a Azienda Sanitaria Provinciale di Agrigento, CSM Licata, Licata, Italy
b Azienda Socio Sanitaria Territoriale Ovest Milanese, Milano, Italy
c Department of Molecular and Developmental Medicine, University of Siena School of Medicine, Italy
d Azienda Unità Sanitaria Locale Toscana Centro, CSM Scandicci, Firenze, Italy
Despite the lack of evidence, use of higher than recommended antipsychotic doses is common in refractory patients with schizophrenia [1, 2]. The Royal College of Psychiatrists (United Kingdom) defines high-dose antipsychotic therapy as “a total daily dose of a single antipsychotic which exceeds the upper limit stated in the Summary of Product Characteristics (SPC) or British National Formulary (BNF) with respect to the age of the patient and the indication being treated…” . In clinical practice, aripiprazole is one of the second-generation antipsychotics most used at high dose . 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 randomised controlled trial (RCT) evaluated safety and efficacy of intramuscular injection of aripiprazole lauroxil 441 mg (300-mg aripiprazole 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 differences in efficacy and safety  although a post hoc analysis of this study found that the higher dose was more effective in patients with more severe illness . Another double-blind RCT study investigated efficacy and safety of different dosages of aripiprazole including overdoses. Forty patients with stable schizophrenia 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 . 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 . In contrast, a study evaluating aripiprazole serum levels for 283 patients under steady-state conditions showed concentration-related side effects . Aripiprazole is an atypical antipsychotic 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 . 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/adrenergic transmission . Results from a naturalistic study suggest that high-dose first-generation antipsychotics may be beneficial in subpopulations . With antipsychotic overdose, one of the major concerns is the frequency of dose-dependent QTc prolongation and extra pyramidal symptoms (EPS) [12, 16]. The low frequency of EPS with high doses, mediated by D2 partial agonism / 5-HT2 receptor antagonism [6, 13, 17], and the capability to reduce QTc interval  make it a safer antipsychotic choice if high dosages are necessary. Differences in absorption, CYP 450 metabolism, penetration across the blood-brain barrier may explain the extensive human pharmacokinetic variability of aripiprazole and subtherapeutic drug plasma levels at a standard dose . 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 adequate trials with two different antipsychotics) should be preferred .
|Source||Age and diagnosis||Aripiprazole dosage||Time (weeks)||Outcome|
|Chavez and Poveda 2006 ||57-year-old patient with schizophrenia||60 mg/d||28||No worsening of symptoms. No adverse effects|
|Duggal and Mendhekar 2006 ||21-year-old patient with schizophrenia||75 mg/d||4||Improvement in psychotic symptoms. No adverse effect except sinus tachycardia|
|Thone 2007 ||31-year-old patient with schizophrenia||60 mg/d||Not available||No improvement in psychotic symptoms. Safety data not reported|
|Wichowicz et al. 2012 ||30-year-old patient with schizophrenia||105 mg/d||2||No improvement in psychotic symptoms. No adverse effect except mild EPS and akathisia|
|Bartova et al. 2015 ||72-year-old patient with schizophrenia||1200 mg/4 weeks (long-acting formulation)||12||Improvement in psychotic symptoms. No adverse effects|
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.
ASPAG, CSM LICATA
c/o Ospedale San Giacomo D'Altopasso
1. Royal College of Psychiatrists. (2014) Consensus statement on high-dose antipsychotic medication. Royal College of Psychiatrists. College Report CR190, 2014. [cited 2022 February 08]. Available from <span class="mat-content ng-tns-c44-42">https://www.rcpsych.ac.uk/docs/default-source/members/faculties/rehabilitation-and-social-psychiatry/rehab-cr190.pdf?sfvrsn=d8397218_4 </span>
2. Andersen SE, Johansson M, Manniche C. The prescribing pattern of a new antipsychotic: a descriptive study of aripiprazole for psychiatric in-patients. Basic Clin Pharmacol Toxicol. 2008 Jul;103(1):75–81. http://dx.doi.org/10.1111/j.1742-7843.2008.00233.x PubMed
4. Duggal HS, Mendhekar DN. High-dose aripiprazole in treatment-resistant schizophrenia. J Clin Psychiatry. 2006 Apr;67(4):674–5. http://dx.doi.org/10.4088/jcp.v67n0420c http://dx.doi.org/10.4088/JCP.v67n0420c PubMed
5. Thone J. Worsened agitation and confusion in schizophrenia subsequent to high-dose aripiprazole. J Neuropsychiatry Clin Neurosci. 2007;19(4):481–2. http://dx.doi.org/10.1176/jnp.2007.19.4.481 PubMed
6. Wichowicz H, Wilkowska A, Landowski J. Daily dose of 105 mg aripiprazole because of delusional origin: a case report. Psychiatr Danub. 2012 Dec;24(4):400–1. Available from: https://pubmed.ncbi.nlm.nih.gov/23132192/ PubMed
7. Bartova L, Dold M, Rieder NP, Heiden NA, Kasper S. Ultra-High-Dose Long-Acting Injectable Aripiprazole in Chronic Refractory Schizophrenia: A Case Report. J Clin Toxicol. 2015;5(5):270. Available from: https://www.longdom.org/open-access/ultrahighdose-longacting-injectable-aripiprazole-in-chronic-refractory-schizophrenia-a-case-report-50460.html http://dx.doi.org/10.4172/2161-0495.1000270
8. Meltzer HY, Risinger R, Nasrallah HA, Du Y, Zummo J, Corey L A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia. J Clin Psychiatry. 2015 Aug;76(8):1085–90. http://dx.doi.org/10.4088/JCP.14m09741 PubMed
9. Potkin SG, Risinger R, Du Y, Zummo J, Bose A, Silverman B Efficacy and safety of aripiprazole lauroxil in schizophrenic patients presenting with severe psychotic symptoms during an acute exacerbation. Schizophr Res. 2017 Dec;190:115–20. http://dx.doi.org/10.1016/j.schres.2017.03.003 PubMed
10. Auby P, Saha A, Ali M, Ingenito G, Wilber R, Bramer S. Safety and tolerability of aripiprazole at doses higher than 30 mg. Eur Neuropsychopharmacol. 2002;12 Suppl 3:S288. Available from: https://www.sciencedirect.com/science/article/pii/S0924977X02804060?dgcid=api_sd_search-api-endpoint http://dx.doi.org/10.1016/S0924-977X(02)80406-0
11. Mace S, Taylor D. Aripiprazole: dose-response relationship in schizophrenia and schizoaffective disorder. CNS Drugs. 2009 Sep;23(9):773–80. http://dx.doi.org/10.2165/11310820-000000000-00000 PubMed
12. Kirschbaum KM, Müller MJ, Malevani J, Mobascher A, Burchardt C, Piel M Serum levels of aripiprazole and dehydroaripiprazole, clinical response and side effects. World J Biol Psychiatry. 2008;9(3):212–8. http://dx.doi.org/10.1080/15622970701361255 PubMed
14. Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology. 2002 Aug;27(2):248–59. http://dx.doi.org/10.1016/S0893-133X(02)00304-4 PubMed
15. Fountoulakis KN, Gonda X, Siamouli M, Moutou K, Nitsa Z, Leonard BE Higher than recommended dosages of antipsychotics in male patients with schizophrenia are associated with increased depression but no major neurocognitive side effects: results of a cross-sectional pilot naturalistic study. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Apr;75:113–9. http://dx.doi.org/10.1016/j.pnpbp.2017.01.013 PubMed
16. Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs. 2002;62(11):1649–71. http://dx.doi.org/10.2165/00003495-200262110-00006 PubMed
17. Crapanzano C, Laurenzi PF, Amendola C, Casolaro I. Clinical perspective on antipsychotic receptor binding affinities. Br J Psychiatry. 2021 Nov-Dec;43(6):680–1. http://dx.doi.org/10.1590/1516-4446-2021-2245 PubMed
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