Circadian rhythm disturbances and conversion to psychosis in ultra high-risk youth.

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 mg/l (laboratory alert level is plasma concentration 4 1,000 mg/L). 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 mg/L (therapeutic reference range = 350-600 mg/L). 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. 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. 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. Anticholinergic medications are often implicated in exacerbating gastroesophageal reflux disease by decreasing lower esophageal sphincter pressure and consequently causing or aggravating heartburn, 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.