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Psychosomatics 46:345-354, August 2005
© 2005 The Academy of Psychosomatic Medicine

Duloxetine for the Treatment of Major Depressive Disorder in Women Ages 40 to 55 Years

Vivien K. Burt, M.D., Ph.D., Madelaine M. Wohlreich, M.D., Craig H. Mallinckrodt, Ph.D., Michael J. Detke, M.D., Ph.D., John G. Watkin, D.Phil., and Donna E. Stewart, M.D.

Received April 20, 2004; revision received Oct. 26, 2004; accepted Nov. 15, 2004. From the Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Los Angeles; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis; the Department of Psychiatry, Indiana University School of Medicine, Indianapolis; the Department of Psychiatry, McLean Hospital, Belmont, Mass.; the Department of Psychiatry, Harvard Medical School, Boston; and the University Health Network, University of Toronto, Ontario, Canada. Address correspondence and reprint requests to Dr. Wohlreich, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285; mwmd{at}lilly.com (e-mail).


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The efficacy of duloxetine in the treatment of major depressive disorder in women of approximately perimenopausal age (40–55 years; 62 placebo subjects and 55 subjects taking duloxetine, 60 mg/day) was compared with that observed in cohorts of younger (<40 years, 94 placebo subjects and 85 duloxetine subjects) and older (>55 years, 26 placebo subjects and 25 duloxetine subjects) women. Women (ages 40–55 years) receiving duloxetine demonstrated significantly greater improvement in total scores on the 17-item Hamilton Rating Scale for Depression compared with placebo at the study endpoint (week 9). Significant advantages for duloxetine over placebo were observed on 17-item Hamilton depression scale subscales (core, Maier, anxiety, retardation, and sleep), in addition to the Clinical Global Impression severity and Patient Global Impression of Improvement Scale, the Quality of Life in Depression Scale, and Visual Analog Scales assessing pain severity. The magnitude of duloxetine’s treatment effect in women ages 40–55 years was similar to that observed in younger (age <40 years) and older (age >55 years) female patients. In the placebo treatment groups, however, mean changes differed substantially by age group with the smallest placebo responses observed in the 40–55 age group. Duloxetine (60 mg/day) was demonstrated to be an effective treatment for major depressive disorder in this cohort of women ages 40–55 years.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Major depressive disorder represents a formidable challenge, both for the clinician and at the public health level. It is currently the fourth leading cause of disease or disability worldwide and is projected to rise to second place by 2020.1 Women display a greater susceptibility to major depressive disorder, exhibiting a lifetime prevalence of 21% compared with 13% for men. This higher prevalence is concentrated between the age of puberty and menopause.2,3 The gender-related disparity in the prevalence of major depressive disorder is thought to be a result of both neurobiological and psychosocial factors, although the relative influence of these factors remains unclear.4,5

The mean age of menopause in Western countries is 51 years,6 with the transition to menopause encompassing ages 40 to 55 years. It has been hypothesized that the changing reproductive hormone levels occurring during the years leading to menopause (perimenopause) may precipitate mood changes similar to those seen during puberty, premenstruum, and the postpartum period.7 Estrogen has been shown to modulate serotonergic function,8 while both estrogen and progesterone have profound effects upon serotonin (5-HT), norepinephrine, and dopamine receptor systems that are also involved in mood regulation.9 However, investigations of a potential link between menopause and depressed mood have yielded inconsistent results. Some studies have reported that women during their perimenopausal years are at somewhat higher risk for mood disturbances10,11 and also exhibit a higher prevalence of major depression12,13 compared with women in younger age groups. In contrast, many studies have failed to find an association between menopause and depression,10,15–17 and it has been suggested that any observed link may be explained by other factors, such as an increase in vasomotor symptoms and sleep problems occurring in the perimenopausal period.18

Fluctuating reproductive hormone levels are not the only precipitating events that may predispose women to depressive episodes during menopause. Psychosocial influences, in particular the altered roles and relationships associated with age-related changes in women’s lives, may be every bit as influential as concurrent neurobiological changes. Stressful midlife events, such as assuming responsibility for elderly parents, signs of aging, loss of a partner, health problems, and adult children’s crises can lead to an increased vulnerability to the onset of depressive symptoms.19,20 For these reasons, therapeutic approaches involving stress reduction, exercise, lifestyle changes, and psychotherapy should be given due consideration in the choice of an appropriate therapy for menopausal women, especially for milder depressive symptoms.

Pharmacological approaches to the treatment of depression in women transitioning to menopause include antidepressant therapies, estrogen therapy,21–23 and the use of estrogen as augmentative therapy to antidepressant treatment.22,24,25 Although several earlier studies of oral estrogen therapy suggested only limited efficacy, more recent investigations of transdermal estradiol patches11,21 have demonstrated noticeable alleviation of depressive symptoms. However, antidepressant therapy has remained the first-line choice for moderate to severe depression.17,26,27 In addition, recent results from the Women’s Health Initiative have highlighted a number of concerns regarding the use of hormone-replacement therapies,28 leading to a reluctance among both patients and physicians to use these treatments.

Duloxetine is a potent dual reuptake inhibitor of 5-HT and norepinephrine that displays low affinity for a range of other neuronal receptors.29 The efficacy and safety of duloxetine in the treatment of major depressive disorder have been demonstrated in a number of double-blind, placebo-controlled studies.30–33 The current post hoc analysis of pooled data assesses the efficacy of duloxetine (60 mg/day) in depressed women ages 40 to 55 years, the years during which most women undergo perimenopause, and provides comparisons with the efficacy observed in cohorts of older (>55 years) and younger (<40 years) women.


  METHOD

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Data
Data were pooled from two identical, but independently conducted, randomized, double-blind studies of duloxetine in the treatment of major depressive disorder. Patients were randomly assigned to receive duloxetine (60 mg/day, N=251) or placebo (N=261) for 9 weeks of acute-phase therapy. Efficacy analyses focused upon the women who participated in these two studies (duloxetine, N=165, and placebo, N=182).

Selection of Patients
The study participants were required to be at least 18 years of age and provided written informed consent in accordance with the Declaration of Helsinki, Finland, before any study procedures were initiated. All subjects met diagnostic criteria for major depressive disorder defined in the DSM-IV.34 The diagnosis was confirmed with the Mini International Neuropsychiatric Interview.35 All subjects were required to have a 17-item Hamilton Rating Scale for Depression36 total score ≥15 and a Clinical Global Impression (CGI)37 severity score ≥4 at two consecutive screening visits.

Exclusion criteria included the presence of any current and primary axis I disorder (other than major depressive disorder), a primary diagnosis of anxiety disorder within a year of study entry, an axis II disorder that could interfere with compliance with the study protocol, a lack of response of the current depression episode to two or more adequate courses of antidepressant therapy or treatment-resistant depression, any serious medical illness, initiating or stopping psychotherapy within 6 weeks before enrollment or initiating psychotherapy at any time during the study, or a history of substance abuse or dependence within a year of study entry, or a positive urine drug screen.

Study Design
The two studies were randomized, double-blind, parallel-group, placebo-controlled studies conducted at approximately 40 centers in the U.S. The study design incorporated double-blind, variable-expected duration placebo lead-in and lead-out periods to blind subjects and investigators to the start and end of active therapy. Qualified subjects were randomly assigned to placebo or duloxetine, 60 mg/day, in a 1:1 ratio. The actual treatment period lasted 9 weeks. The study drug was provided as three capsules (either placebo or 20 mg of duloxetine in each capsule) taken once in the morning. If necessary, the dose could be reduced to two capsules (duloxetine, 40 mg/day, or two capsules of placebo) but had to be titrated up to three capsules after 3 weeks and maintained at this level for the remainder of the study. Concomitant medications with primarily CNS activity were not allowed, with the exception of either chloral hydrate (up to 1000 mg) or zolpidem (up to 10 mg) for insomnia for up to 6 nights during the study. Chronic use of prescription pain medications was not allowed. Antihypertensive medications were not allowed unless the subject had been taking a stable dose for at least 3 months.

Efficacy Measures
The primary efficacy assessment was the 17-item Hamilton depression scale, recorded at every study visit. Secondary measures included the CGI severity scale, the Patient Global Impression of Improvement Scale,37 Visual Analog Scales for pain,38 the Somatic Symptom Inventory,39 and the Quality of Life in Depression Scale.40

Statistical Methods
All randomly assigned subjects with at least one postbaseline assessment were included in the efficacy analyses. The protocols specified the primary efficacy analysis to be a likelihood-based mixed-effects model repeated measures approach for all continuous efficacy measures except the Quality of Life in Depression Scale, which was only collected once postbaseline. The repeated measures model included the fixed categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline and baseline-by-visit interaction. An unstructured approach was used to model the within-subject error correlations. The Kenward-Roger method was used to estimate denominator degrees of freedom.

Response (≥50% reduction in 17-item Hamilton depression rating scale total score from baseline) and remission (total score ≤7) probabilities were estimated with a categorical mixed-effects model repeated-measures approach. The model structure for this categorical analysis was similar to the one used for the continuous variables, with the addition of a probit link function and a binomial error distribution.

Efficacy results presented throughout this article are from the mixed-effects model repeated-measures analyses unless otherwise noted. The term "significant" indicates statistical significance (p≤0.05). Further details of the statistical methods used in the data analyses have been published elsewhere.30,32


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patient Characteristics
A total of 114 women ages 40–55 years who had at least one postbaseline visit were included in the data analysis. Three subjects who had been randomly assigned to placebo left the study before generating any postbaseline data. Demographic characteristics of the 117 randomly assigned subjects are summarized in Table 1. No significant differences were observed between treatment groups in baseline demographic characteristics or psychiatric history.


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TABLE 1. Baseline Demographic Characteristics and Psychiatric Profile of Female Subjects Ages 40 to 55



Efficacy in Women Ages 40 to 55 Years
Women receiving duloxetine (60 mg/day) had significantly greater improvement (t=–3.57, df=86, p<0.001) in Hamilton depression scale total scores compared with placebo-treated women at the study endpoint (Figure 1). Mean changes for duloxetine were significantly greater than for placebo beginning at week 2 (t=–2.65, df=106, p=0.009) and at all subsequent visits. The estimated probability of response for duloxetine-treated subjects (74.7%) was significantly greater than for subjects receiving placebo (47.0% t=2.18, df=459, p=0.03). The estimated probabilities of remission were 41.8% versus 23.4% for duloxetine and placebo, respectively (t=1.83, df=345, p<0.07). Using last-observation-carried-forward analysis, response rates were 58.2% in the duloxetine (60 mg/day) treatment group versus 32.2% for placebo (P=0.003, cell=1, 1, p=0.008), while remission rates were 34.6% versus 18.6% for duloxetine and placebo, respectively (P=0.027, cell=1, 1, p=0.06).



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FIGURE 1.  Mean Change in Total Score on 17-Item Hamilton Rating Scale for Depression for Female Subjects (ages 40–55 years) Taking Placebo or Duloxetine

*Significant difference between groups (p≤0.05).

**Significant difference between groups (p≤0.005).


Analyses of secondary efficacy measures are summarized in Table 2. Duloxetine-treated subjects demonstrated significantly greater improvement, compared with placebo, on all assessed Hamilton depression subscales (core factor, Maier, anxiety, retardation, and sleep) in addition to Hamilton depression scale item 1 (depressed mood) and item 7 (work and activities). Significant differences between treatment groups were observed at week 1 for the Hamilton depression scale core factor and Maier subscales and sustained at all subsequent visits. Significant improvements for duloxetine-treated subjects, compared with placebo, were first seen at week 2 on the Hamilton depression scale anxiety and retardation subscales and subsequently sustained to endpoint. The subjects receiving duloxetine also demonstrated superiority over placebo in global improvement, as rated by physicians (CGI severity score) and patients (Patient Global Impression of Improvement Scale), as well as quality of life, as measured by the Quality of Life in Depression Scale total score.


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TABLE 2. Summary of Primary and Secondary Depression Efficacy Measures for Female Subjects Ages 40 to 55



A visitwise plot of mean changes in overall pain severity is shown in Figure 2. A significant superiority of duloxetine over placebo was observed at week 1 and at all subsequent time points. After 1 week of therapy, the mean change for duloxetine-treated subjects represented an average improvement in pain severity of 22.3% compared with a 22.0% worsening for placebo-treated subjects. At week 9, the average improvement was 43.0% for duloxetine-treated subjects compared with a 9.5% worsening for those receiving placebo. Mean changes for all Visual Analog Scales and Somatic Symptom Inventory outcomes are summarized in Table 3. Treatment group differences tended to be consistent over time for painful physical symptom outcomes, and therefore, the mean changes listed in Table 3 are from the main effect of treatment in the repeated-measures model. In essence, this term represents the average treatment effect pooled across all patient visits and may be interpreted in a manner similar to that of an area-under-the-curve analysis. Given the fact that the subjects were not specifically screened for the presence or severity of pain, baseline severity was low for some outcomes. Therefore, results for physical symptom measures were also expressed as percentage change in order to depict improvement relative to the baseline severity.



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FIGURE 2.  Percent Change in Overall Pain Severity for Female Subjects (age 40–55 years) Taking Placebo or Duloxetine

*Significant difference between groups (p≤0.05).

**Significant difference between groups (p≤0.005).



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TABLE 3. Summary of Efficacy for Painful Physical Symptoms in Women Ages 40 to 55



Duloxetine-treated women demonstrated significantly greater mean changes, compared with placebo, in overall pain, headache, shoulder pain, interference with daily activities, amount of time in pain while awake, and on the Somatic Symptom Inventory. Mean improvements in pain severity for duloxetine-treated women ranged from 26.8% to 50.7% on the six assessed outcomes, whereas the subjects receiving placebo had mean changes ranging from a 21.8% worsening to a 3.8% improvement (Figure 3). Significant differences between groups in mean change were first seen at week 1 for Visual Analog Scales overall pain, head pain, shoulder pain, interference with daily activities, and pain while awake.



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FIGURE 3.  Percent Change in Pain Severity (main effect of treatment after pooling all visits) for Female Subjects (ages 40–55 years) Taking Placebo or Duloxetine

*Significant difference between groups (p≤0.05).

**Significant difference between groups (p≤0.005).


Age-Related Efficacy in Women
The efficacy of duloxetine in women ages 40–55 years was compared with the efficacy observed in younger (age <40 years) and older (age >55 years) women who participated in these two studies. The total number of subjects in the comparator groups was the following: age <40 years: 85 subjects taking duloxetine and 94 subjects taking placebo; age >55 years: 25 subjects taking duloxetine and 26 subjects taking placebo.

Mean changes in the 17-item total score on the Hamilton depression scale for duloxetine-treated women were similar across the three age groups: age <40 years: –10.80; age 40–55 years: –11.77; age >55 years: –11.40 (Figure 4). In the placebo-treatment groups, mean changes differed substantially by age group, with the smallest placebo responses observed in the 40–55 age group: age <40 years: –8.85; age 40–55 years: –6.13; age >55 years: –7.15 (F=2.45, df=2, 279, p<0.09 for treatment-by-age interaction). Effect sizes for mean change in 17-item Hamilton depression rating scale total score were 0.26 (women age <40), 0.81 (women age 40–55), and 0.78 (women age >55).



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FIGURE 4.  Comparison of Mean Changes in 17-Item Hamilton Depression Scale Total Scores for Female Subjects From Three Different Age Groups Taking Placebo or Duloxetine (60 mg/day)a

aAge <40 years (89 placebo subjects and 81 duloxetine subjects), age 40–55 years (59 placebo subjects and 55 duloxetine subjects), age >55 years (25 placebo subjects and 25 duloxetine subjects).

*Significant difference between groups (p<0.05).

**Significant difference between groups (p<0.001).


Similar results were observed in comparisons of the main effect of treatment for overall pain severity across the three age groups (Figure 5). Improvements for duloxetine-treated subjects were of almost equal magnitude across age groups, ranging from 36.4% to 37.9%. In subjects receiving placebo, responses ranged from a 16.7% improvement in pain severity in the youngest group (<40 years) to an 11.3% worsening in the 40–55 age group. Effect sizes for the main effect of treatment in overall pain were 0.21 (women age <40), 0.49 (women age 40–55), and 0.51 (women age >55).



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FIGURE 5.  Comparison of Main Effect of Treatment of Overall Pain Severity for Female Subjects From Three Different Age Groups Receiving Placebo or Duloxetinea

aAge <40 years (88 placebo subjects and 81 duloxetine subjects), age 40–55 years (60 placebo subjects and 55 duloxetine subjects), age >55 years (25 placebo subjects and 24 duloxetine subjects).

*Significant difference between groups (p<0.05).

**Significant difference between groups (p<0.001).


Efficacy in All Patients
A summary of efficacy outcomes (17-item Hamilton depression scale total score and Visual Analog Scales for overall pain) for all patients within the two studies, together with outcomes analyzed separately by gender, is presented in Table 4. Duloxetine was significantly superior to placebo among all study patients for both mean change in 17-item Hamilton depression scale total score (t=–5.06, df=372, p<0.001, effect size=0.49) and Visual Analog Scales overall pain severity (t=–4.10, df=433, p<0.001, effect size=0.26).


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TABLE 4. Summary of Efficacy for All Patients and Subgroups Taking Placebo or Duloxetine



In addition, mean changes in both CGI severity and Patient Global Impression of Improvement Scale scales for all study patients were significantly greater for duloxetine when compared with placebo (CGI severity scale: t=–4.67, df=370, p<0.001, effect size=0.47; Patient Global Impression of Improvement Scale: t=–4.97, df=352, p<0.001; effect size=0.54). For comparison, effect sizes within the cohort of female patients ages 40–55 were 0.63 (CGI severity scale) and 0.74 (Patient Global Impression of Improvement Scale).


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
In this post hoc analysis of pooled data, duloxetine (60 mg/day) was effective in the acute treatment of major depressive disorder in women ages 40–55 years, the years that for most women will include perimenopause. Results of a comparison of duloxetine’s efficacy in women across three age groups (<40 years, 40–55 years, and >55 years) were noteworthy. The magnitude of improvements in depressive symptom severity in the duloxetine treatment arms were very similar across all age groups. However, responses in the placebo treatment groups differed substantially by age, with the smallest response observed in the 40–55 age group and the most robust placebo response occurring in the youngest group (age <40 years).

In women ages 40–55 years, duloxetine demonstrated significant superiority over placebo on measures of overall depressive symptoms, encompassing both clinician-rated (17-item Hamilton depression scale, CGI severity) and patient-rated (Patient Global Impression of Improvement Scale) scales. Duloxetine treatment also resulted in significant improvements in the patients’ self-assessed quality of life (Quality of Life in Depression Scale).

In addition to the efficacy seen on traditional measures of depressive symptoms, duloxetine produced significant improvements on most measures of painful physical symptoms (Visual Analog Scales, Somatic Symptom Inventory). Perimenopause is frequently accompanied by physical symptoms, including vasomotor symptoms, sleep disturbance, joint aches and pain, and increased headaches. Duloxetine-treated women demonstrated significantly greater improvement, compared with placebo, in the severity of overall pain, headache, shoulder pain, interference with daily activities, and amount of time in pain while awake. The results are noteworthy, given that the patient population was not selected for pain and the study was not powered to observe differences on these measures. The observed efficacy in measures of painful physical symptoms is consistent with the hypothesis that a potent dual reuptake inhibitor of both 5-HT and norepinephrine may be effective in alleviating pain. These findings are consistent with those from other placebo-controlled studies (at doses of 40–120 mg/day)30–33 in which duloxetine was shown to provide effective treatment of both emotional and physical symptoms of depression in male and female subjects ages 18 years and older.

Results from some clinical studies have suggested significant gender and/or age differences in antidepressant treatment response,41–48 although this remains an area of some controversy. Kornstein et al.45 reported that women were significantly more likely to show a favorable response to sertraline than imipramine. When stratified by age group, the rates of response to sertraline and imipramine in women were found to be very similar in the 40–50 and >50 age groups, whereas in women age <40, the response rate was significantly higher for sertraline compared with imipramine. In a separate study of antidepressant response in older and younger women, those age ≤44 years had significantly lower 17-item Hamilton depression rating scale scores compared with older women (>50 years) after 8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI), nefazodone, or venlafaxine. No such effect was seen in a comparison group of male patients.42 In a study of melancholic depressed patients, Joyce et al.44 reported that fluoxetine produced significantly higher rates of response than nortriptyline in the 18–24 age group (67% versus 32%, respectively, p<0.05), although in patients age ≥40 years, the rate of response was higher with nortriptyline, compared with fluoxetine (67% versus 38%, respectively, p=0.12). In melancholic women age 18–24, response rates were >80% for fluoxetine compared with <40% for nortriptyline.

Although these data suggest that younger women may be more responsive to serotonergic as opposed to noradrenergic antidepressants, other studies have found women to be equally responsive to SSRIs and tricyclic antidepressants.49 Furthermore, in an analysis of pooled data from nine studies, Quitkin et al.50 concluded that gender and age (<50 years versus >50 years) did not exert any clinically relevant effects on treatment outcomes.50 This study and others51 also found antidepressant treatment response in women to be independent of menopausal status. In the present study, the treatment effects of duloxetine were of similar magnitude in female patients across all age groups, whereas placebo responses in both depression and pain outcomes showed substantial differences between younger and older women. Additional studies will be required to confirm these preliminary observations of age-related differences in placebo response.

The current results, demonstrating the efficacy of duloxetine in treating painful physical symptoms, are also consistent with literature reports of superior efficacy of dual reuptake inhibitors over SSRIs in the alleviation of pain.52,53 The observation of significant improvements in pain severity in this cohort of women has particular relevance given the higher prevalence of painful physical symptoms in women, compared with men.54 Thus, the present data appear to be consistent with the larger literature on the benefits of antidepressants with multiple actions.55,56

The analyses described in this report have a number of limitations. First, they are post hoc analyses of pooled data from two clinical trials. While the study protocol did specify that treatment group differences would be assessed by gender and age, the specific age group stratification used in this report was not declared a priori. Second, the studies did not collect data regarding the menopausal status of female patients, and thus, the age range of subjects within this analysis (40–55 years) was chosen to encompass the menopausal transition in most women (the mean age at menopause is 51 years).6 Furthermore, although the study assessed longitudinal changes in the severity of painful physical symptoms, the frequency and/or severity of menopausal symptoms such as hot flashes, night sweats, and vaginal dryness were not specifically recorded.


  CONCLUSIONS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The present results suggest that duloxetine (60 mg/day) is efficacious in the acute treatment of major depressive disorder in women ages 40–55 years. Further studies will be required to confirm the applicability of the present results to a wider population of perimenopausal depressed women.


  ACKNOWLEDGMENTS

 
Sponsored by Eli Lilly and Company. Drs. Wohlreich, Mallinckrodt, Detke, and Watkin are employed by Eli Lilly and Company.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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