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Desvenlafaxine vs. placebo in the treatment of persistent depressive disorder
Accepted Manuscript
Desvenlafaxine vs. placebo in the treatment of persistent depressive disorder David J. Hellerstein M.D. , Jonathan W. Stewart M.D. , Ying Chen M.D. , Vinushini Arunagiri M.A. , Bradley S. Peterson M.D. , Patrick J. McGrath M.D. PII: DOI: Reference:
S0165-0327(17)32202-4 https://doi.org/10.1016/j.jad.2018.11.065 JAD 10283
To appear in:
Journal of Affective Disorders
Received date: Revised date: Accepted date:
24 October 2017 21 September 2018 3 November 2018
Please cite this article as: David J. Hellerstein M.D. , Jonathan W. Stewart M.D. , Ying Chen M.D. , Vinushini Arunagiri M.A. , Bradley S. Peterson M.D. , Patrick J. McGrath M.D. , Desvenlafaxine vs. placebo in the treatment of persistent depressive disorder, Journal of Affective Disorders (2018), doi: https://doi.org/10.1016/j.jad.2018.11.065
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Highlights
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The SNRI medication desvenlafaxine did not differentiate from placebo on the primary outcome (Hamilton Depression Rating Scale) in non-major persistent depressive disorder. As a negative study, this does not support the use of DVLX for non-major PDD. Statistically significant secondary analyses suggest the overall negative result could be due to sample size or sampling, suggesting further studies of this medication might be appropriate in this population. Twelve week continuation phase of active medication was associated with additional improvement in symptoms and psychosocial functioning, and remission of depressive symptoms was associated with normalization of social functioning score on the SAS.
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revision 9/21/2018 3940 words 4 tables 1 Consort Diagram 1 figure
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Title: Desvenlafaxine vs. placebo in the treatment of persistent depressive disorder
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Authors: David J. Hellerstein, M.D. , Jonathan W. Stewart, M.D. , Ying Chen, M.D. , Vinushini 3 4 1,2 Arunagiri, M.A. , Bradley S. Peterson, M.D. , Patrick J. McGrath, M.D.
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Address for Correspondence: David J. Hellerstein, MD New York State Psychiatric Institute 1051 Riverside Drive, Unit #51 New York, NY 10032 tel. 646-774-8069 fax. 646-774-8034 email: [email protected]
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1. New York State Psychiatric Institute, New York, NY 2. Columbia University College of Physicians and Surgeons, New York, NY 3. Teachers College, Columbia University, New York, NY 4. Institute for the Developing Mind at Children’s Hospital Los Angeles; Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, CA
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Clinicaltrials.gov registration #: NCT01537068
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Abstract Introduction: Pharmacotherapy of non-major persistent depressive disorder (PDD) is little studied. We report a study of the serotonin-norepinephrine reuptake inhibitor (SNRI) desvenlafaxine (DVLX) for PDD.
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Method: Non-psychotic, non-bipolar outpatients aged 20-65 having PDD without concurrent major depression (MDD) were randomized double-blind to desvenlafaxine or placebo for 12 weeks. All
had Hamilton Depression Rating Scale (HDRS-24) score >12. Open-label DVLX was offered for 12 weeks following the acute trial.
Results: Seventy-one subjects having mean baseline HDRS-24 20.27+4.77 were eligible, of whom
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post-RZ data was available for all 59 randomized. The primary 12 week analysis did not
differentiate DVLX-treated subjects’ mean HDRS scores from those on placebo (6.53 + 3.98 vs. 8.24 + 4.96, F=3.33, df=1, p=.07). Several secondary analyses yielded statistically significant results, including Responder, CGI and QIDS.
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Discussion: As the primary analysis did not reach statistical significance, this is a negative study which does not support the use of DVLX for non-major PDD. Nevertheless,
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statistically significant secondary analyses suggest the overall negative result could be due to sample size or sampling, suggesting further studies of this medication might be
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appropriate in this population.
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ClinicalTrials.gov identifier: NCT01537068
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Previous presentation: none
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Introduction
Chronic depression is common, affecting 1.5-5% of the population and produces significant 1-9
functional impairment, negative health outcomes, and social costs, psychosocial burden than acute depression.
10
DSM-5
11
resulting in greater
recognized the importance of chronicity by
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consolidating dysthymic disorder (DD), chronic major depressive disorder (MDD), and residual MDD, into a single classification, Persistent Depressive Disorder (PDD).
Identifying effective treatments for PDD is clearly important to relieve symptoms and improve
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psychosocial and health outcomes. Yet chronic depression remains under-studied: a 2000
Cochrane review, for example, found only 20 placebo-controlled studies of DD (chronic low-grade 12
depression), concluding that antidepressants are effective. A more recent review found 36 studies of pure dysthymia, and 22 studies of chronic major depression or dysthymia with current MDD, with 13
efficacy data on only 5,806 patients world-wide. . Few drugs have been adequately tested, e.g.
13
Other reviews
14-16
suggest these patients may require higher than
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greater efficacy than others
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with 2 or more trials enrolling over 100 patients, though data suggests some medications may have
usual medication doses, combined medication and psychotherapy treatments, or concurrent dosing with two or more classes of medication to achieve optimal outcome, since residual symptoms and
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persistent functional impairment are common. An alternative to combining treatments has been dual-mechanism medications, such as serotonin-norepinephrine reuptake inhibitors (SNRIs),
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though SNRIs may have more side effects
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in this population than other medications. We 18
previously reported efficacy of the SNRI duloxetine in chronic non-major depression.
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Desvenlafaxine (DVLX) (brand name Pristiq®),
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like duloxetine, blocks serotonin and
norepinephrine reuptake, so may also effectively treat chronic depression. Thus, a study of the efficacy of DVLX for non-major PDD seems indicated.
Hypotheses: 1) Efficacy study: We expected that desvenlafaxine would be superior to placebo over a twelve-
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week period in the following outcomes: a.
Improved depression, as measured by HDRS-24 item total score at week 12 (primary outcome).
b.
The percentage of subjects classified as (a) Responders and (b) Remitters at week 12.
c.
Improved secondary measures of depression (Quick Inventory of Depressive
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Symptomatology-Self-Rated (QIDS-SR), Beck Depression Inventory (BDI), Cornell
Dysthymia Rating Scale (CDRS), and overall severity of illness (Clinical Global ImpressionsSeverity (CGI-S)). d.
Improved psychosocial functioning (as measured by the Social Adjustment Scale (SAS) and
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the Sheehan Disability Scale (SDS), global outcome (Global Assessment of Functioning (GAF)), and temperament (Temperament and Character Inventory (TCI)).
2) Open continuation study: In the continuation phase (weeks 13-24) we expected that patients continuing active DVLX would maintain improvement achieved at week 12 and would have additional functional improvements, and that patients initially treated with placebo would respond
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similarly to DVLX-treated patients in the double-blind phase.
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Methods
Study procedures This study was conducted at New York State Psychiatric Institute’s Depression Evaluation Service (DES) and approved by its Institutional Review Board (IRB). The goal was to enroll subjects with
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PDD without a current MDD episode. We conducted a power analysis, based on the results of previous double-blind placebo controlled studies in dysthymic disorder. Assuming a
moderate effect size, with an 80% likelihood of finding a difference at significance p<.05, we calculated that a sample of 30 per arm was sufficient. Potential subjects were evaluated by
20
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research psychiatrists using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) , 21
and 24-item Hamilton Depression Rating Scale (HDRS-24) . Appropriate patients signed IRBapproved consent. A physical examination was performed and blood and urine samples were collected, including urine for pregnancy and toxicology. This study was registered at ClinicalTrials.gov (identifier: NCT01537068). It was funded by Pfizer, Inc. as an investigator-initiated
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trial.
Inclusion criteria were: age 20 to 65 years; baseline HDRS-24 score >=12, chronic (>= 2 years) depression. Exclusion criteria included: DSM-5 diagnosis of current major depression, bipolar
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disorder, schizophrenia or other psychotic disorder; dementia or other cognitive disorder; current (past 6 months) drug or alcohol use disorder; current psychoactive medication use; serious risk for
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suicide during the course of the study; unstable medical conditions; current or planned pregnancy;
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lack of capacity to consent to study participation.
Conduct of study: The study had two phases: 1) a 12-week double blind placebo controlled phase; and 2) a 12-week open treatment phase. Phase 1 RCT: randomization occurred approximately 1 week after intake assessment, with doubleblind treatment assigned based on a random number table generated by an independent
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biostatistician using SAS software (“Random = ranuni (seed)” procedure with a block of 4). Visits at weeks 1, 2, 4, 6, 8, and 12 assessed longitudinal course of presenting symptoms and functioning and emergence of new symptoms. Phase 2, Continuation Treatment: Patients initially treated with DVLX continued effective medication; non-responders were switched to other antidepressants. Patients initially treated with
up, patients were seen every 4 weeks for 12 weeks.
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placebo began active DVLX treatment, up to a maximum of 100 mg/day. During open-label follow-
Clinicians administered the HDRS-24, Cornell Depression Rating Scale (CDRS)
22,23
, Clinical Global 24
Impression (CGI), and the Systemic Assessment for Treatment Emergent Events (SAFTEE) , while 25
(TCI)
26,27
28
, Social Adjustment Scale (SAS),
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patients completed the Beck Depression Inventory (BDI) , Temperament and Character Inventory 29
and Ruminative Responses Scale (RRS) . Study
measures assessed depressive symptoms (BDI, HDRS, CDRS), general and social functioning (SAS, GAF, CGI), and ruminations (RRS). Tolerability was assessed at each visit by self-rated scales and clinician assessment. Clinicians rated adverse events (AEs) using the SAFTEE, and
receiving CGI-Improvement
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rated each AE by duration and severity. Participants verbally re-consented at week 6. Participants scores of 6 (“much worse”) or 7 (“very much worse”) were withdrawn
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Drug Administration:
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from double-blind treatment.
DVLX (50 mg capsules) or matching placebo was begun at visit 2 (week 0); dose could be
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increased after 4 weeks to 100 mg q AM, if tolerated and still depressed (i.e. CGI-Improvement score >2). The blind was broken at Week 12, at which point DVLX was continued in those already
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taking it, or begun in those initially treated with placebo. Those still depressed on DVLX could be switched to another antidepressant.
Statistical Analyses The primary outcome measure was a priori defined as the HDRS-24 item total score. Efficacy was evaluated using chi square tests for response and remission. Paired T-test and repeated measures
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analysis of variance (ANOVA) were applied for changes in scale scores (HDRS, CDRS, GAF, CGI, QIDS-SR, PGI, SAS, SDS, TCI, BDI and RRS). Response was defined as: >50% decrease from baseline in HDRS-24 score and CGI-I score of 1 ("very much improved") or 2 ("much improved"). Remission was defined as: HDRS-17 score < 4 and HDRS item #1 (depressed mood) score = 0. (In this study, as in other PDD studies by our group
18,31
, we defined remission more rigorously than is
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usually done in MDD trials (HDRS score<=6). Because patients with PDD often present with lower symptom severity, inclusion criteria allow a baseline minimum Hamilton Depression Rating Scale-24 item score>=12. If remission was defined as a score <=6 there would be no difference between response and remission for such patients.) Frequencies of side effects are reported. The last
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observation was carried forward (LOCF) as an endpoint score for those who had missing data. Data analyses used IBM SPSS version 24 and SAS (9.4). Week 24 analyses followed a similar pattern. Analyses were run with both raw data and LOCF. Results did not change significantly. Therefore,
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we report results from raw data.
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Results Sample (see Consort Diagram) Seventy-one subjects signed study consent, of whom 61 were assigned to receive blinded medication or placebo. Twelve eligible subjects did not start study medication for reasons described in Consort Diagram. Our intention-to-treat (ITT) group included 61 patients, of whom post-randomization data were available for 59 (two patients were randomized but
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did not receive study medication). Of these 59 patients beginning treatment, 1 placebo-treated
patient dropped out after wk 2, and 2 after wk 6. Of desvenlafaxine-treated patients, 2 dropped out after wk 2, and 2 after wk 8. Table 1 shows demographic characteristics of desvenlafaxine (N=31) and placebo (N=30) treated subjects. Subjects were predominantly (54.1%) female, with mean age
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37.9+13.1 years (range, 20-63); mostly Caucasian (62.3%, 38/61), and most (48/61 = 80%) had
graduated college. Half (30/60) were employed full time. Most (52/61 = 85%) were unmarried. Two thirds of subjects (35/55) had early-onset (before age 21) PDD. Forty-four per cent (27/61) had a lifetime anxiety disorder diagnosis, including GAD (3.2%; 2/61), social phobia (29.5%; 18/61), obsessive-compulsive disorder (9.8%; 6/61), and anxiety disorder NOS (3.3%; 2/61). Prior alcohol
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use disorder was present in 9.8% (6/61) and prior drug abuse was present in 8.2% (5/61). History of eating disorders were found in 11.5% (7/61) of subjects (4 binge eating disorder, 3 bulimia). Prior
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MDD episodes were reported by 47.5% (29/61), with 19.7% (12/61) reporting one prior episode, and 27.9% (17/61) reporting two or more prior episodes. Of 29 patients who had previous MDD
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episodes, 22 had treatment history information; there was no difference between assignment to
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treatment and placebo groups (Pearson chi-square=0.029, df=1, p=0.864).
Mean DVLX or placebo (equivalent) dose at Week 12 was 96.5 mg/day (sd=12), with 7 taking 50
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mg/day, and 52 taking 100 mg/day. The active medication group had 95.5% compliance and mean final dose of 95 (sd = 15.3) mg/day of DVLX, with 3 people taking 50 mg/day and 27 taking 100 mg/day. The placebo group had 95.4% compliance (sd = 14.5); average final dose equivalence (50 mg/capsule) was 93 mg/day (sd = 17.6) of placebo, with 4 people taking 50 and 25 taking 100 mg/day. There was no association between treatment group and dose level and compliance (t=0.02, df=44, p=0.98).
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At week 24, 6 patients were not receiving DVLX. Three initially DVLX-treated patients switched to other antidepressants (two to bupropion, and one to duloxetine); two of the three initially-placebotreated patients did not take antidepressant medication in the follow-up phase, and one received escitalopram. Mean dose for patients remaining on DVLX was 94.0 (sd=22.5) mg/day and mean
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dose for patients who switched from placebo to DVLX was 86.5 (sd=25) mg/day.
Average baseline scores for the rating scales used as outcome measures appear in Table 2. There
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were no significant baseline differences between treatments.
Efficacy analyses Week 12 results Change on rating scales over time
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Primary analysis. As shown in Table 2, HDRS-24 at 12-weeks, covaried for baseline HDRS24, did not significantly differentiate DVLX from placebo (6.53 + 3.98 vs. 8.24 + 4.96, F=3.33,
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df=1, p=.07).
Secondary analyses. Also, in Table 2, are results of analyses of each secondary outcome
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measure (HDRS-17, CDRS, BDI, GAF, CGI-Severity, QIDS-SR, RRS, TCI, SDS, and SAS) with randomization group (active drug or placebo) as the between subjects factor and time (Baseline and
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week 12 or LOCF ratings) as the within subjects factor. All measures of depressive symptoms and psychiatric functioning showed a significant main effect of Time, indicating that on average, subjects
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improved over time, regardless of treatment group. Of the various clinician and patient ratings, the QIDS-SR and the CGI-I-Pt showed significant treatment by time differences; and HDRS-17 scores (Figure 1) favored medication at week 12 at the trend level, while analyses of other measures did not differentiate the treatments.
Treatment response and remission at week 12 Of 59 subjects in the ITT sample who received study medication, response rate at week 12 was
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61.5% (16/26) for DVLX vs. 26.9% (7/26) for placebo (chi sq (df=1, n=52) = 6.32, p=.025); remitter rate was 26.7% (8/30) for DVLX vs. 17.2% (5/29) for placebo (chi sq (df=1,n=59)=.76, p=.38). All responders to active drug (n=16) were taking 100 mg. Responders to placebo (n=7) included 2 taking 50 mg equivalent, and 5 taking 100 mg equivalent. Non-responders to placebo (n=19) included taking 50 mg equivalent and 18 taking 100 mg equivalent; active drug non-responders
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(n=9) were all taking 100 mg/d. Of 27 patients who had previous MDD episodes, 20 had treatment history information and there was no difference between treatment and placebo groups in terms of response at week 12 (Fisher’s exact test p=0.370 (2 sided)). Since most of the cells had counts less
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than 5, we did not further evaluate this variable with other analyses.
Social adjustment and global functioning
At week 12, both treatment groups showed improvements in SAS, SDS and GAF but there was no drug-by-time effect, indicating there was no greater improvement in social functioning with DVLX
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than placebo (Table 2).
Temperament
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The TCI includes four factors of temperament: Harm Avoidance (HA), Novelty Seeking (NS), Reward Dependence (RD), and Persistence (PS). At baseline, HA scores (23.50+7.47 for DVLX
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subjects; 21.39+7.20 for placebo subjects) were approximately 2 SD above community norms of 32
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10.6+6.0 for men and 12.9+6.1 for women, similar to our prior findings.
After 12 weeks of
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treatment, there were no significant changes by group, time or group by time in HA, NS or RD,
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though there was a time effect for PS (Table 2).
Tolerability
There were no significant differences between placebo- and DVLX-treated subjects on the measures of cognitive functioning (MOTCS), sexual functioning (ASEX), or patient-perceived drugrelated cognitive impairment (ABNAS) and pain (BPI); (data not reported). Adverse events (AEs) as collected on the SAFTEE were reported by 19 of the 29 subjects on placebo (65.5%) and 29 of the
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30 (96.7%) subjects on DVLX (Table 3). The mean number of AEs for the DVLX group was 3.32 (sd=2.54) and for the placebo group 1.94 (sd=2.29) with the medication-treated group showing a trend for more AEs (t = -1.80, df = 42, p = 0.08). Most common side effects in DVLX-treated subjects were nausea (30%), dry mouth (23.3%), and dizziness, sweating, agitation and anorgasmia (each 16.7%). Most common side effects in placebo-treated subjects were decreased
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libido (13.8%), GI upset, cognitive impairment, delayed orgasm, and nausea (each 10.3%). Side effects were generally mild to moderate. Only 1 subject (on DVLX) discontinued due to adverse events.
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Week 24 results Continued DVLX
During the continuation period (Table 4, Figure 1), ratings comparing week 12 to week 24 showed significant changes in several patient-rated inventories, including depression (QIDS-SR and BDI), and ruminations (Ruminations Responses Scale (RRS)). Response and remission rates also
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increased by Week 24 (Table 4). Of 8 DVLX remitters by Week 12, 5 (62.5%) remained in remission at week 24 (2 Week 12 remitters declined to continue medication, and 1 previous remitter
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was a nonresponder by Week 24).
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Placebo treated patients beginning DVLX
Patients initially treated with placebo who began open label DVLX at Week 12, generally showed
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significant improvement (Table 4) between weeks 12 and 24 in clinician-rated scales but not in selfrated scales. Compared to baseline, they had significant improvement in nearly all scales, with the
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exception of three temperament measures, RD, NS and PS. Unlike the patients continuing DVLX, there was not a significant improvement in HA with 12 weeks of DVLX treatment in this group.
Response and remission rates at week 24 Patients who continued DVLX had response rate of 82.6% and remission rate of 47.8% at 24 weeks Patients beginning DVLX in continuation phase had response rate of 83.3% and remission rate of
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50.0% at 24 weeks.
Temperament and social functioning (Table 4) At 24 weeks, the only temperamental factor that showed significant change from baseline was Harm Avoidance (HA) in the DVLXDVLX group. No temperamental factor changed significantly in
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the PLACDVLX group. Functional impairment (SDS, SAS, GAF) continued to improve during the continuation phase for the DVLXDVLX group (Table 4). Fewer than half of subjects were within 1SD of the normal mean score for the SAS and HA, suggesting that continued impairment was
common. Remission was associated with normalization of SAS scores: mean SAS score at week
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24 differed significantly between remitters (1.86 ± 0.32) and non-remitters (2.44 ± 0.64), p=0.001.
Remitters' SAS mean scores were within the normal community range. In contrast, responders who
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were not remitters (N=16) had mean SAS scores of 2.36+0.56) suggesting continued impairment.
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Discussion
The DSM-5 recognized the importance of chronicity by creating the category of persistent depressive disorder (PDD).
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Independent of cross-sectional severity, chronicity is a significant risk
factor for poor outcome, both in terms of continuing symptomatology and impaired functioning. Few
analyses
13,17
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studies address the treatment specifically of the various forms of chronic depression. Recent
find efficacy data only on 5806 patients, data for acceptability of pharmacotherapy, 13
17
psychotherapy or combined treatment on 5348 , and safety data on 4769 . Furthermore, while antidepressant medications have widely been shown to be more effective in more severe
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depression (and less effective in milder depression), there are limited data in non-major persistent depression. This situation is likely to continue now that the various forms of chronic depression (more severe chronic major depression, less severe dysthymic disorder, etc.) have been collapsed into the single DSM-5 PDD category. Yet even non-major PDD is associated with high levels of 10,34
psychosocial morbidity
. Hence, it is valuable to define the efficacy of ADMs in less severe PDD.
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To our knowledge, this is the second reported double-blind trial for an SNRI medication in treatment 18
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of non-major persistent depressive disorder (PDD).
Efficacy phase: Our primary analysis of the 12-week double-blind phase of this DVLX study
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reached only trend significance (.07), so this was a negative study that does not support the use of DVLX as treatment for non-major PDD. This negative result could have occurred
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because DVLX is not effective in this population. Alternatively, relative to our other studies, this study had a relatively high improvement in patients assigned placebo,
18,31,35
power may
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have been insufficient or the negative result may have occurred due to sampling. Several positive secondary analyses suggest the value of this study may be in generating hypotheses for further studies. A moderate ES (.436) on the primary outcome measure suggests adequate power (>.8) to demonstrate efficacy with a sample size of 60 per treatment arm; the effect size of studies with DVLX in MDD approximate 0.3
36-39
so this is comparable. Of note, the patient-rated QIDS-SR
and patient-rated CGI-Improvement did differentiate medication from placebo in our study. Contrary
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to expectations, secondary measures of social functioning (SAS, SDS) and global outcome (GAF) did not show significant differences at week 12, nor did temperamental abnormalities (HA, RD, NS on TCI), though ruminations (RRS) showed a time effect.
In contrast, our duloxetine study showed more robust response in the initial (10 week) phase, with
40
below).
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less additional improvement during the 12 week continuation period (see Continuation Phase
This potentially greater initial response to duloxetine might result from differing relative Ki
profiles for these two SNRI medications. Ki, or the inhibitory constant, is related to the
concentration of a drug needed to decrease the activity of a receptor or enzyme by half; a low Ki
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level represents a high level of binding affinity, whereas a high Ki level implies that a relatively high concentration of a drug is required before the binding site is maximally occupied. Duloxetine potently inhibits binding to the human NE and 5-HT transporters, with Ki values of 7.5 and 0.8 nM, 41
respectively, and a Ki ratio of 9.
In comparison, desvenlafaxine has Ki values of 2953 for NE and
61.4 for 5-HT, and a Ki ratio of 48 (values similar to its parent compound venlafaxine: Ki 2480 for 19
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NE and 82 for 5HT receptors, respectively). Whereas duloxetine appears to have both significant NRI and SRI activity, DVLX appears to have predominantly SRI activity, and more limited NRI
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activity. DVLX’s relatively lower NE reuptake effect might have contributed to this study’s less
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robust findings.
Another possible explanation for our study’s negative result relates to dosage. Whereas DVLX has
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been studied in doses up to 400 mg/day, our study respected the FDA approved maximum of 100 mg/day. Three subjects received doses up to 150 mg/day during open continuation treatment
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following the study due to nonresponse at 100 mg/day dose, two reporting further improvement of depressive symptoms subsequent to above-PDR-recommended dosing. In summarizing DVLX efficacy studies, Perry et al.
42
concluded that higher dose did not produce additional benefit;
however, we are unaware of studies of non-responders to DVLX 100 mg/day to assess benefit of increases above the currently FDA-approved range. Andrade
36
has suggested that DVLX might be
essentially an SSRI at lower doses, as has been found for venlafaxine, which requires dosing >150
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mg/day to elicit noradrenergic effects .
Finally, some
44,45
46
but not all studies suggest lower efficacy of antidepressants in milder major
depression. However most studies of non-major persistent depressive disorder (previously called 13,47
dysthymic disorder) suggest that medication is more effective thanplacebo
. The negative result
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of this study does not strongly support either hypothesis; a larger sample, allowing for an analysis of the moderating effect of initial severity of PDD would be helpful in addressing this issue.
DVLX side effects were generally mild, only once resulting in discontinuation. Self-reports
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(MOTCS, ABNAS, ASEX) confirmed the tolerability of DVLX. There was also high compliance, 95.5% for the medication group, perhaps another measure of tolerability.
Significant psychosocial morbidity and costs are associated with PDD regardless of subtype or 10,48
cross-sectional severity.
In this study, duration of illness averaged 12.8+13.5 years, with
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significant impairment by numerous measures. Despite 67.8% of our participants having college or graduate degrees, most were unemployed (38.5%; 15/39) or working part-time (52.5%; 31/59).
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Most subjects (84.8%) were currently unmarried, suggesting impairment in interpersonal relationships. Mean score on the GAF of 63.3+7.3 (n=59), indicates a moderate degree of functional
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impairment, as do baseline mean scores on SAS of 2.50+0.5,12 weeks of over 2 SD above the 49
community mean (1.4+0.5, ), which remained 1.6 SD above this mean following DVLX (2.22+0.4
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LOCF) or placebo (2.29+0.5 LOCF) treatment. Similarly, SDS scores remained elevated posttreatment (10.32+7.27 for placebo and 11.80+7.56 for DVLX) compared to community norms 50
The literature
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(6.1+7.0).
51-54
about continued improvement in psychosocial functioning in PDD is
mixed. Of note, in this study, remission at week 24 was associated with normalization of SAS scores, underscoring its importance as a treatment goal.
Social functioning and Harm Avoidance (which has been associated with functional impairment) did show further improvement between weeks 12 and 24 for patients continuing DVLX, but most
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patients continued to have scores in the abnormal range. Since continued antidepressant 40
monotherapy alone generally does not lead to normalization of psychosocial functioning in PDD , alternative approaches should be investigated more thoroughly, including medication augmentation, combined medication-psychotherapy strategies, particularly including cognitive behavioral 55,56
therapy
and behavioral activation therapy
57,58
. Future studies should aim both to enhance
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remission rates and improve psychosocial outcomes.
Open Continuation Phase: At week 24, most patients (62.5%) who achieved remission by week 12 on DVLX continued to be in remission. Additional improvements were noted in the continuation
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DVLX sample in self-rated scales, including depression (the QIDS-SR and BDI), as well as the
RRS, suggesting benefits of continuation treatment. Findings for continuation treatment at week 24 were consistent with broad improvement—in core depressive scales, in measures of psychosocial impairment, and in the harm avoidance component of temperament as well as in ruminations. This suggests that additional improvement in these areas, at least with DVLX, may require longer
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medication exposure. In contrast our recent study with duloxetine
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showed little additional
improvement between acute treatment and continuation treatment (10 and 22 weeks respectively in 51-54
about continued improvement in psychosocial functioning in persistent
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that study). The literature
depression is mixed. The reasons for discrepant findings for two SNRI medications are unclear; it is
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possible that the maximum dose of each (120 mg/day for duloxetine vs. 100 mg/day for desvenlafaxine) may have differing potency in affecting neurotransmitter reuptake, duloxetine
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possibly having higher relative reuptake inhibition or other effects at doses used in these 19,41
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studies.
Study limitations and future directions This was a negative study and positive secondary analyses should not be overinterpreted. For one reason, the multiple secondary analyses presented were not corrected for multiple comparisons. Therefore, some significant findings could be due to chance. Further, the sample size of 59 limits power to detect differences smaller than “moderate”. The exclusion of acutely suicidal patients, and
ACCEPTED MANUSCRIPT 18
those with medical and psychiatric comorbidities, limits the generalizability of findings. Further study with a larger and more varied sample of individuals with PDD would allow analyses of moderating effects of baseline severity. Higher doses of DVLX could be studied. Future directions in PDD psychopharmacology should include comparative and long-term studies, perhaps following the STAR*D design
59,60
, in which a large cohort of PDD patients are followed for an extended period of
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time and offered various treatments, including the commonly used medication classes such as
SSRIs, SNRIs, bupropion, and other antidepressant agents, as well as psychotherapy, including medication switches, augmentation, and other strategies to enhance response and remission,
particularly to improve social functioning. Because some patients with PDD might respond (or remit)
AN US
with doses above current FDA approved maximum of 100 mg/day, further study should address further treatment of patients with PDD who do not remit with conventional dosing.
Author disclosure: This study received funding from Pfizer, Inc., New York, NY. The study was performed at the New York State Psychiatric Institute/Columbia University Department of Psychiatry, New York, NY
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Role of funding: Funding from Pfizer, Inc. supported conduct of the Investigator Initiated Study (desvenlafaxine vs. placebo clinical trial and open-label continuation treatment) described in this paper, as well as funding for analysis of results. The paper was written without input from Pfizer, Inc. or its employees.
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Contributors: The authors had roles in this paper as follows: David J. Hellerstein, MD: design of study as PI, obtaining funding, treating patients, supervision of conduct of study and analyses of results, writing paper. Jonathan W. Stewart, M.D.: co-investigator in study, treating patients, assisting in interpretation of results, editing manuscript Bradley S. Peterson, M.D.: co-investigator in study, treating patients, assisting in interpretation of results, editing manuscript Vinushini Arunagiri, M.A.: literature review, drafting manuscript, assisting in interpretation of results Ying Chen, M.D.: data management, statistical analyses, describing statistical methods in paper Patrick J. McGrath, M.D.: co-investigator in study, treating patients, assisting in interpretation of results, editing manuscript
Acknowledgements: The authors would like to thank Deborah Deliyannides, MD, Mark Rodriguez, BA, and Donna O’Shea, RN, MS, for assistance in conduct of the study
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Table 1. Demographic characteristics overall and by treatment group (n=61) Treatment Group
Variables
n
DVLX to DVLX (n=31)
Mean (SD) or %
n
Demographics Gender
Mean (SD) or %
Placebo to DVLX (n=30) n
Mean (SD) or %
Male
28
45.9%
12
38.7%
16
53.3%
Female
33
54.1%
19
61.3%
14
46.7%
Marital 43
70.5%
Married
9
14.8%
Separated
2
3.3%
Divorced
7
11.5%
Race
Caucasian
38
Asian
6
Other
7
Ethnicity/Hispanic
54
PT
Non-Hispanic Hispanic
7
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Employment Status
16.4%
71.0%
21
70.0%
6
19.4%
3
10.0%
0
0.0%
2
6.7%
3
9.7%
4
13.3%
p-value
0.252
0.369
0.161
3
9.7%
7
23.3%
62.3%
19
61.3%
19
63.3%
9.8%
3
9.7%
3
10.0%
11.5%
6
19.4%
1
3.3%
M
10
ED
Black/AA
22
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Single
Diff between groups
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Total Sample (n=61)
0.246
88.5%
26
83.9%
28
93.3%
11.5%
5
16.1%
2
6.7% 0.067
30
50.0%
21
67.7%
9
31.0%
Employed part time for pay
15
25.0%
6
19.4%
9
31.0%
Student
3
5.0%
1
3.2%
2
6.9%
Unemployed (< 6months)
5
8.3%
1
3.2%
4
13.8%
Unemployed (> 6months)
7
11.7%
2
6.5%
5
17.2%
Age
61
38.4 (13.0)
31
40.1 (14.1)
30
36.7 (11.7)
0.305
Education
61
15.2 (3.7)
31
15.7 (3.9)
30
14.7 (3.4)
0.270
AC
Employed full time for pay
a
Baseline differences are assessed using t-tests for continuous measures and chi-square test for categorical measures
a
ACCEPTED MANUSCRIPT 24
Table 2. Primary and secondary outcome measures for subjects receiving desvenlafaxine (DVLX; n = 31) versus those receiving placebo (n = 30), with results of repeated measurement ANOVA comparing Week 0 and Week12. Measu res
Week 0 Placebo n=30
SAS RRS TCIRD TCINS TCI-PS
(SD )
Me an
(SD )
Me an
(SD )
20. 03 33. 83 --
4.4 9 11. 04 --
20. 29 36. 52 --
5.0 3 10. 41 --
11. 58 18. 65 2.8 8
6.9 6 11. 41 0.9 5
9.3 5 19. 62 2.2 3
5.8 0 12. 71 0.9 5
0.007
11. 63 19. 17 2.5 1 53. 57 15. 59 19. 72 4.3 5 20. 86
4.0 3 7.5 0 .45
13. 19 21. 07 2.4 7 55. 28 14. 84 18. 21 4.2 9 23. 71
4.0 8 8.3 5 .45
8.0 8 12. 82 2.2 9 41. 78 15. 0 19. 96 4.1 9 20. 27
4.9 2 9.2 0 .46
7.3 5 11. 64 2.2 2 43. 11 15. 92 18. 15 4.6 5 20. 35
4.4 2 6.4 7 .41
0.005
11. 49 4.1 8 4.5 0 1.8 8 8.2 7
0.014
12. 90 4.3 6 5.0 2 2.0 4 7.6 3
8.4 9 4.3 9 4.7 0 2.0 4 7.4 4
0.013
0.6 96 0.6 10 --
5 0 5 0 5 0
0.046
0.5 81 0.5 20 0.2 39 0.5 34 0.0 03 0.0 29 0.0 99 0.1 32
5 0 5 1 4 8 4 6 4 8 4 8 4 8 4 8
0.091
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M 13. 39 3.9 2 5.2 5 1.6 7 6.6 8
P
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Me an
AC
TCIHA
DVLX n=26
(SD )
ED
Patient Rating s QIDSSR BDI
Placebo n=26
Effect Size (Partial Eta Squared) * Treatm Tim D Time x ent e F Treatm ent
Me an
PT
CGI-I
DVLX n=31
CE
Clinicia n Rating s HDRS24 CDRS
Week 12
0.109
0.003 0.003
0.003 0.022 0.001 0.002
0.009
--
0.034 0.004 <0.001 0.078 0.031 0.041 0.024
0.1 12 0.5 13 0.0 17
0.0 30 0.1 87 0.6 63 0.9 81 0.0 49 0.2 20 0.1 58 0.2 82
Key to abbreviations: HDRS: Hamilton Depression Rating Scale, CDRS: Cornell Dysthymia Rating Scale, BDI: Beck Depression Inventory, SAS: Social Adjustment Scale, RRS: Ruminative Responses Scale, TCI: Temperament and Character Inventory, subscales: HA: Harm Avoidance; RD: Reward Dependence; NS: Novelty Seeking; PS: Persistence; CGI-I-PT: CGI-Improvement, patient-rated. * The Effect sizes reported in this table are Partial Eta Squared: 0.01 (small), 0.06 (medium) 0.14 (large)
ACCEPTED MANUSCRIPT 25 Table 3. Adverse events observed with desvenlafaxine (DVLX) or initial placebo followed with DVLX treatment
AC
CE
PT
ED
M
AN US
CR IP T
*Pa tien DVLX, n (%) Placebo, n (%) ts AE Week 12 Week 24 Week 12 Week 24* initi N=30 N=24 N=29 N=23 ally rec Daytime sleepiness 11 (36.7) 5 (20.8) 6 (17.2) 1 (4.4) eivi Decreased sleep 10 (33.3) 9 (37.5) 4 (13.8) 3 (13.0) ng pla Headache 9 (30.0) 4 (16.7) 4 (13.8) 1 (4.4) ceb Nausea 9 (30.0) 8 (33.3) 3 (10.3) 3 (13.0) o Dry mouth 7 (23.3) 5 (20.8) 2 (6.9) 1 (4.4) (we ek Agitation 5 (16.7) 2 (8.4) 0 0 0Dizziness 5 (16.7) 4 (16.7) 0 1 (4.4) 12) Sweating 5 (16.7) 2 (8.4) 2 (6.9) 2 (8.8) wer e Anorgasmia 4 (13.3) 3 (12.5) 2 (6.9) 1 (4.4) trea Decreased appetite 4 (13.3) 4 (16.7) 0 0 ted with Gastrointestinal upset 4 (13.3) 2 (8.4) 3 (10.3) 3 (13.0) des Constipation 3 (10.0) 3 (12.5) 2 (6.9) 2 (8.8) ven Vivid dreams 3 (10.0) 3 (12.5) 0 0 lafa xin Cognitive impairment 2 (6.7) 2 (8.4) 3 (10.3) 5 (21.7) e Decreased concentration 2 (6.7) 1 (4.2) 1 (3.5) 0 (DV Decreased libido 2 (6.7) 2 (8.4) 4 (13.8) 6 (26.1) LX) fro Fatigue 2 (6.7) 2 (8.4) 1 (3.5) 1 (4.4) m Increase of appetite 2 (6.7) 1 (4.2) 1 (3.5) 0 we Palpitations 2 (6.7) 2 (8.4) 0 0 eks 13Yawning 2 (6.7) 2 (8.4) 0 0 24. Anxiety 1 (3.3) 3 (12.5) 1 (3.5) 1 (4.4) Not Delayed orgasm 1 (3.3) 1 (4.2) 3 (10.3) 0 e: In Muscle spasms 1 (3.3) 5 (20.8) 1 (3.5) 2 (8.8) the Spacey feeling 1 (3.3) 1 (4.2) 3 (10.3) 0 foll Tingling 1 (3.3) 1 (4.2) 1 (3.5) 1 (4.4) owSeizure 0 0 1 (3.5) 1 (4.4) up peri od, 9 patients reported no side effects. Among them, 1 was in the continued DVLX treatment group and 8 were in the placeboDVLX treatment group.
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Table 4. Primary and secondary outcome measures for patients treated with desvenlafaxine (DVLX) in phase 1 and phase 2 and patients treated with placebo in phase 1 and DVLX in phase 2 (n = 47).
DVLX DVLX Group (n=24) WK 12
WK24
Me an (SD )
Me an (SD )
Mean (SD)
Phase II: Open Label WK12 vs WK24 Eff d p ect f Siz e*
Overall Changes Pre-tx vs Wk24 Eff ect Siz e
d f
RRs
TCIRD
Eff ect Siz e
d f
p
<0.
<0.
33.7
20.35(1
12.57(
0.5
2
<0.
0.7
2
<0.
001
(11.38)
0.92)
8.99)
13
2
001
84
2
001
0.0
2
0.1
0.8
2
<0.
20.17(
12.52(1
6.17(1.
0.5
2
<0.
0.8
2
67
4
(1.14)
90
3
45
54
3
001
1.07)
.28)
16)
66
2
001
35
2
001
(1.0
(1.2
5)
5)
37.
19.
15.54(
0.1
2
0.0
0.7
2
12.06)
45
3
60
52
3
08
33
(11.
(11.
64)
82)
4.0
2.6
2.21
0.1
2
0.0
0.8
2
4
7
(0.83)
63
3
46
07
3
(0.6
(1.0
9)
1)
7.5
5.92
0.2
2
0.0
0.8
2
25
4
(4.35)
32
3
15
62
(4.4
(4.4 6) 11.
54
96
(8.9
(6.4
<0.
4.22
3.04
2.35
0.3
2
0.0
0.8
2
<0.
001
(0.74)
(0.88)
0(.94)
60
2
01
05
2
001
<0.
12.73
8.68
7.39
0.0
2
0.2
0.6
2
<0.
3
001
(3.88)
(4.75)
(4.27)
68
2
17
20
1
001
ED
5) 21.
PT
13.
7.58
0.3
2
0.0
0.7
2
<0.
19.57
12.91(8
10.17(
0.1
2
0.1
0.5
2
<0.
(6.08)
74
3
01
53
3
001
(8.37)
.95)
6.99)
13
2
09
68
2
001
1)
8)
2.4
2.2
2.08
0.1
2
0.0
0.3
2
0.0
2.49
2.30
2.26
0.0
2
0.9
0.2
2
0.0
2
1
(0.46)
47
3
58
43
3
02
(0.48)
(0.50)
(0.69)
01
2
13
71
2
14
AC
SAS
p
Mean (SD)
7.63
CE
BDI
d f
Mean (SD)
9.2
Patient Ratings QID SSR
Eff ect Siz e*
p
AN US
CGI -S
Mean (SD)
WK24
M
CD RS
20.
Overall Changes Pre-tx vs Wk24
WK12
Clinician Ratings HRS D24
Phase II: Open Label WK12 vs WK24
Pre-tx
CR IP T
Pre -tx
Placebo DVLX Group (n=23)
(0.3
(0.4
9)
3)
54.
41.
37.14
0.2
2
0.0
0.7
2
<0.
52.76(
39.559(
37.14(
0.1
1
0.0
0.6
2
<0.
(8.73)
10
1
30
66
1
001
13.26)
11.90)
10.65)
68
9
70
56
0
001
50
64
(8.2
(10.
3)
36)
15.
16.
15.92
0.0
2
0.1
<0.
2
1.0
15.61
14.52
15.19
0.0
2
0.3
0.0
2
0.5
92
71
(4.44)
90
3
45
001
3
00
(4.82)
(3.99)
(4.32)
67
2
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(3.9
(4.0
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TCIPS
TCIHA
4)
17.
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0.0
2
0.6
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86
93
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11
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15
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96
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38
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Key to abbreviations: Pre-tx: Pre-treatment HDRS: Hamilton Depression Rating Scale, CDRS: Cornell Dysthymia Rating Scale, BDI: Beck Depression Inventory, CGI-I,CGI-S: clinician-rated Clinical Global Impression, Severity of Illness, SAS: Social Adjustment Scale, TCI: Temperament and Character Inventory, subscales: HA: Harm Avoidance; RD: Reward Dependence; NS: Novelty Seeking; PS: Persistence
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* The Effect sizes reported in this table are Cohen’s D: 0.2 (small), 0.5 (medium) and 0.8 (large)
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Figures Consort Diagram: Desvenlafaxine (DVLX) study consort diagram (medication)
Enrollment
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Assessed for eligibility (n=350)
Not eligible (n= 279)
Excluded (n= 10) No longer met inclusion criteria (n= 1) Declined to participate (n= 5) Other reasons (n= 4) 3 lost to follow up, 1 began a new job
Eligible (n= 71)
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Randomized (n= 61)
Allocation (wk RZ) Allocated to Placebo (n= 30) Received allocated intervention (n=29) Did not take allocated intervention (n=1)
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Allocated to Active DVLX (n=31) Received allocated intervention (n=30) Did not take allocated intervention (n=1)
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Lost to follow-up (n= 2) Discontinued intervention Patient request (n= 1)
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End of Acute Phase (wk 12)
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Analyzed (n= 26) Excluded from analysis (n=0)
Lost to follow-up (n= 1) Discontinued intervention Patient request (n= 1) Side effects (n= 1) No improvement (n=1)
Analysis Analyzed (n= 26) Excluded from analysis (n=0)
End of Continuation Phase (wk 24)
Did not finish follow up (n=3) Two placebo responders One placebo non-responder
Did not finish follow up (n=2) Both responded at week16 and never came back for week24 evaluation.
Continuation Phase Analysis Analyzed (n= 23) Placebo DVLX (n=23)
Excluded from analysis (n=0)
Analyzed (n= 24) DVLX DVLX (n=24) Excluded from analysis (n=0)
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Figure 1. Weekly HDRS-24 scores for desvenlafaxine (DVLX) vs. placebo treated subjects 30
Placebo treated patients began active medication at week12
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20
15
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Hamd24 Mean ± SD
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0 6
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DVLX -> DVLX
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Desvenlafaxine vs. placebo in the treatment of persistent depressive disorder David J. Hellerstein M.D. , Jonathan W. Stewart M.D. , Ying Chen M.D. , Vinushini Arunagiri M.A. , Bradley S. Peterson M.D. , Patrick J. McGrath M.D. PII: DOI: Reference:
S0165-0327(17)32202-4 https://doi.org/10.1016/j.jad.2018.11.065 JAD 10283
To appear in:
Journal of Affective Disorders
Received date: Revised date: Accepted date:
24 October 2017 21 September 2018 3 November 2018
Please cite this article as: David J. Hellerstein M.D. , Jonathan W. Stewart M.D. , Ying Chen M.D. , Vinushini Arunagiri M.A. , Bradley S. Peterson M.D. , Patrick J. McGrath M.D. , Desvenlafaxine vs. placebo in the treatment of persistent depressive disorder, Journal of Affective Disorders (2018), doi: https://doi.org/10.1016/j.jad.2018.11.065
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Highlights
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The SNRI medication desvenlafaxine did not differentiate from placebo on the primary outcome (Hamilton Depression Rating Scale) in non-major persistent depressive disorder. As a negative study, this does not support the use of DVLX for non-major PDD. Statistically significant secondary analyses suggest the overall negative result could be due to sample size or sampling, suggesting further studies of this medication might be appropriate in this population. Twelve week continuation phase of active medication was associated with additional improvement in symptoms and psychosocial functioning, and remission of depressive symptoms was associated with normalization of social functioning score on the SAS.
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revision 9/21/2018 3940 words 4 tables 1 Consort Diagram 1 figure
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Title: Desvenlafaxine vs. placebo in the treatment of persistent depressive disorder
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Authors: David J. Hellerstein, M.D. , Jonathan W. Stewart, M.D. , Ying Chen, M.D. , Vinushini 3 4 1,2 Arunagiri, M.A. , Bradley S. Peterson, M.D. , Patrick J. McGrath, M.D.
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Address for Correspondence: David J. Hellerstein, MD New York State Psychiatric Institute 1051 Riverside Drive, Unit #51 New York, NY 10032 tel. 646-774-8069 fax. 646-774-8034 email: [email protected]
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1. New York State Psychiatric Institute, New York, NY 2. Columbia University College of Physicians and Surgeons, New York, NY 3. Teachers College, Columbia University, New York, NY 4. Institute for the Developing Mind at Children’s Hospital Los Angeles; Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, CA
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Clinicaltrials.gov registration #: NCT01537068
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Abstract Introduction: Pharmacotherapy of non-major persistent depressive disorder (PDD) is little studied. We report a study of the serotonin-norepinephrine reuptake inhibitor (SNRI) desvenlafaxine (DVLX) for PDD.
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Method: Non-psychotic, non-bipolar outpatients aged 20-65 having PDD without concurrent major depression (MDD) were randomized double-blind to desvenlafaxine or placebo for 12 weeks. All
had Hamilton Depression Rating Scale (HDRS-24) score >12. Open-label DVLX was offered for 12 weeks following the acute trial.
Results: Seventy-one subjects having mean baseline HDRS-24 20.27+4.77 were eligible, of whom
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post-RZ data was available for all 59 randomized. The primary 12 week analysis did not
differentiate DVLX-treated subjects’ mean HDRS scores from those on placebo (6.53 + 3.98 vs. 8.24 + 4.96, F=3.33, df=1, p=.07). Several secondary analyses yielded statistically significant results, including Responder, CGI and QIDS.
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Discussion: As the primary analysis did not reach statistical significance, this is a negative study which does not support the use of DVLX for non-major PDD. Nevertheless,
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statistically significant secondary analyses suggest the overall negative result could be due to sample size or sampling, suggesting further studies of this medication might be
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appropriate in this population.
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ClinicalTrials.gov identifier: NCT01537068
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Previous presentation: none
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Introduction
Chronic depression is common, affecting 1.5-5% of the population and produces significant 1-9
functional impairment, negative health outcomes, and social costs, psychosocial burden than acute depression.
10
DSM-5
11
resulting in greater
recognized the importance of chronicity by
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consolidating dysthymic disorder (DD), chronic major depressive disorder (MDD), and residual MDD, into a single classification, Persistent Depressive Disorder (PDD).
Identifying effective treatments for PDD is clearly important to relieve symptoms and improve
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psychosocial and health outcomes. Yet chronic depression remains under-studied: a 2000
Cochrane review, for example, found only 20 placebo-controlled studies of DD (chronic low-grade 12
depression), concluding that antidepressants are effective. A more recent review found 36 studies of pure dysthymia, and 22 studies of chronic major depression or dysthymia with current MDD, with 13
efficacy data on only 5,806 patients world-wide. . Few drugs have been adequately tested, e.g.
13
Other reviews
14-16
suggest these patients may require higher than
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greater efficacy than others
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with 2 or more trials enrolling over 100 patients, though data suggests some medications may have
usual medication doses, combined medication and psychotherapy treatments, or concurrent dosing with two or more classes of medication to achieve optimal outcome, since residual symptoms and
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persistent functional impairment are common. An alternative to combining treatments has been dual-mechanism medications, such as serotonin-norepinephrine reuptake inhibitors (SNRIs),
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though SNRIs may have more side effects
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in this population than other medications. We 18
previously reported efficacy of the SNRI duloxetine in chronic non-major depression.
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Desvenlafaxine (DVLX) (brand name Pristiq®),
19
like duloxetine, blocks serotonin and
norepinephrine reuptake, so may also effectively treat chronic depression. Thus, a study of the efficacy of DVLX for non-major PDD seems indicated.
Hypotheses: 1) Efficacy study: We expected that desvenlafaxine would be superior to placebo over a twelve-
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week period in the following outcomes: a.
Improved depression, as measured by HDRS-24 item total score at week 12 (primary outcome).
b.
The percentage of subjects classified as (a) Responders and (b) Remitters at week 12.
c.
Improved secondary measures of depression (Quick Inventory of Depressive
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Symptomatology-Self-Rated (QIDS-SR), Beck Depression Inventory (BDI), Cornell
Dysthymia Rating Scale (CDRS), and overall severity of illness (Clinical Global ImpressionsSeverity (CGI-S)). d.
Improved psychosocial functioning (as measured by the Social Adjustment Scale (SAS) and
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the Sheehan Disability Scale (SDS), global outcome (Global Assessment of Functioning (GAF)), and temperament (Temperament and Character Inventory (TCI)).
2) Open continuation study: In the continuation phase (weeks 13-24) we expected that patients continuing active DVLX would maintain improvement achieved at week 12 and would have additional functional improvements, and that patients initially treated with placebo would respond
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similarly to DVLX-treated patients in the double-blind phase.
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Methods
Study procedures This study was conducted at New York State Psychiatric Institute’s Depression Evaluation Service (DES) and approved by its Institutional Review Board (IRB). The goal was to enroll subjects with
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PDD without a current MDD episode. We conducted a power analysis, based on the results of previous double-blind placebo controlled studies in dysthymic disorder. Assuming a
moderate effect size, with an 80% likelihood of finding a difference at significance p<.05, we calculated that a sample of 30 per arm was sufficient. Potential subjects were evaluated by
20
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research psychiatrists using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) , 21
and 24-item Hamilton Depression Rating Scale (HDRS-24) . Appropriate patients signed IRBapproved consent. A physical examination was performed and blood and urine samples were collected, including urine for pregnancy and toxicology. This study was registered at ClinicalTrials.gov (identifier: NCT01537068). It was funded by Pfizer, Inc. as an investigator-initiated
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trial.
Inclusion criteria were: age 20 to 65 years; baseline HDRS-24 score >=12, chronic (>= 2 years) depression. Exclusion criteria included: DSM-5 diagnosis of current major depression, bipolar
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disorder, schizophrenia or other psychotic disorder; dementia or other cognitive disorder; current (past 6 months) drug or alcohol use disorder; current psychoactive medication use; serious risk for
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suicide during the course of the study; unstable medical conditions; current or planned pregnancy;
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lack of capacity to consent to study participation.
Conduct of study: The study had two phases: 1) a 12-week double blind placebo controlled phase; and 2) a 12-week open treatment phase. Phase 1 RCT: randomization occurred approximately 1 week after intake assessment, with doubleblind treatment assigned based on a random number table generated by an independent
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biostatistician using SAS software (“Random = ranuni (seed)” procedure with a block of 4). Visits at weeks 1, 2, 4, 6, 8, and 12 assessed longitudinal course of presenting symptoms and functioning and emergence of new symptoms. Phase 2, Continuation Treatment: Patients initially treated with DVLX continued effective medication; non-responders were switched to other antidepressants. Patients initially treated with
up, patients were seen every 4 weeks for 12 weeks.
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placebo began active DVLX treatment, up to a maximum of 100 mg/day. During open-label follow-
Clinicians administered the HDRS-24, Cornell Depression Rating Scale (CDRS)
22,23
, Clinical Global 24
Impression (CGI), and the Systemic Assessment for Treatment Emergent Events (SAFTEE) , while 25
(TCI)
26,27
28
, Social Adjustment Scale (SAS),
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patients completed the Beck Depression Inventory (BDI) , Temperament and Character Inventory 29
and Ruminative Responses Scale (RRS) . Study
measures assessed depressive symptoms (BDI, HDRS, CDRS), general and social functioning (SAS, GAF, CGI), and ruminations (RRS). Tolerability was assessed at each visit by self-rated scales and clinician assessment. Clinicians rated adverse events (AEs) using the SAFTEE, and
receiving CGI-Improvement
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rated each AE by duration and severity. Participants verbally re-consented at week 6. Participants scores of 6 (“much worse”) or 7 (“very much worse”) were withdrawn
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Drug Administration:
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from double-blind treatment.
DVLX (50 mg capsules) or matching placebo was begun at visit 2 (week 0); dose could be
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increased after 4 weeks to 100 mg q AM, if tolerated and still depressed (i.e. CGI-Improvement score >2). The blind was broken at Week 12, at which point DVLX was continued in those already
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taking it, or begun in those initially treated with placebo. Those still depressed on DVLX could be switched to another antidepressant.
Statistical Analyses The primary outcome measure was a priori defined as the HDRS-24 item total score. Efficacy was evaluated using chi square tests for response and remission. Paired T-test and repeated measures
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analysis of variance (ANOVA) were applied for changes in scale scores (HDRS, CDRS, GAF, CGI, QIDS-SR, PGI, SAS, SDS, TCI, BDI and RRS). Response was defined as: >50% decrease from baseline in HDRS-24 score and CGI-I score of 1 ("very much improved") or 2 ("much improved"). Remission was defined as: HDRS-17 score < 4 and HDRS item #1 (depressed mood) score = 0. (In this study, as in other PDD studies by our group
18,31
, we defined remission more rigorously than is
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usually done in MDD trials (HDRS score<=6). Because patients with PDD often present with lower symptom severity, inclusion criteria allow a baseline minimum Hamilton Depression Rating Scale-24 item score>=12. If remission was defined as a score <=6 there would be no difference between response and remission for such patients.) Frequencies of side effects are reported. The last
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observation was carried forward (LOCF) as an endpoint score for those who had missing data. Data analyses used IBM SPSS version 24 and SAS (9.4). Week 24 analyses followed a similar pattern. Analyses were run with both raw data and LOCF. Results did not change significantly. Therefore,
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we report results from raw data.
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Results Sample (see Consort Diagram) Seventy-one subjects signed study consent, of whom 61 were assigned to receive blinded medication or placebo. Twelve eligible subjects did not start study medication for reasons described in Consort Diagram. Our intention-to-treat (ITT) group included 61 patients, of whom post-randomization data were available for 59 (two patients were randomized but
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did not receive study medication). Of these 59 patients beginning treatment, 1 placebo-treated
patient dropped out after wk 2, and 2 after wk 6. Of desvenlafaxine-treated patients, 2 dropped out after wk 2, and 2 after wk 8. Table 1 shows demographic characteristics of desvenlafaxine (N=31) and placebo (N=30) treated subjects. Subjects were predominantly (54.1%) female, with mean age
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37.9+13.1 years (range, 20-63); mostly Caucasian (62.3%, 38/61), and most (48/61 = 80%) had
graduated college. Half (30/60) were employed full time. Most (52/61 = 85%) were unmarried. Two thirds of subjects (35/55) had early-onset (before age 21) PDD. Forty-four per cent (27/61) had a lifetime anxiety disorder diagnosis, including GAD (3.2%; 2/61), social phobia (29.5%; 18/61), obsessive-compulsive disorder (9.8%; 6/61), and anxiety disorder NOS (3.3%; 2/61). Prior alcohol
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use disorder was present in 9.8% (6/61) and prior drug abuse was present in 8.2% (5/61). History of eating disorders were found in 11.5% (7/61) of subjects (4 binge eating disorder, 3 bulimia). Prior
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MDD episodes were reported by 47.5% (29/61), with 19.7% (12/61) reporting one prior episode, and 27.9% (17/61) reporting two or more prior episodes. Of 29 patients who had previous MDD
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episodes, 22 had treatment history information; there was no difference between assignment to
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treatment and placebo groups (Pearson chi-square=0.029, df=1, p=0.864).
Mean DVLX or placebo (equivalent) dose at Week 12 was 96.5 mg/day (sd=12), with 7 taking 50
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mg/day, and 52 taking 100 mg/day. The active medication group had 95.5% compliance and mean final dose of 95 (sd = 15.3) mg/day of DVLX, with 3 people taking 50 mg/day and 27 taking 100 mg/day. The placebo group had 95.4% compliance (sd = 14.5); average final dose equivalence (50 mg/capsule) was 93 mg/day (sd = 17.6) of placebo, with 4 people taking 50 and 25 taking 100 mg/day. There was no association between treatment group and dose level and compliance (t=0.02, df=44, p=0.98).
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At week 24, 6 patients were not receiving DVLX. Three initially DVLX-treated patients switched to other antidepressants (two to bupropion, and one to duloxetine); two of the three initially-placebotreated patients did not take antidepressant medication in the follow-up phase, and one received escitalopram. Mean dose for patients remaining on DVLX was 94.0 (sd=22.5) mg/day and mean
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dose for patients who switched from placebo to DVLX was 86.5 (sd=25) mg/day.
Average baseline scores for the rating scales used as outcome measures appear in Table 2. There
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were no significant baseline differences between treatments.
Efficacy analyses Week 12 results Change on rating scales over time
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Primary analysis. As shown in Table 2, HDRS-24 at 12-weeks, covaried for baseline HDRS24, did not significantly differentiate DVLX from placebo (6.53 + 3.98 vs. 8.24 + 4.96, F=3.33,
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df=1, p=.07).
Secondary analyses. Also, in Table 2, are results of analyses of each secondary outcome
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measure (HDRS-17, CDRS, BDI, GAF, CGI-Severity, QIDS-SR, RRS, TCI, SDS, and SAS) with randomization group (active drug or placebo) as the between subjects factor and time (Baseline and
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week 12 or LOCF ratings) as the within subjects factor. All measures of depressive symptoms and psychiatric functioning showed a significant main effect of Time, indicating that on average, subjects
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improved over time, regardless of treatment group. Of the various clinician and patient ratings, the QIDS-SR and the CGI-I-Pt showed significant treatment by time differences; and HDRS-17 scores (Figure 1) favored medication at week 12 at the trend level, while analyses of other measures did not differentiate the treatments.
Treatment response and remission at week 12 Of 59 subjects in the ITT sample who received study medication, response rate at week 12 was
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61.5% (16/26) for DVLX vs. 26.9% (7/26) for placebo (chi sq (df=1, n=52) = 6.32, p=.025); remitter rate was 26.7% (8/30) for DVLX vs. 17.2% (5/29) for placebo (chi sq (df=1,n=59)=.76, p=.38). All responders to active drug (n=16) were taking 100 mg. Responders to placebo (n=7) included 2 taking 50 mg equivalent, and 5 taking 100 mg equivalent. Non-responders to placebo (n=19) included taking 50 mg equivalent and 18 taking 100 mg equivalent; active drug non-responders
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(n=9) were all taking 100 mg/d. Of 27 patients who had previous MDD episodes, 20 had treatment history information and there was no difference between treatment and placebo groups in terms of response at week 12 (Fisher’s exact test p=0.370 (2 sided)). Since most of the cells had counts less
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than 5, we did not further evaluate this variable with other analyses.
Social adjustment and global functioning
At week 12, both treatment groups showed improvements in SAS, SDS and GAF but there was no drug-by-time effect, indicating there was no greater improvement in social functioning with DVLX
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than placebo (Table 2).
Temperament
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The TCI includes four factors of temperament: Harm Avoidance (HA), Novelty Seeking (NS), Reward Dependence (RD), and Persistence (PS). At baseline, HA scores (23.50+7.47 for DVLX
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subjects; 21.39+7.20 for placebo subjects) were approximately 2 SD above community norms of 32
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10.6+6.0 for men and 12.9+6.1 for women, similar to our prior findings.
After 12 weeks of
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treatment, there were no significant changes by group, time or group by time in HA, NS or RD,
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though there was a time effect for PS (Table 2).
Tolerability
There were no significant differences between placebo- and DVLX-treated subjects on the measures of cognitive functioning (MOTCS), sexual functioning (ASEX), or patient-perceived drugrelated cognitive impairment (ABNAS) and pain (BPI); (data not reported). Adverse events (AEs) as collected on the SAFTEE were reported by 19 of the 29 subjects on placebo (65.5%) and 29 of the
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30 (96.7%) subjects on DVLX (Table 3). The mean number of AEs for the DVLX group was 3.32 (sd=2.54) and for the placebo group 1.94 (sd=2.29) with the medication-treated group showing a trend for more AEs (t = -1.80, df = 42, p = 0.08). Most common side effects in DVLX-treated subjects were nausea (30%), dry mouth (23.3%), and dizziness, sweating, agitation and anorgasmia (each 16.7%). Most common side effects in placebo-treated subjects were decreased
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libido (13.8%), GI upset, cognitive impairment, delayed orgasm, and nausea (each 10.3%). Side effects were generally mild to moderate. Only 1 subject (on DVLX) discontinued due to adverse events.
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Week 24 results Continued DVLX
During the continuation period (Table 4, Figure 1), ratings comparing week 12 to week 24 showed significant changes in several patient-rated inventories, including depression (QIDS-SR and BDI), and ruminations (Ruminations Responses Scale (RRS)). Response and remission rates also
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increased by Week 24 (Table 4). Of 8 DVLX remitters by Week 12, 5 (62.5%) remained in remission at week 24 (2 Week 12 remitters declined to continue medication, and 1 previous remitter
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was a nonresponder by Week 24).
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Placebo treated patients beginning DVLX
Patients initially treated with placebo who began open label DVLX at Week 12, generally showed
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significant improvement (Table 4) between weeks 12 and 24 in clinician-rated scales but not in selfrated scales. Compared to baseline, they had significant improvement in nearly all scales, with the
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exception of three temperament measures, RD, NS and PS. Unlike the patients continuing DVLX, there was not a significant improvement in HA with 12 weeks of DVLX treatment in this group.
Response and remission rates at week 24 Patients who continued DVLX had response rate of 82.6% and remission rate of 47.8% at 24 weeks Patients beginning DVLX in continuation phase had response rate of 83.3% and remission rate of
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50.0% at 24 weeks.
Temperament and social functioning (Table 4) At 24 weeks, the only temperamental factor that showed significant change from baseline was Harm Avoidance (HA) in the DVLXDVLX group. No temperamental factor changed significantly in
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the PLACDVLX group. Functional impairment (SDS, SAS, GAF) continued to improve during the continuation phase for the DVLXDVLX group (Table 4). Fewer than half of subjects were within 1SD of the normal mean score for the SAS and HA, suggesting that continued impairment was
common. Remission was associated with normalization of SAS scores: mean SAS score at week
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24 differed significantly between remitters (1.86 ± 0.32) and non-remitters (2.44 ± 0.64), p=0.001.
Remitters' SAS mean scores were within the normal community range. In contrast, responders who
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were not remitters (N=16) had mean SAS scores of 2.36+0.56) suggesting continued impairment.
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Discussion
The DSM-5 recognized the importance of chronicity by creating the category of persistent depressive disorder (PDD).
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Independent of cross-sectional severity, chronicity is a significant risk
factor for poor outcome, both in terms of continuing symptomatology and impaired functioning. Few
analyses
13,17
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studies address the treatment specifically of the various forms of chronic depression. Recent
find efficacy data only on 5806 patients, data for acceptability of pharmacotherapy, 13
17
psychotherapy or combined treatment on 5348 , and safety data on 4769 . Furthermore, while antidepressant medications have widely been shown to be more effective in more severe
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depression (and less effective in milder depression), there are limited data in non-major persistent depression. This situation is likely to continue now that the various forms of chronic depression (more severe chronic major depression, less severe dysthymic disorder, etc.) have been collapsed into the single DSM-5 PDD category. Yet even non-major PDD is associated with high levels of 10,34
psychosocial morbidity
. Hence, it is valuable to define the efficacy of ADMs in less severe PDD.
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To our knowledge, this is the second reported double-blind trial for an SNRI medication in treatment 18
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of non-major persistent depressive disorder (PDD).
Efficacy phase: Our primary analysis of the 12-week double-blind phase of this DVLX study
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reached only trend significance (.07), so this was a negative study that does not support the use of DVLX as treatment for non-major PDD. This negative result could have occurred
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because DVLX is not effective in this population. Alternatively, relative to our other studies, this study had a relatively high improvement in patients assigned placebo,
18,31,35
power may
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have been insufficient or the negative result may have occurred due to sampling. Several positive secondary analyses suggest the value of this study may be in generating hypotheses for further studies. A moderate ES (.436) on the primary outcome measure suggests adequate power (>.8) to demonstrate efficacy with a sample size of 60 per treatment arm; the effect size of studies with DVLX in MDD approximate 0.3
36-39
so this is comparable. Of note, the patient-rated QIDS-SR
and patient-rated CGI-Improvement did differentiate medication from placebo in our study. Contrary
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to expectations, secondary measures of social functioning (SAS, SDS) and global outcome (GAF) did not show significant differences at week 12, nor did temperamental abnormalities (HA, RD, NS on TCI), though ruminations (RRS) showed a time effect.
In contrast, our duloxetine study showed more robust response in the initial (10 week) phase, with
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below).
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less additional improvement during the 12 week continuation period (see Continuation Phase
This potentially greater initial response to duloxetine might result from differing relative Ki
profiles for these two SNRI medications. Ki, or the inhibitory constant, is related to the
concentration of a drug needed to decrease the activity of a receptor or enzyme by half; a low Ki
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level represents a high level of binding affinity, whereas a high Ki level implies that a relatively high concentration of a drug is required before the binding site is maximally occupied. Duloxetine potently inhibits binding to the human NE and 5-HT transporters, with Ki values of 7.5 and 0.8 nM, 41
respectively, and a Ki ratio of 9.
In comparison, desvenlafaxine has Ki values of 2953 for NE and
61.4 for 5-HT, and a Ki ratio of 48 (values similar to its parent compound venlafaxine: Ki 2480 for 19
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NE and 82 for 5HT receptors, respectively). Whereas duloxetine appears to have both significant NRI and SRI activity, DVLX appears to have predominantly SRI activity, and more limited NRI
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activity. DVLX’s relatively lower NE reuptake effect might have contributed to this study’s less
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robust findings.
Another possible explanation for our study’s negative result relates to dosage. Whereas DVLX has
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been studied in doses up to 400 mg/day, our study respected the FDA approved maximum of 100 mg/day. Three subjects received doses up to 150 mg/day during open continuation treatment
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following the study due to nonresponse at 100 mg/day dose, two reporting further improvement of depressive symptoms subsequent to above-PDR-recommended dosing. In summarizing DVLX efficacy studies, Perry et al.
42
concluded that higher dose did not produce additional benefit;
however, we are unaware of studies of non-responders to DVLX 100 mg/day to assess benefit of increases above the currently FDA-approved range. Andrade
36
has suggested that DVLX might be
essentially an SSRI at lower doses, as has been found for venlafaxine, which requires dosing >150
ACCEPTED MANUSCRIPT 16 43
mg/day to elicit noradrenergic effects .
Finally, some
44,45
46
but not all studies suggest lower efficacy of antidepressants in milder major
depression. However most studies of non-major persistent depressive disorder (previously called 13,47
dysthymic disorder) suggest that medication is more effective thanplacebo
. The negative result
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of this study does not strongly support either hypothesis; a larger sample, allowing for an analysis of the moderating effect of initial severity of PDD would be helpful in addressing this issue.
DVLX side effects were generally mild, only once resulting in discontinuation. Self-reports
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(MOTCS, ABNAS, ASEX) confirmed the tolerability of DVLX. There was also high compliance, 95.5% for the medication group, perhaps another measure of tolerability.
Significant psychosocial morbidity and costs are associated with PDD regardless of subtype or 10,48
cross-sectional severity.
In this study, duration of illness averaged 12.8+13.5 years, with
M
significant impairment by numerous measures. Despite 67.8% of our participants having college or graduate degrees, most were unemployed (38.5%; 15/39) or working part-time (52.5%; 31/59).
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Most subjects (84.8%) were currently unmarried, suggesting impairment in interpersonal relationships. Mean score on the GAF of 63.3+7.3 (n=59), indicates a moderate degree of functional
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impairment, as do baseline mean scores on SAS of 2.50+0.5,12 weeks of over 2 SD above the 49
community mean (1.4+0.5, ), which remained 1.6 SD above this mean following DVLX (2.22+0.4
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LOCF) or placebo (2.29+0.5 LOCF) treatment. Similarly, SDS scores remained elevated posttreatment (10.32+7.27 for placebo and 11.80+7.56 for DVLX) compared to community norms 50
The literature
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(6.1+7.0).
51-54
about continued improvement in psychosocial functioning in PDD is
mixed. Of note, in this study, remission at week 24 was associated with normalization of SAS scores, underscoring its importance as a treatment goal.
Social functioning and Harm Avoidance (which has been associated with functional impairment) did show further improvement between weeks 12 and 24 for patients continuing DVLX, but most
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patients continued to have scores in the abnormal range. Since continued antidepressant 40
monotherapy alone generally does not lead to normalization of psychosocial functioning in PDD , alternative approaches should be investigated more thoroughly, including medication augmentation, combined medication-psychotherapy strategies, particularly including cognitive behavioral 55,56
therapy
and behavioral activation therapy
57,58
. Future studies should aim both to enhance
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remission rates and improve psychosocial outcomes.
Open Continuation Phase: At week 24, most patients (62.5%) who achieved remission by week 12 on DVLX continued to be in remission. Additional improvements were noted in the continuation
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DVLX sample in self-rated scales, including depression (the QIDS-SR and BDI), as well as the
RRS, suggesting benefits of continuation treatment. Findings for continuation treatment at week 24 were consistent with broad improvement—in core depressive scales, in measures of psychosocial impairment, and in the harm avoidance component of temperament as well as in ruminations. This suggests that additional improvement in these areas, at least with DVLX, may require longer
M
medication exposure. In contrast our recent study with duloxetine
40
showed little additional
improvement between acute treatment and continuation treatment (10 and 22 weeks respectively in 51-54
about continued improvement in psychosocial functioning in persistent
ED
that study). The literature
depression is mixed. The reasons for discrepant findings for two SNRI medications are unclear; it is
PT
possible that the maximum dose of each (120 mg/day for duloxetine vs. 100 mg/day for desvenlafaxine) may have differing potency in affecting neurotransmitter reuptake, duloxetine
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possibly having higher relative reuptake inhibition or other effects at doses used in these 19,41
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studies.
Study limitations and future directions This was a negative study and positive secondary analyses should not be overinterpreted. For one reason, the multiple secondary analyses presented were not corrected for multiple comparisons. Therefore, some significant findings could be due to chance. Further, the sample size of 59 limits power to detect differences smaller than “moderate”. The exclusion of acutely suicidal patients, and
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those with medical and psychiatric comorbidities, limits the generalizability of findings. Further study with a larger and more varied sample of individuals with PDD would allow analyses of moderating effects of baseline severity. Higher doses of DVLX could be studied. Future directions in PDD psychopharmacology should include comparative and long-term studies, perhaps following the STAR*D design
59,60
, in which a large cohort of PDD patients are followed for an extended period of
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time and offered various treatments, including the commonly used medication classes such as
SSRIs, SNRIs, bupropion, and other antidepressant agents, as well as psychotherapy, including medication switches, augmentation, and other strategies to enhance response and remission,
particularly to improve social functioning. Because some patients with PDD might respond (or remit)
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with doses above current FDA approved maximum of 100 mg/day, further study should address further treatment of patients with PDD who do not remit with conventional dosing.
Author disclosure: This study received funding from Pfizer, Inc., New York, NY. The study was performed at the New York State Psychiatric Institute/Columbia University Department of Psychiatry, New York, NY
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Role of funding: Funding from Pfizer, Inc. supported conduct of the Investigator Initiated Study (desvenlafaxine vs. placebo clinical trial and open-label continuation treatment) described in this paper, as well as funding for analysis of results. The paper was written without input from Pfizer, Inc. or its employees.
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Contributors: The authors had roles in this paper as follows: David J. Hellerstein, MD: design of study as PI, obtaining funding, treating patients, supervision of conduct of study and analyses of results, writing paper. Jonathan W. Stewart, M.D.: co-investigator in study, treating patients, assisting in interpretation of results, editing manuscript Bradley S. Peterson, M.D.: co-investigator in study, treating patients, assisting in interpretation of results, editing manuscript Vinushini Arunagiri, M.A.: literature review, drafting manuscript, assisting in interpretation of results Ying Chen, M.D.: data management, statistical analyses, describing statistical methods in paper Patrick J. McGrath, M.D.: co-investigator in study, treating patients, assisting in interpretation of results, editing manuscript
Acknowledgements: The authors would like to thank Deborah Deliyannides, MD, Mark Rodriguez, BA, and Donna O’Shea, RN, MS, for assistance in conduct of the study
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Table 1. Demographic characteristics overall and by treatment group (n=61) Treatment Group
Variables
n
DVLX to DVLX (n=31)
Mean (SD) or %
n
Demographics Gender
Mean (SD) or %
Placebo to DVLX (n=30) n
Mean (SD) or %
Male
28
45.9%
12
38.7%
16
53.3%
Female
33
54.1%
19
61.3%
14
46.7%
Marital 43
70.5%
Married
9
14.8%
Separated
2
3.3%
Divorced
7
11.5%
Race
Caucasian
38
Asian
6
Other
7
Ethnicity/Hispanic
54
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Non-Hispanic Hispanic
7
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Employment Status
16.4%
71.0%
21
70.0%
6
19.4%
3
10.0%
0
0.0%
2
6.7%
3
9.7%
4
13.3%
p-value
0.252
0.369
0.161
3
9.7%
7
23.3%
62.3%
19
61.3%
19
63.3%
9.8%
3
9.7%
3
10.0%
11.5%
6
19.4%
1
3.3%
M
10
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Black/AA
22
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Single
Diff between groups
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Total Sample (n=61)
0.246
88.5%
26
83.9%
28
93.3%
11.5%
5
16.1%
2
6.7% 0.067
30
50.0%
21
67.7%
9
31.0%
Employed part time for pay
15
25.0%
6
19.4%
9
31.0%
Student
3
5.0%
1
3.2%
2
6.9%
Unemployed (< 6months)
5
8.3%
1
3.2%
4
13.8%
Unemployed (> 6months)
7
11.7%
2
6.5%
5
17.2%
Age
61
38.4 (13.0)
31
40.1 (14.1)
30
36.7 (11.7)
0.305
Education
61
15.2 (3.7)
31
15.7 (3.9)
30
14.7 (3.4)
0.270
AC
Employed full time for pay
a
Baseline differences are assessed using t-tests for continuous measures and chi-square test for categorical measures
a
ACCEPTED MANUSCRIPT 24
Table 2. Primary and secondary outcome measures for subjects receiving desvenlafaxine (DVLX; n = 31) versus those receiving placebo (n = 30), with results of repeated measurement ANOVA comparing Week 0 and Week12. Measu res
Week 0 Placebo n=30
SAS RRS TCIRD TCINS TCI-PS
(SD )
Me an
(SD )
Me an
(SD )
20. 03 33. 83 --
4.4 9 11. 04 --
20. 29 36. 52 --
5.0 3 10. 41 --
11. 58 18. 65 2.8 8
6.9 6 11. 41 0.9 5
9.3 5 19. 62 2.2 3
5.8 0 12. 71 0.9 5
0.007
11. 63 19. 17 2.5 1 53. 57 15. 59 19. 72 4.3 5 20. 86
4.0 3 7.5 0 .45
13. 19 21. 07 2.4 7 55. 28 14. 84 18. 21 4.2 9 23. 71
4.0 8 8.3 5 .45
8.0 8 12. 82 2.2 9 41. 78 15. 0 19. 96 4.1 9 20. 27
4.9 2 9.2 0 .46
7.3 5 11. 64 2.2 2 43. 11 15. 92 18. 15 4.6 5 20. 35
4.4 2 6.4 7 .41
0.005
11. 49 4.1 8 4.5 0 1.8 8 8.2 7
0.014
12. 90 4.3 6 5.0 2 2.0 4 7.6 3
8.4 9 4.3 9 4.7 0 2.0 4 7.4 4
0.013
0.6 96 0.6 10 --
5 0 5 0 5 0
0.046
0.5 81 0.5 20 0.2 39 0.5 34 0.0 03 0.0 29 0.0 99 0.1 32
5 0 5 1 4 8 4 6 4 8 4 8 4 8 4 8
0.091
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M 13. 39 3.9 2 5.2 5 1.6 7 6.6 8
P
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Me an
AC
TCIHA
DVLX n=26
(SD )
ED
Patient Rating s QIDSSR BDI
Placebo n=26
Effect Size (Partial Eta Squared) * Treatm Tim D Time x ent e F Treatm ent
Me an
PT
CGI-I
DVLX n=31
CE
Clinicia n Rating s HDRS24 CDRS
Week 12
0.109
0.003 0.003
0.003 0.022 0.001 0.002
0.009
--
0.034 0.004 <0.001 0.078 0.031 0.041 0.024
0.1 12 0.5 13 0.0 17
0.0 30 0.1 87 0.6 63 0.9 81 0.0 49 0.2 20 0.1 58 0.2 82
Key to abbreviations: HDRS: Hamilton Depression Rating Scale, CDRS: Cornell Dysthymia Rating Scale, BDI: Beck Depression Inventory, SAS: Social Adjustment Scale, RRS: Ruminative Responses Scale, TCI: Temperament and Character Inventory, subscales: HA: Harm Avoidance; RD: Reward Dependence; NS: Novelty Seeking; PS: Persistence; CGI-I-PT: CGI-Improvement, patient-rated. * The Effect sizes reported in this table are Partial Eta Squared: 0.01 (small), 0.06 (medium) 0.14 (large)
ACCEPTED MANUSCRIPT 25 Table 3. Adverse events observed with desvenlafaxine (DVLX) or initial placebo followed with DVLX treatment
AC
CE
PT
ED
M
AN US
CR IP T
*Pa tien DVLX, n (%) Placebo, n (%) ts AE Week 12 Week 24 Week 12 Week 24* initi N=30 N=24 N=29 N=23 ally rec Daytime sleepiness 11 (36.7) 5 (20.8) 6 (17.2) 1 (4.4) eivi Decreased sleep 10 (33.3) 9 (37.5) 4 (13.8) 3 (13.0) ng pla Headache 9 (30.0) 4 (16.7) 4 (13.8) 1 (4.4) ceb Nausea 9 (30.0) 8 (33.3) 3 (10.3) 3 (13.0) o Dry mouth 7 (23.3) 5 (20.8) 2 (6.9) 1 (4.4) (we ek Agitation 5 (16.7) 2 (8.4) 0 0 0Dizziness 5 (16.7) 4 (16.7) 0 1 (4.4) 12) Sweating 5 (16.7) 2 (8.4) 2 (6.9) 2 (8.8) wer e Anorgasmia 4 (13.3) 3 (12.5) 2 (6.9) 1 (4.4) trea Decreased appetite 4 (13.3) 4 (16.7) 0 0 ted with Gastrointestinal upset 4 (13.3) 2 (8.4) 3 (10.3) 3 (13.0) des Constipation 3 (10.0) 3 (12.5) 2 (6.9) 2 (8.8) ven Vivid dreams 3 (10.0) 3 (12.5) 0 0 lafa xin Cognitive impairment 2 (6.7) 2 (8.4) 3 (10.3) 5 (21.7) e Decreased concentration 2 (6.7) 1 (4.2) 1 (3.5) 0 (DV Decreased libido 2 (6.7) 2 (8.4) 4 (13.8) 6 (26.1) LX) fro Fatigue 2 (6.7) 2 (8.4) 1 (3.5) 1 (4.4) m Increase of appetite 2 (6.7) 1 (4.2) 1 (3.5) 0 we Palpitations 2 (6.7) 2 (8.4) 0 0 eks 13Yawning 2 (6.7) 2 (8.4) 0 0 24. Anxiety 1 (3.3) 3 (12.5) 1 (3.5) 1 (4.4) Not Delayed orgasm 1 (3.3) 1 (4.2) 3 (10.3) 0 e: In Muscle spasms 1 (3.3) 5 (20.8) 1 (3.5) 2 (8.8) the Spacey feeling 1 (3.3) 1 (4.2) 3 (10.3) 0 foll Tingling 1 (3.3) 1 (4.2) 1 (3.5) 1 (4.4) owSeizure 0 0 1 (3.5) 1 (4.4) up peri od, 9 patients reported no side effects. Among them, 1 was in the continued DVLX treatment group and 8 were in the placeboDVLX treatment group.
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Table 4. Primary and secondary outcome measures for patients treated with desvenlafaxine (DVLX) in phase 1 and phase 2 and patients treated with placebo in phase 1 and DVLX in phase 2 (n = 47).
DVLX DVLX Group (n=24) WK 12
WK24
Me an (SD )
Me an (SD )
Mean (SD)
Phase II: Open Label WK12 vs WK24 Eff d p ect f Siz e*
Overall Changes Pre-tx vs Wk24 Eff ect Siz e
d f
RRs
TCIRD
Eff ect Siz e
d f
p
<0.
<0.
33.7
20.35(1
12.57(
0.5
2
<0.
0.7
2
<0.
001
(11.38)
0.92)
8.99)
13
2
001
84
2
001
0.0
2
0.1
0.8
2
<0.
20.17(
12.52(1
6.17(1.
0.5
2
<0.
0.8
2
67
4
(1.14)
90
3
45
54
3
001
1.07)
.28)
16)
66
2
001
35
2
001
(1.0
(1.2
5)
5)
37.
19.
15.54(
0.1
2
0.0
0.7
2
12.06)
45
3
60
52
3
08
33
(11.
(11.
64)
82)
4.0
2.6
2.21
0.1
2
0.0
0.8
2
4
7
(0.83)
63
3
46
07
3
(0.6
(1.0
9)
1)
7.5
5.92
0.2
2
0.0
0.8
2
25
4
(4.35)
32
3
15
62
(4.4
(4.4 6) 11.
54
96
(8.9
(6.4
<0.
4.22
3.04
2.35
0.3
2
0.0
0.8
2
<0.
001
(0.74)
(0.88)
0(.94)
60
2
01
05
2
001
<0.
12.73
8.68
7.39
0.0
2
0.2
0.6
2
<0.
3
001
(3.88)
(4.75)
(4.27)
68
2
17
20
1
001
ED
5) 21.
PT
13.
7.58
0.3
2
0.0
0.7
2
<0.
19.57
12.91(8
10.17(
0.1
2
0.1
0.5
2
<0.
(6.08)
74
3
01
53
3
001
(8.37)
.95)
6.99)
13
2
09
68
2
001
1)
8)
2.4
2.2
2.08
0.1
2
0.0
0.3
2
0.0
2.49
2.30
2.26
0.0
2
0.9
0.2
2
0.0
2
1
(0.46)
47
3
58
43
3
02
(0.48)
(0.50)
(0.69)
01
2
13
71
2
14
AC
SAS
p
Mean (SD)
7.63
CE
BDI
d f
Mean (SD)
9.2
Patient Ratings QID SSR
Eff ect Siz e*
p
AN US
CGI -S
Mean (SD)
WK24
M
CD RS
20.
Overall Changes Pre-tx vs Wk24
WK12
Clinician Ratings HRS D24
Phase II: Open Label WK12 vs WK24
Pre-tx
CR IP T
Pre -tx
Placebo DVLX Group (n=23)
(0.3
(0.4
9)
3)
54.
41.
37.14
0.2
2
0.0
0.7
2
<0.
52.76(
39.559(
37.14(
0.1
1
0.0
0.6
2
<0.
(8.73)
10
1
30
66
1
001
13.26)
11.90)
10.65)
68
9
70
56
0
001
50
64
(8.2
(10.
3)
36)
15.
16.
15.92
0.0
2
0.1
<0.
2
1.0
15.61
14.52
15.19
0.0
2
0.3
0.0
2
0.5
92
71
(4.44)
90
3
45
001
3
00
(4.82)
(3.99)
(4.32)
67
2
03
02
2
04
(3.9
(4.0
ACCEPTED MANUSCRIPT 27
TCIPS
TCIHA
4)
17.
17.
18.20
0.0
2
0.6
0.0
2
0.6
18.62
19.87
20.48
0.0
2
0.4
0.2
2
0.0
86
93
(4.47)
11
3
15
08
3
65
(4.55)
(5.08)
(5.76)
05
2
58
63
2
30
(3.8
(4.3
1)
5)
4.6
4.8
5.0
0.0
2
0.5
0.0
2
0.1
4.13
4.13
3.91
0.0
2
0.2
0.0
2
0.4
3
3
(1.91)
15
3
58
87
3
53
(1.96)
(1.60)
(1.78)
63
2
85
12
2
47
(2.0
(1.8
2)
3)
21.
19.
18.79
0.0
2
0.3
0.2
2
0.0
21.87
21.04
(8.96)
40
3
36
42
3
12
(7.81)
(6.95)
96
71
(7.3
(8.2
2)
4)
CR IP T
TCINS
3)
20.62
0.0
2
0.5
0.2
2
0.2
(6.89)
06
2
37
66
2
38
AN US
Key to abbreviations: Pre-tx: Pre-treatment HDRS: Hamilton Depression Rating Scale, CDRS: Cornell Dysthymia Rating Scale, BDI: Beck Depression Inventory, CGI-I,CGI-S: clinician-rated Clinical Global Impression, Severity of Illness, SAS: Social Adjustment Scale, TCI: Temperament and Character Inventory, subscales: HA: Harm Avoidance; RD: Reward Dependence; NS: Novelty Seeking; PS: Persistence
AC
CE
PT
ED
M
* The Effect sizes reported in this table are Cohen’s D: 0.2 (small), 0.5 (medium) and 0.8 (large)
ACCEPTED MANUSCRIPT 28
Figures Consort Diagram: Desvenlafaxine (DVLX) study consort diagram (medication)
Enrollment
CR IP T
Assessed for eligibility (n=350)
Not eligible (n= 279)
Excluded (n= 10) No longer met inclusion criteria (n= 1) Declined to participate (n= 5) Other reasons (n= 4) 3 lost to follow up, 1 began a new job
Eligible (n= 71)
AN US
Randomized (n= 61)
Allocation (wk RZ) Allocated to Placebo (n= 30) Received allocated intervention (n=29) Did not take allocated intervention (n=1)
M
Allocated to Active DVLX (n=31) Received allocated intervention (n=30) Did not take allocated intervention (n=1)
CE
PT
Lost to follow-up (n= 2) Discontinued intervention Patient request (n= 1)
ED
End of Acute Phase (wk 12)
AC
Analyzed (n= 26) Excluded from analysis (n=0)
Lost to follow-up (n= 1) Discontinued intervention Patient request (n= 1) Side effects (n= 1) No improvement (n=1)
Analysis Analyzed (n= 26) Excluded from analysis (n=0)
End of Continuation Phase (wk 24)
Did not finish follow up (n=3) Two placebo responders One placebo non-responder
Did not finish follow up (n=2) Both responded at week16 and never came back for week24 evaluation.
Continuation Phase Analysis Analyzed (n= 23) Placebo DVLX (n=23)
Excluded from analysis (n=0)
Analyzed (n= 24) DVLX DVLX (n=24) Excluded from analysis (n=0)
ACCEPTED MANUSCRIPT 29
Figure 1. Weekly HDRS-24 scores for desvenlafaxine (DVLX) vs. placebo treated subjects 30
Placebo treated patients began active medication at week12
CR IP T
20
15
10
AN US
Hamd24 Mean ± SD
25
5
0 6
AC
CE
PT
ED
Treatment
12
M
0
18
Week
PLAC -> DVLX
DVLX -> DVLX
24