Despite the lack of evidence, use of higher than recommended antipsychotic doses is common in refractory patients with schizo- phrenia [1, 2]. The Royal College of Psychia- trists (United Kingdom) defines high-dose an- tipsychotic therapy as “a total daily dose of a single antipsychotic which exceeds the upper limit stated in the Summary of Product Char- acteristics (SPC) or British National Formulary (BNF) with respect to the age of the patient and the indication being treated…” [1]. In clini- cal practice, aripiprazole is one of the second-generation antipsychotics most used at high dose [2]. Several case reports of aripiprazole at high dose (>30 mg/d) have been published showing mixed results about efficacy and safety (
Table 1) [3–7]. A double blind ran- domised controlled trial (RCT) evaluated safe- ty and efficacy of intramuscular injection of aripiprazole lauroxil 441 mg (300-mg aripipra- zole equivalent), aripiprazole lauroxil 882 mg (600-mg aripiprazole equivalent) or placebo in 623 patients with acute exacerbation of symptoms of schizophrenia. Neither aripiprazole dose showed clinically significant differ- ences in efficacy and safety [8] although a post hoc analysis of this study found that the high- er dose was more effective in patients with more severe illness [9]. Another double-blind RCT study investigated efficacy and safety of different dosages of aripiprazole including overdoses. Forty patients with stable schizo- phrenia spectrum disorders, randomised to aripiprazole 30 mg/d, 45 mg/d, 60 mg/d, 75 mg/d or 90 mg/d for more than 15 days did not show clinically significant differences in efficacy and safety [10]. In line with this study, an analysis performed on efficacy data from five short term RCTs (n = 1605) showed that doses above 20 mg/d did not provide additional benefit or even reduce efficacy [11]. In contrast, a study evaluating aripiprazole se- rum levels for 283 patients under steady-state conditions showed concentration-related side effects [12]. Aripiprazole is an atypical antipsy- chotic characterized by a 5-hydroxytryptamine (5-HT)1A agonism, 5-HT2A antagonism and a partial agonism, low dissociation kinetics and high binding affinity towards dopamine D2/ D3 receptors [13]. A dose of 30 mg/d induces a D2/D3 receptor occupancy of almost 95%, therefore additional doses exert mainly a greater effect on serotonin/histamine/adren- ergic transmission [14]. Results from a natu- ralistic study suggest that high-dose first-gen- eration antipsychotics may be beneficial in subpopulations [15]. With antipsychotic over- dose, one of the major concerns is the fre- quency of dose-dependent QTc prolongation and extra pyramidal symptoms (EPS) [12, 16]. The low frequency of EPS with high doses, me- diated by D2 partial agonism / 5-HT2 receptor antagonism [6, 13, 17], and the capability to reduce QTc interval [18] make it a safer anti- psychotic choice if high dosages are neces- sary. Differences in absorption, CYP 450 me- tabolism, penetration across the blood-brain barrier may explain the extensive human pharmacokinetic variability of aripiprazole and subtherapeutic drug plasma levels at a standard dose [2]. Although some patients experience increased benefit from receiving high-dose antipsychotics, the current evidence does not support this pharmacological strategy in resistant schizophrenia. Switching medication or clozapine (after failure of ade- quate trials with two different antipsychotics) should be preferred [1].
Disclosure statement:
The authors declare that the research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. They also declare no conflicts of interest.
