Subclinical Pancreatitis Related to Mirtazapine - A Case Report

 

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Mirtazapine is an antidepressive agent with proven efficacy [1] [4]. Frequent side effects include sleepiness, sedation, agitation, confusion, increased appetite, weight gain, and edema. Less frequent side-effects are orthostatic hypotension, mania, epileptic seizures, tremor, muscle-jerking, granulocytopenia, increase of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and exanthema [2] [5]. To our knowledge, pancreatitis as a side-effect of mirtazapine has not been described before. In this communication, we will report on a case of subclinical pancreatitis in a patient with a past history of alcohol abuse. The pancreatitis was temporarily related to the combination of mirtazapine treatment and oral food, it ceased 10 days after stopping mirtazapine. There was no alcohol consumption during the entire observation period.

A 54-year-old unemployed hairdresser was admitted to the Department of Psychiatry at the University of Göttingen for a severe episode of a recurrent major depressive disorder (DSM IV 296.33). He had a history of unipolar depression, with previous hospitalizations for depressive episodes in March and October of 1999. He also had a history of alcohol dependence (DSM IV 303.90) dating from adolescence with alcohol-related hallucinations (DSM IV 291.3) which were found to be responsive to pimozide in 1998. Alcohol consumption was stopped after detoxification in August, 1998. On the present admission, the treatment consisted of citalopram at 60 mg, pimozide at 1 mg, and aspirin at 100 mg. Because of the severity of the depressive episode, we decided to add mirtazapine, which had never been tried on this patient. We chose a rapid dosage increase of 15 mg per day up to 60 mg given once a day at nighttime. On day 4, an increase of lipase and pancreas-specific amylase was found after routine blood-sampling, and a further increase of these two enzymes was observed on day 5 (Fig. [1]). We stopped oral food supply that day, and pancreas enzyme serum levels returned to normal on day 7. After introduction of restricted oral food on day 8, however, enzyme serum levels increased again. Although previous reports of elevation of pancreas enzymes related to mirtazapine had not been reported either in the literature or by Organon Pharma, Inc., Munich, we decided to stop mirtazapine on day 14 despite a marked clinical improvement in the depressive symptoms. Serum levels returned to normal levels at day 24, and a reintroduction of unrestricted oral feeding on day 27 caused only a minor increase of serum levels lasting for 3 days. Subsequent samples revealed no abnormalities in the pancreas enzyme serum levels. Samples of AST, ALT, total bilirubin, alkaline phosphatase, gamma glutamyltransferase, C-reactive protein levels and the number of leukocytes taken on day 1 and daily between day 9 and day 34 were within normal limits. The serum ethanol was below a detectable level (< 0.02 ‰) at either sample (day 1, 9, and daily from day 13 to 34). Clinically, the patient never had any subjective complaints of abdominal pain or bowel dysfunction, and only mild pain on epigastral palpation. An abdominal ultrasound on day 6 revealed no sign of pancreatitis. Since the patient's depressive symptoms were largely improved, we decided not to administer any other antidepressive drugs. The patient was discharged on day 34, and will be seen regularly on an outpatient basis.

In this patient, a subclinical elevation of pancreas enzyme serum levels was temporarily associated with mirtazapine treatment and oral food which ceased after mirtazapine was stopped. There was no clinical or biochemical evidence for current alcohol consumption. Mirtazapine is known to interact with enzymes of hepatic metabolization [2], but to our knowledge, there have been no cases of mirtazapine-related pancreatitis published as yet. A contact with the AMSP drug safety program (see Grohmann et al. [3]) revealed one previously unreported case of mirtazapine-related increase of serum lipase in a 48-year-old women with depression after a rapid dosage increase to 60 mg per day within one week. In this patient, the gamma glutamyltransferase was slightly increased; pancreas-specific amylase was not assessed. That patient also had subclinical pancreatitis, and there were no known risk factors such as alcohol abuse history. Lipase and gamma glutamyltransferase returned no normal values after mirtazapine cessation. The mechanism underlying mirtazapine-related pancreatitis remains obscure, and may not necessarily be mirtazapine-specific, since the contact to the AMSP program also revealed 2 cases of paroxetine-related pancreatitis; there are also reports of pancreatitis as a result of tricyclic antidepressant overdoses [6] [7].

We hypothesize that our patient's previous alcohol abuse had caused lasting subclinical damage to his pancreas and, therefore, lowered the threshold for medication-related pancreatitis. On the basis of our observation and our literature research, we recommend pancreas enzyme serum level monitoring and slow dosage increase when introducing mirtazapine in patients with possible or known pancreas dysfunction.

Fig. 1 Upper part: pancreas-specific amylase (left ordinate) and lipase (right ordinate), lower part: daily mirtazapine dose (left ordinate) and food (right ordinate). Food quality is rated as: 0 = no oral food; 1 = tea and bread; 2 = fat-free, very light food; 3 = low-fat, light food; and 4 = unrestricted oral food. Note the increase in pancreas enzyme serum levels associated with mirtazapine and oral food exposure.

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Dr. Martin Sommer

Department of Clinical Neurophysiology
University of Göttingen

v. Siebold-Straße 5
37075 Göttingen
Germany