Use of Antidepressants and Risk of Cutaneous Melanoma: A Prospective Registry-Based Case-Control Study

Figures & data

Table 1 Characteristics of Cases and Controls in the Study Cohort

Characteristics	Cases (n=12,099) No. (%)	Controls (n=118,467) No. (%)
Sex
Men	5985 (49.5)	58,269 (49.2)
Women	6114 (50.5)	60,198 (50.8)
Age at Diagnosis/Index Date, Years
<50	3160 (26.1)	30,319 (25.6)
50–69	5615 (46.4)	55,236 (46.6)
≥70	3324 (27.5)	32,912 (27.8)
Residential Ambient UVR^a Exposure
Low (northern Norway)	716 (5.9)	11,895 (10.0)
Medium (central/western Norway)	1724 (14.3)	19,429 (16.4)
Highest (southern/eastern Norway)	9659 (79.8)	87,143 (73.6)
Parity (Women Only)
No children	1861 (30.4)	18,984 (31.5)
1–3 children	3894 (63.7)	36,901 (61.3)
>3 children	359 (5.9)	4313 (7.2)
Tumor Site
Head/neck	1314 (10.9)	-
Trunk	5657 (46.7)	-
Upper limb	1559 (12.9)	-
Lower limb	2867 (23.7)	-
Other sites	52 (0.4)	-
Unspecified site	650 (5.4)	-
Histological Type
Superficial spreading melanoma	6654 (55.0)	-
Nodular melanoma	2076 (17.2)	-
Other	3369 (27.8)	-
Clinical Stage
Local disease	9828 (81.2)	-
Regional metastasis	572 (4.7)	-
Distant metastasis	635 (5.3)	-
Unspecified	1064 (8.8)	-
Use of Antidepressants
I. Number of Prescriptions
≤1	10,597 (87.6)	102,154 (86.2)
2–7	663 (5.5)	6612 (5.6)
≥8	839 (6.9)	9701 (8.2)
II. By Antidepressant Classes
Non-user^b	10,185 (84.2)	97,823 (82.6)
SSRI^c	699 (5.8)	7358 (6.2)
TCA^d	375 (3.1)	3749 (3.2)
Other^e	317 (2.6)	3486 (2.9)
Mixed^f	523 (4.3)	6051 (5.1)
III. By Cumulative Dose, DDD^g
0	10,185 (84.2)	97,823 (82.6)
1–91	524 (4.3)	5630 (4.8)
92–365	454 (3.8)	4764 (4.0)
366–1460	508 (4.2)	5239 (4.4)
≥1461	428 (3.5)	5011 (4.2)
Ever Use of Other Drugs
Immunosuppressant drugs^h	1862 (15.4)	18,511 (15.6)
Cardiovascular drugs^h	5951 (49.2)	57,264 (48.3)
Other drugs^i	5379 (44.5)	53,033 (44.8)

Notes: ^aUltraviolet radiation; ^b0 prescription; ^cSelective serotonin reuptake inhibitors (N06AB); ^dTricyclic antidepressants (N06AA); ^eOther antidepressants (N06AF, N06AG and N06AX); ^fUse of more than one class of antidepressants; ^gDefined daily dose; ^hIncludes mixed use with other drugs; ⁱIncludes use of other drugs than immunosuppressant or cardiovascular drugs.

Table 2 Rate Ratios (RRs) with 95% Confidence Intervals (CIs) for Melanoma Incidence by Number of Prescriptions of Antidepressants Overall and Stratified by Class of Antidepressants

Number of Prescriptions	No. Case/Controls	RR (95% CI)^a	Ptrend^f
Overall
≤1	10,597/102,154	1.00 (reference)
2–7	663/6612	0.94 (0.87, 1.03)
≥8	839/9701	0.81 (0.75, 0.87)	<0.001
By Antidepressant Classes
SSRI^b
≤1	4736/45,455	1.00 (reference)
≥8	289/3280	0.82 (0.73, 0.93)	0.003
TCA^c
≤1	2782/26,637	1.00 (reference)
≥8	107/1100	0.90 (0.73, 1.10)	0.295
Other^d
≤1	2679/25,576	1.00 (reference)
≥8	84/967	0.81 (0.65, 1.02)	0.036
Mixed^e
≤1	3838/36,528	1.00 (reference)
≥8	359/4354	0.77 (0.69, 0.86)	<0.001

Notes: ^aAdjusted for sex and birth year (by design) and ever use of other drugs and residential ambient ultraviolet radiation; ^bSelective serotonin reuptake inhibitors (N06AB); ^cTricyclic antidepressants (N06AA); ^dOther antidepressants (N06AF, N06AG and N06AX); ^e Use of more than one class of antidepressants; ^fTrend test uses the median number of prescriptions for all prescription categories (≤1; 2−7; ≥8).

Table 3 Rate Ratios (RRs) with 95% Confidence Intervals (CIs) for Melanoma Incidence by Quartiles (Q) of Cumulative Defined Daily Dose (DDD) of Antidepressants Overall and Stratified by Class of Antidepressants

Cumulative Dose, DDD	No. Case/Controls	RR (95% CI)^a	Ptrend^f
Overall
0	10,185/97,823	1.15 (1.04, 1.26)
Q1 (DDD 1–91)	524/5630	1 (Reference)
Q2 (DDD 92–365)	454/4764	1.03 (0.90, 1.17)
Q3 (DDD 366–1460)	508/5239	1.04 (0.91, 1.18)
Q4 (DDD ≥1461)	428/5011	0.91 (0.80, 1.04)	<0.001
By Antidepressant Classes
SSRI^b
0	4617/44,077	1.24 (0.99, 1.55)
Q1 (DDD 1–91)	88/1030	1 (Reference)
Q2 (DDD 92–365)	210/2171	1.12 (0.86, 1.46)
Q3 (DDD 366–1460)	237/2227	1.23 (0.95, 1.59)
Q4 (DDD ≥1461)	164/1930	0.99 (0.75, 1.28)	0.007
TCA^c
0	2628/25,104	1.08 (0.94, 1.23)
Q1 (DDD 1–91)	242/2432	1 (Reference)
Q2 (DDD 92–365)	57/619	0.92 (0.68, 1.25)
Q3 (DDD 366–1460)	60/550	1.09 (0.81, 1.47)
Q4 (DDD ≥1461)	16/148	1.07 (0.62, 1.83)	0.906
Other^d
0	2540/24,156	1.11 (0.94, 1.31)
Q1 (DDD 1–91)	164/1714	1 (Reference)
Q2 (DDD 92–365)	60/781	0.79 (0.58, 1.07)
Q3 (DDD 366–1460)	56/555	1.05 (0.76, 1.46)
Q4 (DDD ≥1461)	37/436	0.87 (0.60, 1.27)	0.077
Mixed^e
0	3838/36,528	1.69 (1.16, 2.45)
Q1 (DDD 1–91)	30/454	1 (Reference)
Q2 (DDD 92–365)	127/1193	1.65 (1.09, 2.50)
Q3 (DDD 366–1460)	155/1907	1.28 (0.85, 1.92)
Q4 (DDD ≥1461)	211/2497	1.33 (0.89, 1.98)	0.103

Notes: ^aAdjusted for sex and birth year (by design) and ever use of other drugs and residential ambient ultraviolet radiation; ^bSelective serotonin reuptake inhibitors (N06AB); ^cTricyclic antidepressants (N06AA); ^dOther antidepressants (N06AF, N06AG and N06AX); ^eUse of more than one class of antidepressants; ^fTrend test uses the median defined daily dosage for all quartiles (0; 1-91; 92-365; 366-1460; ≥1461).

Table 4 Rate Ratios (RRs) with 95% Confidence Intervals (CIs) of Melanoma Incidence for ≥8 Prescriptions of Antidepressants versus ≤1 Prescription, Stratified by Tumor Site, Histological Type, and Clinical Stage at Diagnosis

	No. Case/Controls	≥8 Prescriptions vs ≤1 Prescription
		RR (95% CI)^a	Ptrend^e
Tumor Site
Head/neck	1314/12,818	0.93 (0.75, 1.15)	0.468
Trunk	5657/55,032	0.79 (0.70, 0.88)	<0.001
Upper limb	1559/15,181	0.80 (0.66, 0.97)	0.022
Lower limb	2867/27,962	0.76 (0.65, 0.88)	<0.001
Other	52/511	0.99 (0.37, 2.64)	0.997
Unspecified	650/6354	1.07 (0.79, 1.45)	0.780
Histological Type
SSM^b	6654/64,763	0.80 (0.73, 0.89)	<0.001
NM^c	2076/20,282	0.80 (0.67, 0.96)	0.017
Other^d	3369/32,813	0.83 (0.72, 0.96)	0.013
Clinical Stage
Local disease	9828/95,725	0.79 (0.73, 0.86)	<0.001
Regional metastasis	572/5569	0.89 (0.64, 1.24)	0.438
Distant metastasis	635/6209	0.91 (0.65, 1.27)	0.559
Unspecified	1064/10,328	0.98 (0.75, 1.28)	0.982

Notes: ^aAdjusted for sex and age (by design), ever use of other drugs, and residential ambient ultraviolet radiation; ^bSuperficial spreading melanoma; ^cNodular melanoma; ^dIncludes all other histological types; ^eTrend test uses the median number of prescriptions in all three prescription categories (≤1; 2−7; ≥8).

Table 5 Rate Ratios (RRs) with 95% Confidence Intervals (CIs) of Melanoma Incidence for ≥8 Prescriptions of Antidepressants versus ≤1 Prescription, Stratified by Sex, Age at Diagnosis/Index Date and Residential Ambient Ultraviolet Radiation (UVR) Exposure

Variables	≥8 Prescriptions vs ≤1 Prescription
	RR (95% CI)	Ptrend^d
Sex^a
Men	0.73 (0.64, 0.83)	<0.001
Women	0.86 (0.78, 0.94)	<0.001
Pinteraction	0.029
Age at Diagnosis/Index Date^b, Years
<50	0.99 (0.84, 1.16)	0.877
50–69	0.76 (0.68, 0.85)	<0.001
≥70	0.79 (0.69, 0.90)	<0.001
Pinteraction	0.013
Residential Ambient UVR Exposure^c
Low (northern Norway)	1.12 (0.67, 1.86)	0.600
Medium (central/western Norway)	0.73 (0.55, 0.95)	0.019
Highest (southern/eastern Norway)	0.82 (0.75, 0.89)	<0.001
Pinteraction	0.379

Notes: ^aAdjusted for age (by design), ever use of other drugs and residential ambient UVR exposure; ^bAdjusted for sex (by design) ever use of other drugs and residential ambient UVR; ^cAdjusted for sex and age (by design) and ever use of other drugs; ^dTrend test uses the median number of prescriptions in all three prescription categories (≤1; 2−7; ≥8).