Discussion and Conclusions
The patient has taken a daily overdose of APs and 2 kinds of herbal
preparations for 2 years, but she tolerated these drugs well. We found a
CYP1A2 ultra-rapid metabolizer, which may partially explain why side
effects were minor in this patient. This case adds to the research
evidence of good tolerance for drug overdose in some special
populations.
An important concern in this case is that olanzapine and ziprasidone
were highly overdosed, but serum concentrations were within or close to
therapeutic concentrations. Olanzapine is primarily metabolized by
uridine diphosphate-glucuronosyltransferase (UGT) and CYP1A2, and
partially metabolized by CYP3A4 (5). Ziprasidone is primarily
metabolized by aldehyde oxidase and partially by CYP3A4 and CYP1A2 (5).
According to pharmacogenomic analysis, ultra-rapid metabolizer of CYP1A2
may partially explain why twice the recommend maximum dose of oral
olanzapine resulted in a nearly normal serum drug concentration.
Another concern of this case was that serum concentration of
aripiprazole and sulpiride were highly beyond therapeutic ranges, while
she experienced minimal APs-related adverse or toxic effect. And good
tolerance observed in this case may benefit from the characteristics of
aripiprazole, with partial agonism of D2 and
5-HT1A receptors and partial antagonism of
5-HT2 receptors. When taking a daily dose of
aripiprazole higher than the recommended maximum dose (30mg), the effect
on the serotonergic system was considered to be stronger than the
dopamine system because the occupancy at D2 receptors
cannot further increase (6). Thus, a low propensity to extrapyramidal
symptoms of aripiprazole was attributed to the partial agonism of
D2 and 5-HT1A receptors, and antagonism
of 5-HT2 receptors was a protective factor for
akathisia. As one kind of typical APs, sulpiride has a higher
probability to cause extrapyramidal symptoms than atypical APs. A
previous study reported that side effects such as hyperprolactinemia and
extrapyramidal symptoms increased with D2 receptor
occupancy greater than 72% (7). We hypothesized that 1500 mg sulpiride
taken by this patient may not produce a level of D2occupancy over 72%. This may be one reason for the discrepancy between
manifestations and arrestin beta 2 (ARRB2) gene analysis in this case.
Unfortunately, we could not obtain the data of D2receptor occupancy in this case due to technical and conditional
limitations.
In this case, poor treatment outcome was observed after the combined use
of several kinds of APs. Abnormality or functional changes in the brain
may exist in this patient to explain the poor outcome. Changes in
dopamine receptor density may be one reason. It was revealed that
increasing D2L receptor density could reorient the
preferential recruitment of aripiprazole from Gi1 to β-arrestin2 and
thus impact the pharmacological profiles of aripiprazole (8). Another
reason may be the activity of the P-glycoprotein (P-gp) drug efflux
transporter. Several APs are transportable substrates of P-gp, including
aripiprazole, olanzapine, and risperidone. Studies showed that high P-gp
activity in schizophrenia induced low therapeutic outcomes, and
inhibition or bypassing P-gp activity at the blood-brain barrier (BBB)
or intestine may be effective methods to improve the therapeutic
efficiency of APs (9).
In general, the metabolic type of CYP450 enzymes, drug-food interaction,
receptor density and occupancy, and activity of drug transporter may be
related to the poor treatment efficacy and minor side effects of
overdose APs in this case.
The reasons for poor therapeutic effects and minor adverse reactions of
overdose APs in this case remained inconclusive, CYP1A2 ultra-rapid
metabolizer may be one factor. Monitoring drug concentrations of APs and
education on rational use of drugs are vital in clinical practice.