Is there a role for loading dose regimes in aripiprazole therapy?

To the Editor

When the time taken to achieve the steady-state concentration of a drug is long relative to the urgency of the condition to be treated, loading dose regimes are frequently justified (Brunton et al., 2011). Familiar examples from general medicine include digoxin (Brunton et al., 2011) and phenytoin (DiPiro, 2010). In the case of these two medications, a long half-life and a high degree of plasma protein binding respectively militate against the achievement of steady-state plasma concentrations at a rate compatible with optimal management of the conditions for which they are ordinarily indicated. Loading dose strategies have been proposed for a variety of psychiatric medications, particularly sodium valproate in the setting of acute mania, where there is a clear clinical imperative to bring about rapid reduction in symptomatology (Oluboka et al., 2002).

Aripiprazole is a second-generation antipsychotic distinguished by its unique pharmacodynamic profile, namely partial agonism at the dopamine 2 and serotonin 1A receptors, as well as antagonism at the serotonin 2A receptor (Shapiro et al., 2003). This novel pharmacodynamic profile is thought to at least partially explain aripiprazole’s comparatively minimal liability to cause extrapyramidal side effects and metabolic derangements (Newman-Tancredi, 2010).

Aripiprazole is also distinguished from many other antipsychotics in pharmacokinetic terms. Aripiprazole and its only known active metabolite (dehydro-aripiprazole) have long mean plasma half-lives (75 and 100 h respectively) (Australian Government Therapeutic Goods Administration, 2011). Consequently, steady-state concentrations may take up to 14 days to achieve a time frame that is usually incompatible with the optimal management of acute psychosis or mania. Furthermore, the majority of aripiprazole (sometimes > 99%) is bound to plasma proteins, a property reflected in its high volume of distribution (approximately 4.9 L/kg; Australian Government Therapeutic Goods Administration, 2011). Such pharmacokinetic properties may justify the use of loading dose strategies in aripiprazole therapy.

Clearly, the size of a loading dose is limited by the potential for side effects and toxicities. However, there have been a number of reports suggesting that aripiprazole is tolerable and safe in doses that well exceed the licensed maximum (usually 30 mg daily) (Crossman and Lindenmayer, 2006). Inevitably, however, cautionary reports exist (Thone, 2007).

Although the pharmacodynamics of aripiprazole, particularly its tendency to agonise the dopamine 2 receptor in hypodopaminergic environments, may lead to the worsening of the positive symptoms of psychosis (Ramaswamy et al., 2004), an apparent worsening of positive psychotic symptoms following aripiprazole initiation may also be explained by these pharmacokinetic properties, that is to say, the comparatively lengthy time taken for aripiprazole to reach steady-state plasma concentrations may lead to the worsening of psychotic symptoms which are attributed to the drug’s pharmacodynamic properties, rather than the natural history of untreated psychosis.

Given that aripiprazole possesses pharmacokinetic properties that would ordinarily justify loading dose strategies, and given the comparative absence of toxic effects of aripiprazole at doses well above what is considered to be the ordinary therapeutic range, it is possible that some patients would benefit from a loading dose approach to aripiprazole initiation. Although greater efficacy is not expected from high-dose regimes, a loading dose approach to aripiprazole initiation could lead to a more rapid resolution of target symptomatology.