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Refractory Depression, Fatigue, Irritable Bowel Syndrome, and Chronic Pain: A Functional Medicine Case Report

November 4, 2016

Gregory Plotnikoff, MD, MTS, FACP; Melissa Barber, MSc


Introduction: Single-disorder or single-organ-system clinical practice guidelines are often of limited usefulness in guiding effective management of patients with chronic multidimensional signs and symptoms. The presence of multiple long-standing medical problems in a given patient despite intensive medical effort suggests that addressing systemic core imbalances could complement more narrowly focused approaches.

Case Presentation: A 72-year-old man experiencing longstanding depression, fatigue, irritable bowel syndrome, and chronic pain in the context of additional refractory illnesses was assessed and treated, guided by a system-oriented approach to underlying core imbalances termed functional medicine. This patient was referred from a team of clinicians representing primary care, cardiology, gastroenterology, hematology, and psychology. Prior treatment had been unsuccessful in managing multiple chronic comorbidities. Diagnostic assessment included comprehensive stool and nutritional/metabolic laboratory testing.

Results: The blood-, urine-, or stool-based measurements of relevant markers for multiple systemic issues, including digestion/absorption, inflammation, oxidative stress, and methylation, identified previously unrecognized root causes of his constellation of symptoms. These functional measurements guided rational recommendations for dietary choices and supplementation. The patient experienced steady and significant improvement in his mental health, fatigue, chronic pain, and irritable bowel syndrome—as well as the unexpected resolution of his chronic idiopathic pancytopenia.

Conclusion: The success in this case suggests that other patients with chronic, complex, and treatment-refractory illness may benefit from a system-oriented assessment of core imbalances guided by specialized nutritional/metabolic and digestive laboratory testing.


Single-disorder clinical practice guidelines are often of limited usefulness in guiding effective management of patients with chronic multidimensional signs and symptoms. The presence of multiple long-standing medical problems, despite excellent medical care, suggests that new questions or perspectives may be helpful. For example, assessment of underlying key common pathways for all diseases, such as gastrointestinal dysfunction, proinflammatory imbalance, and oxidative stress, could augment the more traditional organ-system-oriented, discipline-focused approach. The organizing principle of the approach taken here, termed functional medicine, is that restoration of health requires defining and addressing seven potential core imbalances that may underlie any given disease state. These seven categories are 1) assimilation (digestion, absorption, microbiomics, respiration), 2) defense and repair (immune function, inflammation, infection), 3) energy (production, regulation), 4) biotransformation and elimination (toxicity, detoxification), 5) transport (cardiovascular and lymphatic systems), 6) communication (hormones, neurotransmitters, cytokines), and 7) structural integrity (membranes, fascia, bacterial translocation). The core belief is that imbalance in one or more of these seven common disease pathways may be the root cause of many seemingly disparate conditions.

This case illustrates how specialized laboratory testing identified previously unrecognized physiologic and biochemical dysfunction in a complex patient. This dysfunction in several common disease pathways was both clinically relevant and inexpensively modifiable. The result was substantial clinical improvement and a markedly improved patient quality of life.


Initial Visit (February 2012)

A 72-year-old man was referred to a board-certified internist specializing in complex, refractory illnesses in February 2012. The patient’s primary goal, stated at his first visit, was to “walk out of the office with more hope.” He wrote that it was “very hard to function. I wake after 9 hours of sleep and still feel tired. I don’t have the emotional or physical strength to accomplish much. This is frustrating and I am on a cycle of becoming more depressed, more frustrated, and more helpless.”

In addition to chronic fatigue and depression, the patient reported 1) heartburn, frequent gas, bloating, and diarrhea alternating with constipation; 2) right lower quadrant abdominal cramping, worsening after bowel movements; and 3) widespread arthralgias and myalgias. See Table 1 through 6 (Tables 4 and 5 available online at:, and the Sidebar: Important Medical History for a list of the patient’s medical considerations.

Refractory Depression, Fatigue, Irritable Bowel Syndrome

Initial Clinical Findings

Patient-reported outcome instruments (higher scores indicate worse symptoms)

  • Brief Fatigue Inventory: total fatigue interference score of 37/60
  • Brief Pain Inventory: total pain interference score 36/70
  • Patient Health Questionnaire-9: total score 13 (moderate depression 10-14).

Physical Examination

  • Blood pressure 118/54 mmHg, pulse 74 beat/min and regular. Body mass index, 21.6 (calculated as weight in kilograms divided by height in meters squared)
  • Anicteric with clear lungs and normal cardiac examination
  • Abdomen tender to palpation of the right upper quadrant and epigastric area
  • No hepatosplenomegaly
  • Palpation in the left lower quadrant resulted in right lower quadrant discomfort
  • No ascites present
  • No edema in extremities (cool, pale fingers with slow capillary refill)
  • No palmar erythema
  • No asterixis.

Refractory Depression, Fatigue, Irritable Bowel Syndrome

Refractory Depression, Fatigue, Irritable Bowel Syndrome

Refractory Depression, Fatigue, Irritable Bowel Syndrome

Refractory Depression, Fatigue, Irritable Bowel Syndrome


The patient’s concern of a reduced quality of life secondary to depression, fatigue, and gastrointestinal distress was part of a remarkable medical history as a survivor of end-stage liver failure and alcoholism. However, his depression, fatigue, widespread pain, and gastrointestinal symptoms did not resolve from medical treatments of specific diagnoses and individual symptoms. A clinical decision was made to evaluate the root causes of this patient’s symptoms from a functional medicine perspective with comprehensive and structured stool1,2 and nutritional diagnostic panels. A Comprehensive Digestive Stool Analysis 2.0 (CDSA 2.0) and Nutritional Evaluation (NutrEval) from a Clinical Laboratory Improvement Amendments-certified laboratory (Genova Diagnostics, Asheville, NC) were ordered. These kits offer bundled laboratory tests that provide insight into the function and status of several of the core pathways. Additionally, given the presence of environmental stressors and a decreased sense of personal efficacy, he was referred for Resilience Training or Mindfulness-Based Stress Reduction.


This patient had previously been found to be vitamin D deficient. However, he was not on vitamin D supplementation at his first visit and supplementation (2000 IU) was begun. In addition this patient’s dehydroepiandrosterone-sulfate (DHEAS) level was low normal and DHEA 5 mg sublingually each morning was started.3


The patient was evaluated four times between April 2012 and January 2013. With each subsequent visit, he reported steady improvement in his mood, overall energy, and chronic pain. He was compliant with the dietary recommendations and supplements outlined in Table 3. He elected to not pursue Resilience Training or Mindfulness-Based Stress Reduction.

He experienced minor episodes of dizziness with two near syncopal episodes, for which he was referred to his cardiologist. Repeat testing at his local hospital in December 2012 demonstrated persistent pancreatic insufficiency with an undetectable pancreatic elastase 1 and persistent Candida glabrata overgrowth in the stool even though the patient was no longer symptomatic. These findings supported continued prescription of pancreatic enzyme support, probiotics, and a diet rich in prebiotics. The patient’s oncologist noted an “inexplicable resolution” of the patient’s idiopathic pancytopenia in July 2013 and reported that his physical and laboratory examinations were normal at that time.

In January 2013, patient-reported outcomes had improved significantly

  • Brief Fatigue Inventory: total fatigue interference score of 19/60
  • Brief Pain Inventory: total pain interference score 20/70
  • Patient Health Questionnaire-9: total score 10.


Mental health disorders and gastrointestinal complaints are often components of complex, chronic illnesses that can challenge linear pharmacologic management.4,5 System-oriented, functional medicine approaches, supported by laboratory findings, can help engage patient and clinician in a therapeutic partnership to address genetic, environmental, and lifestyle factors that may be important in complex, chronic diseases.6

The intersection of depression, fatigue, widespread pain, and gastrointestinal symptoms in this patient had implications in multiple systems.7,8 This justified a switch in the diagnostic focus from the customary organ-based systems to whole-body systems. Table 3 delineates the systemic issues important in this case, such as inflammation, oxidative stress, or impaired methylation. The blood-, urine-, or stool-based measurements of the relevant markers for each issue guided rational recommendations for dietary choices and supplementation.

Addressing systemic issues in chronic, complex illness complements a more traditional organ-system approach. In this case, addressing one fundamental imbalance may have addressed several disparate conditions. For example, diagnosing and addressing this patient’s digestive dysfunction and the intestinal ecology imbalances not only improved digestive function but also improved several metabolic and nutritional markers known to be correlated with depression, fatigue, and myalgias.

Likewise, the reduction in his myalgias allowed this patient with diabetes with proven atherosclerosis to remain on atorvastatin. HMG Co-A reductase inhibitors (statins) are known to block production of coenzyme Q10; however, supplementation is not routinely recommended. The very low serum coenzyme Q10 measured in this patient suggested that supplementation might be of benefit.8,9The reduction in his arthralgias also allowed this patient who presented with low glutathione levels to avoid acetaminophen (which depletes glutathione). His low levels of glutathione were treated with a diet rich in vitamins C, E, molybdenum, selenium, and methionine- or cysteine-containing amino acids. The improved levels of both coenzyme Q10 and glutathione enhanced native oxidative stress management, known to help reduce pain, depression, and fatigue.10 Finally, correction of all these systemic issues may have contributed to the unexpected resolution of his idiopathic pancytopenia after eight years.


David Sackett, one of the pioneers of evidence-based medicine, said “Without clinical expertise, even excellent evidence may be inappropriate for an individual patient.”11 The comprehensive approach outlined here integrated the clinical expertise found in organ-system-based disciplines with the perspective of functional medicine’s systems-biology approach. This integration was possible because of external evidence from specialized stool and nutritional diagnostic panels. This combination resulted in effective management of multiple comorbidities that had previously been minimally responsive to treatment. The interference score for this patient’s chronic fatigue was reduced by nearly 50% (from 37/60 to 19/60). The interference score for his chronic pain was reduced by nearly 40% (from 36/70 to 20/70). His Patient Health Questionnaire-9 score declined by 25% (13 to 10). His gastrointestinal function improved greatly without significant increases in pharmaceuticals. Therapeutic recommendations were based on measurements of nutritional and digestive status and function. The success in this case suggests that other patients with chronic, complex, and treatment-refractory illness may benefit from a functional medicine, system-oriented approach guided by nutritional and digestive laboratory testing.

Patient Perspective

“I experienced at least a 50% reduction in pain and improvement in my quality of life. My anxiety is reduced, I am more relaxed, and feel stronger. The most helpful has been the work with my gut issues. I am almost like clockwork now.”

Disclosure Statement

The author(s) have no conflicts of interest to disclose. Written consent was obtained from the patient for publication of this case report.


This case report was prepared according to the CARE Guidelines by Gagnier, Kienle, Altman, et al, published in the Journal of Clinical Epidemiology in 2014.

Mary Corrado, ELS, provided editorial assistance.

How to Cite this Article

Plotnikoff G, Barber M. Refractory depression, fatigue, irritable bowel syndrome, and chronic pain: A functional medicine case report. Perm J 2016 Fall;20(4): 15-242. DOI:

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