Psychosomatics 47:440-442, October 2006
doi: 10.1176/appi.psy.47.5.440
© 2006 Academy of Psychosomatic Medicine
Mirtazapine for Severe Gastroparesis Unresponsive to Conventional Prokinetic Treatment
Sung-wan Kim, M.D., Ph.D.,
Il-seon Shin, M.D., Ph.D.,
Jae-min Kim, M.D., Ph.D.,
Ho-cheol Kang, M.D., Ph.D.,
Ji-ung Mun, M.D.,
Su-jin Yang, M.D., Ph.D., and
Jin-sang Yoon, M.D., Ph.D.
Received August 7, 2005; revised August 25, 2005; accepted September 29, 2005. From the Dept. of Psychiatry and Dept. of Internal Medicine, Chonnam National Univ. Medical School; Clinical Trial Center, and Depression Clinical Research Center, Chonnam National University Hospital, Kwangju, Republic of Korea. Address correspondence and reprint requests to Prof. Jin-Sang Yoon, Clinical Trial Center, Chonnam National Univ. Hospital, 8 Hak-dong, Dong-ku, Kwangju 501-757, Republic of Korea. e-mail: jsyoon{at}chonnam.ac.kr
|
ABSTRACT
|
Gastroparesis is a condition of abnormal gastric motility characterized by delayed gastric emptying without evidence of mechanical outlet obstruction. The authors describe complete remission of recurrent postprandial discomfort, nausea, and vomiting within 1 week of starting mirtazapine in a gastroparetic patient who had failed to respond, in 7 months, to conventional prokinetics (erythromycin, metoclopramide, domperidone, perphenazine, itopride, bethanechol, and/or tegaserod) and pyloric injection of botulinum toxin. This is the first report to show that mirtazapine may be an effective alternative when gastroparesis is refractory to conventional measures.
|
INTRODUCTION
|
Gastroparesis, a condition of abnormal gastric motility, is characterized by delayed gastric emptying of solids with no evidence of mechanical outlet obstruction.1 Symptoms suggestive of gastroparesis (e.g., nausea, vomiting, postprandial fullness, early satiety, and abdominal discomfort) are present in approximately 7%–15% of the population.2 Gastroparesis can be confirmed by significant delay on gastric-emptying tests.3 Idiopathic gastroparesis is the most common type (>35% of cases), but known causes include diabetes (the second most common type), gastric surgery, Parkinson’s disease, and collagen vascular disorders.4 Up to 50% of patients with long-standing diabetes mellitus have been reported to have gastroparesis.5 Antral hypomotility and increased gastric-outlet resistance caused by pylorospasm seem to be important physiologic disturbances in gastroparesis.6 Several prokinetic agents, including erythromycin, metoclopramide, domperidone, and cisapride, have been used successfully in controlling symptoms of gastroparesis,7 although properly designed clinical trials are still required to establish their effectiveness.8 Newer medications, such as sildenafil citrate and 5-hydroxytriptamine3 (5-HT3) antagonists (e.g., ondansetron) are currently being evaluated,9,10 and botulinum-toxin injection into the pylorus was reported to relieve symptoms in idiopathic and diabetic gastroparesis.11,12 Controlled studies of these newer therapies are also needed. This report describes a patient who suffered from diabetic gastroparesis with severe recurrent nausea and vomiting. She failed to respond to conventional prokinetics and to botulinum-toxin injection into the pylorus, but she responded fully and rapidly to mirtazapine.
|
Case Report
|
A 27-year-old woman with Type I diabetes mellitus and triopathy was referred to us for treatment of depression associated with uncontrolled nausea and vomiting. During the preceding 7 months, she had been hospitalized six times, for a total of 4 months, to treat postprandial discomfort, nausea, and vomiting. Upper gastrointestinal endoscopy had showed mild hemorrhagic gastritis, multiple shallow duodenal ulcers, and a 2-cm hyperplastic mucosal polyp on the posterior wall of the gastric antrum, but no specific outlet obstruction. Anti-ulcer medications, including a proton-pump inhibitor, were prescribed. Follow-up endoscopy showed healing of the ulcers. Prokinetics, including 500 mg to 1,500 mg of erythromycin, 100 mg of itopride (a dopamine2 receptor-blocker), and 10 mg intravenous (IV) metoclopramide, were administered for over 1 month, but failed to relieve postprandial discomfort, nausea, and vomiting. Furthermore, despite prokinetic treatment, the patient had a markedly delayed gastric-emptying time of 619 minutes (versus the normal limit of 90 minutes), as determined by nuclear scintigraphy (the "gold standard" gastric-emptying tests) after the ingestion of 18.5 MBq of technetium-99m diethylenetriaminepenta-acetate (DTPA) with solid food. A brain CT, performed to rule out CNS lesions, yielded nonspecific findings. Gastroparesis was diagnosed on the basis of objective (i.e., gastric-emptying time) and subjective (i.e., gastric symptoms) findings. Other prokinetics, including 75 mg of bethanechol (a muscarinic agonist), 30 mg of domperidone, and/or 12 mg of tegaserod (5-HT4 partial agonist) were also administered, but nausea and vomiting were not well controlled.
Two months before referral, the patient complained of total insomnia, associated with persistent nocturnal nausea, which was unresponsive to oral benzodiazepine treatment. For 2 months, 2 mg of IV lorazepam was required nearly every evening to induce sleep.
One month before referral, 200 U of botulinum toxin were injected into the pylorus. Gastric symptoms were much improved, and a follow-up nuclear scintigraphy revealed a normal gastric-emptying time (70 minutes). However, about 10 days post-injection, nausea and vomiting reappeared and worsened. The symptoms were unresponsive to the addition of 6 mg of perphenazine (a dopamine antagonist), and the patient could tolerate neither solid nor liquid foods. Follow-up endoscopy showed a large quantity of food still in the stomach after a 16-hour fast, suggesting the recurrence of delayed gastric emptying. The patient started total parenteral nutrition for 7 days, while oral intake (except for oral medications with water) was disallowed. Vomiting resolved with this maneuver, but intermittent nausea persisted, and the patient developed hyponatremia and hypoalbuminemia. When a liquid diet was reintroduced, vomiting and abdominal bloating recurred and worsened.
At this point, the patient was referred for management of her depressive symptoms. She had been suffering from depressed mood, diminished interest, inactivity, suicidal ideation, agitation, sleep disturbances, and poor appetite for a few months, apparently in reaction to her uncontrolled gastric symptoms. Her depressed mood was reported to fluctuate with the severity of nausea and vomiting. At the time of consultation, she had been receiving 1,500 mg of oral erythromycin, 2 mg of IV lorazepam, and 10 mg of IV metoclopramide. She scored 25/60 on the Montgomery-Asberg Depression Rating Scale (MADRS)13 and 29/45 on the Gastroparesis Cardinal Symptom Index (GCSI).14
An evening regimen of mirtazapine, at a dose known to have antiemetic effects (15 mg, as an orally disintegrating tablet), was initiated. The next day, nausea and vomiting were subjectively reduced by 30%, and IV lorazepam and metoclopramide were discontinued. Gastric symptoms resolved gradually, and, within 7 days, she could eat solid foods and had no gastric symptoms (GCSI score: 0). Follow-up nuclear scintigraphy revealed a normal gastric-emptying time (69 minutes). Sleep disturbances and agitation also resolved within a few days after starting mirtazapine, while other depressive symptoms, including interest, activity, and appetite, recovered fully (MADRS score: 0) a few days after the gastric symptoms cleared. The patient was discharged and remained free of symptoms and side effects during 3 months of follow-up.
|
Discussion
|
In this case of diabetic gastroparesis, nausea and vomiting were refractory to mono- and combination therapy with standard prokinetics with differing mechanisms of action, including a macrolide (erythromycin), dopamine-receptor antagonists (metoclopramide, domperidone, perphenazine, and itopride), a 5-HT4 partial agonist (tegaserod), and a muscarinic cholinergic agonist (bethanechol). Severe refractory symptoms associated with multiple hospitalizations are encountered in 2% to 5% of gastroparesis patients and may, as in this case, require more invasive treatment, such as parenteral nutrition and even gastric surgery.7 Botulinum toxin injection temporarily increased this patient’s gastric-emptying rate and decreased the severity of her subjective symptoms, but nausea and vomiting soon redeveloped and worsened. The presence of residual food in her stomach after a 16-hour fast, as seen on follow-up endoscopy, indirectly supported the recurrence of delayed gastric emptying. A recent study of botulinum-toxin injection reported that the response rate (35%) of patients with vomiting as a major symptom of gastroparesis was significantly less than that (57%) of patients without vomiting.12
Mirtazapine is an antidepressant with noradrenergic and specific serotonergic activity. Its specific blockade of 5-HT3 receptors (similar to that of antiemetics such as ondansetron) results in an antiemetic effect. Hence, mirtazapine has been reported to be effective on nausea and vomiting in situations such as cancer chemotherapy, hyperemesis gravidarum, and gastric-bypass surgery.15–18 The refractory nausea and vomiting that persisted for over 7 months in this case improved dramatically within a few days of once-daily mirtazapine dosing. In contrast, other prokinetics required three or more doses daily and were much less effective.
The patient’s depressive symptoms also resolved fully, in tandem with her gastric symptoms. Twenty-three percent of patients with idiopathic gastroparesis (the most common type) had a history of depression or were receiving antidepressants, and 62% of women with idiopathic gastroparesis reported a history of physical (27%) or sexual (58%) abuse.3 Mirtazapine may thus be useful to treat nausea and depression simultaneously in gastroparesis cases with comorbid psychiatric symptoms, such as depressed mood, agitation, poor appetite, or sleep disturbances. In contrast, nausea is a common side effect of conventional antidepressants such as selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors.
Ondansetron, also a specific 5-HT3-receptor antagonist, is recommended as a new therapeutic option for gastroparesis even though its effectiveness is not yet confirmed.10,19 Furthermore, mirtazapine would be less costly (about $75 per month) than ondansetron ($460 per month) or botulinum toxin ($860 per 200 U).12,16
This is the first report to show that mirtazapine may be a good alternative for gastroparesis that is resistant to conventional treatments. It may also be a useful antidepressant when depression and gastroparesis present concurrently. Controlled trials of mirtazapine for gastroparesis are warranted.
|
ACKNOWLEDGMENTS
|
This work was supported by grants of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A050047 and A050174).
|
REFERENCES
|
- Agrawal S, Stollman NH, Rogers AI: University of Miami Division of Clinical Pharmacology Therapeutic Rounds: Update on diagnosis and treatment of gastroparesis. Am J Ther 1999; 6:97–109[Medline]
- Horowitz M, Fraser RJ: Gastroparesis: diagnosis and management. Scand J Gastroenterol 1995; 30(suppl 213):7-16
- Frank L, Kleinman L, Ganoczy D, et al: Upper gastrointestinal symptoms in North America: prevalence and relationship to healthcare utilization and quality of life. Dig Dis Sci 2000; 45:809–818[CrossRef][Medline]
- Soykan I, Sivri B, Sarosiek I, et al: Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci 1998; 43:2398–2404[CrossRef][Medline]
- Horowitz M, Harding PE, Maddox A, et al: Gastric and oesophageal emptying in insulin-dependent diabetes mellitus. J Gastroenterol Hepatol 1986; 1:97–113
- Mearin F, Camilleri M, Malagelada JR: Pyloric dysfunction in diabetics with recurrent nausea and vomiting. Gastroenterology 1986; 90:1919–1925[Medline]
- Syed AA, Rattansingh A, Furtado SD: Current perspectives on the management of gastroparesis. J Postgrad Med 2005; 51:54–60[Medline]
- Sturm A, Holtmann G, Goebell H, et al: Prokinetics in patients with gastroparesis: a systemic analysis. Digestion 1999; 60:422–427[CrossRef][Medline]
- Hasler WL: Are things looking up for the treatment of gastroparesis? sildenafil in animal models of diabetic gastropathy. Gastroenterology 2001; 120:576–578[Medline]
- Amin K, Bastani B: Intraperitoneal ondansetron hydrochloride for intractable nausea and vomiting due to diabetic gastroparesis in a patient on peritoneal dialysis. Perit Dial Int 2002; 22:539–540[Free Full Text]
- Friedenberg F, Gollamudi S, Parkman HP: The use of botulinum toxin for the treatment of gastrointestinal motility disorders. Dig Dis Sci 2004; 49:165–175[CrossRef][Medline]
- Bromer MQ, Friedenberg F, Miller LS, et al: Endoscopic pyloric injection of botulinum toxin A for the treatment of refractory gastroparesis. Gastrointest Endosc 2005; 61:833–839[CrossRef][Medline]
- Montgomery SA, Asberg M: A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 132:382–389
- Revicki DA, Rentz AM, Dubois D, et al: Development and validation of a patient-assessed gastroparesis symptom-severity measure: The Gastroparesis Cardinal Symptom Index. Aliment Pharmacol Ther 2003; 18:141–150[CrossRef][Medline]
- Thompson DS: Mirtazapine for the treatment of depression and nausea in breast and gynecological oncology. Psychosomatics 2000; 41:356–359[Free Full Text]
- Theobald DE, Kirsh KL, Holtsclaw E, et al: An open-label, crossover trial of mirtazapine (15 mg and 30 mg) in cancer patients with pain and other distressing symptoms. J Pain Symptom Manage 2002; 23:442–447[CrossRef][Medline]
- Guclu S, Gol M, Dogan E, et al: Mirtazapine use in resistant hyperemesis gravidarum: report of three cases and review of the literature. Arch Gynecol Obstet 2005; 272:298–300[CrossRef][Medline]
- Teixeira FV, Novaretti TM, Pilon B, et al: Mirtazapine (Remeron) as treatment for non-mechanical vomiting after gastric bypass. Obes Surg 2005; 15:707–709[CrossRef][Medline]
- Nielsen OH, Hvid-Jacobsen K, Lund P, et al: Gastric emptying and subjective symptoms of nausea: lack of effects of a 5-hydroxytryptamine3–antagonist, ondansetron, on gastric emptying in patients with gastric stasis syndrome. Digestion 1990; 46:89–96[Medline]
Get information about faster international access.
Privacy Policy
Copyright © 2006
Academy of Psychosomatic Medicine.
All rights reserved.
Home
| Search
| Current Issue
| Past Issues
| Subscribe
| All APPI Journals
| Help
| Contact Us
|
TOP
ABSTRACT
INTRODUCTION
