Does clozapine work by blocking spikes and sparing bursts?

Abstract

Clozapine works better and produces fewer side effects than other antipsychotics. Existing hypotheses fail to explain why. A new hypothesis, single spike suppression, supposes that psychotic symptoms are mediated by the single spikes of neurons at the D2 receptor. All antipsychotics block these spikes. Clozapine, according to the hypothesis, blocks these spikes but, unlike other antipsychotics, spares the spike bursts that mediate movement, cognition and affect. This study explores the mathematical feasibility of single spike suppression. Could an antipsychotic with the right receptor kinetics selectively block single spikes? Could this selectivity have clinical consequences? To develop the hypothesis, the author made a mathematical model of the receptor occupancy of a synapse, and performed five simulations, varying input data within the range established by research. The effects of hypothetical antipsychotics on single spikes and bursts were compared. The author confirmed that a drug with the right dissociation rate constant (k off) would dissociate slowly enough to block single spikes, but rapidly enough to spare longer bursts. If the hypothesis is correct, this spike-selective, burst-sparing drug would work at relatively low D2 occupancies, and cause minimal D2-related side effects. Single spike suppression may explain the superior properties of clozapine better than competing hypotheses. If so, it would provide a better model for a new generation of safe, effective antipsychotics.