Estimating dose-response for time to remission with instrumental variable adjustment: the obscuring effects of drug titration in Genome Based Therapeutic Drugs for Depression Trial (GENDEP): clinical trial data

BACKGROUND: Threshold regression, in which time to remission is modelled as a stochastic drift towards a boundary, is an alternative to the proportional hazards survival model and has a clear conceptual mechanism for examining the effects of drug dose. However, for both threshold regression and proportional hazard models, when dose titration occurs during treatment, the estimated causal effect of dose can be biased by confounding. An instrumental variable analysis can be used to minimise such bias.

METHOD: Weekly antidepressant dose was measured in 380 men and women with major depression treated with escitalopram or nortriptyline for 12 weeks as part of the Genome Based Therapeutic Drugs for Depression (GENDEP) study. The averaged dose relative to maximum prescribing dose was calculated from the 12 trial weeks and tested for association with time to depression remission. We combined the instrumental variable approach, utilising randomised treatment as an instrument, with threshold regression and proportional hazard survival models.

RESULTS: The threshold model was constructed with two linear predictors. In the naïve models, averaged daily dose was not associated with reduced time to remission. By contrast, the instrumental variable analyses showed a clear and significant relationship between increased dose and faster time to remission, threshold regression (velocity estimate: 0.878, 95% confidence interval [CI]: 0.152-1.603) and proportional hazards (log hazards ratio: 3.012, 95% CI: 0.086-5.938).

CONCLUSIONS: We demonstrate, using the GENDEP trial, the benefits of these analyses to estimate causal parameters rather than those that estimate associations. The results for the trial dataset show the link between antidepressant dose and time to depression remission. The threshold regression model more clearly distinguishes the factors associated with initial severity from those influencing treatment effect. Additionally, applying the instrumental variable estimator provides a more plausible causal estimate of drug dose on treatment effect. This validity of these results is subject to meeting the assumptions of instrumental variable analyses.

TRIAL REGISTRATION: EudraCT, 2004-001723-38; ISRCTN, 03693000. Registered on 27 September 2007.