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Lilly Research Centre, Windlesham, and Gordon Hospital, London, UK
Medical Department, Lilly Spain, Alcobendas, Spain
Lilly Research Laboratories, Indianapolis, Indiana, USA
Imperial College School of Medicine, London, UK
University Hospital of Salamanca, Psychiatric Teaching Area, School of Medicine, University of Salamanca, Salamanca, Spain
Lilly Research Laboratories, Indianapolis and Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, Department of Psychiatry, McLean Hospital, Belmont, Massachusetts and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA
Correspondence: Dr David G. Perahia, Lilly Research Centre, Sunninghill Road, Windlesham, Surrey GU20 6PH, UK. Tel: +44 (0)1276 483 000; fax: +44 (0)1276 483 711; e-mail: d.perahia{at}lilly.com
Declaration of interest D.G.P., I.G., F.W., C.G.W., S.A.H., J.W.C. and M.J.D. are employees and stockholders of Eli Lilly and Company, Indianapolis, Indiana, USA. S.A.M. and A.L.M. have served as paid consultants for Eli Lilly and Company.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Aims Duloxetine, an inhibitor of serotonin and noradrenaline reuptake that is licensed in Europe, the USA and elsewhere for the treatment of depressive episodes, was evaluated with regard to its efficacy, safety and tolerabilityin the prevention of relapse of MDD.
Method Adult out-patients with MDD received duloxetine (60 mg daily) for 12 weeks (n=533). Patients who responded to the drug were then randomised to duloxetine(60 mg daily)(n=136) or orplacebo placebo (n=142) for 26 weeks. The primary measure of efficacy was time to relapse.
Results Patients who received duloxetine (60 mg daily) experienced significantly longer times to relapse of MDD, and better efficacy, global well-being, and quality-of-life outcomes compared with patients who received placebo. It should be noted that adverse events which occur in discontinuation may mimic some signs of depressive relapse, and were not specifically elicited in this study.
Conclusions Duloxetine (60 mg daily) is effective in the prevention of relapse of MDD during continuation treatment.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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METHOD |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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18 and CGI–S
score 4, indicating at least moderate depression. In addition,
participants must have had at least one other major depressive episode before
the episode that was being experienced at the time of entry to the study. Reasons for exclusion from the study included the following: having a current and primary Axis I disorder other than MDD; anxiety disorder as a primary diagnosis within 1 year of entry to the study; treatment-resistant depression; serious suicidal risk; and serious medical illness.
Study design
The design was a randomised active-treatment lead-in double-blind
placebo-controlled multicentre parallel-group study of out-patients who met
the DSM–IV criteria for MDD. The study was conducted in France, Italy,
Spain and the USA. The study design (Fig.
1) was similar to that of previous relapse-prevention studies
(Fava et al, 2002;
Schmidt et al, 2002).
During the initial screening phase and before the second visit (week 0), all
participants underwent screening tests in addition to both psychiatric and
physical examinations.
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Continuation phase
Participants were eligible to enter the continuation phase if they met the
following criteria: HRSD17 score 
9; CGI–S score 42; and
no longer meeting the DSM–IV criteria for MDD in weeks 10 and 12 of the
acute phase. Eligible patients were randomised at week 12 to either duloxetine
(60 mg daily) or placebo for 26 weeks. Patients who were randomised to the
placebo arm were tapered with duloxetine (30 mg daily) for 1 week in a
double-blind manner. All continuing participants were assessed during at least
nine scheduled visits from week 13 to week 38. Re-emergence of depressive
symptoms at any time was defined as an HRSD17 score of 12,
prompting weekly visits until an HRSD17 score of <12 was
obtained or the patient met the criteria for relapse. Relapse was defined in
the protocol as an increased CGI–S score of 2 points compared with
that obtained in week 12, as well as meeting the MINI depression module
criteria for MDD at two consecutive visits at least 2 weeks apart.
Participants who experienced a relapse were offered the option of entry into
the rescue phase.
Rescue phase
Participants who experienced relapse during the continuation phase were
offered the option of entry into the double-blind rescue phase at the
investigator’s discretion. Relapsed patients who had been randomised to
placebo were re-initiated on duloxetine (60 mg daily). Relapsed patients who
had been randomised to duloxetine (60 mg daily) had their dose of duloxetine
increased (to 60 mg twice daily). The rescue phase will be discussed in detail
in a later paper.
Follow-up phase
All of the participants entered the follow-up phase after either completing
or discontinuing either the continuation phase or the rescue phase. If
patients were receiving duloxetine, their duloxetine dose was reduced by 50%
for 3 days. Placebo-treated patients continued to receive placebo. In both
cases, participants received no study drug after the third day of the
follow-up phase. After approximately 1 week, efficacy and safety data were
collected.
Assessments
Efficacy
The primary efficacy measure was time from randomisation to relapse for
participants during the continuation phase. Secondary efficacy measures
included HRSD17 total and sub-scale scores, CGI–S scale
score, Patient Global Impression–Improvement (PGI–I;
Guy, 1976) scale score, painful
physical symptoms as assessed by the Symptom Questionnaire – Somatic
Sub-scale (SQ–SS; Kellner,
1987) and visual analogue scales
(DeLoach et al, 1998),
the Quality of Life in Depression Scale (QLDS;
McKenna & Hunt, 1992)
score and the Sheehan Disability Scale (SDS) score to measure disruption of
the patient’s work, social and home life by their symptoms.
Safety and tolerability
During all of the treatment phases, safety and tolerability were evaluated
by collecting and reporting the incidence, severity and seriousness of adverse
events, the reasons for discontinuation, vital signs, body weight and
laboratory investigation results.
Statistical methods
The primary efficacy analysis compared the time from randomisation to
relapse for patients who were receiving duloxetine (60 mg daily) and patients
who were on placebo, using the log-rank test. Time to relapse was defined as
the number of days from the randomisation date to the relapse date. The
analysis included as patients experiencing relapse only those participants who
satisfied the protocol definition of relapse described above.
During the continuation phase, other continuous measures were compared for duloxetine v. placebo by analysis of covariance (ANCOVA), analysis of variance (ANOVA) and/or mixed-model repeated-measures analysis (Mallinckrodt et al, 2001). Unless otherwise specified, mean changes from baseline to end-point were compared, the baseline and end-point being defined as the initial and last observations respectively during each study phase. The ANCOVA model included baseline, treatment and investigator, the ANOVA model included treatment and investigator, and the mixed-model repeated-measures analysis included baseline, visit, treatment, investigator, treatment x visit interaction and baseline x visit interaction. For categorical measures, treatments were compared by Fisher’s exact test.
During the acute phase, baseline and end-point values were compared within
groups using the paired t-test. The mixed-model repeated-measures
analysis during the acute phase included only visit and investigator.
Statistical significance was defined as P0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Baseline characteristics of patients
There were no significant differences in baseline characteristics (ethnic
origin, age or gender) between patients who received duloxetine (60 mg daily)
and those who received placebo during the continuation phase
(Table 1). At the time of
randomisation in week 12 (and therefore at baseline for the continuation phase
of the study) there were no significant differences between participants who
were randomised to the two treatment groups with regard to HRSD17
total score, CGI–S score, PGI–I score and visual analogue scale
overall score.
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Efficacy
Patients who received duloxetine (60 mg daily) during the continuation
phase had a significantly longer time to relapse than patients who were on
placebo (P=0.004). The Kaplan–Meier plot of time to relapse
showed that patients on duloxetine separated from those on placebo as early as
1 month after randomisation (Fig.
2), and that this separation increased over time. At the end of
the study, the estimated probabilities of relapse were 38.3% and 19.7% for
patients who received placebo and duloxetine (60 mg daily) respectively.
Significantly fewer patients who received duloxetine (60 mg daily) relapsed
compared with patients who received placebo (P<0.05)
(Table 2).
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In total, 26 participants (6 patients from the duloxetine (60 mg daily) treatment group and 20 patients from the placebo treatment group) entered the rescue phase without completely satisfying the protocol’s criteria for the definition of relapse. They did have two consecutive visits which met the requirements for relapse, but the second visit occurred less than 2 weeks after the first one. They were entered into the rescue phase because the investigator judged them to require additional therapy, independent of the protocol criteria. However, their average HRSD17 total score before entry into the rescue phase was 18.8. These patients were not considered to be relapsed in the primary efficacy analysis. This is a statistically conservative approach. If these 26 patients had been included as relapsed in the log-rank test, the relative advantage of duloxetine in preventing relapse compared with placebo would have been even greater (Table 2).
Secondary efficacy measures
At the end-point of the acute phase, patients who were receiving duloxetine
(60 mg daily) had a response rate of 68% (defined as a reduction of 50% in
HRSD17 total score) and a remission rate of 53% (defined as an
HRSD17 total score of 7)
(Table 3). Compared with
baseline (week 0), patients’ HRSD17 total scores had
decreased after 1 week of duloxetine (60 mg daily), and were reduced at all
subsequent visits (P<0.005) throughout the acute phase for
patients who remained in the study (Fig.
3).
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During the continuation phase, patients who received duloxetine (60 mg daily) experienced less worsening of depressive symptoms compared with patients who received placebo (P<0.01), as assessed by their change in HRSD17 total scores at all time points from week 14 to week 38 (Fig. 3). The 29 patients who received duloxetine (60 mg daily) and the 58 patients who received placebo who satisfied the protocol’s criteria for relapse (see Method) or who were judged by the investigator to have relapsed (as described earlier) were then offered the option of entry into the study’s rescue phase (Fig. 1). Response and remission rates at the end-point of the rescue phase are shown in Table 3.
The mean change from baseline to end-point for multiple secondary efficacy measures was also examined during the continuation phase. Patients who received duloxetine (60 mg daily) achieved or maintained significantly greater improvement in physical and emotional symptoms (on all measures except visual analogue scales for overall pain) compared with patients who received placebo (Table 4). In addition, for all visits from week 14 to week 38, duloxetine (60 mg daily) treatment was superior to placebo treatment in terms of patients’ PGI–I scores.
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Tolerability and adverse events
Acute phase
Investigators rated the severity of adverse events as mild, moderate or
severe based on the patient’s discomfort, the health risk and/or
interference with the patient’s activity. The five most frequently
reported treatment-linked adverse events were nausea (n=191 (36%);
90% mild to moderate severity), headache (n=108 (20%); 86% mild to
moderate severity); dry mouth (n=96 (18%); 96% mild to moderate
severity); somnolence (n=72 (14%); 85% mild to moderate severity) and
insomnia (n=56; (11%); 79% mild to moderate severity). Adverse events
that were reported as reasons for discontinuation of treatment during the
acute phase (expressed as number of patients and percentage for whom
‘adverse event’ was given as the reason for discontinuation)
included nausea (n=11; 2.1%), somnolence (n=4; 0.8%),
suicide attempts (n=3; 0.6%) and vomiting (n=3; 0.6%). In
addition, one patient died by suicide on day 16 during the acute phase of the
study. The investigator judged the suicide to be unrelated to the study
drug.
Continuation phase
There were no statistically significant differences in the rate of adverse
event reports between patients who received duloxetine and those who received
placebo. During the continuation phase, anxiety, cholelithiasis, spastic
colon, ejaculation failure and gastroesophageal reflux disease were reported
by 1 patient each as reasons for discontinuation of duloxetine (60 mg daily)
(n=5; 3.7%). Back pain, hypomania, insomnia, abnormal liver function
tests and paraesthesia were each reported by 1 patient who was taking placebo
(n=5; 3.5%) as reasons for study discontinuation.
Follow-up phase
No adverse events were reported as reasons for discontinuation during the
follow-up phase. For patients who entered the follow-up phase from the
continuation phase, adverse event rates of more than 2% were reported by
duloxetine-treated patients for the following: dizziness (13.2%); insomnia
(3.9%); headache, abnormal dreams, asthenia, tinnitus and fatigue (2.6% each).
Abdominal pain (upper) and pruritis were each reported by one placebo-treated
patient.
Cardiovascular safety
There were no clinically significant mean changes in blood pressure or
heart rate between baseline and the end-point in any of the groups in any of
the study phases.
Acute phase
There was no significant mean change in patients’ diastolic blood
pressure between baseline and the end-point during this phase. Average heart
rate increased by approximately 1.7 beats/minute (P<0.005) and
average systolic blood pressure increased by approximately 1.3 mmHg
(P<0.05).
Continuation phase
During this phase there were no significant differences in mean changes in
systolic blood pressure or heart rate between patients who received duloxetine
(60 mg daily) and those who received placebo. Patients who received duloxetine
(60 mg daily) showed increased mean changes in diastolic blood pressure
compared with patients who received placebo (2.0 mmHg v. 71.0 mmHg;
P=0.005).
Laboratory values
There were no clinically significant or persistent changes in laboratory
results for patients who received duloxetine during any of the study phases.
Mild to moderate increases in serum aspartate aminotransferase or alanine
aminotransferase levels were reported for 37 patients during the acute phase.
During the continuation phase, 4 placebo-treated patients and 7
duloxetine-treated patients had elevated alanine aminotransferase levels, and
3 placebo-treated patients and 4 duloxetine-treated patients had elevated
aspartate aminotransferase levels. In all cases, the elevated hepatic enzyme
levels resolved spontaneously and the patients remained in the study. During
the continuation phase, one patient who was treated with placebo for 14 weeks
experienced concomitant elevated transaminase and bilirubin levels, with no
evidence of haemolysis or hyperbilirubinaemia. The patient was withdrawn from
the study and the elevated transaminase and bilirubin levels resolved
spontaneously within 1 month.
One female patient had an increased serum prolactin level (36.5 mg/l; normal range 1.39–54.2 mg/l) 2 days before starting the study drug in the acute phase, and was prescribed nomegestrol acetate for 173 days. At the time of randomisation to duloxetine (60 mg daily) her prolactin level was still elevated (35.6 mcg/l). This patient completed the continuation and follow-up phases of the study.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Continuing treatment
Once an antidepressant has proved to be effective for and well tolerated by
an individual patient during the acute treatment of a depressive episode,
treatment guidelines (e.g. World Health
Organization, 1989) recommend continuing treatment with that
antidepressant for at least a further 6 months to minimise the risk of
depressive relapse. This recommendation is based on data which clearly show
the effectiveness of a number of antidepressants in reducing the risk of
depressive relapse. A recent systematic review of 31 antidepressant trials
found that continuation treatment with antidepressant reduced the odds of
depressive relapse by 70% compared with placebo
(Geddes et al, 2003).
Another recent literature review estimated relapse rates of approximately
33–50% in patients for whom antidepressant treatment is not maintained,
compared with only 10–15% in patients who receive continued treatment
(Hirschfeld, 2001). It must
therefore be possible to demonstrate that an antidepressant has the ability to
prevent relapses of depression as well as having efficacy in the acute
treatment of a depressive episode. In the present study, after 12 weeks of
acute treatment with duloxetine (60 mg daily), 82.6% of patients who were
randomised to continue duloxetine treatment at the same dose for a further 26
weeks remained relapse-free, compared with 71.5% of patients who were
randomised to placebo. This is a statistically and clinically significant
difference which demonstrates the efficacy of duloxetine in the prevention of
depressive relapse. These results are consistent with the findings of similar
studies of other antidepressants, including mirtazapine
(Thase et al, 2001),
citalopram (Montgomery et al,
1993) and escitalopram
(Rapaport et al,
2004).
Symptom resolution
The patient’s expectation of antidepressant therapy is resolution of
the full spectrum of depressive symptoms, and resolution of both the emotional
and somatic symptoms associated with depression is increasingly being
recognised as an important treatment goal
(Fava, 2002). During the
continuation phase of this study, when compared with patients who received
placebo treatment, participants who received duloxetine (60 mg daily)
experienced better maintenance of efficacy as assessed by multiple
clinician-rated and patient self-reported measures of both emotional symptoms
(including the HRSD17 total score, multiple sub-scales of the
HRSD17, PGI–I and CGI–S) and somatic symptoms
(including the HRSD17 item 13 (somatic–general), the
SQ–SS, and 4 out of 5 measures of the visual analogue scales for pain,
namely headaches, back pain, shoulder pain and pain while awake). In addition,
duloxetine-treated patients reported increased interest in daily activities,
improved quality of life (as assessed by the QLDS) and decreased disability
(as assessed by the SDS total score), compared with patients who received
placebo.
Transient worsening and adverse events
Although patients who were treated with duloxetine had better outcomes on
the primary outcome measure and on 17 out of 18 secondary outcome measures
compared with placebo-treated patients, an unexpected finding was the apparent
transient worsening (as indicated by an increase in mean HRSD17
total score) of the condition of patients in both the duloxetine- and
placebo-treated groups for approximately 10 weeks after randomisation, before
there was a subsequent improvement (Fig.
3). The cause of this might be related to a possible state of
uncertainty and anxiety induced in patients who were aware that after the
period of open-label treatment they had a 50% chance of being randomised to
continuation treatment with placebo. Although investigators were also blinded
to the patients’ treatments after randomisation, investigator bias
during the evaluation of patients might also be implicated in this
observation, and it should be noted that the success of blinding for patients
and assessors was not evaluated. A further possible explanation for the
transient worsening of the condition of study participants after randomisation
is the occurrence of adverse events linked to discontinuation in patients who
were randomised to placebo. Such adverse events may mimic the symptoms of a
depressive relapse if they are sufficiently severe and/or long-lived, and were
not explicitly elicited in this study by a specific scale such as the
Discontinuation, Emergent Signs and Symptoms scale
(Rosenbaum et al,
1998). Arguing against this possible explanation is the
observation that transient worsening after randomisation occurred in patients
who were randomised to both placebo and duloxetine, where in the latter group
there was no interruption of duloxetine treatment to permit the appearance of
discontinuation-linked adverse events. The tolerability of duloxetine for
patients with MDD has been well characterised in 6 double-blind
placebo-controlled and active comparator-controlled clinical trials
(Nemeroff et al,
2002). In this study, nausea was the most frequently reported
treatment-linked adverse event during the acute phase. It was most often mild
or moderate in severity, and it was reported as a reason for discontinuation
for 2.1% of patients. These findings are consistent with the results of
previous studies of duloxetine in the acute treatment of MDD. For those
patients who met the entry criteria and proceeded to the continuation phase,
there were no significant differences in the frequencies of treatment-linked
adverse event reporting between patients who received duloxetine and those who
received placebo. The number of adverse events was low overall, with only 5
patients in each treatment group (duloxetine (60 mg daily), n=136;
placebo, n=142) reporting adverse events as reasons for
discontinuation. Among patients in whom duloxetine (60 mg daily) was well
tolerated (as evidenced by completion of the 12-week acute phase) and
efficacious (as evidenced by meeting the criteria for entry into the
continuation phase), only 3.6% reported any treatment-linked adverse events as
reasons for discontinuation over the next 26 weeks of the study. During both
the acute phase and the continuation phase, duloxetine treatment of patients
with MDD was not associated with clinically important changes in
cardiovascular function or laboratory results between baseline and the
end-point. Although in some cases there were statistically significant changes
in some parameters, these changes were of small magnitude and were not
clinically significant, which suggests that overall duloxetine is well
tolerated during long-term therapy, and that its treatment-linked adverse
event profile is similar to that reported previously for duloxetine in acute
trials and for marketed selective serotonin reuptake inhibitors (SSRIs).
Strengths and limitations
Particular strengths of this study include the following: the relatively
large sample size compared with that of similar studies; the similarity of the
acute phase to clinical practice by virtue of the use of open-label treatment;
the reduction of bias during the continuation phase because of the subsequent
double-blinding of both patients and investigators to active treatment
v. placebo and the taper of duloxetine for patients who received
placebo; the multiple and independent measures of both the emotional and
somatic symptoms associated with MDD; and the evaluation of the efficacy of
dose-doubling as a strategy for patients who are experiencing relapse (to be
discussed elsewhere).
The limitations of the study include the fact that the design did not address the comparison of duloxetine with currently available antidepressants. In addition, caution should be exercised when extrapolating the results reported here (and in most clinical trials) to clinical practice, as the patients in this study may not be entirely representative of the general clinical population for a number of reasons, including the use of inclusion and exclusion criteria during the selection of study participants, and the number and frequency of study visits, neither of which are representative of typical clinical practice.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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REFERENCES |
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Received for publication March 25, 2004. Revision received June 14, 2005. Accepted for publication June 20, 2005.
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