of these agents.

It has been found that 5-HT_2A-receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs, of which clozapine is the prototype, and includes, in order of their introduction around the world, melperone, risperidone, zotepine, blonanseine olanzapine, quetiapine, ziprasidone, aripiprazole, sertindole, paliperidone, iloperidone, asenapine, and lurasidone. These drugs are inverseagonists of the 5-HT_2Areceptor; that is, they block the consti-tutive activity of these receptors. These receptors modulate the release of dopamine, norepinephrine, glutamate, GABA and acetylcholine, among other neurotransmiters in the cortex, limbic region, and striatum. Stimulation of 5-HT_2A receptors leads to depolarization of glutamate neurons, but also stabiliza-tion of N-methyl-D-aspartate (NMDA) receptors on postsyn-aptic neurons. Recently, it has been found that hallucinogens can modulate the stability of a complex consisting of 5-HT_2A and NMDA receptors.

5-HT_2C-receptor stimulation provides a further means of modulating cortical and limbic dopaminergic activity. Stimulation of 5-HT_2C receptors leads to inhibition of cortical and limbic dop-amine release. Many atypical antipsychotic drugs, eg, clozapine, asenapine, olanzapine are 5-HT_2C inverse agonists. 5-HT_2C agonists are currently being studied as antipsychotic agents.