Initially, the use of antidepressants was proposed for the large proportion of irritable bowel syndrome patients who also suffered from clinical depression, but it was subsequently discovered that antidepressants, independent of their mood-modulating effects, have neuromodulatory and analgesic properties that make them useful in treating irritable bowel syndrome itself. These effects are usually seen at dosages that are subtherapeutic for the treatment of psychiatric disorders, and they occur more quickly than mood elevation.
Most of the antidepressants used in irritable bowel syndrome treatment are from one of two drug classes: tricyclic antidepressants and selective serotonin reuptake inhibitors. Although reuptake inhibitors are more popular in the treatment of depression, tricyclic antidepressants represent the majority of antidepressant use for irritable bowel syndrome symptoms, mainly because their use is better documented in clinical trials of irritable bowel syndrome, while very few randomized, blinded trials have tested SSRI use in irritable bowel syndrome. However, statistical and patient-selection methods from favorable studies of tricyclic antidepressants in irritable bowel syndrome have been called into question, so the utility of tricyclic antidepressants has not yet been adequately proved.
The three most commonly prescribed tricyclic antidepressants for irritable bowel syndrome are the tertiary amines amitriptyline (AstraZeneca’s Elavil, Roche’s Laroxyl, generics) and imipramine (Novartis/Mallinckrodt’ s Tofranil, generics) and the secondary amine desipramine (Novartis’s Pertofan, Aventis’s Nopramin, generics). Other tricyclic antidepressants such as trim-ipramine (Aventis’s Surmontil) have also been shown to be effective at reducing abdominal pain in irritable bowel syndrome patients. Generally, the tricyclic antidepressants are interchangeable in the treatment of irritable bowel syndrome; the choice of agent depends mostly on physician preference. The most commonly prescribed reuptake inhibitors for irritable bowel syndrome are fluox-etine (Eli Lilly’s Prozac, generics), paroxetine (GlaxoSmithKline’s Paxil), and sertraline (Pfizer’s Zoloft). Because no single SSRI has demonstrated better efficacy than others, the choice of agent is often determined by the physician’s familiarity with a particular agent.
Mechanism Of Action
The exact mechanism by which antidepressants alleviate irritable bowel syndrome symptoms is unclear. These agents may regulate the afferent pathways from the gut to the brain, thereby rectifying the abnormal sensation of pain. Another hypothesis is that antidepressants directly modulate the effect of serotonin (an important chemical regulator of gastrointestinal function, as discussed earlier in the “5-HT Receptor Modulators” section) in the gut. In D-irritable bowel syndrome patients, the anti-cholinergic side effects of some antidepressants cause constipation, an effect that helps combat the predominant diarrhea symptoms.
Imipramine (Novartis/Mallinckrodt’s Tofranil, generics) is a frequently prescribed TCA used in the treatment of irritable bowel syndrome. Tricyclic antidepressants block the synaptic reuptake of serotonin and norepinephrine, and they are potent blockers of cholinergic and histaminergic receptors. Imipramine’s mechanism of action is not entirely understood, but, like all tricyclic antidepressants, it definitely blocks the reuptake of serotonin and norepinephrine. Secondary actions, such as anticholinergic and antiadrenergic effects, have led to its use in irritable bowel syndrome and childhood enuresis.
A study of imipramine showed that it modulates small intestine function both in D-irritable bowel syndrome patients and in controls. Fourteen patients (eight controls, six with D-irritable bowel syndrome) took imipramine for five days, and, while the periodicity of migrating motor complexes (migrating motor complexes) was not affected, phase 3 MMC speed was slowed in all participants. Another study compared imipramine with the SSRI paroxetine (GlaxoSmithKline’s Paxil) and found that, although both agents slowed orocecal transit (from mouth to end of small intestine), only imipramine prolonged whole-gut transit times to relieve diarrhea.
Like all tricyclic antidepressants, imipramine is associated with numerous adverse side effects that often cause compliance problems; up to 40% of patients treated with tricyclic antidepressants discontinue therapy or switch to another agent. tricyclic antidepressants’ adverse effects are related to their action on multiple receptor sites throughout the central nervous system. Because tricyclic antidepressants block the histaminergic receptors, they often cause weight gain and sedation. These agents also block cholinergic receptors; thus, to avoid additional anticholinergic effects (dry mouth, blurred vision, constipation), physicians should be cautious in prescribing tricyclic antidepressants with other anticholinergic agents such as dicyclomine and hyoscyamine. To circumvent these side effects, physicians often start with very low doses and scale up to the minimum dose that proves therapeutic for irritable bowel syndrome symptoms. tricyclic antidepressants cannot be used concurrently with monoamine oxidase inhibitors (MAOIs) because of the risk of hypertensive crisis.
Like all tricyclic antidepressants, amitriptyline (AstraZeneca’s Elavil, Roche’s Laroxyl, generics) inhibits the reuptake of serotonin and norepinephrine, but it might have lower activity in the central nervous system than other agents in this class, making it more gut-specific. Like its active metabolite nortriptyline
(Novartis’s Pamelor, generics), which has also been shown to reduce abdominal pain in irritable bowel syndrome patients when given in combination with fluphenazine (Bristol-Myers Squibb’s Prolixin, generics), amitriptyline exhibits stronger anticholinergic effects than other tricyclic antidepressants, but it does not inhibit norepinephrine reuptake as strongly.
Clinical data on the use of amitriptyline in irritable bowel syndrome patients are scarce. However, in one controlled study, investigators reported an improvement in global well-being, abdominal pain, and bowel pattern following treatment with amitriptyline. They also identified young age and extroversion as predictors of drug response.
As is the case for all tricyclic antidepressants, a high incidence of side effects as a direct result of amitriptyline drug therapy often results in patients discontinuing treatment.
Desipramine (Novartis’s Pertofan, Aventis’s Nopramin, generics) is the active metabolite of imipramine. Compared with other tricyclic antidepressants, desipramine is the strongest and most selective inhibitor of norepinephrine reuptake. The compound works on both the central nervous system and enteric nervous system, where it blocks serotonergic, cholinergic, and adrenergic receptors. In the dorsal nerve fibers, desipramine alleviates pain symptoms of irritable bowel syndrome by reducing the response of mechanosensitive afferent nerves. Desipramine is useful primarily in treating D-irritable bowel syndrome; its slowing of transit times would exacerbate constipation in C-irritable bowel syndrome.
A comparative study of desipramine, atropine, and placebo showed the greatest benefit with desipramine. A four-week observation period followed three six-week test periods in this investigation. Among 28 irritable bowel syndrome patients
(19 with D-irritable bowel syndrome, 9 with C-irritable bowel syndrome), desipramine reduced stool frequency, diarrhea, and abdominal pain and slowed contractions in the D-irritable bowel syndrome patients significantly more than did atropine or placebo.
In an earlier study, which pooled C-irritable bowel syndrome and D-irritable bowel syndrome patients into a single group, desipramine showed a benefit in pain reduction but not in alleviating bowel irregularity. Thus, although the benefit of desipramine in regulating motility is in question, the agent is clearly efficacious against irritable bowel syndrome pain symptoms.
Fluoxetine (Eli Lilly’s Prozac, generics) was the first SSRI introduced to the market (in 1987). The agent is widely used for depression in the United States and Europe but is not yet approved in Japan.
Like all reuptake inhibitors, fluoxetine acts by inhibiting the reuptake of serotonin at the neuronal synapses. Unlike tricyclic antidepressants, reuptake inhibitors have little or no effect on norepinephrine reuptake, nor do they have an effect on the cholinergic, histaminergic, and adrenergic receptors. Because reuptake inhibitors are highly selective for serotonergic receptors, they have almost no anticholinergic or sedating side effects. This factor makes reuptake inhibitors more tolerable for patients with C-irritable bowel syndrome (the anticholinergic side effects of tricyclic antidepressants can cause or worsen constipation). In irritable bowel syndrome management, reuptake inhibitors are used primarily to relieve pain and to improve motility, but the mechanism by which reuptake inhibitors achieve these effects in irritable bowel syndrome is unknown.
No controlled studies have analyzed fluoxetine’s efficacy in irritable bowel syndrome, but some physicians use it off-label for irritable bowel syndrome patients. One study showed treatment with fluoxetine caused a slight but significant reduction in irritable bowel syndrome symptoms.
Among the reuptake inhibitors, fluoxetine has the longest half-life, a factor that offers an advantage in the case of missed doses. All of the reuptake inhibitors discussed in this section, including fluoxetine, have similar side effects, of which the most troubling is sexual dysfunction in both women and men. However, reuptake inhibitors typically cause sexual dysfunction at the higher doses used in treating depression, so this side effect is not as likely to affect irritable bowel syndrome patients taking psychiatrically sub therapeutic doses.
Paroxetine (GlaxoSmithKline’s Paxil) is a commonly used SSRI in the treatment of anxiety disorders and social phobia, in addition to depression. Its mechanism of action is similar to that of fluoxetine, inhibiting the reuptake of serotonin at the neuronal synapses.
A study of paroxetine’s effect on the small intestine found that it caused more frequent migrating motor complexes and increased the propagation velocity of phase 3 contractions. However, this same study (cited earlier in the discussion of imipramine) found that, although paroxetine increases orocecal transit, it has no effect on whole-gut transit time. The demonstrated action of paroxetine on the small intestine suggests that it could be useful for irritable bowel syndrome patients suffering from constipation, but the clinical results are not entirely conclusive.
Sertraline (Pfizer’s Zoloft) is effective as an antidepressant, but, among the three reuptake inhibitors discussed here, it has the least scientific data concerning use in irritable bowel syndrome. Some reports indicate that sertaline can reduce irritable bowel syndrome symptoms, including pain, and that it is associated with fewer side effects. Like all reuptake inhibitors, this agent acts by inhibiting the reuptake of serotonin at the neuronal synapses.