Delayed-Onset Toxicity in an Adolescent Case Following Attempted Suicide with an Overdose of Paliperidone Intake

Abstract

Paliperidone is a relatively novel atypical antipsychotic drug that is currently used to treat schizophrenia in adolescents and adults. The drug was generated by combining the active metabolite of risperidone, 9-hydroxyrisperidone, with osmotic controlled-release oral administration system (OROS) technology. Due to its specific design, the drug has been identified as a different form, albeit an active metabolite of risperidone. Such distinction mainly manifests itself during pharmacokinetic processes, because paliperidone is not affected by CYP2D6 metabolism. On the other hand, this drug is regularly released for a period of 24 hours. Even though it is possible to reach relevant literature on the efficacy and safety of paliperidone use in detail, limited data regarding its toxicity exists. A review of the literature in that sense, has revealed a scarce number of case reports and a retrospective study existing. Bearing in mind the specific form and design of the drug, we have hypothesized its toxicity might cause diverse clinical presentations, in the face of overdose or poisoning. This might in turn, prompt us to switch our usual evaluation and intervention practices. With this case report, we have aimed to discuss delayed onset toxicity with paliperidone overdose in an adolescent case, due to a suicide attempt with excessive intake of the medication.

Introduction

Novel second generation antipsychotics that have been approved for their use in the treatment of adult schizophrenia have been reported just as clinically efficient as typical antipsychotics, and have the benefits of favorable side-effect profile.¹ Extended-release form of paliperidone (paliperidone ER) has been approved for treating schizophrenia in adults and adolescents, in United States of America, European-Union countries and many others.²

As an atypical antipsychotic drug, risperidone is metabolised to its active metabolite, 9-hydroxyrisperidone, via CYP2D6 enzyme system.³ Paliperidone has been identified as the final form following the combination of the active metabolite of risperidone, 9-hydroxyrisperidone, with osmotic controlled-release oral administration system (OROS) technology.⁴ This unique form enables regular and continous release of paliperidone, for a time span of 24 hours, in total.⁵ In addition to this, slow metabolizers might experience reduced clinical effects of risperidone, due to their genetic polimorphisms that affect their CYP2D6 enzyme system functions. Since paliperidone is the active metabolite of risperidone, such individual differences caused by the variations in CYP2D6 metabolism would not be observed, meaning pharmacokinetic characteristics of thedrug remains intact.⁶

Hereby, we have aimed to discuss the clinical process of delayed-onset toxicity in a male adolescent case who was followed up with the diagnosis of Conduct Disorder in a child psychiatry outpatient unit, and attempted suicide with an overdose of paliperidone intake.

Case

The case was a 16-year old male adolescent who was being followed up in an a child psychiatry unit with a primary diagnosis as Conduct Disorder. He was brought to the unit by the nurse of the institution he was residing in due to increasing outbursts of agitation and aggressive behavior towards the staff. At the time of his application, the case was on 1000 mg/day oral Na valproate and 7.5 mg/day oral olanzapine. The case was admitted to the inpatient unit for differential diagnostic process and regulation of the medication regimen. Four hours into the admission, he was slower regarding motor activity, became apathetic and increasingly drowsy. An emergency examination following the observation of such symptoms, the case had mentioned taking 28 paliperidone 9-mg capsules 2 days ago, with suicidal intentions, and no other simultaneous type of medication/drug intake. Shortly after sharing this piece of information, he lost consciousness, and became unresponsive towards initially verbal, and later to painful stimuli. He was immediately transported to Intensive Care Unit of the hospital.

His laboratory test results including routine hematology and biochemical tests were normal, other than an elevated creatine kinase (624 U/L). Although his initial ecocardiography (ECG) did not reveal an elongated QTc interval, a short atrial run with a speed of 110/min, deriving from an atrial node other than the sinus node was determined. Arterial blood pressure was 123/61 mmHg, and heart rate was 108 per minute. The case was monitored in the intensive care unit, and after 36 hours of supportive treatment and monitorization, fully conscious and oriented, and with his vital signs and biochemical test results within normal ranges, apart from elevated creatine kinase levels (417 U/L), the case was transfered to the psychiatry clinic.

Following his transfer to the psychiatry unit, monitorization of his hematological, biochemical test results, ECG and vital signs resumed. Repetitive measures revealed normal test results, other than creatine kinase levels; which indicated a pattern of decline (267 U/L). The case was followed up for 2 more weeks with individual psychotherapeutic sessions and psychopharmacologic treatment regimen as 2 mg/day oral risperidone and 3 mg/day oral lorazepam. Upon maintaining partial remission for his psychiatric condition, he was discharged, to continue his follow up in the outpatient unit.

Discussion

With this case report, we have aimed to present the clinical picture of an adolescent depicting symptoms of delayed- onset toxicity, who had attempted suicide by ingesting 252 mg paliperidone ER. Ingested dose was 21-fold of maximum recommended dose, for the medication, and following intake of given amount, clinical symptoms (decreased motor activity and slowness, apathy, drowsiness) emerged within first 24–48 hours.

Due to its specific design, paliperidone reaches its peak plasma concentration levels gradually, approximately 24 hours following administration of the drug. Its plasma half-life is approximately 23 hours. Therefore, one maintains stable paliperidone concentrations 4–5 days after initial dosage.⁷

Recommended paliperidone ER dosage for adults has been reported as 6 mg once a day, and it also does not require any titration for initial dosage. Some side effects might increase due to increased dosage of the medication, nevertheless one might also experience additional clinical benefits at higher doses. If required, medication dose might be increased up to 12 mg/day. Some patients might respond well to lower medication doses, such as 3 mg/day.⁷ A double-blind randomized clinical study that had aimed to evaluate efficacy and safety of paliperidone in adolescents diagnosed with schizophrenia, and flexible dosing such as 3, 6 or 9 mg were used for this given age group.⁸

In addition to its dopamine D2 and serotonin 5HT2A antagonism, paliperidone also exhibits antagonistic effect on alpha-1 and alpha-2 adrenergic, as well as H1 histaminergic receptors. Paliperidone has no affinity over cholinergic muscarinic, or beta adrenergic receptors.⁹ CYP2D6 and CYP3A4 have limited role in clearing paliperidone, once and for good. Major portion of the drug (60%) is eliminated via urine, unchanged.⁷

In the context of side effects, individuals being treated with 3–12 mg/day oral paliperidone reported more akathisia and other side effects concerning the extrapyramidal system, compared to those who were given placebo.⁶ In a metanalysis that evaluated randomized trials of paliperidone compared to placebo, it was found that most commonly observed side effects linked to the treatment with the drug were motor activity disorders, weight gain and tachycardia, reminiscent of side effects due to risperidone use, as well as significant increase in prolactin levels.¹⁰ In a study conducted with adolescents diagnosed with schizophrenia, most commonly reported side effects during treatment with paliperidone were akathisia, headache, drowsiness, tremor and weight gain.⁸ Moreover, paliperidone might also be responsible for the elongation of QTc interval.¹¹ Although no link was found between risperidone dose and QTc, or plasma risperidone levels and QTc, a study has shown significant positive correlation between plasma paliperidone levels and QTc values.¹²

Data regarding overdose on paliperidone or toxicity remain fairly limited. A literature review on this subject resulted in four case reports, in total.¹³–¹⁶ Similar to the prognosis of our case, all of the cases presented in these forementioned reports recovered by appropriate supportive treatment. Another retrospective study that had aimed to present toxicity related symptoms and clinical outcome following paliperidone exposure failed to report any drug-related death.¹⁷

Another similarity between aforementioned case reports and ours point out the fact that laboratory test results and cardiac functions of all cases remained within normal ranges.¹³–¹⁶ While emergence of tachycardia was linked to paliperidone’s effect on alpha receptors,¹³–¹⁶ one clinical report has stated that although paliperidone is known to have zero affinity over muscarinic-1 receptors while used within therapeutic doses it might, in cases of overdose, putting forward another question mark to be further addressed, regarding action mechanisms of this relatively novel agent. Sedation and confusion observed in the cases might have arisen due to paliperidone’s antagonistic effects on H1 receptors.¹⁴,¹⁶ Although all four case presentations depicted longer periods of follow up due to the risk of toxicity that might develop in later terms, only one has reported a delayed-onset toxicity like our case had.¹⁶ In that sense, our case remaining within asymptomatic phase at least 24 hours prior to the onset of toxicity related symptoms and no significant alteration in his blood tests, other than elevated levels of creatine kinase is important, since this might cause insufficient and inefficient follow up in the emergency room, and possibly an early discharge. We believe the delayed onset paliperidone toxicity in our case is linked to the specific design of paliperidone ER.

To conclude, collecting all given data from our case, other case reports that are limited in number, and information extracted from retrospectively designed studies that focus on the subject, we might speculate paliperidone might be a safe drug, even in the face of toxicity. Apart from that, linked to the unique design of the agent, delayed-onset toxicity with the drug might be an important issue especially for clinicians and health care staff that work in the emergency room, suggesting the need for longer period of monitorization.