Statin Treatment and the Risk of Depression

Supplementary material:

Statin treatment and the risk of depression

Ole Köhler-Forsberg MD1,2, Christiane Gasse PhD2,3,4, Liselotte Petersen PhD2,3,4, Andrew A. Nierenberg MD5,6, Ole Mors MD PhD1,2, Søren Dinesen Østergaard MD PhD2,7,8

1 Psychosis Research Unit, Aarhus University Hospital - Risskov, Risskov, Denmark 2 The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark 3 National Centre for Register-based Research, Aarhus University, Aarhus, Denmark 4 Centre for Integrated Register-based Research at Aarhus University (CIRRAU), Aarhus, Denmark 5 Dauten Family Center for Bipolar Treatment Innovation, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA 6 Harvard Medical School, Boston, MA, USA 7 Aarhus Institute of Advanced Studies, Aarhus University, Aarhus, Denmark 8 Department of Affective Disorders, Aarhus University, Aarhus, Denmark

1 Supplementary Table 1. Competing risk analyses of the association between statin use and the six outcomes of interest in the final propensity score matched study population, stratified into users of simvastatin (n=171,407 and n=171,407 non-users) users of atorvastatin (n=12,658 and n=12,658 non-users), and users of all other statins* (n=9,912 and n=9,912 non-users), respectively

N Total N cases (%) Rate per 10,000 person-years HRR 95%-CI Simvastatin Antidepressant prescription1 Non users 171,407 23,105 (13.7) 233.1 1.0 - Statin users 171,407 29,171 (17.1) 297.7 1.34 1.31; 1.37 Prescription for any other drug2 Non users 171,407 164,102 (95.7) 8,423.3 1.0 - Statin users 171,407 168,502 (98.2) 12,715.0 1.36 1.34; 1.38 Depression hospitalization3 Non users 171,407 1,112 (0.7) 9.5 1.0 - Statin users unadjusted 171,407 1,340 (0.8) 11.5 1.24 1.13; 1.35 adjusted4 171,407 1,340 (0.8) 11.5 1.10 1.01; 1.20 Cardiovascular disease5 Non users 171,407 40,664 (23.7) 278.4 1.0 - Statin users 171,407 26,453 (15.4) 244.8 0.92 0.91; 0.93 Cardiovascular mortality5 Non users 171,407 5,499 (3.2) 54.8 1.0 - Statin users 171,407 4,952 (2.9) 50.2 0.92 0.86; 0.97 All-cause mortality Non users 171,407 17,350 (10.1) 161.7 1.0 - Statin users 171,407 15,976 (9.3) 147.8 0.90 0.88; 0.92 Atorvastatin Antidepressant prescription1 Non users 12,658 2,668 (21.3) 240.1 1.0 - Statin users 12,658 3,204 (25.4) 290.5 1.29 1.22; 1.38 Prescription for any other drug2 Non users 12,658 12,345 (97.5) 5,092.8 1.0 - Statin users 12,658 12,508 (98.8) 6,847.0 1.29 1.23; 1.35 Depression hospitalization3 Non users 12,658 133 (1.1) 9.5 1.0 - Statin users unadjusted 12,658 142 (1.1) 10.2 1.05 0.81; 1.37 adjusted4 12,658 142 (1.1) 10.2 0.93 0.72; 1.20 Cardiovascular disease5 Non users 12,658 4,514 (35.7) 274.3 1.0 - Statin users 12,658 3,191 (25.2) 241.2 0.87 0.84; 0.90 Cardiovascular mortality5

2 Non users 12,658 798 (6.3) 74.8 1.0 - Statin users 12,658 748 (5.9) 70.5 0.91 0.85; 0.97 All-cause mortality Non users 12,658 2,483 (19.6) 201.1 1.0 - Statin users 12,658 2,282 (18.0) 182.6 0.90 0.84; 0.96 Other statins Antidepressant prescription1 Non users 9,912 2,290 (23.3) 234.2 1.0 - Statin users 9,912 2,817 (28.4) 291.2 1.30 1.22; 1.39 Prescription for any other drug2 Non users 9,912 9,801 (98.8) 4,180.2 1.0 - Statin users 9,912 9,860 (99.4) 5,261.9 1.23 1.16; 1.30 Depression hospitalization3 Non users 9,912 124 (1.3) 9.9 1.0 - Statin users unadjusted 9,912 147 (1.5) 11.8 1.13 0.85; 1.49 adjusted4 9,912 147 (1.5) 11.8 0.98 0.75; 1.27 Cardiovascular disease5 Non users 9,912 4,389 (44.3) 298.3 1.0 - Statin users 9,912 2,882 (29.1) 245.5 0.80 0.76; 0.83 Cardiovascular mortality5 Non users 9,912 861 (8.7) 79.1 1.0 - Statin users 9,912 776 (7.8) 76.9 0.92 0.81; 0.98 All-cause mortality Non users 9,912 2,377 (24.0) 219.5 1.0 - Statin users 9,912 2,254 (22.7) 205.1 0.91 0.85; 0.97

Abbreviations: HRR = Hazard rate ratio; 95%-CI = 95% confidence interval; n.a. = not available. 1Defined as a first redemption of antidepressant medication (ATC-code: N06A). 2Defined as a prescription for any drug except for cardiovascular drugs (including statins) or antidepressants. 3Defined as a first hospital contact with depression (ICD-10: F32-33). 4The results on depression hospitalization are adjusted for antidepressant use during follow-up. 5Defined by the ICD-10 codes for cardiovascular disease: I00-99.

When adjusting the analyses of the association between statin treatment and antidepressant prescriptions for prior use of anxiolytics and benzodiazepine-like hypnotics, the HRR was reduced from 1.34 (1.31-1.37) to 1.29 (1.27-1.32) in the simvastatin group, from 1.29 (1.22-1.38) to 1.25 (1.17-1.33) in the atorvastatin group and from 1.30 (1.22-1.39) to 1.26 (1.18- 1.35) in the other statins group. When adjusting the analyses of the association between statin treatment and depression diagnosis for prior use of anxiolytics and benzodiazepine-like hypnotics (in addition to adjusting for antidepressant use following statin treatment), the HRR was reduced from 1.10 (1.01-1.20) to 1.09 (1.00-1.20) in the simvastatin group, from 0.93 (0.72-1.20) to 0.85 (0.65-1.10) in the atorvastatin group and from 0.98 (0.75-1.27) to 0.89 (0.66-1.19) in the other statins group.

3 Supplementary Table 2: Competing risk analyses of the association between statin use and the six outcomes of interest among the 3,921 statin users born between 1969 and 1983 and 3,921 propensity score matched non-users

N Total N cases (%) Rate per 10,000 person-years HRR 95%-CI Antidepressant prescription1 Non users 3,921 312 (8.0) 197.3 1.0 - Statin users 3,921 571 (14.6) 382.7 2.00 1.74; 2.30 Prescription for any other drug2 Non users 3,921 3,380 (86.2) 8,087.0 1.0 - Statin users 3,921 3,693 (94.2) 13,950.5 1.79 1.66; 1.93 Depression hospitalization3 Non users 3,921 31 (0.8) 20.3 1.0 - Statin users unadjusted 3,921 60 (1.5) 39.4 1.88 1.22; 2.91 adjusted4 3,921 60 (1.5) 39.4 1.57 1.04; 2.37 Cardiovascular disease5 Non users 3,921 113 (2.9) 67.5 1.0 - Statin users 3,921 72 (1.3) 53.1 0.95 0.91; 1.00 Cardiovascular mortality 5 Non users 3,921 <5 n.a. 1.0 - Statin users 3,921 <5 n.a. n.a. n.a. All-cause mortality Non users 3,921 7 (0.2) 3.1x10-5 1.0 - Statin users 3,921 7 (0.2) 3.1x10-5 1.00 0.35; 2.85

When adjusting the analysis of the association between statin treatment and antidepressant prescriptions for prior use of anxiolytics and benzodiazepine-like hypnotics, the HRR was reduced from 2.00 (1.74-2.30) to 1.91 (1.66-2.20). When adjusting the analyses of the association between statin treatment and depression diagnosis for prior use of anxiolytics and benzodiazepine-like hypnotics (in addition to adjusting for antidepressant use following statin treatment), the HRR was reduced from 1.57 (1.04-2.37) to 1.31 (0.85-2.00).