Aripiprazole-induced seizure: a second case report

Abstract

Aripiprazole has been recognised as a third generation antipsychotic and is considered to be distinguished from typical and atypical antipsychotics. In clinical trials, researchers did not mention the risk of aripiprazole-induced seizure, but during a literature review a case report was found that discussed this potential side effect. The present report concerns a 54-year-old man with chronic schizophrenia who developed a witnessed grand mal seizure after he had abruptly discontinued clozapine and benzodiazepam (BZD) treatment and concurrently reinitiated aripiprazole treatment as the result of an involuntary clinical error. The possible causes were explored, including clozapine-induced or withdrawal seizure, BZD withdrawal syndrome, psychogenic non-epileptic seizure, hyponatraemia, brain tumour and major physical illness, but none of the hypotheses can explain the seizure observed in this case. This second case is presented to corroborate a previous finding and emphasise the possibility of aripiprazole-induced seizure.

BACKGROUND

Aripiprazole has been recognised as a third generation antipsychotic and is considered to be distinguished from typical and atypical antipsychotics.¹ Its partial agonist activity at dopamine D₂ receptors under hypodopaminergic conditions, which is contrary to its antagonist activity at dopamine D₂ receptors under hyperdopaminergic conditions, is hypothesised to correlate with the improvement of negative symptoms and minimising of extrapyramidal syndrome (EPS),² while the partial agonist activity at serotonin 5-HT_1A receptors is thought to be associated with improving cognitive and negative symptoms.³ Clinical trials had shown it to be effective and safe in the treatment of patients with schizophrenia, and the side effect of seizure had not been reported.^4–7 In our literature review, we found a case report of aripiprazole-induced seizure.⁸ We now present this second case to corroborate the previous finding and emphasise this potential risk of aripiprazole.

CASE PRESENTATION

A 54-year-old man with chronic schizophrenia was admitted to Yuli Hospital⁹ for long-term disposition on 22 January 2007. He was first given ziprasidone, 80 mg daily, until he was transferred to the acute ward on 30 April 2007 on account of having exacerbated symptoms. After being discharged, he began taking risperidone 0.5 mg daily up to a maximum of 2 mg; this continued from 12 June 2007 to 21 January 2008. When the drug proved ineffective in controlling his symptoms, such as auditory hallucinations and odd behaviours, he was switched to 15 mg of aripiprazole daily with 2 mg of estazolam at night and one tablet of clonazepam (0.5 mg) twice daily on 21 January 2008. Unfortunately, the patient experienced an episode of consciousness level change and was difficult to arouse on the morning of 31 March 2008. After receiving an immediate emergency treatment for this episode, 2 days later on 2 April 2008 he was transferred to the acute ward due to the exacerbation of symptoms. In the acute ward he was treated with a 150 mg daily dose of clozapine, with flunitrazepam 2 mg every night; he was discharged on 22 July 2008 to the Shin-Shan Rehabilitation Centre. At the centre he first used the same drug as in the acute ward, which is prescribed for several days on discharge as a matter of course (in this case for 14 days), until 5 August 2008 when his supplies of the drug ran out and he was directed to the outpatient department (OPD) for a refill. At that time, the doctor made a mistake and “ditto’d” the previous OPD prescription made just before the patient’s admission to the acute ward (which the doctor had given to him from 21 January 2008), and did not keep to the drug used in the acute ward and in the first 14 days after discharge. Therefore, he abruptly discontinued clozapine and flunitrazepam and restarted the aripiprazole regimen; subsequently a grand mal seizure was noted on the morning of 8 August 2008. He received a laceration wound during the seizure on his scalp and required five suture stitches.

INVESTIGATIONS

After consulting a neurologist, the electroencephalogram (EEG) revealed nothing out of the ordinary. Although brain CT has not yet been performed, no hard or soft signs were detected to indicate that he might have a brain tumour or similar. The results of laboratory tests and serum electrolyte levels are all within normal limits. The patient has no major physical illnesses, including diabetes or hypertension, so these medical conditions that could potentially cause a seizure can be ruled out.

TREATMENT

After treatment with the anticonvulsant sodium valproate, 1500 mg daily for 7 days, additional seizures did not occur.

OUTCOME AND FOLLOW-UP

After that seizure this patient was still taking 15 mg daily of aripiprazole, and the psychotic symptoms were well controlled until 16 December 2008 when the patient experienced a relapse with odd behaviours and disorganised speech, and was subsequently readmitted to the acute ward.

DISCUSSION

In clinical practice, clozapine is the last-line therapy for schizophrenia; usually doctors do not change clozapine to other drugs. This principle is also applied in our hospital, where currently there are about 2400 resident patients with schizophrenia arranged in different settings according to their mental status, such as the acute ward, chronic ward and rehabilitation centre. For example, if they have exacerbated psychotic symptoms they are admitted to an acute ward for amelioration of conditions. After alleviation, they are discharged to a rehabilitation centre for a series of rehabilitation training programmes.⁹ Usually, when they are transferred from an acute ward to a chronic ward or a rehabilitation centre, the doctors in this hospital continue the stabilisation regimens established in the acute ward, and do not shift from one drug to another. But in this case, because of our negligence, he abruptly discontinued the clozapine, switched to aripiprazole, and then had a seizure. We are reporting this case to try to learn from this clinical error.

Similar to the first report of aripiprazole-induced seizure,⁸ our patient also had a suspected aripiprazole-induced seizure and then after reinitiating the drug he had a witnessed grand mal seizure. The possible causes of this seizure were explored as follows.

Firstly, seizure is one of the major side effects of clozapine, including sedation, sialorrhoea, bodyweight gain, anticholinergic effects, agranulocytosis and so on.¹⁰ About 4% of patients receiving clozapine develop seizure and this risk increases with the dose of clozapine,¹¹ often occurring when the dose is over 400 mg daily. In this case, the patient had only had 150 mg daily and no seizure was noted during the period of ingestion. In addition, this episode occurred after the clozapine had been stopped for 2 or 3 days. Therefore, the seizure is likely not clozapine induced. However, some papers reported that if patients abruptly discontinue clozapine they might develop a series of symptoms known as clozapine withdrawal syndrome, including rebound psychosis¹² and supersensitivity psychosis,¹³ which might be a reason why the patient deteriorated after shifting from clozapine to aripiprazole. However, no paper in the literature mentioned seizure after clozapine withdrawal. Thus, clozapine-withdrawal seizure is not likely.

Secondly, one of the other possible causes of this patient’s seizure was the concurrent abrupt discontinuation of benzodiapine (BZD). Due to the error previously mentioned, the dose of BZD equivalent suddenly dropped from 20–25 mg/day to 2–3 mg/day;¹⁴ therefore, the BZD withdrawal was possibly severe enough to induce a seizure. In addition, one paper mentioned that antipsychotics might aggravate BZD withdrawal symptoms including convulsions.¹⁵ However, due to the long elimination half life of flunepam (36–200 h), the BZD withdrawal seizure is less likely to occur within 2–3 days of discontinuation. We can only speculate that this concurrence of reinitiation of aripiprazole and the abrupt discontinuation of BZD could have potentially induced a seizure.

Thirdly, another possible cause of seizure in this case is a psychogenic non-epileptic seizure. The patient had been given a diagnosis of malingering by a doctor on 31 March 2008, when he was sent to the emergency room of a General Medical Centre that is about 40 km away from our hospital. At that time, he was difficult to arouse in the morning; he then awoke dramatically after one 500 ml bottle of normal saline intravenous drip was given. However, this case concerns a patient who is regressed; his cognitive function has deteriorated and he is not “smart” enough to act out the seizure for any secondary gain. In addition, during his admission in this ward, according to staff observations no malingering behaviours were seen. In fact, this episode of conscious change was probably the postictal state after a seizure induced by aripiprazole, even though there was no eyewitness to this event.

Finally, in patients with psychotic conditions a common cause of seizure is electrolyte imbalance, especially hyponatraemia, which is often caused by the patients’ overconsumption of water (polydipsia). But according to this patient’s chart, he has never demonstrated this curious behaviour.

In conclusion, because none of the above reasons can explain the observed seizure in this case, we hypothesise that the most likely cause of this seizure is aripiprazole, especially when the BZD dose is concurrently discontinued or reduced.

LEARNING POINTS

• We corroborate the previous case report and emphasise the possibility of aripiprazole-induced seizure.

• Further investigations to clarify this risk seem indicated.