Biopharmaceutical characterization, metabolism, and brain penetration of the triple reuptake inhibitor amitifadine.

Amitifadine (EB-1010, formerly DOV 21,947) is a serotonin-preferring triple reuptake inhibitor that is a drug candidate for major depressive disorder. We investigated several relevant biopharmaceutic and drug-like characteristics of amitifadine using in vitro methodology and additionally determined the in vivo brain to plasma ratio of the drug in rats. Amitifadine was highly plasma protein bound with over 99% of drug bound to human plasma proteins. Using Caco-2 cell lines, amitifadine was bidirectionally highly permeable and showed no evidence of active secretion. Amitifadine was metabolized slowly by human hepatocytes and the major metabolite was the lactam EB-10101. In vitro studies using human liver microsomes demonstrated that EB-10101 was formed by monoamine oxidase A (MAO-A) and a NADPHdependent enzyme, possibly a cytochrome P450 (CYP) isoform. Amitifadine was a moderate inhibitor of the human isoforms of the major drug metabolizing enzymes CYP2D6, CYP3A4, CYP2C9, and CYP2C19 (IC50 = 9 - 100 µM), but was a potent inhibitor of human CYP2B6 (IC50 = 1.8 µM). The brain to plasma ratio for amitifadine varied from 3.7 - 6.5 at various time points, indicating preferential partitioning into rat brain versus plasma. The low affinity for the major drug metabolizing CYP enzymes and metabolism by multiple pathways may reduce pharmacokinetic drug-drug interactions and effects of enzyme polymorphisms. Overall, these studies suggest that amitifadine has drug-like characteristics favorable for drug development.

Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study.

OBJECTIVE: To assess maintenance of efficacy and tolerability of gabapentin enacarbil in patients with moderate to severe primary restless legs syndrome (RLS). PATIENTS AND METHODS: This study (conducted April 18, 2006, to November 14, 2007) comprised a 24-week, single-blind (SB) treatment phase (gabapentin enacarbil, 1200 mg) followed by a 12-week randomized, double-blind (DB) phase. Responders from the SB phase (patients with improvements on the International Restless Legs Scale [IRLS] and investigator-rated Clinical Global Impression-Improvement scale at week 24 and stable while taking a gabapentin enacarbil dose of 1200 mg for at least 1 month before randomization) were randomized to gabapentin enacarbil, 1200 mg, or placebo once daily at 5 pm with food. The primary end point was the proportion of patients experiencing relapse (worse scores on the IRLS and investigator-rated Clinical Global Impression of Change scale on 2 consecutive visits at least 1 week apart or withdrawal because of lack of efficacy) during the DB phase. RESULTS: A total of 221 of 327 patients completed the SB phase, 194 (96 in the gabapentin enacarbil group and 98 in the placebo group) were randomized to DB treatment, and 168 (84 in the gabapentin enacarbil group and 84 in the placebo group) completed the DB phase. A significantly smaller proportion of patients treated with gabapentin enacarbil (9/96 [9%]) experienced relapse compared with the placebo-treated patients (22/97 [23%]) (odds ratio, 0.353; 95% confidence interval, 0.2-0.8; P=.02). Somnolence and dizziness were the most common adverse events. One death occurred (unintentional choking during the SB phase) and was judged as being unrelated to the study drug. No clinically relevant changes were observed in laboratory values, in vital signs, or on electrocardiograms. CONCLUSION: Gabapentin enacarbil, 1200 mg, maintained improvements in RLS symptoms compared with placebo and showed long-term tolerability in adults with moderate to severe primary RLS for up to 9 months of treatment.

Sexual functioning assessed in 4 double-blind placebo- and paroxetine-controlled trials of duloxetine for major depressive disorder.

OBJECTIVE: The onset or worsening of sexual dysfunction is a common treatment-emergent side effect of antidepressant medications. Post hoc analyses of pooled data from placebo-controlled studies were utilized to assess sexual functioning in patients receiving duloxetine or paroxetine. METHOD: Acute-phase data were obtained from four 8-week, double-blind, placebo- and paroxetine-controlled trials of similar design in which patients meeting DSM-IV criteria for major depressive disorder were randomly assigned to receive placebo (N = 371), duloxetine (40-120 mg/day; N = 736), or paroxetine (20 mg/day; N = 359). Pooling of data from these studies was anticipated during study design. This represented all available data from duloxetine studies in which the Arizona Sexual Experience Scale (ASEX) was administered both at baseline and endpoint. Long-term data were available from extension phases in 2 of these trials in which acute treatment responders received placebo (N = 129), duloxetine (80-120 mg/day; N = 297), or paroxetine (20 mg/day; N = 140) for an additional 26 weeks. Data were collected between March 2000 and July 2002. RESULTS: The incidence of acute treatment-emergent sexual dysfunction was significantly lower among duloxetine-treated patients compared with those receiving paroxetine (p = .015), although both rates were significantly higher than placebo (p = .007 and p < .001 for duloxetine and paroxetine, respectively). Treatment group differences in the incidence of treatment-emergent dysfunction did not vary significantly by gender. In female patients, acute treatment-emergent sexual dysfunction was significantly lower in the duloxetine treatment group compared with the paroxetine treatment group (p = .032), with both rates being significantly higher than placebo (p = .049 and p < .001 for duloxetine and paroxetine, respectively). In the somewhat smaller group of male patients, acute treatment-emergent dysfunction did not differ significantly between duloxetine and placebo treatment groups, but the incidence was significantly higher in paroxetine-treated male patients compared with male placebo patients (p = .012). The long-term incidence of treatment-emergent dysfunction did not differ significantly between duloxetine-, paroxetine-, and placebo-treated patients. CONCLUSION: In this analysis of pooled data, patients receiving duloxetine (40-120 mg/day) or paroxetine (20 mg/day) had a significantly higher incidence of acute treatment-emergent sexual dysfunction when compared with placebo patients. However, the incidence of acute treatment-emergent dysfunction for duloxetine was significantly lower than that observed for paroxetine.

Cardiovascular profile of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine.

This analysis assessed the effects of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, on indices of cardiovascular safety, including heart rate, blood pressure (BP), and electrocardiograms (ECGs), in a large group of clinical trial patients with depression. Data were available from 8 double-blind, randomized, placebo-controlled (n = 777), and active comparator-controlled depression trials. Duloxetine (n = 1139) doses ranged from 40 to 120 mg/d, and fluoxetine (n = 70) and paroxetine (n = 359) were administered at a dose of 20 mg/d. Patients were treated for 8 to 9 weeks. There was a significant increase for duloxetine compared with placebo for heart rate (1.6 vs. -0.6 beats per minute) and for systolic BP (1.0 vs. -1.2 mm Hg); the difference for diastolic BP (1.1 vs. 0.3) was not significant. There were no significant differences between duloxetine and placebo treatment groups in the incidence of sustained (at least 3 consecutive visits) elevations in systolic (duloxetine 1.0%, placebo 0.4%), diastolic (duloxetine 0.4%, placebo 0.4%), or either (duloxetine 1.3%, placebo 0.8%) BP. Moreover, the effect of duloxetine on mean changes in supine systolic and diastolic BP was not significantly different from that of fluoxetine or paroxetine. Drug-placebo differences in mean changes in electrocardiograms (eg, QTc, PR, and QRS intervals) were neither statistically nor clinically significant, with the exception that duloxetine 120 mg/d had significant decreases in PR and QRS intervals compared with placebo. These data demonstrate that duloxetine has modest effects on heart rate and BP and no clinically meaningful effect on electrocardiogram profiles in a relatively healthy cohort of clinical trial patients. The cardiovascular effects of duloxetine appear to be comparable with medications considered to be first-line options for depression.

Comparison of risperidone and olanzapine in the control of negative symptoms of chronic schizophrenia and related psychotic disorders in patients aged 50 to 65 years.

BACKGROUND: This analysis compares the efficacy of risperidone and olanzapine in controlling negative and positive symptoms of chronic psychosis in older patients. METHOD: Post hoc assessments were made in a subset of risperidone-treated (N = 19) and olanzapine-treated (N = 20) older patients (aged 50 to 65 years) from a large international, multicenter, parallel, double-blind, 28-week study of patients aged 18 to 65 years (N = 339) randomly assigned to receive risperidone (4-12 mg/day) or olanzapine (10-20 mg/day). Assessments were made using repeated-measures analysis. RESULTS: At both 8 weeks and 28 weeks, the magnitude of changes in Positive and Negative Syndrome Scale (PANSS) positive symptom subscale scores did not differ between treatment groups (8 weeks: risperidone, -6.5; olanzapine, -6.8, p = .866; 28 weeks: risperidone, -6.5; olanzapine, -7.0; p = .804). However, by the 8-week timepoint, olanzapine had reduced PANSS negative subscale scores significantly more than risperidone (-8.8 vs. -4.9, p = .032). By the 28-week endpoint, olanzapine had continued to maintain significantly greater reduction in baseline-to-endpoint PANSS negative scores (-8.1 vs. -3.5, p = .032) and led to significantly greater reduction in scores on the Scale for the Assessment of Negative Symptoms (SANS) dimensions of affective flattening (-5.2 vs. -0.6, p = .033) and alogia (-3.8 vs. -0.3, p = .007). Patients in the olanzapine treatment group also demonstrated numerically greater reduction of both SANS summary (-3.7 vs. -1.0, p = .078) and SANS composite scores (-14.1 vs. -4.1, p = .075). CONCLUSION: These data demonstrate that, in older patients with schizophrenia and related psychotic disorders, risperidone and olanzapine have approximately equal efficacy in controlling positive symptoms. However, olanzapine appears to be more efficacious in maintaining control over negative symptoms.

New approaches to developing antidepressants by enhancing monoaminergic neurotransmission.

Major depressive disorder (MDD) is a serious illness with far reaching societal and economic ramifications. The monoamine-deficiency hypothesis that depressive symptoms are associated with reductions in monoamine neurotransmission, particularly serotonin and noradrenaline, is supported by both neurochemical findings and the successful treatment of MDD with compounds that enhance monoaminergic neurotransmission. This review focuses on novel compounds in different stages of development for the treatment of MDD that enhance monoaminergic neurotransmission via a number of different mechanisms, including re-uptake inhibition of one or more monoamines, monoamine oxidase inhibitors, the combination of monoamine antagonists with re-uptake inhibitors and monoamine receptor subtype agonists. Compounds that enhance individual monoamines have antidepressant properties and compounds that enhance multiple monoamines appear to have a synergistic antidepressant effect and potentially faster onset of action. The differing mechanisms of action possessed by these novel monoamine-enhancing compounds will offer greater treatment flexibility in the therapeutic management of MDD.

Dual monoamine modulation for improved treatment of major depressive disorder.

The worldwide scope of depressive illness and lack of fully effective pharmacotherapy mandates significant improvements in treatment paradigms. Current antidepressant medications remain limited by poor efficacy, slow onset of action, and untoward side effects. While the introduction of serotoninspecific reuptake inhibitors (SSRIs) offered significant improvements in tolerability, no improvements in efficacy or speed of onset have been made relative to the traditional and poorly tolerated tricyclic antidepressants (TCA). The dominant efforts toward improving antidepressant medications are guided by cumulative evidence from neurochemical and clinical studies supporting the therapeutic potential of enhancing monoamine function in depression. A number of novel antidepressant drugs, including mirtazapine, milnacipran, venlafaxine, and duloxetine have been developed based on their interaction with both 5-HT and NE. Current clinical evidence suggests that these new agents may offer improved efficacy and/or faster onset of action compared with SSRIs and an improved side effect profile compared with TCAs. Potential neurobiological substrates mediating the enhanced antidepressant activity of dual reuptake inhibitors are discussed.

Duloxetine: A New Treatment for the Emotional and Physical Symptoms of Depression.

BACKGROUND: Depression is underdiagnosed in the primary care setting. Physical symptoms such as aches, pains, and gastrointestinal disturbance are frequently associated with major depressive disorder (MDD) and are often the presenting symptoms. Duloxetine, a dual-reuptake inhibitor of serotonin and norepinephrine, may have a positive effect on physical symptoms in addition to efficacy in treating emotional symptoms of depression. METHOD: Efficacy was evaluated in 6 double-blind, placebo- and/or active comparator-controlled trials of duloxetine for patients with MDD (DSM-IV criteria). Efficacy in depression was determined primarily using the 17-item Hamilton Rating Scale for Depression (HAM-D-17). Secondary efficacy measures included subscales of the HAM-D-17 and assessment of physical symptoms. Safety evaluations included adverse events, vital signs, laboratory analyses, and electrocardiograms. Safety was evaluated by pooling the data from the MDD trials and a study of duloxetine in nondepressed patients. RESULTS: Duloxetine demonstrated significant differences from placebo on core mood symptoms, physical symptoms (e.g., back pain), and global functioning as early as week 1 of treatment. The estimated probabilities of remission in the studies that demonstrated efficacy ranged from 43% to 57%. The most frequently observed adverse events for duloxetine-treated patients included nausea, dizziness, insomnia, fatigue, and somnolence. Duloxetine did not prolong corrected QT intervals, and the rate of sustained elevations of blood pressure did not differ significantly from placebo. CONCLUSION: In these studies, duloxetine was safe and effective in the treatment of both emotional and physical symptoms of MDD. Based on dose assessments, 60 mg q.d. appears to be the optimum starting and therapeutic dose.

Switching to olanzapine from previous antipsychotics: a regional collaborative multicenter trial assessing 2 switching techniques in Asia Pacific.

BACKGROUND: This open-label, multicenter, randomized study compared the efficacy and safety of switching moderately ill Asian patients with schizophrenia from their current regimen of antipsychotic medication to the atypical antipsychotic olanzapine using either a direct switch method or a start-taper switch method. METHOD: Asian inpatients and outpatients with DSM-IV schizophrenia (N = 108) currently treated with predominantly typical antipsychotics were switched to olanzapine (initial dose of 10 mg/day) for 6 weeks. Patients were randomly assigned to 1 of 2 groups: the direct switch group (N = 54) received only olanzapine, while the start-taper switch group (N = 54) received olanzapine and their usual antipsychotic in decreasing doses for the first 2 weeks. A successful switch was defined as completing 6 weeks of therapy without worsening of symptoms (Clinical Global Impressions-Severity of Illness scale [CGI-S]) or extrapyramidal side effects (Simpson-Angus Scale). Overall efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), and safety was assessed by recording adverse events and measuring vital signs. RESULTS: Statistically significant (p < .001) improvements from baseline to endpoint occurred in both switch groups in the CGI-S score and the PANSS total score and subscores. However, no significant differences were observed between the switch groups for any efficacy measure. Both techniques had comparable rates of successful switching (direct switch, 74.1% vs. start-taper switch, 67.9%). The frequency of treatment-emergent adverse events was similar between switch groups with no clinically significant differences in any laboratory value or vital sign. Weight gain occurred in both switch groups (p < .001), but the groups were not statistically different from each other. Both switch groups showed statistically significant (p < .01) improvements from baseline to endpoint on the Simpson-Angus Scale and Barnes Akathisia Scale. CONCLUSION: Moderately ill Asian patients with schizophrenia may experience a decrease in symptom severity and improvement in extrapyramidal symptoms when switched from their current medication to olanzapine therapy.

Duloxetine for the treatment of major depressive disorder.

>55% were observed in two of the studies, while in a third study the probability of remission with duloxetine treatment was nearly three times that observed with placebo (44% versus 16%). Duloxetine also produced significant improvement in painful physical symptoms compared with placebo, in many cases after only 2 weeks of treatment. The discontinuation rate due to adverse events (14.6%) was similar to those observed with selective serotonin reuptake inhibitors. The most frequently reported adverse events were nausea, dry mouth, fatigue, and insomnia. Conclusion. Duloxetine was demonstrated to be safe and effective in the treatment of MDD. The starting dose with the best balance of efficacy and tolerability is 60 mg QD.

The Comparative Peripheral Anticholinergic-Like Adverse Event Profiles of Olanzapine and Risperidone.

OBJECTIVE: To test the hypothesis that reported in vitro muscarinic receptor affinity differences between olanzapine and risperidone would be reflected in peripheral solicited anticholinergic adverse event frequencies. METHOD: Data from a double-blind, randomized trial of olanzapine versus risperidone in 339 patients (age range, 18-65 years) with DSM-IV schizophrenia spectrum acute psychosis were retrospectively analyzed. Subgroups based on the median of the mean daily drug dose were constructed (olanzapine 17 mg; risperidone 6 mg). Mean daily dose of adjunctive anticholinergic medication was compared using ANOVA, and frequencies of treatment-emergent solicited adverse events defined by the Association de Méthodologie et de Documentation en Psychiatrie (AMDP-5) were analyzed using categorical methods. RESULTS: Mean daily anticholinergic dose was significantly higher overall for the risperidone group (0.68 +/- 1.27 mg) than for the olanzapine group (0.27 +/- 0.76 mg) (p =.002). When only patients who did not receive anticholinergic adjunct therapy were considered, no significant differences in the frequency of specific anticholinergic adverse events occurred in olanzapine-treated patients as compared with risperidone-treated patients (p >/=.245). There was also no significant difference between olanzapine and risperidone in the frequency of any anticholinergic adverse event (p =.458). CONCLUSION: At clinically effective doses, olanzapine and risperidone did not differ significantly in frequency of peripheral anticholinergic events. These results support the view that, for olanzapine and risperidone, in vitro anticholinergic receptor binding (K(i) values) may not predict in vivo peripheral events.