Association between depression, anxiety, and treatment adherence in patients with diabetic macular edema

Table 1 Baseline demographic and clinical characteristics of study participants, mean ± SD, n (%)

Characteristic	Total (n = 130)	Depression (n = 58)	No depression (n = 72)	P value
Demographics
Age, years	62.4 ± 11.3	60.8 ± 10.9	63.7 ± 11.5	0.142
Men	70 (53.8)	28 (48.3)	42 (58.3)	0.251
Education ≥ 12 years	78 (60.0)	30 (51.7)	48 (66.7)	0.083
Employed	52 (40.0)	18 (31.0)	34 (47.2)	0.059
Married	86 (66.2)	34 (58.6)	52 (72.2)	0.102
Diabetes characteristics
Type 2 diabetes	118 (90.8)	53 (91.4)	65 (90.3)	0.829
Duration, years	14.6 ± 7.2	15.8 ± 7.5	13.6 ± 6.8	0.086
HbA1c	8.2 ± 1.6	8.6 ± 1.7	7.9 ± 1.5	0.013
Diabetic neuropathy	48 (36.9)	28 (48.3)	20 (27.8)	0.016
Diabetic nephropathy	32 (24.6)	19 (32.8)	13 (18.1)	0.049
Ophthalmologic characteristics
BCVA, logMAR	0.48 ± 0.32	0.56 ± 0.34	0.42 ± 0.29	0.012
CST, μm	412 ± 98	428 ± 102	399 ± 93	0.093
Bilateral DME	72 (55.4)	38 (65.5)	34 (47.2)	0.037
Prior anti-VEGF injections	3.2 ± 4.1	3.8 ± 4.5	2.7 ± 3.7	0.134
Psychological measures
PHQ-9 score	7.3 ± 5.8	12.8 ± 4.2	2.9 ± 1.8	< 0.001
GAD-7 score	6.1 ± 5.2	9.4 ± 5.1	3.4 ± 3.2	< 0.001
Adherence measures
MARS-5 score	18.7 ± 3.2	17.2 ± 2.8	21.6 ± 2.9	< 0.001
Appointment adherence	76.4 ± 18.2	68.2 ± 19.3	83.0 ± 14.6	< 0.001

HbA1c: Glycated hemoglobin; BCVA: Best-corrected visual acuity; LogMAR: Logarithm of the minimum angle of resolution; CST: Central subfield thickness; DME: Diabetic macular edema; Anti-VEGF: Anti-vascular endothelial growth factor; PHQ-9: Patient Health Questionnaire-9; GAD-7: Generalized Anxiety Disorder-7; MARS-5: Medication Adherence Report Scale-5.

Table 2 Distribution of depression and anxiety severity among patients with diabetic macular edema, n (%)

Severity category	Depression (PHQ-9)	Anxiety (GAD-7)
Minimal (0-4)	72 (55.4)	81 (62.3)
Mild (5-9)	36 (27.7)	31 (23.8)
Moderate (10-14)	14 (10.8)	12 (9.2)
Moderately severe/severe (≥ 15)	8 (6.2)	6 (4.6)
Clinical threshold (≥ 10)	22 (16.9)	18 (13.8)
Any symptoms (≥ 5)	58 (44.6)	49 (37.7)
Comorbid depression and anxiety	36 (27.7)

PHQ-9: Patient Health Questionnaire-9; GAD-7: Generalized Anxiety Disorder-7.

Table 3 Medication and appointment adherence by psychological status, n (%)

Adherence measure	Depression status			Anxiety status
	Present (n = 58)	Absent (n = 72)	P value	Present (n = 49)	Absent (n = 81)	P value
MARS-5 score
mean ± SD	17.2 ± 2.8	21.6 ± 2.9	< 0.001	17.2 ± 3.1	21.1 ± 2.8	< 0.001
Poor (< 17),	34 (58.6)	22 (30.6)	0.001	28 (57.1)	28 (34.6)	0.011
Moderate (17-22)	18 (31.0)	25 (34.7)		15 (30.6)	28 (34.6)
Good (≥ 23)	6 (10.3)	25 (34.7)		6 (12.2)	25 (30.9)
Appointment adherence
mean ± SD	68.2 ± 19.3	83.0 ± 14.6	< 0.001	69.8 ± 19.8	80.5 ± 16.1	0.001
< 70%	26 (44.8)	16 (22.2)	0.006	24 (49.0)	18 (22.2)	0.001
70%-89%	22 (37.9)	28 (38.9)		16 (32.7)	34 (42.0)
≥ 90%	10 (17.2)	28 (38.9)		9 (18.4)	29 (35.8)
Injection interval consistency
CV of intervals	38.4 ± 12.6	28.2 ± 10.3	< 0.001	36.8 ± 13.2	30.1 ± 11.4	0.003
Reasons for non-adherence
Forgetfulness	42 (72.4)	28 (38.9)	< 0.001	36 (73.5)	34 (42.0)	< 0.001
Cost concerns	22 (37.9)	18 (25.0)	0.111	19 (38.8)	21 (25.9)	0.120
Transportation issues	18 (31.0)	12 (16.7)	0.049	16 (32.7)	14 (17.3)	0.042
Fear of injections	28 (48.3)	14 (19.4)	< 0.001	31 (63.3)	11 (13.6)	< 0.001

CV: Coefficient of variation; MARS-5: Medication Adherence Report Scale-5.

Table 4 Correlation matrix of psychological symptoms, adherence measures, and clinical outcomes

Variable	1	2	3	4	5	6	7
1 PHQ-9 score	1.00
2 GAD-7 score	0.68c	1.00
3 MARS-5 score	-0.42c	-0.35c	1.00
4 Appointment adherence	-0.38c	-0.33c	0.45c	1.00
5 BCVA change (logMAR)	0.28b	0.22a	-0.31c	-0.36c	1.00
6 CST change (μm)	0.24b	0.19a	-0.26b	-0.29c	0.42c	1.00
7 NEI VFQ-25 composite	-0.48c	-0.41c	0.39c	0.43c	-0.52c	-0.38c	1.00

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

PHQ-9: Patient Health Questionnaire-9; GAD-7: Generalized Anxiety Disorder-7; MARS-5: Medication Adherence Report Scale-5; BCVA: Best-corrected visual acuity; CST: Central subfield thickness; NEI VFQ-25: National Eye Institute Visual Function Questionnaire-25; LogMAR: Logarithm of the minimum angle of resolution.

Table 5 Multivariable logistic regression analysis of factors associated with poor medication adherence (Medication Adherence Report Scale-5 < 17)

Variable	Unadjusted OR (95%CI)	P value	Adjusted OR (95%CI)	P value
PHQ-9 ≥ 10	4.28 (2.18-8.42)	< 0.001	3.42 (1.68-6.95)	0.001
GAD-7 ≥ 10	3.65 (1.78-7.48)	< 0.001	2.86 (1.35-6.04)	0.006
Age (per 10 years)	0.82 (0.68-0.98)	0.032	0.88 (0.72-1.08)	0.214
Men	0.76 (0.42-1.38)	0.365	0.82 (0.43-1.56)	0.548
Diabetes duration > 15 years	1.68 (0.92-3.06)	0.092	1.42 (0.74-2.72)	0.292
HbA1c > 8%	2.14 (1.18-3.88)	0.012	1.86 (0.98-3.52)	0.058
Bilateral DME	1.92 (1.06-3.48)	0.032	1.74 (0.92-3.29)	0.089
Low education (< 12 years)	1.78 (0.98-3.24)	0.059	1.65 (0.87-3.14)	0.126
Living alone	2.35 (1.22-4.52)	0.011	2.12 (1.05-4.28)	0.036
> 5 medications daily	1.94 (1.07-3.52)	0.029	1.68 (0.88-3.21)	0.116

OR: Odds ratio; CI: Confidence interval; PHQ-9: Patient Health Questionnaire-9; GAD-7: Generalized Anxiety Disorder-7; DME: Diabetic macular edema; HbA1c: Glycated hemoglobin.

Table 6 National Eye Institute Visual Function Questionnaire-25 scores by depression and anxiety status, mean ± SD

NEI VFQ-25 subscale	Depression status			Anxiety status
	Present (n = 58)	Absent (n =72)	P value	Present (n = 49)	Absent (n = 81)	P value
Composite score	58.3 ± 14.2	72.6 ± 12.8	< 0.001	60.2 ± 14.8	70.8 ± 13.6	< 0.001
General health	42.2 ± 18.6	56.3 ± 19.2	< 0.001	44.4 ± 19.8	54.6 ± 19.3	0.004
General vision	48.6 ± 16.4	62.8 ± 15.2	< 0.001	50.6 ± 17.2	60.8 ± 16.0	0.001
Ocular pain	72.4 ± 20.3	76.0 ± 18.6	0.292	71.9 ± 20.8	75.9 ± 18.6	0.258
Near activities	52.8 ± 18.9	68.4 ± 16.2	< 0.001	54.7 ± 19.2	66.5 ± 17.3	< 0.001
Distance activities	54.3 ± 19.7	70.2 ± 17.3	< 0.001	56.1 ± 20.3	68.4 ± 18.2	< 0.001
Social functioning	56.9 ± 21.4	76.4 ± 18.2	< 0.001	58.7 ± 22.1	74.2 ± 19.6	< 0.001
Mental health	45.3 ± 19.8	68.2 ± 17.4	< 0.001	47.8 ± 20.6	65.4 ± 19.2	< 0.001
Role difficulties	48.7 ± 22.6	69.8 ± 20.3	< 0.001	51.2 ± 23.4	67.3 ± 21.8	< 0.001
Dependency	52.6 ± 23.8	74.3 ± 21.2	< 0.001	54.8 ± 24.6	71.9 ± 22.4	< 0.001
Driving1	58.2 ± 24.3	72.6 ± 21.8	0.002	60.4 ± 24.8	70.8 ± 22.6	0.026
Color vision	68.5 ± 22.1	82.3 ± 18.4	< 0.001	70.4 ± 22.6	80.9 ± 19.2	0.006
Peripheral vision	62.9 ± 21.7	78.5 ± 19.3	< 0.001	64.8 ± 22.3	76.9 ± 20.1	0.002

¹Driving subscale calculated only for patients who reported driving (n = 86).

NEI VFQ-25: National Eye Institute Visual Function Questionnaire-25.

Table 7 Mediation analysis of the relationship between depression/anxiety and visual outcomes

Pathway	Effect	SE	95%CI	P value	Mediated
Depression - BCVA change
Total effect	0.287	0.062	0.165-0.409	< 0.001	-
Direct effect	0.205	0.058	0.091-0.319	< 0.001	71.4%
Indirect effect via MARS-5	0.082	0.026	0.034-0.138	0.002	28.6%
Depression - NEI VFQ-25
Total effect	-14.32	2.48	-19.24 to -9.40	< 0.001	-
Direct effect	-10.68	2.36	-15.36 to -6.00	< 0.001	74.6%
Indirect effect via MARS-5	-3.64	1.12	-5.92 to -1.48	0.001	25.4%
Anxiety - BCVA change
Total effect	0.224	0.058	0.110-0.338	< 0.001	-
Direct effect	0.162	0.054	0.056-0.268	0.003	72.3%
Indirect effect via appointment adherence	0.062	0.022	0.021-0.108	0.004	27.7%

SE: Standard error; CI: Confidence interval; BCVA: Best-corrected visual acuity; MARS-5: Medication Adherence Report Scale-5; NEI VFQ-25: National Eye Institute Visual Function Questionnaire-25.