Abstract
Clozapine is the only second-generation antipsychotic that has proven efficacy greater than all other antipsychotics [1]. Somewhat ironically, it is also the antipsychotic with potentially the most dangerous side-effect profile, with agranulocytosis, gut dysmotility and seizures being potentially fatal side-effects. This has led to a degree of caution in its prescription. The first two of these are monitored by blood testing and clinical exam, respectively, but it is more difficult to predict if clozapine will induce a seizure in patients. Although a variety of approaches to reduce the risk of seizures are used clinically, such as prophylaxis with sodium valproate if plasma levels >500 µg L−1 or dosages >600 mg day−1[2], none is widely accepted as the norm. The mechanism by which clozapine induces seizures is uncertain but clearly dose related [3], and for this reason clinicians have become increasingly conscious of this at high doses. Reported here is a case of clozapine-induced seizures and clinical response at low dose.
The patient was a 21-year-old man with a confirmed diagnosis of schizophrenia. He presented to services approximately 18 months prior to the initiation of clozapine with delusional beliefs and disorganization sufficient to warrant inpatient admission. He was initially treated with olanzapine and subsequently oral clopixol. Because this was the patient's first episode of psychosis, after 12 months a gradual reduction of antipsychotics was agreed to. Although reduction was initially successful, similar psychotic symptoms re-emerged on 10 mg of olanzapine. Cross-over to quetiapine was unsuccessful at controlling psychotic symptoms.
As the patient described, ‘Before clozapine I was taking olanzapine. I felt it wasn't working. I felt like complete crap. My thinking went into overdrive, constant and non-stop. I was thinking about a whole range of subjects at once. There was clarity in that but not how I usually think. I also felt lethargic and tired.’
The patient's keyworker noted, ‘Thought disorder made communication limited. [The patient] and his family regularly voiced their concerns that [the patient] “just isn't himself”. Even when the positive symptoms began to abate.’ She also noted, ‘[The patient] found it difficult to interact on even a superficial social level. He was taking no responsibility for routine tasks in the family home…’
Because trials of two other antipsychotics proved unsuccessful, clozapine was initiated after a discussion of the risks and benefits of this. The patient was admitted to hospital and initial work-up was unremarkable. He was discharged after 2 weeks and clozapine titration was completed at home to a dose of 100 mg mane, 200 mg nocte. Two weeks after reaching this initial treatment dose the patient had a tonic–clonic seizure at home witnessed by his father. He was taken to hospital where medical work-up including computed tomography and magnetic resonance imaging of the brain were unremarkable. His clozapine plasma level was 420 nmol L−1(120 ng mL−1). Management options including reduction or cessation of clozapine or anticonvulsant prophylaxis were considered with the patient, and the latter chosen. Sodium valproate was initiated and titrated to a dose of 1 g day−1 (serum level 550 µmol L−1).
Follow up of the patient in the following 9 months has been positive. There has been a complete resolution of psychotic symptomatology and social impairment. There have been no further seizures. The patient's mother describes having the ‘old [patient] back’ and the patient is happy with his current management plan. His daily clozapine dose has been maintained at 300 mg day−1 with average clozapine levels of 200 nmol L−1.
Although the lower treatment limits of clozapine therapy have not been firmly identified, the literature would suggest that a therapeutic plasma range of 1050–1260 nmol L−1 (350–420 ng mL−1) is ideal [4]. There are no reports of sustained clinical improvement at average clozapine levels of 200 nmol L−1 (66 ng mL−1) such as that of the present patient. The risk of seizures on clozapine increases with an increasing dose, although there is no defined dose below which seizures do not occur. The risk of seizures at clozapine doses below 300 mg day−1 is reported as <1% [3]. A recent review of 43 papers reporting on clozapine-induced seizures included only one case involving a dose below 400 mg day−1[5]. Although rare, clinicians should be aware of this possibility even without other risk factors.
This case highlights three important points. First early initiation of clozapine, as recommended by the Royal Australian and New Zealand College of Psychiatrists [6], can lead to strongly positive social and symptom outcomes that are recognized by the patient, family and professionals involved in care. Second the lower limit of the effect range, both by dose and by plasma level, is unclear and requires careful clinical review. In the present case, although plasma levels were very low, there was clear and sustained clinical effectiveness. Finally seizures can occur at low doses of clozapine, although this is rare. If they occur they can be effectively controlled with appropriate anticonvulsant medication and, in light of clozapine's proven superior effect, may be more appropriate than cessation of clozapine.