IsrIsr JJ PsychiatryPsychiatry -- Vol. 56 - No 1 (2019) Reboxetine: A Randomized Controlled Open-label Study in Children and Adolescents with Major Depression Paz Toren, MD,1,2 Guy Goldstein, MA,1,3 Galit Ben-Amitay, MD,1,2 Joseph Ben-Sheetrit, MD,1,4 and Michelle Slone, PhD3 1 Tel Aviv Brüll Community Mental Health Center, Clalit Health Services, Tel Aviv, Israel 2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel 4 Geha Mental Health Center, Petah Tikva, Israel INTRODUCTION ABSTRACT Objective: This study is the first to examine the efficacy General rates of adolescents diagnosed as having major of reboxetine in the treatment of children and adolescents depressive disorder (MDD) or dysthymia are approxi- with depression. mately 10% (1), with an annual prevalence of 8%-20% for adolescents and 5% for children (2, 3). Youth depres- Method: In this open-label randomized controlled study, 14 sion may lead to impairment in social and educational youths (aged 9-18 years) with major depression received functioning and can impact mental health through to either reboxetine (4mg/day) or fluoxetine (20mg/day) adulthood (4, 5). Individuals who suffered from depres- in a 2:1 ratio. Primary outcome measures included the sion in their youth are twice or three times more likely to Children’s Depression Rating Scale-Revised (CDRS-R), develop major depression as young adults compared to the Clinical Global Impression-Improvement scale (CGI-I), children and adolescents who did not suffer from depres- and the Children’s Depression Inventory (CDI). Response sion (6, 7). Children and adolescents with MDD are also at was defined by either a 20% reduction in CDRS-R or a increased risk for suicidality compared to non-depressed 2-point reduction in CGI-I. youth (8). Reboxetine is an antidepressant of the selective norepi- Results: Improvement in depression with reboxetine nephrine reuptake inhibitors (NaRIs). Reboxetine’s main was noted within 4 weeks. A further non-significant action is in raising the synaptic levels of norepinephrine improvement was noted after 8 weeks, proceeding through by binding to the norepinephrine transporter and block- week 12. Response was achieved by six subjects (66.7%) ing its reuptake (9). Reboxetine’s selectivity was found by week 4 and eight subjects (88.9%) by week 12. Both to be equal or superior to desipramine and superior to reboxetine and fluoxetine were safe with tolerable adverse imipramine (10). Reboxetine was found to be effective effects, although several non-significant differences in for treating adult depression compared to placebo and efficacy and overall frequency of side effects were found other antidepressants. Reboxetine as effective as imipra- in favor of fluoxetine. mine and fluoxetine, and at least as effective as desipra- Conclusions: Reboxetine was safe and effective in mine (11-14). Recent meta-analyses have addressed the treating youth with major depressive disorder. Further question of the efficacy of reboxetine compared to the studies with long-term follow up are needed in order to selective serotonin reuptake inhibitors (SSRIs) in adults. replicate our findings and determine the relative efficacy Eyding et al. (15) concluded that reboxetine showed no of reboxetine compared to fluoxetine. differences from placebo and was inferior to SSRIs on both response and remission rates, whereas Papakostas et al. (16) concluded that the efficacy of the SSRIs and Address for Correspondence: Joseph Ben-Sheetrit, MD, Tel Aviv Brüll Community Mental Health Center, 9 Hatzvi St., Tel Aviv 6719709, Israel [email protected] 26 PAZ TOREN ET AL. reboxetine were similar, and that the major differences or fluoxetine (20 mg/day) treatment. All participants between them were only in their adverse effects profiles. were intended to receive concomitant dynamic psycho- Reboxetine has a high safety profile (10). Adverse therapy. By the end of the 8th week, the medication dosage effects were found to subside spontaneously with no was gradually reduced until termination. When clinical cardiotoxic potential (13). No differences were found in improvement was noted, the pharmacological treatment the rates of adverse effects of fluoxetine and reboxetine could be continued beyond the 8th week, depending on (15). A previous study reported that the adverse effects clinical considerations. of the NaRIs, including reboxetine are as tolerable as Assessments were made at baseline, after 2 and 4 weeks those of the SSRIs (17). on drug treatment, and every 4 weeks thereafter, and In a previous 6-week open-label study in the Tel Aviv included: Community Mental Health Center clinic (18), we assessed a. A DSM-IV-based psychiatric interview of the child the efficacy of reboxetine (4 mg/day) in the treatment of 31 and an interview with his or her parents, by a senior children and adolescents with attention deficit/hyperactivity child and adolescent psychiatrist (baseline only). disorder (ADHD). A significant improvement was shown b. Clinician-rated (see Study Tools 1-3) and self-report in ADHD symptoms, as well as a decrease in comorbid (see Study Tools 4-6) questionnaires. depressive symptoms, but not in anxiety symptoms. Adverse c. Monitoring of adverse events. effects were generally mild and tolerable, appearing within the first days of treatment and subsiding spontaneously SamPLE SIZE within a few days. The most common adverse effects were Considering a strict criterion of being able to demonstrate drowsiness or sedation and gastrointestinal complaints a significant difference for depression of mild baseline (18). The reduction in depression symptoms and the safety severity (e.g., CDRS-R=55)(20) and assuming an expected profile of the drug suggested that reboxetine may be an standard deviation of SD=9.9 (based on a previous study appropriate antidepressant treatment for this age group. (21)), in order to detect a 20% difference in CDRS-R scores Surprisingly, no data have yet been published regarding (considering α=.05 and 1-β=.80), a total sample size of the efficacy of reboxetine in the treatment of depression N=30 would be required in a 2:1 ratio (i.e., n=20 for the in youth. The present randomized controlled open-label reboxetine group and n=10 for the fluoxetine group), study aimed to assess the efficacy of reboxetine as an anti- which would then yield an effect size of d=1.1. depressant in children and adolescents, and the tolerability of reboxetine compared to fluoxetine as antidepressants SUBJECTS in children and adolescents. Seventeen subjects (11 girls and 5 boys, aged 15.6±2.24 years, range 9-18 years) gave their consent to participate in the study and matched the enrollment criteria. Two METHODS subjects (11.8%, a 15.5-year-old male and a 17-year-old INCLUSION & EXCLUSION CRITERIA female) did not receive the study medication due to All subjects met the Diagnostic and Statistical Manual of baseline ECG abnormalities. Ten participants were ran- Mental Disorders, 4th edition, text revision (DSM-IV-TR) domized to receive reboxetine treatment and 5 to receive (19) criteria for major depressive disorder. The diagnosis fluoxetine treatment. One subject in the reboxetine group was made by a senior child and adolescent psychiatrist. (a 17-year-old male) dropped out before the 2nd week of All participants were drug-naïve or without any medi- treatment due to noncompliance. In the fluoxetine group, cation for at least one month. Exclusion criteria were no dropouts occurred before the 2nd week of the study. a diagnosis of autistic spectrum disorder, psychosis or Fourteen of the 17 (82.3%) subjects who initially signed bipolar disorder. Other mental disorders were allowed to up for the study completed at least 4 weeks of treatment. be documented and included in the study. Children with A full treatment period of 12 weeks was completed by 6 intellectual disability, substance use or chronic medical (66%) subjects of the reboxetine and 5 (100%) of the fluox- illnesses were excluded. etine group. Two subjects (22%) in the reboxetine group completed only 4 weeks of treatment: non-compliance DESIGN & INTERVENTION attributed to symptom improvement (1 subject) and Following baseline assessment, participants were ran- non-compliance due to mild side effects, i.e., mild loss domly assigned to receive either reboxetine (4 mg/day) of appetite and mild insomnia (1 subject). 27 REBOXETINE IN CHILDREN There were no significant differences in the CDRS-R gastrointestinal complaints, headaches and dizziness). baseline scores between of subjects who completed the Weight and height, heart rate, blood pressure and elec- entire treatment period, subjects who completed more trocardiograms (ECGs) were also assessed. Complete than two weeks of treatment, and those who did not have blood counts (CBCs) and liver and kidney functions a minimum of 2 weeks of treatment (F2=0.13, ns). Further, were assessed at baseline and after 4 weeks of treatment, no significant correlations were found between treatment and according to clinical judgement thereafter. length and baseline CDRS-R scores for either of the study groups. The analysis of dropout subjects was made accord- ETHICAL APPROVAL ing to the intention-to-treat method. Two subjects (22%) The study (Clinicaltrials.gov NCT00426946) was approved from the reboxetine group continued to receive reboxetine by the Institutional and the Ministry of Health Review treatment after study termination. One was treated for 6 Boards. All children gave their assent to participate in the months and the other was treated for a year. study and their parents signed an informed consent form. MEASURES DaTA ANALYSIS MAIN OUTCOMES Data analysis was made according to the “intention to 1. The Children’s Depression Rating Scale-Revised treat” principle. Baseline age and gender distribution (CDRS-R) (22) is a semi-structured clinician-rated were analyzed by the two tailed independent sample interview for the assessment of youth depression.