Clozapine Induced Hypertension and its Association with Autonomic Dysfunction

Abstract

Clozapine is a second generation antipsychotic agent which is drug of choice for treatment resistant schizophrenia. Tachycardia and postural hypotension are most frequently observed cardiovascular adverse effects, but reports on new-onset persistently elevated blood pressure are sparse. Mechanisms underlying clozapine induced hypertension also remain unclear. We report the case of a 32 year old normotensive male with persistently elevated systolic and diastolic blood pressure after clozapine initiation. Hypertension persisted throughout the phase of dose optimization and dose stabilization at 300 mg/day, requiring an addition of a beta blocker (atenolol) after a month of observation. The 24 hour urinary catecholamines were within normal limits. Autonomic function tests revealed severe loss of parasympathetic activity and cardiac autonomic tone. The case adds to limited information on autonomic dysfunction as a potential factor in clozapine induced hypertension.

Introduction

Clozapine is a tricyclic dibenzodiazepine with a unique pharmacological profile, interacting with dopaminergic (D1, D2, D4), serotonergic (5-HT1C, 5-HT2A/C, 5-HT3), muscarinic, histaminergic, and adrenergic (α1, α2) receptors. Clozapine is the drug of choice for refractory schizophrenia not responsive to first line antipsychotic agents.¹

The typical cardiovascular effects, due to α1-adrenergic and muscarinic antagonism, are hypotension and tachycardia, respectively. Paradoxically, hypertension has also been reported,² but is thought to be transient. Reports of new-onset hypertension with persistently elevated blood pressure (BP) are sparse.

PubMeD search [(clozapine[MeSH Terms]) AND (hypertension[MeSH Terms]); human studies; Jan 2000- Aug 2021] reveal only seven relevant reports.^3–9 Also, there is no clear consensus on pathophysiology of clozapine induced hypertension in available reports.^3,7,9,10

We report the case of 32 year old old, normotensive male with schizophrenia with prospectively observed persistent hypertension after clozapine initiation which was assessed over course of admission.

Case Report

Mr A, 32 year, unmarried male was a known case of paranoid schizophrenia according to ICD-10¹¹ with a continuous course for nine years. Illness was characterized by hallucinatory behavior, persecutory delusion, negative symptoms, decreased self care and gross decline in socio-occupational functioning. Patient had received multiple trials of typical and atypical antipsychotics with adequate dose and duration leading to no substantial improvement. At the time of first presentation in June 2021, patient was taking tablet risperidone 4 mg/day only. In view of treatment resistance, plan was made for admission and clozapine initiation.

Physical examination was non-significant apart from tinea corporis. BMI was 24.9 Kg/m² and BP was 118/76 mmHg on first day of admission. The routine blood investigations (hemogram, liver and kidney function tests, serum electrolytes, fasting blood sugar) and ECG were within normal limits.

Clozapine was started at 12.5 mg twice a day from day 7 of admission, with a baseline BP of 118/84 mmHg the day before. Dose optimization was made with an increase of 25 mg every 2 days, to a target dose of 300 mg/day, along with a slow cross-taper of risperidone. Soon after the start of clozapine, patient’s BP was found to be raised persistently as recorded on a frequent daily basis. The blood pressure was monitored 6–8 hourly and increase in both systolic and diastolic BP was reflected in recordings for one month after clozapine initiation. (Figure 1) In addition, sedation and tachycardia were also observed as other adverse effects.

Figure 1.

Serial Monitoring of Bp Over the Course of First Month of Clozapine Initiation

Autonomic Function Tests (AFTs) were done on day 45 of admission which revealed a severe loss of parasympathetic reactivity and cardiac autonomic tone, with normal sympathetic reactivity. (Box 1)

Box 1. Autonomic Function Tests.

		RESULTS		NORMAL RANGE
Deep Breathing test
Change in heart rate (HR)		5 bpm		≥15 bpm
E: I Ratioa		1.075		≥1.21
Isometric exercise (hand grip test)
Rise in diastolic BP		+14 mmHg		≥10 mmHg
Postural tests
Δ Systolic BP		+23 mmHg		Fall of ≤10 mmHg
30:15 ratiob		1.04		≥1.04

^aE:I ratio: From continuous ECG, ratio of longest R-R interval (on Expiration) to shortest R-R interval (on Inspiration) after deep breathing as per protocol; ^b30:15 ratio: Ratio of longest R-R (∼30th beat) to shortest R-R interval (∼15th beat) after assuming standing position.

The 24 hour urinary catecholamine estimation was also done on day 51 of admission. Results were as follows: Epinephrine: 11.37 μg/24 h and 6.40 μg/gram creatinine; Norepinephrine: 45.28 μg/24 h and 29.20 μg/gram creatinine, Dopamine: 224.22 μg/24 h and 198.00 μg/gram creatinine; urine 24 h volume: 3700 mL and urine creatinine: 33.18 μg/dL. All were within normal limits

Meanwhile, patient continued to show improvement with 40% reduction in Positive and Negative Symptom Scale (PANSS) score over course of admission. Routine blood investigations, particularly complete hemogram and serum electrolytes (sodium, potassium), continued to be within normal limits.

Besides clozapine, additional medications were clonazepam 0.25–0.50 mg/day (day 1–26 of admission), pantoprazole-domperidone (40 mg+10 mg/day) and antifungal agents in the form of itraconazole 200 mg/day (day 3–30 of admission) and terbinafine 250 mg/day (day 31–47 of admission). Itraconazole was stopped due to its theoretical potential for increasing clozapine level and infrequent association with cardiovascular risks. BP recordings did not show any temporal change after stopping of itraconazole and continued to be rather on a higher side. Maximal recorded daily SBP was 138–165 mmHg and DBP was 108–123 mmHg between day 31 and 38 of admission.

Tablet atenolol 25 mg/day was finally added on day 39 of admission, after which patient’s blood pressure improved than before. The maximal daily BP now remained between 120–130 mmHg systolic and 80–98 mmHg diastolic from day 40 onwards till day 55. Patient was thereafter discharged on clozapine 300 mg/day and atenolol 25 mg/day, with a plan to monitor BP.

Discussion

Persistent arterial hypertension is a less recognized cardiovascular adverse effect observed with clozapine. The Naranjo Adverse Drug Reaction Probability Scale score was 7, indicative of probable relationship.

Various possible mechanisms have been discussed to explain, atleast in part, hypertension induced by clozapine, as follows: α₂ antagonism effects of clozapine leading to prolonged noradrenergic release^8,10; hypokalemic hypertension through renal potassium loss³; sodium and fluid retention possibly due to D4 receptor blockade,¹³ raised urinary catecholamines mimicking phaeochromocytoma caused by clozapine^7,9; and its tricyclic structure leading to blockade in the nor-adrenaline reuptake similar to tricyclic antidepressants. In our patient, potassium levels have always remained within normal limits and there was no evidence for significant sodium or fluid retention. A 24 hour urine catecholamine assessment, which is more reliable than point estimation, was conducted, which came out to be normal. Similar to our report, urinary catecholamines were found to be normal in some prior reports.⁵

We documented a severe loss of parasympathetic activity and cardiac autonomic tone on autonomic function tests, with preserved sympathetic activity. Findings support the possible contribution of autonomic dysfunction in the pathogenesis of clozapine induced hypertension. The imbalance between sympathetic and parasympathetic activity may have implications for regulation of blood pressure. None of the previous case reports on clozapine induced hypertension have assessed or described autonomic function tests. Available studies on clozapine-treated patients, however, indicate a tendency for basal autonomic dysfunction with an increased sympathetic and/or decreased parasympathetic tone.^12,14

A retrospective chart review for patients with schizophrenia found that systolic and diastolic BP was seen to increase after initiation of clozapine.¹⁵ More recently, Norman et al. ⁶ reported that the hypertension with clozapine occurred early in the course of treatment and occurs regardless of the dose. In our case too, elevated BP was observed at lower doses and soon after initiation of clozapine.

Hypertension was initially managed non-pharmacologically, however the BP consistently remained above the normal limits after first month of clozapine initiation, even after titration phase was over. The hypertension associated with clozapine was treated in previous cases by dose reduction or stopping clozapine,⁵ adding an anti hypertensive^4,5,7 or correction of contributing cause such as hypokalemia.³ As this was a case of treatment-resistant schizophrenia, we could not reduce or substitute clozapine for another drug in view of multiple failed trails with first line agents. We added atenolol which appeared to reduce clozapine induced hypertension, with a plan to re-review its need after an optimum control is achieved for few months. There are no existing guidelines with regard to choice or duration of antihypertensives.

Though persistent hypertension with clozapine is an uncommon adverse effect, vigilance is necessary to reduce the cardiovascular morbidity. There is need to institute periodic monitoring of blood pressure, from the first week onwards, in patients initiated on clozapine.

To conclude, clozapine can cause persistently elevated blood pressure in association with severe loss of parasympathetic and cardiac autonomic tone and preserved sympathetic activity. Atenolol appeared to control the clozapine associated hypertension atleast in the short term.