Associations of Benzodiazepines, Z-Drugs, and Other Anxiolytics With Subsequent Dementia in Patients With Affective Disorders: A Nationwide Cohort and Nested Case-Control Study
Abstract
Objective:
Methods:
Results:
Conclusions:
Methods
Study Population and Follow-Up
Outcome Definition
Exposure Definition (Benzodiazepines and Related Drugs)
Covariates
Statistical Analysis
Sensitivity Analysis
Results
Total Cohort | Case Subjects With Dementia | Density-Sampled Control Subjects | ||||
---|---|---|---|---|---|---|
Characteristic | N | % | N | % | N | % |
235,465 | 9,776 | 39,104 | ||||
Female | 144,002 | 61.2 | 6,414 | 65.6 | 26,883 | 68.8 |
Marital status at baseline | ||||||
Unmarried | 75,449 | 32.0 | 657 | 6.7 | 2,988 | 7.7 |
Married | 92,504 | 39.3 | 4,106 | 42.1 | 17,075 | 43.8 |
Divorced | 33,687 | 14.3 | 1,278 | 13.1 | 5169 | 13.3 |
Widowed | 32,048 | 13.6 | 3,716 | 38.1 | 13,774 | 35.3 |
Unknown | 1,777 | 0.8 | 19 | 0.2 | 58 | 0.4 |
Educational level at baseline | ||||||
Primary only (0–7 years of school) | 88,226 | 37.5 | 4,191 | 42.8 | 16,973 | 43.3 |
Middle school | 88,724 | 37.7 | 2,450 | 25.1 | 10,281 | 26.3 |
High school | 34,339 | 14.6 | 926 | 9.5 | 4,142 | 10.6 |
Unknown | 24,176 | 10.3 | 2,209 | 22.6 | 7,708 | 19.7 |
Depression subtype | ||||||
Manic or bipolar disorder | 13,548 | 5.8 | 351 | 3.6 | 1,653 | 4.3 |
Single or recurrent depression, mild | 31,898 | 13.6 | 1,374 | 14.1 | 5,631 | 14.4 |
Single or recurrent depression, moderate | 65,771 | 27.9 | 2,206 | 22.6 | 9,357 | 23.9 |
Single or recurrent depression, severe | 25,995 | 8.1 | 939 | 9.6 | 3,856 | 9.9 |
Single or recurrent depression, other | 87,828 | 37.3 | 4,519 | 46.2 | 16,810 | 43.0 |
Persistent or unspecified affective disorder | 10,425 | 4.4 | 387 | 4.0 | 1,797 | 4.6 |
Psychotropic medication at baseline | ||||||
Antipsychotic drugs | 54,051 | 24.0 | 2,479 | 25.4 | 9,870 | 25.3 |
Antidepressant drugs | 175,307 | 74.5 | 7,258 | 74.2 | 29,620 | 75.8 |
Comorbidity at baseline | ||||||
Anxiety | 37,697 | 16.0 | 1,189 | 12.6 | 4,176 | 10.6 |
Drug and alcohol abuse | 25,221 | 10.7 | 716 | 7.3 | 2,499 | 6.4 |
Diabetes mellitus | 13,750 | 5.8 | 782 | 8.0 | 2,412 | 6.2 |
Cardiovascular disease | 23,134 | 10.3 | 2,040 | 20.9 | 7,769 | 19.9 |
Benzodiazepine and related drug useb | ||||||
Any use | 179,249 | 76.1 | 7,942 | 81.2 | 33,666 | 86.1 |
Any benzodiazepine use | 150,334 | 63.8 | 7,961 | 72.3 | 30,273 | 77.7 |
Any Z-drug use | 128,683 | 54.7 | 5,170 | 52.9 | 23,691 | 60.6 |
Any other anxiolytic use | 31,428 | 13.4 | 700 | 7.2 | 5,066 | 12.6 |
Any long-acting drug use | 93,151 | 39.6 | 4,611 | 47.2 | 19,869 | 50.8 |
Any short- and medium-acting drug use | 165,662 | 70.4 | 7,132 | 72.0 | 30,883 | 79.0 |
Any Use of Benzodiazepines, Related Drugs, and Dementia
Variable | Age- and Gender-Adjusted Model | Fully Adjusted Modela | Fully Adjusted Model Plus Other Drugsb | |||
---|---|---|---|---|---|---|
Cohort study | ||||||
Hazard Ratio | 95% CI | Hazard Ratio | 95% CI | Hazard Ratio | 95% CI | |
Baseline | ||||||
0–2 years of follow-up, number of outcomes (N=5,085) | ||||||
Any use | 0.69 | 0.66, 0.74 | 0.70 | 0.65, 0.75 | NA | |
Benzodiazepine use | 0.72 | 0.67, 0.76 | 0.72 | 0.67, 0.76 | 0.74 | 0.69, 0.78 |
Z-drug use | 0.77 | 0.73, 0.82 | 0.79 | 0.74, 0.84 | 0.82 | 0.78, 0.88 |
Long-acting drug use | 0.80 | 0.75, 0.85 | 0.80 | 0.75, 0.84 | 0.82 | 0.77, 0.87 |
Short- and medium-acting drug use | 0.73 | 0.69, 0.77 | 0.74 | 0.70, 0.78 | 0.75 | 0.71, 0.80 |
Other anxiolytic use | 0.79 | 0.68, 0.91 | 0.85 | 0.73, 0.98 | 0.88 | 0.76, 1.02 |
2–20.1 years of follow-up, number of outcomes (N=4,691) | ||||||
Any use | 0.99 | 0.92, 1.06 | 0.95 | 0.88, 1.02 | NA | |
Benzodiazepine use | 1.01 | 0.95, 1.09 | 0.97 | 0.91, 1.04 | 0.97 | 0.92, 1.05 |
Z-drug use | 0.95 | 0.89, 1.00 | 0.96 | 0.90, 1.02 | 0.96 | 0.90, 1.02 |
Long-acting drug use | 1.03 | 0.98, 1.04 | 0.99 | 0.94, 1.05 | 0.99 | 0.93, 1.05 |
Short- and medium-acting drug use | 0.98 | 0.92, 1.04 | 0.97 | 0.91, 1.03 | 0.97 | 0.91, 1.03 |
Other anxiolytic use | 0.95 | 0.80, 1.10 | 1.00 | 0.85, 1.18 | 1.01 | 0.86, 1.18 |
Nested case-control study | ||||||
Odds Ratio | 95% CI | Odds Ratio | 95% CI | Odds Ratio | 95% CI | |
2 years before index date (1995) | ||||||
Any use | 1.04 | 0.99, 1.10 | 0.97 | 0.92, 1.02 | NA | |
Benzodiazepine use | 1.11 | 1.06, 1.16 | 1.03 | 0.98, 1.08 | 1.04 | 0.98, 1.09 |
Z-drug use | 1.01 | 0.97, 1.06 | 0.96 | 0.91, 1.01 | 0.95 | 0.91, 1.00 |
Long-acting drug use | 1.10 | 1.05, 1.15 | 1.02 | 0.97, 1.08 | 1.02 | 0.97, 1.02 |
Short- and medium-acting drug use | 1.07 | 1.02, 1.12 | 1.01 | 0.96, 1.06 | 1.01 | 0.95, 1.06 |
Other anxiolytic use | 0.98 | 0.88, 1.09 | 0.91 | 0.81, 1.01 | 0.91 | 0.81, 1.01 |
Cumulated Duration and Dose of Benzodiazepines and Dementia
Measure | All Drugs | Benzodiazepines | Z-Drugs | Long-Acting Drugs | Short-Acting Drugs | Other Drugs | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Hazard ratio | 95% CI | Hazard ratio | 95% CI | Hazard ratio | 95% CI | Hazard ratio | 95% CI | Hazard ratio | 95% | Hazard ratio | 95% CI | |
Cohort study (2–20.1 years of follow-up) | ||||||||||||
Number of prescriptions | ||||||||||||
None | 1 | 1 | 1 | 1 | 1 | 1 | ||||||
1–2 | 0.94 | 0.84, 1.04 | 1.00 | 0.92, 1.09 | 0.95 | 0.88, 1.03 | 0.99 | 0.91, 1.08 | 0.96 | 0.88, 1.04 | 0.94 | 0.77, 1.16 |
3–25 | 0.95 | 0.87, 1.03 | 0.97 | 0.90, 1.04 | 0.95 | 0.88, 1.02 | 0.98 | 0.92, 1.06 | 0.98 | 0.91, 1.05 | 1.13 | 0.86, 1.47 |
26 (maximum) | 0.95 | 0.87, 1.04 | 0.95 | 0.87, 1.04 | 0.98 | 0.87, 1.09 | 1.01 | 0.91, 1.11 | 0.98 | 0.89, 1.07 | 0.96 | 0.43, 2.15 |
Total defined daily dose | ||||||||||||
None | 1 | 1 | 1 | 1 | 1 | 1 | ||||||
Lowest third | 0.99 | 0.84, 1.03 | 0.99 | 0.90, 1.08 | 0.96 | 0.87, 1.05 | 0.95 | 0.86, 1.03 | 0.99 | 0.90, 1.08 | 0.97 | 0.76, 1.24 |
Middle | 0.95 | 0.86, 1.03 | 0.97 | 0.89, 1.05 | 0.92 | 0.84, 1.00 | 1.02 | 0.93, 1.11 | 0.94 | 0.84, 1.02 | 1.02 | 0.78, 1.36 |
Highest third | 0.94 | 0.86, 1.03 | 0.97 | 0.89, 1.04 | 0.98 | 0.90, 1.00 | 1.00 | 0.92, 1.08 | 0.98 | 0.89, 1.05 | 1.00 | 0.72, 1.40 |
Odds ratio | 95% CI | Odds ratio | 95% CI | Odds ratio | 95% CI | Odds ratio | 95% CI | Odds ratio | 95% CI | Odds ratio | 95% CI | |
Nested case-control study (2 years before index date, 1995) | ||||||||||||
Number of prescriptions | ||||||||||||
None | 1 | 1 | 1 | 1 | 1 | 1 | ||||||
1–2 | 1.23 | 1.12, 1.35 | 1.16 | 1.06, 1.26 | 1.11 | 1.03, 1.20 | 1.07 | 0.99, 1.16 | 1.20 | 1.10, 1.31 | 1.09 | (0.94–1.26) |
3–25 | 1.01 | 0.95, 1.07 | 1.06 | 1.00, 1.13 | 0.98 | 0.92, 1.04 | 1.08 | 1.01, 1.15 | 1.05 | 0.99, 1.11 | 0.88 | (0.74–1.05) |
26 (maximum) | 0.87 | 0.82, 0.93 | 0.94 | 0.88, 1.00 | 0.84 | 0.79, 0.90 | 0.91 | 0.84, 0.97 | 0.90 | 0.84, 0.96 | 0.51 | 0.37, 0.69 |
Total defined daily dose | ||||||||||||
None | 1 | 1 | 1 | 1 | 1 | 1 | ||||||
Lowest third | 1.08 | 1.01, 1.15 | 1.08 | 1.01, 1.15 | 1.25 | 1.17, 1.35 | 1.05 | 0.95, –1.13 | 1.11 | (1.05–1.19) | 1.15 | 0.97, 1.36 |
Middle | 0.99 | 0.92, 1.05 | 1.07 | 1.00, 1.14 | 1.07 | 0.98, 1.14 | 1.10 | 1.02, 1.12 | 0.97 | (0.87–1.10) | 0.86 | 0.71, 1.03 |
Highest third | 0.83 | 0.77, 0.88 | 0.91 | 0.85, 0.91 | 0.92 | 0.86, 1.00 | 0.92 | 0.85, 0.98 | 0.86 | 0.80, 0.92 | 0.73 | 0.66, 0.88 |
Sensitivity Analyses
Discussion
Comparison With Other Studies
Strengths and Limitations
Explanations and Implications
Supplementary Material
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