In this month’s issue of the Journal of Psychosocial Nursing and Mental Health Services (JPN), Rogers and Aronoff (2013) have written a thoughtful letter to the editor in response to my July column on antidepressant drugs and infectious disease (Howland, 2013). In their letter, they bring up several issues that I believe would be of interest to readers for further discussion.
Rogers and Aronoff (2013) claim that there are now three studies showing an apparent relationship between depression and Clostridium difficile infection (CDI) (Dalton, Lye-Maccannell, Henderson, Maccannell, & Louie, 2009; Kazakova et al., 2006; Rogers et al., 2013). The article by Dalton et al. (2009), which I reviewed and critiqued in my July article, did not provide any data on depression symptoms, assessments, or diagnoses. This study only described an incidental and unexpected association between CDI and anti-depressant drug exposure. Antidepressant drugs are commonly prescribed for many non-depression labeled and off-label psychiatric uses (e.g., various anxiety disorders) as well as for many medical conditions, including inflammatory and functional bowel diseases. Hence, the findings from this study cannot be used to support an association between CDI and depression.
The study by Kazakova et al. (2006) investigated risk factors for C. difficile-associated disease (CDAD) using a case-control design. A simple comparison of CDAD cases and non-CDAD controls indeed showed a higher prevalence for “psychoses and depression” diagnoses among the cases (p. 2521), but there was also a higher prevalence of chronic obstructive pulmonary disease, presence of fluid or electrolyte disorders, greater hospital length of stay (LOS), and greater antibiotic (cephalosporin and fluoroquinolone) drug exposure, histamine-2 blocker drug exposure, and proton pump inhibitor (PPI) drug exposure among the cases. No data on antidepressant or other psychotropic drug exposures were reported in this study. When the authors conducted a multivariate analysis by including significant risk factors in their statistical model, only four risk factors remained significant (LOS and PPI, cephalosporin, and fluoroquinolone drug exposures). Notably, depression was not included in a discussion of their findings. They did mention that PPI drugs have antibacterial properties that could affect the lower intestinal flora and increase the risk of CDAD in that way. This point is analogous to my comments about the antimicrobial properties of antidepressant agents and other psychotropic drugs.
Rogers and Aronoff (2013) describe in vitro studies of microbial inhibition with various drugs as being of lower quality, and they express caution regarding reliance on them (presumably compared to in vivo studies). Although it is true that the U.S. Food and Drug Administration (2013) generally requires in vivo clinical studies when evaluating potential anti-infective agents, this requirement is not absolute. Moreover, the requirement for adequate clinical trials pertains to the marketing approval and labeling of a drug for an infectious disease indication. Unlike most other human drug products, antimicrobial drug products do not usually exert their intended therapeutic effect directly on humans. Instead, the human therapeutic effect is a by-product of the drug’s ability to kill or inhibit the growth of microorganisms. For this reason, in vitro microbiological testing is vital not only to the development of anti-infective drugs, but also for determining and monitoring the susceptibility and resistance of microorganisms over time in the absence of additional clinical studies (Turnidge & Paterson, 2007). With regard to a potential causal relationship between antidepressant drugs and CDI, it is imperative to consider the antimicrobial properties of these drugs.
It is beyond the scope of my July commentary or this column to describe the infection-defense hypothesis, but a close reading of the evidence used to formulate the hypothesis does not support the contention by Rogers and Aronoff (2013) that the evidence is lower quality. My intention in citing the two articles on the hypothesis (Anders, Tanaka, & Kinney, 2013; Tanaka, Anders, & Kinney, 2012) was to convey the complex bidirectional relationships among depression, immune system function, and infectious disease. I did not argue that depression would necessarily be expected to prevent infectious disease (in this case CDI). On the contrary, there is considerable evidence from preclinical and clinical studies that acute or chronic infectious disease can increase the risk of developing depression (as well as developing other neuropsychiatric disorders), and this causal effect is mediated by the induction of pro-inflammatory cytokines (Benros et al., 2013; Capuron & Miller, 2011; Hornig, 2013). Cytokine receptors have been identified in the brain, and cytokines have been demonstrated to activate the hypothalamic-pituitary-adrenal axis and to alter neurotransmitter function, both of which are relevant to the pathogenesis of depression. Gut microbiota has a role in priming and regulating whole-body immunoregulatory activity and can influence brain function and behavior (Cryan & Dinan, 2012; Raison, Lowry, & Rook, 2010). Bacteria can also directly activate nociceptor sensory neurons, which can stimulate pain directly and can modulate inflammation (Chiu et al., 2013). The state of depression itself does not cause elevated levels of inflammatory cytokines (Hannestad, DellaGioia, & Bloch, 2011), and depression itself is not likely to be the cause of altered gut microbiota.
Antidepressant drugs, other psychotropic drugs, and other antidepressant therapies can suppress or attenuate pro-inflammatory processes, although the presence of inflammatory biomarkers is associated with a less than optimal response to standard antidepressant drugs (Lotrich, 2012; Raison et al., 2013). As a result, novel agents that target inflammatory processes, either directly or indirectly, are of interest as potential antidepressant therapies are now being investigated (Lotrich, 2012; Raison et al., 2013). Similar to considering the antimicrobial properties of antidepressant drugs, it also is important to consider their effect on the immune system when evaluating the plausibility of a potential causal relationship between antidepressant drug exposure and CDI.
In asserting that individuals with depression who take antidepressant drugs are more likely to develop CDI, Rogers and Aronoff (2013) are over-interpreting or misinterpreting their data. With the exception of the mirtazapine-trazodone interaction finding, the magnitudes of their identified associations are uniformly small. Such weak associations are likely to be false, and they can be attributable to confounding by indication, collinearity, unmeasured variables, and other sources of bias (Grimes & Schulz, 2012). Although the magnitude of the mirtazapine-trazodone association is larger, the number of exposures to this unusual drug combination is small. A small statistical p value in and of itself does not validate this singular finding, which was based on a secondary analysis of their data. This finding is likely to be spurious and attributable to bias.
The methodology of all three CDI studies, and their various sources of bias, make it impossible to assess the causal validity of the association between CDI and depression or antidepressant drugs. Establishing causality from observed associations requires evidence from a variety of different scientific perspectives (Glass, Goodman, Hernán, & Samet, 2013; Grimes & Schulz, 2012; Hill, 1965). Unless there is a clearly established public health imperative, I would agree with Rogers and Aronoff that a prospective randomized trial of antidepressant drugs dedicated to investigating the risk of developing CDI is unlikely. However, long-term controlled relapse prevention studies of antidepressant therapies (for depression or other psychiatric disorders) are often conducted as Phase III or Phase IV investigations. It would be practical and feasible to piggy-back an ancillary study investigating the risk of developing CDI in these types of studies.
I am thankful to Rogers and Aronoff for their letter and their interest in JPN. This debate is important for nurses and other readers working in clinical care or research.
- Anders, S., Tanaka, M. & Kinney, D.K. (2013). Depression as an evolutionary strategy for defense against infection. Brain, Behavior, and Immunity, 31, 9–22. doi:10.1016/j.bbi.2012.12.002 [CrossRef]
- Benros, M.E., Waltoft, B.L., Nordentoft, M., Ostergaard, S.D., Eaton, W.W., Krogh, J. & Mortensen, P.B. (2013). Autoimmune diseases and severe infections as risk factors for mood disorders: A nationwide study. JAMA Psychiatry, 70, 812–820. doi:10.1001/jamapsychiatry.2013.1111 [CrossRef]
- Capuron, L. & Miller, A.H. (2011). Immune system to brain signaling: Neuropsycho-pharmacological implications. Pharmacology Therapeutics, 130, 226–238. doi:10.1016/j.pharmthera.2011.01.014 [CrossRef]
- Chiu, I.M., Heesters, B.A., Ghasemlou, N., Von Hehn, C.A., Zhao, F., Tran, J. & Woolf, C.J. (2013). Bacteria activate sensory neurons that modulate pain and inflammation. Nature. Advance online publication. doi:10.1038/nature12479 [CrossRef]
- Cryan, J.F. & Dinan, T.G. (2012). Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour. Nature Reviews: Neuroscience, 13, 701–712. doi:10.1038/nrn3346 [CrossRef]
- Dalton, B.R., Lye-Maccannell, T., Henderson, E.A., Maccannell, D.R. & Louie, T.J. (2009). Proton pump inhibitors increase significantly the risk of Clostridium difficile infection in a low-endemicity non-outbreak hospital setting. Alimentary Pharmacology Therapeutics, 29, 626–634. doi:10.1111/j.1365-2036.2008.03924.x [CrossRef]
- Glass, T.A., Goodman, S.N., Hernán, M.A. & Samet, J.M. (2013). Causal inference in public health. Annual Review of Public Health, 34, 61–75. doi:10.1146/annurev-publhealth-031811-124606 [CrossRef]
- Grimes, D.A. & Schulz, K.F. (2012). False alarms and pseudo-epidemics: The limitations of observational epidemiology. Obstetrics & Gynecology, 120, 920–927. doi:10.1097/AOG.0b013e31826af61a [CrossRef]
- Hannestad, J., DellaGioia, N. & Bloch, M. (2011). The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: A meta-analysis. Neuropsycho-pharmacology, 36, 2452–2459. doi:10.1038/npp.2011.132 [CrossRef]
- Hill, A.B. (1965). The environment and disease: Association or causation?Proceedings of the Royal Society of Medicine, 58, 295–300.
- Hornig, M. (2013). The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness. Current Opinion in Rheumatology, 25, 488–495. doi:10.1097/BOR.0b013e32836208de [CrossRef]
- Kazakova, S.V., Ware, K., Baughman, B., Bilukha, O., Paradis, A., Sears, S. & McDonald, L.C. (2006). A hospital outbreak of diarrhea due to an emerging epidemic strain of Clostridium difficile. Archives of Internal Medicine, 166, 2518–2524. doi:10.1001/archinte.166.22.2518 [CrossRef]
- Lotrich, F. (2012). Inflammatory cytokines, growth factors, and depression. Current Pharmaceutical Design, 18, 5920–5935. doi:10.2174/138161212803523680 [CrossRef]
- Raison, C.L., Lowry, C.A. & Rook, G.A. (2010). Inflammation, sanitation, and consternation: Loss of contact with coevolved, tolerogenic microorganisms and the pathophysiology and treatment of major depression. Archives of General Psychiatry, 67, 1211–1224. doi:10.1001/archgenpsychiatry.2010.161 [CrossRef]
- Raison, C.L., Rutherford, R.E., Woolwine, B.J., Shuo, C., Schettler, P., Drake, D.F. & Miller, A.H. (2013). A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers. JAMA Psychiatry, 70, 31–41. doi:10.1001/2013.jamapsychiatry.4 [CrossRef]
- Rogers, M.A.M. & Aronoff, D.M. (2013). Depression and Clostridium difficile infection. Journal of Psychosocial Nursing and Mental Health Services, 51(10), 5. doi:10.3928/02793695-20130903-01 [CrossRef]
- Rogers, M.A.M., Greene, M.T., Young, V.B., Saint, S., Langa, K.M., Kao, J.Y. & Aronoff, D.M. (2013). Depression, antidepressant medications, and risk of Clostridium difficile infection. BMC Medicine, 11, 121. doi:10.1186/1741-7015-11-121 [CrossRef]
- Tanaka, M., Anders, S. & Kinney, D.K. (2012). Environment, the immune system, and depression: An integrative review and discussion of the infection-defense hypothesis. In Dietert, R.R. & Luebke, R.W. (Eds.), Immunotoxicity, immune dysfunction, and chronic disease (pp. 345–385). New York: Springer-Verlag. doi:10.1007/978-1-61779-812-2_14 [CrossRef]
- Turnidge, J. & Paterson, D.L. (2007). Setting and revising antibacterial susceptibility breakpoints. Clinical Microbiology Reviews, 20, 391–408. doi:10.1128/CMR.00047-06 [CrossRef]
- U.S. Food and Drug Administration. (2013). Clinical/antimicrobial guidances. Retrieved from http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInforma-tion/Guidances/ucm064980.htm