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American Journal of Kidney Diseases

Anxiety Symptoms in Patients Treated With Hemodialysis: Measurement and Meaning

      Related Article, p. 158
      It took a long time for the nephrology community to appreciate depression as an important problem in patients with kidney failure treated by maintenance dialysis. Some believed that dialysis patients were depressed because dialysis is depressing. Although the pioneering work of Burton and colleagues
      • Burton H.
      • Kline S.A.
      • Lindsay R.M.
      • Heidenheim A.P.
      The relationship of depression to survival in chronic renal failure.
      and perhaps more importantly, Norman Levy,
      • Levy N.
      in psychonephrology conferences and publications, highlighted the ubiquity and gravity of the problem, independent relationships between a diagnosis of major depressive disorder or between depressive symptoms and adverse outcomes, including mortality, took decades to establish.
      • Kimmel P.L.
      • Peterson R.A.
      • Weihs K.L.
      • et al.
      Multiple measurements of depression predict mortality in a longitudinal study of chronic hemodialysis outpatients.
      • Boulware L.E.
      • Liu Y.
      • Fink N.E.
      • et al.
      Temporal relation among depression symptoms, cardiovascular disease events, and mortality in end-stage renal disease: contribution of reverse causality.
      • Palmer S.C.
      • Vecchio M.
      • Craig J.C.
      • et al.
      Association between depression and death in people with CKD: a meta-analysis of cohort studies.
      Time-varying covariate analyses were critical in establishing links because many studies of psychosocial status in dialysis patients commence at researcher convenience, rather than at the start of renal replacement therapy or the occurrence of signal events in the course of patients’ illnesses. Using this methodology in analyses of mortality in hemodialysis (HD) patients, pioneered by Edward Lowrie with biochemical measures,
      • Culp K.
      • Flanigan M.
      • Lowrie E.G.
      • Lew N.
      • Zimmerman B.
      Modeling mortality risk in hemodialysis patients using laboratory values as time-dependent covariates.
      provided the field with robust analyses suggesting strong associations between depression and death in HD patients.
      • Kimmel P.L.
      • Peterson R.A.
      • Weihs K.L.
      • et al.
      Multiple measurements of depression predict mortality in a longitudinal study of chronic hemodialysis outpatients.
      • Boulware L.E.
      • Liu Y.
      • Fink N.E.
      • et al.
      Temporal relation among depression symptoms, cardiovascular disease events, and mortality in end-stage renal disease: contribution of reverse causality.
      For a long time, lectures on the topic started with the pious invocation that “depression is the most common psychiatric disorder in dialysis patients,” uttered in the absence of validated epidemiologic work assessing the prevalence of various psychosocial factors and psychiatric diagnoses in patients with kidney failure. More recently, clinicians have become aware that anxiety is common in patients treated with maintenance HD and that the syndrome can result in behavior that may seem irrational and combative to dialysis staff and nephrologists, affecting adherence and other clinically meaningful outcomes.
      • Cohen S.D.
      • Cukor D.
      • Kimmel P.L.
      Anxiety in patients treated with hemodialysis.
      In addition, it is recognized that mental illnesses and psychosocial factors (including sleep disorders, sexual dysfunction, pain, limitations in social support, marital status and familial factors, neighborhood and residential characteristics, poverty, and perception of racism)
      • Star R.A.
      • Moxey-Mims M.M.
      • Norton J.M.
      • et al.
      Social determinants of racial disparities in CKD.
      • Cukor D.
      • Cohen S.D.
      • Peterson R.A.
      • Kimmel P.L.
      Psychosocial aspects of chronic disease: ESRD as a paradigmatic illness.
      • Williams D.R.
      • Mohammed S.A.
      Discrimination and racial disparities in health: evidence and needed research.
      interact in a complex, perhaps reifying fashion that may constitute a threat to patient well-being and survival. Anxiety and depression are frequently comorbid and are strongly correlated with psychosocial factors and patients’ perceptions of quality of life. Mental health disorders comorbid with other psychiatric or medical illnesses are more resistant to treatment.
      • Gorman J.M.
      Comorbid depression and anxiety spectrum disorders.
      In the context of the significance of the topic, the limited appreciation of the problem, and the dearth of good data, this issue of AJKD contains a report from Schouten et al
      • Schouten R.W.
      • Haverkamp G.L.
      • Loosman W.L.
      • et al.
      Anxiety symptoms, mortality and hospitalization in patients receiving maintenance dialysis: a cohort study.
      that provides important information. The data arise from a relatively small, multiethnic, mostly unemployed cohort of dialysis patients in the Netherlands followed longitudinally. Schouten et al found a high prevalence of depression (using cutoffs) in their patients, consistent with other studies in different populations. More than 1 in 7 patients had increased levels of anxiety symptoms. The majority of patients with anxiety had an increased level of depressive symptoms. More than a third of patients with depression had high levels of anxiety symptoms. These values are generally comparable to the rates we found in a different patient population.
      • Cukor D.
      • Coplan J.
      • Brown C.
      • Peterson R.A.
      • Kimmel P.L.
      Course of depression and anxiety diagnosis in patients treated with hemodialysis: a 16-month follow-up.
      Using time-varying covariate analyses, Schouten et al showed that anxiety symptoms, as well as depressive affect, measured as continuous variables, are independently associated with increased risk for hospitalization and death in HD patients.
      The role of ethnicity is an important consideration in such studies. Almost half the population in the Stouchen study were immigrants. Was the identified anxiety associated with difficulty understanding the language and assimilating into the majority culture? Were these the salient problems for the participants in the study setting, and were they associated with outcomes? Are patients in other countries who are socially isolated, have language barriers, or lack trust in caregivers at increased risk for anxiety and therefore for morbidity and mortality?
      The overlap between anxiety and depression is an issue that perpetually confounds psychiatric nosology. The overlap exists conceptually (symptoms are dually present in anxiety and depression diagnostic criteria) and empirically (patients present with both disorders or elements of both) and may also be compounded by measurement error. In a study attempting to discriminate between depression and anxiety, use of the Beck Anxiety Inventory, as by Schouten et al, may be a reasonable measure given its focus on somatic concerns. However, one must be aware that the Beck Anxiety Inventory may be more predictive of panic disorder than the full gamut of anxiety disorders
      • Cox B.J.
      • Cohen E.
      • Direnfeld D.M.
      • Swinson R.P.
      Does the Beck Anxiety Inventory measure anything beyond panic attack symptoms?.
      and may detect symptoms of physical diseases common in dialysis patients. Furthermore, the construct of “anxiety” serves as a core feature in a variety of psychiatric disorders.
      • Stein M.B.
      • Sareen J.
      Clinical practice. Generalized anxiety disorder.
      Unlike depression, in which symptom severity and duration differentiate some of the diagnoses, each anxiety diagnosis has a unique presentation, so a general “anxiety” score may be of somewhat lesser clinical utility.
      Limitations of the research conducted by Schouten et al, which do not undermine its importance, include its observational nature (which precludes inferences of causality) and its relatively small sample size. The fact that it is not an incident study adds the potential for increased bias. Was anxiety or depression the mechanistic cause of death in these patients, was it rather the interaction of the 2 disorders, or is there a third confounding variable that best explains the association? How these psychological states interact with the biological mediators of mortality remains to be determined. In interpreting the results and extrapolating them to other populations, knowledge of the practice patterns regarding hospitalization of HD patients in the Netherlands compared with other countries is critical.
      Nevertheless, these data have profound implications regarding the quality and quantity of life of HD patients. As is typical with pathbreaking research, the findings perhaps pose even more questions than answers. Where do we go from here? A major clinical challenge to nephrologists and large dialysis organizations is the recognition of anxiety and depression in HD patients and the provision of appropriate treatment for patients with these conditions. Strides have been made in this arena in the United States as a result of Medicare’s Quality Improvement Program, which requires screening for depression. However, patients may not be amenable to treatment of depression in HD care settings.
      • Pena-Polanco J.E.
      • Mor M.K.
      • Tohme F.A.
      • Fine M.J.
      • Palevsky P.M.
      • Weisbord S.D.
      Acceptance of antidepressant treatment by patients on hemodialysis and their renal providers.
      Structural changes in caregiving should be considered. All dialysis units are staffed, by regulation in the United States, with social workers. Shouldn’t social workers be deployed, as they are trained, to attend to the psychological status of the patients as well as their transportation and insurance needs?
      The present study should be confirmed in larger populations in different countries, and the role of race and ethnicity, perception of racial discrimination,
      • Williams D.R.
      • Mohammed S.A.
      Discrimination and racial disparities in health: evidence and needed research.
      and other social determinants of health in predicting outcomes associated with anxiety and depression should be clarified. Health literacy and health beliefs of the participants, as well as trust in physicians and care organizations, should be addressed in such research.
      Further elucidation of the mechanistic pathways between anxiety, morbidity, and mortality is needed. Randomized controlled trials of interventions directed more specifically at depression or anxiety symptoms (or their combination) might help clarify mediation of adverse outcomes. Future research needs to hone in on which anxiety diagnoses or features are particularly pathogenic for patients treated with HD. Studies also should consider the role of illicit and licit drugs as mediating factors, as well as the prevalence and possible adverse effects of the combination of anxiolytic therapies with benzodiazepines in HD patients.
      • Moore N.
      • Pariente A.
      • Bégaud B.
      Why are benzodiazepines not yet controlled substances?.
      The findings of Schouten et al suggest that in HD populations, mental illness is as important a comorbidity as are medical conditions. The time is still ripe for studies of psychosocial interventions in patients with anxiety or depression (or both) with mortality as an outcome. Recent studies show that patients treated with maintenance HD can participate in clinical trials of medication or cognitive behavioral therapy for depression, highlighting the feasibility of such interventions in the population.
      • Mehrotra R.
      • Cukor D.
      • Unruh M.
      • et al.
      Comparative efficacy of therapies for treatment of depression for patients undergoing maintenance hemodialysis: a randomized clinical trial.
      If we thought there was a common cause of morbidity and mortality, such as staphylococcal or streptococcal bacteremia in our patients, would we not treat them? Should we not study the treatment of anxiety and depression in our patients, and seek interventions that might reduce their burden of suffering, hospitalization, and premature death?

      Article Information

      Authors’ Full Names and Academic Degrees

      Paul L. Kimmel, MD, MACP, FRCP, and Daniel Cukor, PhD.

      Support

      None.

      Financial Disclosure

      The authors declare that they have no relevant financial interests.

      Peer Review

      Received April 2, 2019, in response to an invitation from the journal. Accepted April 2, 2019, after editorial review by an Associate Editor and a Deputy Editor.

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