We identified 3,397,470 antidepressant users contributing 1,287,446 person-years of observation during which 4,222 incident SD/VAs occurred. shows the unadjusted incidence rates of SD/VA among users of each antidepressant. The incidence rate among antidepressant-exposed beneficiaries was 3.28 (95% CI, 3.18 – 3.38) per 1,000 person-years, ranging from 0 per 1,000 for protriptyline and maprotiline to 12.64 (0.32 – 70.42) per 1,000 for trimipramine. Unadjusted IRRs, using paroxetine as the referent, are also presented in . As eight of the 21 antidepressants had < 30 events, they were excluded from further, multivariable analyses.
Unadjusted incidence rate of sudden death and ventricular arrhythmia (as a first-listed emergency department or principal inpatient diagnosis) in beneficiaries exposed to antidepressants, by pharmacologic class
shows characteristics of users of the remaining 13 antidepressants. Users were predominantly female and non-elders, and included considerable numbers of minorities, as is representative of the Medicaid population under study. Compared to the other antidepressants, a larger proportion of mirtazapine users were elderly (35.9%). The proportion of antidepressant prescriptions dispensed while a beneficiary was a nursing home resident was generally low across different users (2.9% to 15.6%) except for mirtazapine, in which 31.6% of its prescriptions were in such beneficiaries, consistent with its more frequent use in elders. Chronic disease diagnoses were also generally consistent across users, except for some diagnoses capturing specific indications of a particular antidepressant. For instance, 66.1% of lithium’s prescriptions were accompanied by a prior diagnosis of bipolar disorder, as lithium is principally used for this condition. In contrast, no more than 20% of any other antidepressant’s prescriptions were accompanied by such a diagnosis. Furthermore, given the age distribution of its users, mirtazapine prescriptions had the highest proportions of the following prior chronic disease diagnoses versus other antidepressants: anemia, arrhythmia/conduction disorder, cancer, cerebrovascular disease, coronary artery disease, enuresis, heart failure/cardiomyopathy, hypertension, hypothyroidism, kidney disease, organic psychosis, pulmonary circulation disease, and valvular heart disease. Drug markers of chronic disease exhibited a similar pattern. Current use of drugs was generally consistent across users.
Characteristics of beneficiaries filling prescriptions for antidepressants with sufficient numbers of events to permit their study
shows HRs for each antidepressant in a model adjusted for age, sex, race, state, nursing home residence, an ever-past diagnosis of bipolar disorder, and ever-past use of an angiotensin-converting enzyme inhibitor or angiotensin-II receptor blocker. The former five covariates were forced into each model while the latter two were identified as confounders via the change-in-estimate approach. Compared to paroxetine, mirtazapine had an elevated HR of 1.26 (1.11 – 1.42) and bupropion had a reduced HR of 0.80 (0.67 – 0.95). HRs for the remaining antidepressants were not statistically significantly different from that of paroxetine, although doxepin’s point estimate (HR = 1.24, 0.93 – 1.65) was nearly identical to that of mirtazapine. The forward-stepwise confounder selection model results were very similar to the change-in-estimate confounder selection results above, and are therefore not presented.
FIGURE 1 Adjusted* hazard ratios for SD/VA associated with antidepressant exposure, using paroxetine as the reference
A secondary analysis including person-time of only the first prescription for a given agent found no elevated risks with mirtazapine (HR = 1.01, 0.77 – 1.33) or doxepin (HR = 0.80, 0.43 – 1.47), in a model adjusted for the same covariates listed above. HRs for other antidepressants were slightly attenuated, but similar to the primary analysis. Other secondary analyses, excluding enrollees in managed care plans and excluding those with cancer, yielded point estimates generally similar to those of the primary analysis. In particular, the HRs for mirtazapine remained elevated at 1.35 (1.07 – 1.71) and 1.27 (1.09 – 1.48), respectively. The HRs for doxepin were 0.91 (0.48 – 1.72) and 1.24 (0.86 – 1.78), respectively. The reduced hazard associated with bupropion was no longer statistically significant, with HRs of 0.73 (0.52 – 1.02) and 0.88 (0.71 – 1.09), respectively.
As dose and clearance inhibitor analyses were intended to confirm statistically elevated or protective risks demonstrated in the primary analysis, we report only the effect estimates for mirtazapine and bupropion. In a model adjusted for age, sex, race, state, nursing home residence, number of prior antidepressant prescriptions, and an ever-past substance abuse diagnosis, HRs for the second through fourth mirtazapine dose quartiles (i.e., > 15 and ≤ 22.5 mg; > 22.5 and ≤ 30 mg; > 30 mg) were 0.81 (0.49 – 1.35), 1.05 (0.86 – 1.28), and 0.95 (0.70 – 1.29) respectively, compared to the lowest dose quartile (i.e., ≤ 15 mg). In a model adjusted for the same covariates, HRs for the second and third bupropion dose tertiles (i.e., 300 mg; > 300 mg) were 0.67 (0.48 – 0.94) and 0.84 (0.45 – 1.58) respectively, compared to the lowest dose tertile (i.e., < 300 mg).
In a model adjusted for age, sex, race, state, and nursing home residence, HRs for mirtazapine plus a known or suspected arrhythmogenic 1A2, 2D6, and 3A4 (isozymes responsible for mirtazapine’s metabolism) inhibitor were 1.85 (1.47 – 2.33), 2.13 (1.50 – 3.03), and 1.58 (1.06 – 2.35) respectively, compared to mirtazapine in the absence of such an inhibitor. The HRs for mirtazapine plus a non-arrhythmogenic 1A2, 2D6, and 3A4 inhibitor were 1.49 (0.70 – 3.15), 1.25 (1.03 – 1.53), and 1.61 (1.22 – 2.11) respectively, compared to mirtazapine in the absence of such an inhibitor. In a model adjusted for the same covariates, the HR for bupropion plus a known or suspected arrhythmogenic 2C19 (an isozyme responsible for bupropion’s metabolism) inhibitor was 1.64 (0.60 – 4.44). The HR for bupropion plus a non-arrhythmogenic 2C19 inhibitor was 1.25 (0.86 – 1.80). There was no concomitant prescribing of bupropion and a 2B6 inhibitor, another isozyme responsible for the drug’s metabolism. In these clearance inhibitor models, we were unable to assess for confounding by covariates other than those mentioned above because of too few events occurring during concomitant prescribing of the antidepressants and inhibitors.