The first cohort was drawn from 1,528 patients with at least one billing code diagnosis of major depressive disorder (ICD-9 codes 296.2–296.3) and who were identified as having treatment-resistant or treatment-responsive depression using the natural language processing single-visit and longitudinal classification algorithms. Of this cohort, 1,245 (81%) patients were exposed to NSAIDs or NSAID-like medications, and 283 (19%) were unexposed.
summarizes this cohort’s sociodemographic and clinical characteristics. Patients with NSAID exposure were significantly more likely to be older, female, and non-White, as well as to have public rather than private insurance. As anticipated, NSAID-exposed patients also demonstrated significantly greater medical comorbidity and use of health care services.
Sociodemographic and Clinical Characteristics of Patients Exposed and Unexposed to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in the i2b2 Treatment-Resistant Cohort
Crude and partially adjusted odds ratios for association between NSAID exposure and outcome category are listed in and illustrated in . NSAID exposure in the broad analysis was significantly associated with risk for treatment-resistant depression. This effect appeared to be confined to the NSAIDs-only group, since no significant association was observed in the COX-2 inhibitor and salicylate treatment groups (). In the fully adjusted model (model 2 in ), which incorporated medical comorbidity and health care utilization measures, the beta coefficient for NSAID use changed by more than 10%, a conventional albeit imperfect indicator of confounding (19
), and was no longer statistically significant (odds ratio=1.17, 95% confidence interval [CI]=0.83–1.64, p=0.38). When the analysis was limited to NSAIDs only, the effect in the fully adjusted model was likewise reduced but remained significant (odds ratio=1.31, 95% CI=1.03–1.76, p=0.04).
Unadjusted and Adjusted Odds Ratios for Treatment Resistance by Medication Class in the i2b2 Treatment-Resistant Cohorta
Crude and Partially Adjusted Odds Ratios for Association Between Nonsteroidal Anti-Inflammatory Drug (NSAID) Exposure and Outcome Categorya
We conducted a secondary analysis in the i2b2 treatment-resistant depression cohort to distinguish between chronic NSAID use and intermittent use. Of the 1,245 patients who were prescribed at least one NSAID, 1,012 (81%) had chronic treatment (>2 prescriptions, excluding as-needed basis only) and 233 (19%) had intermittent treatment (≤2 prescriptions or as-needed basis only prescriptions). Demographic and clinical characteristics were similar between patients with chronic NSAID use and those with intermittent use (see Table S1 in the data supplement
accompanying the online edition of this article). In the fully adjusted model (model 2), patients with chronic NSAID use continued to have increased risk for treatment-resistant depression relative to patients without NSAID use (odds ratio=1.47, 95% CI=1.03–1.76, p=0.02), but no increased risk was observed in patients with intermittent use. (For details of the results in the secondary analysis, see Table S2
, Table S3
, and Figure S1 in the online data supplement
We next reanalyzed the STAR*D cohort to better characterize potential confounding variables, particularly those that might mediate confounding by indication (i.e., medical comorbidity). Patients who were exposed or unexposed to NSAIDs or NSAID-like medications differed on most sociodemographic and clinical characteristics (). As previously reported by Warner-Schmidt et al. (3
), without adjusting for confounding variables, NSAID exposure was associated with nonremission at level 1 in STAR*D (crude odds ratio=1.23, 95% CI=1.06–1.44, p<0.01) (). However, in fully adjusted logistic regression models including terms for Cumulative Illness Rating Scale severity in each category, the effect size was markedly diminished and no longer statistically significant. We observed a pattern similar to that in the i2b2 treatment-resistant depression cohort: the significant effects appeared to be limited to the NSAIDs-only treatment group rather than the NSAID-like treatment groups.
Sociodemographic and Clinical Characteristics of Patients Exposed and Unexposed to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in the Sequenced Treatment Alternatives to Relieve Depression Study
Unadjusted and Adjusted Odds Ratios for Nonremission by Medication Class in the Sequenced Treatment Alternatives to Relieve Depression Study Cohorta
To better understand the potential for confounding by pain, we conducted two follow-up analyses. First, we examined narcotic exposure among non-NSAID-treated patients in STAR*D. Although this analysis might carry the risk of the same potential confounding effects observed in the Warner-Schmidt et al. (3
) study, it does not consider the same molecular mechanisms. As we expected, narcotic exposure was associated with nonremission (). We observed similar evidence of confounding; in a fully-adjusted model, the effect was no longer statistically significant.
Second, we examined the effect of NSAID treatment chronicity in STAR*D. We defined a priori a chronic/subacute treatment group (with initiation of NSAID treatment 14 or more days before entering STAR*D, N=337) and an acute treatment group (with initiation of NSAID treatment within 14 days of entering level 1 of STAR*D or during level-1 treatment, N=262). In our comparison of the chronic/subacute treatment group and the no-NSAIDs group, a significant effect on odds of nonremission was observed (fully adjusted model odds ratio=1.44, 95% CI=1.10–1.90, p<0.01). In our comparison of the acute treatment group and the no-NSAIDs group, a substantially more modest and nonsignificant effect was observed (fully adjusted odds ratio=1.07, 95% CI=0.80–1.42, p=0.66).
Finally, we examined NSAID association with response to CBT in level 2 of STAR*D, again to consider an intervention with a presumed different mechanism of action. Among 147 patients receiving CBT (alone or as augmentation of citalopram), 25 (17.0%) also received concomitant NSAID treatment during this level. As observed in the level-1 analyses, NSAID administration was associated with greater likelihood of nonremission in an unadjusted model, with more modest effects in a fully adjusted model, although none of these effects were statistically significant, most likely because of the modest sample size.