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Gastrointestinal Disorders and "Medical Depression"

Michael K. Popkin, MD

Published: November 15, 2015

See article by Lurie et al

This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions.

Moving beyond recent formidable work in animal models, Lurie and colleagues1 provide evidence from a sizable human database that recurrent antibiotic exposure is associated with increased risk for depression and anxiety. This focus on the “gut-brain axis” is exciting and deserves to be viewed in the context of earlier explorations of the links between gastrointestinal disease and psychiatric conditions.

Perhaps the most pertinent and intriguing body of past work is that dealing with the puzzling, still unresolved relationship between pancreatic cancer and depression.2,3 Long before the advent of psychotropic medications, Yaskin4 in 1931 reported that clinical depression may be the earliest manifestation of a pancreatic carcinoma. Later work demonstrated that pancreatic cancer is the entity with the highest incidence of depression among all tumors of the digestive system.5 Louhivuori and Hakama6 reported that gastrointestinal malignancies confer the greatest risk of suicide among all cancers.

Pancreatic carcinoma is a challenging condition to diagnose, often requiring more than 18 months to establish the diagnosis. In retrospect, clinicians have often thought that depression was its heralding sign. This temporal sequencing has been used to argue against depression as a “reactive response” to the psychological insult of the cancer. (The patient is not aware of the diagnosis for months.) The basis for the association between depression and pancreatic carcinoma has been presumed to involve a paraneoplastic process with gut neuropeptides, which are comparable, if not identical, to brain neuropeptides.

The work of Lurie et al1 introduces anew the question of the role of gut neuropeptides in depression. In turn, the link between depression and pancreatic carcinoma leads to the broader question of “medical depression.” Is depression arising in the context of a medical illness a discrete or different clinical entity versus depression that emerges in the patient free of any medical condition? Medical depression is curious in that it has no gender preponderance and few genetic linkages, but it has specific electroencephalographic accompaniments and appears to respond less favorably to psychotropic interventions than depression in those without concurrent medical illness.7

Over the past 10-15 years, depression in the medically ill has come to be seen as a two-way street or a bidirectional process. Those with primary medical conditions are at increased risk for the development of clinical depression (not merely as a reactive response but because of intrinsic physiologic changes—including, perhaps, those in gut flora?), and those with depression are at increased risk for an acceleration of their medical illness or other adverse sequelae. Much attention has been directed to the interplay between depression and coronary artery disease.8-10

Rates of depression in the setting of different medical illnesses vary widely.11 Highest rates are encountered in Cushing’s disease (approaching 70% prevalence), but in other conditions rates of depression barely exceed those found in the general population.11 Rates of depression in neurologic illnesses are surprisingly consistent, ranging from 30%-50% prevalence in Huntington’s disease, Parkinson’s disease, stroke, dementia of the Alzheimer type, and multiple sclerosis with cortical involvement.11 These conditions, of course, have in common structural changes or lesions of the central nervous system, not merely changes in neurotransmitters.

With regard to other forms of bowel disease, there is an older literature linking inflammatory bowel disease and irritable bowel syndrome with psychiatric disorders and symptomatology.12-14 More recent work in this domain again underscores the theme of bidirectionality of psychiatric and, in this case, gastrointestinal comorbidities.15 Alterations in gut flora (dysbiosis) induced by the administration of antibiotic therapy may prove to be a fascinating window into the larger question of the physiological alterations driving the emergence of clinical depression. We now know that clinical depression evokes or brings extensive changes to immune, autonomic, and hematologic functions—conversely, altering the basic physiologic integrity of organ systems seems quite capable of inducing psychiatric disorders.

Lurie and colleagues1 close by calling for studies of microbiota composition in psychiatric disorders. In addition, the issue of treatment interventions must be addressed. Will the changes in gut flora resolve of their accord or will corrective measures be required?

Author affiliations: University of Minnesota Medical School, Minneapolis.

Potential conflicts of interest: None reported.

Funding/support: None reported.


1. Lurie I, Yang YX, Haynes K, et al. Antibiotic exposure and the risk for depression, anxiety, or psychosis: a nested case-control study. J Clin Psychiatry. 2015;76(11):1522-1528

2. Carney CP, Jones L, Woolson RF, et al. Relationship between depression and pancreatic cancer in the general population. Psychosom Med. 2003;65(5):884-888. PubMed doi:10.1097/01.PSY.0000088588.23348.D5

3. Mayr M, Schmid RM. Pancreatic cancer and depression: myth and truth. BMC Cancer. 2010;10(1):569. PubMed doi:10.1186/1471-2407-10-569

4. Yaskin J. Nervous symptoms as earliest manifestations of cancer of the pancreas. JAMA. 1931;96(20):1664-1668. doi:10.1001/jama.1931.02720460010003

5. Fras I, Litin EM, Pearson JS. Comparison of psychiatric symptoms in carcinoma of the pancreas with those in some other intra-abdominal neoplasms. Am J Psychiatry. 1967;123(12):1553-1562. PubMed doi:10.1176/ajp.123.12.1553

6. Louhivuori KA, Hakama M. Risk of suicide among cancer patients. Am J Epidemiol. 1979;109(1):59-65. PubMed

7. Popkin MK. Consultation-liaison psychiatry. In: Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry. 6th ed. Baltimore, MD: Williams and Wilkins; 1995:1592-1605.

8. Khawaja IS, Westermeyer JJ, Gajwani P, et al. Depression and coronary artery disease: the association, mechanisms, and therapeutic implications. Psychiatry (Edgmont). 2009;6(1):38-51. PubMed

9. Carney RM, Blumenthal JA, Catellier D, et al. Depression as a risk factor for mortality after acute myocardial infarction. Am J Cardiol. 2003;92(11):1277-1281. PubMed doi:10.1016/j.amjcard.2003.08.007

10. O’ Connor CM, Jiang W, Kuchibhatla M, et al; SADHART-CHF Investigators. Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial. J Am Coll Cardiol. 2010;56(9):692-699. PubMed doi:10.1016/j.jacc.2010.03.068

11. Popkin MK, Tucker GJ. Mental disorders due to a general medical condition and substance induced disorders: mood, anxiety, psychotic, catatonic, and personality disorders. DSM-IV Sourcebook. Washington, DC: APA Office of Research; 1994:243-276.

12. Lydiard RB. Irritable bowel syndrome, anxiety, and depression: what are the links? J Clin Psychiatry. 2001;62(suppl 8):38-45, discussion 46-47. PubMed

13. Andrews H, Barczak P, Allan RN. Psychiatric illness in patients with inflammatory bowel disease. Gut. 1987;28(12):1600-1604. PubMed doi:10.1136/gut.28.12.1600

14. Helzer JE, Chammas S, Norland CC, et al. A study of the association between Crohn’s disease and psychiatric illness. Gastroenterology. 1984;86(2):324-330. PubMed

15. Fadgyas-Stanculete M, Buga AM, Popa-Wagner A, et al. The relationship between irritable bowel syndrome and psychiatric disorders: from molecular changes to clinical manifestations. J Mol Psychiatry. 2014;2(1):4. PubMed doi:10.1186/2049-9256-2-4

Submitted: September 8, 2015; accepted September 10, 2015.

Corresponding author: Michael K. Popkin, MD, University of Minnesota/Community University Health Care Center, 2001 Bloomington Ave S, Minneapolis, MN 55404 (

J Clin Psychiatry 2015;76(11):e1485-e1486

© Copyright 2015 Physicians Postgraduate Press, Inc.

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