Mechanisms of action of antipsychotic drugs of different classes, refractoriness to therapeutic effects of classical neuroleptics, and individual variation in sensitivity to their actions: Part II

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.

Keywords: Antipsychotic drugs; D1 receptors; D2 receptors; atypical antipsychotic agents.; cholinergic interneurones; individualized dose; muscarinic M1 receptors; muscarinic M4 receptors; neuroleptic drugs; neuroleptic threshold.

Fig. (1)

Events prior to and on discontinuation of chronic regimes of classical (D2-blocking) antipsychotic drugs, and clozapine. See text. 1: On withdrawal of chronic regimes of D2-blocking drugs, release of cAMP production, and psychotic rebound, if it occurs, is not severe. 2: On withdrawal of clozapine, cAMP production increases with little to hold it back (in the short term), and psychotic rebound may be severe. 3: Likewise, on withdrawal of clozapine, substitution by D2-blocking drugs (dashed trace) may produce motor side effects more severe than such drugs would produce prior to clozapine treatment.

Fig. (2)

A (Upper): Plot, for 558 individual psychotic patients treated with haloperidol, of clinical response (expressed as z-score, on vertical axis) versus plasma concentration (ng/ml, log scale, on horizontal axis). See Table II for details of studies from which data were obtained. B (Lower): The same data as in A, with patients divided into 46 overlapping subgroups according to ranges of plasma haloperidol levels. For each subgroup, the graph shows mean clinical response (filled circles) ± SD, and the proportion of patients who failed to give greater-than-placebo clinical response (z≥1) (filled squares). (Left-most subgroup: n=9; subgroups with plasma levels between 7 and 14.5 ng/ml: n=36; all other subgroups: n=18; each patient represented in each of two adjacent groups).

Fig. (3)

Diagram to illustrate one possible interpretation of spread of data points in Fig. (2)A. Left: a number of S-shaped individual dose response curves, each “blurred” in the vertical dimension, are displaced to different degrees in horizontal dimension (representing different individual sensitivities to neuroleptic drugs). Right: If all the curves in the left-hand diagram are standardized to the individual “neuroleptic threshold, so that they all overlap, the distinction between “responders” and “non-responders” becomes clearer.