Partial agonists of dopamine receptors: theoretical principles of combining antipsychotics including partial agonists to treat schizophrenia

Abstract

SUMMARY Partial agonists such as aripiprazole are often used in addition to a full antagonist such as amisulpride, risperidone or olanzapine in an attempt to mitigate side-effects such as sedation, hyperprolactinaemia and weight gain. However, there can be unintended consequences, including worsening of psychosis. Moreover, previous exposure to a partial agonist may impair the subsequent response to a potent antipsychotic such as haloperidol used to control symptoms of relapse. To understand the mechanisms involved, a method is needed to compare potency in the pharmacological effects of different drugs used in combinations. This article is intended to explore and explain the theoretical principles based on the dopamine hypothesis of schizophrenia. We apply the method to analyse a recently described trial in which two full antagonists (olanzapine and amisulpride) are compared individually and in combination.

Partial agonists of dopamine receptors: clinical effects and dopamine receptor interactions in combining aripiprazole with a full antagonist in treating psychosis

“…We have seen in a previous article (Cookson 2023c) that increasing doses of a partial agonist with 25% intrinsic activity, given alone, can achieve antagonistic occupancy up to a maximum of 75%.…”

“…The maximum degree of antagonist occupancy that can be achieved by aripiprazole is 75%, assuming intrinsic activity of 25% (see Cookson 2023c). This means that by combining the two drugs in varying proportions at high doses, the level of antagonistic occupancy can be manipulated to anywhere between 73% (aripiprazole 30 mg/day alone) and 91% (amisulpride 1200 mg/day); at lower doses it is between 68% (aripiprazole 10 mg/day alone) and 80% (amisulpride 600 mg/day).…”

“…We base this analysis on the levels of dopamine D 2 /D 3 receptor occupancy required at different stages of schizophrenia – namely, 66% occupancy for treating a first episode or in long-term maintenance to prevent relapse and 70–80% occupancy to treat an acute relapse. The figures associated with 50% occupancy of D 2 /D 3 receptors in the striatum by individual antipsychotics, as reported previously, are assumed (Cookson 2023c).…”

“…We have previously reviewed the nature of partial agonism of dopamine receptors (Cookson 2023a) and the qualities of three partial agonists, aripiprazole, brexpiprazole and cariprazine (Cookson 2023b). We have also described the practice of combining different antipsychotics, possible rationales and a theoretical model to analyse dopamine receptor occupancy with single or combined antipsychotics (Cookson 2023c).…”

Rhyme or reason in therapeutics

“…Finally, to add further reason to the rhyme of prescribing antipsychotics, a series of papers address the use of partial agonists at dopamine receptors and alone or in combination with other antipsychotics (Cookson 2023a(Cookson , 2023b(Cookson , 2023c(Cookson , 2023d.…”