INTRODUCTION

The inability of schizophrenia patients to comply with the treatment still remains an important problem in the management of the disorder. It was shown that more than 35% of the patients had compliance problems in the first few weeks of treatment and only 25% were fully compliant after two years (1). Long-acting injectable (LAI) formulations of antipsychotic agents have been reported to provide advantages in the acute treatment and maintenance of schizophrenia patients having difficulties with oral medication leading to a risk of relapse (2,3). Paliperidone palmitate (PP), a benzisoxazole derivative which is hydrolyzed to release the active part of the paliperidone and absorbed into the systemic circulation, belongs to the latest generation of antipsychotics developed for long-term effective injection (4). Following intramuscular administration of a single dose, a higher peak concentration of 28% is observed after injection into the deltoid muscle compared to the gluteal muscle. However, after four injections, the maximum plasma concentrations between the two injection sites are balanced (4,5). Therefore, administration of two initial doses into the deltoid muscle on days 1 and 8 will ensure rapid availability of therapeutic drug concentrations (6).

In addition to the benefits of atypical antipsychotic drugs for the patients, serious side effects limiting the clinical use of these new agents can be seen. Especially appropriate prescription and dosing of LAIs are required because of their long half-lives, delayed release, and risk of post-injection side effects. In terms of reliability, it has been reported that atypical antipsychotic agents can cause reversible or irreversible movement disorders such as tardive dyskinesia, increase in sleep time, weight gain, and impaired glucose and lipid metabolism (7-9). Common adverse events with PP use were headache, vomiting, limb pain, and injection site pain (10). Patients with schizophrenia who developed acute persistent circulatory failure and extrapyramidal symptoms requiring vasopressors and mechanical ventilation with death resulting after receiving injections of PP have been reported in the literature (11,12), as have cases with delirium and liver enzyme elevation caused by PP (13,14). In this article, we present a case of high fever and high liver function tests (LFT) immediately after the first dose of PP.

CASE

A male patient, aged 25 years, single, high school graduate, with a diagnosis of acute exacerbation of schizophrenia was hospitalized at the psychiatry clinic for treatment. Written informed consent for the publication of the case was obtained from the patient. The patient had been unable to work for 2 years and lived with his parents. Psychiatric examination found intense persecution and reference delusions. It was learned that he believed aliens were implanted in the bodies of his parents. He attacked his mother with a knife because of auditory hallucinations of these creatures and their neighbors interpreting and directing him. He had delusions suggesting that all his actions were followed by external cameras placed in his home. When the outpatient psychiatric clinic records were examined, it was observed that he had not been compliant with oral medication treatment for the last two years. He had discontinued his medications many times, and he reported to the emergency service with acute agitation. Routine blood tests (fasting glucose, hemogram, thyroid function tests, LFTs, urea, creatinine, hepatitis markers, lipid profile, B12, folic acid, ferritin, vitamin D) were requested on the first day of hospitalization, and results were found in the normal range. A PP injection was administered once in the inpatient service at a dose of 150mg because of treatment compliance problems. One day after the injection, high fever (39.5°C), diarrhea, nausea, weakness, muscle pain, and increased LFT values appeared. In the physical examination, he was conscious and there was no increase in muscle tonus, there was no sign of rigidity in the neck or the four extremities. Following these developments, the patient was evaluated by specialists for infectious and internal diseases. Suggested tests were performed for medical differential diagnosis. Detailed viral, autoimmune, and serological tests were within normal limits and urine tests were negative. Serology was negative for viral hepatitis (HBsAg=0.10IU/mL, anti-HBsIg G=6mIU/mL, anti-HCV=0.08S/CO), HIV (anti-HIV=0.3S/CO), acute infection with cytomegalovirus (Anti-CMV IgM=3S/CO), herpes simplex (HSV-1 IgM=16U/mL), and Epstein-Barr viruses (Anti EBV IgG=0.4ISR). Antinuclear antibody (ANA<1/40)), liver-kidney microsomal antibody (LKM<1/40), antimitochondrial antibody (AMA<1/40), smooth muscle antibody (SMA<1/40) and perinuclear antineutrophil cytoplasmic antibody (PANCA=4U) were also negative. Therefore, infection-induced and autoimmune causes were excluded. Upper and lower abdomen ultrasound scan was found to be normal. Acute hepatotoxicity in the patient was attributed to PP. In order to provide hydration, 3000cc/day balanced electrolyte solution was administered intravenously for 2 days. Peripheral cold application was performed. Body temperature returned to normal on day 4. When the blood tests were examined retrospectively, it was determined that LFT values were increased after injection on the first day of hospitalization. (AST=155, ALT=200, GGT=260) (Table 1). CPK levels were also within the normal range. The PP 8th day dose was not administered. It was found that there was no previous medical history of any general medical illness and no liver dysfunction in the family history. At the end of the 3rd week, LFT values gradually decreased. After LFT values returned to normal, the patient was followed up for 1 week without psychotropic medication. Then, oral haloperidol 10 mg/day was followed by treatment with lorazepam 1.25 mg/day in order to maintain sleep continuity. The patient was discharged with partial improvement of his psychotic symptoms and without elevation in his LFT values.

DISCUSSION

In this case report, a young adult schizophrenia patient who developed acute hepatotoxicity after PP has been presented. LAI antipsychotics provide a consistent distribution of drugs, regardless of the ability or willingness to take them orally on a regular basis, reducing the risk of taking too much or too little medication intentionally or accidentally and minimizing dose deviations. Due to these advantages, they have been chosen with greater frequency in the treatment of schizophrenia over the last 10 years (15,16). According to double-blind, placebo-controlled acute treatment studies, the most common adverse events associated with PP were EPS (0-5%), injection site reactions (0-10%), dizziness (2-6%), and drowsiness/sedation (5-7%). In four fixed-dose, double-blind, placebo-controlled trials, the frequency of PP therapy was reported to be 5.8% due to adverse events (10,17-19). When reviewing the literature, only few case reports about the elevation of LFT related to PP are found. In a female patient who had a deterioration of the LFT after the first dose of PP, it was seen that the enzyme levels returned to normal at the 6th day. After administration of the 2nd dose of PP, they increased again, and the drug was discontinued (14). Moreover, acute-onset delirium was seen after the second PP dose in an adolescent with schizophrenia (13). In our case, the use of the LAI form of haloperidol was not considered due to transaminitis reported in the literature (20-22). Risperidone-induced hepatotoxicity has also been reported in another patient using synthetic cannabinoid (23). When the patient was evaluated in terms of differential diagnosis, he did not show any evidence of autonomic system imbalance and there were no rigidity or other features indicative of neuroleptic malignant syndrome. In our case, LFT returned to a normal level in the third week, and in the long term, the patient was followed with a typical long-acting antipsychotic treatment (zuclopenthixol decanoate 200 mg/2 weeks). The role of liver metabolism in cytochrome P450 2D6 and 3A4 was limited because 60% of paliperidone was excreted unchanged in the urine. It has been reported that in case of renal insufficiency, dose adjustment is recommended for creatinine clearance, whereas in mild and moderate liver failure no dose adjustment is required (24). Although a psychotropic effect in liver failure has been suggested (25), in the presence of individual sensitivities as in this case it is appropriate to monitor LFT and other clinical parameters if fever is observed when starting PP. Our report raises clinicians’ awareness of this rare side effect, thus contributing to the literature. Controlled and longitudinal studies are required to assess the short- and long-term hepatotoxic effects of PP.

Informed Consent: Written informed consent was obtained from the patient.

Peer-review: Externally peer-reviewed.

Conflict of Interest: Authors have not reported any conflict of interest.

Financial Disclosure: The authors did not receive any financial support.

REFERENCES