Combining Aripiprazole and Haloperidol: Focus on D2 Receptor.

Abstract

Antipsychotic polypharmacy, defined as coprescription of 2 or more antipsychotics, is a common treatment for resistant schizophrenia. While one of the most frequently employed combinations is aripiprazole and clozapine, the clinical and pharmacological effects of coadministration of aripiprazole and haloperidol remains understudied and is far from an exhaustive characterization.1,2 From a pharmacological perspective, when aripiprazole is used in combination with haloperidol, 3 substances are competing to bind dopamine receptors: aripiprazole, haloperidol, and endogenous dopamine. Aripiprazole, a partial agonist of low intrinsic activity (57%), is characterized by stronger binding affinity towardD2 receptors (D2Rs) (Ki = 0.11 nM) and slower dissociation kinetics (koff = 31 min), when compared to both haloperidol (Ki = 0.57 nM, koff = 1min) and dopamine (Ki = 16 nM, koff = 24min).3–5 Chronic use of D2 antagonists such as haloperidol has been linked to compensatory up-regulation of D2R in the mesolimbic pathway that may increase the functional dopaminergic activity of D2 agonist aripiprazole; nevertheless, clozapine, a weak D2 antagonist, does not induce dopamine supersensitivity.1,2 Therefore, according to pharmacodynamics, when aripiprazole is added to a stable haloperidol treatment, it displaces the latter off D2R sites and exerts its partial agonist intrinsic activity, exposing the patient to a potential relapse of positive symptoms.3 On the other hand, aripiprazole may attenuate antipsychoticinduced adverse effects such as hyperprolactinemia and ameliorating negative symptoms.1,2 Conversely, the addition of haloperidol to aripiprazole may yield a stronger D2 blockade and subsequently an improvement of positive symptoms, while at same time potentially reduce some of the benefits of aripiprazole’s atypicality, namely, its activity on serotoninergic and dopaminergic transmission (dopamine D2/D3 partial agonism, serotonin 5-HT1A agonism, 5HT2A antagonism).1–3 While our discussion on this topic has been limited to speculative considerations, some of those are generalizable to combinations between antagonists with high affinity for D2R (eg, pimozide, fluphenazine) such as haloperidol may cause dopamine supersensitivity and D2R partial agonists (eg, cariprazine, brexpiprazole) such as aripiprazole may induce excessive dopaminergic activity via the high D2R density induced by long-term exposure to D2R antagonists.