Severe GI distress: Is clozapine to blame?
Mr. F, age 29, is being treated with clozapine for schizophrenia. He reports severe GI symptoms, especially after eating. Is clozapine the culprit?
The authors’ observations
Mr. F and his family are opposed to starting a dopamine antagonist such as metoclopramide or domperidone (the latter is not FDA-approved but is available by special application to the FDA). These are first-line treatments for gastroparesis, but Mr. F and his family do not want them because of the risk of tardive dyskinesia. This is consistent with their previously expressed concerns regarding first-generation antipsychotics, and is why Mr. F has only been treated with a very low dose of haloperidol while the clozapine was titrated. Instead, Mr. F, his family, the psychiatry treatment team, and the GI specialist agree to pursue a combination of a GI hypomotility diet—which includes frequent small meals (4 to 6 per day), ideally with low fiber, low fat, and increased fluid intake—and a trial of the second line agent for gastroparesis, erythromycin, a medication with known hepatic cytochrome P450 (CYP) drug-drug interactions that impacts the clearance of clozapine.
Shared decision making is an evidence-based approach to engaging patients in medical decision making. It allows clinicians to provide education on potential treatment options and includes a discussion of risks and benefits. It also includes an assessment of the patient’s understanding of their condition, explores attitudes towards treatment, and elicits patient values specific to the desired outcome. Even in very ill patients with schizophrenia, shared decision making has been demonstrated to increase patient perception of involvement in their own care and knowledge about their condition.2 Using this framework, Mr. F and his family, as well as the GI and psychiatric teams, felt confident that the agreed-upon approach was the best one for Mr. F.
TREATMENT Erythromycin and continued clozapine
Mr. F. is started on erythromycin, 100 mg 3 times a day. Erythromycin is a prokinetic agent that acts as a motilin agonist and increases the rate of gastric emptying. The liquid formulation of the medication is a suspension typically taken in 3- to 4-week courses, with 1 week “off” to prevent tachyphylaxis.3 Compared to the tablet, the liquid suspension has higher bioavailability, allows for easier dose adjustment, and takes less time to reach peak serum concentrations, which make it the preferred formulation for gastroparesis treatment.
Per the GI consultant’s recommendation, Mr. F receives a total of 3 courses of erythromycin, with some improvement in the frequency of his nausea noted only during the third erythromycin course. His clozapine levels are closely monitored during this time, as well as symptoms of clozapine toxicity (ie, sedation, confusion, hypersalivation, seizures, myoclonic jerks), because erythromycin can directly affect clozapine levels.4,5 Case reports suggest that when these 2 medications are taken concomitantly, erythromycin inhibits the metabolism of hepatic enzyme CYP3A4, causing increased plasma concentrations of clozapine. Before starting erythromycin, Mr. F’s clozapine levels were 809 ng/mL at 350 mg/d. During the erythromycin courses, his levels are 1,043 to 1,074 ng/mL, despite reducing clozapine to 300 mg/d. However, he does not experience any adverse effects of clozapine (including seizures), which were being monitored closely.
The authors’ observations
Clozapine is the most effective medication for treatment-refractory schizophrenia.6 Compared to the other second-generation antipsychotics, it is associated with a lower risk of rehospitalization and treatment discontinuation, a significant decrease of positive symptom burden, and a reduction in suicidality.7,8 Unfortunately, clozapine use is not without significant risk. FDA black box warnings highlight severe neutropenia, myocarditis, seizures, and hypotension as potentially life-threatening adverse effects that require close monitoring.9
Recently, clinicians have increasingly focused on the underrecognized but well-established finding that clozapine can cause significant GI adverse effects. While constipation is a known adverse effect of other antipsychotics, a 2016 meta-analysis of 32 studies estimated that the pooled prevalence of clozapine-associated constipation was 31.2%, and showed that patients receiving clozapine were 3 times more likely to be constipated than patients receiving other antipsychotics (odds ratio 3.02, CI 1.91-4.77, P < .001, n = 11 studies).10 A 2012 review of 16 studies involving potentially lethal adverse effects of clozapine demonstrated that rates of agranulocytosis and GI hypomotility were nearly identical, but that mortality from constipation was 3.6 to 12.5 times higher than mortality from agranulocytosis.11
In 2020, the FDA issued an increased warning regarding severe bowel-related complications in patients receiving clozapine, ranging in severity from mild discomfort to ileus, bowel obstruction, toxic megacolon, and death.9
As exemplified by Mr. F’s case, upper GI symptoms associated with clozapine also are distressing and can have a significant impact on quality of life. Dyspepsia is a common complaint in patients with chronic psychiatric illness. A study of 79 psychiatric inpatients hospitalized long-term found that 80% reported at least 1 symptom of dyspepsia.12 There are few older studies describing the effect of clozapine on the upper GI system. We and others previously reported on significantly increased use of—not only antacids—but also H2 blockers and prokinetic agents after initiating clozapine, but sample sizes are small.13-15 These older data and newer studies suggest that GERD is a common upper GI disorder diagnosis following clozapine initiation, perhaps reflecting a knowledge gap and infrequent use of the more complex testing required to confirm a diagnosis of GI motility disorders such as gastroparesis.
In a study of 17 patients receiving clozapine, wireless motility capsules were used to measure whole gut motility, including gastric emptying time, small bowel transit time, and colonic transit time. In 82% of patients, there was demonstrated GI hypomotility in at least 1 region, and 41% of participants exhibited delayed gastric emptying, with a cut-off time of >5 hours required for a gastroparesis diagnosis.16 This is significantly higher than the prevalence of gastroparesis observed in studies of the general community.17 The Table18,19 summarizes the differences between GERD and gastroparesis.
OUTCOME Some improvement
Mr. F experiences limited improvement of some of his nausea symptoms during the third erythromycin cycle and returns to the gastroenterologist for a follow-up appointment. The GI specialist decides to discontinue erythromycin in view of potential drug-drug interactions and Mr. F’s elevated clozapine levels and the associated risks that might entail. Mr. F is again offered the D2 dopamine antagonist metoclopramide, but again refuses due to the risk for tardive dyskinesia. He is asked to continue the GI dysmotility diet. Mr. F finds some relief of nausea symptoms from an over-the-counter product for nausea (a nasal inhalant containing essential oils) and is advised to follow up with the GI specialist in 3 months. Shortly thereafter, he is discharged to live in a less restrictive supportive housing environment, and his follow-up psychiatric care is provided by an assertive community treatment team. Over the next several months, the dosage of clozapine is decreased to 250 mg/d. Mr. F initially experiences worsening psychiatric symptoms, but stabilizes thereafter. He then moves out of state to be closer to his family.
Bottom Line
In patients receiving clozapine, frequent nausea along with clustering of heartburn, abdominal pain, bloating, early satiety, and vomiting (especially after meals) may signal gastroparesis rather than gastroesophageal reflux disease. Such patients may require consultation with a gastroenterologist, a scintigraphy-based gastric emptying test, and treatment if gastroparesis is confirmed.
