Page 97 - Read Online

Cendrós et al. J Transl Genet Genom 2020;4:210-20 I http://dx.doi.org/10.20517/jtgg.2020.21 Page 217

involvement of ABCB1 in the evolution of PANSS, but only in patients with decreased CYP2D6 activity, and
also only for the rs2032582 (2677G>T/A) polymorphism in ABCB1, but not rs1045642 (3435C>T), which
is the one used in the present study. Other authors, however, have been able to find an effect of 3435C>T
on clinical improvement [18,40] . The effect of ABCB1 3435C>T might be limited to specific substrates or apply
only to haplotypes.

It was found that CYP1A2 genetic variants were directly associated with changes in psychological UKU. As
expected, higher CYP1A2 activity is related to less psychological adverse effects due to the dose-dependent
nature of most adverse drug reactions. The association of CYP1A2 variants with psychological UKUs was
stronger than that of age, highlighting its importance. While drug dose was associated with UKUs in most
cases, this was not true for psychological adverse effects, which suggests that metabolic activity is more
important than the actual dose regarding this class of adverse reactions. Local metabolism in the brain,
as opposed to liver metabolism, could lead to changes in local exposure not reflected by plasma levels.
CYP1A2 is expressed in the rat brain, and has also been reported to be expressed in human brains [42,43] . As
clozapine, a CYP1A2 substrate, is the drug that was used in more patients than any of the other agents, this
study was better powered to detect differences regarding CYP1A2. It is possible that the lack of significant
results for other genes is due to the lower relative abundance of substrates for the corresponding pathways.
It is also expected that dose is related to overall side effects, but this association was not seen for autonomic
or psychic UKUs. This makes the effect of CYP1A2 on the latter particularly interesting, because it revealed
a marker for adverse effects that cannot be predicted with dose. Knowing which side effects are most likely
to happen can help physicians with follow-up of their patients, so that they can focus on psychic adverse
effects in those patients with lower CYP1A2 activity scores.

There are some limitations in this study that might have hampered the discovery of other associations.
While the sample size of the whole study was moderate, it was not possible to divide into groups based on
medications, as these groups would have been too small. Furthermore, it would have been interesting to
check the possibility of drug-drug interactions, as some medications are known to be inhibitors or inducers
or CYPs and/or ABCB1, so a patient can have an actual phenotype that differs from what one would predict
based on genotype. However, most patients were on antipsychotic monotherapy and concomitant treatment
should not have significantly affected the results. Other factors such as smoking habits and diet could
not be considered due to the lack of specific information. Further studies should address these possible
confounding factors.

In conclusion, there is a possible association between CYP1A2 and psychic adverse effects, which is
concordant with the known properties of clozapine. This association should be considered preliminary until
it is confirmed in an independent study. None of the other studied genes showed any effect on treatment, as
measured by changes in PANSS and UKU scores. These results suggest that patients with higher CYP1A2
activity would be less likely to experience psychic adverse effects.

DECLARATIONS
Acknowledgments
We are extremely grateful to all participants. We thank the Spanish Ministry of Economy, Industry, and
the European Funds for Regional Development (Fondo Europeo de Desarrollo Regional, FEDER) for their
support. We are indebted to the IDIBAPS Biobank, integrated in the Spanish National Biobank Network,
for samples and data procurement.

Authors’ contributions
Study design: Cendrós M, Arranz MJ, Catalán R
Conducted pharmacogenetic studies: Cendrós M, Ibáñez L, Serra A, Arranz MJ