The serotonin (5HT) hypothesis of schizophrenia actually pre-dates that of DA. The ability of the hallucinogen lysergic acid diethylamide (LSD) to antagonize the effects of 5HT on smooth muscle led to the hypothesis that schizophrenia was caused by a decrease in central serotonergic function.11 This theory, largely predicated on the similarities between schizophrenic psychosis and LSD-induced hallucination, was modified with the discovery that LSD could act as a 5HT agonist in some systems. These findings led to the search for endogenous psychotogens, an effort that never bore convincing fruit. With the discovery of chlorpromazine 1, interest in DA D2 receptors rapidly supplanted interest in the 5HT system. The observation that 5HT2A antagonism is a defining characteristic of the newer 'atypical' antipsychotics, together with recent evidence that all effective antipsychotics are 5HT2A inverse agonists,12 has reawakened interest in the role of 5HT in schizophrenia. To date there has been no compelling evidence to suggest a global increase in brain 5HT markers in schizophrenia. However, there are significant interactions between the 5HT and DA systems suggesting that a more subtle alteration in 5HT may be involved.
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