Clozapine-induced hypertension: A case report and review of literature.

There are very few reports which suggest an association between clozapine and hypertension. We report a case in which a direct link of initiation of clozapine to development of hypertension which required pharmacological intervention. A 32-year-old male who did not have any history of hypertension and had normal blood pressure at the baseline developed high blood pressure (i.e., 150/90 mmHg) while on clozapine 100 mg/day. Reduction of the dose of clozapine to 75 mg/day led to the return of blood pressure to baseline, with increase in blood pressure to 150/90 mmHg on increasing the dose of clozapine again, requiring tablet atenolol 50 mg/day for normalization of blood pressure with concomitant continuation of atenolol. Later, clozapine was increased to 350 mg/day, with no recurrence of raise in blood pressure. After 6 months, tablet atenolol was stopped with no evidence of hypertension in follow-up. To conclude, this case report suggests that clozapine can rarely lead to hypertension during the initial phase of treatment.

Clozapine has a unique receptor-binding profile (high dopamine D4 affinity, significant serotonergic, histaminergic, muscarinic, and alpha-adrenergic blocking properties) which makes it superior to other antipsychotics and at the same time leads to the development of various side effects.[1] In terms of its effect on blood pressure, clozapine is reported to be associated with orthostatic hypotension, with incidence rate reported to be about 9% during the initial phase of treatment due to its strong alpha-adrenergic blocking properties.[2] However, very rarely clozapine has also been reported to be associated with hypertension during the initial phase of treatment.[3456] In this report, we present the case of a 32-year-old man who developed hypertension after the initiation of clozapine which required pharmacological intervention.

CASE REPORT

Mr. A, 32-year-old graduate, hailing from an urban area presented with a long-standing psychotic illness since the age of 17 years. The illness was of insidious onset, precipitated by a psychosocial stressor, and ran a chronic course. The illness was characterized by irritability, smiling to self, muttering to self, delusion of persecution, discussing auditory hallucinations, formal thought disorder, and negative symptoms in the form of alogia, anhedonia, asociality, and emotional withdrawal. His treatment history revealed that he had received four adequate trials of antipsychotics (amisulpride, trifluoperazine, haloperidol, and risperidone) with good compliance but without much benefit. He had a history of a suicide attempt, which was precipitated by marital disharmony and impending divorce. At the time of presentation, he was receiving tablet olanzapine 30 mg/day and his positive and negative symptom scale (PANSS) score was 93 at the time of admission to the inpatient unit.

A diagnosis of undifferentiated schizophrenia was considered, and after proper preclozapine evaluation, he was started on clozapine and olanzapine was tapered off. His blood pressure before starting clozapine was 100/70 mmHg. Clozapine was started at 25 mg/day, and it was increased by 25 mg/day every 3rd day till 100 mg/day with monitoring of total leukocyte count, total platelet count, and orthostatic hypotension. On the 10th day of initiation of clozapine (2 days after increasing the dose to 100 mg/day), patient's blood pressure was recorded as 150/90 mmHg with fluctuating pulse rate in the range 80–120/min. He was monitored closely for tachycardia and fever (to look out for the development of myocarditis). Detail cardiac workup did not reveal any evidence of myocarditis and his blood counts during this period were found to be within normal range. Urine catecholamine levels were also in the normal range. His blood pressure was constantly monitored and for next 3 days and his systolic blood pressure kept on fluctuating between 140 and 160 mmHg and diastolic blood pressure ranged from 90 to 110 mmHg. In view of persistently high blood pressure, clozapine was reduced to 75 mg/day, with which his blood pressure normalized. After 4 days, clozapine was increased to 87.5 mg/day with which his blood pressure remained in the normal range. As he was showing some improvement in psychosis with clozapine, dose was again increased to 100 mg/day. Again within a day, his blood pressure increased to 150/90 mmHg. Patient and family were explained about the possible association of hypertension with clozapine, and option was given to stop clozapine. In view of some improvement with clozapine, a joint decision was taken to continue clozapine along with the use of antihypertensive medication. He was started on tablet atenolol 50 mg/day with which his blood pressure settled down (systolic 110–120 mmHg and diastolic 70–80 mmHg). Throughout this period, the patient did not report any clinical manifestations which could be attributed to high blood pressure. After his blood pressure settled down, the dose of clozapine was increased slowly with every increment at 12.5 mg/day on every 3rd day with monitoring of blood pressure and hematological parameters. Over the period of 3 months, clozapine was increased to 350 mg/day along with continuation of tablet atenolol 50 mg/day without any recurrence of hypertension. During this period, his PANSS score came down to 48, and he was discharged from the inpatient unit. After 6 months of starting clozapine, tablet atenolol was initially reduced to 25 mg/day and then stopped. However, there was no recurrence of hypertension after stopping atenolol. He continues to follow-up regularly (about 2.5 years), and there has been no recurrence of hypertension with continued used of clozapine. He continues to maintain the improvement seen with clozapine, and his PANSS score at the time of the last follow-up was 36.

DISCUSSION

There are very few case reports[34567] and few studies suggest an association between clozapine and hypertension.[8910] The case reports which have suggested association of clozapine with hypertension suggest that it usually occurs during the initial phase of treatment with the doses varying from 62.5 to 250 mg/day.[34567] In the index case, hypertension was noted with clozapine 100 mg/day. As was true for our case, the cases of clozapine-induced hypertension have been reported among males only, aged 32–49 years,[34567] who had no history of hypertension in the past.[3467] However, the onset of hypertension during clozapine initiation was associated with other abnormalities such as myocarditis,[111213] pseudopheochromocytoma,[14151617] and hypokalemia.[7] Hence, whenever a patient develops hypertension with use of clozapine, it is important to thoroughly evaluate for other possible causes, which could contribute or lead to hypertension. In some of these reports, reduction in the dose of clozapine or stoppage had led to reduction in blood pressure too.[4] However, in most of the cases, clozapine could be continued along with use of antihypertensive medications such as atenolol,[3] propranolol,[4] losartan,[6] and perindopril and metoprolol.[7] However, there are no guidelines with regard to when to stop the antihypertensives. In the index case, we did so, after 6 months of continuation of atenolol.

Kane et al. (1988) in the initial double-blind comparison study reported hypertension in 12% of patients managed with clozapine which was higher than 5% reported among patients receiving chlorpromazine.[18] A retrospective chart review of 82 patients on clozapine for a period of 5 years revealed that 27% of patients on clozapine had to be given treatment for hypertension which occurred following initiation of clozapine.[8] Another claim-based study, which involved 552 patients receiving clozapine and 2461 patients receiving typical antipsychotics, reported no increased risk of hypertension with use of clozapine.[19] In a previous study from our center, which prospectively followed up, patients receiving clozapine for 3 months reported systolic blood pressure more than 130 mmHg at baseline in 13 out of 60 patients which increased to 17 out of 60 patients at 3 months, whereas diastolic blood pressure more than 90 mmHg was noted in 9 out of 60 patients in baseline and 17 cases at 3-month follow-up. Overall blood pressure more than 130/85 mmHg was recorded in 16 out of 60 patients at baseline which increased to 22 out of 60 patients at 3-month follow-up with absolute increase 10%.[10] Similar results were also reported by another prospective 3-year follow-up study.[9]

Development of paradoxical hypertension with clozapine is attributed to its strong alpha-adrenoreceptor blockade property (alpha 2 > alpha 1), which may lead to increase in noradrenergic plasma levels.[20] Another possible explanation which has been put forth is its strong alpha-2-adrenergic receptor antagonism, which leads to rise in norepinephrine plasma levels[2122] and hence hypertension along various other nonspecific symptoms such as hyperglycemia, panic attacks, and weight loss.[17152316]

In our case, reduction in dose of clozapine led to reduction in blood pressure, which reoccurred at the same dose again. Hence, finding of the present study suggests that hypertension may be related to dose of clozapine. The Naranjo's probability score for the index case was 8 suggesting a probable association.[24]

Accordingly, it can be concluded that clozapine can rarely lead to hypertension. Hence, patients started on clozapine must be monitored for raise in blood pressure.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.