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

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.

The More, the Merrier…? Antipsychotic Polypharmacy Treatment Strategies in Schizophrenia From a Pharmacology Perspective

“…In this regard, a systematic review and meta-analysis of randomized controlled trials comparing APP and monotherapy found no differences regarding intolerability-related treatment discontinuation ( 4 ). Moreover, again attesting to the above, it is more likely that APP strategies involving a greater total antipsychotic dose, and thus net target (e.g., D2 receptor) occupancy ( 8 )—at least by antagonist agents [see, e.g., ( 19 )]—would be more liable to increase the AE burden. Conversely, therapeutically useful effects on AE outcome may be achieved by partial DA agonist add-on to CLZ, RIS, OLA, or HAL, to relieve metabolic- and prolactin (PRL)-derived issues ( vide infra ).…”

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

“…The antipsychotics most commonly combined with aripiprazole are clozapine and olanzapine, but only the combination with clozapine has shown greater effectiveness in preventing hospital admission than the antagonist (clozapine) alone in naturalistic studies (Tiihonen 2019); this may reflect better adherence to medication when side-effects such as weight gain are addressed. Such uses have – in contrast to the combination of full antagonists – a possible theoretical basis (Reynolds 2021).…”

Open issues in bipolar and antipsychotic treatments

“…Bipolar disorder treatment frequently requires antipsychotics, but monotherapy, despite being suggested by guidelines (Taylor et al , 2021), is often less common than polytherapy in clinical practice, though with a large variability across centers (Dell’Osso et al , 2020). Polytherapy may be useful in some specific cases (Lähteenvuo and Tiihonen, 2021); however, the combination of full dopamine D2 receptor agonists with partial agonists is debated, given the scarce evidence available (Reynolds, 2021).…”