Oseltamivir was developed for prophylactic and therapeutic use against influenza, specifically targeting the viral enzyme's highly-conserved active site. In recent years, there have been case reports of neuropsychiatric events during or after oseltamivir treatment, in Japan and other countries. However, a search of the literature revealed no such cases in South Korea. We present the case of a 15-year-old female adolescent diagnosed with depressive episode after taking oseltamivir. Oseltamivir is generally well tolerated. Its most frequent adverse effects include nausea and vomiting, diarrhea, and abdominal pain. In influenza patients taking oseltamivir, neuropsychiatric adverse events include delirium, behavioral disturbance, suicide, delusion, panic attack, convulsion, depressed mood, loss of consciousness, etc. Reportedly, such neuropsychiatric adverse events were more common in children than in adults and generally occurred within 48 hours of administration. Here, we report a retrospective review case of an oseltamivir-related neuropsychiatric event in a female adolescent in South Korea.
Worldwide, seasonal influenza generally arises each year, due to a recombination of the influenza virus.
Oseltamivir was well tolerated, with an adverse effect incidence comparable to that of the placebo recipients in its clinical trials.
Recently, several reports from Japan showed that some oseltamivir-treated children had experienced adverse neuropsychiatric events.
A search of the literature revealed few cases of oseltamivir-induced depressive episodes in South Korea. We present a case involving a 15-year-old girl with depressive neuropsychiatric symptoms after receiving oseltamivir for the treatment of influenza.
A 15-year-old girl visited our outpatient clinic with symptoms of agitation, euphoric mood, flight of ideas, excessive talking, auditory hallucinations, and decreased need for sleep. She was attending an international school in Thailand and had a very good record at school.
Looking at her premorbid features, she fulfilled her responsibility for school life and was sincere in every work. She underwent normal development. In a Thailand international school, she enjoyed school life and had good relationship with friends. Her favorite activities were reading and drawing. She could easily concentrate on something and performed good academic achievement. She had no family history of mood disorder or psychotic disorder.
She had complained of stuffy nose, sore throat, and high fever symptoms 3 months ago, and she had gone to the hospital for a physical examination. At that time, she received a rapid diagnostic test for influenza A virus infection. The doctor suspected an influenza A virus infection and prescribed oseltamivir for her, as 75 mg of oral oseltamivir, twice daily, for five days. Her symptoms improved one day after beginning the medicine.
On her third day taking oseltamivir, the patient became extremely nervous and had difficulty making decisions. However, she completed the 5-day oseltamivir treatment. On that 5th day, she had no need for sleep. She could not sleep at all. She was depressed, experienced loss of appetite, and found it hard to concentrate on conversation and her schoolwork, such as reading books. She experienced a very intense suicidal ideation, reporting that she thought, "How about falling from a balcony?"
The patient visited a psychiatry clinic and received a 2-month prescription for antidepressants. Subsequently, her mood improved slightly and she could sleep. Her suicidal ideation stopped. Therefore, the clinic reduced her antidepressants. A week before her visit to our clinic, her aspect became very different. She felt herself to be the most special person. She felt very confident, with a greatly elated mood. She was more energetic than usual, sleeping less and talking more. She thought that she understood everything. As the week passed, her symptoms worsened, and she began experiencing auditory hallucinations.
The patient visited our psychiatry clinic with the above symptoms, accompanied by her mother. We believed she was in a manic state and prescribed lithium and antipsychotic drugs: 150 mg/day lithium and 100 mg/day quetiapine, to start. We then increased the drug dosage systematically. Her symptoms began to improve within a few days and resolved completely after a month.
Oral oseltamivir administration is a known efficacious therapy for influenza in children, when given within 48 hours of the illness's onset. Oseltamivir treatment is generally well tolerated, with a low incidence of adverse effect. The most common adverse effects, nausea and vomiting at the start of treatment, generally are mild to moderate and resolve in 1-2 days. In children taking oseltamivir, emesis of mild or moderate intensity and short duration was more frequently reported.
Reportedly, adverse neuropsychiatric events in influenza patients treated with oseltamivir were more common in children and generally occurred within 48 hours of the influenza illness's onset and the initiation of treatment. When Toovey et al.
In the present case, a 15-year-old girl had complained of insomnia, agitation, irritability, and impulsive suicidal ideation from the 3rd day after oseltamivir administration began. This patient developed numerous adverse reactions similar to those reported from Japan. She experienced a depressive episode, lasting 2 months, after receiving oseltamivir treatment for influenza. Unfortunately, we did not receive depression scale score of her depressive episode from the hospital of Thailand. Her school grades greatly dropped below the level she had achieved prior to the onset. We thought that she suffered a depressive episode because she had depressive mood, psychomotor agitation, irritability, insomnia, diminished ability to think or concentrate, recurrent suicidal ideation, and significant impairment in social and academic functioning. We did not consider that she had a bipolar disorder or major depressive disorder because she didn't have a family history of bipolar disorder, major depressive disorder, cyclothymic disorder, or dysthymic disorder and premorbid episode of mood fluctuation or depressive symptom. But it may be possible that her manic symptom was related with antidepressant use. Although it was uncertain, we became assured that her neuropsychiatric symptoms were related with the oseltamivir.
After oral administration, oseltamivir is rapidly absorbed from the gastrointestinal tract and is then extensively metabolized, predominantly by hepatic esterases, into its only active metabolite, oseltamivir carboxylate. Oseltamivir carboxylate is eliminated by a first-order process, primarily through glomerular filtration and renal tubular secretion. Oral oseltamivir at 75 mg twice daily, for 5 days, significantly reduces the duration of naturally-acquired febrile influenza.
The pharmacological mechanism of the abnormal behaviors observed during oseltamivir administration is unknown. One study showed increased dopamine metabolism changes in the medial prefrontal cortices of rats after systemic oseltamivir administration. The researchers reported that oseltamivir treatment was correlated with the manifestation of abnormal behaviors.
However, some researchers suggest it is difficult to distinguish the treatment's effects from those of the disease. Prospective clinical studies found no evidence of a higher incidence of neuropsychiatric events in patients receiving oseltamivir compared to those receiving placebo. These studies support the idea that the disease itself, rather than oseltamivir, more likely causes such neuropsychiatric events.
In this patient, who developed prominent neuropsychiatric symptoms immediately after taking oseltamivir, we suggest that oseltamivir might increase her potential risk for experiencing neuropsychiatric episodes. To our knowledge, this is the first reported case of oseltamivir-associated neuropsychiatric events in South Korea. Although there are many different arguments, we hope our report will lead clinicians to monitor for oseltamivir's potential neuropsychiatric adverse events.