Posted by jrbecker on January 25, 2005, at 10:54:17
Duloxetine in the treatment of Major Depressive Disorder: A comparison of
efficacy in patients with and without melancholic featuresBMC Psychiatry 2005, 5:1 doi:10.1186/1471-244X-5-1
Craig H Mallinckrodt (cmallinc@lilly.com)
John G Watkin (watkinjg@lilly.com)
Chaofeng Liu (chaofeng_liu@lilly.com)
Madelaine M Wohlreich (mwmd@lilly.com)
Joel Raskin (joel.raskin@lilly.com)
ISSN 1471-244X
Article type Research article
Submission date 8 Apr 2004
Acceptance date 4 Jan 2005
Publication date 4 Jan 2005
Article URL http://www.biomedcentral.com/1471-244X/5/1
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Duloxetine in the treatment of Major Depressive Disorder:
A comparison of efficacy in patients with and without
melancholic features
Craig H. Mallinckrodt, John G. Watkin, Chaofeng Liu,
Madelaine M. Wohlreich, and Joel Raskin
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285
E-mail addresses:
Craig H. Mallinckrodt cmallinc@lilly.com
John G. Watkin watkinjg@lilly.com
Chaofeng Liu chaofeng_liu@lilly.com
Madelaine M. Wohlreich mwmd@lilly.com
Joel Raskin joel.raskin@lilly.com
Corresponding Author:
Craig H. Mallinckrodt, Ph.D., Lilly Corporate Center, Indianapolis, IN 46285. Phone:
(317) 277 2209; FAX: (317) 651 6269; e-mail: cmallinc@lilly.com.
Abstract
Background. The most prominent feature of melancholic depression is a near-total loss
of the capacity to derive pleasure from activities or other positive stimuli. Additional
symptoms can include psychomotor disturbances, anorexia, excessive guilt, and early
awakening from sleep. Melancholic patients may exhibit treatment responses and
outcomes that differ from those of non-melancholic patients. Pooled data from doubleblind,
placebo-controlled studies were utilized to compare the efficacy of duloxetine in
depressed patients with and without melancholic features.
Methods. Efficacy data were pooled from 8 double-blind, placebo-controlled clinical
trials of duloxetine. The presence of melancholic features (DSM-IV criteria) was
determined using results from the Mini International Neuropsychiatric Interview (MINI).
Patients (aged =18 years) meeting DSM-IV criteria for major depressive disorder (MDD)
received duloxetine (40-120 mg/d; melancholic, N=759; non-melancholic, N=379) or
placebo (melancholic, N=519; non-melancholic, N=256) for up to 9 weeks. Efficacy
measures included the 17-item Hamilton Rating Scale for Depression (HAMD17) total
score, HAMD17 subscales (Maier, anxiety, retardation, sleep), the Clinical Global
Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I)
scales, and Visual Analog Scales (VAS) for pain.
Results. In data from all 8 studies, duloxetine’s advantage over placebo did not differ
significantly between melancholic and non-melancholic patients (treatment-bymelancholic
status interactions were not statistically significant). Duloxetine
demonstrated significantly greater improvement in depressive symptom severity,
compared with placebo, within both melancholic and non-melancholic cohorts (p<.001
for HAMD17 total score, CGI-S and PGI-I). When analyzed by gender, the magnitude of
improvement in efficacy outcomes did not differ significantly between duloxetine-treated
male and female melancholic patients. In the two studies that assessed duloxetine 60
mg once-daily dosing, duloxetine-treated melancholic patients had significantly greater
improvement compared with placebo on HAMD17 total score, CGI-S, PGI-I, 3 of 4
subscales of the HAMD17, and VAS overall pain severity (p<.01). Estimated probabilities
of response and remission were significantly greater for melancholic patients receiving
duloxetine 60 mg QD compared with placebo (response 74.7% vs. 42.2%, respectively,
p<.001; remission 44.4% vs. 24.7%, respectively, p=.002).
Conclusions: In this analysis of pooled data, the efficacy of duloxetine in patients with
melancholic features did not differ significantly from that observed in non-melancholic
patients.Background
Although the first appearance of the term “melancholia” dates back to antiquity
[1], its use was in decline until it was re-adopted in 1980 by the authors of the Diagnostic
and Statistical Manual of Mental Disorders, 3rd Edition (DSM-III) to describe a subtype of
major depressive disorder (MDD). Although revised in DSM-III-R, the current DSM-IV
“With Melancholic Features Specifier” represents a return to the older DSM-III definition.
According to DSM-IV criteria, the principal diagnostic feature exhibited by patients with
melancholic depression is a loss of pleasure in all, or almost all, activities or a lack of
reactivity to usually pleasurable stimuli [2]. Additional symptoms include diurnal variation
(depression worse in the morning), psychomotor disturbances, anorexia, excessive guilt,
and early awakening from sleep. Estimates of the prevalence of melancholic features
among patients diagnosed with MDD range from 16% to 53% [3-6], although the
prevalence may be as high as 76% among inpatients [6].
Melancholia is encountered equally in both genders [7], but is observed more
frequently in older patients [4,8]. While melancholia is associated with an increased
comorbidity of anxiety disorders, panic disorder, and phobia [9], melancholic patients
have a significantly lower suicide rate than non-melancholics [10].
A considerable body of evidence suggests that biological differences exist
between melancholic and non-melancholic depression. The hypercortisolism of
melancholia has been described as perhaps the best documented finding in biological
psychiatry [11]. Many of the features exhibited by melancholic patients closely resemble
those that occur reflexively in non-depressed populations during acutely stressful or
threatening situations [12]. Thus, depressed patients with melancholic features
consistently demonstrate an activation of the hypothalamic-pituitary-adrenocortical
(HPA) axis [13], resulting in laboratory findings of dexamethasone non-suppression.
Melancholic patients also have an activated corticotrophin-releasing hormone (CRH)
system and may have diminished activities of the growth hormone and reproductive
axes [14]. When compared with non-melancholic depressed patients, melancholics
have also been shown to exhibit lower concentration of nighttime serum melatonin [15],
lower plasma serotonin (5-HT) concentrations [16,17], and an impaired in vivo immune
response [18,19].
Given the distinct clinical and physiological features associated with melancholia,
it is perhaps not surprising that melancholic patients may exhibit treatment responses
and outcomes that differ from those of non-melancholic depressed patients. In
reviewing a number of long-term studies, Parker et al concluded that melancholics
appear to respond well to treatment of individual episodes but have frequent
recurrences, while non-melancholics may respond less rapidly and less completely in
any individual episode but show a general pattern of improvement over time [20].
Overall, melancholics appear to have higher rehospitalization rates and greater illness
morbidity over an extended period [20].
Melancholic patients are less likely to respond to non-specific supportive
therapies, such as cognitive behavior therapy or interpersonal psychotherapy, and more
often require pharmacotherapy to achieve a successful treatment outcome [21,22].
Within the context of clinical trials, this apparent lack of response to non-specific
therapies is frequently manifested in the form of a markedly lower placebo response rate
among melancholic, when compared with non-melancholic, patients [23-27]. Thus, in
some studies, antidepressant-treated melancholic patients have demonstrated
significantly greater improvements compared with placebo while a non-melancholic
cohort has failed to achieve separation from placebo. However, the drug response is
usually of similar magnitude in all patients, and the difference in outcome can be traced
to significantly different placebo responses within melancholic and non-melancholic
patients [26,28].
Although a number of studies have investigated the relative efficacy of specific
classes of antidepressant medications in melancholic patients, results have been
somewhat inconsistent [26]. While tricyclic antidepressants (TCAs) have demonstrated
superiority over selective serotonin reuptake inhibitors (SSRIs) in some studies of
melancholic depression [29-32], results from other head-to-head studies have failed to
support these findings [33-35]. Thus, the current consensus is that SSRIs and TCAs
demonstrate comparable efficacy for the treatment of melancholic depression [13,36].
With regard to safety and tolerability, however, SSRIs offer considerable advantages
since they lack the anticholinergic, antihistaminergic, and cardiotoxic effects associated
with TCAs [37]. As a result, SSRIs are now recognized as the first-line treatment for
melancholia.
The antidepressant duloxetine is a balanced and potent dual reuptake inhibitor of 5-
HT and norepinephrine (NE). The efficacy of duloxetine in the treatment of MDD has been
established in randomized, double-blind, placebo-controlled studies of up to 9 weeks
duration [38]. In the present study, pooled data from 8 clinical trials of duloxetine were
utilized to compare treatment outcomes in melancholic patients with those in nonmelancholic
patients.Methods
Study Design
All 8 studies included in these analyses were randomized, multicenter, doubleblind,
placebo-controlled clinical trials and represented all of the double-blind studies
included in the New Drug Application reviewed by regulatory agencies for duloxetine’s
indication in MDD. All studies incorporated double-blind, variable-expected duration
placebo lead-in periods to blind patients and investigators to the start of active therapy.
Six studies also utilized an active comparator - fluoxetine (20 mg QD) in Studies 1 and 2,
and paroxetine (20 mg QD) in Studies 3, 4, 7, and 8. Study protocols were reviewed
and approved by the ethical review board at each center, in accordance with the
principles of the Declaration of Helsinki, and all patients provided written informed
consent prior to the administration of any study procedures or study drug. The numbers
of patients randomized in each study are summarized in Table 1. Detailed safety and
efficacy results from Studies 1 [39], 4 [40], 5 [41], and 6 [42] have been published
previously.
Patients
In all studies, patients were 18 years of age or older and met criteria for MDD as
defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSMIV)
[43]. The diagnosis of MDD was confirmed by the Mini International
Neuropsychiatric Interview (MINI) [44], a standardized diagnostic interview based on
DSM-IV criteria. Patients had a 17-item Hamilton Rating Scale for Depression (HAMD17)
[45] total score >15 and a Clinical Global Impression of Severity (CGI-S) [46] score >4 at
the screening and second study visits. The presence of melancholic features (DSM-IV
criteria) was determined using results from the MINI:
“Either feature 1 or 2 in Criteria A AND three (or more) features from Criteria B
must be present to qualify for melancholic features.
A. Either of the following, occurring during the most severe period of the current
episode.
1. Loss of pleasure in all, or almost all, activities;
2. Lack of reactivity to usually pleasurable stimuli
B. Three (or more) of the following:
1. Distinct quality of depressed mood;
2. Depression regularly worse in the morning;
3. Early morning awakening (at least 2 hours before usual time of awakening);
4. Marked psychomotor retardation or agitation;
5. Significant anorexia or weight loss;
6. Excessive or inappropriate guilt.“
Patients were excluded for the following reasons: a current and primary Axis I
disorder, other than MDD; an Axis II disorder which could interfere with protocol
compliance; lack of response of the current depressive episode to two or more adequate
courses of antidepressant therapy; serious medical illness; a serious risk of suicide; a
history of substance abuse or dependence within the last year, or a positive urine drug
screen.
Concomitant medications with primarily central nervous system activity were not
permitted, with the exception of episodic use of chloral hydrate or zolpidem for insomnia.
Chronic use of prescription analgesic medications was not allowed; episodic use was
permitted at the discretion of the physician in charge of the study. Use of anti-9
hypertensive medications was not permitted unless the patient had been on a stable
dose for at least 3 months prior to study entry.
Data Pooling Strategies
Efficacy analyses were performed on three sets of data, obtained using the
following pooling strategies:
(A) “All Studies” - data from all 8 studies were pooled. Placebo: melancholic
(n=519; 67.0%), non-melancholic (n=256; 33.0%). Duloxetine (40-120 mg/d):
melancholic (n=759; 66.7%), non-melancholic (n=379; 33.3%). Duloxetine was
compared with placebo in one set of analyses. In a second set of analyses using data
from the 6 SSRI-controlled studies, duloxetine was compared with fluoxetine and
paroxetine: Placebo: melancholic (n=348; 67.6%), non-melancholic (n=167; 32.4%).
Duloxetine (40-120 mg/d): melancholic (n=602; 67.8%), non-melancholic (n=286;
32.2%). SSRI: melancholic (n=294; 68.5%), non-melancholic (n=135; 31.5%);
(B) “Positive Studies” - data from placebo- and duloxetine-treated patients were
pooled from the 6 studies (1, 4, 5, 6, 7, and 8) that demonstrated a significant advantage
for duloxetine over placebo on the primary efficacy measure. Placebo: melancholic
(n=415; 67.9%), non-melancholic (n=196; 32.1%). Duloxetine (40-120 mg/d):
melancholic (n=594; 67.4%), non-melancholic (n=287; 32.6%);
(C) “Focus Studies” - data were pooled from the 2 studies (5 and 6) that
compared duloxetine 60 mg once-daily with placebo. Placebo: melancholic (n=171;
65.8%), non-melancholic (n=89; 34.2%). Duloxetine (60 mg/d): melancholic (n=157;
62.8%), non-melancholic (n=93; 37.2%).
Strategy A facilitated assessments of differential efficacy in the largest possible
data set. While the inclusion of all available data has obvious advantages, the presence
of failed studies could mask differential treatment effects. If a study failed to detect an
overall effect it is unlikely to help detect differential subgroup effects. Therefore strategy
B essentially served as a robustness check for strategy A. Pooling strategy C facilitated
assessments at the recommended target dose.
Efficacy Measures
In all 8 studies, the primary efficacy outcome was mean change from baseline to
endpoint in HAMD17 total score. Other efficacy measures assessed in all studies
included HAMD17 subscales: anxiety/somatization (Items 10, 11, 12, 13, 15, and 17),
Maier (Items 1, 2, 7, 8, 9, and 10), retardation (Items 1, 7, 8, and 14), and sleep (Items 4,
5, and 6); the CGI-S scale; and the Patient Global Impression of Improvement (PGI-I)
scale [46]. Response was defined as a decrease from baseline of at least 50% on the
HAMD17 total score. Remission was defined as a HAMD17 total score 7. In Studies 3 -
8, the severity of painful physical symptoms was assessed using Visual Analog Scales
(VAS) for pain [47].
Statistical analyses
Patients with missing melancholia status were not included in the analyses. All
other patients with a baseline and at least one postbaseline observation were included in
the analyses. Mean changes from baseline to last observation (carried forward) in
HAMD17 total score, CGI-S, and PGI-I were assessed using an analysis of covariance
(ANCOVA) with models that included baseline score, treatment, melancholia status
(features present Yes/No), investigator, and the treatment-by-melancholia status
interaction as independent variables. Hereafter this analysis is referred to as LOCF
mean change.
The treatment-by-melancholic status interaction was the main basis upon which
differential treatment effects between the subgroups were assessed. Contrasts between
duloxetine and placebo within the melancholic and non-melancholic subgroups were
used to assess the clinical relevance of treatment effects.
Longitudinal mean changes and categorical changes (estimated probabilities)
were assessed using a likelihood-based mixed-effects model repeated measures
(MMRM) approach. Models for mean changes included treatment, visit, investigator,
baseline HAMD17 value, melancholia status, and the two-way and three-way interactions
between treatment, visit, and melancholia status. Hereafter this analysis is referred to
as MMRM mean change. The categorical longitudinal analyses were similar in concept
to the longitudinal mean change analyses, but simplifications were necessary to reduce
the computational complexity.
The categorical analyses were applied only to patients with melancholic features
so that the main effect of melancholic status and its two-way and three-way interactions
with visit and treatment could be deleted. Therefore, the model for the categorical
analyses included treatment, visit, investigator, baseline HAMD17 value, and the
treatment-by-visit interaction. A logit link function and a binomial error structure were
included to account for the non-linearity of the response and the non-normality of the
data, respectively. Hereafter, this analysis is referred to as categorical MMRM.
Remission and response rates at last observation were assessed using Fisher’s Exact
test.
The LOCF mean change analysis of HAMD17, CGI-S and PGI-I was applied to all
three databases. The focus for the analyses was on all studies and the positive studies
with the primary aim of detecting differential effects of duloxetine in patients with and
without melancholic features. The MMRM mean change and categorical MMRM
analyses were then applied to a wide variety of outcomes from the focus studies in order
to gain an in-depth perspective on the efficacy of duloxetine in patients with melancholic
features. In addition, LOCF analyses of data from the focus studies were conducted in
order to assess robustness of the MMRM results.Results
Patient characteristics
Baseline patient demographics are summarized in Table 2. The prevalence of
melancholic features in the overall patient population was 67.1% (1572/2342). The
melancholic cohort had a significantly higher proportion of females compared with the
non-melancholic group (69.5% vs. 60.8%, p<.001). Melancholic patients also had a
significantly lower mean body weight than non-melancholics (77.7 kg vs. 81.3 kg,
p<.001). Mean age at enrollment did not differ significantly between melancholic and
non-melancholic patients.
Mean baseline HAMD17 total scores and CGI-S scores were significantly higher
(more severe illness) in melancholic patients compared with non-melancholics (HAMD17:
22.3 vs. 20.5, p<.001; CGI-S: 4.41 vs. 4.26, p<.001). There was a marginally significant
difference in VAS overall pain severity at baseline (31.7 vs. 31.0 for melancholic and
non-melancholic groups, respectively; p=.053), although the clinical relevance of this
small difference is questionable.
Efficacy - All Studies and Positive Studies
Analyses of mean changes from baseline to last observation (LOCF mean
change) from all eight studies and the six positive studies are summarized in Table 3. In
both melancholic and non-melancholic patients, duloxetine demonstrated significant
advantages over placebo in HAMD17 total score, CGI-S and PGI-I (p<.001). Treatmentby-
melancholic status interactions were not significant for HAMD17 total score, CGI-S, or
PGI-I, in either data set (p>.50 for each comparison). Using pooled data from all studies,
the effect size for HAMD17 total score was 0.33 in melancholic patients and 0.32 in non-
14
melancholics. In the six positive studies, the effect size for HAMD17 total score was 0.39
in melancholic patients compared with 0.43 in non-melancholics.
Within the subset of melancholic patients, treatment-by-gender interactions for
mean change in HAMD17 total score, mean change in CGI-S score, and mean endpoint
PGI-I score were not statistically significant, indicating that duloxetine’s efficacy was
similar in male and female melancholic patients (Table 4). In pooled data from all
studies, the effect size for HAMD17 total score was 0.29 in male melancholic patients
compared with 0.35 in female melancholics. Effect sizes for CGI-S score were 0.35 vs.
0.33 for male and female melancholic patients, respectively, while PGI-I effect sizes
were 0.26 (males) vs. 0.34 (females).
In melancholic patients, treatment-by-age interactions for mean change in
HAMD17 total score were not significant at thresholds of age 55 (p=.777), age 60
(p=.387), or age 65 (p=.540), indicating that the efficacy of duloxetine did not differ
between older and younger melancholic patients irrespective of the old/young age
threshold.
In the 6 studies that included an SSRI comparator, there were no significant
differences in baseline-to-endpoint changes in efficacy measures between duloxetine
and SSRI treatment groups (Table 5). In addition, treatment-by-therapy interactions for
mean change in HAMD17 total score, mean change in CGI-S score, and mean endpoint
PGI-I score were not statistically significant, indicating that the relative efficacy of
duloxetine and SSRIs did not differ significantly between melancholic and nonmelancholic
patients (Table 5).
Efficacy - Focus Studies
Analyses of mean changes from baseline to Week 9 (MMRM mean change) for
melancholic patients in the two focus studies (Studies 5 and 6) are summarized in Table
15
6. Melancholic patients receiving duloxetine had significantly greater improvement in
mean HAMD17 total score and HAMD17 Maier subscale compared with those receiving
placebo (p<.001). Significant differences from placebo first occurred at Week 1 (Maier
subscale, Figure 1) or Week 2 (total score) and were present at all subsequent visits.
Significant advantages for duloxetine over placebo for mean changes to Week 9 among
melancholic patients were also observed on the HAMD17 retardation and sleep
subscales, but not for the anxiety subscale (p=.230). On both clinician-rated (CGI-S)
and patient-rated (PGI-I) assessments of global improvement, duloxetine-treated
melancholic patients had significantly greater mean improvements compared with
melancholics receiving placebo (p<.001). Robustness of the MMRM results was
confirmed in that significant differences were also observed in LOCF mean change
analyses.
Mean changes from baseline (MMRM mean change) for VAS overall pain were
also assessed. Figure 2 shows a visitwise plot of mean changes in VAS overall pain
severity for melancholic patients. For the main effect of treatment (pooling results from
all visits - interpreted similar to an area under the curve analysis) duloxetine-treated
melancholic patients had significantly greater improvement compared with placebo.
Duloxetine’s advantage over placebo in treating the painful physical symptoms did not
vary substantially between patients with and without melancholic features. However, the
response profiles were somewhat different in that response to placebo was generally
lower in patients with melancholic features compared with non-melancholic patients. For
example, the mean percentage improvement in overall pain among non-melancholic
patients receiving placebo was 15.6%, compared with a 0.5% worsening in overall pain
among placebo-treated melancholic patients.
Estimated probabilities (categorical MMRM analyses) of remission at Week 9
were significantly higher for melancholic patients treated with duloxetine (60 mg QD)
16
compared with placebo (44.4% vs. 24.7%, respectively; p=.002). The estimated
probability of response among melancholic patients was 74.7% for duloxetine compared
with 42.2% for placebo (p<.001). The advantage of duloxetine over placebo in remission
and response rates was also significant in LOCF analyses (p =.032 and p=.002,
respectively).Discussion
The magnitude of duloxetine’s advantage over placebo was generally similar in
melancholic and non-melancholic patients. Treatment-by-melancholic status
interactions were not significant for any of the three assessed efficacy measures
(HAMD17 total score, CGI-S, PGI-I). These results suggest that duloxetine’s efficacy
does not differ substantially between melancholic and non-melancholic patients.
Furthermore, within the group of melancholic patients, duloxetine’s treatment effects
were similar in male and female patients (treatment-by-gender interactions were not
statistically significant). One exception was noted in the anxiety subscale of the
HAMD17. In the two focus studies, duloxetine did not achieve separation from placebo in
patients with melancholic features, but demonstrated efficacy in non-melancholic
patients. The reason for the disparity in outcomes between melancholic and nonmelancholic patients on the HAMD17 anxiety subscale is unclear.
In previous studies, the prevalence of melancholic features in populations of
depressed outpatients has ranged from 16% to 53%. The substantial variation in the
reported rates of melancholia may be a result of the numerous criteria used to define
melancholic features over the past two decades, including DSM-III, DSM-III-R, DSM-IV,
and the Newcastle 1 Depression Rating Scale Patients (N1) [48]. In the present study of
depressed outpatients, the prevalence of melancholic features was substantially higher
(67.1%) than previous estimates, and merits further comment. At baseline screening all
patients were required to meet DSM-IV criteria for MDD, while the presence of
melancholic features (DSM-IV criteria) was determined using results from the MINI
(further details are provided in the Methods section). The high prevalence of
melancholic features was consistent across all 8 clinical trials regardless of geographic
location (two studies were conducted in Eastern Europe, six were conducted in the
United States). Given the large number of investigative sites (over 140 sites across the
8 studies), and the fact that melancholic features were not used as an inclusion or
exclusion criterion in any of the studies, it is unlikely that raters were artificially inflating
the number of patients classified as melancholic. A more likely explanation appears to
be that the screening method (i.e. the MINI plus DSM-IV criteria) produced a substantial
number of false positive results with regard to melancholic features. It is possible that
the use of an alternative melancholia screening tool, such as the CORE scale developed
by Parker et al [49], would have identified a smaller and more well-defined group of
melancholic patients. Thus, in a study evaluating the CORE measure of melancholia
against the DSM-IV construct, the CORE criteria identified patients with neuroendocrine
disturbance whereas DSM-IV criteria did not [50]. In a wider context, the fact that such a
high proportion of patients in the current study met DSM-IV criteria for melancholia may
raise questions regarding the validity of melancholia as a separate clinical entity [50],
and whether it should be considered simply as a variant of MDD which differs only in
severity [51,52]. Although the current results cannot directly address concerns as to the
validity of melancholia, the unusually high proportion of melancholic patients identified at
baseline suggests that the use of the MINI together with DSM-IV criteria may well be an
inadequate screening tool for such purposes.
There was no significant difference in age between melancholic and nonmelancholic
patient groups, despite the fact that melancholic features are more common
in older patients. Patients with melancholic features had significantly lower mean body
weight at baseline compared to non-melancholics, with a between-group difference of
3.6 kg (8.0 lbs). Since one of the DSM-IV criteria for melancholic features is “significant
anorexia or weight loss”, this result does not appear surprising. However, given that the
melancholic cohort contained a significantly greater proportion of females when
compared with the non-melancholic group, the lower body weight among melancholics
may be an artifact of gender rather than of MDD subtype. For example, in a recent
study of 1694 depressed patients, Berlin et al reported that the presence of melancholic
features was not associated with lower body mass index [53].
As expected, melancholic patients exhibited a greater severity of illness at
baseline compared with non-melancholics, with a mean baseline HAMD17 score almost
two points higher (approximately one-half standard deviation) in the melancholic group.
Melancholic patients also had significantly higher baseline CGI-S scores when
compared to those without melancholic features. Although melancholic patients had a
slightly higher overall pain severity at baseline (as assessed using the self-rated VAS
measure of overall pain), the difference only approached statistical significance and its
clinical relevance is questionable.
A frequent finding in placebo-controlled antidepressant studies is that placebo
responses among melancholic patients are smaller than those observed in nonmelancholic patients [23-25,54], although this is not always the case [55]. In the present assessment, mean changes in HAMD17, CGI-S or PGI-I scores among both placebo- and duloxetine-treated melancholic patients were slightly larger than those of nonmelancholic patients, resulting in a very similar drug-placebo difference in both patient groups. However, in measures of pain severity there was evidence of greater placebo response among non-melancholic patients; however, duloxetine’s advantage over placebo was similar in melancholic and non-melancholic patients, since patients without melancholic features exhibited more robust responses to both drug and placebo, when compared with non-melancholic patients.
There does not appear to be a clear consensus as to which class of
antidepressant medication is most efficacious for depressed patients exhibiting
melancholic features. Some studies have demonstrated advantages for TCAs over
SSRIs in the treatment of melancholia [29-32], and these results have found support
from patient-rated assessments of antidepressant efficacy. When melancholic patients
were asked to judge the extent to which previous antidepressant therapies had been
effective, 38% of those who had received TCAs rated them as moderately or totally
effective, compared with 22% of those who had received SSRIs [56]. However, other
studies have found no significant differences in efficacy between SSRIs and TCAs in
melancholic patients [33,35], or in some cases superiority of an SSRI (fluvoxamine) over
a TCA (imipramine) [34,57]. In the absence of clear evidence for superior efficacy of any
one class of medication, the safety and tolerability profile of the SSRIs has led to their
emergence as first line treatment for melancholia. The present study found no
significant differences in efficacy between duloxetine and SSRI comparators within the
subgroup of melancholic patients, although we note that the studies were not powered to
detect such differences. These results suggest that pharmacological treatment of
patients with melancholic features should be assessed on a case-by-case basis, and
emphasize that distinct class effects have yet to be demonstrated consistently within this
group of patients.
Results from the present investigation must be considered in light of several
limitations. Firstly, this was a post-hoc analysis of pooled clinical trial data. Although
subgroup analyses of efficacy assessments stratified by melancholic status were prespecified
in each protocol, the pooling strategies and some of the analyses conducted in
the present investigation were not pre-specified. Secondly, while melancholic features
were evaluated as part of the MINI at study entry, specific melancholic features were not
an entry requirement and randomization was not stratified by melancholic status.
Furthermore, as discussed previously in some detail, the MINI is not an ideal tool for
assessing the presence of melancholic features. Thirdly, the HAMD17 scale has only
limited capability to assess improvement in melancholic symptoms. Anhedonia, one of
the key features of melancholia, is only assessed indirectly as a part of question 7, while
psychomotor agitation is only partially addressed by question 9. Furthermore, items
such as diurnal variation in mood are not specifically measured by the HAMD17.
Fourthly, the group of patients receiving the recommended target dose of duloxetine (60
mg QD) could not be compared head-to-head with SSRIs, as these two studies did not
feature active comparator treatment groups. Finally, although duloxetine demonstrated
significant advantage over placebo on a number of efficacy measures, the individual
studies were powered on the basis of the primary outcome – mean change in HAMD17
total score. Therefore, results from other efficacy measures should be viewed as
secondary in nature. Together, these limitations necessitate that the results from the
present investigation cannot be considered confirmatory. A prospectively designed
clinical trial will be required to confirm the results suggested by the current set of
analyses.Conclusions
In these analyses of pooled data, the efficacy of duloxetine in patients with
melancholic features did not differ significantly from that observed in non-melancholic
patients. Additional prospectively designed clinical trials evaluating duloxetine’s efficacy
in melancholic patients will be required to substantiate the preliminary findings described
here.Competing Interests
Drs. Mallinckrodt, Watkin, Liu, Wohlreich, and Raskin are employees of Eli Lilly
and Company.
Authors’ Contributions
CHM proposed the data pooling strategies, designed the statistical analyses, and
participated in interpretation of data and drafting of the manuscript. MMW, JR, and JGW
participated in interpretation of data and drafting of the manuscript. CL performed the
statistical analyses. All authors read and approved the final manuscript.
Acknowledgements
This work was sponsored by Eli Lilly and Company. All of the authors accept full
responsibility for the conduct of this trial. The authors had full access to all data from the
trial and participated in the decision to publish the data.References
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