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. 2026 Feb 12;16:110. doi: 10.1038/s41398-026-03828-7

Depression and anxiety in interstitial lung disease: a systematic review, meta-analysis and Mendelian randomization

Dongru Du 1,2,3,#, Jiangyue Qin 4,#, Guangyue Zhang 5, Lijuan Gao 1,2,6, Yanqiu Wu 1,2,6, Zhenni Chen 7, Chun Wan 1,2,6, Ting Yang 1,2,6, Fengming Luo 1,2,3,✉, Yongchun Shen 1,2,6,8,✉
PMCID: PMC12923813  PMID: 41680136

Abstract

Objective

To investigate the prevalence of depression and anxiety in interstitial lung disease (ILD) and reveal whether ILD is causally associated with depression and anxiety via Mendelian randomization (MR).

Methods

Eligible studies were identified and selected from Web of Science, PubMed and Scopus. The pooled prevalence of depression and anxiety in ILD, as well as the clinical characteristics of ILD with depression or anxiety, were assessed. Sensitivity analyses, subgroup analyses and meta-regression were applied for heterogeneity assessments. Data of MR analysis were derived from the UK biobank and Finngen cohort, and the inverse variance weighting approach was selected as the main approach for causality evaluation.

Results

A total of 35 studies were included in this meta-analysis, with 34 studies reporting depression in ILD and 21 reporting anxiety in ILD. The pooled prevalence of depression and anxiety in ILD were 22% (95% CI 17%, 26%, I2 = 97%) and 25% (95% CI 18%, 32%, I2 = 98%), respectively. There was no significant difference in the prevalence of depression (p = 0.41) or anxiety (p = 0.39) across various subtypes of ILD. ILD patients with depression had a lower BMI (MD −2.11, 95% CI −3.82, −0.41, p = 0.02). Results of MR analysis revealed no causal associations for either the ILD-depression (OR 1.000, 95% CI 0.997, 1.003; p = 0.962) or the ILD-anxiety (OR 1.000, 95% CI 0.998, 1.002; p = 0.888) relationships.

Conclusion

Although the prevalence of depression and anxiety were high in patients with ILD, no causal relationship was observed. Future studies are needed to investigate the intricate association between ILD and mental health.

Subject terms: Psychiatric disorders, Depression

Introduction

Interstitial lung disease (ILD) is a heterogeneous condition characterized by inflammation or fibrosis within the lung interstitium [1]. From 1990–2019, the incidence of and number of deaths from ILD increased by 118.6 and 166.6%, respectively [2]. More than 200 subtypes of ILD have been documented, including idiopathic pulmonary fibrosis (IPF), connective tissue disease-associated interstitial lung disease (CTD-ILD), hypersensitivity pneumonitis, drug-induced ILD, infection-related ILD and unclassifiable ILD [3]. ILD may also be accompanied by comorbidities, including pulmonary hypertension and ischemic heart disease, thereby increasing the complexity of its management [4, 5].

Depression and anxiety are two prevalent mental disorders ranking the top 2 leading causes of disability-adjusted life-years [6, 7]. An epidemiological cross-sectional study revealed that the weighted prevalence of depressive and anxiety disorders reached 6.8 and 7.6%, respectively, in China [8]. Depression and anxiety may also serve as important comorbidities affecting the prognosis of respiratory diseases. A meta-analysis reported that the prevalence of depression reached 34.5% in patients with chronic obstructive pulmonary disease (COPD) [9]. Further evidence suggested that anxiety and depression may increase the risk of 30-day readmission and acute exacerbation in patients with COPD [10]. Another Mendelian randomization study revealed that COPD did not causally contribute to depression, whereas depression causally increased the risk of COPD [11]. However, few studies have summarized the prevalence of depression and anxiety in ILD patients, and whether there is a causal association linking ILD with depression and anxiety is still unknown.

Therefore, we aimed to investigate the pooled prevalence of depression and anxiety in ILD patients via a systematic review and meta-analysis. We further performed Mendelian randomization (MR) utilizing single nucleotide polymorphisms (SNPs) to explore whether ILD causally increases the risk of depression and anxiety.

Methods

Systematic review and meta-analysis

This systematic review and meta-analysis has been registered at PROSPERO (CRD42025635866) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [12].

Literature search

Two investigators independently searched Web of Science, PubMed and Scopus from the inception of the databases to November 2024. The detailed strategies used for the literature search were shown in Table S1. References of related reviews or systematic reviews were manually checked to prevent omissions.

Study selection

The detailed inclusion criteria were as follows: (1) Patients with a clear diagnosis of ILD (including pulmonary sarcoidosis) as well as a clear diagnosis of with or without depression or anxiety. (2) A population of more than 50 individuals is needed to reduce potential bias [13]. (3) The prevalence of depression or anxiety in patients with ILD is known. The detailed exclusion criteria were as follows: (1) Different studies that used data from the same institution or database. In this case, only one study with the largest sample size was included. (2) Not published in English. (3) Review, comments or meta-analysis. (4) Based on highly-selective cohorts, such as patients with certain stages of sarcoidosis.

Data extraction and quality assessments

We extracted the following data for further analyses: (1) Baseline information of each study: author and publication year, geographical location, source of data, study type, total number of patients with ILD, number of ILD patients with depression or anxiety and type of ILD. (2) Diagnostic criteria of ILD, depression and anxiety. (3) Number of total ILD, ILD with depression and/or ILD with anxiety. (4) Baseline characteristics of the patients enrolled: age, male proportion, body mass index (BMI), proportion of forced expiratory volume in 1 s (FEV1%), proportion of forced vital capacity (FVC%), FEV1/FVC, smoking history, proportion of diffusion lung capacity for carbon monoxide (DLCO%), 6 min walk distance (6MWD), and history of gastroesophageal reflux disease (GERD), obstructive sleep apnea (OSA), pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), coronary artery disease (CAD), cancer, hypertension and diabetes. Quality assessments were evaluated via the Newcastle‒Ottawa Scale, and the total score was divided into “low quality (0--3)”, “moderate quality (4--6) and “high quality (7--9)” [14].

Statistical analyses

We calculated the pooled prevalence with 95% confidence intervals (CIs) to explore the prevalence of depression and anxiety in patients with ILD. The prevalence of depression and anxiety in different subtypes of ILD was also calculated. We then evaluated the clinical characteristics of ILD patients with depression or anxiety compared with those of ILD patients without depression and anxiety. The results were presented as the mean difference (MD) or odds ratio (OR) with 95% CIs. Heterogeneity assessments were conducted via the I2 test and the Q statistic. A fixed effects model was applied if I2 < 50% or p < 0.1 was observed; otherwise, a random effects model was applied. Sensitivity analyses, subgroup analyses and meta-regression were further performed to address this issue. All the statistical analyses were conducted via R (version 4.4.1), and p < 0.05 was considered statistically significant.

Mendelian randomization

Basic principles of MR analysis

MR is a novel approach utilizing genetic data to investigate the potential causal relationship between exposure and outcome [15]. In this study, MR was employed to examine whether interstitial lung disease causally contributes to depression and anxiety using SNPs as instrumental variables (IVs).

To perform MR analyses, three principles should be followed to reach valid causal estimation. (1) IVs should be strongly associated with exposure. (2) Genetic variants were independent of confounding factors. (3) Genetic variants affect outcomes through exposure. The MR design used in this study was shown in Figure S1 [16].

Data source and IV selection

Summary-level data of ILD were obtained from the Finngen cohort (About FinnGen | FinnGen), with a population of 453,733 (5097 cases and 448,636 controls). Summary-level data of depression and anxiety were obtained from the United Kingdom biobank (UK Biobank - UK Biobank), with populations of 462,933 (26,595 cases and 436,338 controls) and 463,010 (1523 cases and 461,487 controls), respectively. p < 5e-06 was set as the threshold for the selection of SNPs. Linkage disequilibrium was assessed according to r2 = 0.001 and kb = 10,000 to ensure the independence of the SNPs. The F-statistic was then calculated to evaluate the strength of SNPs, and only SNPs with F > 10 were eligible for further analyses.

Statistical analyses

Five approaches, including inverse variance weighting (IVW), MR egger, weighted median, simple mode and weighted model, were applied to evaluate the potential causal associations, and the IVW approach was applied as the main approach. MR egger regression and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were performed for the detection of horizonal pleiotropy. The Cochrane Q test was performed for heterogeneity assessment, and leave-one-out analysis was performed to identify potential outliers. All the statistical analyses were conducted via R (version 4.4.1).

Results

Systematic review and meta-analysis

Selection of eligible studies and quality assessments

A total of 3107 records were identified. After duplicate removal, title and abstract screening and full text screening, 35 eligible studies [17–51] were included in this meta-analysis (Figure S2). The baseline characteristics of the eligible studies were shown in Table 1, with all studies reaching moderate to high quality.

Table 1.

Baseline characteristics of eligible studies (n = 35) in this systematic review and meta-analysis.

Author year Continent Study type Number of centers Type of ILD Diagnostic criteria of ILD Diagnostic criteria of depression Diagnostic criteria of anxiety ILD depression (n) ILD anxiety (n) Total ILD (n) Quality
Ortiz [17] Europe Cohort P Multi-center IPF ATS/ERS/JRS/ALAT Doctors or medical records N 18 N 232 7
Lee [18] North America Cohort R Multi-center IPF Doctors or medical records Doctors or medical records N 50 N 389 6
He [19] China Cohort R Single-center IPF ATS/ERS/JRS/ALAT PHQ-9 ≥ 5 GAD-7 ≥ 5 21 14 56 8
Chenivesse [20] Europe Cohort R Single-center IPF and fNSIPs Doctors or medical records HADS-D > 11 HADS-A > 11 31 60 166 7
Chaudhuri [21] Europe Cross-sectional Multi-center CTD-ILD and other ILDs (not IPF) Doctors or medical records Doctors or medical records Doctors or medical records 179 226 1335 6
Mena-Vázquez [22] Europe Cohort P Multi-center CTD-ILD ATS/ERS/JRS/ALAT ICD-10 ICD-10 15 26 110 8
Lee [23] Asia Cohort R Multi-center IPF ICD-10 and RID ICD-10 ICD-10 3142 4238 21,111 7
Edwards [24] Europe Cohort R Single-center IPF Doctors or medical records HADS-D ≥ 11 HADS-A ≥ 11 39 37 235 6
Prior [25] Europe Cohort R Multi-center unclassifiable ILD Doctors or medical records Doctors or medical records N 19 N 249 7
Prasad [26] Oceania Cohort P Single-center IPF ATS/ERS/JRS/ALAT HADS-D N 16 N 54 7
Nasser [27] Europe Cohort R Multi-center PF-ILD other than IPF ICD-10 Doctors or medical records N 2953 N 14,413 7
Kelly [28] North America Cohort R Multi-center IPF ICD-9/ICD-10 ICD-9/ICD-10 N 573 N 2913 7
Davidsen 2021 [29] Europe Cohort P Multi-center CTD-ILD Doctors or medical records Doctors or medical records N 182 N 805 5
Bloem [30] Europe Cross-sectional Single-center IPF and Sarcoidosis medical records HADS-D ≥ 11 HADS-A ≥ 11 10 12 121 6
Tzouvelekis [31] Europe Cross-sectional Single-center IPF ATS/ERS/JRS/ALAT BDI-II > 13 N 42 N 98 5
Shen [32] Asia Cross-sectional Single-center IPF, CTD-ILD and others ATS/ERS/JRS/ALAT HADS-D > 8 HADS-A > 8 20 19 63 7
Leuschner [33] Europe Cohort R Multi-center IPF ATS/ERS/JRS/ALAT WHO-5 Well-Being Index WHO-5 Well-Being Index 57 38 1009 8
Hur [34] North America Cohort P Multi-center All fibrotic ILDs without systemic disease Doctors or medical records HADS-D ≥ 8 HADS-A ≥ 8 21 24 111 7
Frank [35] Europe Cross-sectional Multi-center IPF and Sarcoidosis ICD-10 ICD-10 N 4635 N 23,559 7
Cho [36] Oceania Cross-sectional Single-center N Doctors or medical records HADS-D ≥ 8 HADS-A ≥ 8 33 34 101 6
Ungprasert [37] North America Cohort R Multi-center Sarcoidosis Doctors or medical records Doctors or medical records N 38 N 148 5
Matsuda [38] Asia Cross-sectional Single-center IPF ATS/ERS/JRS/ALAT HADS-D ≥ 8 HADS-A ≥ 8 27 26 121 6
Lee [39] Asia Cohort P Single-center IPF ATS/ERS/JRS/ALAT HADS-D ≥ 8 HADS-A ≥ 8 29 24 112 8
Glaspole [40] Oceania Cohort P Multi-center IPF Doctors or medical records HADS-D ≥ 11 HADS-A ≥ 11 45 55 417 (depression), 408 (anxiety) 7
Atkins [41] North America Cross-sectional Single-center IPF and Sarcoidosis ATS/ERS/JRS/ALAT; histological evidence HADS-D ≥ 8 HADS-A ≥ 8 31 49 150 6
Ahmadi[42] Europe Cohort P Multi-center Most IPF Doctors or medical records N Doctors or medical records N 138 208 6
Ryerson [43] North America Cohort P Multi-center IPF and other ILD ATS/ERS/JRS/ALAT Geriatric Depression Scale N 28 N 54 6
Hyldgaard [44] Europe Cohort R Single-center IPF ATS/ERS/JRS/ALAT Doctors or medical records N 8 N 121 5
Holland [45] Oceania Cohort R Single-center IPF, CTD-ILD, others Doctors or medical records HADS-D ≥ 11 N 9 15 124 6
de Boer [46] Oceania Cross-sectional Single-center Sarcoidosis Doctors or medical records HADS-D ≥ 8 HADS-A ≥ 8 6 14 56 6
Wallaert [47] Europe Cohort R Single-center IPF, NSIP ATS/ERS/JRS/ALAT HADS-D ≥ 8 HADS-A ≥ 8 14 27 50 8
Kleijn [48] Europe Cross-sectional Single-center Sarcoidosis World Association of Sarcoidosis and Other Granulomatous Disorders guidelines CESD-10 ≥ 16 Stateand Trait Anxiety Inventory≥40 102 128 274 6
Balaji [49] Asia Cross-sectional Single-center Sarcoidosis Pathology HDRS ≥ 7 N 38 N 148 5
Goracci [50] Europe Cross-sectional Single-center Sarcoidosis Biopsy and ATS/ERS guidelines DSM-IV DSM-IV 20 4 80 6
Chang [51] North America Cross-sectional Multi-center Sarcoidosis Doctors or medical records CESD-10 ≥ 9 N 110 N 154 7
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ILD interstitial lung disease, P prospective, R retrospective, IPF idiopathic pulmonary fibrosis, ATS American Thoracic Society, ERS European Respiratory Society, JRS Japanese Respiratory Society, ALAT Latin American Thoracic Society, PHQ-9 patient health questionnaire-9, GAD-7 generalized anxiety disorder-7, fNSIPs fibrotic non-specific interstitial pneumonia, HADS-D hospital anxiety and depression Scale-depression, HADS-A hospital anxiety and depression Scale-anxiety, CTD connective tissue disease, ICD international classification of diseases, RID Rare Intractable Diseases, CESD-10 center for epidemiologic studies depression Scale-10, HDRS Hamilton depression rating scale, DSM the diagnostic and statistical manual of mental disorders.

Prevalence of depression and anxiety in ILD patients

Among 35 eligible studies, 34 reported the prevalence of depression in patients with ILD [17–41, 43–51], and 21 reported the prevalence of anxiety in patients with ILD [19–24, 30, 32–34, 36, 38–42, 45–48, 50]. The pooled prevalence of depression and anxiety in patients with ILD reached 22% (95% CI 17%, 26%, I2 = 97%) and 25% (95% CI 18%, 32%, I2 = 98%), respectively (Fig. 1). We then summarized studies with clear diagnoses of specific types of ILD to evaluate the prevalence of depression and anxiety in different ILD subtypes. The prevalence of depression in IPF, CTD-ILD and sarcoidosis patients was 17% (95% CI 13%, 22%). 19% (95% CI 10%, 27%) and 26% (95% CI 14%, 39%), respectively. The prevalence of anxiety in IPF, CTD-ILD and sarcoidosis patients were 18% (95% CI 13%, 23%), 24% (95% CI 16%, 33%) and 25% (95% CI 9%, 40%), respectively (Fig. 2). No significant difference was observed in the prevalence of depression (p = 0.41) or anxiety (p = 0.39) among the different subtypes of ILD.

Fig. 1. Prevalence of depression and anxiety in patients with ILD.

Fig. 1

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A Depression in ILD. B Anxiety in ILD. ILD: interstitial lung disease.

Fig. 2. Prevalence of depression and anxiety in patients with different types of ILD.

Fig. 2

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Only studies with clear diagnoses of specific ILD types were analyzed in this part. A Depression in ILD. B Anxiety in ILD. ILD: interstitial lung disease.

Clinical characteristics of ILD patients with depression and anxiety

Compared with ILD patients without depression, ILD patients with depression had a lower BMI (MD −2.11, 95% CI −3.82, −0.41; p = 0.02). No significant differences were observed in age (p = 0.07), DLCO% (p = 0.85), FVC% (p = 0.88), male sex (p = 0.45) or smoking status (p = 0.18) (Table 2). Compared with ILD patients without anxiety, no significant differences were observed in age (p = 0.19), DLCO% (p = 0.93), FVC% (p = 0.33), BMI (p = 0.69), male sex (p = 0.35) or smoking status (p = 0.43).

Table 2.

Clinical characteristics of interstitial lung disease with depression or anxiety compared to those without.

Clinical characteristics OR/MD Studies (n) Participants (n) Effect (95%CI) p I2
Depression
Age MD 3 292 2.03 (−0.15, 4.21) p = 0.07 19%
DLCO% MD 3 292 1.28 (−11.57, 14.13) p = 0.85 63%
FVC% MD 3 292 −0.44 (−6.21, 5.32) p = 0.88 0%
BMI MD 2 180 −2.11 (−3.82, −0.41) p = 0.02 3%
Male sex OR 3 292 0.57 (0.17, 1.85) p = 0.45 51%
Smoking OR 2 168 0.61 (0.30, 1.25) p = 0.18 0%
Anxiety
Age MD 3 290 −1.62 (−4.07, 0.82) p = 0.19 0%
DLCO% MD 3 290 −0.34 (−7.52, 6.83) p = 0.93 49%
FVC% MD 3 290 −5.14 (−15.49, 5.22) p = 0.33 67%
BMI MD 2 180 −0.33 (−1.98, 1.31) p = 0.69 49%
Male sex OR 3 290 0.57 (0.17, 1.85) p = 0.35 51%
Smoking OR 2 168 0.38 (0.04, 4.08) p = 0.43 76%
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OR odds ratio, MD mean difference, DLCO diffusion lung capacity for Carbon Monoxide, FVC forced vital capacity, BMI body mass index.

Sensitivity analyses, subgroup analyses and meta-regression

Results of sensitivity analyses were shown in Figure S3-4, indicating that the prevalence of depression and anxiety remained stable during the leave-one-out process. Subgroup analyses revealed differences in the prevalence of depression in patients with ILD according to study design (p = 0.03), diagnosis of ILD (p = 0.03) and diagnosis of depression (p < 0.01), which may have contributed to the heterogeneity of the results (Table 3). For the prevalence of anxiety in ILD patients, no significant subgroup differences were observed in location (p = 0.54), study design (p = 0.85), number of centers (p = 0.78), diagnosis of ILD (p = 0.34) or diagnosis of anxiety (p = 0.11) (Table 3). According to meta-regression analyses, different factors affected the heterogeneity of depression and anxiety in patients with ILD. GERD was a significant moderator of depression (p = 0.046), whereas both OSA (p = 0.002) and PH (p < 0.001) were significant moderators of anxiety (Table 4).

Table 3.

Subgroup analyses focusing on prevalence of depression and anxiety in interstitial lung disease.

Subgroup Number of studies Prevalence (95 CI%) I2 Subgroup difference (p)
Depression
Location 0.22
Europe 16 0.18 (0.13, 0.23) 98%
North America 7 0.30 (0.13, 0.46) 97%
Asia 5 0.25 (0.19, 0.31) 88%
Oceania 5 0.17 (0.07, 0.28) 88%
Study design 0.03
Prospective cohort 8 0.22 (0.13, 0.31) 93%
Retrospective cohort 13 0.15 (0.11, 0.19) 98%
Cross-sectional 13 0.28 (0.19, 0.37) 96%
Number of centers 0.53
Multi-center 16 0.20 (0.12, 0.28) 98%
Single-center 18 0.23 (0.18, 0.28) 90%
Diagnostic criteria of ILD 0.03
Guidelines 16 0.25 (0.18, 0.31) 95%
Doctors or medical records 14 0.19 (0.10, 0.27) 96%
ICD 4 0.19 (0.16, 0.21) 99%
Diagnostic criteria of depression <0.01
Doctors or medical records 8 0.14 (0.09, 0.18) 96%
HADS-D ≥ 11 5 0.12 (0.08, 0.16) 74%
ICD 4 0.18 (0.15, 0.20) 98%
HADS-D ≥ 8 8 0.23 (0.18, 0.28) 61%
Others 9 0.36 (0.24, 0.48) 98%
Anxiety
Location 0.54
Europe 10 0.28 (0.14, 0.41) 99%
North America 2 0.27 (0.16, 0.38) 75%
Asia 5 0.21 (0.19, 0.23) 0%
Oceania 4 0.20 (0.10, 0.30) 85%
Study design 0.85
Prospective cohort 5 0.29 (0.11, 0.48) 98%
Retrospective cohort 7 0.23 (0.11, 0.35) 99%
Cross-sectional 9 0.24 (0.16, 0.33) 95%
Number of centers 0.78
Multi-center 7 0.24 (0.09, 0.38) 99%
Single-center 14 0.26 (0.19, 0.33) 94%
Diagnostic criteria of ILD 0.34
Guidelines 10 0.26 (0.16, 0.36) 98%
Doctors or medical records 10 0.25 (0.14, 0.36) 97%
ICD 1 0.20 (0.20, 0.21) N
Diagnostic criteria of anxiety 0.11
Doctors or medical records 3 0.29 (0.00, 0.66) 100%
HADS-A ≥ 11 4 0.19 (0.07, 0.30) 92%
ICD 2 0.20 (0.20, 0.21) 0%
HADS-A ≥ 8 8 0.29 (0.23, 0.36) 72%
Others 4 0.22 (0.04, 0.40) 98%
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ILD interstitial lung disease, ICD international classification of diseases, HADS-D hospital anxiety and depression Scale-depression, HADS-A hospital anxiety and depression Scale-anxiety.

Table 4.

Meta-regression of depression and anxiety in interstitial lung disease.

Variables Number of studies Coefficient Standard error z p Lower 95% CI Upper 95% CI
Depression
Age 25 −0.003 0.002 −1.399 0.162 −0.008 0.001
Male proportion 27 −0.0005 0.0006 −0.792 0.428 −0.002 0.001
BMI 16 −0.017 0.013 −1.334 0.182 −0.042 0.008
FEV1% 9 −0.002 0.005 −0.280 0.780 −0.012 0.009
FVC% 18 0.0002 0.003 0.077 0.938 −0.006 0.006
FEV1/FVC 3 −0.009 0.011 −0.764 0.445 −0.030 0.013
Smoking 13 −0.114 0.455 −0.250 0.803 −1.005 0.778
DLCO% 14 0.002 0.003 0.697 0.486 −0.003 0.007
6MWD 9 −0.0004 0.001 −0.510 0.610 −0.002 0.001
GERD 10 0.164 0.082 1.994 0.046 0.003 0.325
OSA 7 0.438 0.283 1.549 0.121 −0.116 0.992
PH 9 0.315 0.331 0.952 0.341 −0.333 0.963
COPD 8 0.113 0.069 1.641 0.101 −0.022 0.247
CAD 12 0.146 0.197 0.738 0.460 −0.241 0.532
Cancer 4 −0.113 0.398 −0.282 0.778 −0.893 0.668
Hypertension 11 0.116 0.087 1.341 0.180 −0.054 0.286
Diabetes 13 0.183 0.173 1.056 0.291 −0.156 0.522
Anxiety
Age 17 −0.001 0.004 −0.226 0.821 −0.010 0.008
Male proportion 17 −0.002 0.002 −1.067 0.286 −0.007 0.002
BMI 13 0.002 0.021 0.075 0.940 −0.039 0.042
FEV1% 8 −0.005 0.007 −0.656 0.512 −0.019 0.009
FVC% 14 0.002 0.004 0.688 0.492 −0.005 0.010
FEV1/FVC 3 −0.008 0.011 −0.720 0.471 −0.029 0.013
Smoking 10 −0.093 0.356 −0.262 0.793 −0.791 0.604
DLCO% 10 0.001 0.003 0.399 0.690 −0.005 0.007
6MWD 5 −0.001 0.001 −1.039 0.299 −0.002 0.001
GERD 3 0.086 0.062 1.392 0.164 −0.035 0.208
OSA 3 −2.264 0.748 −3.027 0.002 −3.730 −0.798
PH 4 −1.152 0.342 −3.372 <0.001 −1.821 −0.482
COPD 5 0.073 0.131 0.557 0.578 −0.184 0.330
CAD 7 −0.078 0.520 −0.150 0.881 −1.098 0.942
Hypertension 5 0.250 0.195 1.286 0.199 −0.131 0.632
Diabetes 6 −0.022 0.480 −0.045 0.964 −0.962 1.060
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BMI body mass index, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, DLCO diffusion lung capacity for Carbon Monoxide, 6MWD 6 min walk distance, GERD gastro-esophageal reflux disease, OSA obstructive sleep apnea, PH pulmonary hypertension, COPD chronic obstructive pulmonary disease, CAD coronary artery disease.

Mendelian randomization

A total of 13 SNPs were selected for the ILD-depression association (Tables S2), and 4 SNPs were selected for the ILD-anxiety association (Table S3). Results of IVW method suggested that no causal association was observed in both ILD-anxiety (OR 1.000 95% CI 0.998, 1.002, p = 0.888) or ILD-depression (OR 1.000, 95% CI 0.997, 1.003, p = 0.962), and both were supported by the other four approaches (all p > 0.05) (Fig. 3). Leave-one-out analyses revealed stable results for both the ILD-depression (Figure S5) and the ILD-anxiety (Figure S6) associations. No evidence of heterogeneity or pleiotropy was detected in either association (Table S4-5, all p > 0.05).

Fig. 3. Causal association between ILD and mental disorders.

Fig. 3

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Mendelian randomization of whether ILD causally associated with depression and anxiety.

Discussion

Depression and anxiety have already been shown to be prevalent comorbidities of respiratory diseases [9, 52]. With a total of 35 eligible studies, this systematic review and meta-analysis revealed that the prevalence of depression and anxiety reached 22 and 25% in ILD patients, respectively, which is higher than that reported in the general population [8]. Moreover, the prevalence of depression and anxiety has remained stable across different subtypes of ILD. The results above suggest that mental health should be measured along with routine examinations for patients with ILD, and future studies may focus on the potential effects of psychological interventions for ILD patients with mental disorders. However, the results of MR analysis did not support the causality of either the ILD-depression or the ILD-anxiety associations, suggesting that ILD may be indirectly rather than directly associated with depression and anxiety. Patients with ILD may manifest a constellation of symptoms, including persistent cough, dyspnea upon exertion, and a diminished capacity for physical activity, which may exacerbate their psychological burden and increase the risk of mental disorders [53, 54]. Moreover, hypoxia has been shown to represent a fundamental pathophysiological hallmark of ILD. Severe hypoxia or abnormal hypoxia adaptation may also promote the pathogenesis of depression and anxiety [55–57].

Previous studies have summarized the prevalence of depression and anxiety in patients with multiple respiratory diseases. Xie et al. reported that the prevalence of depression in COPD patients reached 34.5%, which was 3.53 times higher than that in healthy controls [9]. Chang et al. reported that depression and anxiety accounted for 31 and 34%, respectively, of patients with bronchiectasis [58]. Ye et al. reported that the prevalence of anxiety symptoms and anxiety disorders were 32 and 24%, respectively. in patients with asthma [59]. Compared with those of other respiratory diseases, the prevalence of depression and anxiety in patients with ILD seemed lower. Future studies could consider direct comparisons of susceptibility to depression and anxiety between patients with ILD and those with other respiratory diseases.

Results of this study also revealed that, compared with ILD patients without depression, ILD patients with depression had a lower BMI. As low baseline BMI has been identified as a potential risk factor of mortality in patients with ILD, those with low baseline BMI may be associated with worsening disease conditions and increased susceptibility of developing mental disorders [60, 61]. Moreover, different diagnostic criteria of ILD and depression may significantly affect the prevalence of depression in patients with ILD. Further studies with large sample sizes may apply standard diagnostic criteria to reduce potential bias. Additionally, results of the meta-regression suggested that GERD may contribute to the heterogeneity of depression in ILD patients, whereas OSA and PH may contribute to the heterogeneity of anxiety in ILD patients. As GERD, OSA and PH have been shown to be highly prevalent in patients with ILD [4, 5, 62], the intricate connections between different comorbidities and mental health warrant further investigations.

Additionally, few studies have investigated the efficacy of different treatment approaches for ILD patients with mental disorders. A meta-analysis summarized the effect of pulmonary rehabilitation on depressive and anxiety symptoms in ILD patients, which was insufficient to reach a valid conclusion due to small sample size and heterogeneity among studies [52]. Another observational study suggested that short-term application of nintedanib may alleviate anxiety and depression in 56 patients with IPF, which was insufficient to draw a valid conclusion because of the observational design and small sample size [19]. Future prospective studies with large sample sizes are needed to investigate the optimal treatment approaches for ILD patients with depression and anxiety.

We also observed that although not statistically significant, the prevalence of depression and anxiety was greater in patients with sarcoidosis than in those with IPF and CTD-ILD. Patients with pulmonary sarcoidosis may also have other comorbid symptoms, including uveitis, skin lesions and sarcoid arthritis [63]. These concomitant multisystem symptoms may affect patients’ quality of life, thereby exerting a detrimental effect on their mental health. Moreover, some cases of sarcoidosis require differentiation from cancer or tuberculosis, which may increase the risk of depression and anxiety in patients due to additional psychological pressure. However, as no significant difference was observed in this study, further studies are still needed to address this issue.

This study also has several limitations. (1) The substantial heterogeneity observed in the results may introduce bias, as subgroup analyses and meta-regression can only partly explain the source of heterogeneity. (2) Few studies have reported the clinical characteristics of ILD patients with depression or anxiety, making these results less robust. (3) Few studies have reported whether ILD patients with depression or anxiety are associated with poorer survival than those without depression or anxiety, which warrants further investigation. (4) Heterogeneity also exists within different subtypes of ILD. For example, the sarcoid population is highly heterogeneous in terms of organ involvement, symptoms, and therapeutic approaches. Patients with CTD-ILD are also highly heterogeneous due to the presence of multiple subtypes of CTD. Future prospective studies with systematically collected phenotypic and treatment data are warranted to validate our findings across more homogenous subgroups. (5) The number of instrumental variables is relatively small. Only 13 and 4 SNPs were included in the ILD-depression and ILD-anxiety associations, respectively, which may reduce the explained variance in the exposure and increase the risk of weak instrument bias.

Conclusion

The prevalence of depression and anxiety in ILD patients were 22% and 25%, respectively, which remained stable among the different types of ILD. However, no causal associations were observed for either the ILD-depression or the ILD-anxiety relationship. Future prospective studies with large sample sizes are needed to reveal the intricate connections between ILD and mental health.

Supplementary information

Supplementary materials (1,023.6KB, docx)
PRISMA checkliist (32.3KB, docx)

Author contributions

DD and JQ: Conceptualization, Data curation, Methodology and Writing - original draft. ZG, LG, YW, ZC, CW and TY: Data curation and Formal analysis. FL and YS: FL and YS: Conceptualization, Funding acquisition, Resources, Supervision and Writing - review & editing. DD and JQ contributed equally to this work.

Funding

This work was supported by the National Science and Technology Major Project (2025ZD0549201), the National Natural Science Foundation of China (82470062, 82170046, 82100047, and 82300050),1•3•5 Project of State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital of Sichuan University (RHM24207), Program from Science and Technology Department of Sichuan Province (2024NSFSC1522, 2024YFFK0279, 2025ZNSFSC1543), China Postdoctoral Science Foundation (2021M702350). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability

All data are available from the corresponding authors with reasonable request.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Dongru Du, Jiangyue Qin.

Contributor Information

Fengming Luo, Email: fengmingluo@outlook.com.

Yongchun Shen, Email: shen_yongchun@126.com.

Supplementary information

The online version contains supplementary material available at 10.1038/s41398-026-03828-7.

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Associated Data

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Supplementary Materials

Supplementary materials (1,023.6KB, docx)
PRISMA checkliist (32.3KB, docx)

Data Availability Statement

All data are available from the corresponding authors with reasonable request.

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