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A randomized, controlled trial of duloxetine alone vs. duloxetine plus a telephone intervention in the treatment of depression
Journal of Affective Disorders 108 (2008) 33 – 41 www.elsevier.com/locate/jad
Research report
A randomized, controlled trial of duloxetine alone vs. duloxetine plus a telephone intervention in the treatment of depression David G.S. Perahia a,b,⁎, Deborah Quail a , Paul Gandhi c , Daniel J. Walker d , Robert C. Peveler c a
c
Lilly Research Centre, Windlesham, UK b The Gordon Hospital, London, UK University of Southampton, School of Medicine, Southampton, UK d Lilly Research Laboratories, Indianapolis, Indiana, USA
Received 9 February 2007; received in revised form 29 August 2007; accepted 30 August 2007 Available online 1 October 2007
Abstract Objective: We hypothesized that combining antidepressant medication with a standardized telephone adherence support intervention would lead to superior outcomes in the treatment of depression compared with antidepressant medication alone. Method: Patients with depression were randomized to receive the antidepressant duloxetine alone (DLX), or duloxetine plus a standardized telephone intervention (DLX + TI), for 12 weeks of open-label treatment. The primary outcome measure was remission (HAMD17 total score ≤7) at study endpoint. Safety and tolerability were assessed via reporting of treatment-emergent adverse events (AEs), vital signs and laboratory measures. The TI was delivered approximately 1, 4, and 9 weeks after initiation of duloxetine. Results: The DLX (N = 485) and DLX + TI (N = 477) groups did not differ significantly at baseline. At study endpoint, remission rates (42.8% vs. 43.5%, P = 0.87), response rates (56.6% vs. 58.4%, P = 0.58) and other secondary outcomes were similar between the groups. A similar proportion of patients in each group completed the study, and adverse event discontinuation rates were not significantly different (10.7% vs. 13.0%, P = 0.318). More AEs were reported by patients in the DLX + TI group, however, and constipation (3.5% vs. 10.1%, P b 0.001) and hot flush (0.2% vs. 1.7%, P = 0.020) were reported by more DLX + TI patients. Adherence to medication was high (N 90% at every visit) in both groups. Conclusions: A telephone intervention in combination with antidepressant medication (duloxetine) did not improve depression outcomes compared with antidepressant alone in this clinical trial, perhaps due to high drug adherence in both treatment groups. Addition of a telephone intervention was, however, associated with increased reporting of AEs. © 2007 Elsevier B.V. All rights reserved. Keywords: Duloxetine; Major depressive disorder; Telephone intervention; Adherence
1. Introduction ⁎ Corresponding author. Lilly Research Centre, Erl Wood, Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK. Tel.: +44 1256 315000; fax: +44 1276 483711. E-mail address: [email protected] (D.G.S. Perahia). 0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.08.023
Telephone interventions have been investigated in a variety of conditions (obsessive compulsive disorder, diabetes, post-myocardial infarction) and for a variety of
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uses (screening, diagnosis, symptom severity rating, compliance monitoring) (Adkins et al., 2006; Bambauer et al., 2005; Farmer et al., 2005; Lapointe et al., 2006; Mataix-Cols and Marks, 2006). Most of the studies focus on the usefulness of telephone support in improving adherence to treatments, but relatively few data are available on the use of telephone support in improving depression outcomes — a 2006 review of the literature found just 6 published papers on telephone interventions for patients with depression (Leach and Christensen, 2006). Despite this, the UK National Institute for Clinical Excellence (NICE) states in its 2004 depression clinical guideline that telephone support “should be considered for all patients, in particular for the monitoring of antidepressant medication regimes” and that such support “can improve the effectiveness of treatments offered” (National Institute for Clinical Excellence (NICE), 2004; Gensichen et al., 2005; Tutty et al., 2000; Hunkeler et al., 2000). Simon and colleagues (2000) demonstrated that feedback (a detailed report on each patient 8 and 16 weeks after the initial prescription) accompanied by treatment plus managed care (a 5 minute telephone call to patients after randomization and at 8 and 16 weeks) resulted in significantly improved scores on depression outcomes compared with usual care. A subsequent trial with a similar study design by Simon et al. (2004) also found that telephone interventions were helpful in improving treatment outcomes in primary care patients with depression. A standardized telephone intervention that had been shown to improve outcomes in depression would be a welcome addition to current treatment options. Our objective, therefore, was to test the hypothesis that the addition of such a telephone intervention to a defined antidepressant drug regimen would improve treatment outcomes in patients with depression. The antidepressant used in this study was duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI) that has been shown to be an effective treatment for patients with major depressive disorder (MDD) (Detke et al., 2002a,b, 2004; Goldstein et al., 2002, 2004; Nemeroff et al., 2002; Perahia et al., 2006).
12 weeks of open-label treatment where eligible patients were randomized to receive either duloxetine 60– 120 mg/day alone (DLX) or duloxetine 60–120 mg/ day plus telephone intervention (DLX + TI). Patients could, at the discretion of the investigator, enter a 2– 3 week medication taper period (study period III) if they completed study period II or discontinued from the study having completed at least 2 weeks of treatment. The primary outcome measure was the proportion of patients achieving a score of ≤ 7 on the 17-item Hamilton Rating Scale for Depression (Hamilton, 1960) (HAMD17) total score (i.e., remission of depressive symptoms) at the end of study period II. Remission, effectively a symptom-free state, should be the goal of therapy as it is associated with a lower risk of relapse and improved functioning. Secondary outcomes included safety, tolerability, and other efficacy measures. The study protocol was approved by each site's ethics committee, in accordance with the principles of the Declaration of Helsinki, and patients provided written informed consent prior to participation in any procedures. All investigators were psychiatrists or primary care physicians with experience of treating patients with depression.
2. Methods
Patients were randomly assigned in a 1:1 ratio to duloxetine 60–120 mg/day alone (DLX) or duloxetine 60– 120 mg/day plus the telephone intervention (DLX + TI). Patients initially received duloxetine 60 mg/day which could be increased or decreased in 30 mg steps after 2 weeks of treatment within the range of 60 to 120 mg/day according to response or tolerability issues. During the optional taper period, duloxetine was gradually discontinued over a maximum of two weeks.
2.1. Study design This was a multi-site, randomized study comprising 12-weeks of treatment in outpatients with major depressive disorder (MDD). Study period I was a 3– 9 day screening phase to determine eligibility of the patient to participate (Fig. 1). Study period II comprised
2.2. Patients Male and female outpatients of at least 18 years of age who, in the opinion of the investigator, met criteria for MDD as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), were recruited from 88 study centers in 11 European countries. Patients were required to have a HAMD17 total score of ≥ 15 at baseline and access to a telephone. Exclusion criteria included any current primary DSMIV Axis I diagnosis other than MDD; lack of response to at least 2 adequate courses of antidepressant therapy during the current episode; and serious suicide risk and/ or a score ≥ 3 on Item 3 (suicide) of the HAMD17 at visit 1 and/or 2 (randomization). 2.3. Treatments
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Fig. 1. Study design. Patients who discontinued the study at Visit 3 or thereafter, or completed Study Period II, could enter the taper period at the investigator's discretion (described in Methods). The intervention (telephone calls) occurred 3 times during the study and are shown as TI1, TI2 and TI3.
Adherence to study medication was expressed as the number of pills taken (calculated from the number of pills dispensed and returned) as a percentage of the number of pills prescribed at each visit. Adherence to study medication was also assessed using the Morisky Medication Adherence Questionnaire (MMAQ) (Morisky et al., 1986). 2.4. The telephone intervention (TI) This was an adjunctive psychoeducational intervention, delivered by a healthcare professional with experience in the clinical management of MDD, via 3 telephone calls over 12 weeks. It was designed to provide information and modify beliefs about the illness and its treatment. It was modeled on a face-to-face intervention utilized in a clinical trial by Peveler et al. (1999) which improved antidepressant drug adherence. The content of the intervention was based on the assumption that psychological factors predicting adherence behaviour are described by 2 relevant health psychology theories — the “common sense” model (CSM; Leventhal et al., 2003) and the Theory of Planned Behaviour (TPB; Fishbein and Ajzen, 2005). The intervention consisted of modules (such as “Review of Symptoms,” “Discussion of Diagnosis” and
“Perceived Competence”) which aim to change these elements of CSM and TPB, and consequently adherence behaviour. Investigators were trained to administer the telephone intervention prior to their participation, with instructions to address the modules item by item with the patient over the telephone using a specially written guidance document. The initial telephone call was expected to last around 30 minutes, and included review of symptoms and discussion about MDD (diagnosis, causes, consequences and treatments) and the patients' emotional and rational responses to treatment. The 2 subsequent calls reviewed progress and experiences on treatment, and followed up on issues or themes arising from the initial call(s). Each of the 3 calls was intended to be made within a specific timeframe, as indicated in Fig. 1. 2.5. Efficacy measures Efficacy was assessed using the HAMD17 total score and subscales (Faries et al., 2000; Maier and Philipp, 1985; Tollefson and Holman, 1993), the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, (Guy, 1976) Visual Analog Scales (VAS) for pain (DeLoach et al., 1998), Beliefs about Medicines Questionnaire (BMQ)
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(Horne and Weinman, 1999), EuroQOL Questionnaire (EQ-5D) (Kind, 1996), 36-item Short-Form Health Survey (SF-36) (Ware et al., 1993), and the Symptom Questionnaire, Somatic Subscale (SQ-SS) (Kellner, 1987). In addition, VAS for Patient Satisfaction with Medication and Treatment Overall (both single-item 100 mm visual analogue scales) were included. 2.6. Safety and tolerability assessments Spontaneously reported adverse events (AEs) and vital signs were recorded at baseline and all subsequent visits. Furthermore, patients in the DLX + TI group could report AEs during the TI calls. An AE was considered treatment emergent if it was new or a worsening of a pre-existing symptom. Vital signs and weight were recorded and blood taken for analysis at baseline and at endpoint. Urinalysis and a drug screen were undertaken during the screening phase. A patient was considered to have a sustained elevation of blood pressure if either: (1) systolic blood pressure was ≥ 140 mm Hg and ≥ 10 mm Hg greater than baseline for 3 consecutive visits, and/or (2) diastolic pressure was ≥ 90 mm Hg and ≥ 10 mm Hg greater than baseline for 3 consecutive visits. 2.7. Statistical analyses The study aimed to enroll 470 patients per treatment arm in order to have 80% power to detect a difference of 10% in remission rate between the DLX alone and DLX + TI groups at the end of study period II, assuming a 43% remission rate on DLX alone (from a meta-analysis of remission rates with duloxetine in placebo-controlled trials with a selective serotonin reuptake inhibitor comparator (Thase et al., 2007)). All analyses were conducted on an intent-to-treat basis meaning that for efficacy analyses, all randomly assigned patients were included if they had a baseline and a post-baseline evaluation of the analysis variable. For baseline, descriptive, and safety analyses, all treated patients were included. Treatment effects were evaluated against a 2-sided significance level of 0.05. The primary outcome measure (remission rate), response rate (a ≥50% decrease from baseline to endpoint on the HAMD17), and the MMAQ were compared between the treatment groups using Cochran–Mantel– Haenszel tests controlling for country, pooling countries with fewer than 10 randomized patients. Analysis of variance (ANOVA) or of covariance (ANCOVA) models were used to analyze continuous variables containing terms for treatment and country and also baseline score for
analyses of changes, e.g. in HAMD17 total score. Both ANCOVA and van Elteren tests controlling for country were used to analyze changes in laboratory analytes since some analytes did not meet distributional assumptions for ANCOVA. In all comparisons where baseline and endpoint were used, baseline refers to the last non-missing observation at or before the randomization visit (visit 2), and endpoint refers to the last non-missing observation after randomization. Fisher's exact test was used to compare the groups with respect to safety variables such as AEs and discontinuation rates. A repeated measures analysis was also conducted for each of the efficacy variables. The model included the fixed categorical effects of treatment, country, visit and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline score and baseline-by-visit interaction. 3. Results 3.1. Patient characteristics Nine hundred sixty-two patients (485 in the DLX group and 477 in the DLX + TI group) were randomly assigned to treatment (Fig. 2). This included 4 patients who were inadvertently placed into the DLX treatment group rather than randomly allocated; these patients were included in the safety but not the efficacy analyses. Mean age of patients was 46 years with almost all being Caucasian and nearly two-thirds female (Table 1). Patients had moderate disease severity at baseline (mean HAMD17 total score of almost 22 and CGI-S mean score of 4.3 in both groups). 3.2. Patient disposition The percentage of patients completing the study was similar between DLX (n = 366 [75.5%]) and DLX + TI (n = 366 [76.7%]) groups. No significant differences were observed in overall AE discontinuation rates (n = 52 [10.7%]) vs. n = 62 [13.0%], P = 0.318), nor in discontinuation due to any individual AE. Nausea was the AE most commonly leading to discontinuation (DLX 3.3% vs. DLX + TI 4.4%, P = 0.405). 3.3. Adherence As measured by pill counts, the percentage of patients adhering to study drug was high and not significantly different between treatment groups. Adherence rates for DLX vs. DLX + TI groups were (least-squares means from ANOVA): baseline to week 2, 98.0% vs. 96.2%;
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Fig. 2. Patient flow diagram. Four patients were inadvertently placed by investigators into the DLX alone treatment group rather than randomly allocated. These patients were included in the safety analyses, but were not included in the efficacy analyses.
week 2 to week 6, 95.7% vs. 95.3%; and week 6 to week 12, 92.1% vs. 92.6%. The percentage of patients adhering to treatment as assessed by the MMAQ did not differ significantly between groups at any visit. The mean (SD) for the last prescribed dose of duloxetine was 78.9 (22.3) mg/day for DLX and 78.0 (21.6) mg/day for DLX + TI. The median and modal dose was 60 mg/day in both treatment groups. 3.4. Efficacy There was no statistically significant difference between groups on the primary outcome, remission rate at endpoint (DLX, 42.8%; DLX + TI, 43.5%, P = 0.873). Response rates were also similar between the treatment groups (DLX, 56.6%; DLX + TI, 58.4%, P = 0.581), and visitwise comparisons of HAMD17 total score mean change from baseline did not differ significantly (Fig. 3). Overall, no significant differences were seen between DLX and DLX + TI groups in change
from baseline to endpoint (or at endpoint for PGI-I and VAS for Patient Satisfaction) on any of the secondary efficacy measures (Table 2), although within-group changes were statistically significant (P ≤ 0.05) for all secondary measures in both groups. 3.5. Safety and tolerability Twenty-eight patients experienced serious AEs during the study (DLX, N = 13; DLX + TI, N = 15) including 1 suicide in the DLX + TI group. The suicide was, in the investigator's opinion, not related to protocol procedures or to study medication. The percentage of patients reporting at least 1 AE was significantly greater in the DLX + TI group (69.8%) than in the DLX group (62.9%, P = 0.024). The most common AE in both groups was nausea. Only constipation (DLX, 3.5%; DLX + TI, 10.1%, P b 0.001) and hot flush (DLX, 0.2%; DLX + TI, 1.7%, P = 0.020) were significantly different between groups (Table 3).
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Table 1 Baseline characteristics
Table 2 Secondary outcomes
Measure
Duloxetine alone Duloxetine + (N = 485) TI (N = 477)
Measure a
Age, years a Ethnicity, n (%) Caucasian African descent Asian Other Gender, n (%) Female Male Age at first MDD episode a Had a previous episode of MDD, % Number of previous episodes a, b Duration of current episode, weeks a Baseline HAMD17 a Baseline CGI-S a
46.4 (12.9)
45.9 (13.2)
482 (99.4) 1 (0.2) 1 (0.2) 1 (0.2)
471 (98.7) 0 (0.0) 5 (1.0) 1 (0.2)
309 (63.7) 176 (36.3) 37.5 (13.3) 68.9 5.1 (7.1) 33.8 (64.5) 21.7 (4.2) 4.3 (0.8)
308 (64.6) 169 (35.4) 37.0 (14.1) 72.4 5.6 (16.5) 30.5 (64.3) 21.6 (4.0) 4.3 (0.8)
HAMD17 total score − 12.42 (0.40) − 12.59 (0.40) CGI-S − 1.89 (0.07) − 1.96 (0.07) PGI-I b 2.49 (0.08) 2.49 (0.08) SF-36 Mental Component 16.33 (0.79) 16.05 (0.79) SF-36 Physical Component 2.16 (0.39) 2.10 (0.39) BMQ Concerns 1.66 (0.22) 1.69 (0.22) BMQ Difference − 1.06 (0.29) − 1.15 (0.29) BMQ Necessity 0.61 (0.22) 0.51 (0.22) EuroQol Health State 0.24 (0.02) 0.24 (0.02) EuroQol VAS 22.5 (1.3) 22.3 (1.4) SQSS (somatic score) − 3.40 (0.23) − 3.42 (0.23) VAS overall pain −11.15 (1.33) − 11.49 (1.34) Satisfaction with medication 66.2 (1.83) 69.4 (1.83) during study b Satisfaction with treatment 73.4 (1.68) 75.2 (1.67) overall b
TI = Telephone Intervention. a Mean (SD). b Refers to only those patients with 1 or more previous episodes. Patients from 11 European countries participated in this study.
When AEs reported during the telephone calls were excluded, the percentage of patients reporting at least 1 AE was not significantly different between the DLX + TI (63.9%) and the DLX (62.9%, P = 0.738) groups. Frequencies of constipation (DLX, 3.5%; DLX + TI, 9.4%, P b 0.001) and hot flush (DLX, 0.2%; DLX + TI, 1.5%, P = 0.037) remain significantly different however. During the optional taper phase, the percentage of patients reporting at least 1 discontinuation-emergent adverse event (DEAE) was not significantly different between groups (DLX, 9.1%; DLX + TI, 10.7%, P = 0.450). The most common DEAE in both groups was dizziness (2.3% in both). Baseline-to-endpoint mean changes in vital signs were generally small and not significantly different
Fig. 3. HAMD17 total score change over the 12-week treatment period.
Duloxetine (N = 481)
Duloxetine + TI P (N = 477) value 0.717 0.362 0.950 0.754 0.887 0.907 0.780 0.670 0.765 0.916 0.955 0.820 0.120 0.344
a Least Squares (LS) mean change (standard error) except where noted (LOCF: last observation carried forward). LS means were adjusted by country and baseline value where appropriate. P values from ANCOVA or ANOVA model. b Endpoint scores. All within-group changes were statistically significant (P ≤ 0.05).
between groups (data not shown). Five (1.3%) DLX patients and 4 (1.1%) DLX + TI patients met criteria for sustained elevation of blood pressure. There were no statistically significant differences in mean change from baseline to endpoint for any of the 30 laboratory analytes measured except for direct bilirubin (P = 0.043 measured using an ANCOVA model) and inorganic phosphorous (P = 0.026 measured by van Elteren's test), and these differences were not considered to be clinically significant.
Table 3 Treatment-emergent adverse events⁎ Adverse event
Duloxetine (N = 485)
Duloxetine + TI (N = 477)
n
%
n
%
Any AE Nausea Headache Constipation Hyperhidrosis Fatigue Diarrhea Dizziness Dry mouth Hot flush
305 116 65 17 40 43 36 23 26 1
62.9 23.9 13.4 3.5 8.2 8.9 7.4 4.7 5.4 0.2
333 119 54 48 46 40 38 31 41 8
69.8 24.9 11.3 10.1 9.6 8.4 8.0 6.5 8.6 1.7
P value
0.024 0.764 0.330 b0.001 0.498 0.819 0.809 0.264 0.057 0.020
⁎Adverse events that occurred at a rate of at least 5% in 1 treatment group or that were significantly different between treatment groups.
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4. Discussion The addition of a telephone adherence support intervention to a standardized antidepressant regimen did not improve depression outcomes in our study — remission and response rates did not differ significantly between the DLX and DLX + TI treatment groups, and while all efficacy and health outcome measures showed significant within-group improvements in both treatment groups, no significant differences were seen between groups on any of these measures. The lack of at least a trend favouring the DLX + TI group in efficacy outcomes was a surprise, and runs contrary to much of the published literature. Our hypothesis was that patients in the DLX + TI group would show greater symptom improvement as a consequence of improved adherence to antidepressant medication, which would itself result from the education provided by the TI about MDD and the antidepressant medication. Instead, though both treatment groups fared well overall in terms of efficacy outcomes; the patients who received the TI in addition to their antidepressant fared no better than those who received drug alone. The lack of an incremental benefit in the DLX + TI group is consistent with the lack of a difference between the treatment groups in study drug adherence, which was extremely high at every study visit and not different between the study groups. Such high levels of adherence to antidepressant medication, which are unusual in clinical practice (Peveler et al., 1999; Churchill et al., 2001; Katon et al., 2005), meant there was little or no room for improvement in adherence with the result that the TI was unable to influence depression outcomes via this route (Churchill et al., 2001; Katon et al., 2005). While the high levels of treatment adherence may have limited the ability of the TI to influence depression outcomes in this study, there are other possible reasons for a lack of difference between treatment groups. As stated earlier, patients were, as part of the informed consent process, provided with a detailed description of the possible side effects of duloxetine both verbally and in writing. Because such a description was also an element of the TI, patients in the DLX alone treatment group in effect received part of the TI, albeit in a less detailed form and as a one-off experience. Similar information could conceivably also have been obtained by patients in the DLX alone treatment group from other non-study sources. Further factors which may have limited the ability of the TI to influence patient outcomes were that the intervention was not sufficiently effective in producing demonstrable changes in patients' beliefs or behaviour,
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insufficient time was spent on the telephone calls, and/or the frequency of telephone calls was too low. In contrast to our results, a study of nearly 300 patients taking SSRIs for depression found that patients receiving 12–14 psychoeducational telephone calls from nurses in a 16-week period experienced a significant improvement in depressive symptoms after 6 weeks and 6 months compared with patients assigned to usual care (Hunkeler et al., 2000). Consistent with this, Tutty et al. (2000) found that weekly telephone counseling (involving cognitive-behavioral strategies) in addition to antidepressant treatment over a 6-week period resulted in significant improvement in depressive symptoms at a 3-month follow up compared with usual care. An interesting finding was that patients in the DLX + TI treatment group reported significantly more AEs than patients taking DLX alone. One possible reason for this difference is that patients in the DLX + TI group were, by virtue of likely more extensive knowledge of the possible side effects of the antidepressant, ‘primed’ to expect certain side effects, and therefore more likely to notice and hence report these. Another explanation is that patients in the DLX + TI group simply had more opportunity to report AEs because they had 3 telephone contacts with the investigative site in addition to study visits. This hypothesis is at least in part borne out by data from our study — when AEs reported during the scheduled telephone calls are excluded from the AE analysis, there is no longer a significant difference in the overall incidence of patient-reported AEs between the treatment groups. However, a statistically significant excess of constipation and hot flush in the DLX + TI group remains even after AEs reported during the telephone calls are excluded. This finding cannot be easily explained. Further limitations must be kept in mind when interpreting the results of this study. Firstly, the trial was not blinded, introducing the possibility of observer bias. Secondly, the selected nature of the patient population (e.g. inclusion/exclusion criteria, almost exclusively Caucasian) means that data from this study should be extrapolated to a real-life clinical setting with caution. 5. Conclusions Use of a psychoeducational telephone intervention in combination with duloxetine did not improve MDD outcomes compared with duloxetine alone (likely due to the high drug adherence in both treatment groups) but was associated with increased AE reporting. Further study of this evidence-based telephone intervention in a
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more naturalistic setting (in which patient behaviour more resembles that found in clinical practice) is warranted. Role of funding source Funding for this study was provided by Eli Lilly and Company (Indianapolis, IN, USA) and Boehringer Ingelheim (Ingelheim, Germany). The employees of these companies participated in study design; collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Conflict of interest Drs. Perahia, Quail, and Walker are employees of Eli Lilly and Company. Dr. Gandhi is a former employee of Eli Lilly and Company. Drs. Perahia and Gandhi are stockholders of Eli Lilly and Company. Dr. Peveler has received fees for speaking and/or consultancy from the makers of antidepressants including Lilly, Organon, Wyeth, GSK and Pfizer. Acknowledgements This work was sponsored by Eli Lilly and Company (Indianapolis, IN, USA) and Boehringer Ingelheim (Ingelheim, Germany). Some of the data contained in this paper was presented at the 159th annual meeting of the American Psychiatric Association in Toronto, Ontario from May 20–25, 2006. We thank Elizabeth Agostinelli, MA for editorial assistance.
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Fishbein, M., Ajzen, I, 2005. Theory-based behavior change interventions: comments on Hobbis and Sutton. Journal of Health Psychology 10, 27–31. Gensichen, J., Torge, M., Peitz, M., et al., 2005. Case management for the treatment of patients with major depression in general practicesrationale, design and conduct of a cluster randomized controlled trialPRoMPT (Primary care Monitoring for depressive Patient's Trial) [ISCRTN66386086]-study protocol. BMC Public Health 5, 101. Goldstein, D.J., Mallinckrodt, C., Lu, Y., et al., 2002. Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. Journal of Clinical Psychiatry 63, 225–231. Goldstein, D.J., Lu, Y., Detke, M.J., et al., 2004. Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. Journal of Clinical Psychopharmacology 24, 389–399. Guy, W., 1976. ECDEU Assessment Manual for Psychopharmacology, Revised. US Department of Health, Education, and Welfare publication (ADM). National Institute of Mental Health, Rockville, MD, pp. 76–338. Hamilton, M., 1960. A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 56–62. Horne, R., Weinman, J, 1999. Patients' beliefs about prescribed medicines and their role in adherence to treatment in chronic physical illness. Journal of Psychosomatic Research 47, 555–567. Hunkeler, E.M., Meresman, J.F., Hargreaves, W.A., et al., 2000. Efficacy of nurse telehealth care and peer support in augmenting treatment of depression in primary care. Archives of Family Medicine 9, 700–708. Katon, W., Cantrell, C.R., Sokol, M.C., et al., 2005. Impact of antidepressant drug adherence on comorbid medication use and resource utilization. Archives of Internal Medicine 165, 2497–2503. Kellner, R., 1987. A symptom questionnaire. Journal of Clinical Psychiatry 48, 268–274. Kind, P., 1996. The EuroQoL instrument: an index of health-related quality of life, In: Spilker, B. (Ed.), Quality of Life and Pharmacoeconomics in Clinical Trials, 2nd ed. Lippincott-Raven Publishers, Philadelphia, PA, pp. 191–201. Lapointe, F., Lepage, S., Larrivee, L., et al., 2006. Surveillance and treatment of dyslipidemia in the post-infarct patient: can a nurseled management approach make a difference? Canadian Journal of Cardiology 22, 761–767. Leach, L.S., Christensen, H., 2006. A systematic review of telephonebased interventions for mental disorders. Journal of Telemedicine and Telecare 12, 122–129. Leventhal, H., Brissette, I., Leventhal, E.A., 2003. The common sense model of self-regulation of health and illness. In: Cameron, L.D., Leventhal, H. (Eds.), The Self-regulation of Health and Illness Behavior. Taylor & Francis Books, London, UK, pp. 42–65. Maier, W., Philipp, M., 1985. Improving the assessment of severity of depressive states: a reduction of the Hamilton Depression Scale. Pharmacopsychiatry 18, 114–115. Mataix-Cols, D., Marks, I.M., 2006. Self-help with minimal therapist contact for obsessive–compulsive disorder: a review. European Psychiatry 21, 75–80. Morisky, D.E., Green, L.W., Levine, D.M., 1986. Concurrent and predictive validity of a self-reported measure of medication adherence. Medicine Care 24, 67–74. National Institute for Clinical Excellence (NICE), 2004. Depression: management of depression in primary and secondary care. Clinical Guideline 23 Available at: www.nice.org.uk/CG023NICEguideline. Nemeroff, C.B., Schatzberg, A.F., Goldstein, D.J., et al., 2002. Duloxetine for the treatment of major depressive disorder. Psychopharmacology Bulletin 36, 106–132.
D.G.S. Perahia et al. / Journal of Affective Disorders 108 (2008) 33–41 Perahia, D.G., Gilaberte, I., Wang, F., et al., 2006. Duloxetine in the prevention of relapse of major depressive disorder: double-blind placebo-controlled study. British Journal of Psychiatry 188, 346–353. Peveler, R., George, C., Kinmonth, A.-L., et al., 1999. Effect of antidepressant drug counselling and information leaflets on adherence to drug treatment in primary care: randomised controlled trial. British Medical Journal 319, 612–615. Simon, G.E., VonKorff, M., Rutter, C., et al., 2000. Randomised trial of monitoring, feedback, and management of care by telephone to improve treatment of depression in primary care. British Medical Journal 320, 550–554. Simon, G.E., Ludman, E.J., Tutty, S., et al., 2004. Telephone psychotherapy and telephone care management for primary care patients starting antidepressant treatment: a randomized controlled trial. JAMA 292, 935–942.
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Thase, M.E., Pritchett, Y.L., Ossanna, M.J., et al., 2007. Efficacy of duloxetine and selective serotonin reuptake inhibitors: comparisons as assessed by remission rates in patients with major depressive disorder. Journal of Clinical Psychopharmacology 27, 672–676. Tollefson, G.D., Holman, S.L., 1993. Analysis of the Hamilton Depression Rating Scale factors from a double-blind, placebocontrolled trial of fluoxetine in geriatric major depression. International Clinical Psychopharmacology 8, 253–259. Tutty, S., Simon, G., Ludman, E., 2000. Telephone counseling as an adjunct to antidepressant treatment in the primary care system. A pilot study. Effective Clinical Practice 3, 170–178. Ware, J.E., Snow, K.K., Kosinski, M., et al., 1993. SF-36 Health Survey Manual and Interpretation Guide. The Health Institute, New England Medical Center, Boston, MA.
Research report
A randomized, controlled trial of duloxetine alone vs. duloxetine plus a telephone intervention in the treatment of depression David G.S. Perahia a,b,⁎, Deborah Quail a , Paul Gandhi c , Daniel J. Walker d , Robert C. Peveler c a
c
Lilly Research Centre, Windlesham, UK b The Gordon Hospital, London, UK University of Southampton, School of Medicine, Southampton, UK d Lilly Research Laboratories, Indianapolis, Indiana, USA
Received 9 February 2007; received in revised form 29 August 2007; accepted 30 August 2007 Available online 1 October 2007
Abstract Objective: We hypothesized that combining antidepressant medication with a standardized telephone adherence support intervention would lead to superior outcomes in the treatment of depression compared with antidepressant medication alone. Method: Patients with depression were randomized to receive the antidepressant duloxetine alone (DLX), or duloxetine plus a standardized telephone intervention (DLX + TI), for 12 weeks of open-label treatment. The primary outcome measure was remission (HAMD17 total score ≤7) at study endpoint. Safety and tolerability were assessed via reporting of treatment-emergent adverse events (AEs), vital signs and laboratory measures. The TI was delivered approximately 1, 4, and 9 weeks after initiation of duloxetine. Results: The DLX (N = 485) and DLX + TI (N = 477) groups did not differ significantly at baseline. At study endpoint, remission rates (42.8% vs. 43.5%, P = 0.87), response rates (56.6% vs. 58.4%, P = 0.58) and other secondary outcomes were similar between the groups. A similar proportion of patients in each group completed the study, and adverse event discontinuation rates were not significantly different (10.7% vs. 13.0%, P = 0.318). More AEs were reported by patients in the DLX + TI group, however, and constipation (3.5% vs. 10.1%, P b 0.001) and hot flush (0.2% vs. 1.7%, P = 0.020) were reported by more DLX + TI patients. Adherence to medication was high (N 90% at every visit) in both groups. Conclusions: A telephone intervention in combination with antidepressant medication (duloxetine) did not improve depression outcomes compared with antidepressant alone in this clinical trial, perhaps due to high drug adherence in both treatment groups. Addition of a telephone intervention was, however, associated with increased reporting of AEs. © 2007 Elsevier B.V. All rights reserved. Keywords: Duloxetine; Major depressive disorder; Telephone intervention; Adherence
1. Introduction ⁎ Corresponding author. Lilly Research Centre, Erl Wood, Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK. Tel.: +44 1256 315000; fax: +44 1276 483711. E-mail address: [email protected] (D.G.S. Perahia). 0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.08.023
Telephone interventions have been investigated in a variety of conditions (obsessive compulsive disorder, diabetes, post-myocardial infarction) and for a variety of
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uses (screening, diagnosis, symptom severity rating, compliance monitoring) (Adkins et al., 2006; Bambauer et al., 2005; Farmer et al., 2005; Lapointe et al., 2006; Mataix-Cols and Marks, 2006). Most of the studies focus on the usefulness of telephone support in improving adherence to treatments, but relatively few data are available on the use of telephone support in improving depression outcomes — a 2006 review of the literature found just 6 published papers on telephone interventions for patients with depression (Leach and Christensen, 2006). Despite this, the UK National Institute for Clinical Excellence (NICE) states in its 2004 depression clinical guideline that telephone support “should be considered for all patients, in particular for the monitoring of antidepressant medication regimes” and that such support “can improve the effectiveness of treatments offered” (National Institute for Clinical Excellence (NICE), 2004; Gensichen et al., 2005; Tutty et al., 2000; Hunkeler et al., 2000). Simon and colleagues (2000) demonstrated that feedback (a detailed report on each patient 8 and 16 weeks after the initial prescription) accompanied by treatment plus managed care (a 5 minute telephone call to patients after randomization and at 8 and 16 weeks) resulted in significantly improved scores on depression outcomes compared with usual care. A subsequent trial with a similar study design by Simon et al. (2004) also found that telephone interventions were helpful in improving treatment outcomes in primary care patients with depression. A standardized telephone intervention that had been shown to improve outcomes in depression would be a welcome addition to current treatment options. Our objective, therefore, was to test the hypothesis that the addition of such a telephone intervention to a defined antidepressant drug regimen would improve treatment outcomes in patients with depression. The antidepressant used in this study was duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI) that has been shown to be an effective treatment for patients with major depressive disorder (MDD) (Detke et al., 2002a,b, 2004; Goldstein et al., 2002, 2004; Nemeroff et al., 2002; Perahia et al., 2006).
12 weeks of open-label treatment where eligible patients were randomized to receive either duloxetine 60– 120 mg/day alone (DLX) or duloxetine 60–120 mg/ day plus telephone intervention (DLX + TI). Patients could, at the discretion of the investigator, enter a 2– 3 week medication taper period (study period III) if they completed study period II or discontinued from the study having completed at least 2 weeks of treatment. The primary outcome measure was the proportion of patients achieving a score of ≤ 7 on the 17-item Hamilton Rating Scale for Depression (Hamilton, 1960) (HAMD17) total score (i.e., remission of depressive symptoms) at the end of study period II. Remission, effectively a symptom-free state, should be the goal of therapy as it is associated with a lower risk of relapse and improved functioning. Secondary outcomes included safety, tolerability, and other efficacy measures. The study protocol was approved by each site's ethics committee, in accordance with the principles of the Declaration of Helsinki, and patients provided written informed consent prior to participation in any procedures. All investigators were psychiatrists or primary care physicians with experience of treating patients with depression.
2. Methods
Patients were randomly assigned in a 1:1 ratio to duloxetine 60–120 mg/day alone (DLX) or duloxetine 60– 120 mg/day plus the telephone intervention (DLX + TI). Patients initially received duloxetine 60 mg/day which could be increased or decreased in 30 mg steps after 2 weeks of treatment within the range of 60 to 120 mg/day according to response or tolerability issues. During the optional taper period, duloxetine was gradually discontinued over a maximum of two weeks.
2.1. Study design This was a multi-site, randomized study comprising 12-weeks of treatment in outpatients with major depressive disorder (MDD). Study period I was a 3– 9 day screening phase to determine eligibility of the patient to participate (Fig. 1). Study period II comprised
2.2. Patients Male and female outpatients of at least 18 years of age who, in the opinion of the investigator, met criteria for MDD as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), were recruited from 88 study centers in 11 European countries. Patients were required to have a HAMD17 total score of ≥ 15 at baseline and access to a telephone. Exclusion criteria included any current primary DSMIV Axis I diagnosis other than MDD; lack of response to at least 2 adequate courses of antidepressant therapy during the current episode; and serious suicide risk and/ or a score ≥ 3 on Item 3 (suicide) of the HAMD17 at visit 1 and/or 2 (randomization). 2.3. Treatments
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Fig. 1. Study design. Patients who discontinued the study at Visit 3 or thereafter, or completed Study Period II, could enter the taper period at the investigator's discretion (described in Methods). The intervention (telephone calls) occurred 3 times during the study and are shown as TI1, TI2 and TI3.
Adherence to study medication was expressed as the number of pills taken (calculated from the number of pills dispensed and returned) as a percentage of the number of pills prescribed at each visit. Adherence to study medication was also assessed using the Morisky Medication Adherence Questionnaire (MMAQ) (Morisky et al., 1986). 2.4. The telephone intervention (TI) This was an adjunctive psychoeducational intervention, delivered by a healthcare professional with experience in the clinical management of MDD, via 3 telephone calls over 12 weeks. It was designed to provide information and modify beliefs about the illness and its treatment. It was modeled on a face-to-face intervention utilized in a clinical trial by Peveler et al. (1999) which improved antidepressant drug adherence. The content of the intervention was based on the assumption that psychological factors predicting adherence behaviour are described by 2 relevant health psychology theories — the “common sense” model (CSM; Leventhal et al., 2003) and the Theory of Planned Behaviour (TPB; Fishbein and Ajzen, 2005). The intervention consisted of modules (such as “Review of Symptoms,” “Discussion of Diagnosis” and
“Perceived Competence”) which aim to change these elements of CSM and TPB, and consequently adherence behaviour. Investigators were trained to administer the telephone intervention prior to their participation, with instructions to address the modules item by item with the patient over the telephone using a specially written guidance document. The initial telephone call was expected to last around 30 minutes, and included review of symptoms and discussion about MDD (diagnosis, causes, consequences and treatments) and the patients' emotional and rational responses to treatment. The 2 subsequent calls reviewed progress and experiences on treatment, and followed up on issues or themes arising from the initial call(s). Each of the 3 calls was intended to be made within a specific timeframe, as indicated in Fig. 1. 2.5. Efficacy measures Efficacy was assessed using the HAMD17 total score and subscales (Faries et al., 2000; Maier and Philipp, 1985; Tollefson and Holman, 1993), the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, (Guy, 1976) Visual Analog Scales (VAS) for pain (DeLoach et al., 1998), Beliefs about Medicines Questionnaire (BMQ)
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(Horne and Weinman, 1999), EuroQOL Questionnaire (EQ-5D) (Kind, 1996), 36-item Short-Form Health Survey (SF-36) (Ware et al., 1993), and the Symptom Questionnaire, Somatic Subscale (SQ-SS) (Kellner, 1987). In addition, VAS for Patient Satisfaction with Medication and Treatment Overall (both single-item 100 mm visual analogue scales) were included. 2.6. Safety and tolerability assessments Spontaneously reported adverse events (AEs) and vital signs were recorded at baseline and all subsequent visits. Furthermore, patients in the DLX + TI group could report AEs during the TI calls. An AE was considered treatment emergent if it was new or a worsening of a pre-existing symptom. Vital signs and weight were recorded and blood taken for analysis at baseline and at endpoint. Urinalysis and a drug screen were undertaken during the screening phase. A patient was considered to have a sustained elevation of blood pressure if either: (1) systolic blood pressure was ≥ 140 mm Hg and ≥ 10 mm Hg greater than baseline for 3 consecutive visits, and/or (2) diastolic pressure was ≥ 90 mm Hg and ≥ 10 mm Hg greater than baseline for 3 consecutive visits. 2.7. Statistical analyses The study aimed to enroll 470 patients per treatment arm in order to have 80% power to detect a difference of 10% in remission rate between the DLX alone and DLX + TI groups at the end of study period II, assuming a 43% remission rate on DLX alone (from a meta-analysis of remission rates with duloxetine in placebo-controlled trials with a selective serotonin reuptake inhibitor comparator (Thase et al., 2007)). All analyses were conducted on an intent-to-treat basis meaning that for efficacy analyses, all randomly assigned patients were included if they had a baseline and a post-baseline evaluation of the analysis variable. For baseline, descriptive, and safety analyses, all treated patients were included. Treatment effects were evaluated against a 2-sided significance level of 0.05. The primary outcome measure (remission rate), response rate (a ≥50% decrease from baseline to endpoint on the HAMD17), and the MMAQ were compared between the treatment groups using Cochran–Mantel– Haenszel tests controlling for country, pooling countries with fewer than 10 randomized patients. Analysis of variance (ANOVA) or of covariance (ANCOVA) models were used to analyze continuous variables containing terms for treatment and country and also baseline score for
analyses of changes, e.g. in HAMD17 total score. Both ANCOVA and van Elteren tests controlling for country were used to analyze changes in laboratory analytes since some analytes did not meet distributional assumptions for ANCOVA. In all comparisons where baseline and endpoint were used, baseline refers to the last non-missing observation at or before the randomization visit (visit 2), and endpoint refers to the last non-missing observation after randomization. Fisher's exact test was used to compare the groups with respect to safety variables such as AEs and discontinuation rates. A repeated measures analysis was also conducted for each of the efficacy variables. The model included the fixed categorical effects of treatment, country, visit and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline score and baseline-by-visit interaction. 3. Results 3.1. Patient characteristics Nine hundred sixty-two patients (485 in the DLX group and 477 in the DLX + TI group) were randomly assigned to treatment (Fig. 2). This included 4 patients who were inadvertently placed into the DLX treatment group rather than randomly allocated; these patients were included in the safety but not the efficacy analyses. Mean age of patients was 46 years with almost all being Caucasian and nearly two-thirds female (Table 1). Patients had moderate disease severity at baseline (mean HAMD17 total score of almost 22 and CGI-S mean score of 4.3 in both groups). 3.2. Patient disposition The percentage of patients completing the study was similar between DLX (n = 366 [75.5%]) and DLX + TI (n = 366 [76.7%]) groups. No significant differences were observed in overall AE discontinuation rates (n = 52 [10.7%]) vs. n = 62 [13.0%], P = 0.318), nor in discontinuation due to any individual AE. Nausea was the AE most commonly leading to discontinuation (DLX 3.3% vs. DLX + TI 4.4%, P = 0.405). 3.3. Adherence As measured by pill counts, the percentage of patients adhering to study drug was high and not significantly different between treatment groups. Adherence rates for DLX vs. DLX + TI groups were (least-squares means from ANOVA): baseline to week 2, 98.0% vs. 96.2%;
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Fig. 2. Patient flow diagram. Four patients were inadvertently placed by investigators into the DLX alone treatment group rather than randomly allocated. These patients were included in the safety analyses, but were not included in the efficacy analyses.
week 2 to week 6, 95.7% vs. 95.3%; and week 6 to week 12, 92.1% vs. 92.6%. The percentage of patients adhering to treatment as assessed by the MMAQ did not differ significantly between groups at any visit. The mean (SD) for the last prescribed dose of duloxetine was 78.9 (22.3) mg/day for DLX and 78.0 (21.6) mg/day for DLX + TI. The median and modal dose was 60 mg/day in both treatment groups. 3.4. Efficacy There was no statistically significant difference between groups on the primary outcome, remission rate at endpoint (DLX, 42.8%; DLX + TI, 43.5%, P = 0.873). Response rates were also similar between the treatment groups (DLX, 56.6%; DLX + TI, 58.4%, P = 0.581), and visitwise comparisons of HAMD17 total score mean change from baseline did not differ significantly (Fig. 3). Overall, no significant differences were seen between DLX and DLX + TI groups in change
from baseline to endpoint (or at endpoint for PGI-I and VAS for Patient Satisfaction) on any of the secondary efficacy measures (Table 2), although within-group changes were statistically significant (P ≤ 0.05) for all secondary measures in both groups. 3.5. Safety and tolerability Twenty-eight patients experienced serious AEs during the study (DLX, N = 13; DLX + TI, N = 15) including 1 suicide in the DLX + TI group. The suicide was, in the investigator's opinion, not related to protocol procedures or to study medication. The percentage of patients reporting at least 1 AE was significantly greater in the DLX + TI group (69.8%) than in the DLX group (62.9%, P = 0.024). The most common AE in both groups was nausea. Only constipation (DLX, 3.5%; DLX + TI, 10.1%, P b 0.001) and hot flush (DLX, 0.2%; DLX + TI, 1.7%, P = 0.020) were significantly different between groups (Table 3).
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Table 1 Baseline characteristics
Table 2 Secondary outcomes
Measure
Duloxetine alone Duloxetine + (N = 485) TI (N = 477)
Measure a
Age, years a Ethnicity, n (%) Caucasian African descent Asian Other Gender, n (%) Female Male Age at first MDD episode a Had a previous episode of MDD, % Number of previous episodes a, b Duration of current episode, weeks a Baseline HAMD17 a Baseline CGI-S a
46.4 (12.9)
45.9 (13.2)
482 (99.4) 1 (0.2) 1 (0.2) 1 (0.2)
471 (98.7) 0 (0.0) 5 (1.0) 1 (0.2)
309 (63.7) 176 (36.3) 37.5 (13.3) 68.9 5.1 (7.1) 33.8 (64.5) 21.7 (4.2) 4.3 (0.8)
308 (64.6) 169 (35.4) 37.0 (14.1) 72.4 5.6 (16.5) 30.5 (64.3) 21.6 (4.0) 4.3 (0.8)
HAMD17 total score − 12.42 (0.40) − 12.59 (0.40) CGI-S − 1.89 (0.07) − 1.96 (0.07) PGI-I b 2.49 (0.08) 2.49 (0.08) SF-36 Mental Component 16.33 (0.79) 16.05 (0.79) SF-36 Physical Component 2.16 (0.39) 2.10 (0.39) BMQ Concerns 1.66 (0.22) 1.69 (0.22) BMQ Difference − 1.06 (0.29) − 1.15 (0.29) BMQ Necessity 0.61 (0.22) 0.51 (0.22) EuroQol Health State 0.24 (0.02) 0.24 (0.02) EuroQol VAS 22.5 (1.3) 22.3 (1.4) SQSS (somatic score) − 3.40 (0.23) − 3.42 (0.23) VAS overall pain −11.15 (1.33) − 11.49 (1.34) Satisfaction with medication 66.2 (1.83) 69.4 (1.83) during study b Satisfaction with treatment 73.4 (1.68) 75.2 (1.67) overall b
TI = Telephone Intervention. a Mean (SD). b Refers to only those patients with 1 or more previous episodes. Patients from 11 European countries participated in this study.
When AEs reported during the telephone calls were excluded, the percentage of patients reporting at least 1 AE was not significantly different between the DLX + TI (63.9%) and the DLX (62.9%, P = 0.738) groups. Frequencies of constipation (DLX, 3.5%; DLX + TI, 9.4%, P b 0.001) and hot flush (DLX, 0.2%; DLX + TI, 1.5%, P = 0.037) remain significantly different however. During the optional taper phase, the percentage of patients reporting at least 1 discontinuation-emergent adverse event (DEAE) was not significantly different between groups (DLX, 9.1%; DLX + TI, 10.7%, P = 0.450). The most common DEAE in both groups was dizziness (2.3% in both). Baseline-to-endpoint mean changes in vital signs were generally small and not significantly different
Fig. 3. HAMD17 total score change over the 12-week treatment period.
Duloxetine (N = 481)
Duloxetine + TI P (N = 477) value 0.717 0.362 0.950 0.754 0.887 0.907 0.780 0.670 0.765 0.916 0.955 0.820 0.120 0.344
a Least Squares (LS) mean change (standard error) except where noted (LOCF: last observation carried forward). LS means were adjusted by country and baseline value where appropriate. P values from ANCOVA or ANOVA model. b Endpoint scores. All within-group changes were statistically significant (P ≤ 0.05).
between groups (data not shown). Five (1.3%) DLX patients and 4 (1.1%) DLX + TI patients met criteria for sustained elevation of blood pressure. There were no statistically significant differences in mean change from baseline to endpoint for any of the 30 laboratory analytes measured except for direct bilirubin (P = 0.043 measured using an ANCOVA model) and inorganic phosphorous (P = 0.026 measured by van Elteren's test), and these differences were not considered to be clinically significant.
Table 3 Treatment-emergent adverse events⁎ Adverse event
Duloxetine (N = 485)
Duloxetine + TI (N = 477)
n
%
n
%
Any AE Nausea Headache Constipation Hyperhidrosis Fatigue Diarrhea Dizziness Dry mouth Hot flush
305 116 65 17 40 43 36 23 26 1
62.9 23.9 13.4 3.5 8.2 8.9 7.4 4.7 5.4 0.2
333 119 54 48 46 40 38 31 41 8
69.8 24.9 11.3 10.1 9.6 8.4 8.0 6.5 8.6 1.7
P value
0.024 0.764 0.330 b0.001 0.498 0.819 0.809 0.264 0.057 0.020
⁎Adverse events that occurred at a rate of at least 5% in 1 treatment group or that were significantly different between treatment groups.
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4. Discussion The addition of a telephone adherence support intervention to a standardized antidepressant regimen did not improve depression outcomes in our study — remission and response rates did not differ significantly between the DLX and DLX + TI treatment groups, and while all efficacy and health outcome measures showed significant within-group improvements in both treatment groups, no significant differences were seen between groups on any of these measures. The lack of at least a trend favouring the DLX + TI group in efficacy outcomes was a surprise, and runs contrary to much of the published literature. Our hypothesis was that patients in the DLX + TI group would show greater symptom improvement as a consequence of improved adherence to antidepressant medication, which would itself result from the education provided by the TI about MDD and the antidepressant medication. Instead, though both treatment groups fared well overall in terms of efficacy outcomes; the patients who received the TI in addition to their antidepressant fared no better than those who received drug alone. The lack of an incremental benefit in the DLX + TI group is consistent with the lack of a difference between the treatment groups in study drug adherence, which was extremely high at every study visit and not different between the study groups. Such high levels of adherence to antidepressant medication, which are unusual in clinical practice (Peveler et al., 1999; Churchill et al., 2001; Katon et al., 2005), meant there was little or no room for improvement in adherence with the result that the TI was unable to influence depression outcomes via this route (Churchill et al., 2001; Katon et al., 2005). While the high levels of treatment adherence may have limited the ability of the TI to influence depression outcomes in this study, there are other possible reasons for a lack of difference between treatment groups. As stated earlier, patients were, as part of the informed consent process, provided with a detailed description of the possible side effects of duloxetine both verbally and in writing. Because such a description was also an element of the TI, patients in the DLX alone treatment group in effect received part of the TI, albeit in a less detailed form and as a one-off experience. Similar information could conceivably also have been obtained by patients in the DLX alone treatment group from other non-study sources. Further factors which may have limited the ability of the TI to influence patient outcomes were that the intervention was not sufficiently effective in producing demonstrable changes in patients' beliefs or behaviour,
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insufficient time was spent on the telephone calls, and/or the frequency of telephone calls was too low. In contrast to our results, a study of nearly 300 patients taking SSRIs for depression found that patients receiving 12–14 psychoeducational telephone calls from nurses in a 16-week period experienced a significant improvement in depressive symptoms after 6 weeks and 6 months compared with patients assigned to usual care (Hunkeler et al., 2000). Consistent with this, Tutty et al. (2000) found that weekly telephone counseling (involving cognitive-behavioral strategies) in addition to antidepressant treatment over a 6-week period resulted in significant improvement in depressive symptoms at a 3-month follow up compared with usual care. An interesting finding was that patients in the DLX + TI treatment group reported significantly more AEs than patients taking DLX alone. One possible reason for this difference is that patients in the DLX + TI group were, by virtue of likely more extensive knowledge of the possible side effects of the antidepressant, ‘primed’ to expect certain side effects, and therefore more likely to notice and hence report these. Another explanation is that patients in the DLX + TI group simply had more opportunity to report AEs because they had 3 telephone contacts with the investigative site in addition to study visits. This hypothesis is at least in part borne out by data from our study — when AEs reported during the scheduled telephone calls are excluded from the AE analysis, there is no longer a significant difference in the overall incidence of patient-reported AEs between the treatment groups. However, a statistically significant excess of constipation and hot flush in the DLX + TI group remains even after AEs reported during the telephone calls are excluded. This finding cannot be easily explained. Further limitations must be kept in mind when interpreting the results of this study. Firstly, the trial was not blinded, introducing the possibility of observer bias. Secondly, the selected nature of the patient population (e.g. inclusion/exclusion criteria, almost exclusively Caucasian) means that data from this study should be extrapolated to a real-life clinical setting with caution. 5. Conclusions Use of a psychoeducational telephone intervention in combination with duloxetine did not improve MDD outcomes compared with duloxetine alone (likely due to the high drug adherence in both treatment groups) but was associated with increased AE reporting. Further study of this evidence-based telephone intervention in a
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more naturalistic setting (in which patient behaviour more resembles that found in clinical practice) is warranted. Role of funding source Funding for this study was provided by Eli Lilly and Company (Indianapolis, IN, USA) and Boehringer Ingelheim (Ingelheim, Germany). The employees of these companies participated in study design; collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Conflict of interest Drs. Perahia, Quail, and Walker are employees of Eli Lilly and Company. Dr. Gandhi is a former employee of Eli Lilly and Company. Drs. Perahia and Gandhi are stockholders of Eli Lilly and Company. Dr. Peveler has received fees for speaking and/or consultancy from the makers of antidepressants including Lilly, Organon, Wyeth, GSK and Pfizer. Acknowledgements This work was sponsored by Eli Lilly and Company (Indianapolis, IN, USA) and Boehringer Ingelheim (Ingelheim, Germany). Some of the data contained in this paper was presented at the 159th annual meeting of the American Psychiatric Association in Toronto, Ontario from May 20–25, 2006. We thank Elizabeth Agostinelli, MA for editorial assistance.
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