On the mechanism of action of antipsychotic drugs: a chemical reaction not receptor blockade.

Over forty years ago, biochemist Lauro Galzigna conducted an in-vitro experiment showing that the antipsychotic chlorpromazine reacted with the putative psychotogen adrenochrome to form a polymer resembling melanin. The field of psychopharmacology has essentially ignored that simple but illustrative experiment in the intervening time. The present study reproduces principle elements of Galzigna's experiment and expands the scope to include the antipsychotic medications olanzapine and minocycline. The rate of reaction was slow, with maximal yield of black polymer being achieved by 4, 10 and 7 days with chlorpromazine, olanzapine and minocycline, respectively. Changing the pH was most informative for chlorpromazine and minocycline reactions, where yield increased sharply between pH 6.1 and 6.9, and decreased slightly between pH 6.9 and 7.8, consistent with reaction profiles expected for aromatic substitution. Preincubation of olanzapine with iodine doubled the polymer yield, facilitated by the addition of iodine to the aromatic ring and presumably followed by its departure as a "leaving group". Increasing the salt concentration 1.5-fold depressed yields for all three drugs, most likely via ionic shielding of charged functional groups, diminishing reactivity. The results are discussed in regards to the mechanism of action of antipsychotic medications, casting doubt on commonly held theories. The time course of the chemical reactions presented here and the concentrations required, are much more consistent with clinical results than are models concerning receptor-mediated mechanisms. Furthermore, minocycline was effective in this model, but does not appear to have affinity for the primary receptor families thought by many to mediate antipsychotic efficacy.