Research paperDesvenlafaxine vs. placebo in the treatment of persistent depressive disorder☆
Introduction
Chronic depression is common, affecting 1.5–5% of the population and produces significant functional impairment, negative health outcomes, and social costs, (Kessler et al., 2005, Berndt et al., 2000, Rappaport et al., 2005, Keller, 1994, Friedman, 1993, Hays et al., 1995, Kocsis et al., 1997, Klein et al., 2006, Klein et al., 2000) resulting in greater psychosocial burden than acute depression. (Hellerstein et al., 2010) DSM-5 Association AP (2013) recognized the importance of chronicity by 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 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 depression), (Lima and Moncrieff, 2000) 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 efficacy data on only 5,806 patients world-wide (Kriston et al., 2014). Few drugs have been adequately tested, e.g. with 2 or more trials enrolling over 100 patients, though data suggests some medications may have greater efficacy than others (Kriston et al., 2014). Other reviews (Pampallona et al., 2004; Dunner, 2000; Geddes et al., 2003) suggest these patients may require higher than 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 persistent functional impairment are common. An alternative to combining treatments has been dual-mechanism medications, such as serotonin-norepinephrine reuptake inhibitors (SNRIs), though SNRIs may have more side effects (Meister et al., 2016) in this population than other medications. We previously reported efficacy of the SNRI duloxetine in chronic non-major depression (Hellerstein et al., 2012). Desvenlafaxine (DVLX) (brand name Pristiq®), (Deecher et al., 2006) 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.
- 1)
Efficacy study: We expected that desvenlafaxine would be superior to placebo over a twelve-week period in the following outcomes:
- a
Improved depression, as measured by HDRS-24 item total score at week 12 (primary outcome).
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The percentage of subjects classified as (a) Responders and (b) Remitters at week 12.
- c
Improved secondary measures of depression (Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), Beck Depression Inventory (BDI), Cornell Dysthymia Rating Scale (CDRS), and overall severity of illness (Clinical Global Impressions-Severity (CGI-S)).
- d
Improved psychosocial functioning (as measured by the Social Adjustment Scale (SAS) and the Sheehan Disability Scale (SDS), global outcome (Global Assessment of Functioning (GAF)), and temperament (Temperament and Character Inventory (TCI)).
- a
- 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 similarly to DVLX-treated patients in the double-blind phase.
Section snippets
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 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
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 did not receive study medication). Of these 59 patients beginning treatment, 1 placebo-treated patient dropped out
Discussion
The DSM-5 recognized the importance of chronicity by creating the category of persistent depressive disorder (PDD). (Association, 2013) Independent of cross-sectional severity, chronicity is a significant risk factor for poor outcome, both in terms of continuing symptomatology and impaired functioning. Few studies address the treatment specifically of the various forms of chronic depression. Recent analyses (Kriston et al., 2014; Meister et al., 2016) find efficacy data only on 5806 patients,
Author disclosure
The study was performed at the New York State Psychiatric Institute/Columbia University Department of Psychiatry, New York, NY
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.
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.:
Acknowledgments
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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ClinicalTrials.gov identifier: NCT01537068.