A Case of Pseudopheochromocytoma Associated with Clozapine Therapy

Background: An elevated plasma noradrenaline level is a consistent clinical effect of clozapine, which is due to its potent effect on α2-adrenergic receptors. Clozapine, a tricyclic dibenzodiazepine derivative, is used to treat refractory schizophrenia. In this report we present a case of pseudopheochromocytoma in a schizophrenic patient treated with clozapine. Case: A 55-year-old female diagnosed with schizophrenia referred from psychiatry clinic to endocrinology clinic detected with bilateral adrenal masses. She was hypertensive and she used nifedipine. Urine catecholamines, especially normetanephrine, were extremely elevated; however, she did not have any pheochromocytoma-related symptoms. Adrenal imaging was not compatible with pheochromocytoma. Following psychiatric consultation, clozapine was withdrawn for 1 week, and then 24-h urine catecholamineswere normal. Metaiodobenzylguanidine (MIBG) scan was normal. Conclusion: Given the potentially significant morbidity associated with paranoid schizophrenia, especially in undiagnosed cases, we recommend timely urinary catecholamine screening in patients that develop hypertension or other typical symptoms following the use of clozapine.


Introduction
Pheochromocytomas [Pheos] are catecholamine-producing tumors derived from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia, of which 95% exist in the adrenal glands. Clinical manifestations arise as a result of their excessive production of catecholamines.
The symptoms of Pheos include sustained or paroxysmal hypertension, palpitations, headache, sweating, anxiety attacks, weight loss, and hyperglycemia. The clinical presentation of Pheos varies from incidental adrenal adenomas to life-threatening hypertensive crises [1].
The prevalence of Pheos in patients with adrenal incidentalomas is 0.3%-5% [2] however; the most critical reported issue related to adrenalincidentalomasis that the diagnosis of Pheos must be rule out. The recommended initial biochemical investigation for Pheos is measurement of plasma or urine metanephrines and normetanephrines. A level >4-fold urine level of catecholamines [ULC] indicates that Pheos is highly probable [3]. The 24-h metanephrine level (metanephrines and normetanephrines) is the most sensitive test for diagnosing Pheos. Negative test results exclude functional Pheos, except for dopamine-secreting Pheos or small tumors [4,5]. Radiologically Pheos appear circumscribed, and non homogeneous with cystic and hemorrhagic changes, based on CT scanning. The unenhanced attenuation value of Pheos on CT is usually >30 HU. On the other hand, they exhibit high signal intensity on T2weighted MRI. All of them are not specific for Pheos [6,7].
False positive Pheos test results may cause patient anxiety, leading to unnecessary imaging studies. False positive results for Pheos are due to physiological variations, laboratory errors, and drug interference [8,9]. Drug-related false positive elevations of ULC have been reported, and tricyclic antidepressants are among most common causes of false positive elevations of ULC [8,10,11]. Others medications reported to cause false-positive serum or urine studies are acetaminophen, phenoxybenzamine, amitriptyline, labetalol, haloperidol, levodopa, tamsulosin, venlafaxine, hydrochlorothiazide, and buspirone [12]. Selective serotonin re-uptake inhibitors [SSRIs] have been associated with false positive upper limits of normal [1].
Clozapine, a tricyclic dibenzodiazepine derivative, has an established role in the treatment of refractory schizophrenia. The literature includes a few case reports of a pseudopheochromocytoma syndrome associated with clozapine treatment. Elevation of the plasma noradrenaline level has been reported as a consistent clinical effect of clozapine, which is due to its potent effect on α2-adrenergic receptors [1][2][3]. Paradoxical hypertension with an elevated concentration of urinary catecholamines has also been reported in association with clozapine treatment, although rarely, and in association with other antipsychotic medications [13]. Here we present a patient with paranoid schizophrenia that was treated with clozapine and developed laboratory mimicking pheochromocytoma.

Case Report
A 55-year-old female diagnosed with paranoid schizophrenia, recurrent depressive illness, and generalized anxiety disorder based on ICD-10 criteria presented to Sakarya University Training and Research Hospital, Department of Endocrinology with bilateral adrenal masses. She had a history of hypertension and hyperlipidemia.
She used nifedipine for hypertension, atorvastatin for hyperlipidemia, and clozapine for schizophrenia. Size of her adrenal masses in the righta drenal 12×22 mm and int he left adrenal gland were 38×26 mm, respectively.
The adrenal masses did not exhibit contrast enhancement in the out phase of sequence, which was consistent with adenoma according to an experienced radiologist. The 24-h urine catecholamines findings based on HPLC were as follows: vanil-mandelic acid was 8.3 mg/ 24h, which was within the upper limit of normal (0-6 mg/24h); metanephrine was normal; normetanephrine was 1641 µg/24h, which was significantly higher than normal (0-400 µg/24h). The patient did not have any pheochromocytoma-related symptoms, episodes of hypertension, palpitations, or flushing. Her adrenal imaging findings were not consistent with pheochromocytoma (Figures 1, 2 and 3).

MIBG scan was performed and it also was normal (Figures 4, 5)
Based on these findings, clozapine-induced pseudo pheochromocytoma was considered; a review of the literature showed that a few cases similar to the presented case have been reported [12,13]. Comprehensive investigations excluded all other causes of hypertension and elevated urinary catecholamines, and the final diagnosis was clozapine-induced pseudo pheochromocytoma.
The risks versus benefits of discontinuing clozapine were considered in collaboration with the treating specialist physicians, and discontinuation of clozapine was advised. Following psychiatric consultation, clozapine was withdrawn for 1 week, after which 24-h urine catecholamines were normal: 5-hidroxyindolacetic acid: 4.6 mg/ 24h; metanephrine 119 µg/24h; normetanephrine: 283 µg/24h; vanilmandelic acid: 3.3 mg/ 24h. In addition, plasma renin activity [PRA] and the plasma aldosterone concentration [PAC] were 0.94 ng/mL/h and 23 ng/dl, respectively. The PAC to PRA ratio was 24.8, but she did not have hypopotassemia. Due to the high PAC to PRA ratio (>20) thesaline infusion test was performed. Following 4-h saline infusion (500 mL/h) PAC decreased to 2 ng/dL (<5 ng/dL), and primary hyperaldosteronism was therefore also excluded.

Discussion
Clozapine is a tricyclic dibenzodiazepine derivate used for the treatment of schizophrenia. It's side effects include agranulocytosis and paradoxical hypertension with elevated 24-h catecholamines [13,14]. The neuropharmacological mechanisms of action of clozapine are complex, and include affinity for 5-HT2 receptors and α2adrenergic receptors in vitro [15]. Clozapine has been reported to cause an elevated plasma noradrenaline concentration, perhaps via inhibition of presynaptic reuptake mediated by α2-adrenergic receptors [16]. The other mechanism of clozapine-induced elevation in plasma NE levels is both increased spillover and decreased clearance or combination of them [17].  The clinical effects of urine catecholamines remain uncertain. Some researchers have reported there are clinical effects [18,19], whereas others have reported there are no clinical effects, as in the presented patient [20]. Similar to the presented case, Li et al. [13] reported a 27year-old male with mimicking pheochromocytoma; their patient used clozapine to treat catatonic schizophrenia, and developed hypertension and elevated urinary catecholamines. Following withdrawal of clozapine their patient's blood pressure and urinary catecholamines returned to normal. Krentzet al. [14] reported 4 patients with pseudo pheochromocytoma syndrome that were treated with clozapine; following the withdrawal of clozapine the symptoms resolved and the urine catecholamine concentration returned to normal in all cases.
The association between clozapine treatment and onset of hypertension is controversial. In the literature, prevalence of hypertension associated with clozapine therapy was reported 4-16% in various studies [21,22].
Given the potential for significant morbidity associated with pseudo pheochromocytoma syndrome, as undiagnosed cases are unlikely to receive clozapine treatment, we recommend early urinary catecholamine screening in all patients that develop hypertension or other typical symptoms following the initiation of clozapine treatment. The manufacturers of clozapine must develop international clinical guidelines for early diagnosis and management of pseudopheochromocytoma syndrome.