Clozapine-induced esophagitis at therapeutic dose: a case report

The pharmacological profile of clozapine, which is often described as a “broad spectrum” antagonist, is different from that of other antipsychotics. It is thought that the side effects reported with clozapine may be attributed in part to its anti-serotonin action together with its anti-α-adrenergic, anticholinergic, and antihistaminic effects.¹

A 58-year-old chronic schizophrenic patient had been treated with haloperidol for over 10 years. Haloperidol was eventually replaced with a combination of antipsychotics (olanzapine/zuclopenthixol and later aripiprazole/zuclopenthixol). Given the persistence of major psychotic symptoms, clozapine was gradually introduced in combination with the following treatments: aripiprazole (10 mg/d), zopiclone (7.5 mg/day, as needed), tropatepine (15 mg/day), and lorazepam (7.5 mg/d). During the first month of treatment, the dose of clozapine was gradually increased to 275 mg/d (at the end of 1 month). However, various side effects were observed, leading to the increase in tropatepine (30 mg/d) for extrapyramidal side effects and to the introduction of macrogol 4,000 (30 g/d) for constipation, heptaminol (563.4 mg/d) for orthostatic hypotension, and paracetamol (3 to 4 g/d) for headaches.

After a second month of treatment the patient continued to describe somatic complaints, including nausea. Aripiprazole was stopped, and tropatepine was gradually reduced to 10 mg/d. In the meantime, clozapine was gradually increased based on good hematologic tolerance since the start of treatment. Nefopam was also introduced for the management of hemorrhoid pain as needed, at 20 mg/d (po). After an additional 35 days of treatment with clozapine at 350 mg/d, one night the patient had hematemesis and diffuse abdominal pain. The next morning, she experienced vomiting and complained of epigastric pain. The patient was treated with domperidone (30 mg/d) and metoclopramide (20 mg/d, po, as needed). Clinical examination revealed reflux esophagitis (grade 4) associated with a hiatal hernia (4 cm). A blood test showed plasma clozapine levels of 980 μg/l (laboratory alert level is plasma concentration > 1,000 μg/L).² In this context, pantoprazole was introduced at a dosage of 20 mg/d, whereas domperidone was stopped after 1 week. Clozapine was gradually reduced to 200 mg/d. After 15 days, gastroesophageal symptoms had diminished and clozapine levels had fallen to 633 μg/L (therapeutic reference range = 350-600 μg/L).² About 2 months after esophagitis, a gastroscopic control was performed, demonstrating complete esophageal healing. Table 1 synthesizes the clozapine dose changes following intoxication along with the plasma levels of clozapine.

Table 1
Summary of changes on dosage and plasma clozapine levels following clozapine intoxication with available leucocyte and platelet counts

Days	Clozapine dose (mg/day)	Clozapine level (μg/l) (n = 350-600 μg/l)*	Leukocyte count (x 109/L)	Platelet count (x 103/L)
D1 - Day before blood collection	350	980	10.1	235
D2	-	-	11.2	236
D3 - Gastroscopy: grade 4 reflux esophagitis
D11	-	-	9.4	503
D17	250	633	6.9	481
D36	200	238	-	-
D43	200	192	-	-
D67 - Gastroscopy: fully healed esophagus
D77	250	270	-	-
D84	250	263	-	-

Some disorders affecting the gastrointestinal tract, including cases of esophagitis with hiatal hernias, have been reported with the use of clozapine, but very few have been published.³ These gastrointestinal disturbances appear in connection with hypomotility and changes in digestive secretion induced by clozapine, as a result of its antiserotoninergic and anticholinergic properties.³ Anticholinergic medications are often implicated in exacerbating gastroesophageal reflux disease by decreasing lower esophageal sphincter pressure and consequently causing or aggravating heartburn by, but such conditions were not identified in our patient before the occurrence of esophagitis.

In our patient, the combined use of clozapine, tropatepine, and aripiprazole (stopped a week before the adverse effect but with a long half-life) may have enhanced the effects of clozapine by contributing to anticholinergic and antiserotoninergic effects respectively (nefopam was only administered on 2 days: 4 and 24 days before esophagitis). However, the dramatic increase in clozapine blood concentration seems sufficient to account for the adverse effect. To the best of our knowledge, this is the first case of clozapine-induced severe esophagitis correlated to a measured-level of plasma clozapine to be published in the literature.

References

• ¹
  Naheed M, Green B. Focus on clozapine. Curr Med Res Opin. 2001;17:223-9.
• ²
  Hiemke C, Baumann P, Bergemann N, Conca A, Dietmaier O, Egberts K, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44:195-235.
• ³
  Laker MK, Cookson JC. Reflux oesophagitis and clozapine. Int Clin Psychopharmacol. 1997;12:37-9.

Publication Dates

• Publication in this collection
  June 2016

History

• Received
  31 July 2015
• Accepted
  9 Nov 2015