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Comparing venlafaxine extended release and fluoxetine for preventing the recurrence of major depression: Results from the PREVENT study
Journal of Psychiatric Research 45 (2011) 412e420
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Comparing venlafaxine extended release and fluoxetine for preventing the recurrence of major depression: Results from the PREVENT studyq Michael E. Thase a, *, Alan Gelenberg b, Susan G. Kornstein c, James H. Kocsis d, Madhukar H. Trivedi e, Philip Ninan f, Thomas Li g, Ron Pedersen f, Martin Keller h a
University of Pennsylvania, Philadelphia, PA, United States Penn State Hershey College of Medicine, Hershey, PA, United States Virginia Commonwealth University, Richmond, VA, United States d Weill Cornell Medical College, New York, NY, United States e University of Texas Southwestern Medical School, Dallas, TX, United States f Pfizer Inc, formerly Wyeth Research, Collegeville, PA, United States g Formerly with Wyeth Research, Collegeville, PA, United States h Brown University, Providence, RI, United States b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 April 2010 Received in revised form 19 July 2010 Accepted 21 July 2010
This secondary analysis from the Prevention of Recurrent Episodes of Depression with Venlafaxine Extended Release (ER) for Two Years (PREVENT) study compared the efficacy of venlafaxine ER and fluoxetine for the prevention of recurrence in patients with a history of recurrent major depressive disorder (MDD). Patients received double-blind treatment with venlafaxine ER (75e300 mg/d) or fluoxetine (20e60 mg/d) for 10 weeks (acute phase). Responders (17-item Hamilton Rating Scale for Depression [HAM-D17] score 12 and 50% reduction from baseline) continued on the same treatment during the 6-month continuation phase. At the start of the first and second 12-month maintenance phases, venlafaxine ER responders were randomly assigned to receive venlafaxine ER or placebo, whereas patients receiving fluoxetine continued to receive fluoxetine throughout both maintenance phases. The primary outcome was time to recurrence (HAM-D17 > 12, reduction in HAM-D17 score 50% from acute baseline, and meeting DSM-IV criteria for a diagnosis of MDD), which was assessed using KaplaneMeier estimates. Using the primary definition of recurrence, the estimated probability of not experiencing a recurrence was 71.9% for venlafaxine ER (n ¼ 160) and 55.8% for fluoxetine (n ¼ 99) across 24 months of maintenance treatment. For this primary analysis, the overall effect of venlafaxine ER treatment was not statistically significant (p ¼ 0.399) compared with fluoxetine; however, a significant treatment-by-time interaction was observed (p ¼ 0.034). No significant between-group differences were observed with any of the secondary efficacy variables. Venlafaxine ER and fluoxetine were similarly well tolerated across 2 years of maintenance-phase therapy. Ó 2010 Elsevier Ltd. All rights reserved.
Keywords: Venlafaxine extended release Fluoxetine Major depressive disorder PREVENT study
1. Introduction Recurrences following the successful resolution of a major depressive episode (MDE) are common (Mueller et al., 1999). Rates of recurrence approximating 40% within the first year (Solomon et al., 2000) and 85% within 15 years (Mueller et al., 1999) of an
q Research supported by Pfizer Inc, formerly Wyeth Research, Collegeville, PA. * Corresponding author. University of Pennsylvania School of Medicine, 3535 Market Street, Suite 670, Philadelphia, PA 19104-3309, United States. Tel.: þ1 215 746 6680; fax: þ1 215 573 0759. E-mail address: [email protected] (M.E. Thase). 0022-3956/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2010.07.009
index MDE have been observed in naturalistic studies. In addition, the observed risk for recurrence has been shown to correspondingly increase with each new MDE, while the duration of recovery decreases (Solomon et al., 2000; Mueller et al., 1999). To offset such high risks, treatment guidelines recommend maintenance antidepressant therapy in patients with a history of recurrent MDEs (American Psychiatric Association, 2000). In populations of such patients, placebo-controlled studies have established the efficacy of longer-term (12 months) treatment with tricyclic antidepressants (Geddes et al., 2003), selective serotonin reuptake inhibitors (SSRIs) (Lepine et al., 2004; Gilaberte et al., 2001; Hochstrasser et al., 2001), and serotonin-norepinephrine reuptake inhibitors (SNRIs) (Montgomery et al., 2004; Rouillon et al., 2000; Perahia et al., 2006).
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However, few long-term maintenance studies have compared the efficacy of multiple active treatments (Keller, 2006; Shelton, 2004). The Prevention of Recurrent Episodes of Depression with Venlafaxine Extended Release (ER) for Two Years (PREVENT) trial was a multiphase, double-blind study conducted in patients with a history of recurrent major depressive disorder (MDD) treated with venlafaxine ER, fluoxetine, or placebo. Results from other analyses of the PREVENT study (i.e., venlafaxine ER vs. fluoxetine during the acute and continuation phases (Keller et al., 2007b) and venlafaxine ER vs. placebo during the 2 maintenance phases (Kocsis et al., 2007; Keller et al., 2007a)) have been previously reported. The results of the fluoxetine and venlafaxine ER analysis for the 24 months of maintenance treatment are presented here. 2. Materials and methods 2.1. Study design Outpatients with recurrent MDD were enrolled at 36 sites in the United States. The study was conducted from August 2000 through October 2005 in accordance with the Declaration of Helsinki and its amendments. The institutional review boards of each study site approved the study protocol, and all study participants provided written informed consent. Because the primary aim of the study was to compare the efficacy of venlafaxine ER vs. placebo across 1 and 2 years of maintenance therapy, 3 times as many patients were initially randomly assigned to receive double-blind treatment with venlafaxine ER (75e300 mg/d) compared with fluoxetine (20e60 mg/d) at the start of the acute phase (Fig. 1). Patients who experienced a satisfactory therapeutic response (defined as
413
a 17-item Hamilton Rating Scale for Depression [HAM-D17] (Hamilton, 1960) total score 12 and 50% decrease from acutephase baseline) or remission (defined as HAM-D17 7) during the acute phase, moved on to the 6-month continuation phase, with the double-blind preserved. Patients who continued to demonstrate a response at the end of the continuation phase entered the first of 2 successive 12-month maintenance phases (maintenance phase A). At the beginning of maintenance phase A, patients who were receiving venlafaxine ER were randomly assigned to either continue receiving venlafaxine ER or were switched to placebo. Patients continuing to respond to venlafaxine ER at the end of maintenance phase A were randomly assigned again to treatment with either venlafaxine ER or placebo for an additional 12 months (maintenance phase B). Patients who were responders to fluoxetine and who did not relapse during the continuation phase continued double-blind treatment with this medication throughout the 2 maintenance phases. 2.2. Study population 2.2.1. Inclusion criteria Eligible patients included men and women aged 18 years or older who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association, 1994) criteria for MDD, had depressive symptoms for 1 month prior to study enrollment, and met the following criteria for recurrent depression: history of 2 or more prior episodes of MDD in the past 5 years (excluding the current episode) and a well interval of at least 2 months between the end of the previous episode and the beginning of the current episode. In addition, a HAM-D17 total score
Fig. 1. PREVENT Study design. Source: Adapted with permission from Kornstein, 2006 (Kornstein, 2006).
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20 was required at screening and a HAM-D17 18 was required at randomization. 2.2.2. Exclusion criteria Patients who had previously failed to respond to an adequate trial of fluoxetine, venlafaxine, or venlafaxine ER during the current episode of MDD, or during the past 3 years did not respond to 3 previous adequate trials of 2 classes of antidepressant medication, electroconvulsive therapy, or 2 adequate trials of psychotherapy, were excluded. Patients with known hypersensitivity to venlafaxine or fluoxetine were excluded, as were individuals with a history or presence of any clinically significant medical illnesses (Keller et al., 2007a,b; Kocsis et al., 2007). 2.3. Treatment protocol Patients who responded to treatment with venlafaxine ER and who did not relapse during the continuation phase were randomly assigned in a double-blind fashion at a 1:1 ratio to either continue receiving venlafaxine ER or to be switched to placebo at the start of maintenance treatment. As previously noted, fluoxetine-treated patients continued double-blind treatment during the maintenance phases. Patients were administered the same dose received at the end of the continuation phase, with increases allowed to optimize treatment response (up to a maximum dose of venlafaxine ER 300 mg/d or fluoxetine 60 mg/d). Upon study completion or early withdrawal, patients underwent a 4-week taper period, during which each patient’s daily dose was reduced by 1 capsule (i.e., venlafaxine 75 mg/d or fluoxetine 20 mg/d) at weekly intervals, until the patient discontinued the study medication. The taper period was omitted or prolonged if clinically indicated. For patients who withdrew before week 2, or were on the minimum maintenance dose, tapering of study medication was not required. A post-study visit took place approximately 4e10 days after the last dose of the taper period. For patients randomly assigned to placebo, a single down-titration kit, which tapered the dose of venlafaxine ER over 4 weeks, was dispensed at the start of the applicable maintenance phase. 2.4. Efficacy assessments 2.4.1. Primary efficacy assessments The primary efficacy measure was the HAM-D17, which was administered at each monthly visit. The primary outcome was the estimated probability of not experiencing a recurrence of MDD during the 2 years of the combined maintenance treatment (from the start of the first maintenance phase). Recurrence was defined as a HAM-D17 > 12, a reduction in HAM-D17 score from acute-phase baseline 50% at 2 consecutive visits or at the last valid visit prior to study discontinuation, and meeting DSM-IV criteria for MDD as determined by a clinical investigator. 2.4.2. Secondary efficacy assessments A secondary, broader clinical definition of recurrence was also evaluated. This definition included patients who had 1 visit with a HAM-D17 > 12 and a HAM-D17 reduction from baseline 50%, and did not meet the primary definition of recurrence. A committee of experienced study investigators assessed whether each of these patients experienced a recurrence after reviewing the blinded clinical data. Secondary outcome assessments included the Clinical Global ImpressionseSeverity (CGIeS) (Guy, 1976) and Inventory for Depressive SymptomatologyeSelf Report (IDSeSR) (Rush et al., 1986), which were administered monthly, and the Hamilton Rating Scale for Anxiety (Hamilton, 1959), 36-item Short-Form
Health Survey (Ware and Snow, 1993), Quality of Life Enjoyment and Satisfaction Questionnaire (Endicott et al., 1993), Life Enjoyment ScaleeShort Version (Fawcett et al., 1983) and Social Adjustment ScaleeSelf Report (Weissman and Bothwell, 1976), which were administered at each 3-month visit. Additional secondary efficacy measures evaluated during the maintenance phases were the percentage of patients who met alternate definitions of clinical response ([1] reduction in HAM-D17 score of 50% from acute-phase baseline and [2] CGIeS score 2) and rates of remission (HAM-D17 total score 7) and sustained remission (defined as meeting remission criteria at 2 consecutive visits). 2.5. Safety assessments Safety was assessed by monitoring adverse events (AEs), vital sign measurements, and clinical laboratory evaluations. AEs, including date of occurrence, severity, and relationship to study medication, were recorded by study personnel at baseline (day e 1) and every 30 days during the maintenance phases through the end of the study (day 970). Reporting of AEs was based on signs and symptoms reported by the patient and those observed by the investigator. Clinical laboratory parameters (e.g., hematology, hemoglobin, and blood chemistry values) were evaluated at screening, at the beginning of maintenance phase A (day 250), at the end of maintenance phase A (day 610), and at the end of maintenance phase B (day 970). Vital signs (e.g., weight, supine pulse, and blood pressure) were measured at screening, at baseline, and every 30 days during the maintenance phases for the duration of the study (day 970). Serious AEs also were recorded. 2.6. Analysis populations The intent-to-treat (ITT) population included all patients who took at least 1 dose of study medication and had at least 1 HAM-D17 assessment during the maintenance phase in question. The safety population, which was used for all safety analyses, was defined as patients who took at least 1 dose of study medication during the maintenance phases of the study. Patients who were given study medication, but for whom it was not known whether the medication was taken, were assumed to have been treated. A dispensing error that occurred during maintenance phase A caused patients that were assigned to receive placebo to mistakenly receive venlafaxine down-titration kits at more than 1 visit, which necessitated use of efficacy evaluable and safety evaluable populations in the reports of the primary analyses comparing venlafaxine ER and placebo (Kocsis et al., 2007; Keller et al., 2007a). These populations excluded patients who were directly impacted by this error as well as those who were randomly assigned at the same time that this error occurred. Because patients who received placebo were not included in the current analyses, the complete ITT and safety populations for venlafaxine ER and fluoxetine were used, which resulted in the inclusion of 31 and 20 additional patients randomly assigned to venlafaxine ER and fluoxetine, respectively. 2.7. Statistical analyses Statistical analyses were performed using SAS, version 8 software (SAS Institute Inc., Cary, NC). The results from any statistical comparisons of the treatment groups were presented as 2-sided p values rounded to 3 places. The criterion for statistical significance in all comparisons was a p value less than 0.050, unless stated otherwise. The probability of no recurrence for both primary and secondary definitions was estimated using KaplaneMeier methods and compared between the venlafaxine ER and fluoxetine groups using log-rank tests. The survival curves of the placebo arms are
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plotted for illustrative purposes, as no statistical tests comparing placebo are made in this report. The results from the analyses comparing venlafaxine ER and placebo have been published elsewhere (Keller et al., 2007a,b; Kocsis et al., 2007). Safety results were summarized descriptively. 3. Results 3.1. Patients A total of 268 patients who had responded to treatment with venlafaxine ER or fluoxetine during the acute and continuation phases were enrolled in the maintenance treatment period (Fig. 2). During maintenance phase A, a similar percentage of patients withdrew from the study in the venlafaxine ER treatment group (81/164; 49%) compared with the fluoxetine treatment group (57/ 104; 55%). The most common reason for discontinuation in both
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groups was unsatisfactory response with regard to efficacy (venlafaxine ER: 17%; fluoxetine: 16%; Fig. 2). Forty patients who maintained a positive treatment response while receiving venlafaxine ER at the end of maintenance phase A were randomly assigned to receive placebo at the start of maintenance phase B and were censored from the analyses of the second year of maintenance treatment. During the second maintenance phase, 28% (12/43) of patients discontinued treatment with venlafaxine ER and 40% (19/ 47) of patients discontinued treatment with fluoxetine. The most commonly reported reason for discontinuation during maintenance phase B for the venlafaxine ER group was unsatisfactory response with regard to efficacy (4/43; 9%); for the fluoxetine group the most common reason for discontinuation was failure to return (5/47; 11%). Patients received study medication for a mean total duration of approximately 240 days during maintenance phase A at a mean (SD) daily dose of venlafaxine ER 225 69 mg or fluoxetine
Fig. 2. Study flow chart.
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53 13 mg. During maintenance phase B, the mean total duration of venlafaxine treatment was 290 107 days (excluding the taper period), administered at a mean daily dose of 214 75 mg. The mean total duration of fluoxetine treatment was slightly lower (242 133 days [excluding the taper period]), and patients received a mean daily dose of 52 10 mg. 3.2. Demographics and clinical characteristics Overall, the patient demographics and clinical characteristics of the venlafaxine ER and fluoxetine treatment groups were similar at the start of double-blind maintenance-phase therapy (Table 1). At the beginning of the maintenance phases, mean HAM-D17 scores were 4.5 for the venlafaxine ER group and 4.4 for the fluoxetine group and the majority of patients in both groups met remission criteria. 3.3. Efficacy 3.3.1. Primary efficacy outcome Using the primary definition of recurrence, the KaplaneMeier estimated probability of not experiencing a recurrence was 71.9% for the group treated with venlafaxine ER and 55.8% for the group treated with fluoxetine. The difference between treatment groups was not statistically significant (c2 ¼ 0.713; [df ¼ 1]; p ¼ 0.399) (Table 2). However, using a Cox multiple regression analysis, a significant treatment-by-time interaction was observed using the primary definition of recurrence (c2 ¼ 4.480; [df ¼ 1]; p ¼ 0.034), suggesting that the risk for recurrence varied differently over time for the 2 treatments (see Fig. 3A). The analysis using the secondary definition of recurrence also found no statistically significant difference between the groups treated with venlafaxine ER (59.5%) vs. fluoxetine (43.3%; c2 ¼ 2.207; [df ¼ 1]; p ¼ 0.137) over the combined maintenance phases (Fig. 3B). The treatment-by-time interaction analysis using the secondary definition of recurrence did not reach statistical significance (c2 ¼ 2.838; [df ¼ 1]; p ¼ 0.092).
3.3.2. Secondary efficacy outcomes Other secondary and quality of life outcomes were comparable for the venlafaxine ER and fluoxetine treatment groups (Table 3). Response rates during the 2 maintenance phases were generally similar across definitions and comparable for the 2 treatment groups. Likewise, remission rates were comparable for the 2 treatments throughout both maintenance phases. Rates of sustained remission, defined as meeting the criteria for remission for the final 2 visits of the study period, were also comparable for both treatment groups during maintenance phases A and B (Table 3). 3.4. Safety The AEs most commonly reported during the maintenance phases are presented in Table 4. The percentage of patients who discontinued during maintenance phase A due to AEs was comparable in the venlafaxine ER (4%; 6/164) and the fluoxetine (4%; 4/104) treatment groups. During maintenance phase B, discontinuation rates due to AEs were 9% for the fluoxetine treatment group and 2% for the venlafaxine ER group. Small changes in mean vital sign values (from acute baseline to maintenance end point) were observed in the venlafaxine ER and fluoxetine treatment groups. During maintenance phase A, the most commonly reported clinically significant changes in vital signs were decreased supine systolic blood pressure (venlafaxine ER: 4%; fluoxetine: 0%); decreased standing systolic blood pressure (venlafaxine ER: 5%; fluoxetine: 1%); and sustained supine diastolic hypertension (venlafaxine ER: 3%; fluoxetine: 2%). The most commonly reported clinically significant changes in vital signs during maintenance phase B were increased supine and standing systolic blood pressure (venlafaxine ER: 2%; fluoxetine: 0%), and sustained supine diastolic hypertension (venlafaxine ER: 0%; fluoxetine: 2%). During maintenance phase B, 1% of patients treated with venlafaxine ER experienced a clinically significant decrease in pulse rate (40 beats/min [bpm]), and 1% of fluoxetine-treated patients experienced a significant increase in pulse rate (120 bpm). Rates of significant weight gain or loss (7% baseline
Table 1 Patient baseline characteristics and demographics, safety populationa. Maintenance phase Ab
Characteristic
Maintenance phase Bc
Venlafaxine ER (n ¼ 164)
Fluoxetine (n ¼ 104)
Venlafaxine ER (n ¼ 43)
Fluoxetine (n ¼ 47)
Gender, n (%) Male Female
56 (34) 108 (66)
40 (38) 64 (62)
17 (40) 26 (60)
22 (47) 25 (53)
Age, years (range)
42.1 10.5 (22e72)
43.9 11.5 (20e69)
44.8 11.3 (25e72)
46.7 12.9 (21e69)
Duration of current MDD episode, months (range)
6.7 7.0 (1e49)
8.0 7.4 (1e39)
7.0 7.0 (1e35)
7.3 7.5 (1e39)
Ethnicity, n (%) White Black Asian Hispanic Other
137 (84) 12 (7) 4 (2) 6 (4) 5 (3)
90 (87) 5 (5) 1 (<1) 6 (6) 2 (2)
35 (81) 1 (2) 1 (2) 4 (9) 2 (5)
40 (85) 3 (6) 0 (0) 3 (6) 1 (2)
HAM-D17 total Acute phase baseline (range)
22.2 3.3 (18e35)
22.4 3.1 (18e32)
22.2 3.0 (18e30)
22.6 3.1 (18e31)
Maintenance phase baseline (range)
4.5 3.3 (0e16)
4.4 3.4 (0e14)
4.8 2.6 (0e10)
3.9 3.4 (0e18)
HAM-D17 ¼ 17-item Hamilton Rating Scale for Depression; ER ¼ extended release; MDD ¼ major depressive disorder. a Data presented as mean standard deviation unless otherwise indicated. b Acute-phase baseline. c Maintenance-phase baseline.
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Table 2 KaplaneMeier estimates of the probability of no recurrence of MDD with venlafaxine ER or fluoxetine treatment. Venlafaxine ER
Fluoxetine
Estimated probability of no recurrence
Estimated probability of no recurrence
Primary definition of recurrence Month 12 78.3% Month 24 71.9%
75.2% 55.8%
Secondary definition of recurrence Month 12 71.5% Month 24 59.5%
60.5% 43.3%
ER ¼ extended release; MDD ¼ major depressive disorder.
weight) were comparable between the venlafaxine ER and fluoxetine treatment groups during both maintenance phases, with a greater number of patients experiencing significant weight gain than weight loss during maintenance phase A (weight gain in 32% and 29% and weight loss in 17% and 23% of patients in the venlafaxine ER and fluoxetine treatment groups, respectively) and maintenance phase B (weight gain in 47% and 30% and weight loss in 9% and 13% of patients in the venlafaxine ER and fluoxetine treatment groups, respectively). Mean increases in weight from baseline were observed for patients in both treatment groups at the end of maintenance phase A (venlafaxine ER: þ4.3 1.1 kg; fluoxetine: þ4.0 1.6 kg) and at the end of maintenance phase B (venlafaxine ER: þ6.39 11.6 kg; fluoxetine: þ1.61 15.1 kg). There also were few clinically significant changes in laboratory assessments. During maintenance phase A, there were 2 cases of clinically significant hematologic values in the venlafaxine ER treatment group (1 patient [1.2%] had hemoglobin <95 g/dL and 1 patient [1.2%] had a hematocrit <0.32). In addition, there were 12 cases of significant blood chemistry values (venlafaxine ER ¼ 7; fluoxetine ¼ 5) during maintenance phase A. Seven patients (6%) in the venlafaxine ER group and 5 patients (7%) in the fluoxetine group had significant increases in cholesterol. During maintenance phase B, there were 4 cases of clinically significant blood chemistry values (venlafaxine ER ¼ 3; fluoxetine ¼ 1), all of which were increased cholesterol.
4. Discussion During the 2 years of maintenance-phase therapy in the PREVENT study, the groups treated with venlafaxine ER and fluoxetine did not differ significantly with respect to the likelihood of recurrence or secondary outcomes such as measures of depressive symptoms or quality of life. Overall, the recurrence rates observed during the first year of therapy in this study are generally consistent with what has been observed in other longer-term studies of maintenance antidepressant therapy (Geddes et al., 2003; Shelton, 2004). For example, a systematic review of placebo-controlled antidepressant studies using similar designs to evaluate relapse and recurrence prevention in patients with MDD found average recurrence rates of 18% among patients who remained on active therapy for 12 months and 24% during 18e36 months of maintenance treatment. No apparent differences were observed across the various classes of antidepressants that were studied (Geddes et al., 2003). Such cross-study comparisons should be interpreted cautiously due to differences in patient populations and study design, including duration of treatment prior to randomization, duration of follow-up, and definitions of recurrence. The effect of varying time factors as well as symptom criteria used to determine recurrence is illustrated by the results of this study. For example, the estimated probability of recurrence risk
Fig. 3. A) KaplaneMeier estimated probability of no recurrence (primary definition), combined maintenance phases (ITT population). (B) KaplaneMeier estimated probability of no recurrence (secondary definition), combined maintenance phases (ITT population). ER ¼ extended release; ITT, intent to treat.
based on the broader secondary definition of recurrence was up to 14% higher than the rates determined using the primary definition. Looking across both years of double-blind therapy there was a statistically significant treatment-by-time interaction with respect to the primary outcome variable, which reflects a difference in the time course of recurrence risk among the patients treated with the 2 study drugs. Specifically, whereas the groups had similar risks of recurrence during the first year of maintenance-phase treatment, only about 10% of those treated with venlafaxine ER experienced a recurrence during the second year of double-blind
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Table 3 Secondary outcomes (ITT population), Months 12 and 24. Month 12 Venlafaxine ER (n ¼ 160) Symptomatic Assessmentsh HAM-D17 total CGIeS IDSeSR Total Anxiety arousal scale HAM-A Responsea HAM-D17 primaryb HAM-D17 secondaryc CGIc Remissiona,d Sustained remissiona,e QOL and Functional Assessmentsh SF-36f Physical functioning Role functioning-physical Bodily pain General health Vitality Social functioning Role functioning-emotional Physical component summary Mental component summary Q-LES-Qf LESeSf SASeSRg
Month 24 Fluoxetine (n ¼ 99)
Venlafaxine ER (n ¼ 43)
Fluoxetine (n ¼ 45)
7.1 (0.5) 1.9 (0.1)
7.1 (0.7) 2.0 (0.1)
4.8 (0.9) 1.6 (0.2)
5.9 (0.9) 1.7 (0.1)
15.6 (1.0) 5.2 (0.4) 6.2 (0.5)
15.5 (1.3) 5.4 (0.5) 6.1 (0.6)
11.1 (1.9) 3.7 (0.7) 4.9 (0.9)
13.1 (1.8) 4.3 (0.7) 6.5 (0.8)
129 119 116 107 95
(81) (74) (73) (67) (59)
79 67 71 67 52
(80) (68) (72) (68) (53)
40 37 38 33 31
(93) (86) (88) (77) (72)
37 34 35 32 25
(82) (76) (78) (71) (56)
86.9 75.0 75.4 74.6 51.1 71.9 69.6 53.0 44.4 72.9 62.8 1.9
(1.1) (3.0) (1.7) (1.3) (1.9) (1.8) (3.3) (0.6) (1.0) (1.1) (1.7) (0.0)
85.7 80.5 77.9 75.0 56.3 74.7 71.0 53.4 45.3 74.4 65.5 1.9
(1.5) (3.9) (2.2) (1.6) (2.5) (2.3) (4.3) (0.8) (1.4) (1.4) (2.2) (0.0)
87.2 78.7 78.3 74.8 61.2 72.9 86.7 52.5 48.8 76.5 67.9 1.8
(2.3) (6.1) (3.3) (2.4) (3.5) (3.5) (6.2) (1.2) (2.0) (2.1) (3.2) (0.1)
85.4 75.5 74.4 71.5 53.5 69.0 79.0 51.3 46.0 72.4 63.8 1.9
(2.2) (5.9) (3.2) (2.4) (3.4) (3.4) (5.9) (1.2) (1.9) (2.0) (3.2) (0.1)
ER ¼ extended release; HAM-D17 ¼ 17-item Hamilton Rating Scale for Depression; CGIeS ¼ Clinical Global ImpressionseSeverity; IDSeSR ¼ Inventory of Depressive SymptomologyeShort Form; HAM-A ¼ Hamilton Rating Scale for Anxiety; QOL ¼ Quality of Life; SF-36 ¼ 36-Item Short-Form Health Survey; Q-LES-Q ¼ Quality of Life Enjoyment and Satisfaction Questionnaire; LESeS ¼ Life Enjoyment ScaleeShort Version; SASeSR ¼ Social Adjustment ScaleeSelf Report. a Data for clinical response and remission rates presented as n (%). b Primary definition of response was HAM-D17 total score 12 and 50% reduction in HAM-D17 total score vs. acute baseline. c Alternate definitions of response were 50% reduction in HAM-D17 total score vs. acute baseline or CGI score 2with. d Remission defined as HAM-D17 7. e Sustained remission defined as HAM-D17 7 at 2 consecutive study visits. f For this scale, higher scores indicate better functioning. g For this scale, lower scores indicate less impairment. h Data are presented as least squares mean (standard error) unless otherwise indicated.
therapy, as compared with approximately one-third of those treated with fluoxetine. Although a difference of this magnitude could be considered clinically significant, it is also true that none of the other efficacy analyses pertaining to outcomes during the Table 4 Most common treatment-emergent adverse events (10% in Either Treatment Group), safety population. Adverse event, n (%)
Month 12
Month 24
Venlafaxine Fluoxetine Venlafaxine Fluoxetine ER (n ¼ 164) (n ¼ 104) ER (n ¼ 43) (n ¼ 47) Accidental injury Asthenia Headache Infection Pain Dry mouth Weight gain Abnormal dreams Anxiety Dizziness Insomnia Libido decreased Somnolence Upper respiratory infection Sweating Abnormal ejaculationa
16 14 40 11 10 26 19 16 5 20 21 18 8 27 26 20
(10) (9) (24) (7) (6) (16) (12) (10) (3) (12) (13) (11) (5) (16) (16) (12)
15 8 15 6 10 4 14 5 5 3 12 12 10 19 10 9
(14) (8) (14) (6) (10) (4) (13) (5) (5) (3) (12) (12) (10) (18) (10) (9)
ER ¼ extended release; NR ¼ not reported. a Males only (venlafaxine ER ¼ 40; fluoxetine ¼ 29).
8 (19) 2 (5) 6 (14) 4 (9) 2 (5) NR 1 (2) 2 (5) 3 (7) 6 (14) 4 (9) 0 (0) 1 (2) 10 (23) 2 (5) NR
2 (4) 4 (9) 7 (15) 5 (11) 5 (11) NR 2 (4) 1 (2) 5 (11) 2 (4) 4 (9) 3 (6) 0 (0) 3 (6) 2 (4) NR
second year of maintenance-phase treatment documented statistically significant between-group differences and a post hoc adjustment for multiple statistical comparisons would likewise render the difference on the primary analysis non-significant. One possible explanation for the loss of antidepressant efficacy over time is tachyphylaxis (Solomon et al., 2005), which has been suggested to occur more frequently with SSRIs than dual-acting antidepressants (Posternak and Zimmerman, 2005). In another secondary analysis of data from the PREVENT study, the occurrence and predictors of tachyphylaxis, which was defined as the emergence of apathetic depressive symptoms (e.g., loss of energy and motivation, weight gain, cognitive impairment) following a positive treatment response, were assessed in patients treated with venlafaxine ER, fluoxetine and placebo. Although the KaplaneMeier estimates of tachyphylaxis between the active treatment groups were not significantly different, the percentage of fluoxetine-treated patients (26e30%) who met tachyphylaxis criteria and experienced a recurrence during maintenance therapy was statistically significant (p < 0.01) whereas the proportion of venlafaxine ER treated patients (11e15%) who met criteria for tachyphylaxis and experienced a recurrence was not (Rothschild et al., 2009). When results of these 2 sets of analysis are considered together, the findings of the PREVENT study fall short of confirming that there are clinically meaningful differences in recurrence rates across 2 years of maintenance-phase therapy with venlafaxine ER and fluoxetine. Nevertheless, the study was not designed to have
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adequate statistical power to detect moderate-sized differences between the 2 drugs and further research on this topic with larger samples is certainly warranted. As in most clinical trials, the inclusion and exclusion criteria likely resulted in a study sample that is not fully representative of patients in clinical practice, which may limit the generalizability of these results. Further, as is the case in almost all studies of maintenance-phase antidepressant therapy, the study design is considered to be “enriched,” because only patients who responded during the acute phase and did not relapse during the continuation phase entered the maintenance-phase study (Greenhouse et al., 1991). Thus, the same magnitude of preventive efficacy may not be expected if patients who were initially treated with other strategies were placed on these medications for maintenance-phase therapy. A third limitation pertains to attrition, which reduced statistical power, particularly during the second year of maintenance therapy. Finally, the design of the study did not permit valid comparisons between fluoxetine and placebo, nor was there adequate statistical power to detect more modest, but possibly clinically meaningful, between-group differences in recurrence rates or relevant secondary outcomes at the end of 24 months of therapy. Although practice guidelines recognize the importance of achieving remission and using maintenance treatment to prevent relapse and recurrence, treatment guidelines remain nonspecific with regard to the optimal duration of maintenance antidepressant therapy (American Psychiatric Association, 2000). This analysis of the PREVENT study further demonstrates the clinical utility of maintaining antidepressant treatment for up to 2 years following successful acute- and continuation-phase treatment, and provides a valuable addition to the limited number of clinical trials of this duration. Further research is still needed to better characterize differences between antidepressants in maintaining response. Conclusion The PREVENT study showed that 2 years of maintenance treatment with venlafaxine ER was at the least as effective as fluoxetine in preventing recurrence of MDD among patients with recurrent MDD who had achieved and maintained a response to treatment during acute and continuation therapy. Role of funding source This analysis was sponsored by Wyeth Research, Collegeville, Pennsylvania, which was acquired by Pfizer Inc. in October 2009. Wyeth Research had a role in the study design and the decision to submit this manuscript for publication. Contributors Drs. Thase, Gelenberg, Kornstein, Kocsis, Trivedi, Ninan, Keller, and Li, as well as Mr. Pedersen, contributed to the study design, protocol, and analysis of data. All authors contributed to and approved the final manuscript. Conflict of interest Dr. Thase has been an advisor or consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Schering-Plough, Shire, Supernus, Transcept, and Pfizer (formerly Wyeth Research). He has received grant support from Eli Lilly, GlaxoSmithKline, the National Institute of Mental Health, and Sepracor. Dr. Thase has been on the speakers bureau for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Pfizer (formerly Wyeth Research), and holds equity in MedAvante. Dr. Thase receives royalties from American Psychiatric Publishing,
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Guilford Publications, Herald House, and W.W. Norton and Company. His spouse is employed by Embryon, LLC, A Division of Advanced Health Media, LLC (formerly Medesta Publications Group, A Business of Advogent). Dr. Gelenberg has been a consultant to AstraZeneca, Best Practice, Eli Lilly, eResearch Technology, GlaxoSmithKline, Jazz Pharmaceuticals, Lundbeck, Pfizer, Takeda, Wyeth, and ZARS Pharmaceuticals. He has also received grant funding from Eli Lilly and owns stock in Healthcare Technology Systems. Dr. Kornstein has received grants/research support from AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, the Department of Health and Human Services, Eli Lilly, Forest, the National Institute of Mental Health, Novartis, Pfizer, Sepracor, Sanofi-Synthelabo, Takeda, and Wyeth. She has been on advisory boards for Bristol-Myers Squibb, Eli Lilly, Endo, Forest, Neurocrine, Pfizer, Sepracor, Takeda, and Wyeth, and receives book royalties from Guilford Press. Dr. Kocsis has received grants/contracts from AstraZeneca, Burroughs Wellcome Trust, CNS Response, the National Institute on Drug Abuse, the National Institute of Mental Health, Novartis, Pritzker Consortium, Roche, and Sanofi-Aventis. Dr. Kocsis has been on the speakers bureau for AstraZeneca, Merck, Pfizer, and Wyeth, and has been on advisory boards for Pfizer and Wyeth. Dr. Trivedi has received research support from the Agency for Healthcare Research and Quality, Corcept Therapeutics, Cyberonics, Merck, the National Alliance for Research in Schizophrenia and Depression, the National Institute of Mental Health, the National Institute on Drug Abuse, Novartis, Pharmacia and Upjohn, Predix Pharmaceuticals (Epix), Solvay, and Targacept. He has received consulting and speaker fees from Abbott, Abdi Ibrahim, Akzo (Organon Pharmaceuticals), AstraZeneca, BristolMyers Squibb, Cephalon, Evotec, Fabre Kramer Pharmaceuticals, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson PRD, Eli Lilly, Meade Johnson, Medtronic, Neuronetics, Otsuka, Parke-Davis, Pfizer, Sepracor, Shire Development, VantagePoint, and WyethAyerst. Drs Ninan and Li, and Mr Pedersen, are employees of Pfizer Inc, formerly Wyeth Research, Collegeville, Pennsylvania. Dr. Keller has been a consultant for and/or received honoraria from Abbott, Bristol-Myers Squibb, CENEREX, Cephalon, Cypress Bioscience, GlaxoSmithKline, Forest, Janssen, JDS, Medtronic, Organon, Novartis, Pfizer, Roche, Sierra-Neuropharmaceuticals, Solvay, and Wyeth. He has received grant/research support from Pfizer and Wyeth, and has served on advisory boards for Abbott, Bristol-Myers Squibb, CENEREX, Cyberonics, Cypress Bioscience, Forest, Janssen, Neuronetics, Organon, and Pfizer. Acknowledgments Medical writing support was funded by Wyeth and provided by Dennis Stancavish, MA, of Embryon, LLC, A Division of Advanced Health Media, LLC (formerly Medesta Publications Group, A Business of Advogent). References American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: 1994 American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Second Edition. Arlington, VA: 2000. p. vii-87 Endicott J, Nee J, Harrison W, Blumenthal R. Quality of life enjoyment and satisfaction questionnaire: a new measure. Psychopharmacology Bulletin 1993;29:321e6. Fawcett J, Clark DC, Scheftner WA, Gibbons RD. Assessing anhedonia in psychiatric patients. Archives of General Psychiatry 1983;40:79e84.
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Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. The Lancet 2003;361:653e61. Gilaberte I, Montejo AL, de la Gandara J, Perez-Sola V, Bernardo M, Massana J, et al. Fluoxetine in the prevention of depressive recurrences: a double-blind study. Journal of Clinical Psychopharmacology 2001;21:417e24. Greenhouse JB, Stangl D, Kupfer DJ, Prien RF. Methodologic issues in maintenance therapy clinical trials. Archives of General Psychiatry 1991;48:313e8. Guy W, ed. Clinical Global Impressions. Publication ADM 76-338. In: ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare, 1976. p. 217-222 Hamilton M. The assessment of anxiety states by rating. British Journal of Medical Psychology 1959;32:50e5. Hamilton M. A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry 1960;23:56e62. Hochstrasser B, Isaksen PM, Koponen H, Lauritzen L, Mahnert FA, Rouillon F, et al. Prophylactic effect of citalopram in unipolar, recurrent depression: placebocontrolled study of maintenance therapy. British Journal of Psychiatry 2001;178:304e10. Keller MB. Long-term treatment of patients with recurrent unipolar major depression: evidence to clinical practice. CNS Spectrums 2006;11:4e5. Keller MB, Trivedi MH, Thase ME, Shelton RC, Kornstein SG, Nemeroff CB, et al. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: outcomes from the two-year and combined maintenance phases. Journal of Clinical Psychiatry 2007a;68:1246e56. Keller MB, Trivedi MH, Thase ME, Shelton RC, Kornstein SG, Nemeroff CB, et al. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: outcomes from the acute and continuation phases. Biological Psychiatry 2007b;62:1371e9. Kocsis JH, Thase ME, Trivedi MH, Shelton RC, Kornstein SG, Nemeroff CB, et al. Prevention of recurrent episodes of depression with venlafaxine ER in a 1-year maintenance phase from the PREVENT Study. Journal of Clinical Psychiatry 2007;68:1014e23. Kornstein SG. Beyond remission: rationale and design of the Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study. CNS Spectrums 2006;11(12 suppl 15):28e34. Lepine JP, Caillard V, Bisserbe JC, Troy S, Hotton JM, Boyer P. A randomized, placebo-controlled trial of sertraline for prophylactic treatment of highly
recurrent major depressive disorder. American Journal of Psychiatry 2004;161:836e42. Montgomery SA, Entsuah R, Hackett D, Kunz NR, Rudolph RL. Venlafaxine versus placebo in the preventive treatment of recurrent major depression. ournal of Clinical Psychiatry 2004;65:328e36. Mueller TI, Leon AC, Keller MB, Solomon DA, Endicott J, Coryell W, et al. Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. American Journal of Psychiatry 1999;156:1000e6. Perahia DG, Gilaberte I, Wang F, Wiltse CG, Huckins SA, Clemens JW, et al. Duloxetine in the prevention of relapse of major depressive disorder: double-blind placebo-controlled study. British Journal of Psychiatry 2006;188:346e53. Posternak MA, Zimmerman M. Dual reuptake inhibitors incur lower rates of tachyphylaxis than selective serotonin reuptake inhibitors: a retrospective study. ournal of Clinical Psychiatry 2005;66:705e7. Rothschild AJ, Dunlop BW, Dunner DL, Friedman ES, Gelenberg A, Holland P, et al. Assessing rates and predictors of tachyphylaxis during the Prevention of Recurrent Episodes of Depression With Venlafaxine ER for Two Years (PREVENT) Study. sychopharmacology Bulletin 2009;42:5e20. Rouillon F, Warner B, Pezous N, Bisserbe JC. Milnacipran efficacy in the prevention of recurrent depression: a 12-month placebo-controlled study. Milnacipran recurrence prevention study group. nternational Clinical Psychopharmacology 2000;15:133e40. Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C. The Inventory for Depressive Symptomatology (IDS): preliminary findings. sychiatry Research 1986;18:65e87. Shelton CI. Long-term management of major depressive disorder: are differences among antidepressant treatments meaningful? ournal of Clinical Psychiatry 2004;65(Suppl. 17):29e33. Solomon DA, Keller MB, Leon AC, Mueller TI, Lavori PW, Shea MT, et al. Multiple recurrences of major depressive disorder. merican Journal of Psychiatry 2000; 157:229e33. Solomon DA, Leon AC, Mueller TI, Coryell W, Teres JJ, Posternak MA, et al. Tachyphylaxis in unipolar major depressive disorder. ournal of Clinical Psychiatry 2005;66:283e90. Ware JE, Snow KK. SF-36 health survey manual and information guide. Boston, Massachusetts: The Health Institute, New England Medical Center; 1993. Weissman MM, Bothwell S. Assessment of social adjustment by patient self-report. Archives of General Psychiatry 1976;33:1111e5.
Contents lists available at ScienceDirect
Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires
Comparing venlafaxine extended release and fluoxetine for preventing the recurrence of major depression: Results from the PREVENT studyq Michael E. Thase a, *, Alan Gelenberg b, Susan G. Kornstein c, James H. Kocsis d, Madhukar H. Trivedi e, Philip Ninan f, Thomas Li g, Ron Pedersen f, Martin Keller h a
University of Pennsylvania, Philadelphia, PA, United States Penn State Hershey College of Medicine, Hershey, PA, United States Virginia Commonwealth University, Richmond, VA, United States d Weill Cornell Medical College, New York, NY, United States e University of Texas Southwestern Medical School, Dallas, TX, United States f Pfizer Inc, formerly Wyeth Research, Collegeville, PA, United States g Formerly with Wyeth Research, Collegeville, PA, United States h Brown University, Providence, RI, United States b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 April 2010 Received in revised form 19 July 2010 Accepted 21 July 2010
This secondary analysis from the Prevention of Recurrent Episodes of Depression with Venlafaxine Extended Release (ER) for Two Years (PREVENT) study compared the efficacy of venlafaxine ER and fluoxetine for the prevention of recurrence in patients with a history of recurrent major depressive disorder (MDD). Patients received double-blind treatment with venlafaxine ER (75e300 mg/d) or fluoxetine (20e60 mg/d) for 10 weeks (acute phase). Responders (17-item Hamilton Rating Scale for Depression [HAM-D17] score 12 and 50% reduction from baseline) continued on the same treatment during the 6-month continuation phase. At the start of the first and second 12-month maintenance phases, venlafaxine ER responders were randomly assigned to receive venlafaxine ER or placebo, whereas patients receiving fluoxetine continued to receive fluoxetine throughout both maintenance phases. The primary outcome was time to recurrence (HAM-D17 > 12, reduction in HAM-D17 score 50% from acute baseline, and meeting DSM-IV criteria for a diagnosis of MDD), which was assessed using KaplaneMeier estimates. Using the primary definition of recurrence, the estimated probability of not experiencing a recurrence was 71.9% for venlafaxine ER (n ¼ 160) and 55.8% for fluoxetine (n ¼ 99) across 24 months of maintenance treatment. For this primary analysis, the overall effect of venlafaxine ER treatment was not statistically significant (p ¼ 0.399) compared with fluoxetine; however, a significant treatment-by-time interaction was observed (p ¼ 0.034). No significant between-group differences were observed with any of the secondary efficacy variables. Venlafaxine ER and fluoxetine were similarly well tolerated across 2 years of maintenance-phase therapy. Ó 2010 Elsevier Ltd. All rights reserved.
Keywords: Venlafaxine extended release Fluoxetine Major depressive disorder PREVENT study
1. Introduction Recurrences following the successful resolution of a major depressive episode (MDE) are common (Mueller et al., 1999). Rates of recurrence approximating 40% within the first year (Solomon et al., 2000) and 85% within 15 years (Mueller et al., 1999) of an
q Research supported by Pfizer Inc, formerly Wyeth Research, Collegeville, PA. * Corresponding author. University of Pennsylvania School of Medicine, 3535 Market Street, Suite 670, Philadelphia, PA 19104-3309, United States. Tel.: þ1 215 746 6680; fax: þ1 215 573 0759. E-mail address: [email protected] (M.E. Thase). 0022-3956/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2010.07.009
index MDE have been observed in naturalistic studies. In addition, the observed risk for recurrence has been shown to correspondingly increase with each new MDE, while the duration of recovery decreases (Solomon et al., 2000; Mueller et al., 1999). To offset such high risks, treatment guidelines recommend maintenance antidepressant therapy in patients with a history of recurrent MDEs (American Psychiatric Association, 2000). In populations of such patients, placebo-controlled studies have established the efficacy of longer-term (12 months) treatment with tricyclic antidepressants (Geddes et al., 2003), selective serotonin reuptake inhibitors (SSRIs) (Lepine et al., 2004; Gilaberte et al., 2001; Hochstrasser et al., 2001), and serotonin-norepinephrine reuptake inhibitors (SNRIs) (Montgomery et al., 2004; Rouillon et al., 2000; Perahia et al., 2006).
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However, few long-term maintenance studies have compared the efficacy of multiple active treatments (Keller, 2006; Shelton, 2004). The Prevention of Recurrent Episodes of Depression with Venlafaxine Extended Release (ER) for Two Years (PREVENT) trial was a multiphase, double-blind study conducted in patients with a history of recurrent major depressive disorder (MDD) treated with venlafaxine ER, fluoxetine, or placebo. Results from other analyses of the PREVENT study (i.e., venlafaxine ER vs. fluoxetine during the acute and continuation phases (Keller et al., 2007b) and venlafaxine ER vs. placebo during the 2 maintenance phases (Kocsis et al., 2007; Keller et al., 2007a)) have been previously reported. The results of the fluoxetine and venlafaxine ER analysis for the 24 months of maintenance treatment are presented here. 2. Materials and methods 2.1. Study design Outpatients with recurrent MDD were enrolled at 36 sites in the United States. The study was conducted from August 2000 through October 2005 in accordance with the Declaration of Helsinki and its amendments. The institutional review boards of each study site approved the study protocol, and all study participants provided written informed consent. Because the primary aim of the study was to compare the efficacy of venlafaxine ER vs. placebo across 1 and 2 years of maintenance therapy, 3 times as many patients were initially randomly assigned to receive double-blind treatment with venlafaxine ER (75e300 mg/d) compared with fluoxetine (20e60 mg/d) at the start of the acute phase (Fig. 1). Patients who experienced a satisfactory therapeutic response (defined as
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a 17-item Hamilton Rating Scale for Depression [HAM-D17] (Hamilton, 1960) total score 12 and 50% decrease from acutephase baseline) or remission (defined as HAM-D17 7) during the acute phase, moved on to the 6-month continuation phase, with the double-blind preserved. Patients who continued to demonstrate a response at the end of the continuation phase entered the first of 2 successive 12-month maintenance phases (maintenance phase A). At the beginning of maintenance phase A, patients who were receiving venlafaxine ER were randomly assigned to either continue receiving venlafaxine ER or were switched to placebo. Patients continuing to respond to venlafaxine ER at the end of maintenance phase A were randomly assigned again to treatment with either venlafaxine ER or placebo for an additional 12 months (maintenance phase B). Patients who were responders to fluoxetine and who did not relapse during the continuation phase continued double-blind treatment with this medication throughout the 2 maintenance phases. 2.2. Study population 2.2.1. Inclusion criteria Eligible patients included men and women aged 18 years or older who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association, 1994) criteria for MDD, had depressive symptoms for 1 month prior to study enrollment, and met the following criteria for recurrent depression: history of 2 or more prior episodes of MDD in the past 5 years (excluding the current episode) and a well interval of at least 2 months between the end of the previous episode and the beginning of the current episode. In addition, a HAM-D17 total score
Fig. 1. PREVENT Study design. Source: Adapted with permission from Kornstein, 2006 (Kornstein, 2006).
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20 was required at screening and a HAM-D17 18 was required at randomization. 2.2.2. Exclusion criteria Patients who had previously failed to respond to an adequate trial of fluoxetine, venlafaxine, or venlafaxine ER during the current episode of MDD, or during the past 3 years did not respond to 3 previous adequate trials of 2 classes of antidepressant medication, electroconvulsive therapy, or 2 adequate trials of psychotherapy, were excluded. Patients with known hypersensitivity to venlafaxine or fluoxetine were excluded, as were individuals with a history or presence of any clinically significant medical illnesses (Keller et al., 2007a,b; Kocsis et al., 2007). 2.3. Treatment protocol Patients who responded to treatment with venlafaxine ER and who did not relapse during the continuation phase were randomly assigned in a double-blind fashion at a 1:1 ratio to either continue receiving venlafaxine ER or to be switched to placebo at the start of maintenance treatment. As previously noted, fluoxetine-treated patients continued double-blind treatment during the maintenance phases. Patients were administered the same dose received at the end of the continuation phase, with increases allowed to optimize treatment response (up to a maximum dose of venlafaxine ER 300 mg/d or fluoxetine 60 mg/d). Upon study completion or early withdrawal, patients underwent a 4-week taper period, during which each patient’s daily dose was reduced by 1 capsule (i.e., venlafaxine 75 mg/d or fluoxetine 20 mg/d) at weekly intervals, until the patient discontinued the study medication. The taper period was omitted or prolonged if clinically indicated. For patients who withdrew before week 2, or were on the minimum maintenance dose, tapering of study medication was not required. A post-study visit took place approximately 4e10 days after the last dose of the taper period. For patients randomly assigned to placebo, a single down-titration kit, which tapered the dose of venlafaxine ER over 4 weeks, was dispensed at the start of the applicable maintenance phase. 2.4. Efficacy assessments 2.4.1. Primary efficacy assessments The primary efficacy measure was the HAM-D17, which was administered at each monthly visit. The primary outcome was the estimated probability of not experiencing a recurrence of MDD during the 2 years of the combined maintenance treatment (from the start of the first maintenance phase). Recurrence was defined as a HAM-D17 > 12, a reduction in HAM-D17 score from acute-phase baseline 50% at 2 consecutive visits or at the last valid visit prior to study discontinuation, and meeting DSM-IV criteria for MDD as determined by a clinical investigator. 2.4.2. Secondary efficacy assessments A secondary, broader clinical definition of recurrence was also evaluated. This definition included patients who had 1 visit with a HAM-D17 > 12 and a HAM-D17 reduction from baseline 50%, and did not meet the primary definition of recurrence. A committee of experienced study investigators assessed whether each of these patients experienced a recurrence after reviewing the blinded clinical data. Secondary outcome assessments included the Clinical Global ImpressionseSeverity (CGIeS) (Guy, 1976) and Inventory for Depressive SymptomatologyeSelf Report (IDSeSR) (Rush et al., 1986), which were administered monthly, and the Hamilton Rating Scale for Anxiety (Hamilton, 1959), 36-item Short-Form
Health Survey (Ware and Snow, 1993), Quality of Life Enjoyment and Satisfaction Questionnaire (Endicott et al., 1993), Life Enjoyment ScaleeShort Version (Fawcett et al., 1983) and Social Adjustment ScaleeSelf Report (Weissman and Bothwell, 1976), which were administered at each 3-month visit. Additional secondary efficacy measures evaluated during the maintenance phases were the percentage of patients who met alternate definitions of clinical response ([1] reduction in HAM-D17 score of 50% from acute-phase baseline and [2] CGIeS score 2) and rates of remission (HAM-D17 total score 7) and sustained remission (defined as meeting remission criteria at 2 consecutive visits). 2.5. Safety assessments Safety was assessed by monitoring adverse events (AEs), vital sign measurements, and clinical laboratory evaluations. AEs, including date of occurrence, severity, and relationship to study medication, were recorded by study personnel at baseline (day e 1) and every 30 days during the maintenance phases through the end of the study (day 970). Reporting of AEs was based on signs and symptoms reported by the patient and those observed by the investigator. Clinical laboratory parameters (e.g., hematology, hemoglobin, and blood chemistry values) were evaluated at screening, at the beginning of maintenance phase A (day 250), at the end of maintenance phase A (day 610), and at the end of maintenance phase B (day 970). Vital signs (e.g., weight, supine pulse, and blood pressure) were measured at screening, at baseline, and every 30 days during the maintenance phases for the duration of the study (day 970). Serious AEs also were recorded. 2.6. Analysis populations The intent-to-treat (ITT) population included all patients who took at least 1 dose of study medication and had at least 1 HAM-D17 assessment during the maintenance phase in question. The safety population, which was used for all safety analyses, was defined as patients who took at least 1 dose of study medication during the maintenance phases of the study. Patients who were given study medication, but for whom it was not known whether the medication was taken, were assumed to have been treated. A dispensing error that occurred during maintenance phase A caused patients that were assigned to receive placebo to mistakenly receive venlafaxine down-titration kits at more than 1 visit, which necessitated use of efficacy evaluable and safety evaluable populations in the reports of the primary analyses comparing venlafaxine ER and placebo (Kocsis et al., 2007; Keller et al., 2007a). These populations excluded patients who were directly impacted by this error as well as those who were randomly assigned at the same time that this error occurred. Because patients who received placebo were not included in the current analyses, the complete ITT and safety populations for venlafaxine ER and fluoxetine were used, which resulted in the inclusion of 31 and 20 additional patients randomly assigned to venlafaxine ER and fluoxetine, respectively. 2.7. Statistical analyses Statistical analyses were performed using SAS, version 8 software (SAS Institute Inc., Cary, NC). The results from any statistical comparisons of the treatment groups were presented as 2-sided p values rounded to 3 places. The criterion for statistical significance in all comparisons was a p value less than 0.050, unless stated otherwise. The probability of no recurrence for both primary and secondary definitions was estimated using KaplaneMeier methods and compared between the venlafaxine ER and fluoxetine groups using log-rank tests. The survival curves of the placebo arms are
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plotted for illustrative purposes, as no statistical tests comparing placebo are made in this report. The results from the analyses comparing venlafaxine ER and placebo have been published elsewhere (Keller et al., 2007a,b; Kocsis et al., 2007). Safety results were summarized descriptively. 3. Results 3.1. Patients A total of 268 patients who had responded to treatment with venlafaxine ER or fluoxetine during the acute and continuation phases were enrolled in the maintenance treatment period (Fig. 2). During maintenance phase A, a similar percentage of patients withdrew from the study in the venlafaxine ER treatment group (81/164; 49%) compared with the fluoxetine treatment group (57/ 104; 55%). The most common reason for discontinuation in both
415
groups was unsatisfactory response with regard to efficacy (venlafaxine ER: 17%; fluoxetine: 16%; Fig. 2). Forty patients who maintained a positive treatment response while receiving venlafaxine ER at the end of maintenance phase A were randomly assigned to receive placebo at the start of maintenance phase B and were censored from the analyses of the second year of maintenance treatment. During the second maintenance phase, 28% (12/43) of patients discontinued treatment with venlafaxine ER and 40% (19/ 47) of patients discontinued treatment with fluoxetine. The most commonly reported reason for discontinuation during maintenance phase B for the venlafaxine ER group was unsatisfactory response with regard to efficacy (4/43; 9%); for the fluoxetine group the most common reason for discontinuation was failure to return (5/47; 11%). Patients received study medication for a mean total duration of approximately 240 days during maintenance phase A at a mean (SD) daily dose of venlafaxine ER 225 69 mg or fluoxetine
Fig. 2. Study flow chart.
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53 13 mg. During maintenance phase B, the mean total duration of venlafaxine treatment was 290 107 days (excluding the taper period), administered at a mean daily dose of 214 75 mg. The mean total duration of fluoxetine treatment was slightly lower (242 133 days [excluding the taper period]), and patients received a mean daily dose of 52 10 mg. 3.2. Demographics and clinical characteristics Overall, the patient demographics and clinical characteristics of the venlafaxine ER and fluoxetine treatment groups were similar at the start of double-blind maintenance-phase therapy (Table 1). At the beginning of the maintenance phases, mean HAM-D17 scores were 4.5 for the venlafaxine ER group and 4.4 for the fluoxetine group and the majority of patients in both groups met remission criteria. 3.3. Efficacy 3.3.1. Primary efficacy outcome Using the primary definition of recurrence, the KaplaneMeier estimated probability of not experiencing a recurrence was 71.9% for the group treated with venlafaxine ER and 55.8% for the group treated with fluoxetine. The difference between treatment groups was not statistically significant (c2 ¼ 0.713; [df ¼ 1]; p ¼ 0.399) (Table 2). However, using a Cox multiple regression analysis, a significant treatment-by-time interaction was observed using the primary definition of recurrence (c2 ¼ 4.480; [df ¼ 1]; p ¼ 0.034), suggesting that the risk for recurrence varied differently over time for the 2 treatments (see Fig. 3A). The analysis using the secondary definition of recurrence also found no statistically significant difference between the groups treated with venlafaxine ER (59.5%) vs. fluoxetine (43.3%; c2 ¼ 2.207; [df ¼ 1]; p ¼ 0.137) over the combined maintenance phases (Fig. 3B). The treatment-by-time interaction analysis using the secondary definition of recurrence did not reach statistical significance (c2 ¼ 2.838; [df ¼ 1]; p ¼ 0.092).
3.3.2. Secondary efficacy outcomes Other secondary and quality of life outcomes were comparable for the venlafaxine ER and fluoxetine treatment groups (Table 3). Response rates during the 2 maintenance phases were generally similar across definitions and comparable for the 2 treatment groups. Likewise, remission rates were comparable for the 2 treatments throughout both maintenance phases. Rates of sustained remission, defined as meeting the criteria for remission for the final 2 visits of the study period, were also comparable for both treatment groups during maintenance phases A and B (Table 3). 3.4. Safety The AEs most commonly reported during the maintenance phases are presented in Table 4. The percentage of patients who discontinued during maintenance phase A due to AEs was comparable in the venlafaxine ER (4%; 6/164) and the fluoxetine (4%; 4/104) treatment groups. During maintenance phase B, discontinuation rates due to AEs were 9% for the fluoxetine treatment group and 2% for the venlafaxine ER group. Small changes in mean vital sign values (from acute baseline to maintenance end point) were observed in the venlafaxine ER and fluoxetine treatment groups. During maintenance phase A, the most commonly reported clinically significant changes in vital signs were decreased supine systolic blood pressure (venlafaxine ER: 4%; fluoxetine: 0%); decreased standing systolic blood pressure (venlafaxine ER: 5%; fluoxetine: 1%); and sustained supine diastolic hypertension (venlafaxine ER: 3%; fluoxetine: 2%). The most commonly reported clinically significant changes in vital signs during maintenance phase B were increased supine and standing systolic blood pressure (venlafaxine ER: 2%; fluoxetine: 0%), and sustained supine diastolic hypertension (venlafaxine ER: 0%; fluoxetine: 2%). During maintenance phase B, 1% of patients treated with venlafaxine ER experienced a clinically significant decrease in pulse rate (40 beats/min [bpm]), and 1% of fluoxetine-treated patients experienced a significant increase in pulse rate (120 bpm). Rates of significant weight gain or loss (7% baseline
Table 1 Patient baseline characteristics and demographics, safety populationa. Maintenance phase Ab
Characteristic
Maintenance phase Bc
Venlafaxine ER (n ¼ 164)
Fluoxetine (n ¼ 104)
Venlafaxine ER (n ¼ 43)
Fluoxetine (n ¼ 47)
Gender, n (%) Male Female
56 (34) 108 (66)
40 (38) 64 (62)
17 (40) 26 (60)
22 (47) 25 (53)
Age, years (range)
42.1 10.5 (22e72)
43.9 11.5 (20e69)
44.8 11.3 (25e72)
46.7 12.9 (21e69)
Duration of current MDD episode, months (range)
6.7 7.0 (1e49)
8.0 7.4 (1e39)
7.0 7.0 (1e35)
7.3 7.5 (1e39)
Ethnicity, n (%) White Black Asian Hispanic Other
137 (84) 12 (7) 4 (2) 6 (4) 5 (3)
90 (87) 5 (5) 1 (<1) 6 (6) 2 (2)
35 (81) 1 (2) 1 (2) 4 (9) 2 (5)
40 (85) 3 (6) 0 (0) 3 (6) 1 (2)
HAM-D17 total Acute phase baseline (range)
22.2 3.3 (18e35)
22.4 3.1 (18e32)
22.2 3.0 (18e30)
22.6 3.1 (18e31)
Maintenance phase baseline (range)
4.5 3.3 (0e16)
4.4 3.4 (0e14)
4.8 2.6 (0e10)
3.9 3.4 (0e18)
HAM-D17 ¼ 17-item Hamilton Rating Scale for Depression; ER ¼ extended release; MDD ¼ major depressive disorder. a Data presented as mean standard deviation unless otherwise indicated. b Acute-phase baseline. c Maintenance-phase baseline.
M.E. Thase et al. / Journal of Psychiatric Research 45 (2011) 412e420
417
Table 2 KaplaneMeier estimates of the probability of no recurrence of MDD with venlafaxine ER or fluoxetine treatment. Venlafaxine ER
Fluoxetine
Estimated probability of no recurrence
Estimated probability of no recurrence
Primary definition of recurrence Month 12 78.3% Month 24 71.9%
75.2% 55.8%
Secondary definition of recurrence Month 12 71.5% Month 24 59.5%
60.5% 43.3%
ER ¼ extended release; MDD ¼ major depressive disorder.
weight) were comparable between the venlafaxine ER and fluoxetine treatment groups during both maintenance phases, with a greater number of patients experiencing significant weight gain than weight loss during maintenance phase A (weight gain in 32% and 29% and weight loss in 17% and 23% of patients in the venlafaxine ER and fluoxetine treatment groups, respectively) and maintenance phase B (weight gain in 47% and 30% and weight loss in 9% and 13% of patients in the venlafaxine ER and fluoxetine treatment groups, respectively). Mean increases in weight from baseline were observed for patients in both treatment groups at the end of maintenance phase A (venlafaxine ER: þ4.3 1.1 kg; fluoxetine: þ4.0 1.6 kg) and at the end of maintenance phase B (venlafaxine ER: þ6.39 11.6 kg; fluoxetine: þ1.61 15.1 kg). There also were few clinically significant changes in laboratory assessments. During maintenance phase A, there were 2 cases of clinically significant hematologic values in the venlafaxine ER treatment group (1 patient [1.2%] had hemoglobin <95 g/dL and 1 patient [1.2%] had a hematocrit <0.32). In addition, there were 12 cases of significant blood chemistry values (venlafaxine ER ¼ 7; fluoxetine ¼ 5) during maintenance phase A. Seven patients (6%) in the venlafaxine ER group and 5 patients (7%) in the fluoxetine group had significant increases in cholesterol. During maintenance phase B, there were 4 cases of clinically significant blood chemistry values (venlafaxine ER ¼ 3; fluoxetine ¼ 1), all of which were increased cholesterol.
4. Discussion During the 2 years of maintenance-phase therapy in the PREVENT study, the groups treated with venlafaxine ER and fluoxetine did not differ significantly with respect to the likelihood of recurrence or secondary outcomes such as measures of depressive symptoms or quality of life. Overall, the recurrence rates observed during the first year of therapy in this study are generally consistent with what has been observed in other longer-term studies of maintenance antidepressant therapy (Geddes et al., 2003; Shelton, 2004). For example, a systematic review of placebo-controlled antidepressant studies using similar designs to evaluate relapse and recurrence prevention in patients with MDD found average recurrence rates of 18% among patients who remained on active therapy for 12 months and 24% during 18e36 months of maintenance treatment. No apparent differences were observed across the various classes of antidepressants that were studied (Geddes et al., 2003). Such cross-study comparisons should be interpreted cautiously due to differences in patient populations and study design, including duration of treatment prior to randomization, duration of follow-up, and definitions of recurrence. The effect of varying time factors as well as symptom criteria used to determine recurrence is illustrated by the results of this study. For example, the estimated probability of recurrence risk
Fig. 3. A) KaplaneMeier estimated probability of no recurrence (primary definition), combined maintenance phases (ITT population). (B) KaplaneMeier estimated probability of no recurrence (secondary definition), combined maintenance phases (ITT population). ER ¼ extended release; ITT, intent to treat.
based on the broader secondary definition of recurrence was up to 14% higher than the rates determined using the primary definition. Looking across both years of double-blind therapy there was a statistically significant treatment-by-time interaction with respect to the primary outcome variable, which reflects a difference in the time course of recurrence risk among the patients treated with the 2 study drugs. Specifically, whereas the groups had similar risks of recurrence during the first year of maintenance-phase treatment, only about 10% of those treated with venlafaxine ER experienced a recurrence during the second year of double-blind
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Table 3 Secondary outcomes (ITT population), Months 12 and 24. Month 12 Venlafaxine ER (n ¼ 160) Symptomatic Assessmentsh HAM-D17 total CGIeS IDSeSR Total Anxiety arousal scale HAM-A Responsea HAM-D17 primaryb HAM-D17 secondaryc CGIc Remissiona,d Sustained remissiona,e QOL and Functional Assessmentsh SF-36f Physical functioning Role functioning-physical Bodily pain General health Vitality Social functioning Role functioning-emotional Physical component summary Mental component summary Q-LES-Qf LESeSf SASeSRg
Month 24 Fluoxetine (n ¼ 99)
Venlafaxine ER (n ¼ 43)
Fluoxetine (n ¼ 45)
7.1 (0.5) 1.9 (0.1)
7.1 (0.7) 2.0 (0.1)
4.8 (0.9) 1.6 (0.2)
5.9 (0.9) 1.7 (0.1)
15.6 (1.0) 5.2 (0.4) 6.2 (0.5)
15.5 (1.3) 5.4 (0.5) 6.1 (0.6)
11.1 (1.9) 3.7 (0.7) 4.9 (0.9)
13.1 (1.8) 4.3 (0.7) 6.5 (0.8)
129 119 116 107 95
(81) (74) (73) (67) (59)
79 67 71 67 52
(80) (68) (72) (68) (53)
40 37 38 33 31
(93) (86) (88) (77) (72)
37 34 35 32 25
(82) (76) (78) (71) (56)
86.9 75.0 75.4 74.6 51.1 71.9 69.6 53.0 44.4 72.9 62.8 1.9
(1.1) (3.0) (1.7) (1.3) (1.9) (1.8) (3.3) (0.6) (1.0) (1.1) (1.7) (0.0)
85.7 80.5 77.9 75.0 56.3 74.7 71.0 53.4 45.3 74.4 65.5 1.9
(1.5) (3.9) (2.2) (1.6) (2.5) (2.3) (4.3) (0.8) (1.4) (1.4) (2.2) (0.0)
87.2 78.7 78.3 74.8 61.2 72.9 86.7 52.5 48.8 76.5 67.9 1.8
(2.3) (6.1) (3.3) (2.4) (3.5) (3.5) (6.2) (1.2) (2.0) (2.1) (3.2) (0.1)
85.4 75.5 74.4 71.5 53.5 69.0 79.0 51.3 46.0 72.4 63.8 1.9
(2.2) (5.9) (3.2) (2.4) (3.4) (3.4) (5.9) (1.2) (1.9) (2.0) (3.2) (0.1)
ER ¼ extended release; HAM-D17 ¼ 17-item Hamilton Rating Scale for Depression; CGIeS ¼ Clinical Global ImpressionseSeverity; IDSeSR ¼ Inventory of Depressive SymptomologyeShort Form; HAM-A ¼ Hamilton Rating Scale for Anxiety; QOL ¼ Quality of Life; SF-36 ¼ 36-Item Short-Form Health Survey; Q-LES-Q ¼ Quality of Life Enjoyment and Satisfaction Questionnaire; LESeS ¼ Life Enjoyment ScaleeShort Version; SASeSR ¼ Social Adjustment ScaleeSelf Report. a Data for clinical response and remission rates presented as n (%). b Primary definition of response was HAM-D17 total score 12 and 50% reduction in HAM-D17 total score vs. acute baseline. c Alternate definitions of response were 50% reduction in HAM-D17 total score vs. acute baseline or CGI score 2with. d Remission defined as HAM-D17 7. e Sustained remission defined as HAM-D17 7 at 2 consecutive study visits. f For this scale, higher scores indicate better functioning. g For this scale, lower scores indicate less impairment. h Data are presented as least squares mean (standard error) unless otherwise indicated.
therapy, as compared with approximately one-third of those treated with fluoxetine. Although a difference of this magnitude could be considered clinically significant, it is also true that none of the other efficacy analyses pertaining to outcomes during the Table 4 Most common treatment-emergent adverse events (10% in Either Treatment Group), safety population. Adverse event, n (%)
Month 12
Month 24
Venlafaxine Fluoxetine Venlafaxine Fluoxetine ER (n ¼ 164) (n ¼ 104) ER (n ¼ 43) (n ¼ 47) Accidental injury Asthenia Headache Infection Pain Dry mouth Weight gain Abnormal dreams Anxiety Dizziness Insomnia Libido decreased Somnolence Upper respiratory infection Sweating Abnormal ejaculationa
16 14 40 11 10 26 19 16 5 20 21 18 8 27 26 20
(10) (9) (24) (7) (6) (16) (12) (10) (3) (12) (13) (11) (5) (16) (16) (12)
15 8 15 6 10 4 14 5 5 3 12 12 10 19 10 9
(14) (8) (14) (6) (10) (4) (13) (5) (5) (3) (12) (12) (10) (18) (10) (9)
ER ¼ extended release; NR ¼ not reported. a Males only (venlafaxine ER ¼ 40; fluoxetine ¼ 29).
8 (19) 2 (5) 6 (14) 4 (9) 2 (5) NR 1 (2) 2 (5) 3 (7) 6 (14) 4 (9) 0 (0) 1 (2) 10 (23) 2 (5) NR
2 (4) 4 (9) 7 (15) 5 (11) 5 (11) NR 2 (4) 1 (2) 5 (11) 2 (4) 4 (9) 3 (6) 0 (0) 3 (6) 2 (4) NR
second year of maintenance-phase treatment documented statistically significant between-group differences and a post hoc adjustment for multiple statistical comparisons would likewise render the difference on the primary analysis non-significant. One possible explanation for the loss of antidepressant efficacy over time is tachyphylaxis (Solomon et al., 2005), which has been suggested to occur more frequently with SSRIs than dual-acting antidepressants (Posternak and Zimmerman, 2005). In another secondary analysis of data from the PREVENT study, the occurrence and predictors of tachyphylaxis, which was defined as the emergence of apathetic depressive symptoms (e.g., loss of energy and motivation, weight gain, cognitive impairment) following a positive treatment response, were assessed in patients treated with venlafaxine ER, fluoxetine and placebo. Although the KaplaneMeier estimates of tachyphylaxis between the active treatment groups were not significantly different, the percentage of fluoxetine-treated patients (26e30%) who met tachyphylaxis criteria and experienced a recurrence during maintenance therapy was statistically significant (p < 0.01) whereas the proportion of venlafaxine ER treated patients (11e15%) who met criteria for tachyphylaxis and experienced a recurrence was not (Rothschild et al., 2009). When results of these 2 sets of analysis are considered together, the findings of the PREVENT study fall short of confirming that there are clinically meaningful differences in recurrence rates across 2 years of maintenance-phase therapy with venlafaxine ER and fluoxetine. Nevertheless, the study was not designed to have
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adequate statistical power to detect moderate-sized differences between the 2 drugs and further research on this topic with larger samples is certainly warranted. As in most clinical trials, the inclusion and exclusion criteria likely resulted in a study sample that is not fully representative of patients in clinical practice, which may limit the generalizability of these results. Further, as is the case in almost all studies of maintenance-phase antidepressant therapy, the study design is considered to be “enriched,” because only patients who responded during the acute phase and did not relapse during the continuation phase entered the maintenance-phase study (Greenhouse et al., 1991). Thus, the same magnitude of preventive efficacy may not be expected if patients who were initially treated with other strategies were placed on these medications for maintenance-phase therapy. A third limitation pertains to attrition, which reduced statistical power, particularly during the second year of maintenance therapy. Finally, the design of the study did not permit valid comparisons between fluoxetine and placebo, nor was there adequate statistical power to detect more modest, but possibly clinically meaningful, between-group differences in recurrence rates or relevant secondary outcomes at the end of 24 months of therapy. Although practice guidelines recognize the importance of achieving remission and using maintenance treatment to prevent relapse and recurrence, treatment guidelines remain nonspecific with regard to the optimal duration of maintenance antidepressant therapy (American Psychiatric Association, 2000). This analysis of the PREVENT study further demonstrates the clinical utility of maintaining antidepressant treatment for up to 2 years following successful acute- and continuation-phase treatment, and provides a valuable addition to the limited number of clinical trials of this duration. Further research is still needed to better characterize differences between antidepressants in maintaining response. Conclusion The PREVENT study showed that 2 years of maintenance treatment with venlafaxine ER was at the least as effective as fluoxetine in preventing recurrence of MDD among patients with recurrent MDD who had achieved and maintained a response to treatment during acute and continuation therapy. Role of funding source This analysis was sponsored by Wyeth Research, Collegeville, Pennsylvania, which was acquired by Pfizer Inc. in October 2009. Wyeth Research had a role in the study design and the decision to submit this manuscript for publication. Contributors Drs. Thase, Gelenberg, Kornstein, Kocsis, Trivedi, Ninan, Keller, and Li, as well as Mr. Pedersen, contributed to the study design, protocol, and analysis of data. All authors contributed to and approved the final manuscript. Conflict of interest Dr. Thase has been an advisor or consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Schering-Plough, Shire, Supernus, Transcept, and Pfizer (formerly Wyeth Research). He has received grant support from Eli Lilly, GlaxoSmithKline, the National Institute of Mental Health, and Sepracor. Dr. Thase has been on the speakers bureau for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Pfizer (formerly Wyeth Research), and holds equity in MedAvante. Dr. Thase receives royalties from American Psychiatric Publishing,
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Guilford Publications, Herald House, and W.W. Norton and Company. His spouse is employed by Embryon, LLC, A Division of Advanced Health Media, LLC (formerly Medesta Publications Group, A Business of Advogent). Dr. Gelenberg has been a consultant to AstraZeneca, Best Practice, Eli Lilly, eResearch Technology, GlaxoSmithKline, Jazz Pharmaceuticals, Lundbeck, Pfizer, Takeda, Wyeth, and ZARS Pharmaceuticals. He has also received grant funding from Eli Lilly and owns stock in Healthcare Technology Systems. Dr. Kornstein has received grants/research support from AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, the Department of Health and Human Services, Eli Lilly, Forest, the National Institute of Mental Health, Novartis, Pfizer, Sepracor, Sanofi-Synthelabo, Takeda, and Wyeth. She has been on advisory boards for Bristol-Myers Squibb, Eli Lilly, Endo, Forest, Neurocrine, Pfizer, Sepracor, Takeda, and Wyeth, and receives book royalties from Guilford Press. Dr. Kocsis has received grants/contracts from AstraZeneca, Burroughs Wellcome Trust, CNS Response, the National Institute on Drug Abuse, the National Institute of Mental Health, Novartis, Pritzker Consortium, Roche, and Sanofi-Aventis. Dr. Kocsis has been on the speakers bureau for AstraZeneca, Merck, Pfizer, and Wyeth, and has been on advisory boards for Pfizer and Wyeth. Dr. Trivedi has received research support from the Agency for Healthcare Research and Quality, Corcept Therapeutics, Cyberonics, Merck, the National Alliance for Research in Schizophrenia and Depression, the National Institute of Mental Health, the National Institute on Drug Abuse, Novartis, Pharmacia and Upjohn, Predix Pharmaceuticals (Epix), Solvay, and Targacept. He has received consulting and speaker fees from Abbott, Abdi Ibrahim, Akzo (Organon Pharmaceuticals), AstraZeneca, BristolMyers Squibb, Cephalon, Evotec, Fabre Kramer Pharmaceuticals, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson PRD, Eli Lilly, Meade Johnson, Medtronic, Neuronetics, Otsuka, Parke-Davis, Pfizer, Sepracor, Shire Development, VantagePoint, and WyethAyerst. Drs Ninan and Li, and Mr Pedersen, are employees of Pfizer Inc, formerly Wyeth Research, Collegeville, Pennsylvania. Dr. Keller has been a consultant for and/or received honoraria from Abbott, Bristol-Myers Squibb, CENEREX, Cephalon, Cypress Bioscience, GlaxoSmithKline, Forest, Janssen, JDS, Medtronic, Organon, Novartis, Pfizer, Roche, Sierra-Neuropharmaceuticals, Solvay, and Wyeth. He has received grant/research support from Pfizer and Wyeth, and has served on advisory boards for Abbott, Bristol-Myers Squibb, CENEREX, Cyberonics, Cypress Bioscience, Forest, Janssen, Neuronetics, Organon, and Pfizer. Acknowledgments Medical writing support was funded by Wyeth and provided by Dennis Stancavish, MA, of Embryon, LLC, A Division of Advanced Health Media, LLC (formerly Medesta Publications Group, A Business of Advogent). References American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: 1994 American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Second Edition. Arlington, VA: 2000. p. vii-87 Endicott J, Nee J, Harrison W, Blumenthal R. Quality of life enjoyment and satisfaction questionnaire: a new measure. Psychopharmacology Bulletin 1993;29:321e6. Fawcett J, Clark DC, Scheftner WA, Gibbons RD. Assessing anhedonia in psychiatric patients. Archives of General Psychiatry 1983;40:79e84.
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Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. The Lancet 2003;361:653e61. Gilaberte I, Montejo AL, de la Gandara J, Perez-Sola V, Bernardo M, Massana J, et al. Fluoxetine in the prevention of depressive recurrences: a double-blind study. Journal of Clinical Psychopharmacology 2001;21:417e24. Greenhouse JB, Stangl D, Kupfer DJ, Prien RF. Methodologic issues in maintenance therapy clinical trials. Archives of General Psychiatry 1991;48:313e8. Guy W, ed. Clinical Global Impressions. Publication ADM 76-338. In: ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare, 1976. p. 217-222 Hamilton M. The assessment of anxiety states by rating. British Journal of Medical Psychology 1959;32:50e5. Hamilton M. A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry 1960;23:56e62. Hochstrasser B, Isaksen PM, Koponen H, Lauritzen L, Mahnert FA, Rouillon F, et al. Prophylactic effect of citalopram in unipolar, recurrent depression: placebocontrolled study of maintenance therapy. British Journal of Psychiatry 2001;178:304e10. Keller MB. Long-term treatment of patients with recurrent unipolar major depression: evidence to clinical practice. CNS Spectrums 2006;11:4e5. Keller MB, Trivedi MH, Thase ME, Shelton RC, Kornstein SG, Nemeroff CB, et al. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: outcomes from the two-year and combined maintenance phases. Journal of Clinical Psychiatry 2007a;68:1246e56. Keller MB, Trivedi MH, Thase ME, Shelton RC, Kornstein SG, Nemeroff CB, et al. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: outcomes from the acute and continuation phases. Biological Psychiatry 2007b;62:1371e9. Kocsis JH, Thase ME, Trivedi MH, Shelton RC, Kornstein SG, Nemeroff CB, et al. Prevention of recurrent episodes of depression with venlafaxine ER in a 1-year maintenance phase from the PREVENT Study. Journal of Clinical Psychiatry 2007;68:1014e23. Kornstein SG. Beyond remission: rationale and design of the Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study. CNS Spectrums 2006;11(12 suppl 15):28e34. Lepine JP, Caillard V, Bisserbe JC, Troy S, Hotton JM, Boyer P. A randomized, placebo-controlled trial of sertraline for prophylactic treatment of highly
recurrent major depressive disorder. American Journal of Psychiatry 2004;161:836e42. Montgomery SA, Entsuah R, Hackett D, Kunz NR, Rudolph RL. Venlafaxine versus placebo in the preventive treatment of recurrent major depression. ournal of Clinical Psychiatry 2004;65:328e36. Mueller TI, Leon AC, Keller MB, Solomon DA, Endicott J, Coryell W, et al. Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. American Journal of Psychiatry 1999;156:1000e6. Perahia DG, Gilaberte I, Wang F, Wiltse CG, Huckins SA, Clemens JW, et al. Duloxetine in the prevention of relapse of major depressive disorder: double-blind placebo-controlled study. British Journal of Psychiatry 2006;188:346e53. Posternak MA, Zimmerman M. Dual reuptake inhibitors incur lower rates of tachyphylaxis than selective serotonin reuptake inhibitors: a retrospective study. ournal of Clinical Psychiatry 2005;66:705e7. Rothschild AJ, Dunlop BW, Dunner DL, Friedman ES, Gelenberg A, Holland P, et al. Assessing rates and predictors of tachyphylaxis during the Prevention of Recurrent Episodes of Depression With Venlafaxine ER for Two Years (PREVENT) Study. sychopharmacology Bulletin 2009;42:5e20. Rouillon F, Warner B, Pezous N, Bisserbe JC. Milnacipran efficacy in the prevention of recurrent depression: a 12-month placebo-controlled study. Milnacipran recurrence prevention study group. nternational Clinical Psychopharmacology 2000;15:133e40. Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C. The Inventory for Depressive Symptomatology (IDS): preliminary findings. sychiatry Research 1986;18:65e87. Shelton CI. Long-term management of major depressive disorder: are differences among antidepressant treatments meaningful? ournal of Clinical Psychiatry 2004;65(Suppl. 17):29e33. Solomon DA, Keller MB, Leon AC, Mueller TI, Lavori PW, Shea MT, et al. Multiple recurrences of major depressive disorder. merican Journal of Psychiatry 2000; 157:229e33. Solomon DA, Leon AC, Mueller TI, Coryell W, Teres JJ, Posternak MA, et al. Tachyphylaxis in unipolar major depressive disorder. ournal of Clinical Psychiatry 2005;66:283e90. Ware JE, Snow KK. SF-36 health survey manual and information guide. Boston, Massachusetts: The Health Institute, New England Medical Center; 1993. Weissman MM, Bothwell S. Assessment of social adjustment by patient self-report. Archives of General Psychiatry 1976;33:1111e5.