Effects of Levomilnacipran ER on Fatigue Symptoms Associated with Major Depressive Disorder
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Effects of levomilnacipran ER on fatigue symptoms associated with major depressive disorder The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Freeman, Marlene P., Maurizio Fava, Carl Gommoll, Changzheng Chen, William M. Greenberg, and Adam Ruth. 2016. “Effects of levomilnacipran ER on fatigue symptoms associated with major depressive disorder.” International Clinical Psychopharmacology 31 (2): 100-109. doi:10.1097/YIC.0000000000000104. http:// dx.doi.org/10.1097/YIC.0000000000000104. Published Version doi:10.1097/YIC.0000000000000104 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:25658426 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA 100 Original article Effects of levomilnacipran ER on fatigue symptoms associated with major depressive disorder Marlene P. Freemana, Maurizio Favaa, Carl Gommollb, Changzheng Chenb, William M. Greenbergb and Adam Ruthc The aim of this study was to evaluate the effects of significantly greater with levomilnacipran ER versus levomilnacipran extended-release (ER) on depression- placebo in both low (least squares mean difference = − 2.8, related fatigue in adults with major depressive disorder. P = 0.0018) and high (least squares mean difference = − 3.1, Post-hoc analyses of five phase III trials were carried out, P < 0.0001) fatigue subgroups. Levomilnacipran ER with evaluation of fatigue symptoms based on score treatment was effective in reducing depression-related changes in four items: Montgomery–Åsberg Depression fatigue in adult patients with major depressive disorder and Rating Scale (MADRS) item 7 (lassitude), and 17-item was associated with remission of fatigue symptoms. Int Hamilton Depression Rating Scale (HAMD17) items 7 (work/ Clin Psychopharmacol 31:100–109 Copyright © 2016 activities), 8 (retardation), and 13 (somatic symptoms). Wolters Kluwer Health, Inc. All rights reserved. Symptom remission was analyzed on the basis of score International Clinical Psychopharmacology 2016, 31:100–109 shifts from baseline to end of treatment: MADRS item 7 and HAMD item 7 (from ≥ 2to≤ 1); HAMD items 8 and 13 Keywords: age factors, antidepressant, clinical trial, depression, lassitude, 17 17 sex factors (from ≥ 1 to 0). The mean change in MADRS total score was analyzed in patients with low and high fatigue (MADRS item aDepartment of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, bForest Research Institute (an Allergan affiliate), 7 baseline score < 4 and ≥ 4, respectively). Patients Jersey City, New Jersey and cPrescott Medical Communications Group, Chicago, receiving levomilnacipran ER had significantly greater mean Illinois, USA improvements and symptom remission (no/minimal Correspondence to Marlene P. Freeman, MD, Department of Psychiatry, Harvard residual fatigue) on all fatigue-related items: lassitude (35 Medical School, Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital, 185 Cambridge Street, 2nd Floor, Boston, MA 02114, USA vs. 28%), work/activities (43 vs. 35%), retardation (46 vs. Tel: + 1 617 643 6403; fax: + 1 617 643 3080; e-mail: mfreeman@partners.org 39%), somatic symptoms (26 vs. 18%; all Ps < 0.01 versus placebo). The mean change in MADRS total score was Received 16 April 2015 Accepted 16 September 2015 Introduction patients with MDD among whom greater than 90% had Major depressive disorder (MDD) is a common yet het- fatigue-related symptoms (Lam et al., 2012) the majority erogeneous disorder, and identifying variables that may reported that lack of motivation (59%), low energy (58%), predict response to specific treatments is an important and feeling physically slowed down (52%) substantially public health concern (Leuchter et al., 2009). Medications interfered with their ability to work. Similar findings were are often selected on the basis of predominant symptoms, reported in a post-hoc analysis of data from the much although this is not always an evidence-based practice. larger Sequenced Treatment Alternatives to Relieve Fatigue is one such symptom, and daily fatigue or loss of Depression (STAR*D) clinical trial, which found that energy is recognized as one of the diagnostic criteria for greater than 90% of 2868 patients had substantial fatigue MDD (American Psychiatric Association, 2013). In at baseline (Ferguson et al., 2014). The STAR*D study addition to the physical manifestations of fatigue (tired- also showed that moderate-to-severe functional impair- ness, low energy, weakness, heaviness, slowness), there ment was more common in patients with severe fatigue are associated cognitive (decreased concentration or (59.5%) than in patients with moderate or mild fatigue attention, slowed thinking) and emotional (decreased (37.4 and 28.8%, respectively) and that higher levels of motivation, loss of interest, feelings of boredom, aversion baseline fatigue significantly reduced the likelihood of to effort) symptoms that require focused treatment remission (Ferguson et al., 2014). These findings support (Arnold, 2008). the need for MDD treatments that address fatigue in addition to other symptoms of depression. Fatigue can negatively affect daily functioning. For example, in a clinic-based study of 164 consecutive Another important finding of the STAR*D trial was that 60.8% of patients had residual fatigue after receiving up This is an open-access article distributed under the terms of the Creative to 14 weeks of treatment with a selective serotonin Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC- et al. ND), where it is permissible to download and share the work provided it is properly reuptake inhibitor (SSRI; Ferguson , 2014). cited. The work cannot be changed in any way or used commercially. Compared with patients with remitted fatigue symptoms, 0268-1315 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/YIC.0000000000000104 Effects of levomilnacipran ER on fatigue Freeman et al. 101 patients with residual fatigue had significantly worse activity, such as reduced motivation and energy, loss of outcomes in mental and physical functioning, as well as a interest, and decreased pleasure or enjoyment (Nutt et al., reduced likelihood of remission of MDD. These results 2007). Therefore, the goals of this post-hoc analysis were were consistent with findings from an earlier study that to identify and characterize patients with MDD who had found residual fatigue in 48.8% of patients who had high levels of fatigue, to evaluate the effects of levo- responded to antidepressant treatment and were in full or milnacipran ER on depression-related fatigue symptoms, partial remission; notably, 8.6% had residual fatigue that and to assess the effects of treatment in patients who had was considered moderate to severe (Fava et al., 2006). high and low levels of fatigue at baseline. Other studies have shown that fatigue may be difficult to treat, with slow response to medication or psychotherapy Methods and low rates of clinically significant changes Study designs et al. (Demyttenaere , 2005). Few studies have been Post-hoc analyses were carried out using data from 2598 published that evaluate residual fatigue in patients with patients who participated in five randomized, double- MDD, and continued efforts are needed to better address blind, placebo-controlled studies of 40–120 mg/day et al. this important facet of depression (Fava , 2013). levomilnacipran ER for the treatment of MDD (Asnis Current research indicates that the neurobiology of fati- et al., 2013; Montgomery et al., 2013; Bakish et al., 2014; gue is complex (Harrington, 2012), which may explain Gommoll et al., 2014; Sambunaris et al., 2014a). These why SSRIs alone may not adequately resolve fatigue in included four US-based studies with 8 weeks of double- patients with MDD (Arnold, 2008; Fava et al., 2013). blind treatment, two of which evaluated fixed doses of Neuroimaging studies in patients with disease-related levomilnacipran ER (Asnis et al., 2013; Bakish et al., 2014) fatigue have shown atrophy or other damage in the and two of which used flexible dosing (Gommoll et al., striatum and cortex (Harrington, 2012). Ascending path- 2014; Sambunaris et al., 2014a), and one non-US study ways that control arousal and motivation are also believed with 10 weeks of double-blind treatment and flexible to play a key role in the clinical manifestation of fatigue. dosing (Montgomery et al., 2013). These pathways include projections from serotonergic Detailed methodology for all five studies has been pub- neurons in the raphé nuclei, noradrenergic neurons in the lished previously. In brief, the studies included female locus coeruleus, dopaminergic neurons in the periaque- and male patients, between 18 and 80 years of age, who ductal gray, histaminergic neurons in the tuberomamillary met MDD diagnostic criteria and had a current major nucleus, and cholinergic neurons in the pedunculo- depressive episode. Other key inclusion and exclusion pontine and tuberomamillary nuclei. Inflammatory factors criteria are listed in Table 1. The primary endpoint in all may contribute to the neurobiology of disease, including studies was defined as the mean change from baseline in the negative effects of cytokines and glial activation