Depression-Free Days as a Summary Measure of the Temporal Pattern of Response and Remission in the Treatment of Major Depression: A Comparison of Venlafaxine, Selective Serotonin Reuptake Inhibitors, and Placebo
J Clin Psychiatry 2003;64:321-330
© Copyright 2014 Physicians Postgraduate Press, Inc.
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Background: This article develops and
applies depression-free days (DFDs) as a summary measure of the
temporal pattern of response and remission in a comparison of
venlafaxine (a dual-action serotonin-norepinephrine reuptake
inhibitor) with selective serotonin reuptake inhibitors (SSRIs)
Method: Weekly data on the 17-item
Hamilton Rating Scale for Depression (HAM-D-17) from 2046
patients with DSM-III-R/IV-established moderate-to-severe major
depression, participating in 1 of 8 randomized, double-blind,
controlled studies that compared venlafaxine with an SSRI
(fluoxetine, paroxetine, or fluvoxamine) or with both placebo and
an SSRI, were used to estimate DFDs. Maximum DFDs were imputed to
maintained HAM-D-17 scores <= 7 (asymptomatic
depression) over time, minimum DFDs to persistent HAM-D-17 scores
>= 15 (acutely symptomatic depression), and prorated DFDs to
intermediate HAM-D-17 scores. A secondary construct
was developed to test sensitivity to a less stringent upper
threshold of acutely symptomatic depression (HAM-D-17 score >=
22). Using a tertiary construct, sensitivity to a more stringent
lower threshold representing elimination of residual symptoms was
also evaluated. The construct validity of the primary and the
secondary DFDs measures was assessed in terms of their
correlation with sustained low clinical global severity of
illness (scores of 1 or 2 on the Clinical Global
Impressions-Severity of Illness scale). For each construct, DFDs
were compared across the 3 treatment groups and corresponding
effect sizes were generated.
Results: Overall, sustained low clinical global
severity of illness was associated with 38.3 median
(interquartile range, 29.8 to 44.2) DFDs relative to 5.7
(interquartile range, 0 to 20.6) median DFDs associated with
nonsustained low clinical global severity; similar differences
emerged in terms of sustained asymptomatic depression. The
venlafaxine group (N = 851) experienced a median of 18.8
(interquartile range, 0.4 to 34.6) DFDs compared with a median of
13.6 (interquartile range, 0 to 29.8) DFDs in the SSRI group (N =
749) and 7.4 (interquartile range, 0 to 26.2) DFDs in the placebo
group (N = 446) (p < .0001 overall; venlafaxine vs. SSRIs, p =
.0015, effect size = 0.2; venlafaxine vs. placebo, p < .0001,
effect size = 0.4; and SSRIs vs. placebo, p = .0007, effect size
= 0.2). The secondary and tertiary DFDs constructs yielded
similar, albeit narrower, differences in all comparisons.
Conclusion: The construct of DFDs was
found to be a useful summary measure of sustained remission.
Active treatments were associated with more DFDs than placebo,
and venlafaxine with more DFDs than SSRIs, consistent with
corresponding differences in sustained remission.