Gastrointestinal Issues Associated With Psychiatric Medications

Antidepressant-related gastrointestinal (GI) adverse effects are class-specific: The older tricyclic agents are typically associated with constipation secondary to their anticholinergic activity, whereas the newer selective serotonin reuptake inhibitors (SSRIs) are typically associated with nausea and diarrhea.
•Upper GI transit is more rapid with paroxetine.
•Constipation is reported in over 20% of patients receiving second-generation antipsychotics, commonly referred to as “atypical antipsychotics,” including newer agents, such as olanzapine, risperidone, quetiapine, and ziprasidone.
•Clozapine has been shown to impede GI motility, known as clozapine-induced GI hypomotility (CIGH) or clozapine-related “slow gut,” leading to constipation, and has been reported in up to 80% of patients receiving clozapine.
•Constipation can be life threatening and is associated with perforation or necrosis.
•CIGH is defined as an acquired state of delayed transit through the GI tract with transit time >2 standard deviations above the mean.
•The use of some mood-stabilizer agents has been associated with the development of diarrhea: 33% of patients taking lithium and 25% taking carbamazepine have diarrhea.

Etiology & Risk Factors

•Serotonin plays a major regulatory role in the motor and sensory regulation of the GI tract and influences GI motility. The mechanism of constipation is not clearly known, but is postulated to be due to anticholinergic, antihistaminergic, and serotonergic effects. It has been established that drugs with effects on serotonin levels can affect gastric motility.
•Serotonergic agents that act on central 5-HT3 receptors may lead to nausea and vomiting.
•There is also a known lack of physical activity among the patients taking these sedating medications.
•Constipation due to GI hypomotility is one commonly reported and potentially serious adverse effect. Antipsychotics such as clozapine, which have high affinity for muscarinic cholinergic receptors, are the most frequently implicated agents in antipsychotic-related GI hypomotility.
•CIGH resulting from clozapine’s pharmacologic actions on the enteric nervous system results in increased mean transit times up to four times longer than normal.
•Progression from constipation to ileus, intestinal obstruction, bowel ischemia, megacolon, and death is not uncommon in antipsychotic-treated patients, particularly those on clozapine. The mechanism is obstruction caused by an impacted stool bolus, also known as a pseudo-obstruction, which can increase intraluminal pressure proximal to the impaction, consequently causing ischemia, distention, which may result in perforation.
•Aspiration pneumonia may result from inhalation of feculent vomitus or as a result of dysphagia.
•Antipsychotic-treated patients with serious GI hypomotility often underreport symptoms and present late due to the sedative and analgesic effects of psychotropic drugs resulting in the patients’ diminished sensitivity to pain and difficulty in communicating their symptoms to health care providers. Therefore patients may present late with considerably more advanced GI pathology.

Treatment

Approach to Treatment

•Taking SSRIs with food or at bedtime may reduce the risk of nausea.
•General strategies for managing the adverse effects of antipsychotics and antidepressants include both nonpharmacologic and pharmacologic interventions.
•The goals of constipation management include improving symptoms, restoring normal GI function, increasing bowel transit, and facilitating defecation.
•The following strategies should be considered in the treatment of patients with medication-related GI adverse effects:
- 1.Standard anticonstipation remedies (dietary fiber, exercise, motility agents, laxatives) should be prescribed to treat constipation in people with constipation induced by antipsychotic or antidepressant medication.
- 2.The use of prophylactic laxatives for all clozapine users is recommended.
- 3.If these are ineffective, modifications of the medication regimen may be considered:
  - a.Lower the dose of the medication.
  - b.Switch to an antidepressant with a different adverse effect profile.

First-Line Treatment

•Laxatives should be used for treating patients with medication-related constipation.
•Several types of conventional bowel agents are used: Bulk-forming, emollient, osmotic, and stimulant aperients.
•Bulk-forming laxatives such as psyllium have been shown to be effective and their long-term use is associated with fewer long-term effects than the use of stimulant laxatives.
•Other agents in treating constipation include misoprostol, lubiprostone, tegaserod, renzapride, prucalopride, linaclotide, and elobixibat.
•The benefits of stool softeners such as docusate sodium are unclear.

Pharmacologic Therapy

•Osmotic laxatives work by drawing fluid into the bowels to make stools looser.
•Stimulant laxatives increase peristalsis in the bowels to help move stools.

Osmotic Laxatives

•Polyethylene glycol (PEG) is a gentle laxative. Up to 48 hr of treatment is required before the effect is produced. Patients need to maintain adequate daily hydration.
•Lactulose is a strong osmotic laxative the effect of which is typically achieved in 1 to 4 hr. Lactulose can cause significant gas and abdominal discomfort.

Stimulant Laxatives

•Sennoside, a gentle laxative, achieves its effect in 6 to 10 hr, but tolerance can develop, and patients may require increased doses.
•Bisacodyl is a strong laxative whose effects are seen after 15 min to 1 hr. It is commonly used as bowel prep for colonoscopy. Tolerance and dependence can develop.

First-Line Therapy for Antipsychotic- or Antidepressant-Related Constipation

Start osmotic agents:

•Polyethylene glycol (PEG). Start at 17 grams daily and increase up to 17 grams twice daily (BID) as needed.
•Lactulose. Start at 15 to 30 ml daily, and increase up to 30 ml BID.
•Do not use combination of both lactulose and PEG 3350.

Second-Line Therapy for Antipsychotic- or Antidepressant-Related Constipation

Start stimulant laxatives:

•Sennoside
•Bisacodyl

Third-Line Therapy for Antipsychotic- or Antidepressant-Related Constipation

Introduce fiber and bulk-forming products (patient should be well hydrated since they can worsen constipation in underlying dehydration). Bulk-forming, fiber-based laxatives are generally not recommended for slow-transit constipation such as that caused by anticholinergic effects.

Nonpharmacologic & Supportive Care

•Dietary modification and exercise interventions should be considered as adjunct to laxative therapy. Unfortunately, neither dietary modification nor exercise interventions alone are likely to improve clozapine-induced constipation.
•A high-fiber diet is recommended.
•Increasing physical activity is encouraged.

Special Considerations

Clozapine

•CIGH, one of the most serious complications of clozapine therapy, is very common and develops in 50% to 80% of clozapine-treated patients. Patients with CIGH have mean colonic transit times that are four times longer than normal. All regions of the colon are affected. There is a significant risk of serious complications of CIGH, such as ileus and pseudo-obstruction. In some of these patients, obstruction can lead to bowel perforation. The less serious but highly prevalent manifestations, including dysphagia, dyspepsia, esophageal reflux, gastroparesis, and chronic constipation, affect quality of life for many clozapine users. There is no consistent relationship between age, dose, or duration of treatment and the onset of life-threatening CIGH.
•There is no evidence for the use of surfactant agents, also known as “stool softeners,” such as docusate sodium for chronic constipation.These agents lower the surface tension of stool but are not effective at preventing and treating medication-induced constipation.
•The use of prophylactic laxatives for all clozapine users is recommended.

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)

•Some of the most frequently reported side effects associated with the use of SSRIs and SNRIs include nausea, diarrhea, dyspepsia, GI bleeding, and abdominal pain.
•Approximately half of all patients started on these agents experience GI side effects mainly in the first few days or weeks following initiation of treatment.
•Based on clinical trials, venlafaxine is associated with higher rates of nausea and vomiting than other antidepressants, while sertraline appeared to be associated with a higher incidence of diarrhea.
•Many patients with mild adverse effects will not require specific pharmacotherapy, as the nausea tends to abate with prolonged treatment with SSRIs, with gradual desensitization of 5-HT3 receptors.
•The most effective drug for the treatment of SSRI-related adverse effects on the GI tract is ondansetron, a serotonin 5-HT3 receptor antagonist that blocks the effects of serotonin in the brain and GI tract. The risk of side effects including serotonin syndrome with this intervention should be considered.

Follow-Up

Monitoring

Patients should be screened regularly for constipation and monitored for GI hypomotility, especially patients with a known history of constipation.

Complications

Constipation can be severe and even life threatening. Serious complications of CIGH such as ileus and pseudo-obstruction can result in perforation or necrosis. Those complications are potentially preventable with appropriate monitoring and preventive therapy.

Prognosis

While dietary modification and exercise interventions are important, they are not likely to be sufficient in preventing or addressing constipation due to antidepressant or antipsychotic medications. Laxatives are required in most patients, especially those receiving clozapine.

Referral

•Referral to a gastroenterologist is recommended if initial symptoms of constipation are not resolved within a reasonable period of time of the initiation of the therapy.
•Symptoms concerning for bowel distention or perforation require emergency evaluation and surgical consultation. Any delay may result in the development of life-threatening consequences or death.
•Referral to a nutritionist is recommended for dietary modification.

Admission Criteria

Severe constipation resulting in abdominal distention, abdominal pain, and persistent vomiting

Summary

•Tricyclic antidepressants are typically associated with constipation and dry mouth due to their anticholinergic activity. Nortriptyline is the least anticholinergic tricyclic antidepressant and is therefore least likely to cause constipation.
•Selective serotonin reuptake inhibitors (SSRIs) are sometimes associated with nausea and diarrhea. Paxil, the most anticholinergic of the SSRIs, has a risk of constipation equal to the risk associated with nortriptyline.
•Taking SSRIs with food and taking them at bedtime may reduce the symptoms of nausea.
•Constipation is reported in over 20% of patients receiving second-generation antipsychotics.
•Prevention and early recognition of GI side effects are critical.
•Up to 80% of patients receiving clozapine develop clozapine-induced GI hypomotility (CIGH), which can lead to constipation and pseudo-obstruction. Despite the prevalence of hypomotility in patients treated with clozapine, only a relatively small proportion of patients (14%) present with constipation. When it occurs, constipation can be life threatening and could result in bowel perforation or necrosis. Careful monitoring of bowel function is recommended for all patients receiving anticholinergic medications, including tricyclic antidepressant agents, and especially clozapine.
•Laxatives should be used for treating patients with antidepressant-related constipation.
•The use of prophylactic laxatives for all clozapine users is recommended.
•Recommended management strategies include adequate hydration; use of osmotic agents such as sorbitol, lactulose, or polyethylene glycol; and stimulant laxatives such as senna or bisacodyl. The benefits of stool softeners such as docusate sodium are unclear. Bulk-forming, fiber-based laxatives are generally not recommended as first-line therapy for slow-transit constipation such as that caused by anticholinergic effects.

Alarm Signs & Symptoms

•Severe abdominal distention, adnominal pain, severe nausea, and vomiting are signs of abdominal catastrophe (such as bowel obstruction and/or perforation) and require immediate referral to the emergency department for surgical evaluation.
•Patients with persistent nausea and vomiting should be evaluated for dehydration.

References

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Gastrointestinal Issues Associated With Psychiatric Medications