Abstract
Rapid-onset psychotic rebound is uncommon on discontinuation of most antipsychotic drugs, as might be expected for antipsychotic drugs with (hypothetically) indirect actions at their final target receptors. Rapid-onset psychosis is more common on withdrawal of clozapine, which might be expected if its action is direct. Drugs other than clozapine (notably thioridazine) may have hitherto unrecognised similarities to clozapine (but without danger of agranulocytosis), and may be useful in treatment of refractory psychosis. Quetiapine fulfils only some criteria for a clozapine-like drug. Clinical response to neuroleptics varies widely at any given plasma level. Haase’s “neuroleptic threshold” concept suggests that the dose producing the slightest motor side effects produces most or all of the therapeutic benefit, but analyses presented here suggest that antipsychotic actions are not subject to a sharp “all-or-none” threshold but increase over a small dose range. This concept could provide a method for quantitative determination of individualized optimal doses.
Highlights
Rapid-onset psychotic rebound is uncommon on discontinuation of most antipsychotic drugs, as might be expected for antipsychotic drugs with indirect actions at their final target receptors
Apart from the pattern described by Chouinard and colleagues, how is one to understand the two other patterns of events, after withdrawal, respectively of standard neuroleptic drugs, and of clozapine? For clozapine withdrawal, the evidence provides many hints of compensatory change in receptor numbers, leading transiently to severe pathology
Six variables are represented: (i) the number of D2 receptors; (ii) the release of ACh from these neurones; (iii) the number of muscarinic M4 receptors; (iv) the intracellular synthesis of cAMP, which is reduced if the M4 receptors are activated by any available extracellular ACh or agonist drug; (v) the M1 receptors located on the same neu
Summary
Rapid-onset psychotic rebound is uncommon on discontinuation of most antipsychotic drugs, as might be expected for antipsychotic drugs with (hypothetically) indirect actions at their final target receptors. Due to proliferation of previously-blocked M1 receptors, any typical neuroleptic, used to protect against rebound psychosis, acting by acceleration of ACh release, will produce motor side effects more severe than produced by these drugs prior to the use of clozapine.
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