Abstract
Levetiracetam is an anticonvulsant medication used as add-on therapy for the treatment of partial-onset seizures in adults. It is an S-enantiomer of etiracetam, structurally similar to the prototypical nootropic drug piracetam. Levetiracetam's presumed novel mechanism includes binding to a synaptic vesicle protein, SV2A. This is believed to impede nerve r-aminobutyric acid (conduction across synapses, suppression of inhibition of r-aminobutyric acid-GABA) and glycine-gated currents by zinc and also by partial inhibition of voltage gated calcium channels [1]. Although it has a generally good side-effect profile, psychiatric effects can be significant. Patients affected may report symptoms such as depression, agitation, hostility and psychotic behaviour [2]. We now report a case of levetiracetam-induced psychosis.
The patient was a 53-year-old woman who had her first seizure in early 2008 and had eight seizures in the subsequent 5 months. Following the onset of her seizures, she had a computed tomography scan that showed lacunar infarcts in the periventricular region and also deep white matter ischaemic changes. There was no history of psychiatric illness, head injuries, febrile convulsions or any other medical conditions.
Five months following the onset of seizures the patient presented to the emergency department with an episode of partial seizures and myoclonic jerks of the right side of the neck. The patient was in an altered conscious state for 24 h, as part of a post-ictal phase. Her neurological examination was otherwise normal apart from hyperreflexia. The patient was admitted to the medical ward for further investigations and for control of her seizures. On the third day of her admission, electroencephalography showed no epileptic focus and a slow irregular rhythm in the anterior regions bilaterally and the left temporal region. On the fifth day of admission levetiracetam 500 mg daily was added to her seizure treatment regimen to provide more effective control of her seizures. The patient was taking sodium valproate 500 mg twice daily since the onset of her seizures. On the 16th day of admission the patient became acutely psychotic and was referred for a psychiatric assessment. The patient was agitated and paranoid as she was concerned for her safety and that of her sons. She was experiencing auditory hallucinations, hearing voices of god reassuring her and she was observed to be responding to these hallucinations. Physical examination and laboratory tests were unremarkable.
On the basis of the aforedescribed presentation, levetiracetam was implicated as a cause of her psychosis and discontinued while the sodium valproate was continued. Within 3 days of discontinuing levetiracetam the psychotic symptoms resolved. The patient has remained asymptomatic in the subsequent 5 months, but has had one further seizure (status epilepticus). The valproate dose was increased to 1000 mg twice daily without any side effects noted.
The prevalence of psychiatric adverse reactions with the use of levetiracetam has been reported to be 13% [2] and the prevalence rate of levetiracetam-induced psychosis in preclinical trials is reported to be 0.7% [3]. The mechanism of levetiracetam-induced psychosis is unknown, but it is thought to be due in part to its novel mechanism of action. Given that it has a Naranjo score of 5, levetiracetam initiating psychotic symptoms is probable according to the Naranjo scale [4].
The hypotheses for levetiracetam-induced psychosis are as follows.
Levetiracetam could trigger psychosis in individuals with an underlying cerebral vulnerability [5], whether this be psychiatric or due to an organic brain disease such as cerebral infarction as in the present case. Forced normalization can be described as a pharmacologic-induced disappearance of clinical and subclinical seizure manifestations and as a result psychotic symptoms appear [5]. It is thought to be as a result of an antagonistic relationship between psychosis and epilepsy. This has been illustrated through the use of anticonvulsants such as vigabatrin. A drug interaction between levetiracetam and sodium valproate could also account for the patient's psychosis. Levetiracetam, however, does not affect the plasma concentrations of existing anti-epileptic drugs such as sodium valproate, consequently a drug interaction between valproate and levetiracetam is a less likely explanation [6]. Levetiracetam may also cause psychosis like other anticonvulsants by either enhancing the GABAergic system or by depressing the glutamergic system [3].
Levetiracetam is an appropriate adjunct therapy for partial epilepsy, but it can induce psychosis in vulnerable patients. Clinicians need to be aware of this when administering levetiracetam [7], especially in the early stages of treatment.