Year : 2022 | Volume
: 6 | Issue : 2 | Page : 181--183
Vrushti Bharat Patil, Kshirod Kumar Mishra, Sally John, Ahmed Mushtaq Reshamvala
Department of Psychiatry, Mahatma Gandhi Institute of Medical Sciences, Wardha, Maharashtra, India
Dr. Vrushti Bharat Patil
Department of Psychiatry, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha - 442 102, Maharashtra
Clozapine, a second-generation antipsychotic, is known to have a significant effect on the cardiovascular system, especially on blood pressure. Previous reports show about 4% incidence of clozapine-induced hypertension. However, there are very few cases reported in females. We report a case of clozapine-induced hypertension in a 30-year-old female diagnosed with schizophrenia. When she showed no response to two antipsychotics, clozapine was started. Within a few days, she developed hypertension, not manageable with simultaneous use of antihypertensive medication. Her blood pressure returned to normal after stopping clozapine. Hence, it is important to take appropriate measures to check for rare side effects like hypertension in patients receiving clozapine and to evaluate for all other possible causes.
|How to cite this article:|
Patil VB, Mishra KK, John S, Reshamvala AM. Clozapine-induced hypertension.Ann Indian Psychiatry 2022;6:181-183
|How to cite this URL:|
Patil VB, Mishra KK, John S, Reshamvala AM. Clozapine-induced hypertension. Ann Indian Psychiatry [serial online] 2022 [cited 2022 Dec 4 ];6:181-183
Available from: https://www.anip.co.in/text.asp?2022/6/2/181/354127
Clozapine is a second-generation antipsychotic considered to be the most effective in treatment-resistant schizophrenia. Clozapine has an extensive receptor profile and works on dopaminergic, serotonergic, adrenergic, muscarinic, and histaminic neurotransmitter systems. Clozapine is commonly associated with postural hypotension (9%), due to strong alpha-adrenergic blocking properties. Incidence of hypertension although lesser as compared to hypotension is around 4%. There are a few case reports of patients with schizophrenia developing increased blood pressure after initiation of clozapine.
Here, we discuss a case of a 30-year-old woman, suffering from schizophrenia, who developed hypertension after the initiation of clozapine. Most cases have been reported in males in the past, making this case a rare one.
Miss A, a 30-year-old female, educated up to 11th grade, living in a rural area with no history of diabetes or hypertension, presented to Psychiatric Outpatient Department with a history of mental illness for 10 years. Three of her siblings were also suffering from schizophrenia. Her illness was insidious in onset and gradual in progression. She presented with irritability, withdrawn behavior, self-muttering, poor personal care, irrelevant talking, disturbances of sleep and appetite, and poor food intake. She was treated in the past with olanzapine (10 mg) at night for a period of 2 weeks. She did not continue the medications due to financial constraints and poor social support as all her other 3 siblings were also suffering from psychiatric illness. On Mental Status Examination, she was found to be poorly groomed, uncooperative, with poor eye contact, poor rapport, blunt affect, decreased productivity of speech, and irrelevant speech.
After a detailed evaluation, she was diagnosed to have schizophrenia with a Positive and Negative Symptom Scale (PANSS) score of 116. The patient was admitted in psychiatry ward in view of poor oral intake and also as she needed further psychiatric and medical evaluation. Baseline investigations and radiological imaging of the brain revealed no abnormality. She was initially treated with tablet olanzapine 10 mg/day which was gradually increased to 20 mg/day. She had no improvement in symptoms after 2 weeks of starting the medication. Later, a combination of tablet trifluoperazine 5 mg with trihexyphenidyl 2 mg/day was added which was increased to 15 mg/day. Even after 4 weeks of giving sequentially both antipsychotics, her PANSS score remained high at 113. As she had predominant negative symptoms and was inadequately treated in the past, she was started on tablet clozapine 25 mg/day. Her blood pressure before starting clozapine was 106/70 mmHg. On day 2 of the initiation of clozapine, her blood pressure was found to be high (130–140 mmHg systolic and 90–100 mmHg diastolic). She had no tachycardia or fever. There was no sign of myocarditis or any other cardiac abnormalities on evaluation. Blood counts and serum electrolytes were within normal limits. Blood pressure readings remained between the range of 140–150 mmHg of systolic and 90–110 mmHg diastolic pressure for the next 3 days. Therefore, a physician's opinion was sought. A detailed evaluation and available investigations were carried out by the physician to rule out other causes of hypertension. She was started on tablet amlodipine 10 mg/day. Her blood pressure slowly returned to normal. Clozapine was continued at a dose of 25 mg/day and was slowly increased to 75 mg/day over 6 days. Blood pressure remained between 120 and 130 mmHg of systolic pressure and diastolic between 80 and 90 mmHg. At a dose of 75 mg/day, she developed frequent episodes of vomiting which did not respond to medications over a period of 2 days. Clozapine was gradually tapered and stopped. Her vomiting subsided totally while blood pressure persisted between 100 and 110 mmHg of systolic pressure and between 70 and 80 mmHg of diastolic pressure. Clozapine was resumed along with antihypertensive medication after a drug holiday of 7 days at a dose of 12.5 mg/day with slow up-titration every 5th day to 150 mg/day. Her blood pressure was maintained within normal limits and her PANSS score came down to 96. As the patient and caregiver were not willing for long-term inpatient care, she was discharged and is on regular follow-up on an outpatient basis. Clozapine was uptitrated to 275 mg/day. Over a period of 5 months, her blood pressure continued to be at a normal level with the help of antihypertensive medication.
One of the mechanisms postulated for clozapine causing paradoxical hypertension due to increased noradrenergic activity is the strong alpha-adrenergic antagonistic property (alpha 2 >alpha 1). Strong alpha-2-adrenergic receptor antagonism which leads to a rise in norepinephrine plasma levels has also been suggested as another mechanism. Research that studied the effects of clozapine on rats' aorta found disruption of endothelial nitric oxide signaling with increasing doses of clozapine which is the possible mechanism for hypertension and other cardiovascular adverse effects.
Another mechanism of clozapine's hypertensive adverse effect could be due to its blockage of the D4 receptor, as germline deletion of the D4 receptor causes hypertension in mice. Increased renal expression of the angiotensin type 1 receptor and renal expression of sodium exchangers, transporters, and pumps, such as NHE3, NKCC2, NCC, and NCC, may contribute to the hypertension produced by germline deletion of the D4 receptor.
There is a study which suggests a relationship between the initiation of clozapine and hypertension. Very few cases of clozapine-induced hypertension have been reported in the past and still fewer in female patients. In our case report, hypertension was noted at 140/110 mmHg on the 3rd day of starting clozapine. This is similar to other reports, suggesting that hypertension can appear in the initial stages of treatment in a patient with no history of hypertension. With the reduction of the dose of clozapine, some studies reported normalization of blood pressure. In some cases, a re-challenge with a gradual increase in the dose of clozapine was done after stabilizing the blood pressure using antihypertensive. In our case, blood pressure remained high with intractable vomiting after restarting clozapine along with antihypertensive medication. However, later further re-challenge with very slow optimization of the dose of clozapine was found to be better tolerated and the patient improved symptomatically.
Our patient had no other comorbidities; however, some case reports of clozapine-related hypertension are associated with comorbidities such as hypokalemia, pheochromocytoma, and myocarditis. Hence, it is important to do an adequate evaluation of all possible causes of clozapine-induced hypertension. Bai et al., in their study, found that hypertension after clozapine treatment is two times more in males than in females.
As a concluding remark, it can be said that although hypotension is a common side-effect of clozapine, we need to watch for patients developing hypertension in the course of the treatment. This emphasizes the importance of adequate medical evaluation and regular monitoring of all patients receiving clozapine.
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
Conflicts of interest
There are no conflicts of interest.
|1||Ruiz P. Comprehensive Textbook of Psychiatry. Sadock BJ, Sadock VA, editors. Philadelphia, PA: Lippincott Williams and Wilkins; 2009.|
|2||Baldessarini RJ, Frankenburg FR. Clozapine. A novel antipsychotic agent. N Engl J Med 1991;324:746-54.|
|3||Grover S, Sahoo S, Mahajan S. Clozapine-induced hypertension: A case report and review of literature. Ind Psychiatry J 2017;26:103-5.|
|4||Shiwach RS. Treatment of clozapine induced hypertension and possible mechanisms. Clin Neuropharmacol 1998;21:139-40.|
|5||Davidson M, Kahn RS, Stern RG, Hirschowitz J, Apter S, Knott P, et al. Treatment with clozapine and its effect on plasma homovanillic acid and norepinephrine concentrations in schizophrenia. Psychiatry Res 1993;46:151-63.|
|6||Nair GM, Skaria DS, James T, Kanthlal SK. Clozapine disrupts endothelial nitric oxide signaling and antioxidant system for its cardiovascular complications. Drug Res (Stuttg) 2019;69:695-8.|
|7||Xu P, Kelly DL, Kitchen C, Gildea JJ, Schiermeyer KA, Jose PA, et al. Abstract P321: Clozapine-induced hypertension: Role of the Dopamine Type 4 Receptor (D4R) in Human Renal Proximal Tubule Cells (RPTC). Hypertension 2017;70 Suppl 1:AP321.|
|8||Henderson DC, Daley TB, Kunkel L, Rodrigues-Scott M, Koul P, Hayden D. Clozapine and hypertension: A chart review of 82 patients. J Clin Psychiatry 2004;65:686-9.|
|9||Barry AR, Windram JD, Graham MM. Clozapine-associated myocarditis: Case report and literature review. Can J Hosp Pharm 2015;68:427-9.|
|10||Bai YM, Lin CC, Chen JY, Chen TT, Su TP, Chou P. Association of weight gain and metabolic syndrome in patients taking clozapine: An 8-year cohort study. J Clin Psychiatry 2011;72:751-6.|