Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Feedback
    • Reprint Information
    • Subscriptions
  • ASN Kidney News
  • Other
    • ASN Publications
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • ASN Publications
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Feedback
    • Reprint Information
    • Subscriptions
  • ASN Kidney News
  • Visit ASN on Facebook
  • Follow CJASN on Twitter
  • CJASN RSS
  • Community Forum
Perspectives
Open Access

Treatment of Depression in CKD Patients with an SSRI

Why Things Don’t Always Turn Out as You Expect

Daniel Cukor and Paul L. Kimmel
CJASN June 2018, 13 (6) 943-945; DOI: https://doi.org/10.2215/CJN.14421217
Daniel Cukor
1Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, New York; and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul L. Kimmel
2Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University, Washington, DC
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • View PDF
Loading
  • Humans
  • Depression
  • Depressive Disorder
  • Major
  • Kidney Failure
  • Chronic
  • Publications
  • Research

An extensive literature has been developed over the last four decades regarding the associations of a diagnosis of major depressive disorder and extent of depressive symptoms with outcomes in patients with ESKD (1). The field has moved from descriptive studies and analyses evaluating comparisons between two groups to sophisticated observational studies using administrative databases as well as direct participant evaluation and participation (1). Depression has been strongly and consistently linked to mortality in this population (2), but of course, direct linkages and causality cannot be inferred from such research.

Although current nomenclature conventions link ESKD with CKD, the former patients represent only the numerical tip of the iceberg for the group. Patients with ESKD who require dialysis experience a substantial burden in terms of morbidity, mortality, prescribed medications, and diminished perception of quality of life in addition to financial concerns, role transformations, and potential disruption of occupational, marital, and financial obligations (1). The remaining overwhelming majority of patients with CKD make up an extremely heterogeneous group. The kidney diseases that they suffer from are multitudinous, and the range of kidney function in this population, conservatively estimated, spans mild decreases in function to almost total absence.

CKD extends from slight decreases in kidney function to severe decrements, usually termed uremia, a constellation of signs and symptoms, including lack of appetite, dysgeusia, nausea, and vomiting, and a diverse set of neurologic, psychologic, and behavioral impairments on a spectrum from lassitude and lack of interest to somnolence, delirium, coma, seizures, and ultimately, death. In most cases, however, uremia is only encountered with severe diminution in kidney function, and patients with greater levels of GFR have been considered relatively asymptomatic.

In general, less is known about the relationship of depression and affective disorders with outcomes in patients with CKD, perhaps in part because of the heterogeneity of the diseases. Specifically, the true prevalence of major depressive disorder in patients with CKD not ready for renal replacement is unknown but likely varies in populations worldwide. The consequences of depression in this population are also less clear than in patients treated with dialysis. The hypothesized pathways that link ESKD to worse medical outcome span common autonomic dysregulation and behavioral nonadherence (1). The degree to which these extend to patients with earlier-stage CKD is unclear. As an example, it is unknown if depression is associated with mortality in patients with CKD.

More saliently, the essential operative question seems to be, “Is depression in patients with CKD different from depression in a population of patients without chronic comorbid medical illness?” The construct of “comorbid” or “double” depression, in which depression coexists with another medical or psychiatric illness, is traditionally thought of as a condition of greater complexity and resistance to treatment. It is unknown whether the severity of coexistent CKD modifies outcomes in patients with the additional depression diagnosis or whether any treatment modifications are required. Related questions include the following. Is depression different in patients with CKD, perhaps rendering it more difficult to treat? Are there different neural pathways involved in the pathogenesis of this syndrome in patients with and without a specific chronic illness, such as CKD? Are such pathways modified by decrements in kidney function? Is the severity of depressive affect a determinant of outcomes with medical antidepressant therapy? Is the severity of kidney dysfunction a determinant of outcomes with medical antidepressant therapy? Might subtle symptoms associated with kidney disease, perhaps consistent with those attributed to major depressive disorder, affect patient therapeutic outcomes?

To provide answers to the types of questions raised above and elucidate mechanisms, well designed randomized, controlled trials are necessary. Hedayati et al. (3) presented a well designed, well conducted trial of pharmacologic therapy for depressed patients with CKD using the selective serotonin reuptake inhibitor (SSRI) sertraline. Rates of adherence were excellent. Unexpectedly, there was no difference between outcomes in the group of patients treated with the SSRI compared with the patients treated with placebo. Some of the purported reasons for this surprising outcome were addressed both by the investigators (3) and in an editorial accompanying the report (4), including assessment of the possible role of the placebo effect.

Some questions about the study require elucidation before key issues that have been raised can be addressed. Screening is a constant challenge in the design of studies of treatment of depression. The study by Hedayati et al. (3) screened 14,658 patients to arrive at a group of 201 patients with a median GFR of 27.5 ml/min per 1.73 m2 to be randomized. This small selected group raises the issues of whether a biased study sample was created. It is not clear whether differences existed between the final study population and the eligible population. (Under current Institutional Review Board regulations, such detailed analyses probably cannot be performed.) Why did such a high percentage of people go through the screening process but not want to participate in the trial? (Weisbord and colleagues [5] addressed this in part in patients with ESKD treated with dialysis, but as noted, this is a very different patient group.) Why was there such a small proportion of women in the trial (approximately 27%), quite atypical for depression trials in particular? What is the significance of the high lifetime history of depression (approximately 40%) for this group? What were the patients’ expectations for treatment? Was the choice of a cutoff of 11 or greater on the Quick Inventory of Depression Symptomatology scale as the inclusion criterion too low? Were changes in appetite, sleep, or sexual functioning present due to the comorbid medical illnesses in the population or their treatment with drugs for kidney and/or psychiatric disease, and were these changes, therefore, conflated with the presence of depression?

The final study population was not characterized by severe depression or stage 5 CKD. It would stand to reason that the study population would be skewed away from more severe depression, because patients with severe depression are likely to be treated and are not available for a clinical trial with equipoise. However, the efficacy of SSRIs in moderate depression, even in nonmedical populations, is controversial, with a treatment advantage being reliably shown only for those with severe depression (6).

Perhaps, due to the generally asymptomatic nature of earlier stages of CKD and the generally moderate levels of depression commonly found in outpatient populations, other treatment options should be considered. Individual cognitive behavioral therapy (CBT) of patients with increased depressive affect has had remarkably salutary results in the general population and in a small study of patients with ESKD treated with dialysis (7). This therapy holds the promise of addressing the maladaptive thoughts and feelings of patients with major depressive disorder in the absence of the kind of adverse effects associated with drug therapies. CBT may be a particularly good choice for patients with CKD due to its substantial empirical base, its effectiveness at treating moderate depression, and its flexibility, allowing adaptation to any potential unique challenges of the CKD population.

Nevertheless, the study by Hedayati et al. (3) is important in spite of its unexpected results, because it provides critical information for the design of more definitive research. Future studies might consider national, multicenter approaches with a registry, enrolling a broader spectrum of patients with CKD who are depressed in a trial of CBT versus drug therapy, which would test effectiveness. Perhaps pragmatic approaches may make such studies more feasible as well as affordable.

In addition, the results of the study by Hedayati et al. (3) raise the question of the homogeneity of the small group of patients available after screening. Precision medicine or the notion that specific markers, perhaps genetic or physiologic, might be used to determine individuals within populations more likely to respond to a given treatment or medication is currently vigorously advocated. Recently, the notion of endophenotype has been considered in evaluating studies that are inconclusive. Characteristics within a diagnostic class may prove useful in subcategorizing patients who will respond well or adversely to a specific therapy. Latent class analytic techniques have proven to be useful in identifying groups with particular outcomes in therapeutic studies (8). Such analyses should be applied to the data in this study, where it might be useful to evaluate the associations between severity of kidney disease and depression in relation to a variety of outcomes of drug therapy, although the database is relatively small. Finally, innovative therapeutic approaches, such as the use of drug combinations (such as an SSRI and bupropion or an atypical antipsychotic) or the combination of pharmacologic and talk therapies, should be considered.

We must, however, await the publication of subgroup analyses from the Systolic Blood Pressure Intervention Trial (SPRINT) (9), which assessed perceptions of quality of life and level of depressive affect in a large sample of patients with CKD compared with patients with hypertension in the absence of CKD to evaluate whether there is something unique about the relationship of depression to CKD, and A Trial of Sertraline versus CBT for End-Stage Renal Disease Patients with Depression (ASCEND) (10), which will determine if CBT and sertraline are equally effective in depressed patients with ESKD treated with dialysis to plan better studies for patients with CKD at less severe stages and patients with more moderate levels of depression.

Disclosures

None.

Acknowledgments

The content of this article does not reflect the views or opinions of the American Society of Nephrology (ASN), the Clinical Journal of the American Society of Nephrology (CJASN), or any other organization or federal agency. Responsibility for the information and views expressed therein lies entirely with the author(s).

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • Copyright © 2018 by the American Society of Nephrology

References

  1. ↵
    1. Cukor D,
    2. Cohen SD,
    3. Peterson RA,
    4. Kimmel PL
    : Psychosocial aspects of chronic disease: ESRD as a paradigmatic illness. J Am Soc Nephrol 18: 3042–3055, 2007
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Kimmel PL,
    2. Peterson RA,
    3. Weihs KL,
    4. Simmens SJ,
    5. Alleyne S,
    6. Cruz I,
    7. Veis JH
    : Multiple measurements of depression predict mortality in a longitudinal study of chronic hemodialysis outpatients. Kidney Int 57: 2093–2098, 2000
    OpenUrlCrossRefPubMed
  3. ↵
    1. Hedayati SS,
    2. Gregg LP,
    3. Carmody T,
    4. Jain N,
    5. Toups M,
    6. Rush AJ,
    7. Toto RD,
    8. Trivedi MH
    : Effect of sertraline on depressive symptoms in patients with chronic kidney disease without dialysis dependence: The CAST randomized clinical trial. JAMA 318: 1876–1890, 2017
    OpenUrl
  4. ↵
    1. Walther CP,
    2. Shah AA,
    3. Winkelmayer WC
    : Treating depression in patients with advanced CKD: Beyond the generalizability frontier. JAMA 318: 1873–1874, 2017
    OpenUrl
  5. ↵
    1. Pena-Polanco JE,
    2. Mor MK,
    3. Tohme FA,
    4. Fine MJ,
    5. Palevsky PM,
    6. Weisbord SD
    : Acceptance of antidepressant treatment by patients on hemodialysis and their renal providers. Clin J Am Soc Nephrol 12: 298–303, 2017
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Fournier JC,
    2. DeRubeis RJ,
    3. Hollon SD,
    4. Dimidjian S,
    5. Amsterdam JD,
    6. Shelton RC,
    7. Fawcett J
    : Antidepressant drug effects and depression severity: A patient-level meta-analysis. JAMA 303: 47–53, 2010
    OpenUrlCrossRefPubMed
  7. ↵
    1. Cukor D,
    2. Ver Halen N,
    3. Asher DR,
    4. Coplan JD,
    5. Weedon J,
    6. Wyka KE,
    7. Saggi SJ,
    8. Kimmel PL
    : Psychosocial intervention improves depression, quality of life, and fluid adherence in hemodialysis. J Am Soc Nephrol 25: 196–206, 2014
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Calfee CS,
    2. Delucchi K,
    3. Parsons PE,
    4. Thompson BT,
    5. Ware LB,
    6. Matthay MA
    ; NHLBI ARDS Network: Subphenotypes in acute respiratory distress syndrome: Latent class analysis of data from two randomised controlled trials. Lancet Respir Med 2: 611–620, 2014
    OpenUrl
  9. ↵
    1. Berlowitz DR,
    2. Foy CG,
    3. Kazis LE,
    4. Bolin LP,
    5. Conroy MB,
    6. Fitzpatrick P,
    7. Gure TR,
    8. Kimmel PL,
    9. Kirchner K,
    10. Morisky DE,
    11. Newman J,
    12. Olney C,
    13. Oparil S,
    14. Pajewski NM,
    15. Powell J,
    16. Ramsey T,
    17. Simmons DL,
    18. Snyder J,
    19. Supiano MA,
    20. Weiner DE,
    21. Whittle J
    ; SPRINT Research Group: Effect of intensive blood-pressure treatment on patient-reported outcomes. N Engl J Med 377: 733–744, 2017
    OpenUrl
  10. ↵
    1. Hedayati SS,
    2. Daniel DM,
    3. Cohen S,
    4. Comstock B,
    5. Cukor D,
    6. Diaz-Linhart Y,
    7. Dember LM,
    8. Dubovsky A,
    9. Greene T,
    10. Grote N,
    11. Heagerty P,
    12. Katon W,
    13. Kimmel PL,
    14. Kutner N,
    15. Linke L,
    16. Quinn D,
    17. Rue T,
    18. Trivedi MH,
    19. Unruh M,
    20. Weisbord S,
    21. Young BA,
    22. Mehrotra R
    : Rationale and design of a trial of sertraline vs. cognitive behavioral therapy for end-stage renal disease patients with depression (ASCEND). Contemp Clin Trials 47: 1–11, 2016
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Clinical Journal of the American Society of Nephrology: 13 (6)
Clinical Journal of the American Society of Nephrology
Vol. 13, Issue 6
June 07, 2018
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in CJASN.
Enter multiple addresses on separate lines or separate them with commas.
Treatment of Depression in CKD Patients with an SSRI
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Treatment of Depression in CKD Patients with an SSRI
Daniel Cukor, Paul L. Kimmel
CJASN Jun 2018, 13 (6) 943-945; DOI: 10.2215/CJN.14421217

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Treatment of Depression in CKD Patients with an SSRI
Daniel Cukor, Paul L. Kimmel
CJASN Jun 2018, 13 (6) 943-945; DOI: 10.2215/CJN.14421217
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Disclosures
    • Acknowledgments
    • Footnotes
    • References
  • Info & Metrics
  • View PDF

More in this TOC Section

  • A Body Size–Adjusted Maximum Ultrafiltration Rate Warning Level Is Not Equitable for Larger Patients
  • Food Insecurity and Kidney Disease
  • What Is the Best Maintenance Therapy for ANCA Vasculitis?
Show more Perspectives

Cited By...

  • No citing articles found.
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Keywords

  • humans
  • depression
  • Depressive Disorder
  • Major
  • kidney failure
  • chronic
  • publications
  • research

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Trainee of the Year
  • Author Resources
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • CJASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About CJASN
  • CJASN Email Alerts
  • CJASN Key Impact Information
  • CJASN Podcasts
  • CJASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals

© 2022 American Society of Nephrology

Print ISSN - 1555-9041 Online ISSN - 1555-905X

Powered by HighWire