High dose antipsychotic polypharmacy and dopamine partial agonists - time to rethink guidelines?

Gavin P Reynolds

doi:10.1177/02698811211026456

Abstract

Guidelines for the treatment of schizophrenia limit the use of antipsychotic agents to clinically-established maximum doses. This acknowledges both the absence of additional efficacy of dopamine D2 receptor antagonists above a receptor occupancy threshold, and the increases in side effects that can occur at higher doses. These limits restrict the dosing of combinations of antipsychotics as they do single agents; drugs sharing the major antipsychotic mechanism of D2 receptor antagonism will act additively in blocking these receptors.Several newer antipsychotic drugs, including aripiprazole and cariprazine, act as partial agonists at the D2 receptor site and avoid action at several other receptors, effects at which are responsible for some non-dopaminergic adverse effects. This pharmacology imparts different characteristics to the drugs resulting often in a more favourable side effect profile. Their partial agonism, along with high affinities for the D2 receptor, also means that these drugs given adjunctively may in part replace, rather than enhance, the D2 antagonism of other antipsychotic agents. This can result in an improvement in certain side effects without loss of antipsychotic efficacy.This article makes the case for distinguishing the D2 partial agonists from antagonists in defining maximum doses of combined treatments, which would increase the options available to the prescriber, emphasising that pharmacological mechanisms need to be understood in identifying optimal treatments for psychotic illness.

Highlights

Guidelines for the treatment of schizophrenia limit the use of antipsychotic agents to clinically-established maximum doses
The rationale is clear: Combining two D2 antagonists at half maximum dose should approximate to the effects of one drug at maximum dose, it is limited by inconsistencies in determining maximum doses, with newer drugs generally having more constrained dose ranges
The availability of aripiprazole and cariprazine, as well as brexpiprazole in many countries outside the UK, has provided psychiatry with useful alternatives to the various dopamine D2 receptor antagonists that have been the mainstay in the treatment of psychosis for over 60 years

Summary

Introduction

Guidelines for the treatment of schizophrenia limit the use of antipsychotic agents to clinically-established maximum doses. Barnes TR, Drake R, Paton C, et al (2020) Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology.

Results

Conclusion