A double-blind, placebo-controlled study of edivoxetine as an adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment

Three studies examined whether edivoxetine (a highly selective norepinephrine reuptake inhibitor) had efficacy as adjunctive therapy for patients with major depressive disorder (DSM-IV-TR) who were partial responders to selective serotonin reuptake inhibitor (SSRI) treatment of at least 6 weeks' duration. Studies were 8-week randomized, placebo-controlled trials with a 3-week double-blind placebo lead-in phase, conducted from December 16, 2010, to October 21, 2013. Patients entered the double-blind adjunctive treatment phase if they met randomization criteria (< 25% improvement on Montgomery-Asberg Depression Rating Scale [MADRS] and MADRS total score ≥ 14); patients not randomized remained on adjunctive placebo. Study 1 compared fixed-dose edivoxetine (12 or 18 mg daily) + SSRI (N = 231 and N = 230, respectively) with placebo + SSRI (N = 240); study 2 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 232) and fixed-dose edivoxetine (6 mg daily) + SSRI (N = 226) with placebo + SSRI (N = 231); and study 3 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 230) with placebo + SSRI (N = 219). The primary outcome was mean change from randomization baseline to week 8 in MADRS total score, analyzed using repeated measures analysis. Each trial failed to meet the primary and most of the secondary objectives. The least-squares mean changes in MADRS total score were as follows-study 1: -8.5 (edivoxetine 12 mg + SSRI), -8.7 (edivoxetine 18 mg + SSRI), and -7.8 (placebo + SSRI); study 2: -9.4 (edivoxetine 12-18 mg + SSRI), -9.6 (edivoxetine 6 mg + SSRI), and -9.4 (placebo + SSRI); and study 3: -8.7 (edivoxetine 12-18 mg + SSRI) and -8.5 (placebo + SSRI). Adjunctive edivoxetine treatment for patients with major depressive disorder who were partial responders to SSRIs did not significantly improve efficacy outcomes. ClinicalTrials.gov identifiers: NCT01173601, NCT01187407, NCT01185340.

P.2.f.009 - Antidepressant augmentation and co-initiation treatment in acute major depressive disorder: a systematic review, meta-analysis and metaregression analysis

P01-101 - Unique: assessing the efficacy of quetiapine fumarate augmentation of SSRI or SNRI treatment in SSRI- or SNRI-resistant major depressive disorder

Long-term safety, tolerability, and efficacy of adjunctive edivoxetine hydrochloride (hereafter edivoxetine), a highly selective and potent norepinephrine reuptake inhibitor, was assessed in patients with major depressive disorder (MDD) experiencing partial response to selective serotonin reuptake inhibitor treatment. Data are from a multicenter, 54-week, open-label trial of adjunctive edivoxetine 12 to 18 mg once daily in patients with MDD who had experienced partial response by history to 6 or more weeks of current selective serotonin reuptake inhibitor therapy and who had a 17-item GRID Hamilton Rating Scale for Depression total score 16 or higher at study entry. Safety measures included discontinuation rate, treatment-emergent adverse events, serious adverse events, and vital signs. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale. Of 608 patients, 328 (54%) completed the open-label adjunctive treatment. Study discontinuation due to adverse events occurred in 17.0%, and there were 13 serious adverse events (1 death). Treatment-emergent adverse events 5% or higher were nausea, hyperhidrosis, constipation, headache, dry mouth, dizziness, vomiting, insomnia, and upper respiratory tract infection. Mean increases were observed in systolic blood pressure (range, 0.0-2.3 mm Hg), diastolic blood pressure (range, 1.9-3.3 mm Hg), and pulse (range, 5.9-8.4 beats per minute). Mean improvements on the Montgomery-Åsberg Depression Rating Scale (-17.0) were observed from baseline to week 54. The safety profile from this study provides an overview of outcomes associated with edivoxetine and norepinephrine reuptake inhibition as an adjunctive treatment in patients with MDD who were treated up to 1 year.

The Effects of Pharmacological Treatment on Functional Brain Connectome in Obsessive-Compulsive Disorder

P01-39 - Adjunctive aripiprazole in patients with major depressive disorder: efficacy data from three short-term studies

Most examinations of the clinical efficacy of drugs used to treat depression pool subjects across gender and age groups. This investigation compared these patient subpopulations on the basis of remission and response rates associated with venlafaxine and selective serotonin reuptake inhibitor (SSRI) treatment. A meta-analysis of original data from 8 comparable double-blind, active-controlled, randomized clinical trials (4 also placebo-controlled) was conducted. Antidepressant efficacy was assessed for patients (N = 2,045) aged 18 to 83 years (subgroups: < or = 40, 41-54, 55-64, and > or = 65 years) who met DSM-III-R criteria for major depression or DSM-IV criteria for major depressive disorder and were randomly assigned to receive venlafaxine (immediate release, N = 474; extended release, N = 377), one of several SSRIs (N = 748), or placebo (N = 446) for up to 8 weeks. Symptoms of depression were assessed using the Hamilton Rating Scale for Depression (HAM-D). Remission was defined as a HAM-D-17 score < or = 7, response was defined as > or = 50% decrease in HAM-D-21 score, and absence of depressed mood was defined as a HAM-D depressed mood item score of 0. We detected no significant age-by-treatment, gender-by-treatment, or age-by-gender-by-treatment interactions; men and women of different ages within a given antidepressant treatment group exhibited similar rates of remission, response, and absence of depressed mood. Regardless of age or gender, remission rates during venlafaxine therapy were significantly higher than during SSRI therapy (remission rates at week 8: venlafaxine, 40%-55% vs. SSRI, 31%-37%; p < .05). Regardless of patient age or gender, onset of remission was more rapid with venlafaxine than with SSRI treatment. By contrast, rates of absence of depressed mood with venlafaxine (34%-42%) and SSRIs (31%-37%) did not differ significantly and tended to be similar for all patient subgroups. These data suggest that men and women have comparable responses to SSRIs and venlafaxine across various age groups. Moreover, patients exhibited a more rapid onset and a greater likelihood of remission with venlafaxine therapy than with SSRI therapy regardless of age or gender.

Highly significant elevations in regional brain monoamine oxidase A (MAO-A) binding were recently reported during major depressive episodes (MDEs) of major depressive disorder (MDD). The relationship between MAO-A levels and selective serotonin reuptake inhibitor (SSRI) treatment, recovery, and recurrence in MDD is unknown. To determine whether brain MAO-A binding changes after SSRI treatment, whether brain MAO-A binding normalizes in subjects with MDD in recovery, and whether there is a relationship between prefrontal and anterior cingulate cortex MAO-A binding in recovery and subsequent recurrence of MDE. Case-control study. Tertiary care psychiatric hospital. Twenty-eight healthy subjects, 16 subjects with an MDE secondary to MDD, and 18 subjects with MDD in recovery underwent carbon 11-labeled harmine positron emission tomography scans. Subjects with MDE were scanned before and after 6 weeks of SSRI treatment. All were otherwise healthy, nonsmoking, and medication free. Subjects with MDD in recovery were followed up for 6 months after MAO-A binding measurement. Monoamine oxidase A V(T), an index of MAO-A density, was measured in the prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, dorsal putamen, ventral striatum, thalamus, anterior temporal cortex, midbrain, and hippocampus. Monoamine oxidase A V(T) was significantly elevated in each brain region both during MDE and after SSRI treatment as compared with healthy controls. During recovery, MAO-A V(T) was significantly elevated in each brain region; however, those who went on to recurrence had significantly higher MAO-A V(T) in the prefrontal and anterior cingulate cortex than those who did not. Elevated MAO-A binding after SSRI treatment indicates persistence of a monoamine-lowering process not present in health. This provides a strong conceptual rationale for continuing SSRI treatment during early remission. Greater MAO-A binding in the prefrontal and anterior cingulate cortex in subjects with MDD in recovery and its association with subsequent recurrence argue that deficient monoamine neuromodulation may persist into recovery and contribute to recurrence.

BackgroundBioimpedance has been shown to be a safe technique when used in a number of biomedical applications. In this study, we used the Electro Interstitial Scan (EIS) to perform bioimpedance measurements to follow up the efficacy of selective serotonin reuptake inhibitor (SSRI) treatment in subjects diagnosed to have major depressive disorder.MethodsWe recruited 59 subjects (38 women, 21 men) aged 17–76 (mean 47) years diagnosed with major depressive disorder by psychiatric assessment at the Botkin Hospital according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Baseline Clinical Global Impression scores and EIS (electrical conductivity and dispersion α parameter) measurements were done before starting SSRI therapy. Treatment follow-up was undertaken using EIS bioimpedance measurements and by treatment response based on the Hamilton Depression Scale and Clinical Global Impression, every 15 days for 60 days. At day 45, we classified the patients into two groups, ie, Group 1, including treatment responders, and Group 2, including nonresponders. At day 60, patients were classified into two further groups, ie, Group 3, comprising treatment responders, and Group 4, comprising nonresponders.ResultsComparing Group 1 and Group 2, electrical conductivity measurement of the pathway between the two forehead electrodes had a specificity of 72% and a sensitivity of 85.3% (P < 0.0001), with a cutoff >4.32. Comparing Group 3 and Group 4, electrical conductivity measurements in the same pathway had a specificity of 47.6% and a sensitivity of 76.3% (P < 0.16), with a cutoff >5.92. Comparing Group 1 and Group 2, the electrical dispersion α parameter of the pathway between the two disposable forehead electrodes had a specificity of 80% and a sensitivity of 85.2% (P < 0.0001) with a cutoff >0.678. Comparing Group 3 and Group 4, the electrical dispersion α parameter of the same pathway had a specificity of 100%, a sensitivity of 89.5% (P < 0.0001), and a cutoff >0.692.ConclusionElectrical conductivity measurement of the forehead pathway using EIS has a high specificity and sensitivity at day 45 when comparing treatment responders and nonresponders, but decreases at day 60. The EIS electrical dispersion α parameter of the forehead pathway has a high specificity and sensitivity at day 45 when comparing treatment responders and nonresponders, and increases at day 60. The EIS system may be a noninvasive, easily administered, low-cost technique that could be used as an adjunct to DSM-IV and Clinical Global Impression scores for monitoring of efficacy of treatment in patients with major depressive disorder.

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed medications for patients with anxiety/depression. These patients often have problems with substance use, but it remains unclear whether the risk of substance misuse is influenced by SSRI treatment. We aimed to determine whether SSRI treatment is associated with a decreased risk of acute substance misuse-related outcomes. Cohort study following individuals through Swedish nation-wide registers between July 2005 and December 2013 and comparing the risk of substance misuse outcomes during periods on- versus off-treatment within the same individual. Swedish general population. Individuals with a newly dispensed prescription of SSRIs between July 2006 and December 2013 and an ICD-10 diagnosis of anxiety/depressive disorder before the first treatment initiation. The cohort included 146 114 individuals (60.7% women). Substance misuse outcomes included ICD-10 diagnoses of acute intoxications (F10.0-F19.0), accidental poisonings by alcohol or drugs (X41-X42, X45-X46) and substance-related criminal offenses. The absolute rate of substance misuse increased sharply before the onset of SSRI treatment and decreased after treatment initiation. Stratified Cox regression models showed an elevated risk [hazard ratio (HR)=1.70, 95% confidence interval (CI)=1.62-1.78] of substance misuse outcomes during a 1-month period preceding treatment initiation, compared with the reference period of more than 1month before treatment start. The on-treatment estimates (1-30days, HR=1.29, 95% CI=1.23-1.37; 31-120days, HR=1.30, 95% CI=1.24-1.35; and >120days, HR=1.24, 95% CI=1.18-1.30 after treatment initiation] were consistently lower than the 1-month pre-treatment estimate, but still elevated compared with the reference period. For people with anxiety/depression, the risk of substance misuse appears to be particularly elevated immediately before initiating selective serotonin reuptake inhibitor (SSRI) treatment, which may reflect the emergence or worsening of substance use problems concurrently with anxiety/depression. SSRI treatment appears to be associated with a lower risk of substance misuse compared with the 1-month period preceding treatment initiation, but causality remains uncertain.

Objective The relationship between childhood trauma (CT) and the outcomes of selective serotonin reuptake inhibitor (SSRI) treatment for major depressive disorder (MDD) remains uncertain. The objective of this study is to investigate the overall association between CT and treatment outcomes in patients with MDD and the associations of different CT subtypes with the treatment outcomes of various MDD symptom dimensions.Methods A post hoc analysis of 285 adult patients with MDD from a multicenter, prospective study in China. Patients who completed the Childhood Trauma Questionnaire-Short Form (CTQ-SF) and 8-week SSRI treatment were included. Depressive symptoms were evaluated using the 17-item Hamilton Rating Scale for Depression (HRSD-17) at baseline and at 2, 4, and 8 weeks. The primary outcome was defined as the percentage reduction in the total HRSD-17 score at the 8th week. The secondary outcomes included the percentage reduction in anhedonia and insomnia, derived from the HRSD-17. Linear regression analyses were conducted to evaluate the associations between the CTQ-SF score and treatment outcomes.Results Emotional neglect (EN) was associated with lower percentage reductions in HRSD-17 scores (β=-3.035, p=0.019), anhedonia (β=-4.227, p=0.044) and insomnia (β=-7.054, p=0.045) at 8 weeks. The total CTQ-SF score and other subscale scores were not significantly associated with treatment outcomes.Conclusion EN was associated with poorer SSRI treatment outcomes in MDD patients, with less improvement in overall depressive symptoms and anhedonia and insomnia in particular. EN should be prioritized in MDD treatment.

The association between selective serotonin reuptake inhibitor (SSRI) treatment and lower bone mineral density (BMD) remains controversial, and further research is required. This study aimed to compare the BMD, levels of bone formation and bone metabolism markers in medicated premenopausal Singaporean women with major depressive disorder (MDD) and matched healthy controls. We examined 45 women with MDD who received SSRI treatment (mean age: 37.64 ± 7) and 45 healthy controls (mean age: 38.1 ± 9.2). BMD at the lumbar spine, total hip and femoral neck were measured using dual-energy X-ray absorptiometry. We also measured bone formation markers, procollagen type 1 N-terminal propeptide (P1NP) and bone metabolism markers, osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa-Β ligand (RANKL). There were no significant differences in the mean BMD in the lumbar spine (healthy controls: 1.04 ± 0.173 vs. MDD patients: 1.024 ± 0.145, p = 0.617, left hip (healthy controls: 0.823 ± 0.117 vs. MDD patients: 0.861 ± 0.146, p = 0.181) and right hip (healthy controls: 0.843 ± 0.117 vs. MDD patients: 0.85 ± 0.135, p = 0.784) between healthy controls and medicated patients with MDD. There were no significant differences in median P1NP (healthy controls: 35.9 vs. MDD patients: 37.3, p = 0.635), OPG (healthy controls: 2.6 vs. MDD patients: 2.7, p = 0.545), RANKL (healthy controls: 23.4 vs. MDD patients: 2178.93, p = 0.279) and RANKL/OPG ratio (healthy controls: 4.1 vs. MDD patients: 741.4, p = 0.279) between healthy controls and medicated patients with MDD. Chronic SSRI treatment might not be associated with low BMD in premenopausal Singaporean women who suffered from MDD. This finding may help female patients with MDD make an informed decision when considering the risks and benefits of SSRI treatment.

Impact of antidepressant treatment on complete blood count parameters and inflammatory ratios in adolescents with major depressive disorder

Clopidogrel dose responsiveness, poststroke survival and SSRI treatment, and discontinuation of physician–pharmacist intervention

Studies generally do not examine patients' prestroke depression diagnoses and treatments. To examine the association of depression diagnosis and prestroke and/or poststroke selective serotonin reuptake inhibitor (SSRI) treatment with poststroke mortality. We conducted a retrospective study of the medical records of a cohort of veterans with a stroke diagnosis between July 31, 2000, and September 30, 2001. Data regarding demographics, comorbidities, depression diagnosis, and treatment were abstracted from automated databases and electronic medical records for 6 months before and 1 year after the stroke index date. The survival rates of veterans who received an SSRI before and/or after the stroke were estimated using Kaplan-Meier survival analysis. Time-dependent Cox proportional hazards regression model was used to assess the association between risk factors and mortality. Among 870 veterans, 80 died less than 60 days after their stroke. Among the remaining 790, 12% died within 1 year, 26% died by the end of follow-up (May 1, 2007), and more than 62% were alive at the end of follow-up. Veterans were 3 times as likely to die if they had been treated for depression with an SSRI only before their stroke (hazard ratio [HR], 3.12; 95% CI 1.60 to 6.09). In the time-dependent model, SSRI treatment both before and after the stroke was protective compared with no SSRI treatment during the year following the stroke (HR 0.31; 95% CI 0.11 to 0.86). However, the survival curves crossed over and SSRI treatment before and after stroke conferred greater risk at the end of 7 years (HR 1.36; 95% CI 1.00 to 1.87). Depression diagnosis was associated with greater risk of mortality (HR 1.87; 95% CI 1.24 to 2.82). Poststroke SSRI treatment was associated with longer survival even though depression diagnosis was associated with earlier mortality in the unadjusted model. After a stroke, SSRI initiation or resumption of treatment should be considered as part of a medication therapy management service, especially if the patient has a history of depression or was taking an SSRI before the stroke.