Baseline characteristics of participants
Table 1 presents baseline characteristics of the study participants. The mean age of 397 participants was 63.3 ± 7.1 years and mean BMI was 29.6 ± 4.9. Of them, 196 (49.4%) participants were female and 201 (50.6%) were allocated to the treatment group. At baseline, 296 (74.6%) participants were identified as not suffering from depression, 70 (17.6%) were identified as suffering from mild depression, and 31 (7.8%) were identified as suffering from moderate to severe depression. The presence of any depression in this study was 25.4% (according to the PHQ-9), 5.8% participants had self-reported depression and 4.3% used anti-depressant medications.
Table 1. Baseline characteristics of participants (N= 397)
|
Mean/ Numbers
|
SD/ Percentage
|
Age (years)
|
63.3
|
7.1
|
Female sex (n, %)
|
193
|
48.6
|
Body mass index (kg/m2)
|
29.6
|
4.9
|
Serum 25-(OH)D levels (nmol/L)
|
43.7
|
12.2
|
Treatment group (n, %)
|
201
|
50.6
|
PHQ-9 score
|
|
|
0-4
|
296
|
74.6
|
5-9
|
70
|
17.6
|
≥ 10
|
31
|
7.8
|
Anti-depressant medication use (n, %)
|
17
|
4.3
|
Education
|
|
|
School only (n, %)
|
49
|
12.4
|
High school (n, %)
|
96
|
24.4
|
University or higher (n, %)
|
249
|
63.2
|
Work status
|
|
|
Full-time employed (n, %)
|
114
|
28.9
|
Part-time/causal employment (n, %)
|
83
|
21.0
|
Unemployed/home duties/retired (n, %)
|
198
|
50.1
|
Work type
|
|
|
Manual (n, %)
|
128
|
32.8
|
Office/professional (n, %)
|
262
|
67.2
|
WOMAC score
|
|
|
Pain (0-500)
|
136.4
|
87.0
|
Function (0-1700)
|
477.9
|
30.9
|
Stiffness (0-200)
|
62.0
|
40.7
|
Multi-site joint pain, (n, %)
|
|
|
No pain
|
240
|
60.5
|
One site
|
133
|
33.5
|
More than one site
|
24
|
6.0
|
Comorbidity, (n, %)
|
|
|
No comorbidity
|
162
|
40.8
|
One comorbidity
|
221
|
55.7
|
More than one comorbidity
|
14
|
3.5
|
PHQ-9, patient health questionnaire depression scale; WOMAC, Western Ontario and McMaster Universities Arthritis Index.
Factors associated with the presence of depression
As shown in Table 2, being younger, female, and having a higher BMI, greater scores of WOMAC pain (Figure 1A), WOMAC function (Figure 1B) and WOMAC stiffness, a lower education level, and more than one comorbidity were significantly associated with a higher presence of depression in univariable analyses. After adjustment for age, sex, BMI and baseline 25-(OH)D level, the associations persisted except for female sex, which was no longer statistically significant. Having two or more sites of pain was significantly associated with a higher presence of depression in multivariable analyses. Age was not significantly associated with the presence of depression in either univariable or multivariable analysis. Results were similar, when self-reported depression was used as the outcome or if the analyses were adjusted for anti-depressant medication use (data not shown).
Table 2. Factors associated with the prevalence of mild to severe depression at baseline (N= 397)
|
Univariable
|
Multivariable*
|
PR (95% CI)
|
PR (95% CI)
|
Age (years)
|
0.96 (0.94, 0.99)
|
0.96 (0.94, 0.99)
|
Female sex (n, %)
|
1.55 (1.10, 2.18)
|
1.38 (0.98, 1.96)
|
BMI (kg/m2)
|
1.05 (1.02, 1.09)
|
1.05 (1.02, 1.08)
|
Education
|
|
|
School only (n, %)
|
Reference
|
Reference
|
High school (n, %)
|
0.63 (0.40, 1.00)
|
0.61 (0.39, 0.95)
|
University or higher (n, %)
|
0.49 (0.33, 0.73)
|
0.50 (0.34, 0.74)
|
Work status
|
|
|
Full-time employed (n, %)
|
Reference
|
Reference
|
Part-time/causal employment (n, %)
|
0.80 (0.49, 1.29)
|
0.78 (0.49, 1.25)
|
Unemployed/home duties/retired (n, %)
|
0.84 (0.57, 1.22)
|
1.10 (0.71, 1.70)
|
Work type
|
|
|
Manual (n, %)
|
Reference
|
Reference
|
Office/professional (n, %)
|
0.88 (0.62, 1.25)
|
0.85 (0.60, 1.22)
|
WOMAC score/ 10 unit
|
|
|
Pain (0-50)
|
1.05 (1.03, 1.07)
|
1.05 (1.03, 1.07)
|
Function (0-170)
|
1.02 (1.01, 1.02)
|
1.02 (1.01, 1.02)
|
Stiffness (0-20)
|
1.08 (1.04, 1.12)
|
1.05 (1.02, 1.09)
|
Multi-site joint pain, (n, %)
|
|
|
No pain
|
Reference
|
Reference
|
One site
|
1.21 (0.85, 1.74)
|
1.06 (0.75, 1.51)
|
More than one site
|
1.64 (0.93, 2.88)
|
1.73 (1.00, 2.98)
|
Comorbidity, (n, %)
|
|
|
No comorbidity
|
Reference
|
Reference
|
One comorbidity
|
1.08 (0.75, 1.55)
|
1.14 (0.80, 1.65)
|
More than one comorbidity
|
2.13 (1.18, 3.86)
|
1.98 (1.03, 3.80)
|
* All multivariable analyses were adjusted for age, sex, BMI and baseline 25-(OH)D level, except for age (adjusted for sex, BMI and baseline 25-(OH)D level), sex (adjusted for age, BMI and baseline 25-(OH)D level) and BMI (adjusted for age, sex and baseline 25-(OH)D level).
Mild to severe depression was defined as PHQ-9 scores ≥ 5.
Factors associated with incident depression
340 participants completed the follow-up. 28 out of 249 participants (11.2%) without depression at baseline had incident mild to severe depression at 24 months. Table 3 shows the factors associated with incident depression. Being female and having a higher WOMAC pain (Figure 1C) and WOMAC function (Figure 1D) score were significantly associated with greater incident depression over 24 months in univariable and multivariable analyses. The presence and incidence of depression were higher in females than in males (31.1% vs 20.1%, p=0.01 for presence, and 27.3% vs 16.5%, p=0.02 for incidence). Having two or more painful sites was significantly associated with greater incident depression over 24 months in the multivariable analyses. In a sensitivity analysis further adjusting for anti-depressant medication, the results were largely unchanged (data not shown). In contrast, there were no significant associations between age, BMI, education, WOMAC stiffness, comorbidity and incident depression.
Table 3. Factors associated with the incidence of mild to severe depression at 24 months amongst participants without depression at baseline (N= 249)
|
Univariable
|
Multivariable*
|
RR (95% CI)
|
RR (95% CI)
|
Age (years)
|
0.98 (0.94, 1.03)
|
1.00 (0.95, 1.04)
|
Female sex (n, %)
|
2.47 (1.19, 5.13)
|
2.51 (1.17, 5.37)
|
Body mass index (kg/m2)
|
1.00 (0.92, 1.09)
|
1.01 (0.93, 1.09)
|
Education
|
|
|
School only (n, %)
|
Reference
|
Reference
|
High school (n, %)
|
0.82 (0.23, 2.88)
|
0.68 (0.20, 2.27)
|
University or higher (n, %)
|
0.75 (0.24, 2.34)
|
0.68 (0.23, 1.98)
|
Work status
|
|
|
Full-time employed (n, %)
|
Reference
|
Reference
|
Part-time/causal employment (n, %)
|
0.85 (0.29, 2.55)
|
0.74 (0.25, 2.18)
|
Unemployed/home duties/retired (n, %)
|
1.22 (0.53, 2.81)
|
1.40 (0.54, 3.67)
|
Work type
|
|
|
Manual (n, %)
|
Reference
|
Reference
|
Office/professional (n, %)
|
0.83 (0.40, 1.72)
|
0.68 (0.33, 1.38)
|
WOMAC score/ 10 unit
|
|
|
Pain (0-50)
|
1.05 (1.01, 1.09)
|
1.05 (1.02, 1.09)
|
Function (0-170)
|
1.01 (1.01, 1.03)
|
1.02 (1.01, 1.03)
|
Stiffness (0-20)
|
1.03 (0.95, 1.12)
|
1.03 (0.95, 1.11)
|
Multi-site joint pain, (n, %)
|
|
|
No pain
|
Reference
|
Reference
|
One site
|
1.43 (0.68, 3.01)
|
1.22 (0.58, 2.57)
|
More than one site
|
2.73 (0.91, 8.22)
|
3.55 (1.31, 9.58)
|
Comorbidity, (n, %)
|
|
|
No comorbidity
|
Reference
|
Reference
|
One comorbidity
|
1.02 (0.50, 2.08)
|
1.13 (0.54, 2.38)
|
More than one comorbidity
|
1.51 (0.23, 9.83)
|
1.34 (0.21, 8.66)
|
* All multivariable analyses were adjusted for age, sex, BMI, baseline 25-(OH)D level, and intervention, except for age (adjusted for sex, BMI baseline 25-(OH)D level and intervention), sex (adjusted for age, BMI, baseline 25-(OH)D level and intervention) and BMI (adjusted for age, sex, baseline 25-(OH)D level and intervention).
Mild to severe depression was defined as PHQ-9 scores ≥ 5.
Temporal relationship between baseline depression severity and changes in joint symptoms overtime
Table 4 describes the longitudinal association of baseline depression with changes in knee joint symptoms over 24 months. Although participants with mild to severe depression had greater decreases in WOMAC symptoms compared to participants without depression at baseline in the univariable analyses, the significant associations disappeared in the multivariable analyses. In addition, the results were consistent when either self-reported depression at baseline was used as the exposure or if the analyses were adjusted for anti-depressant medication use (data not shown). When considering the potential modification effect of treatment, the associations were examined separately for treatment and placebo groups. The results remained largely unchanged, except for the negative association between baseline depression and change in knee pain in the treatment group (Supplementary Table 1 and 2). Participants with mild or moderate/severe depression had significant decreases in WOMAC pain score in the treatment group, while participants with mild or moderate/severe depression had non-significant increases in WOMAC pain score in the placebo group. Similar trends were observed for change in WOMAC function and stiffness.
Table 4. The association between depression severity at baseline and change in joint symptom over 24 months (N= 337)
|
Univariable
β (95% CI)
|
Multivariable
β (95% CI)
|
WOMAC score
|
|
|
Pain (0-500) †
|
|
|
No depression
|
Reference
|
Reference
|
Mild depression
|
-35.8 (-63.7, -7.9)
|
-12.4 (-36.7, 11.8)
|
Moderate to severe depression
|
-100.3 (-143.1, -57.4)
|
-32.0 (-72.2, 8.2)
|
Function (0-1700) ‡
|
|
|
No depression
|
Reference
|
Reference
|
Mild depression
|
-139.9 (-222.2, -57.7)
|
-67.8 (-145.4, 9.7)
|
Moderate to severe depression
|
-225.4 (-357.5, -93.2)
|
-90.3 (-220.3, 39.7)
|
Stiffness (0-200) §
|
|
|
No depression
|
Reference
|
Reference
|
Mild depression
|
-13.2 (-26.0, -0.5)
|
-5.2 (-16.5, 6.1)
|
Moderate to severe depression
|
-29.4 (-49.0, -9.8)
|
-11.8 (-30.0, 6.5)
|
† Multivariable analysis was adjusted for age, sex, BMI, baseline 25-(OH)D level, treatment arm and baseline WOMAC pain score.
‡ Multivariable analysis was adjusted for age, sex, BMI, baseline 25-(OH)D level, treatment arm and baseline WOMAC function score.
§ Multivariable analysis was adjusted for age, sex, BMI, baseline 25-(OH)D level, treatment arm and baseline WOMAC stiffness score.