Open Journal of Psychiatry, 2014, 4, 131-140 Published Online April 2014 in SciRes. http://www.scirp.org/journal/ojpsych http://dx.doi.org/10.4236/ojpsych.2014.42017 Safety and Tolerability of Edivoxetine for Long-Term Treatment of Major Depressive Disorder in Adult Patients Tina M. Oakes1*, James M. Martinez1, Mary Anne Dellva1, Celine Goldberger1, Beth A. Pangallo1, Mark E. Bangs1, Jonna Ahl1, William B. White2 1Eli Lilly and Company, Indianapolis, USA 2University of Connecticut School of Medicine, Farmington, USA Email: *[email protected] Received 13 March 2014; revised 7 April 2014; accepted 14 April 2014 Copyright © 2014 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/ Abstract This 12-month open-label, but dose-blinded extension phase, evaluated the safety and tolerability of flexibly-dosed edivoxetine (6, 9, 12 or 18 mg once daily) in patients (N = 397) with major de- pressive disorder, who completed the 10-week randomized, double-blind, placebo-controlled acute phase of the study. All patients were treated with edivoxetine during the extension phase. The mean age of the patients was 45 years, and most were white females. Safety evaluations in- cluded assessment of treatment-emergent adverse events (TEAEs), laboratory and vital sign mea- sures, and suicidality. Within-group t-tests based on a 2-sided significance level of 0.05 and 95% confidence levels were used to assess whether changes from baseline were statistically significant from zero. The overall completion rate was 54%. Adverse event was the most common (14.4%) reason for discontinuation, which included blood pressure increased (1.3%), heart rate increased (1.3%), anxiety (1.0%), and tachycardia (1.0%). At least 1 TEAE was reported by 72.3% of patients, of which headache (10.8%) and hyperhidrosis (10.1%) were the most common; 2.8% of patients had ≥1 serious adverse events, and there were no completed suicides. No clinically relevant changes were observed in most laboratory measures. Potentially clinically significant changes in ALT values occurred in 1.8% of patients, and either normalized or had decreased by the last as- sessment. Mean increases in blood pressure and pulse were consistent with those observed in the acute phase and appeared to reach a plateau within 3 to 5 months of treatment. In conclusion, safety and tolerability findings during this long-term extension phase evaluation of edivoxetine were consistent with its norepinephrine reuptake inhibition profile. *Corresponding author. How to cite this paper: Oakes, T.M., et al. (2014) Safety and Tolerability of Edivoxetine for Long-Term Treatment of Major Depressive Disorder in Adult Patients. Open Journal of Psychiatry, 4, 131-140. http://dx.doi.org/10.4236/ojpsych.2014.42017 T. M. Oakes et al. Keywords Edivoxetine, Norepinephrine, Major Depressive Disorder, Safety, Tolerability 1. Introduction Major depressive disorder is a chronic and debilitating disorder that usually requires long-term treatment [1]. Patients with MDD often experience relapses and recurrences, and it is estimated that only a third of patients re- ceiving antidepressant therapy achieve full remission with monotherapy [2]. After acute treatment (up to 12 weeks) as many as one-third to one-half of MDD patients who initially responded, will relapse if treatment is not continued for at least 3 - 9 months beyond acute symptom resolution [1]. Successful long-term treatment is de- pendent, in part, on patient and physician education regarding the nature of depression, as well as the long-term safety and tolerability of antidepressant treatment [3]. All currently available antidepressants affect neurotransmission of at least one of these three neurotransmitters: serotonin, norepinephrine, and dopamine. Globally, these antidepressants include monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhi- bitors (SNRI), selective norepinephrine reuptake inhibitors (NRI), and other agents [3] [4]. Edivoxetine is a highly selective and potent NRI that is being studied for the treatment of MDD. This was a 62-week study of flexibly-dosed edivoxetine in patients with MDD that was comprised of a 10-week double- blind placebo-controlled acute phase followed by a 52-week open-label extension phase. The acute phase has been published [5]; herein we present the safety and tolerability results of the extension phase. 2. Materials and Methods 2.1. Overview This was a 62-week Phase II/III multicenter study with a 10-week randomized, double-blind, placebo-controlled, flexible-dose, parallel-arm acute treatment phase comparing edivoxetine 6, 9, 12, and 18 mg once daily (QD) with placebo, followed by a 1-year open-label but dose-blinded, flexible-dose extension phase, and a 2-week ta- per off drug phase. The study was conducted at 43 sites across five countries: the United States, Finland, Poland, Russia, and Argentina. Enrollment for the acute phase began in November 2008, and the 1-year extension phase was completed in March 2011. The institutional review boards approved the protocol and all patients provided written informed consent. This study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki, and are consistent with Good Clinical Practices and applicable laws and regula- tions. 2.2. Patient Selection The study included female and male outpatients aged 18 to 65 years who met criteria for MDD without psy- chotic features, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) (APA, 2000) and confirmed by the Mini-International Neuropsychiatric Interview (MINI) [6]. Patients were required to have a GRID 17-item Hamilton Rating Scale for Depression (GRID- HAMD17) [7] total score ≥18, and Clinical Global Impressions-Severity (CGI-S) [8] score ≥4. Key exclusion criteria included: any additional ongoing DSM-IV-TR Axis I condition other than major de- pression or any anxiety disorder (excluding specific phobias) preceding the onset of depression, which was con- sidered the primary diagnosis within 1 year prior to enrollment in the acute phase of the study. Patients were al- so excluded if they were judged by the investigator to be at risk for harm to self or others. Patients were also to be excluded if they had an unstable medical condition or had any diagnosed medical condition, which could be exacerbated by noradrenergic agents including unstable hypertension or unstable heart disease, tachycardia or tachyarrhythmia, narrow angle glaucoma, or urinary hesitancy or retention. 2.3. Study Design All patients who completed the acute phase of the study were eligible to enter the 1-year open-label dose- 132 T. M. Oakes et al. blinded extension phase (Figure 1). Patients randomized to edivoxetine during the acute phase entered the ex- tension phase on their current blinded dose of edivoxetine. Patients randomized to placebo during the acute phase began dose-blinded treatment in the 1-year extension phase with edivoxetine 6 mg QD and were titrated to 9 mg QD after 1 week. Even though investigators and patients were blinded to the dose of edivoxetine, investi- gators were given the option to request a dose increase at scheduled visits, or a dose decrease at any time based on treatment response and safety and tolerability. For all patients in the extension phase, the patient’s dose was to be increased if the CGI-S score was ≥3 unless the patient was unable to tolerate an increased dose. If the CGI-S score was <3 and the patient was tolerating the current dose, the investigator could increase the dose to optimize response. Patients unable to tolerate an increased dose could be returned to the previously tolerated dose. However, if unable to tolerate that dose, investigators used their clinical judgment on whether to continue that dose or discontinue the patient’s participation in the study. In the 2-week taper phase, patients who com- pleted the extension phase of the study or discontinued early from the study for any reason were tapered as fol- lows: patients whose current dose was edivoxetine 18 mg received 12 mg QD for 1 week followed by 6 mg QD for 1 week; patients whose current dose was edivoxetine 12, 9, or 6 mg received 6 mg QD for 2 weeks. 2.4. Outcome Measures and Assessments Safety and tolerability assessments included spontaneously reported treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), discontinuation rates, clinical laboratory tests (chemistry, hematology, and urinalysis), vital signs (blood pressure, pulse, weight), and electrocardiograms (ECGs). The occurrence, se- verity, and frequency of suicide-related events (behavior and/or ideation) were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS) [9], as well as unsolicited adverse event reporting. Measures to evaluate the effect of edivoxetine in improving depression and related symptoms included: the Montgomery-Åsberg Depression Rating Scale (MADRS) [10]; CGI-S; Fatigue Associated with Depression questionnaire (FAsD) [11]; and Sheehan Disability Scale (SDS) [12]. Response was defined as at least a 50% reduction from baseline on the MADRS total score. Remission was defined as a MADRS total score ≤10. Figure 1. Study Design. Abbreviations: EDX, edivoxetine; PBO, placebo. 133 T. M. Oakes et al. 2.5. Statistical Analysis All analyses were conducted on an intent-to-treat basis, and included only those patients who entered the 1-year extension phase. Baseline for analysis of safety measures, as well as efficacy and health outcomes, was the last visit in the acute treatment phase at Week 10. For changes in ECGs and laboratory tests, the last nonmissing value from the acute phase, including unscheduled visits, was utilized as the baseline. Because all patients re- ceived edivoxetine in the extension phase, results were subgrouped and summarized by the acute phase treat- ment assignments.