Abstract
A 49-year-old Caucasian male, known to have suffered from paranoid schizophrenia for 10 years, was treated with clozapine several times with satisfactory results. However, during this treatment he developed periorbital oedema repeatedly, leading to a switch of antipsychotic at his request. While he was on clozapine it was also difficult to regulate his hypertension. Considering the relatively high, but less known incidence of hypertension during clozapine treatment (4%), we recommend routinely monitoring of blood pressure during the initial phase of clozapine treatment.
Clozapine treatment is regarded as the gold standard for treatment-resistant schizophrenia. However, because of its broad-spectrum receptor affinity this atypical antipsychotic has many side effects [1]. We will describe a case of periorbital oedema, a rare skin reaction to clozapine. Although medically harmless, for the patient this side effect was a (cosmetic) reason to stop the treatment. The same patient also had paradoxical hypertension, a side effect which requires attention, particularly in patients with pre-existing hypertension or cardiovascular disease [2].
A 49 year old Caucasian male with no somatic history of note had been suffering from paranoid schizophrenia for nine years. Since 1999 he had been treated with clozapine 325 mg/dag, oxazepam and temazepam. In 2005 he spontaneously developed swelling of both eyelids and sharply demarcated bilateral periorbital oedema. The results of additional laboratory tests were normal. The periorbital oedema persisted until surgical correction in April 2007. The patient continued clozapine. In January 2008 the periorbital oedema recurred on one side, and at the patient's own request he was put on risperidone as of August 2008. Because of extrapyramidal symptoms this was replaced by quetiapine in September 2008. After a TV programme about the metabolic side effects of antipsychotics, the patient refused all antipsychotic medication from October 2008 onwards. The periorbital oedema disappeared. A paranoid psychosis recurred, leading to involuntary admission in April 2009. Treatment with haloperidol had no effect; the patient was put on clozapine again with good results, but within four weeks periorbital oedema recurred bilaterally.
During a check-up by his psychiatrist in 2006 the patient was found to have hypertension (200/120 mmHg). Additional testing revealed tachycardia with left ventricle hypertrophy and mild renal insufficiency. Treatment with metoprolol had insufficient effect, and in August 2008 the patient was put on enalapril. In September 2008 the patient was admitted urgently for somatic complaints: in addition to an allergic reaction to enalapril, for four days he had suffered progressive hemiparesis of the right arm and leg with hypertension (173/117 mmHg). The diagnosis was ‘hemiparesis due to a lacunar infarct with hypertension without known cause’. The enalapril was stopped. Three different antihypertensives were prescribed to control the severe hypertension. However, when the patient was admitted in April 2009 due to recurring paranoid psychosis he still had hypertension (190/110 mmHg). His antihypertensive medication was reviewed. His blood pressure dropped to 140/90 mmHg. When treatment with clozapine 500 mg/dag was restarted, his blood pressure increased up to a maximum of 175/125 mmHg, after which the dose was halved. However, the hypertension worsened, rising up to 225/150 mmHg highest. The combination and dosage of the anithypertensives were readjusted, without satisfactory results. In August 2009 clozapine was replaced with quetiapine XR 600 mg/day. The patient's blood pressure gradually dropped to 140/90 mmHg. Three months after stopping clozapine the periorbital oedema disappeared completely.
In our opinion, this patient's recurring periorbital oedema and the hypertension which was so difficult to control were both induced by clozapine. The case described above also illustrates the potential risks associated with clozapine treatment for patients with cardiovascular disease.
Our conclusion is that when clozapine is prescribed, it should be borne in mind that the patient's blood pressure may rise or fall. The prevalence of hypotension and hypertension among clozapine users is 9% and 4% respectively, regardless of the duration of treatment [3]. A possible explanation for the hypertension, which is ‘paradoxical’ in view of clozapine's receptor affinity, may be increased noradrenergic plasma levels due to a stronger α2 than α1 adrenoceptor blockade [4]. Unfortunately there is no explanation for the lack of adaptation to this blockade.
There are practically no reports of recurrent periorbital oedema as a side effect of clozapine. The suspected clozapine-induced D4 receptor blockade could lead to sodium retention, fluid retention, oedemas and hypertension [5]. However, this seems unlikely since there is no systemic oedema. Nevertheless, because of the subjective burden of suffering and the risk of treatment non-compliance, it is important to take patients seriously when skin reactions like this occur.
Hypertension: in view of its considerable prevalence (4%), we advise clinicians to be aware of the possibility of hypertension as a side effect of clozapine. Secondly, we recommend routine blood pressure readings when treatment starts, after 3 months, after 6 months, and thereafter annually.
This recommendation is in line with several contributions published previously in this journal, which suggest that, apart from the obligatory white blood cell monitoring, an appropriate amount of attention should be paid to other disabling and potentially fatal complications associated with clozapine [6,7].
Acknowledgement
This article is an abridged republication based on a case report first written for the Tijdschrift voor Psychiatrie [8].