International Foundation for Functional Gastrointestinal Disorders Phone: 414-964-1799 700 W. Virginia St., #201 Toll-Free (In the U.S.): 888-964-2001 Milwaukee, WI 53204 Fax: 414-964-7176 Internet: www.iffgd.org Copyright 2001-2012 by the International Foundation for Functional Gastrointestinal Disorders Antidepressants and Functional Gastrointestinal By: Kevin W. Olden, M.D. Division of Gastroenterology Mayo Clinic Scottsdale, Arizona Antidepressants are commonly prescribed for the treatment of functional gastrointestinal disorders. They are unique drugs, which have a number of properties that make them particularly useful. In order to fully understand their usefulness in functional gastrointestinal disorders, three areas should be understood . .

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Antidepressants and Functional Gastrointestinal Disorders By: Kevin W. Olden, M.D., Division of Gastroenterology, Mayo Clinic Scottsdale, Arizona Copyright 2001-2012 by the International Foundation for Functional Gastrointestinal Disorders Antidepressants are commonly prescribed for the The first of these drugs was amitriptyline (Elavil). This treatment of functional gastrointestinal disorders; they was followed subsequently by imipramine (Tofranil), are unique drugs, which have a number of properties desipramine (Norpramin), and others. [Table 1] that make them particularly useful. In order to fully Although these drugs belong to the same family, they understand their usefulness in functional have different properties. Some of them tend to be more gastrointestinal disorders, three areas should be anticholinergics – they block the activity of the nerves responsible for gut motion, salivary production, and in The first is the mechanism of action of part, heart rate control. These medicines are more likely antidepressants, how they exert their effect. The second to produce dry mouth, constipation, and a feeling of is the relationship between the brain and the gut, the so- dizziness upon arising, which is called orthostatic called "brain-gut axis." Finally is the role of hypotension. Other drugs, such as doxepin, tend to be antidepressants in treating the various symptoms of more antihistaminic and thus tend to stimulate appetite, functional gastrointestinal disorders. The purpose of and promote sleep. this article is to review all three of these topics to help The tricyclic antidepressants have been shown to put the use of antidepressants in functional be, by and large, quite safe. However, if taken in gastrointestinal disorders in perspective, and to help the overdose, they can produce changes in heart rhythm, reader participate more fully with their physician in which can be quite serious and occasionally fatal. The deciding whether this would be an appropriate course of drugs, when prescribed under a physician's direction, in treatment for them. doses used for depression (or in lower doses, as is common in treating gastrointestinal disorders) are rarely associated with any serious adverse Antidepressant drugs first appeared in the early 1950's. It was noted by a number of physicians who were In the 1970's and 1980's, newer drugs were treating patients with tuberculosis using the drug developed which were not tricyclic antidepressants but Isoniazid that some of the patients, who had symptoms were unique in their structure. These are the so-called of depression, tended to have improvements in their atypical antidepressants. Trazodone (Desyrel), mood and sense of well-being when they received the bupropion (Wellbutrin), and more recently nefazodone drug. This led to speculation that there was an (Serzone) best represent this group. "antidepressant" property to this anti-tuberculosis drug. The latest addition to the therapeutic store has been Researchers found that Isoniazid had a tendency to the selective serotonin reuptake inhibitors (SSRIs), the inhibit an enzyme called monoamine oxidase (MAO), prototype of which was fluoxetine (Prozac). The which is involved in the breakdown of norepinephrine growing list of drugs in this category is outlined in (adrenaline). This led, in the early 1950's, to the Table I. The SSRIs tend to have a lower side-effect development of a number of drugs specifically designed profile than the tricyclic antidepressants, and do not to maximize this tendency to inhibit MAO. These so- cause constipation, blurred vision, orthostatic called MAO inhibitors (MAOIs) were shown to be hypotension, or cardiac arrhythmias. For this reason effective for the treatment of depression. However, the they are seen in Psychiatry as a major advance. drugs were problematic in that they interacted with a Numerous studies have shown that the SSRIs per se number of other chemicals in the body. One of these have shown no real advantage over the tricyclics in was tyramine, a substance found in many foods terms of treating depression. However, the drugs are including most nuts, chocolate, wines, and other foods. better accepted both by patients and physicians because When a patient ingested foods containing tyramine, the of their tendency to have fewer side effects. MAOI's would impair ability to metabolize this Nevertheless, like any drug, these drugs are not substance and lead to elevated blood levels of tyramine; completely free of side effects. SSRIs tend to produce this can cause dramatic and dangerous elevations in headaches, GI upset (particularly diarrhea), nausea, and blood pressure. The need to adhere to a strict diet when occasionally vomiting, as well as a "caffeine-like" taking the MAOI's led to a search for other, easier-to- effect with tremors and increased anxiety. Patients not infrequently experience impaired sexual function, In the 1950's and 1960's the tricyclic particularly inability to have an orgasm. This latter side- antidepressants were developed. These drugs have a effect has been particularly annoying for patients and chemical structure consisting of three chemical rings, may lead to discontinuation of the drug. hence the name "tricyclic." There are some very rare but dangerous neurologic Interestingly, these drugs have also been shown to be conditions associated with use of SSRIs, particularly very helpful for many anxiety disorders, including when used in combination with other psychiatric panic disorder, obsessive-compulsive disorder, post- medications. The best known of these, the so-called traumatic stress disorder, and generalized anxiety "serotonergic syndrome," can be life-threatening and is disorder. The drugs of all classes – MAOIs, tricyclics, characterized by seizures, very high fevers, and cardiac atypical antidepressants, and SSRIs – share most of arrhythmias. This syndrome has been reported only in these properties. However the SSRIs have no ability to very ill psychiatric patients taking multiple medications affect the uptake of norepinephrine, which is why they of a psychiatric nature. It has never been reported in a are called selective serotonin reuptake inhibitors. patient taking SSRIs for a functional gastrointestinal It has been recognized for some time that the enteric nervous system of the gut, beginning in the esophagus and extending all the way into the anorectal area, is richly innervated with nerves that contain large amounts of norepinephrine and serotonin. Indeed, the largest amount of serotonin is not found in the brain and spinal Classes of Antidepressants
cord, but rather in the gut. This fact led a number of investigators to begin using tricyclic antidepressants for the treatment of functional gastrointestinal disorders. I. Tricyclic Antidepressants
The initial studies were done treating irritable bowel Amitriptyline (Elavil)
syndrome (IBS). Subsequent studies have looked at Clomipramine (Anafranil)
esophageal dysmotility, functional dyspepsia, and Desipramine (Norpramin)
functional vomiting. Although the tricyclic Doxepin (Sinequan)
antidepressants have been most extensively studied, Imipramine (Tofranil)
recent articles have begun to study the usefulness of the Nortriptyline (Pamelor)
SSRIs. These finding will be summarized below. II. Selective Serotonin Re-Uptake Inhibitors
Antidepressants for Irritable Bowel Syndrome

Citalopram (Celexa)
Antidepressants have been used for the treatment of Fluoxetine (Prozac)
irritable bowel syndrome for over thirty years. Fluvoxamine (Luvox)
Numerous studies have been published but one study in Paroxetine (Paxil)
particular is worthy of note. In 1987, Greenbaum and Mirtazapine (Remeron)
colleagues studied a group of patients with irritable Sertraline (Zoloft)
bowel syndrome, both diarrhea-predominant and constipation-predominant, and treated them with either the tricyclic desipramine (Norpramin) or atropine. III. Antidepressants with Unique Properties
Atropine is an anticholinergic drug that decreases colonic motion, and is useful in treating diarrhea and Nefazodone (Serzone)
intestinal spasms. Greenbaum and colleagues chose to Venlafaxine (Effexor)
compare desipramine to atropine to see whether it was Bupropion (Wellbutrin)
the anticholinergic effect of desipramine that actually made it useful, or if it was something unique to the antidepressant drug. Their results were interesting. They showed that desipramine was superior to atropine for both diarrhea-predominant and The Brain-Gut Axis
constipation-predominant irritable bowel syndromes. How do these drugs work? Simply stated, the major Interestingly, in addition to improvement in their antidepressant effect of these drugs comes from their gastrointestinal symptoms, the patients also had a better ability to block the reuptake of either norepinephrine sense of their overall well being. To control for the (NE) or serotonin, which is also known by its chemical antidepressant effect of the drug, Greenbaum did not name, 5-hydroxytriptamine (5-HT). It is felt by brain include in his study patients with a diagnosable researchers that an impaired ability for the brain to psychiatric disorder. (Greenbaum, 1987) utilize NE and 5-HT results in depleted levels of these This study is important because it showed two chemicals in the brain cells and subsequent things. First, it showed that antidepressants were useful development of the clinical syndrome we know as in themselves, and not merely because of their anticholinergic effect. Second, the study also demonstrated that the usefulness A recent meta-analysis, looking at the quality of all the of antidepressants in treating irritable bowel syndrome studies published in the literature using antidepressants was independent of the accompanying presence of a for functional gastrointestinal disorders by and large psychiatric disorder and seemed to be a unique effect of showed these drugs to be useful and safe to use. the drug. Numerous other studies have been performed studying desipramine, as well as other tricyclic antidepressants, in the treatment of irritable bowel Future Direction
syndrome. By and large, these studies have been Where do we go from here? It is clear that the treatment positive, although many of them have methodological for functional gastrointestinal disorders is evolving. In flaws. Trials are underway looking at the usefulness of the past, the treatment of functional GI disorders the SSRIs in treating irritable bowel syndrome. focused on a purely medical approach emphasizing the use of gut specific medicines, such as fiber, Antidepressants for Non-Cardiac Chest
antispasmodics, and other motility agents. These agents Pain (NCCP)
certainly play an important role in the treatment of In the 1970's, it was discovered that many patients who functional gastrointestinal disorders. However, recent complained of chest pain did not have a cardiac origin research has shown that use of the biopsychosocial to their pain, but rather were having pain because of model, where multiple dimensions of the patient's life, esophageal dysmotility. Again, building on the including gut function, overall well being, as well as knowledge that the esophagus was rich in serotonin, overall quality of life and emotional status seems Cannon and colleagues studied a group of patients with reasonable. (Drossman, 1998) We clearly need to focus non-cardiac chest pain, and carefully tested them for future research on the use of multimodal treatment. The any evidence of cardiac pathology, psychiatric disorder, use of dietary modification, antispasmodics, or other gastrointestinal disorders, such as peptic ulcer antidiarrheals, antidepressants, and behavioral disease, independent of their diagnosis of esophageal interventions such as biofeedback, psychotherapy, and dysmotility. Cannon used the tricyclic antidepressant relaxation therapy all play a synergistic and important imipramine (Tofranil) and compared it to an inert role in improving outcomes in functional placebo, and to clonidine (an antihypertensive agent), gastrointestinal disorders. The final key is the informed which has no serotonergic activity but is a very strong patient. The mere fact that you are reading this fact blocker of norepinephrine in the brain. sheet supports the tenet that you are interested in Cannon's findings were dramatic. Patients who acquiring new knowledge about irritable bowel were treated with imipramine had significantly better syndrome and the other functional gastrointestinal improvement in their chest pain symptoms compared to disorders. It is clear that an informed patient who can patients who received clonidine or placebo. Likewise, participate more fully in their care can greatly the GI symptom improvement due to imipramine was contribute to a successful outcome for these disabling independent of any changes induced by motility of the esophagus, or by any changes in the patients' psychiatric status, as measured by psychological Opinions expressed are an author's own and not necessarily those testing. What the patients did report was a significant of the International Foundation for Functional Gastrointestinal Disorders (IFFGD). IFFGD does not guarantee or endorse any product improvement in their gastrointestinal symptoms as well in this publication nor any claim made by an author and disclaims all as improvement in their overall sense of well being. liability relating thereto. These finding are very similar to Greenbaum's findings This article is in no way intended to replace the knowledge or diagnosis of your doctor. We advise seeing a physician whenever a in irritable bowel syndrome. More recently, Handa and health problem arises requiring an expert's care. coworkers in Korea showed the usefulness of the SSRI IFFGD is a nonprofit education and research organization. Our paroxetine (Paxil) in the treatment of non-cardiac chest mission is to inform, assist, and support people affected by gastrointestinal disorders. For more information, or permission to pain. (Handa, 1999) It is clear that this is a promising reprint this article, write to IFFGD, W. Virginia St., #201, Milwaukee, WI 53204. Toll free: 888-964-2001. Visit our websites at: www.iffgd.org or www.aboutibs.org. Other Functional Gastrointestinal Disorders

In addition to irritable bowel syndrome and non- cardiac chest pain, investigators over the last five years have shown the benefit of tricyclic antidepressants in functional vomiting (Prakash, 1998) and functional dyspepsia (Mertz, 1998).

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