Symptoms of depression and anxiety in patients with transfusion-dependent thalassemia after hematopoietic stem cell transplantation: a single-center study

Abstract

Background:

Patients with transfusion-dependent thalassemia frequently experience significant psychological distress, with high rates of anxiety and depression reported. Despite this, the psychological status of thalassemia patients after hematopoietic stem cell transplantation (HSCT) remains less explored. Gaining insights into the symptoms of depression and anxiety in this population is crucial, as it can inform tailored support and improve quality of life.

Objectives:

This study aimed to assess the prevalence of anxiety and depression in post-HSCT thalassemia patients and to identify potential risk factors.

Design:

This was a cross-sectional study.

Methods:

A cross-sectional study involved 170 transfusion-dependent thalassemia patients who underwent HSCT from January 2017 to November 2022. The Hospital Anxiety and Depression Scale (HADS), a self-report questionnaire, was used to evaluate the levels of anxiety and depression.

Results:

The prevalence of anxiety and depression was 11.2% and 8.8%, respectively. Patients with a history of splenectomy and those with chronic graft-versus-host disease (cGVHD) exhibited significantly higher HADS scores (p < 0.01). Correlation analysis revealed positive associations between these variables and HADS scores, with correlation coefficients of 0.256 for splenectomy with HADS-Anxiety (HADS-A) and 0.227 with HADS-Depression (HADS-D) scores. For cGVHD, the correlation coefficients were 0.290 with HADS-A and 0.388 with HADS-D scores.

Conclusion:

The study revealed the psychological burden faced by post-transplant thalassemia patients, particularly those with a history of splenectomy and cGVHD. These findings underscore the need for targeted psychological support and interventions for this vulnerable patient group.

Keywords

anxiety depression hematopoietic stem cell transplantation thalassemia

Introduction

Thalassemia is a group of inherited hematological disorders characterized by a reduced synthesis of functional alpha or beta globin chains, which are essential components of hemoglobin. This dysregulation of globin chain synthesis leads to the premature destruction of red blood cells, resulting in chronic anemia. The phenotypic expression of thalassemia is variable and depends on the type and severity of genetic mutations affecting the alpha or beta globin genes. In the most severe forms, patients require regular blood transfusions to maintain hemoglobin levels, leading to a classification of transfusion-dependent thalassemia (TDT), where individuals receive eight or more blood transfusions annually, and non-transfusion-dependent thalassemia.¹

Depression, a complex mood disorder with multifactorial etiology, is characterized by a heterogeneous presentation of symptoms. Common manifestations include persistent low mood, anhedonia, impaired concentration, sleep disturbances, and fatigue. In severe cases, functional impairment and suicidal ideation may occur.² Anxiety is an aversive emotional state characterized by feelings of inner tension, fear, or anticipation of an adverse event.² The main diagnostic methods for depression and anxiety are scales and questionnaires, including the Patient Health Questionnaire,³ Hospital Anxiety and Depression Scale (HADS), Symptom Checklist-90,⁴ Hamilton Depression Scale,⁵ Hamilton Anxiety Scale,⁶ and so on. The HADS is a common diagnostic tool in clinics.

Patients with thalassemia frequently encounter psychological and behavioral challenges.⁷ Research suggests that approximately 80% of pediatric patients with thalassemia are at risk of developing psychological conditions, including anxiety and depression.^8,9 These issues are often linked to the frequent hospital visits for blood transfusions and the resultant frequent absences from school.¹⁰ The chronic nature of thalassemia can markedly affect the self-esteem of affected children.¹¹ A decrease in self-esteem can, in turn, intensify the prevalence of anxiety and depression, potentially leading to a detrimental impact on the long-term quality of life for these patients.

Currently, there is a substantial body of literature that has documented the anxiety and depression status in patients with TDT. Studies report varying prevalence rates of anxiety and depression in TDT patients, ranging from 19.3% to 51.7% and from 13.3% to 61.3%, respectively.^12–14 However, there is a notable dearth of literature concerning the evaluation of anxiety and depression in TDT patients following hematopoietic stem cell transplantation (HSCT). The objectives of this study are twofold: (1) to determine the incidence of anxiety and depression in patients post-HSCT for TDT; (2) to identify the factors associated with anxiety and depression in this patient population. This research aims to contribute to developing targeted psychological interventions to enhance these patients’ mental health and quality of life.

Methods

Patients and data collection

The study included TDT patients who underwent HSCT at the First Affiliated Hospital of Guangxi Medical University from January 2017 to November 2022. Inclusion criteria: (1) meeting the diagnostic criteria for TDT; (2) being aged 12 or older when completing the questionnaire; (3) having normal cognitive abilities to complete the questionnaire independently. Exclusion criteria: (1) patients who had undergone a second transplantation; (2) patients with other severe mental illnesses; (3) patients who could not be contacted. This cross-sectional study was conducted in 2024 by contacting patients via telephone and sending electronic questionnaires. The purpose and method of the study were explained to the patients and their parents over the telephone. Clinical data of the patients were extracted from the hospital’s electronic medical records.

Anxiety and depression symptoms

The HADS was utilized to evaluate the levels of anxiety and depression among participants.¹⁵ The HADS is a well-established and frequently used diagnostic tool for gauging the psychological well-being of individuals within healthcare contexts.¹⁶ The scale consists of 14 items, with 7 items dedicated to assessing anxiety and the remaining 7 focused on depression. Scoring for each item is based on a four-point Likert scale, where 0 represents the absence of symptoms and 3 indicates the most severe symptoms. The established thresholds for interpreting HADS-A (Anxiety) and HADS-D (Depression) scores are as follows: scores of 0–7 are considered normal, 8–10 indicate mild symptoms, 11–14 suggest moderate symptoms, and scores of 15 or above are indicative of severe symptoms. The HADS is recognized for its reliability, with Cronbach’s alpha coefficients of 0.80 for anxiety and 0.76 for depression, reflecting strong internal consistency for both subscales.¹⁷

Definitions

The severity of acute graft-versus-host disease (aGVHD) was classified following the criteria established by the 1994 Consensus Conference on Acute GVHD Grading.¹⁸ The grading system delineates the disease’s severity into four stages, ranging from mild to very severe, based on the manifestations in various organs such as the skin, liver, and gastrointestinal tract. Chronic GVHD (cGVHD) was scored for severity using the National Institutes of Health consensus criteria,¹⁹ which assess the objective manifestations in each affected organ to determine an overall score categorizing the condition as mild, moderate, or severe. Neutrophil engraftment was identified when a participant exhibited a neutrophil count of at least 0.5 × 10⁹/l in peripheral blood on the first of two consecutive days without the use of granulocyte colony-stimulating factor. Platelet engraftment was defined as the first of seven consecutive days with an untransfused platelet count of at least 20 × 10⁹/l.

Statistical analysis

All statistical analyses were completed with SPSS 26.0 software (IBM Corp., Armonk, NY, USA). General characteristics of the patients were presented in terms of percentage, mean, standard deviation, and median for data not normally distributed. For HADS, both HADS-A score and HADS-D score were presented in terms of mean and standard deviation. Independent t-test, nonparametric test, and chi-square test were used for comparison of normally distributed quantitative variables, non-normally distributed quantitative variables, and qualitative variables, respectively. Pearson and Spearman correlation coefficients were calculated to examine the relationship between scores of depression and anxiety with the variables. p < 0.05 was considered statistically significant.

Results

Characteristics of patients at transplantation

Between January 2017 and November 2022, a cohort of 502 patients diagnosed with TDT underwent HSCT at our hospital. The patient selection criteria and process are delineated in Figure 1. The study population was refined by excluding one patient who underwent a second HSCT, 274 patients aged less than 12 years at the time of questionnaire administration, and 23 patients who had deceased. Additionally, 16 patients who had changed their contact information and were thus untraceable were excluded, as were 18 patients who failed to complete the questionnaire. This exclusion process yielded a response rate of 90.4%. Consequently, 170 patients were eligible for and included in the subsequent analysis. The sociodemographic and clinical characteristics of these patients are shown in Table 1. Most of the included patients had β-TDT, accounting for 98.2%, with a median age at transplantation of 10 (8–12) years. They had significant iron overload, with a median serum ferritin level of 3817.67 (2670.11–5746.96) ng/ml. Among the patients eligible for analysis, 57.1% (97/114) had liver iron overload, and 16.5% (28/113) had cardiac iron overload. The types of transplantation were Matched-Related Donor (41.8%), Matched-Unrelated Donor (31.2%), Haploidentical Donor (22.4%), and Mismatched Unrelated Donor (4.7%). The sources of the graft were primarily granulocyte colony-stimulating factor–bone marrow (G-BM) and peripheral blood stem cells (PBSCs; 53.5%) and G-PBSCs (34.7%). Neutrophil engraftment and platelet engraftment occurred at day +11(10–13) and day +14 (12–18), respectively. The incidence of aGVHD and cGVHD was 42.4% (72/170) and 22.9% (39/170), respectively, with grade II–IV aGVHD accounting for 12.4% and moderate to severe aGVHD accounting for 14.1%.

Figure 1.

Patient selection process.

Table 1.

Characteristics of patients at transplantation.

Variables	n = 170
Genotype, n (%)
α-TDT	3 (1.8)
β-TDT	167 (98.2)
Sex, n (%)
Male	109 (64.1)
Female	61 (35.9)
Age (years), median (IQR)	10 (8–12)
Hepatomegaly, cm, n (%)
Liver size <5	161 (94.7)
Liver size ⩾5	9 (5.3)
Splenectomy, n (%)	34 (20.0)
Serum ferritin, ng/ml, median (IQR)	3817.67 (2670.11–5746.96)
Cardiac MRI T2* (ms), n (%)
T2* ⩾20	85 (50.0)
T2* <20	28 (16.5)
LIC (mg Fe/g dw), n(%)
LIC ⩽ 1.8	17 (10.0)
1.8 < LIC < 7	12 (7.1)
7 < LIC < 15	18 (10.6)
LIC ⩾ 15	67 (39.4)
Type of transplantation, n (%)
Matched-Related Donor	71 (41.8)
Matched-Unrelated Donor	53 (31.2)
Mismatched Unrelated Donor	8 (4.7)
Haploidentical Donor	38 (22.4)
Graft type, n (%)
G-BM	4 (2.4)
G-PBSCs	59 (34.7)
G-BM and PBSCs	91 (53.5)
G-BM and CB	16 (9.4)
Neutrophil engraftment, days, median (IQR)	11 (10–13)
Platelet engraftment, days, median (IQR)	14 (12–18)
aGVHD, n (%)	72 (42.4)
Grade I	51 (30)
Grade II–IV	21 (12.4)
cGVHD, n (%)	39 (22.9)
Mild	15 (8.8)
Moderate to severe	24 (14.1)

aGVHD, acute graft-versus-host disease; BM, bone marrow; CB, umbilical cord blood; cGVHD, chronic graft-versus-host disease; G, granulocyte colony-stimulating factor; LIC, liver iron concentration; MRI, magnetic resonance imaging; PBSCs, peripheral blood stem cells; T2*, spin-spin relaxation time; TDT, transfusion-dependent thalassemia.

Outcomes of scales’ scores

The outcomes of scales’ scores are shown in Table 2. The HADS-A subscale scores for these patients’ mean is 3.90 ± SD 3.25, with 19 patients scoring above 7, resulting in an anxiety prevalence rate of 11.2%, including 5.3% with mild anxiety, 5.3% with moderate anxiety, and 0.6% with severe anxiety. The HADS-D subscale scores were 3.77 ± 2.93, with 15 patients scoring above 7, resulting in a depression prevalence rate of 8.8%, including 4.7% with mild depression and 4.1% with moderate depression. In the anxiety scoring scale, patients with a history of cGVHD and splenectomy had significantly higher scale scores than those without cGVHD and splenectomy (5.79 ± 4.02 vs 3.43 ± 2.86, p < 0.001; 5.82 ± 3.78 vs 3.33 ± 2.85, p < 0.001). Similarly, in the depression scoring scale, patients with a history of splenectomy and cGVHD also had significantly higher scores (5.29 ± 3.65 vs 3.39 ± 2.60, p = 0.003; 6.23 ± 3.71 vs 3.04 ± 2.19, p < 0.001). Additionally, male patients had significantly higher depression scale scores than female patients (4.22 ± 3.21 vs 2.97 ± 2.16, p = 0.021). There were no significant differences in the scores of the HADS-A and HADS-D subscales across different transplant ages, age at the time of completing the questionnaire, time post-transplantation, ferritin, or hepatomegaly status.

Table 2.

Data from the HADS.

HADS	Anxiety	p	Depression	p
All patients scores	3.90 ± 3.25	—	3.77± 2.93	—
Severity		—		—
Normal (scores of < 8), n(%)	151 (88.8)		155 (91.2)
Mild (scores of 8–10), n(%)	9 (5.3)		8 (4.7)
Moderate (scores of 11–14), n(%)	9 (5.3)		7 (4.1)
Severe (scores of ⩾15), n(%)	1 (0.6)		0 (0)
Sex		0.162		0.021*
Male	4.25 ± 3.51		4.22 ± 3.21
Female	3.28 ± 2.65		2.97 ± 2.16
Age at transplantation, years		0.722		0.433
<7	3.44 ± 2.45		4.44 ± 1.94
⩾7	3.93 ± 3.30		3.73 ± 2.98
Age group, years		0.691		0.866
12–17	3.82 ± 3.10		3.71 ± 2.80
⩾18	4.61 ± 4.36		4.28 ± 3.90
Years after transplantation		0.897		0.161
2–5	4.09 ± 3.57		3.78 ± 3.13
>5	3.28 ± 1.76		3.75 ± 2.20
Serum ferritin, ng/ml		0.435		0.617
<2500	4.08 ± 2.98		3.78 ± 3.43
⩾2500	3.85 ± 3.34		3.77 ± 2.78
Hepatomegaly, cm		0.277		0.493
Liver size <5	3.77 ± 3.07		3.70 ± 2.81
Liver size ⩾5	6.22 ± 5.38		5.11 ± 4.64
Splenectomy		<0.001***		0.003**
Yes	5.79 ± 4.02		5.29 ± 3.65
No	3.43 ± 2.86		3.39 ± 2.60
aGVHD		0.745		0.365
Yes	3.99 ± 3.22		4.10 ± 3.24
No	3.84 ± 3.29		3.53 ± 2.67
cGVHD		<0.001***		<0.001***
Yes	5.82 ± 3.78		6.23 ± 3.71
No	3.33 ± 2.85		3.04 ± 2.19

p < 0.05. **p < 0.01. ***p < 0.001.

aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; HADS, Hospital Anxiety and Depression Scale.

Outcomes of correlation analyses

From the results of the correlation analysis (Table 3), we can observe that the occurrence of cGVHD and a history of splenectomy are significantly and positively correlated with the scores of the two subscales of the HADS. The correlation coefficients of cGVHD with the total HADS scale and the HADS subscales were 0.290 and 0.388, respectively. The correlation coefficients of splenectomy with the total HADS scale and the HADS subscales were 0.256 and 0.227, respectively. Other variables did not show statistically significant correlations with either subscale.

Table 3.

Correlations with HADS depression and anxiety subscales and variables of interest.

Variables	Anxiety	Depression
Sex	−0.107	−0.177
Age at transplantation	0.126	−0.005
Age at questionnaire completion	0.073	0.000
Years after transplantation	−0.095	0.043
Hepatomegaly	0.084	0.053
Splenectomy	0.256**	0.227**
Serum ferritin	0.076	0.096
LIC	−0.146	−0.046
Cardiac MRI T2*	−0.096	−0.029
Neutrophil engraftment	−0.089	−0.102
Platelet engraftment	−0.063	−0.145
aGVHD	0.025	0.070
cGVHD	0.290**	0.388**

**p < 0.01.

aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; HADS, Hospital Anxiety and Depression Scale; LIC, liver iron concentration; MRI, magnetic resonance imaging; T2*, spin-spin relaxation time.

Discussion

While anxiety and depressive symptoms are well-documented in individuals with TDT, their prevalence following HSCT remains poorly characterized. This study is the largest cohort that evaluates anxiety and depression in post-transplant TDT patients. Our research shows that 11.2% of patients report significant anxiety, and 8.8% report depression symptoms, both of which are significantly lower than the findings from Cikili-Uytun et al.²⁰ In their investigation involving 13 post-transplant TDT patients, Cikili-Uytun et al. found that anxiety was present in 53.8% of cases and depression in 15.4%.

Compared to the nontransplant TDT patients assessed with the same scales as reported in the literature, our study shows that the prevalence of anxiety and depression among post-transplant TDT patients is significantly lower. The literature reports an incidence of anxiety and depression ranging from 19.3% to 51.7% and from 13.3% to 61.3%, respectively.^12–14 When compared with the general healthy population as reported in the literature, the prevalence of anxiety and depression among post-transplant TDT patients in our study is similar to that of the general population. Investigations employing the HADS in the general population have revealed that the prevalence of individuals experiencing significant anxiety symptoms ranges from 7% to 33%, while the prevalence of those with significant depressive symptoms is from 5% to 11%.^21–23 Collectively, these data suggest that HSCT may reduce the prevalence of anxiety and depression in TDT patients. This reduction is due to the curative nature of the treatment, which significantly enhances the quality of life by eliminating the need for frequent blood transfusions and enabling patients to gradually resume a lifestyle akin to that of healthy individuals.

In our study, we report for the first time in the field of thalassemia that cGVHD is positively correlated with anxiety and depression scores in post-transplant TDT patients. Similar findings have been observed in non-thalassemic hematological disorders. Cheon et al. reported a cohort of 67 post-transplant patients, indicating a significant association between cGVHD and depression.²⁴ Another study corroborated this finding that reported a substantial correlation between cGVHD and depression (r = 0.16).²⁵ Self-reported depression is associated with lower overall survival (OS).^26,27 Patients with cGVHD and self-reported depression or anxiety represent a highly vulnerable population at risk for poor clinical outcomes and substantial morbidity from their illness.²⁸ This may be because patients’ psychological states affect their adherence to treatment.¹⁷ cGVHD is one of the major complications following HSCT, with an incidence rate reported to range from 8% to 18% in previous studies.^29–31 It has a significant negative impact on the quality of life of patients.³² Taken together, this suggests that actively managing cGVHD in post-transplant patients and monitoring their anxiety and depression are essential for improving their disease prognosis.

Our study also reveals a significant positive correlation between a history of splenectomy and elevated scores on HADS. To the best of our knowledge, no prior studies have explicitly investigated the relationship between splenectomy and the development of anxiety or depression in thalassemia patients. In our study, a total of 34 patients underwent splenectomy. The median age at transplantation was 12 (10.5, 14.5) years. Hepatomegaly was observed in 17.6% (6/34) of these patients. 76.4% (26/34) of the patients had serum ferritin levels greater than 2500 ng/ml. Among them, 92.5% (25/27) had liver iron deposition, and 46.1% (12/26) had cardiac iron deposition. The incidence of aGVHD was 35.2% (12/34), and cGVHD occurred in 32.3% (11/34) of the patients. These splenectomized patients often had low-income family economics, and thus could not undergo regular blood transfusions and iron chelation therapy. As a result, they were older at transplantation and had more severe disease manifestations. Studies have shown that patients who underwent splenectomy had more late complications after transplantation,³³ and their 5-year OS was significantly lower than that of non-splenectomized patients (75.00% vs 91.78%, p = 0.06).³⁴ This may be attributable to the higher anxiety and depression scores in these patients.

It should be noted that the study cohort experienced the COVID-19 pandemic, which overlapped with the transplantation period. The pandemic may have imposed additional psychological stressors, such as prolonged social isolation, school closures, limited social activities, and reduced access to routine medical care, potentially affecting depression and anxiety levels. However, the questionnaires were administered in 2024, when all patients were clinically stable post-HSCT and no longer required immunosuppressive therapy, hospitalization, or blood transfusions. Patients were typically followed every 6 months during the first 3 years post-transplantation and annually thereafter, ensuring regular medical supervision and clinical stability. Thus, the psychological outcomes observed are more likely to reflect long-term sequelae of HSCT in thalassemia patients, although pandemic-related stressors may have contributed to some extent.

By elucidating the prevalence of anxiety and depression in post-transplant thalassemia patients and identifying associated factors, more targeted psychological support and intervention measures can be implemented. This approach enhances overall treatment outcomes and quality of life for patients, enabling them to better manage their daily lives and social roles.

Our study has some limitations. First, the absence of pre-transplantation psychological assessments precludes direct comparison with post-transplantation psychological states. Second, the cross-sectional nature of our study design limits our ability to track and analyze long-term psychological trajectory changes in these patients. Lastly, we did not conduct psychological interventions for these patients, and therefore did not further assess the effects of such interventions. Future research should address these limitations by conducting longitudinal studies that include pre- and post-transplantation psychological assessments. Additionally, implementing and evaluating psychological interventions could provide valuable insights into their effectiveness in improving the psychological outcomes for post-transplant thalassemia patients. Such endeavors would contribute significantly to the evidence base for optimizing the holistic care of these individuals.

Conclusion

In conclusion, our study provides valuable insights into the psychological well-being of post-transplant thalassemia patients. The significant positive correlation between a history of splenectomy and cGVHD with increased anxiety and depression scores underscores the need for specialized attention to these high-risk groups.

Supplemental Material

sj-docx-1-tah-10.1177_20406207251392930 – Supplemental material for Symptoms of depression and anxiety in patients with transfusion-dependent thalassemia after hematopoietic stem cell transplantation: a single-center study

Supplemental material, sj-docx-1-tah-10.1177_20406207251392930 for Symptoms of depression and anxiety in patients with transfusion-dependent thalassemia after hematopoietic stem cell transplantation: a single-center study by Xiao Liang, Yumei Huang, Gaohui Yang, Lingling Shi, Lianjin Liu, Hongwen Xiao, Jian Dai, Zhenbin Wei, Lingyuan Pan, Zhaoping Gan, Yu Lin, Yibin Yao, Ying Tang, Huicheng Huang, Xuemei Zhou, Yongrong Lai and Rongrong Liu in Therapeutic Advances in Hematology

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Xiao Liang

Hongwen Xiao

Yongrong Lai

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

Please find the following supplemental material available below.

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