Hypertension induced by sudden clozapine withdrawal in a schizophrenia patient with metabolic syndrome: A case report

Abstract

BACKGROUND

Clozapine remains the gold therapeutic standard for treatment-resistant schizophrenia, and is associated with a range of adverse effects. Although autonomic dysregulation (e.g., psychosis and cholinergic rebound) during clozapine withdrawal is well documented, hypertension, as a withdrawal manifestation, has not yet been reported.

CASE SUMMARY

A 60-year-old man with treatment-resistant schizophrenia and metabolic syndrome developed refractory hypertension following sudden clozapine discontinuation. Despite escalating doses of antihypertensive medications, the patient’s blood pressure (BP) remained uncontrolled for 25 days. Secondary causes were excluded based on normal levels of aldosterone, cortisol, and adrenocorticotropic hormones. Hypertension resolved after reintroducing clozapine, titrated to 200 mg/day, and BP was stabilized at 115/74 mmHg during a 3-month follow-up.

CONCLUSION

Sudden clozapine withdrawal may precipitate severe hypertension in patients with metabolic syndrome, even in those receiving antihypertensive therapy. It is essential for clinicians to closely monitor BP during clozapine discontinuation, consider a gradual tapering protocol, and recognize the reintroduction of clozapine as a viable therapeutic option for managing withdrawal-associated hypertension.

Key Words: Schizophrenia; Metabolic syndrome; Clozapine withdrawal; Hypertension; Case report

Core Tip: This case is the first to describe severe, refractory hypertension as a consequence of sudden clozapine withdrawal in a patient with treatment-resistant schizophrenia and metabolic syndrome. Blood pressure remained uncontrolled despite intensive antihypertensive therapy, but normalized rapidly after clozapine reintroduction. These findings demonstrate that hypertension may be an unrecognized manifestation of clozapine withdrawal and highlight the critical importance of vigilant blood pressure monitoring, gradual tapering, and, when necessary, reintroduction of clozapine. This report contributes to the understanding of clozapine withdrawal syndromes and provides valuable clinical guidance for the safe management of affected patients.

INTRODUCTION

Clozapine, a dibenzodiazepine derivative and multi-acting receptor-targeted antipsychotic, remains the gold standard for treatment-resistant schizophrenia (TRS) due to its superior efficacy in reducing psychotic symptoms, hospitalization rates, and suicide risk compared with other antipsychotics[1-3]. Despite its clinical benefits, the use of clozapine is often constrained by complex and potentially severe adverse effects, including hematologic (e.g., agranulocytosis), metabolic (e.g., weight gain, insulin resistance), and cardiovascular complications[4-6]. Consequently, clinicians may be required to discontinue clozapine due to the onset of emergent, potentially life-threatening adverse drug reactions.

Abrupt clozapine discontinuation may precipitate withdrawal syndromes characterized by autonomic dysregulation, including withdrawal-associated psychosis, cholinergic rebound, extrapyramidal symptoms, catatonia, and serotonergic discontinuation syndrome[7,8]. Moreover, clozapine discontinuation may induce cardiovascular effects, including tachycardia[9], cardiomyopathy, and myocarditis[10,11]. However, hypertension, as a manifestation of clozapine withdrawal, has not been previously documented. This study described a novel case of severe, refractory hypertension occurring in close association with the abrupt discontinuation of clozapine in a patient with schizophrenia and pre-existing metabolic syndrome (MetS). This case report highlighted a rare but clinically significant adverse effect of clozapine withdrawal and explored its underlying mechanisms to inform clinical practice. Informed consent was obtained from the patient prior to his participation.

CASE PRESENTATION

Chief complaints

A 60-year-old, unmarried, homeless man with a 40-year history of TRS (International Classification of Diseases-10 F20.0) was hospitalized for long-term rehabilitation since 2010 due to marked socio-occupational impairment and the absence of guardianship. His disease was characterized by persistent hallucinatory behavior, persecutory delusions, prominent negative symptoms, severe self-neglect, and significant socio-occupational impairment. Despite several trials of both typical and atypical antipsychotics, the symptoms remained refractory to treatment. Since 2010, the patient had achieved clinical stabilization on clozapine at a dose of 200-225 mg/day.

History of present illness

During hospitalization, the patient presented with severe, intractable constipation (no bowel movement for 72 hours) that was unresponsive to his usual regimen of Maren soft capsules and other supportive treatments. The discomfort was remarkable and significantly impacted his well-being. After excluding other potential causes and considering the known pharmacological properties of clozapine, along with a Naranjo Adverse Drug Reaction Probability Scale score of 8 (Table 1), clozapine was identified as the most likely etiological factor. Consequently, clozapine was abruptly discontinued due to the refractory and distressing nature of this adverse effect.

Table 1 Adverse Drug Reaction Probability Scale.

	Yes	No	Do not know	Score
Are there previous conclusive reports on this reaction?	+1	0	0	1
Did the adverse event appear after the suspected drug was administered?	+2	-1	0	2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0	1
Did the adverse reaction reappear when the drug was readministered?	+2	-1	0	2
Are there alternative causes (other than the drug) that could on their own have caused the reaction?	-1	+2	0	0
Did the reaction reappear when a placebo was given?	-1	+1	0	0
Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?	+1	0	0	0
Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?	+1	0	0	1
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0	1
Total score	8

History of past illness

His medical history included type 2 diabetes mellitus, diagnosed in 2006, and managed with metformin (500 mg, three times a day) and acarbose (50 mg, three times a day). Additionally, he was diagnosed with hypertension in 2011 and treated with amlodipine (5 mg/day) and irbesartan (150 mg/day).

Personal and family history

The patient had no significant personal and family history.

Physical examination

Before clozapine withdrawal, physical examination was unremarkable aside from central obesity (waist circumference, 106 cm) and a body mass index of 22.34 kg/m². Blood pressure (BP) was 124/76 mmHg.

Laboratory examinations

Results of routine laboratory tests (hemogram, liver and renal function tests, serum electrolytes, fasting glucose) and electrocardiogram were within normal limits. The patient met the American Heart Association/National Heart, Lung, and Blood Institute criteria for MetS[12], particularly fulfilling the following criteria: Central obesity (waist > 102 cm), hyperglycemia (known type 2 diabetes mellitus on treatment), and hypertension (known hypertension on treatment) (Table 2).

Table 2 Diagnostic criteria for metabolic syndrome.

Criterion	Definition	Patient portrait	Yes/no
Abdominal obesity	Waist circumference ≥ 102 cm for men	106 cm	Yes
Hyperglycemia	Fasting plasma glucose ≥ 100 mg/dL or ongoing treatment	Ongoing treatment	Yes
Low HDL-cholesterol	HDL < 40 mg/dL for men or ongoing treatment	39 mg/dL	Yes
Hypertriglyceridemia	Triglycerides ≥ 150 mg/dL or ongoing treatment	145.14 mg/dL	No
Hypertension	Blood pressure ≥ 130/85 mmHg or ongoing treatment	Ongoing treatment	Yes

HDL: High-density lipoprotein.

Imaging examinations

No imaging examinations were conducted.

FINAL DIAGNOSIS

Severe, refractory hypertension occurring in close association with the abrupt discontinuation of clozapine.

TREATMENT

On day 1 of clozapine discontinuation, aripiprazole (5 mg twice daily) was initiated as an alternative antipsychotic. Baseline BP was 140/82 mmHg. Following clozapine withdrawal, frequent BP monitoring (every 8-12 hours) revealed a persistent and significant elevation in both systolic BP (SBP) and diastolic BP (DBP), which sustained for nearly one month (Figure 1 and Table 3). On day 6, amlodipine was replaced with nifedipine (30 mg/day), which was later increased to 60 mg/day on day 21, while BP remained uncontrolled (days 6-25: SBP 160-190 mmHg, DBP 87-110 mmHg; Figure 1 and Table 3). Irbesartan (150 mg/day) treatment was continued. Repeat investigations, including complete hemogram (sodium, potassium), electrolytes, aldosterone (46.9 pg/mL, reference: 28-376 pg/mL), adrenocorticotropic hormone (9 AM) (47.1 pg/mL, reference: 6.0-48 pg/mL), and cortisol (18.80 μg/dL, reference: 7.26-32.28 μg/dL), were within normal ranges.

Figure 1 Blood pressure changes before and after clozapine withdrawal (day 0), and after clozapine re-initiation (day 25). BP: Blood pressure.

Table 3 Detailed medication, blood pressure and clinical course after clozapine withdrawal.

Days since discontinuation	Antihypertensive dosage	Clozapine restart	Blood pressure readings	Clinical course
1	Amlodipine besylate tablets 5 mg + irbesartan tablets 150 mg	No	140/82 mmHg	No
2	Amlodipine besylate tablets 5 mg + irbesartan tablets 150 mg	No	NA	No
3	Amlodipine besylate tablets 5 mg + irbesartan tablets 150 mg	No	NA	No
4	Amlodipine besylate tablets 5 mg + irbesartan tablets 150 mg	No	NA	No
5	Amlodipine besylate tablets 5 mg + irbesartan tablets 150 mg	No	143/90 mmHg	No
6	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg + felodipine sustained-release tablets 5 mg	No	160/90 mmHg	Headache tachycardia
7	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg	No	NA	No
8	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg	No	166/99 mmHg	Tachycardia
9	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg	No	NA	No
10	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg + nifedipine sustained-release tablets 20 mg	No	165/97 mmHg	No
11	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg + nifedipine sustained-release tablets 20 mg	No	170/90 mmHg	Tachycardia
12	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg	No	NA	No
13	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg	No	NA	No
14	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg	No	NA	No
15	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg + nifedipine sustained-release tablets 20 mg	No	190/90 mmHg	Headache tachycardia
16	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg	No	NA	No
17	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg	No	168/110 mmHg	No
18	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg + nifedipine sustained-release tablets 20 mg	No	170/100 mmHg	No
19	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg	No	NA	No
20	Nifedipine controlled-release tablets 30 mg + irbesartan tablets 150 mg + nifedipine controlled-release tablets 30 mg	No	181/105 mmHg	Tachycardia
21	Nifedipine controlled-release tablets 60 mg + irbesartan tablets 150 mg	No	187/96 mmHg	No
22	Nifedipine controlled-release tablets 60 mg + irbesartan tablets 150 mg + nifedipine sustained-release tablets 20 mg	No	180/95 mmHg	No
23	Nifedipine controlled-release tablets 60 mg + irbesartan tablets 150 mg	No	NA	No
24	Nifedipine controlled-release tablets 60 mg + irbesartan tablets 150 mg + captopril tablets 25 mg	No	172/87 mmHg	No
25	Nifedipine controlled-release tablets 60 mg + irbesartan tablets 150 mg + nifedipine sustained-release tablets 20 mg	No	186/98 mmHg	No
26	Nifedipine controlled-release tablets 60 mg + captopril tablets 75 mg + metoprolol succinate sustained-release tablets 23.75 mg + nifedipine sustained-release tablets 20 mg	100 mg	180/96 mmHg	Tachycardia
27	Nifedipine sustained-release tablets 40 mg + captopril tablets 75 mg + metoprolol tartrate tablets 100 mg + nifedipine sustained-release tablets 20 mg	100 mg	175/102 mmHg	Tachycardia
28	Nifedipine sustained-release tablets 40 mg + captopril tablets 75 mg + metoprolol tartrate tablets 100 mg	100 mg	180/100 mmHg	No
29	Nifedipine sustained-release tablets 40 mg + captopril tablets 75 mg + metoprolol tartrate tablets 100 mg + nifedipine sustained-release tablets 20 mg	100 mg	179/99 mmHg	No
30	Nifedipine sustained-release tablets 40 mg + captopril tablets 75 mg + metoprolol tartrate tablets 100 mg	100 mg	176/98 mmHg	No
31	Nifedipine sustained-release tablets 40 mg + captopril tablets 75 mg + metoprolol tartrate tablets 100 mg	150 mg	174/100 mmHg	No
32	Nifedipine sustained-release tablets 40 mg + captopril tablets 75 mg + metoprolol tartrate tablets 100 mg	150 mg	174/96 mmHg	No
33	Nifedipine sustained-release tablets 40 mg + captopril tablets 75 mg + metoprolol tartrate tablets 100 mg	150 mg	173/93 mmHg	No
34	Nifedipine sustained-release tablets 40 mg + captopril tablets 75 mg + metoprolol tartrate tablets 100 mg + nitroglycerin injection 10 mg	150 mg	210/115 mmHg	Headache tachycardia
35	Nifedipine sustained-release tablets 40 mg + captopril tablets 150 mg + metoprolol tartrate tablets 100 mg	200 mg	150/88 mmHg	No
36	Nifedipine sustained-release tablets 40 mg + captopril tablets 150 mg + metoprolol tartrate tablets 100 mg	200 mg	145/94 mmHg	No
37	Nifedipine sustained-release tablets 40 mg + captopril tablets 150 mg + metoprolol tartrate tablets 100 mg	200 mg	183/96 mmHg	Tachycardia
38	Nifedipine sustained-release tablets 40 mg + captopril tablets 150 mg + irbesartan tablets 150 mg	200 mg	155/89 mmHg	No
39	Nifedipine sustained-release tablets 40 mg + captopril tablets 150 mg + metoprolol tartrate tablets 100 mg	200 mg	NA	No
40	Nifedipine sustained-release tablets 40 mg + captopril tablets 150 mg + metoprolol tartrate tablets 100 mg + urapidil hydrochloride injection 25 mg	200 mg	186/108 mmHg	Headache tachycardia
41	Nifedipine sustained-release tablets 80 mg + captopril tablets 150 mg + irbesartan tablets 150 mg	200 mg	155/90 mmHg	No
42	Nifedipine sustained-release tablets 80 mg + captopril tablets 150 mg + irbesartan tablets 150 mg	200 mg	156/94 mmHg	No
43	Nifedipine sustained-release tablets 80 mg + captopril tablets 150 mg + irbesartan tablets 150 mg	200 mg	143/92 mmHg	No
44	Nifedipine sustained-release tablets 80 mg + captopril tablets 150 mg + irbesartan tablets 150 mg	200 mg	NA	No
45	Nifedipine sustained-release tablets 80 mg + captopril tablets 150 mg + irbesartan tablets 150 mg	200 mg	NA	No
46	Nifedipine sustained-release tablets 80 mg + captopril tablets 150 mg + irbesartan tablets 150 mg	200 mg	137/79 mmHg	No
47	Nifedipine sustained-release tablets 80 mg + captopril tablets 150 mg + irbesartan tablets 150 mg	200 mg	152/94 mmHg	No
48	Nifedipine sustained-release tablets 80 mg + captopril tablets 150 mg + irbesartan tablets 150 mg	200 mg	154/94 mmHg	No
49	Nifedipine sustained-release tablets 80 mg + captopril tablets 150 mg + irbesartan tablets 150 mg	200 mg	137/88 mmHg	No
50	Nifedipine sustained-release tablets 80 mg + captopril tablets 150 mg + irbesartan tablets 150 mg	200 mg	133/78 mmHg	No
3-month follow-up	Nifedipine sustained-release tablets 80 mg + irbesartan tablets 150 mg	250 mg	115/74 mmHg	No
6-month follow-up	Amlodipine besylate tablets 5 mg + irbesartan tablets 150 mg	225 mg	122/78 mmHg	No

NA: No assessment.

Given the persistent hypertension and lack of other identifiable causes, clozapine withdrawal was considered as a potential etiological factor. On day 26, clozapine was cautiously reinitiated at 100 mg/day and aripiprazole was discontinued. On day 27, the BP remained elevated at 175/102 mmHg, prompting the addition of captopril (25 mg three times a day). Despite this, the BP remained high (174/100 mmHg) on day 31, necessitating a dose increase of clozapine to 150 mg/day. Further titration of clozapine to 200 mg on day 35 and 200 mg by discharge, alongside intensification of antihypertensive therapy (captopril increased to 50 mg three times a day, addition of irbesartan 150 mg/day on day 38, and nifedipine increased to 80 mg/day on day 41), gradually resulted in BP control. By day 50, BP had decreased to 133/78 mmHg, with subsequent measurements stabilizing in the range of 133-154 mmHg for SBP and 78-94 mmHg for DBP from day 43 onward (Figure 1 and Table 3). The patient was discharged on day 57 with a regimen of clozapine (200 mg/day), amlodipine (5 mg/day), and irbesartan (150 mg/day).

OUTCOME AND FOLLOW-UP

At the 3-month follow-up, BP was 115/74 mmHg. At the 4-month follow-up, nifedipine was replaced with amlodipine (5 mg/day), restoring the pre-withdrawal regimen [clozapine (250 mg/day), amlodipine (5 mg/day), and irbesartan (150 mg/day)]. The patient’s BP was 122/78 mmHg at the 6-month follow-up (Table 3).

DISCUSSION

To our knowledge, this is the first reported case of severe, refractory hypertension following the abrupt discontinuation of clozapine in a patient with TRS and MetS. Schizophrenia is a chronic psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive impairment. The prevalence of MetS in patients with schizophrenia is estimated to be as high as 41%, which is 2-3 times greater than in the general population[13]. As a major driver of cardiovascular morbidity, MetS contributes to a shortened life expectancy by 15-20 years in this population[14,15]. Clozapine remains the most effective therapy for TRS, while it is widely recognized for its metabolic adverse effects and cardiovascular risks. Orthostatic hypotension and tachycardia are well-recognized adverse effects; however, clozapine-induced hypertension is increasingly reported, but remains under-recognized[16-18]. In patients with MetS, the risk of BP instability may be particularly remarkable during clozapine initiation, dose titration, or discontinuation.

Clozapine has a complex pharmacologic profile, interacting with dopaminergic (dopamine receptor subtypes 1, 2, 4), serotonergic (5-hydroxytryptamine, 5-hydroxytryptamine receptor subtypes 1C, 2A/C, 3), muscarinic, histaminergic, and adrenergic (α1, α2) receptors[19]. Several mechanisms may contribute to hypertension during clozapine exposure or withdrawal. α2-adrenergic receptor antagonism can increase noradrenaline release, while high affinity for dopamine receptor subtypes 4 receptors, which are implicated in hypertensive phenotypes in animal models, may further exacerbate BP elevation[20]. Long-term α2-antagonism may also lead to receptor upregulation, and abrupt cessation may induce a hyperadrenergic rebound, enhancing central sympathetic output and contributing to hypertension. The halogenated structure of clozapine may activate the aryl hydrocarbon receptor, providing an additional mechanism through which clozapine is linked to metabolic disruption and hypertension[21]. Conversely, α1-adrenergic receptor blockade exerts vasodilatory effects that may reduce BP, highlighting the bidirectional nature of clozapine’s cardiovascular actions[22].

The present case report provides clinical insights into this pharmacodynamic complexity. BP gradually improved when clozapine was re-started at doses exceeding 200 mg/day, demonstrating a dose-dependent antihypertensive effect mediated by the restoration of α1-adrenoceptor blockade. MetS likely heightened susceptibility to hypertensive crises by promoting sympathetic overactivity and endothelial dysfunction through insulin resistance[23]. These metabolic disturbances may also explain the patient’s initial refractoriness to standard antihypertensives. Reinstating clozapine restored vascular regulatory balance, highlighting MetS as a critical vulnerability factor and emphasizing the importance of individualized dosing strategies. Gradual tapering of clozapine, such as reducing the dose by increments of 25-50 mg every 2-3 days, is essential to mitigate the risk of withdrawal-induced hypertension. Similar precautions may be required for antipsychotics with comparable receptor-binding profiles, such as olanzapine. Future research should elucidate whether α2-adrenergic receptor-mediated mechanisms contribute to withdrawal-associated hypertension in this pharmacological class.

Limitations

This case report has several limitations. As a single case study, its generalizability is restricted. Additionally, the absence of clozapine plasma level measurements limits mechanistic interpretation, particularly regarding pharmacokinetic-pharmacodynamic relationships.

CONCLUSION

This case report confirms that abrupt clozapine discontinuation may precipitate severe hypertension, even in patients receiving standard antihypertensive therapy. Clinicians must consider clozapine withdrawal as a potential cause of treatment-resistant hypertension, particularly in patients with pre-existing metabolic or cardiovascular comorbidities. This case report highlights the need for close monitoring of cardiovascular parameters during clozapine discontinuation. Weekly BP monitoring for 4-6 weeks following clozapine discontinuation is recommended for patients with MetS to mitigate risks and promote timely intervention.