Pre-transplant depression decreased overall survival of patients receiving allogeneic hematopoietic stem cell transplantation: a nationwide cohort study

Studies investigating association of depression with overall survival (OS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) yielded conflicting results. A nationwide cohort study, which included all adult patients [n = 7,170; depression group, 13.3% (N = 956); non-depression group, 86.7% (N = 6,214)] who received allo-HSCT from 2002 to 2018 in South Korea, analyzed risk of pre-transplant depression in OS of allo-HSCT. Subjects were followed from the day they received allo-HSCT, to occurrence of death, or last follow-up day (December 31, 2018). Median age at allo-HSCT for depression and non-depression groups were 50 and 45 (p < 0.0001), respectively. Two groups also differed in rate of females (depression group, 55.8%; non-depression group, 43.8%; p < 0.0001) and leukemia (depression group, 61.4%; non-depression group, 49.7%; p < 0.0001). After a median follow-up of 29.1 months, 5-year OS rate was 63.1%. Cox proportional-hazard regression evaluated an adjusted risk of post-transplant mortality related to depression: OS decreased sequentially from no depression (adjusted hazard ratio [aHR] = 1) to pre-transplant depression only (aHR = 1.167, CI: 1.007–1.352, p = 0.04), and to having both depression and anxiety disorder (aHR = 1.202, CI: 1.038–1.393, p = 0.014) groups. Pre-transplant anxiety (anxiety only) did not have significant influence in OS. Additional medical and psychiatric care might be necessary in patients who experienced depression, especially with anxiety, before allo-HSCT.

Survival outcome: total cohort (N = 7,170). After a median follow-up of 29.1 months (range 0 to 207), the estimated overall survival (OS) rates at 5 years were 63.1% (supplementary Fig. 1). Supplementary Table 1 summarizes the unadjusted analyses comparing allo-HCT outcomes between depression and non-depression group. Patients with pre-transplant depression (depression only group) and anxiety (anxiety only group) had lower 5 year-OS than those who neither had depression nor anxiety (none group), and 5 year-OS was the lowest in patients having both depression and anxiety (both depression and anxiety group) (Fig. 1A).
The factors found to be significant in the univariable analysis were all included in the final multivariable analysis ( Table 2). The post-transplantation OS decreased sequentially from none group (adjusted hazard ratio [aHR] = 1) to depression only group (aHR = 1.167, CI: 1.007-1.352, p = 0.04), and to both depression and anxiety group (aHR = 1.202, CI: 1.038-1.393, p = 0.014). However, anxiety only group did not have significant influence in OS.
Survival outcome: landmark cohort (N = 6,391). Among 7,170 adult patients who received allo-HSCT, 6,391 patients were alive at the designated 100 days landmark and were included in the landmark analysis (supplementary Fig. 2 for OS). In line with total cohort, depression only group and anxiety only group had lower Scientific RepoRtS | (2020) 10:15265 | https://doi.org/10.1038/s41598-020-71208-2 www.nature.com/scientificreports/ 5 year-OS, with the both depression and anxiety group having the lowest 5 year-OS (Fig. 1B). The factors found to be significant in the univariable analysis (supplementary Table 2) were all included in the final multivariable analysis (Table 3). However, the multivariable analysis of the landmark cohort showed that the OS after transplantation was significantly lower only in both depression and anxiety group (aHR = 1.253, CI: 1.061-1.479, p < 0.001), and neither depression only nor anxiety only group showed statistical significance.

Subgroup analysis of patients with leukemia.
In the multivariable analysis of total and landmark cohort, hematologic disease had the highest aHR (2.083-3.063 for total cohort and 3.006-4.785 for landmark cohort) (Tables 2, 3). In order to completely eliminate disease as a co-factor, we conducted sub-group analysis in patients with a more homogenous group, leukemia only. A total of 3,809 patients received allo-HSCT due to leukemia, and their baseline demographic and clinical data are summarized in Table 4, and OSs are shown in supplementary Fig. 3. Same trend was noted for univariable analyses (supplementary Table 3) and multi- www.nature.com/scientificreports/ variable model (Table 5). Unadjusted analyses showed that depression only group, anxiety only group, and both depression and anxiety group all had lower 5 year-OS than none group (Fig. 2). Once again, the association was not detected for anxiety only group after adjusting for significant variables. In line with the total cohort, OS decreased sequentially from none group (aHR = 1) to depression only group (aHR = 1.220, CI: 1.031-1.444, p = 0.021), and to both depression and anxiety disorder group (aHR = 1.238, CI: 1.046-1.465, p = 0.0132).

Discussion
Our results showed that pre-transplant depression, independent from anxiety, decreased OS of adult patients receiving allo-HSCT. We also showed that co-occurrence of depression with anxiety disorder further decreased post-transplant OS, but pre-transplantation anxiety disorder did not independently increase mortality after allo-HSCT. In terms of sub-group analysis, same trend was found in patients who received allo-HSCT due to leukemia. The post-transplantation OS decreased sequentially from neither depression nor anxiety group (none; aHR = 1) to having depression only (aHR = 1.202), and then to having both depression and anxiety (aHR = 1.231). However, in the landmark analysis at 100 days post-transplantation, OS after transplantation was significantly lower only in patients having both depression and anxiety (aHR = 1.253). Numerous studies suggested association of pre-transplantation depression with lower OS in allo-HSCT 15,[20][21][22] . However, only one large sized longitudinal cohort study conducted in the US using CIBMTR data showed that depression history decreases the OS with aHR of 1.13 16 . To the best of our knowledge, this is the largest nationwide cohort study conducted in Asia, or outside US, showing the risk of pre-transplantation depression in OS of allo-HSCT. We replicated previous research and showed that pre-transplant depression decreases OS with aHR of 1.167, which was very similar to the HR reported by El-Jawahri et al. By carefully sub-classifying patients according to their anxiety disorder history, we were able to eliminate overlapping impact of pre-transplant anxiety from that of depression. Thus, our findings more specifically confirmed that pre-transplant depression independently decreases OS of allo-HSCT regardless of anxiety disorder. We also extended previous work by showing that OS decrement was more pronounced in patients who had both depression and anxiety before allo-HSCT (aHR = 1.202).
Interestingly, we did not detect significant association between anxiety disorder and OS of allo-HSCT. Anxiety is a frequent response to threat, so it is commonly found in patients having severe medical conditions 23 . Consequently, it is difficult to accurately distinguish normal anxiety or adjustment reaction from that of true morbid anxiety 24 . Thus, patients having anxiety reaction could have been over-diagnosed as having anxiety disorder in our cohort, which might have led to decreased significance in OS. In line with this hypothesis, patients in our cohort had twice more history of anxiety than depression. Previous study also showed that patients having pre-transplantation depression more concordantly experienced clinically significant depression even after transplantation, whereas patients having pre-transplant anxiety tended to experience anxiety symptoms less continuously 17,25,26 . Thus, depression might had longer impact than anxiety in OS of patients receiving allo-HSCT. In addition, landmark analyses performed at 100 days post-transplant, which excluded patients at high risk of early mortality post-transplant, showed that OS was significantly lower only in patients who had both depression and anxiety disorder. Thus, prospective studies which include more complete predictors of mortality in allo-HSCT are needed to confirm complicated relationship among depression, anxiety, and survival outcome after allo-HSCT.
Our results have additional strengths. First, by conducing a nationwide cohort study, we included all adult patients who received allo-HSCT from 2002 to 2018. We were able to prevent selection bias and minimize  www.nature.com/scientificreports/ recruitment setting effect, so our results have higher generalizability. Second, a more stringent definition was used to determine pre-transplant depression. Rather than using a single questionnaire or retrospective chart review, all patients with pre-transplant depression visited hospital due to exact diagnosis of depression [ICD-10 code for major depressive disorder (F32 × or F33 ×)]. Thus, we further prevented selection and reporting bias. Lastly, by conducting a subgroup analysis comprising of patients with leukemia only, we eliminated underlying hematologic disease as a possible co-factor and confirmed the negative impact of depression, and additive effect of anxiety, in post-transplant mortality.
The pathophysiological basis of pre-transplantation depression having a negative impact in OS of patients receiving allo-HSCT is still obscure. Nevertheless, our findings could be predicted by association of depression with immune system dysregulations 27 . Studies showed that depression is often accompanied by inflammatory diseases including irritable bowel syndrome, type 2 diabetes, arthritis and autoimmune disorders, which can activate the peripheral and central inflammatory response 28 . Furthermore, other studies illustrated that depression and acute graft-versus-host-disease (GVHD) share common pro-inflammatory reactions: increment of inflammatory cytokines (i.e. tumor necrosis factor-alpha) and shifting toward T helper 1 response system 29,30 . Likewise, past study showed that pre-HCT depression increased the incidence of acute GVHD 16 . Poor treatment adherence due to depression is another important cause of higher mortality 31 . However, additional prospective www.nature.com/scientificreports/ studies focusing on biological mechanism are needed to define common pathway linking depression, and anxiety, with that of post-transplantation mortality in patients receiving allo-HSCT. Several limitations should also be noted. First, occurrence of depression was based on clinical diagnosis with hospital visit records rather than using objective depressive scale measurements. As a result, we were unable to assess mortality difference depending on the depression severity. Since the depression severity is not known, some patients in the non-depression group may have had depression but have been undiagnosed. Second, we were also unable to investigate antidepressant effect, or treatment effect, in the risk of mortality. Likewise, depression episodes after transplantation were not considered. Thus, the effect of depression recurrence or chronicity in the post-transplant mortality were not studied. Third, whether time to diagnosis from depression and anxiety or duration of their illnesses influenced OS were not analyzed. Fourth, unbalanced baseline characteristics between depression group and non-depression group could harbor possible bias. Fifth, the cause of death, and relapse related and non-relapse related mortality according to depression were not investigated. In addition, other important clinical factors such as GVHD and infection episodes after transplantation, pre-transplantation conditioning, performance score, remission status at time of transplant, type of donor, smoking history, and alcohol status were not considered. Lastly, although Korea has a mandatory public health insurance system providing a comprehensive medical coverage to all residents of Korea, socioeconomic status could still have influenced the OS. Table 3. Multivariable analysis of factors affecting overall survival of allo-HSCT in landmark cohort (N = 6,391). COPD Chronic obstructive pulmonary disease; CVD Cerebro-or cardiovascular disease; HSCT Hematopoietic stem cell transplantation; MDS Myelodysplastic syndrome; MPN myeloproliferative neoplasm. www.nature.com/scientificreports/ In conclusion, pre-transplant depression, independent from anxiety, decreased OS of adult patients receiving allo-HSCT. The mortality risk was higher in patients who had both depression and anxiety than patients having neither. Same trend was noted in patients who received allo-HSCT due to leukemia. Thus, our results suggest that patients having depression, especially both depression and anxiety, before allo-HSCT have a higher risk of post-transplantation mortality needing more intensive care.

Methods
Data source and study population. The Korean National Health Insurance Service (KNHIS) is a mandatory public health insurance system of Korea and offers comprehensive medical coverage to all residents of Korea. Data were acquired from the KNHIS database, which contains all medical claims for the population covered under the KNHIS. The database has been widely used in various epidemiological studies and is described in detail elsewhere [32][33][34] .
Adult patients (≥ 18 years) who underwent allo-HSCT between 2002 and 2018 were identified using KNHIS database procedure codes X5061 for bone marrow and X5063 for peripheral blood allo-HSCT. For those who received second allo-HSCT, we used first allo-HSCT data as their baseline values. As a result, nearly all allo-HSCTs performed in Korea during the study period were included in the analysis. Comorbidities including hypertension, diabetes mellitus, chronic obstructive pulmonary disease, cerebro-or cardiovascular disease, and anxiety disorder were also extracted using International Classification of Diseases, Tenth Revision (ICD-10) codes. This study was approved by the institutional review board of Seoul St. Mary's Hospital, Seoul, Korea (KC19ZNSI0396). Consent from individual subjects were not needed because the study used publicly open, anonymous data. www.nature.com/scientificreports/ Outcome variable and statistical analysis. The primary endpoint of this study was OS difference after allo-HSCT according to pre-transplant depression history. In order to utilize more conservative definition of depression, patients having ICD-10 code for major depressive disorder (F32 × or F33 ×) and visited hospital due to the same code within five years prior to the allo-HSCT was defined as having pre-transplant depression. Difference between the two groups (depression group and non-depression group) in baseline demographic and clinical characteristics were compared using student's-T test for continuous variables and Chi-squared test for categorical variables.
To investigate independent risk of pre-transplant depression, and prevent overlapping impact of anxiety, we also identified patients who were diagnosed with and visited hospital due to anxiety disorder (F30 ×) before allo-HSCT. Thus, patients were subdivided in to four groups; no history of depression and anxiety disorder (none), depression history without anxiety (depression only), anxiety disorder without depression (anxiety only), and having both depression and anxiety disorder (both depression and anxiety).
Retrospective cohorts were followed from the day they received allo-HSCT to the occurrence of death or the last follow-up day (December 31, 2018), whichever came first. The OS rate represents the proportion of patients who were alive at the specified time after the date of transplantation and was associated with death due to any cause. Cox proportional-hazard regression evaluated risk of post-transplant mortality related to depression. All risk factors with p < 0.10 in univariable analysis were included in the single multivariable model. Thereafter, the factors found to be significant in this single multivariable model with depression variable were all included in the final multivariable model. For all statistical analysis, we used R statistical software (ver. 3.1.1, R Foundation for Statistical Computing, Vienna, Austria, 2012).