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. 2020 Oct;86(10):2051-2062.
doi: 10.1111/bcp.14300. Epub 2020 Apr 27.

The effects of aripiprazole and olanzapine on pupillary light reflex and its relationship with pharmacogenetics in a randomized multiple-dose trial

Dora Koller  1 , Miriam Saiz-Rodríguez  1 , Pablo Zubiaur  1 , Dolores Ochoa  1   2 , Susana Almenara  1 , Manuel Román  1   2 , Daniel Romero-Palacián  1 , Alejandro de Miguel-Cáceres  1 , Samuel Martín  1   2 , Marcos Navares-Gómez  1 , Gina Mejía  1   2 , Aneta Wojnicz  1 , Francisco Abad-Santos  1   2
Affiliations

The effects of aripiprazole and olanzapine on pupillary light reflex and its relationship with pharmacogenetics in a randomized multiple-dose trial

Dora Koller et al. Br J Clin Pharmacol. 2020 Oct.

Abstract

Aims: Pupillography is a noninvasive and cost-effective method to determine autonomic nerve activity. Genetic variants in cytochrome P450 (CYP), dopamine receptor (DRD2, DRD3), serotonin receptor (HTR2A, HTR2C) and ATP-binding cassette subfamily B (ABCB1) genes, among others, were previously associated with the pharmacokinetics and pharmacodynamics of antipsychotic drugs. Our aim was to evaluate the effects of aripiprazole and olanzapine on pupillary light reflex related to pharmacogenetics.

Methods: Twenty-four healthy volunteers receiving 5 oral doses of 10 mg aripiprazole and 5 mg olanzapine tablets were genotyped for 46 polymorphisms by quantitative polymerase chain reaction. Pupil examination was performed by automated pupillometry. Aripiprazole, dehydro-aripiprazole and olanzapine plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry.

Results: Aripiprazole affected pupil contraction: it caused dilatation after the administration of the first dose, then caused constriction after each dosing. It induced changes in all pupillometric parameters (P < .05). Olanzapine only altered minimum pupil size (P = .046). Polymorphisms in CYP3A, HTR2A, UGT1A1, DRD2 and ABCB1 affected pupil size, the time of onset of constriction, pupil recovery and constriction velocity. Aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics were significantly affected by polymorphisms in CYP2D6, CYP3A, CYP1A2, ABCB1 and UGT1A1 genes.

Conclusions: In conclusion, aripiprazole and its main metabolite, dehydro-aripiprazole altered pupil contraction, but olanzapine did not have such an effect. Many polymorphisms may influence pupillometric parameters and several polymorphisms had an effect on aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics. Pupillography could be a useful tool for the determination of autonomic nerve activity during antipsychotic treatment.

Keywords: antipsychotics; genetics and pharmacogenetics; pharmacodynamics; pharmacokinetics; schizophrenia.

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Conflict of interest statement

F. Abad‐Santos and D. Ochoa have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Janssen‐Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva and Zambon. The remaining authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Changes in pupillometric parameters after aripiprazole and olanzapine administration. MAX, maximum pupil diameter, MIN, minimum pupil diameter; CON, percentage of constriction; LAT, latency; ACV, average constriction velocity; MCV, maximum constriction velocity; ADV, average dilation velocity; T75, total time taken by the pupil to recover 75% of the initial resting pupil size
FIGURE 2
FIGURE 2
The influence of HTR2A rs6314 and DRD2 rs1800497 polymorphisms on pupillometric parameters. (A) The influence of HTR2A rs6314 on minimum pupil diameter (MIN) during aripiprazole treatment. (B) The influence of HTR2A rs6314 on total time taken by the pupil to recover 75% of the initial resting pupil size (T75) during aripiprazole treatment. (C) The influence of DRD2 rs1800497 on maximum pupil diameter (MAX) during olanzapine treatment
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