Patient Response Trajectories in Major Depressive Disorder.

Objective: To investigate whether the efficacy of antidepressants can be understood in terms of patient response-trajectory classes. Experimental Design: Patient-level data were analysed from 1357 adults with MDD randomised to either escitalopram 20 mg/day (n = 676) or placebo (n = 681) in five 8-week randomised placebo-controlled trials. Growth mixture models (GMMs) were used to identify the response trajectories; longitudinal latent class analysis (LLCA) was used to corroborate the findings. Principal Observations: Three classes of response were identified for escitalopram and placebo based on the trajectory of the patients' Montgomery-Åsberg Depression Rating Scale (MADRS) total scores during treatment. All three classes had similar mean baseline MADRS scores, but the change from baseline after 8 weeks differed: -4.2 MADRS points for non-responders, -18.4 MADRS points for slow responders, and -26.7 points for fast responders. The proportions of non-responders, slow responders and fast responders were 53%, 38% and 9%, respectively, with placebo and 27%, 58% and 14%, respectively, with escitalopram. Receiver operating curve analysis showed that a cut-off of ≥43% improvement from baseline to week 2 predicted fast responders, and a cut-off of ≥28% improvement from baseline to week 4 predicted responders (fast or slow). There were no clinically useful differences at baseline that predicted the trajectory class to which a patient would belong. Conclusions: The presence of fast-, slow- and non-responder classes has a clear clinical relevance for guiding treatment decisions; individual patients can be classified by the change in their MADRS score from baseline at 2 or 4 weeks.

The cardiovascular safety profile of escitalopram.

The cardiovascular effects of escitalopram were examined in a large group of participants in double-blind, randomized, placebo-controlled studies. Escitalopram (n=3298) was administered at doses between 5 and 20mg/day. Patients were treated in acute (8-12 weeks) and long-term (24 weeks) studies. Assessment of cardiovascular safety included heart rate, blood pressure (BP), treatment-emergent adverse events (TEAEs) and electrocardiograms (ECGs). In the short-term, there was a small, but statistically significant 2 beats per minute decrease in heart rate with escitalopram compared with placebo. The difference compared to placebo in systolic or diastolic BP was not clinically or statistically significant. Valid ECG assessments at both baseline and last assessment were available for 2407 escitalopram patients and 1952 placebo patients. Escitalopram-placebo differences in mean changes in ECG values were not clinically meaningful. The mean difference to placebo in the corrected QT [Fridericia's (QTcF)] interval was 3.5 ms (all escitalopram doses); 1.3 ms (escitalopram 10mg) and 1.7 ms (escitalopram 20mg) (p=0.2836 for 10 versus 20 mg). One out of 2407 escitalopram patients had a QTcF interval >500 ms and a change from baseline >60 ms. The incidence and types of cardiac-associated adverse events were similar between patients treated for 8-12 weeks with placebo (2.2%) or escitalopram (1.9%) and for 24 weeks with placebo (2.7%) or escitalopram (2.3%). Analyses of data from long-term studies and studies of the elderly showed similar results. In conclusion, these data demonstrate that escitalopram, like other SSRIs, has a statistically significant effect on heart rate and no clinically meaningful effect on ECG values, BP, with a placebo-level incidence of cardiac-associated adverse events.

Assessing the 'true' effect of active antidepressant therapy v. placebo in major depressive disorder: use of a mixture model.

BACKGROUND: There is controversy about the implications of relatively small average drug-placebo differences observed in randomised controlled trials of antidepressant medications. AIMS: To investigate whether efficacy is better understood as a large effect in a subgroup of patients. METHOD: The mixture model was used to identify patient subgroups (patients benefiting or not benefiting from treatment) to directly model the skewness of Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week 8. RESULTS: The MADRS scores improved by 15.9 points (95% CI 15.2-16.6) among patients who benefited from treatment. The proportion of patients who benefited from escitalopram and not from placebo treatment was 19.5%, corresponding to a number needed to treat of 5. CONCLUSIONS: This model gave a considerably better fit to the data than the analysis of covariance model in which all patients were assumed to benefit from treatment. The small average antidepressant-placebo difference obscures a much larger effect in a clinically meaningful subgroup of patients.