A Serotonin Hypothesis of Schizophrenia

Chronic widespread stress-induced serotonergic overdrive in the cerebral cortex in schizophrenia, especially in the anterior cingulate cortex (ACC) and dorsolateral frontal lobe, is the basic cause of the disease. The concept of excessive serotonergic stimulation is supported by NMR spectroscopy; peripheral depletion of phospholipids, serotonergic 5-HT2A receptors being linked to phospholipase A2; positron emission tomography data with serotonergic ligands; and the fact that blockade of serotonergic 5-HT2A receptors by atypical neuroleptics slows down the course of the disease. Disruption of glutamate signalling by serotonergic overdrive leads to neuronal hypometabolism and ultimately synaptic atrophy and grey matter loss according to principles of brain plasticity. Normal dopamine input to an impaired ACC causes positive symptoms. Frontal lobe hibernation causes negative symptoms and cognitive impairment.