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Page 216 Cendrós et al. J Transl Genet Genom 2020;4:210-20 I http://dx.doi.org/10.20517/jtgg.2020.21

(clozapine and olanzapine) and non-substrates of CYP1A2. Although antipsychotic0*CYP1A2 bordered on
the significance threshold for total UKU, it was statistically not significant (P = 0.06).

The combined effect of all CYPs was explored using a dichotomic variable representing whether each
patient had an altered metabolism for the drug they were taking or not. In these tests, the antipsychotic
was added as a covariable. However, altered metabolism was not found to be associated with plasma levels,
change in PANSS or change in any of the UKU scores, although the model itself was marginally significant
in relation to neurologic UKUs (P = 0.05).

DISCUSSION
The aim of this study was to investigate the effects of genetic variants in pharmacokinetic genes on
clinical endpoints to compare their influence on the outcome of treatment. The effect of metabolism on
adverse effects was observed for CYP1A2 on psychological UKUs, but not for other clinical endpoints. No
correlation between any of the investigated genetic factors with PANSS was found.

The association between CYP1A2, CYP2C19, CYP2D6 and ABCB1 and plasma levels, despite the very
low P-values, may have explanations other than genetic variation. Unlike clinical dose data, which was
transformed to olanzapine equivalents, plasma levels did not receive any standardizing transformation, and
since different molecules reach different concentrations in blood, even in normal circumstances, the type
of antipsychotic that can reach significance by itself, with P-values even lower than those observed for any
of the antipsychotic-gene interactions, is observed at the end of Table 3. Therefore, the association observed
with the interaction is most likely driven by the antipsychotic component of the interaction, which would
be expected to be significant even without a real influence of the genotype. This does not rule out a true
contribution of metabolism or transport on plasma levels. In fact, there have been numerous reports on the
association of CYP2D6 with plasma levels of risperidone, aripiprazole, haloperidole, zuclopenthixole, and
[35]
pimozide [3,6,10,11,13,33,34] and CYP1A2 with olanzapine , which is consistent with their metabolic pathways.
For clozapine, the existing data shows a clear association with CYP1A2 activity, including the inducer effect
of smoking on plasma levels but the effect of genetic variation itself has failed to show an association in
some studies [36-38] . There are also reports on the association of ACBC1 with plasma levels of aripiprazole and
quetiapine [39,40] . It should be noted that CYP2D6 had the strongest association, at one order of magnitude
lower than the other three genes, which could reflect a higher influence.

Regarding changes in PANSS scores, none of the CYPs or ABCB1 genetic variants investigated showed
any effect. In fact, no predictors of clinical efficacy were found at all in this study. CYPs are expected to be
related more to side effects than efficacy, because most genetic variations lead to decreased metabolism,
whereas the lack of efficacy is expected to be observed when metabolism is increased. Studies that have
[3]
addressed the effect of metabolism on efficacy have had contradictory results. A large study by Jukic et al.
found that both very high and very low CYP2D6 metabolism (PMs or UMs) are predictors for treatment
switch from risperidone. It should be noted that treatment switching could be due to the lack of efficacy
[15]
but also, from intolerable adverse effects. van de Bilt et al. investigated the possibility that ultrarapid
metabolism might lead to the lack of improvement, but could not confirm this hypothesis. Regarding
CYP1A2, the studied polymorphism leads to increased expression, and thus it is reasonable to think
that carriers would have a lower change in PANSS due to increased metabolism. This was observed by
[35]
Czerwensky et al. reporting an inverse correlation between predicted CYP1A2 activity and improvement
of symptoms in patients treated with clozapine and olanzapine. Nonetheless, increased metabolism has
[41]
also been described as a factor for good response. Piatkov et al. observed in their clozapine-treated
cohort that increased metabolism through CYP2C19 leads to a lower risk of diabetes and a higher chance
[17]
of clinical improvement. ABCB1 has also been studied regarding efficacy. Papazisis et al. found an