Advances in Pharmacotherapy for Pediatric Anxiety Disorders.

The evidence base for psychopharmacologic interventions in children and adolescents with anxiety disorders has significantly increased, and our understanding of the relative efficacy and tolerability of interventions has expanded contemporaneously. Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacologic treatment for pediatric anxiety due to their robust efficacy although other agents may have efficacy. This review summarizes the data concerning the use of SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, atypical anxiolytics (eg, 5HT1A agonists, alpha agonists), and benzodiazepines in pediatric anxiety disorder cases (ie, generalized anxiety disorder, separation anxiety disorder, social anxiety disorder, and panic disorder). The extant data suggest that SSRIs and SNRIs are effective and well tolerated. SSRIs as monotherapy and SSRIs + cognitive behavioral therapy reduce symptoms in youth with anxiety disorders. However, randomized controlled trials do not suggest efficacy for benzodiazepines or the 5HT1A agonist, buspirone, in pediatric anxiety disorder cases.

A randomized, double-blind, placebo-controlled study of flexible doses of levomilnacipran ER (40-120 mg/day) in patients with major depressive disorder.

OBJECTIVE: Levomilnacipran ER is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD). Efficacy and safety have been evaluated in five Phase II/III studies, four of which met the pre-specified primary efficacy outcome. Results of the negative trial (ClinicalTrials.gov NCT00969150) are reported here. METHODS: A Phase III randomized, double-blind, placebo-controlled trial comparing flexible-dose levomilnacipran ER 40-120 mg/day with placebo was conducted in outpatients with MDD. Patients met the DSM-IV-TR criteria for MDD, had a current episode of depression of at least 4 weeks' duration, and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥30. The study comprised a 1-week, single-blind, placebo lead-in, 8-week double-blind treatment, and a 2-week down-taper. The primary and secondary efficacy measures were change from baseline to Week 8 in MADRS and Sheehan Disability Scale (SDS) total scores, respectively, analyzed using a mixed-effects model for repeated measures approach. Safety outcomes included adverse events (AEs), laboratory and vital sign measures, the Columbia-Suicide Severity Rating Scale, and the Arizona Sexual Experiences Scale (ASEX). RESULTS: Three hundred and fifty-five patients received the study drug and had ≥1 post-baseline MADRS total score assessment (ITT Population); 81.9% of placebo and 77.1% of levomilnacipran ER patients completed the study. For levomilnacipran ER vs placebo, MADRS (-15.7 vs -14.2) and SDS (-8.8 vs -8.2) total score improvements, and rates of MADRS response (38.5% vs 34.8%) and remission (25.3% vs 23.8%) were numerically greater but differences were not statistically significant. Levomilnacipran ER was generally well tolerated. More levomilnacipran ER patients vs placebo reported AEs; the most common AEs for levomilnacipran ER were nausea (17%) and headache (16%). Mean changes in most safety measures were small and similar between groups. There were no meaningful differences in total ASEX scores between groups. LIMITATIONS: Short duration of treatment, inclusion and exclusion criteria, and lack of an active comparator. CONCLUSION: Numerical improvements for levomilnacipran ER vs placebo were detected in this study, but the differences were not statistically significant; levomilnacipran ER was generally well tolerated.

A Randomized, Double-blind, Placebo-controlled Trial of the Efficacy and Safety of Levomilnacipran ER 40-120mg/day for Prevention of Relapse in Patients with Major Depressive Disorder.

OBJECTIVE: Major depressive disorder is often chronic, with relapse and recurrence common. Levomilnacipran extended-release is a potent and selective serotonin and reuptake inhibitor approved in the United States for treatment of major depressive disorder in adults. The objective of this study (NCT01085812) was to evaluate the efficacy, safety, and tolerability of levomilnacipran extended-release in the prevention of relapse in patients with major depressive disorder. DESIGN: A 24-week Phase III randomized, double-blind, controlled trial comparing levomilnacipran extended-release 40-120mg/day with placebo for relapse prevention in patients with major depressive disorder who had responded to 12-week, open-label treatment with levomilnacipran extended-release. Statistical power was calculated on the assumption that 38 percent of placebo and 20 percent of levomilnacipran extended-release patients would relapse. SETTING: Thirty-six outpatient study centers throughout the United States and Canada. PARTICIPANTS: Of 348 patients who met randomization criteria and entered double-blind treatment, three discontinued prior to treatment, 112 were randomized to placebo, and 233 to levomilnacipran extended-release. PRIMARY OUTCOME: Time to relapse was analyzed using the Cox proportional hazard-regression model with treatment group and baseline Montgomery-Åsberg Depression Rating Scale score as explanatory variables. Safety was also evaluated. RESULTS: Time to relapse was longer for levomilnacipran extended-release versus placebo (hazard ratio [95% confidence interval] = 0.68 [0.40][1.17]), but the treatment difference was not statistically significant (P=0.165). A relatively low percentage of patients from either group relapsed (placebo=20.5%, levomilnacipran extended-release=13.9%). CONCLUSION: This study did not detect between-treatment group differences, potentially due to lower than expected relapse rates in the placebo group. Levomilnacipran extended-release was generally well tolerated.

Usefulness of milnacipran in treating phantom limb pain.

BACKGROUND: Amputation of an extremity often results in the sensation of a "phantom limb" where the patient feels that the limb that has been amputated is still present. This is frequently accompanied by "phantom limb pain". We report here the use of milnacipran, a serotonin and norepinephrine reuptake inhibitor, to treat phantom limb pain after amputation of injured or diseased limbs in three patients. METHODS AND RESULTS: The severity of phantom pain before and during treatment was quantified using a visual analog scale. In one case, phantom limb pain responded partially to treatment with high doses of paroxetine, and then replacement with milnacipran further improved the pain relief and long-term full pain relief was achieved. In the two other cases, milnacipran was used as first-line treatment and phantom limb pain responded rapidly. CONCLUSION: These results suggest that milnacipran administration may be useful in phantom limb pain, possibly as a first-line treatment.