Functional Dyspepsia and Tricyclic Antidepressant Use in a Naval Flight Officer

Functional dyspepsia (FD) is marked by at least one chronic symptom of postprandial fullness, early satiety, epigastric pain, or epigastric burning in the absence of structural disease.¹ It is estimated that one in five individuals in the general population suffers from symptoms of dyspepsia.² Among these patients, 80% will meet criteria for the diagnosis of FD.²

FD presents several aeromedical concerns for the flight surgeon. Core symptoms of abdominal pain and postprandial discomfort may be distracting in flight.³ There is also a significant association between FD and anxiety, which is independently disqualifying for flight duties.^4,5 Proton pump inhibitors (PPI) are an effective first-line treatment for FD and are commonly approved for aeromedical waiver.^2,4 Second-line options, including prokinetics and tricyclic antidepressants, are not commonly waived in flying status personnel due to their side-effect profiles.^2,4 The chief concerns with tricyclic antidepressant use are drowsiness and the degradation of cognitive performance.^6,7

We present the case of a Naval Flight Officer with FD, refractory to PPI use and lifestyle modification, who was successfully treated with amitriptyline and returned to flight status. The aeromedical disposition in this patient involved the use of neuropsychological testing to assess for a possible medication effect on performance.

CASE REPORT

A 23-yr-old male Naval Flight Officer presented to his flight surgeon in October 2018 with 3 mo of postprandial epigastric pain, nausea, and vomiting. Symptoms occurred several times per week and lasted 5–10 min after meals. These episodes occurred throughout the day but were most strongly associated with breakfast. Infrequently, episodes were associated with triggers other than food, including strong smells and brushing teeth. Stress and poor sleep also contributed to the frequency of his episodes. The patient had no pertinent past medical history or family history and no previous aeromedical waivers. Physical examination was notable for mild tenderness to palpation over the epigastrium.

The patient’s flight surgeon empirically prescribed a course of omeprazole, which did not alter his symptoms. The patient was referred to Gastroenterology. Labs including complete blood count, complete metabolic panel, lipase, thyroid stimulating hormone, and a morning cortisol level were unremarkable. He underwent an upper endoscopy, which was unremarkable. Biopsies were negative for H. pylori.

Reassured by these results, the patient learned to control his symptoms through dietary and lifestyle modification. Interventions included delaying breakfast, eating small portions, and avoiding greasy foods. As a result of these changes, the frequency and severity of his episodes both decreased significantly over a period of weeks. He reported minimal symptoms over the following 18 mo.

In the summer of 2020, the patient’s epigastric symptoms gradually returned, with nausea once per week and emesis once per month. Symptom recurrence coincided with the coronavirus disease pandemic and his redeployment to the United States from Asia. Symptoms were refractory to his lifestyle techniques and episodes began to occur in the absence of typical postprandial triggers.

In October of 2020, the patient presented to his flight surgeon endorsing nausea several times per week, with vomiting once per week. A review of systems was negative for dysphagia, hematemesis, hematochezia, diarrhea, and constipation. The patient denied extraintestinal symptoms, including anxiety and depression. Examination was notable for mild tenderness to palpation over the epigastrium. A trial of pantoprazole by the flight surgeon was unsuccessful. Complete blood count, complete metabolic panel, lipase, and H. pylori studies were repeated and were normal. On follow-up, the patient’s symptoms had progressed, and now occurred daily. The Patient Health Questionnaire-9 and General Anxiety Disorder-7 were elevated for anxiety and depression. The patient was grounded from flight duties. Referrals were placed to Gastroenterology and Behavioral Health for further evaluation.

The patient’s gastroenterologist performed a repeat endoscopy, which was normal, as were the results of a gastric emptying study and MRI of the brain. With these results, his gastroenterologist made a diagnosis of FD and recommended a trial of amitriptyline 25 mg nightly. After three doses of medication, the patient reported complete resolution of his episodes. The patient was able to eat larger meals without recurrence of symptoms. On follow-up at 1 and 4 wk with the flight surgeon, the patient denied any side-effects of the medication, including drowsiness, dizziness, anxiety, depression, and suicidal ideation. His Patient Health Questionnaire-9 and General Anxiety Disorder-7 scores normalized. His psychologist diagnosed him with “anxiety disorder due to another medical condition” as the patient’s anxiety centered around his health, increased proportionally to his gastrointestinal symptoms, and decreased once they resolved. His gastroenterologist and psychologist recommended that he be returned to flight status.

After 1 mo of observation in sustained remission, the patient’s flight surgeon wrote to the Naval Aerospace Medical Institute (NAMI) regarding the possibility of an aeromedical waiver submission for FD and long-term amitriptyline use. NAMI requested the patient undergo evaluation with neuropsychological testing to rule out subtle cognitive impairment.⁸ In consultation with neuropsychology and the pharmacy, a protocol was devised to compare performance during expected peak and trough levels of medication. The patient would take the assessment twice: once approximately 4 h after the last dose of medication, and again after a wash-out period of approximately four half-lives. Both tests were administered at midmorning to optimize circadian variables and the patient timed his medication accordingly. While holding amitriptyline for the wash-out period, the patient noted that his dyspepsia symptoms recurred, although his anxiety did not, and his dyspepsia resolved again once he resumed medication.

After review, the NAMI Department of Neuropsychology determined there was no evidence of cognitive impairment due to the medication. The patient reported mild postprandial nausea during the time he was holding his medication, which resolved when he resumed his usual dosing. An aeromedical waiver was formally requested to NAMI and was approved in time for him to embark on his next deployment. The patient’s waiver is contingent on remaining asymptomatic of FD and following up with his flight surgeon annually.

DISCUSSION

Based on our correspondence with NAMI, our case is only the second aeromedical waiver in U.S. Navy history for the long-term use of a tricyclic antidepressant to treat a gastrointestinal disorder (Hashey BS. Personal communication; July 2023). This case highlights several aspects of the diagnosis and management of FD considered through the lens of aerospace medicine. An important element of this case is the use of neuropsychological testing to inform an aeromedical disposition.

The Rome IV Criteria outline the necessary features of an FD diagnosis.¹ Symptoms of dyspepsia are partitioned into two syndromes: postprandial distress syndrome (PDS), characterized by postprandial fullness and early satiety, and the Epigastric Pain Syndrome (EPS), characterized by epigastric pain and burning.¹ To satisfy Rome IV criteria for FD, patients must exhibit symptoms of postprandial distress syndrome or EPS at least 3 d/wk for at least 3 mo.¹ The diagnosis also requires exclusion of organic disease by routine investigations, including upper endoscopy.¹ The evaluation in our patient also included a gastric emptying study to evaluate for gastroparesis and MRI of the brain to rule out an occult central nervous system lesion. These studies were included due to the presence of vomiting, which is uncommon in FD.²

The empiric trial of a PPI prior to our patient’s extensive workup is supported by current American College of Gastroenterology guidelines, which recommend a trial of acid suppression in patients under 60 yr of age after the exclusion or eradication of H. pylori.⁹ Unfortunately, one-half of patients with dyspepsia will experience persistent symptoms with PPI use.⁹ In these patients, it is important to establish a diagnosis of FD by ruling out organic pathology prior to pursuing second-line therapies, including prokinetic agents and tricyclic antidepressants.⁹ In a randomized control trial, amitriptyline showed a significant reduction in FD symptoms over placebo, with 53% of patients reporting relief of symptoms.¹⁰ Treatment response was most pronounced in patients with EPS and with normal gastric emptying.¹⁰ Options for prokinetic therapy include metoclopramide and domperidone.⁹ Current American College of Gastroenterology guidelines do not provide a clear preference between antidepressant and prokinetic therapy.⁹

The symptoms of FD and its treatment pose aeromedical concerns for the flight surgeon. Symptoms of FD may impair the performance of flight duties.³ Patients with FD commonly engage in restrictive eating habits and exclusion diets to self-manage their symptoms, which may have detrimental effects on aviation performance.¹¹ Furthermore, patients with disorders of gut–brain interaction are at increased risk of anxiety and depression, which are independently disqualifying for flight duties.^4,5 For this reason, aircrew may be hesitant to report psychiatric symptoms due to fears of grounding.⁴ Our patient did develop anxiety symptoms at the peak of his gastrointestinal illness; however, the content of his anxiety was focused on his dyspepsia, and quickly resolved once these symptoms were treated by low-dose amitriptyline. Therefore, Behavioral Health concluded that his psychological symptoms were secondary to his FD. The interactions between the central nervous system and enteric nervous system in disorders of gut–brain interaction are complex and both may be affected by a low-dose tricyclic antidepressant (TCA).⁵ From a practical standpoint, flight surgeons should screen for psychological symptoms that persist despite the treatment of FD. Such patients may be more appropriately managed with cognitive behavioral therapy and/or a selective serotonin reuptake inhibitor (SSRI) rather than a low-dose TCA, and may require more time to achieve remission.⁴

PPIs are generally well-tolerated in the flight environment and are commonly approved for aeromedical waiver.^3,4 By contrast, antidepressant use is generally restricted to SSRIs for the treatment of primary psychiatric disorders.⁴ In our correspondence with NAMI, there had only been one other approved waiver for a TCA in a flight surgeon with sphincter of Oddi dysfunction (Hashey BS. Personal communication; July 2023). There were no instances involving an unrestricted line officer whose career depends on regular flight hours. We asked Gastroenterology whether an SSRI would be an acceptable alternative in this case given the more established waiver process for these medications. Unfortunately, SSRIs are inferior to TCA in the treatment of FD, with escitalopram no more effective than placebo in a randomized control trial.¹⁰ The chief concern for TCA use in aviation is cognitive side-effects, especially drowsiness.^6,7 Prokinetic medications such as metoclopramide are considered disqualifying for aviation due to their side-effect profiles, particularly the risk of tardive dyskinesia.^4,12

Despite the lack of precedent for TCA use in FD in naval aviation, we felt our patient was an ideal candidate for an aeromedical waiver given his excellent response to therapy and absence of side-effects. NAMI proposed neuropsychological testing as an objective method to rule out subtle cognitive impairment from amitriptyline. We used a computer-based screening tool normed to a population of civilian airline pilots.⁸ The patient was assessed in multiple domains, including attention, reaction time, and logical problem-solving, as proxies for performance in aviation-related tasks.⁸ This evaluation is a standard requirement to approve the use of SSRIs in flight personnel diagnosed with psychiatric disorders.⁴

We used neuropsychological testing to compare our patient’s performance between peak and trough levels of amitriptyline. Consultation with a pharmacist was necessary to determine the timing of doses and testing based on expected pharmacokinetics. Laboratory assays of serum amitriptyline levels were not obtained. We administered both assessments at midmorning to optimize circadian variables and retimed his last dose prior to the first assessment to obtain the desired conditions.

Our case demonstrates that TCAs may be used in aviators with PPI-refractory FD on an individualized basis. While published guidance on antidepressant use in flight personnel remains focused on the SSRIs, there are a few disease entities, such as the disorders of gut–brain interaction, where TCAs remain the antidepressant class of choice. In patients who respond favorably to TCA use, neuropsychiatric testing may be used to objectively assess for cognitive impairment in the flight environment. The generalizability of our case is limited by our patient’s excellent response to therapy and absence of side-effects, factors that were critical to his aeromedical disposition. We also emphasize the need for close follow-up due to the chronic and recurrent nature of FD symptoms, and their association with psychiatric disorders. Nevertheless, in select individuals, TCAs may be considered as a viable treatment option for functional gastrointestinal disorders.