Mental illness in chronic kidney disease : prognosis, drug utilization, and treatment outcomes

Chronic kidney disease (CKD) is a common yet heterogeneous condition, covering a wide spectrum of disease severity ranging from mildly decreased kidney function to kidney failure. Patients with CKD can often encounter mental health conditions that are related to poor prognosis. Depression is the most studied mental illness, while previous research has primarily focused on patients with kidney failure undergoing dialysis. Antidepressant medications are the main pharmacological approach for treating depression, with selective serotonin reuptake inhibitors (SSRIs) being the most frequently prescribed type. Notably, antidepressants may have different risk-benefit profiles in CKD patients, for whom dose adjustments are recommended. However, the implementation of SSRI dose adjustment in routine care is largely unknown. Despite the widespread use, there remains uncertainty about the efficacy and safety of antidepressants in the CKD population due to limited clinical evidence, whereas a few observational studies have reported several adverse health outcomes associated with antidepressant use in patients with CKD. In addition, little is known about the burden of bipolar disorder and schizophrenia, less common but severe mental illnesses, in patients with CKD.

This thesis aims to expand existing knowledge about the prevalence and impact of mental illnesses, as well as the utilization and safety of antidepressants in patients with CKD.

Study I evaluated to what extent patients’ kidney function influences SSRI dosing in routine practice. We found that a lower estimated glomerular filtration rate (eGFR) was moderately associated with being prescribed SSRIs with a reduced initial or maintenance dose. Nonetheless, two-fifths of patients with severely decreased eGFR received SSRI prescriptions without proper dose reduction, potentially exposed to a higher risk of adverse drug reactions.

Study II examined the association between an incident diagnosis of depression and adverse clinical outcomes in patients with non-dialysis CKD. We found significant associations between incident depression and hospitalization, CKD progression, major adverse cardiovascular events, and all-cause mortality in patients with non-dialysis CKD. The association with CKD progression became more evident one year after the depression diagnosis, while the associations with the other outcomes were more pronounced within the first year after diagnosis.

Study III investigated the comparative safety of antidepressant treatment in patients with CKD and incident depression, using the target trial emulation framework. We found that compared with non-initiation, initiation of antidepressants was associated with a higher risk of short-term adverse events such as hip fracture and upper gastrointestinal bleeding, but was not associated with long-term outcomes, including all-cause mortality, major adverse cardiovascular events, CKD progression, and suicidal behavior. Selection of the appropriate type and dosage of antidepressants is crucial to improve treatment safety. Initiating mirtazapine versus SSRIs was associated with a lower risk of upper gastrointestinal bleeding but a higher risk of mortality. Initiating SSRIs with a reduced dose versus a standard dose was associated with lower risks of upper gastrointestinal bleeding and CKD progression but a higher risk of cardiac arrest.

Study IV described the prevalence of three severe mental illnesses (i.e., depression, bipolar disorder, and schizophrenia) and examined their impact on clinical outcomes in patients with CKD. In a nationwide cohort of nephrologist-referred CKD patients, we estimated a prevalence of 5.4% for depression, 1.9% for bipolar disorder, and 0.5% for schizophrenia, amounting to an overall prevalence of 7% for any of these disorders, which was 60% higher than the general population. We found that each of the disorders was associated with a higher mortality rate and bipolar disorder was also associated with a faster eGFR decline. Nevertheless, CKD patients with bipolar disorder or schizophrenia exhibited a lower rate of initiating kidney replacement therapy, suggesting potential inequities in access to this life-sustaining treatment.

In conclusion, the present thesis highlights the commonness and negative impact of mental illness in patients with CKD and provides real-world evidence on the prescribing and safety of antidepressants in the CKD population.

List of scientific papers

I. Zhu N, Lisinski A, Lagerberg T, Johnell K, Xu H, Carrero JJ, Chang Z. Kidney function and prescribed dose in middle-aged and older patients starting selective serotonin reuptake inhibitors. Pharmacoepidemiology and Drug Safety. 2022;31(10):1091-101.
https://doi.org/10.1002/pds.5515

II. Zhu N, Virtanen S, Xu H, Carrero JJ, Chang Z. Association between incident depression and clinical outcomes in patients with chronic kidney disease. Clinical Kidney Journal. 2023;16(11):2243-53.
https://doi.org/10.1093/ckj/sfad127

III. Zhu N, Xu H, Lagerberg T, Johnell K, Carrero JJ, Chang Z. Comparative safety of antidepressants in adults with CKD. Clinical Journal of the American Society of Nephrology. 2023 December 1.
https://doi.org/10.2215/CJN.0000000000000348

IV. Zhu N, Faucon AL, Kuja-Halkola R, Landén M, Xu H, Carrero JJ, Evans M, Chang Z. Prevalence and impact of severe mental illness in patients with chronic kidney disease. [Submitted]