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\begin{document}

\title{Multiple extremely overdose of antipsychotics with minimal side effects:
A case report}



\author[1]{Min Yang}%
\author[2]{Yudong Cao}%
\author[1]{Haishan Wu}%
\author[1]{Li Zhang}%
\affil[1]{Second Xiangya Hospital Department of Psychiatry}%
\affil[2]{Kangning Psychiatric Hospital, Linwu County, Chenzhou 424399, Hunan, China}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\textbf{Title page}

\textbf{Multiple extremely overdose of antipsychotics with minimal side
effects: A case report}

\textbf{Min Yang\textsuperscript{1}, Yudong Cao\textsuperscript{2},
Haishan Wu\textsuperscript{1}, Li Zhang\textsuperscript{1*}}

1 Department of Psychiatry, National Clinical Research Center on Mental
Disorders (Xiangya), the Second Xiangya Hospital of Central South
University, Changsha 410011, Hunan, China.

2 Kangning Psychiatric Hospital, Linwu County, Chenzhou 424399, Hunan,
China

* \textbf{Correspondence:}

Li Zhang

505260@csu.edu.cn

\textbf{Abstract}

\textbf{Background}

Liver cytochrome P450 (CYP450) enzymes play an important role in
metabolizing antipsychotics (APs) and other drugs. Excessive use of
drugs can impair liver function and even other organs, thus causing
several adverse effects. In addition, metabolizer types of CYP450
enzymes may influence the therapeutic effects and drug reactions. In
this case report, we introduce a 52-year-old female with a 23-year
history of schizophrenia who took overdose of multiple kinds of APs and
other herbal preparations together for nearly two years, and she
presented with poor treatment effects and minor side effects of APs.
This case adds clinical examples for those patients with poor efficacy
and alarming drug tolerance.

\textbf{Case presentation}

At admission, the patient showed obviously positive symptoms. She
urgently underwent a drug concentration test, and was considered ``drug
intoxication''. She was given an emergency infusion to increase drug
excretion. The drug treatment of the patient was adjusted. After
pharmacogenomic examination, we found this patient was a CYP1A2
ultra-rapid metabolizer. At discharge, the clinical symptoms of the
patient have decreased, and her condition was stable.

\textbf{Conclusions}

CYP1A2 ultra-rapid metabolizer may explain part of the poor therapeutic
effects and small adverse effects in this case who took multiple kinds
of overdose drugs. Many factors may be involved in the rare
presentations in this patient.

\textbf{Keywords:CYP1A2, ultra-rapid metabolizer, schizophrenia,
overdose antipsychotics, side effects}

\textbf{Background}

Schizophrenia is a severe mental disorder with heavy burden of
comorbidity (1), which make difficulties in the clinical treatment and
management of schizophrenia and its comorbidities. The most common
therapy for schizophrenia is antipsychotics (APs), most of which are
metabolized by the cytochrome P450 (CYP450) system in the liver.
Previously, studies had reported that some people can tolerate overdose
of APs and this may be explained by pharmacogenetic mechanisms (2). It
was found that CYP2D6 ultra-rapid metabolizers were associated with
lower risperidone-related adverse events than poor/intermediate
metabolizers (3). Therefore, genetic profiling in drug metabolism may
help guide clinical treatment in psychiatric diseases (4).

In this case, we described a female patient with schizophrenia who took
several kinds of drugs in overdose daily for 2 years, but only slight
side effects were observed. This condition attracts our attention and
provides some inspiration and reference for the clinical treatment of
mental disorders.

\textbf{Case presentation}

The patient is a 52-year-old female with a 23-year history of
schizophrenia, aggravated in the last 2 years. She has hypertension,
hyperlipidemia, and coronary heart disease. And she is allergic to
penicillin. In her family, a maternal aunt has a history of psychiatric
disease.

This case first became ill in 1999 (Age 29), with the symptoms of
soliloquy, delusion of persecution and reference, and social withdrawal.
She was diagnosed of schizophrenia and treated with sulpiride and
perphenazine (dosage unknown). The psychotic symptoms were controlled
after a month of medication, and the drug regimen was maintained for
another 3 months. Then she interrupted medication on her own due to the
disappearance of symptoms, and had no recurrence in the next 6 years. In
2006 (Age 36), the symptoms of sensitivity and suspiciousness
reappeared, accompanied by headache and abdominal pain. She resumed
therapy and her condition improved after treatment with sulpiride and
quetiapine (dosage unknown) for a month. Thereafter, she persisted her
medication and her condition was stable from 2007 to 2013. From 2014 to
2020, her condition deteriorated twice with the symptoms of delusion of
persecution and reference, soliloquy, sensitivity, depression, suicidal
ideation, as well as abdominal discomfort and constipation. And she was
also diagnosed with hypertension, hyperlipidemia, and coronary heart
disease during this period, then she started taking jiangzhining tablets
and propranolol (unknown dosage).

Over the following years, she refused to seek medical help and gradually
upregulated the dosages of APs on her own by reading package inserts
online because of the poor effects of APs on her symptoms. Until 2020,
details of the doses she took are given in \textbf{Table 1} . Over the
next 2 years, she did not adjust her medication regimen. In 2022, she
was unresponsive and scatterbrained with delusion of reference and
jealousy, hypomnesis, aprosexia, lack of insight, and hypersalivation.
To seek further treatment, she was again hospitalized.

The timeline of this case is presented in \textbf{Figure 1} .

\textbf{Clinical Assessment and Therapeutic Intervention}

Urgent assessment of serum concentrations of APs at admission was
conducted. Serum concentrations of ziprasidone, risperidone,
aripiprazole, sulpiride, olanzapine, and clozapine were at 174.34 ng/mL,
62.29 ng/mL, 986.91 ng/mL, 6551.00 ng/mL, 83.78 ng/mL, and 336.52 ng/mL.
Physical examination (including blood, urine, stool tests, and head
Magnetic Resonance Imaging (MRI)) showed no abnormality, and her vital
signs were stable. An electrocardiogram (ECG) showed sinus rhythm,
incomplete right bundle branch block, and partial T-wave changes.
Admission assessment of psychiatric symptoms showed the existence of
delusion, aprosexia, retardation, hypobulia, and lack of insight. The
scores of Scale for Assessment of Negative Symptoms (SANS), Scale for
Assessment of Positive Symptoms (SAPS), and Treatment Emergent Symptom
Scale (TESS) were 47, 23, and 0. Pharmacogenomic examination is shown in
\textbf{Supplementary Table 1} .

The patient was diagnosed with ``schizophrenia, drug intoxication'', an
infusion of 2000 ml isotonic solution was given daily to accelerate drug
excretion with vital signs were closely monitored. Medication was
adjusted to ``risperidone 6 mg/day, clozapine 300 mg/day,
trihexyphenidyl 4 mg/day, propranolol 20 mg/day, and vitamin complex 3
tablets''. Serum concentrations of sulpiride, olanzapine, and
aripiprazole decreased to \textless{}10 ng/mL, 12.61 ng/mL, and 414.91
ng/mL at the fourth day, and infusion and monitoring was stopped.

Since reducing the dose of medication, clinical symptoms were weekly
assessed by clinical scales, the results showed that symptoms did not
decrease at the first two weeks. And the patient started to become
anxious and worried that her symptoms would worsen. And she had no bowel
movements for 3 days. We added sertraline 50mg daily to treat her
anxiety, and then the dose was increased to 100 mg/day due to poor
effect at the next week. Lactulose oral solution (20 mL/day) was
administered for short-term bowel movements.

At discharge, her condition was stable and the medication regime was
``risperidone 6 mg/day, clozapine 275 mg/day, sertraline 100 mg/day,
trihexyphenidyl 4 mg/day, and propranolol 20 mg/day''. Three months
later, she came to the clinic for review. Details of drug doses are
``risperidone 6 mg/day, clozapine 275 mg/day, sertraline 150 mg/day,
trihexyphenidyl l4 mg/day, and propranolol 20 mg/day''. The scores of
SANS, SAPS, TESS, Hamilton Anxiety Scale (HAMA), and Bech-Rafaelsdn
Mania Rating Scale (BMRS) were 18, 4, 4, 14, and 2. Sertraline dose was
increased to 175 mg/day for anxiety symptoms.

\textbf{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 D\textsubscript{2} and
5-HT\textsubscript{1A} receptors and partial antagonism of
5-HT\textsubscript{2} 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 D\textsubscript{2} receptors
cannot further increase (6). Thus, a low propensity to extrapyramidal
symptoms of aripiprazole was attributed to the partial agonism of
D\textsubscript{2} and 5-HT\textsubscript{1A} receptors, and antagonism
of 5-HT\textsubscript{2} 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 D\textsubscript{2} receptor
occupancy greater than 72\% (7). We hypothesized that 1500 mg sulpiride
taken by this patient may not produce a level of
D\textsubscript{2}occupancy 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
D\textsubscript{2}receptor 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 D\textsubscript{2L} receptor density could reorient the
preferential recruitment of aripiprazole from Gi1 to \selectlanguage{greek}β-\selectlanguage{english}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.

\textbf{List of abbreviations}

cytochrome P450 CYP450

APs antipsychotics

MRI Magnetic Resonance Imaging

ECG electrocardiogram

SANS Scale for Assessment of Negative Symptoms

SAPS Scale for Assessment of Positive Symptoms

TESS Treatment Emergent Symptom Scale

HAMA Hamilton Anxiety Scale

BMRS Bech-Rafaelsdn Mania Rating Scale

UGT uridine diphosphate-glucuronosyltransferase

ARRB2 Arrestin beta 2

P-gp P-glycoprotein

BBB blood-brain barrier

\textbf{Declarations}

\textbf{Ethics approval and consent to participate}

This research has been approved by the Ethics Committee of the Second
Xiangya Hospital of Central South University (approved number:
LYF2023038). Written informed consent was obtained from the patient and
her legal guardian for the publication of any potentially identifiable
images or data included in this article.

\textbf{Consent for publication}

Written informed consent was obtained from the patient for publication
of this case report and any accompanying images. A copy of the written
consent is available for review by the Editor-in-Chief of this journal.

\textbf{Availability of data and materials}

The datasets are available from the corresponding author Dr. LI Zhang
(E-mail: \emph{505260@csu.edu.cn}) on reasonable request.

\textbf{Acknowledgements}

We thank the subject who agreed to report her medical conditions. We
thank Shanghai Enyuan Medical Laboratory Co., LTD for pharmacogenomic
examination.

\textbf{Authors' contributions}

MY wrote the draft of the manuscript. YC collected the case. LZ and HW
conceived the article and made multiple revisions to the manuscript.

\textbf{Competing interests}

The authors declare that they have no competing interests.

\textbf{Funding}

The study was supported by the Natural Science Foundation of China
(82171518 to Li Zhang), and the Natural Science Foundation of Hunan
Province, China (2020JJ5844 to Li Zhang).

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2. Toba-Oluboka T, Tibbo PG, Dempster K, Alda M. Genetic factors
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3. Rossow KM, Oshikoya KA, Aka IT, Maxwell-Horn AC, Roden DM, Van Driest
SL. Evidence for Pharmacogenomic Effects on Risperidone Outcomes in
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8. Ferraiolo M, Ponthot R, Atik H, Koener B, Hanson J, Hermans E.
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9. Hoosain FG, Choonara YE, Tomar LK, Kumar P, Tyagi C, du Toit LC, et
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\textbf{Figure 1.} Timeline of the case

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