Dissociative disorder induced by clarithromycin combined with rabeprazole in a patient with gastritis

Abstract

Clarithromycin and rabeprazole are both valued for their safety profile. Very few cases of adverse side-effects related to these drugs, when given individually, have been reported; serious side-effects of clarithromycin in combination with rabeprazole have never been reported. The present case reports on a 51-year-old woman with gastritis who received clarithromycin combined with rabeprazole for Helicobacter pylori infection. After taking 500 mg clarithromycin and 10 mg rabeprazole orally she displayed acute psychotic symptoms of dissociative disorder, including: impairment of orientation and attention; the feeling of dreaming; disintegration of thinking; stereotyped speech; flattened emotion; amnesia. Routine blood investigations, computed tomography scans and electroencephalography showed no abnormalities. All symptoms disappeared without antipsychotic treatment ∼48 h after she had taken the two drugs. Combining clarithromycin with rabeprazole might increase the risk of neurotoxicity, particularly in susceptible individuals. This should be a concern in clinical practice.

Introduction

Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, pneumonia, and skin or skin structure infections. In addition, it is sometimes used to treat legionellosis, Helicobacter pylori infection and Lyme disease. Rabeprazole is a proton pump inhibitor used as an antiulcer drug. Clinically, clarithromycin is commonly prescribed in combination with rabeprazole or other antibiotics to eliminate H. pylori. ¹ The present case reports the appearance of a dissociative disorder in a woman taking clarithromycin in combination with rabeprazole. The study was approved by the Ethics Committee of The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. The patient’s written consent was obtained before publishing this case report.

Case report

A 51-year-old woman with a thyroid nodule and gastritis was brought to the emergency department of The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China, because of her strange behaviour and disturbance of consciousness during the previous 6 h, on 5 December 2011. The patient had a history of allergy to penicillin and norfloxacin. She had no history of mental disorder or substance abuse, and no history of operation or trauma. Before the onset of the mental abnormality, her ability to occupy herself and her interpersonal communications were normal. One afternoon, her work colleagues reported that she suddenly displayed abnormal speech and behaviour, and they told her to go home and rest. Her husband reported that his wife called him from home in the afternoon, telling him of a strange feeling and declaring “I feel I’m dreaming”. Her husband quickly returned home and found the patient watching the television. She could not recall what had happened to her and asked repeatedly “What day is it?” with flattened emotion. Her husband thought that she had acute psychosis and immediately took her to hospital.

One day earlier she had been prescribed medication for gastritis from her primary care physician. The medication was 500 mg clarithromycin twice daily and 10 mg rabeprazole twice daily for presumed H. pylori gastritis. At noon on the day of onset of the gastritis, the patient started the medication and took 500 mg clarithromycin and 10 mg rabeprazole. The psychotic symptoms emerged ∼2 h later and were noticed by her colleagues.

When the patient was brought to the general hospital at about 19:00 h, she was immediately given a physical examination. Her vital signs were stable: temperature 36.7°C; blood pressure 125/70 mmHg; and heart rate 80 beats/min. Auscultation of the heart and lungs showed no changes. There were no abnormal abdominal or neurological signs. The emergency department physician found that the patient’s level of consciousness was decreased. She was disoriented with respect to time, place and person. The patient felt that she was dreaming. She was not agitated or impulsive, but her attention was poor and she could not communicate continuously with the physician. The content of her speech was monotonous and irrelevant. No hallucination or illusion was found. In the clinic the patient repeated the question “What day is it today?”. No persecutory or other delusion was found. Her facial expression was reduced and emotional retardation was apparent. Importantly, the patient did not recall what had happened to her at work or how she was brought to the hospital.

All routine blood investigations were normal. Computed tomography scans and electroencephalography showed no cerebral abnormalities. Psychiatric consultation was conducted. The psychiatrist performed a mental status examination and collected information on the patient’s current, past and medication history. The patient complied with the recommendation to stay for 24 h of observation in the emergency department and was diagnosed with drug-induced acute psychosis. At the same time, clarithromycin and rabeprazole therapies were stopped. An antipsychotic was recommended in the event of agitation or impulsiveness, but was not required in this case. In the evening and during sleep the patient had no other psychotic symptoms.

On the second morning at 08:00 h the patient was examined by the liaison psychiatrist and her previous symptoms had all clearly improved. Her consciousness had recovered and was clear by ∼18 h after admission to hospital. There were, however, still some residual symptoms related to attention and cognitive function. She had no memory of events from the onset of her psychiatric illness to admittance to the emergency department, her speech was slightly slowed, and there was still slight impairment of vigilance. Routine blood investigations were repeated and the findings were normal. The patient was discharged and was asked to attend regularly for review as an outpatient. A follow-up telephone call to the patient indicated that she had recovered very well by the third day and had no psychotic symptoms after discharge. The patient had returned to work.

Discussion

A middle-aged woman with no history of mental disorders or substance abuse developed acute disturbance of consciousness after treatment with 500 mg clarithromycin combined with 10 mg rabeprazole. The psychotic syndrome included impairment of orientation and attention, the feeling of dreaming, disintegration of thinking, stereotyped speech, flatted emotion and amnesia. This syndrome disappeared during the 48 h after the patient took the two drugs, and the patient had no residual psychotic symptoms after stopping the medications. Evidently, clarithromycin or rabeprazole induced the mental disturbance. Clarithromycin and rabeprazole are commonly used in gastroenterology. ¹ Unusual adverse effects of these drugs on the central nervous system should be of concern to physicians.

Rabeprazole is widely valued because of its placebo-like side-effect profile. Adverse effects of rabeprazole in the central nervous system have been reported only rarely in the past 10 years. One patient presented with an atypical symptom, a progressive course, subjective psychological distress and intemperate consumption of healthcare resources over a relatively brief period after oral treatment with rabeprazole. ² In another case report, rabeprazole was associated with psychiatric symptoms of marked anxiety with repeated panic attacks. ³ Several lines of evidence indicate that gastrin-releasing peptide and its receptor occur in brain areas such as the dorsal hippocampus and amygdala, where they are involved in the regulation of synaptic plasticity and aspects of behaviour that might be altered in disorders such as anxiety, depression and dementia. ⁴ Rabeprazole has a greater capacity to increase gastrin levels than other proton pump inhibitors.^5,6 This might explain why, in the present case, the patient’s panic symptoms disappeared after rabeprazole was switched to esomeprazole. The mechanism whereby high serum concentrations of rabeprazole induce psychotic disorder is unknown, however.

Clarithromycin is a relatively new antibiotic belonging to the macrolide family and was welcomed for its improved side-effect profile, dosing schedule and microbiological activity relative to its parent compound, erythromycin. ⁷ Thirty-eight cases of clarithromycin-induced neurotoxicity have been reported. ⁸ According to the evidence reported in the literature, it seems more likely that the psychotic symptoms in the present case were induced by clarithromycin rather than by rabeprazole.

Clarithromycin-induced adverse effects in the central nervous system were first found in seven out of 13 elderly patients treated with high-dose therapy (clarithromycin 1200 mg/day); the affected patients had concomitant minor renal failure. ⁹ Most reported patients receive ≤1000 mg/day of the antibiotic. The present patient had taken only 500 mg. Neurological side-effects may, therefore, appear even when low doses of clarithromycin are prescribed. ⁸

Side-effects in the central nervous system appear as different psychotic symptoms, which can include confusion, dizziness, light-headedness and insomnia. ⁸ Unusual severe symptoms (such as delirium,^10–12 hallucinosis,^13–15 mania,^16–19 major depressive episodes ²⁰ and serotonin syndrome ²¹ ) have also been reported. Dissociative symptoms induced by clarithromycin combined with rabeprazole have not been reported in the past ∼15 years, however. Among the 38 reported cases of clarithromycin-induced neurotoxicity mentioned above, 68% had comorbidity or risk factors for developing an altered mental status (psychiatric illness, ageing, cardiopathy, arterial hypertension, respiratory disease, HIV infection or chronic renal failure). ⁷ The allergic constitution of the patient in the present case was probably a factor in her susceptibility. Clearly, the physical condition and susceptibility of the patient should be considered by the physician when clarithromycin is prescribed.

Drug interaction is also an important cause of side-effects. Transitory carbamazepine overdose induced by clarithromycin has been reported.^22,23 Serotonin syndrome can occur with coprescription of paroxetine and clarithromycin. ²¹ A patient with acquired immunodeficiency syndrome receiving highly active antiretroviral therapy developed psychotic symptoms of delirium after treatment with clarithromycin. ²⁴ Medications that have a heightened risk of interaction with macrolides include tetracyclic antidepressants, calcium channel blockers, cyclosporine and cisapride. ²⁵ Inhibition or induction of cytochrome P450 plays an important role in the mechanism of drug interaction. ²⁶ Clarithromycin is metabolized in the liver by cytochrome P450 isoenzymes of the CYP3A family, and also inhibits CYP3A activity.^27–28 Because rabeprazole is metabolized by the P450 isoenzymes CYP3A4 and CYP2C19, its concentration may be increased as a result of CYP3A inhibition by clarithromycin. In addition, because clarithromycin is also metabolized by the CYP3A family, its inhibition of CYP3A activity may affect its own metabolism. A high serum concentration of the drug may increase its neurotoxicity in susceptible individuals.

The adverse effects seen in the present case may be explained by the direct toxicity of clarithromycin or rabeprazole in the central nervous system, increased blood levels of the drugs through inhibition of the CYP3A isoenzyme and the biological susceptibility of the patient. Because plasma drug concentrations were not monitored in the present case, however, drug–drug interaction as the cause is merely a possibility.

In conclusion, the combination of clarithromycin and rabrepazole might carry an increased risk of neurotoxicity, particularly in susceptible individuals. With the trend for combining clarithromycin with rabeprazole in clinical practice, clinicians should be aware of possible side-effects.