ABSTRACT
OBJECTIVE: When patients with major depressive disorder (MDD) are partial responders to antidepressant therapy, adjunctive treatment with an agent that has a different mode of action may provide additional benefit. We investigated the efficacy of edivoxetine, a highly selective norepinephrine reuptake inhibitor (NRI), as adjunctive treatment to selective serotonin reuptake inhibitors (SSRIs) in the prevention of re-emergence of depressive symptoms in patients with MDD (ClinicalTrials.gov identifier: NCT01299272). METHODS: Adult outpatients with MDD who were partial responders to SSRI treatment (N = 1249) entered an open-label 8 week flexibly dosed (12-18 mg/day) adjunctive edivoxetine period. Patients who achieved remission (Montgomery-Åsberg Depression Rating Scale total score ≤10 at week 8) entered a 12 week open-label fixed-dose (12 mg or 18 mg/day) stabilization period, and those still in remission at each of weeks 18, 19, and 20 were randomized to continue treatment at the same dose of edivoxetine or switch to placebo for a 24 week double-blind withdrawal period. All patients remained on SSRI therapy throughout the study. The primary outcome was time to re-emergence of depressive symptoms during double-blind withdrawal. RESULTS: Two hundred and ninety-four patients were randomized to continue adjunctive edivoxetine and 292 were switched to adjunctive placebo. Comparing adjunctive edivoxetine with adjunctive placebo, differences were not significant for time to re-emergence of symptoms (Kaplan-Meier log-rank p = 0.485), rates of symptom re-emergence (9.9% vs 8.2%, p = 0.565) or rates of sustained remission (75.4% vs 76.7%, p = 0.771). Treatment-emergent adverse events were consistent with the noradrenergic mechanism of action. CONCLUSIONS: Edivoxetine failed to demonstrate superiority vs placebo as adjunctive treatment in the prevention of symptom re-emergence during maintenance treatment in SSRI partial responders with MDD. While no selective NRIs are approved for adjunctive treatment to SSRIs in MDD, the use of NRIs in this population is nonetheless accepted practice, but our data do not support the efficacy of this approach.
Subject(s)
Antidepressive Agents/therapeutic use , Depressive Disorder, Major/drug therapy , Morpholines/therapeutic use , Phenylethyl Alcohol/analogs & derivatives , Selective Serotonin Reuptake Inhibitors/therapeutic use , Adolescent , Adult , Aged , Antidepressive Agents/administration & dosage , Double-Blind Method , Female , Humans , Male , Middle Aged , Morpholines/administration & dosage , Norepinephrine/metabolism , Phenylethyl Alcohol/administration & dosage , Phenylethyl Alcohol/therapeutic use , Psychiatric Status Rating Scales , Selective Serotonin Reuptake Inhibitors/administration & dosage , Treatment Outcome , Young AdultABSTRACT
ACTG 266 was designed as a randomized study to evaluate two doses of the human monoclonal antibody directed against CMV gH (MSL-109) versus placebo, each in combination with standard antiviral therapy for the treatment of newly diagnosed Cytomegalovirus (CMV) retinitis in AIDS patients. A total of 82 subjects were enrolled and received either placebo (n = 28), or MSL-109 at 15 mg (n = 26) or 60 mg (n = 28) every 2 weeks until disease progression was diagnosed. The primary endpoint, disease progression, was determined by masked reading of retinal photographs taken every 4 weeks read by a single investigator. The median time to progression was 8.0, 8.3, and 12.1 weeks in the placebo, MSL-109 15mg and MSL-109 60 mg cohorts, respectively (P = 0.087, placebo versus 60 mg cohort). There were 22 deaths during the study period (9, 9, and 4 in the placebo, MSL-109 15 mg and MSL-109 60 mg cohorts, respectively (P = 0.0058, placebo versus 60 mg cohort)). MSL-109 was well tolerated with no significant adverse events attributable to study medication. The unexplained survival advantage in the higher dose cohort was discordant with the findings of the parallel Studies of Ocular Complications of AIDS Research Group (SOCA)-Monoclonal Anti-CMV Retinitis Trial (MACRT), which was prematurely halted because of increased mortality in subjects treated with high-dose MSL-109, recognizing that A266 enrolled subjects with newly diagnosed, whereas the MACRT enrolled subjects with relapsed, CMV retinitis.
Subject(s)
AIDS-Related Opportunistic Infections/therapy , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , Cytomegalovirus Retinitis/therapy , Viral Envelope Proteins/immunology , AIDS-Related Opportunistic Infections/mortality , AIDS-Related Opportunistic Infections/virology , Adult , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/immunology , Antiviral Agents/administration & dosage , Cytomegalovirus/drug effects , Cytomegalovirus Retinitis/mortality , Cytomegalovirus Retinitis/virology , Double-Blind Method , Drug Therapy, Combination , Female , Foscarnet/administration & dosage , Foscarnet/therapeutic use , Ganciclovir/administration & dosage , Ganciclovir/therapeutic use , Humans , Male , Treatment OutcomeABSTRACT
Older age is a strong predictor of accelerated human immunodeficiency virus (HIV) disease progression. We investigated the possible immunologic basis of this interaction by comparing older (>/=45 years) and younger (=30 years) HIV-infected adults with simultaneously enrolled, aged-matched, healthy volunteers. Cross-sectional comparisons suggested age-associated reductions in naive CD8(+) cells and in the expression of CD28(+) on CD8(+) cells among both HIV-infected subjects and control subjects. Opposite patterns of CD4(+) and CD8(+) cell differences were apparent between these subject groups. HIV infection, but not age, was associated with impairments in delayed-type hypersensitivity responses, lymphoproliferation, and spontaneous apoptosis and with alterations in expression of chemokine receptors CCR5 and CXCR4. Reduced thymic volumes were associated with age and with HIV infection among younger, but not older, subjects. Because of their common association with age and HIV disease, naive CD8(+) cell depletion, diminished CD28 expression on CD8(+) cells, and reduced thymic volumes are possible correlates of the interaction of age with HIV disease.