Mary Anne Dellva

OLANZAPINE VERSUS HALOPERIDOL : ACUTE PHASE RESULTS OF THE INTERNATIONAL DOUBLE-BLIND OLANZAPINE TRIAL

A 6-week acute phase of an international 1-year double-blind study was conducted comparing three dose ranges of olanzapine (5 +/- 2.5 mg/day, 10 +/- 2.5 mg/day, and 15 +/- 2.5 mg/day) with a fixed dose of olanzapine (1.0 mg/day) and with a dose range of haloperidol (15 +/- 5 mg/day) in the treatment of 431 patients with schizophrenia. The purpose was to determine whether olanzapine demonstrated a dose-related ability to decrease overall psychopathology with minimal associated extrapyramidal symptoms in patients with schizophrenia. The high-dose olanzapine group showed statistically significantly greater improvement in overall psychopathology based on mean change in the CGI Severity score and statistically significantly greater improvement in positive psychotic symptoms based on mean change in both the BPRS positive score and the PANSS positive score compared with the 1.0-mg/day olanzapine group. Analyses indicated that an increasing dose-response curve was observed across the range of all olanzapine dose groups. Acute extrapyramidal syndromes were reported less frequently among all olanzapine groups compared with the haloperidol group. Endpoint mean change on both the Simpson-Angus Scale and the Barnes Akathisia Scale reflected improvement for all olanzapine treatment groups compared with worsening for the haloperidol group. Olanzapine was associated with weight gain but did not appear to have any clinically meaningful effect on vital signs. Although olanzapine was associated with some increase in prolactin concentrations, increases were transient, occurred less often, and were of lesser magnitude than those observed with haloperidol.

Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo

The abrupt appearance of clozapine discontinuation symptoms represents a particularly unique situation that has not been characterized in a double-blind, placebo-controlled trial. A randomized, double-blind comparison of placebo (N = 53) and olanzapine 10 mg (N = 53) for 3 to 5 days following the abrupt discontinuation of clozapine (< 300 mg/day) was carried out. Subjects were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale of Severity, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Evaluation. Subsequently both groups received open-label olanzapine (10-25 mg/day) for an additional 9 weeks. Statistically significantly more placebo-treated (24.5%) than olanzapine-treated (7.5%) patients experienced clozapine discontinuation symptoms (p = 0.017). Core symptoms included delusions, hallucinations, hostility, and paranoid reaction and translated into a significantly higher worsening from baseline on the PANSS total, PANSS General Psychopathology subscale, and MADRS among subjects randomly assigned to receive placebo. After open-label treatment with olanzapine for 9 weeks, both groups were clinically stable, suggesting that the discontinuation symptoms were transient. However, subjects who had been randomly assigned to the 3- to 5-day placebo discontinuation segment achieved somewhat less global clinical improvement. Although a pharmacologic interpretation is speculative, evidence of a clozapine discontinuation syndrome was apparent. In most cases, the direct substitution of a pharmacologically similar agent (olanzapine) prevented the syndrome. Clozapine discontinuation or noncompliance should be considered in the differential assessment of an acutely emergent psychosis. The possibility that subjects who experience a clozapine discontinuation syndrome may take longer or are less likely to clinically restabilize warrants further investigation.

A study of the effects of LY2216684, a selective norepinephrine reuptake inhibitor, in the treatment of major depression

The current study sought to test the efficacy and safety of the novel selective norepinephrine reuptake inhibitor LY2216684 compared to placebo in patients with major depressive disorder (MDD). Escitalopram was used as a control for assay sensitivity. Adult outpatients with MDD, confirmed at screening by the Mini International Neuropsychiatric Interview, a Self-Rated Quick Inventory of Depressive Symptomatology (QIDS-SR) score of at least 12 and a Clinical Global Impression-Severity Score of at least 4, were randomly assigned to LY2216684 (N=269), placebo (N=138), or escitalopram (N=62). Efficacy, safety, and tolerability outcomes were compared during 8 weeks of double-blind treatment. LY2216684 plasma concentrations were measured. LY2216684 did not show statistically significant improvement from baseline compared to placebo in the primary analysis of the Hamilton depression rating scale (HAM-D(17)) total score. Escitalopram demonstrated significant improvement compared to placebo on the HAM-D(17) total score, suggesting adequate assay sensitivity. Both LY2216684 and escitalopram showed statistically significant improvement from baseline on the patient-rated QIDS-SR total score compared to placebo. Headache, nausea, constipation, dry mouth, and insomnia were the most frequently reported adverse events in the LY2216684 group. A 3-6 beats per minute mean increase from baseline in pulse rate was observed in the LY2216684 group. LY2216684 plasma concentrations increased as the dose increased from 3 mg to 12 mg. The results of this initial investigation of LY2216684s efficacy suggest that it may have antidepressant potential. More definitive data to confirm this is necessary. Its safety profile does not preclude further clinical development.

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

BACKGROUND This phase 2 study examined the efficacy and tolerability of edivoxetine, a highly selective norepinephrine reuptake inhibitor, as an adjunctive treatment for patients with major depressive disorder (MDD) who have a partial response to selective serotonin reuptake inhibitor (SSRI) treatment. METHODS Study design consisted of double-blind, 10-week therapy of adjunctive edivoxetine (6-18 mg once daily) or adjunctive placebo with SSRI. Inclusion/entry criteria included partial response to current SSRI by investigator opinion and a GRID 17-item Hamilton Rating Scale for Depression (HAMD17) total score ≥16. The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Safety measures included treatment-emergent adverse events (TEAE) and vital signs. RESULTS For the primary evaluable population (n=63 for adjunctive edivoxetine and n=68 for adjunctive placebo), the treatment groups did not differ significantly on the primary outcome of change from baseline to week 8 in the MADRS total score; the effect size of edivoxetine treatment was 0.26. Significant treatment differences, favoring adjunctive edivoxetine (p≤.05), were shown for improvements in role functioning and the functional impact of fatigue. For the adjunctive edivoxetine randomized group (N=111), the most frequent TEAEs were hyperhidrosis (7.2%), nausea (7.2%), erectile dysfunction (6.3%) and testicular pain (6.3%). Hemodynamic changes were observed in blood pressure and pulse rate between treatment groups. LIMITATIONS Study was underpowered for an alpha 2-sided 0.05 significance level for the primary outcome. CONCLUSIONS For patients with MDD who had a partial response to SSRIs, adjunctive edivoxetine treatment was not statistically superior to adjunctive placebo on the primary outcome measure. However, pending further study, improved functioning and remission rate suggest a potential role for edivoxetine for patients with depression.

Edivoxetine compared to placebo as adjunctive therapy to selective serotonin reuptake inhibitors in the prevention of symptom re-emergence in major depressive disorder

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.

Safety and tolerability of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor antidepressants for patients with major depressive disorder.

Objective: The aim of this analysis was to assess the safety profile of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor (SSRI) antidepressants. Methods: A pooled analysis was conducted on data obtained from the integrated safety database of edivoxetine as adjunctive treatment to SSRIs. Safety and tolerability assessments included discontinuation rates, spontaneously reported treatment-emergent adverse events (TEAEs), clinical laboratory tests, blood pressure (BP) and pulse, and electrocardiograms (ECGs). Results: The analysis included 1260 patients treated with adjunctive edivoxetine and 806 treated with adjunctive placebo. Study completion rates were 85.2% and 84.5% (p=0.994), respectively. Discontinuations due to adverse events were 4.9% and 3.5% (p=0.07), respectively. Significantly more patients in the adjunctive edivoxetine group compared with adjunctive placebo group reported at least one TEAE (56.8 vs 43.7%, p<0.001). The most common TEAEs (occurred ≥5% frequency) were hyperhidrosis, nausea, and tachycardia. Mean changes in sitting BP and pulse at the last visit were increased significantly in patients treated with adjunctive edivoxetine compared with adjunctive placebo (SBP: 2.7 vs 0.5 mm Hg, p<0.001; DBP: 4.1 vs 0.8 mm Hg, p<0.001; pulse: 8.8 vs −1.3 bpm, p<0.001). There were no clinically significant changes in laboratory measures. Conclusions: The tolerability and safety profile of edivoxetine as adjunctive treatment to SSRI antidepressants was consistent with its norepinephrine reuptake inhibitor mechanism of action, and was comparable with edivoxetine monotherapy treatment in patients with major depressive disorder.