Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder.

LY354740, a potent and selective mGlu (metabotropic glutamate receptor)2/3 agonist, has shown efficacy in the treatment of generalized anxiety disorder (GAD). LY544344 is a LY354740 prodrug that increases LY354740 bioavailability. This 8-week study was designed to evaluate the efficacy, safety, and tolerability of LY544344 in the treatment of GAD. Participants had a diagnoses of GAD, baseline Hospital Anxiety and Depression Scale anxiety subscale scores > or = 10, and moderate illness severity. Patients were randomized to double-blind treatment with LY544344 16 mg b.i.d. (n = 28), LY544344 8 mg b.i.d. (n = 36), or placebo (n = 44). LY544344 16 mg b.i.d.-treated patients showed significantly greater improvement from baseline in Hamilton Anxiety and Clinical Global Impression-Improvement scores, as well as response and remission rates compared with placebo-treated patients. LY544344 was well tolerated and there were no significant differences in the incidence of treatment-emergent adverse events among the three treatment groups. However, the trial was discontinued early based on findings of convulsions in preclinical studies. In conclusion, the findings of this study support the potential efficacy of mGlu2/3 receptor agonist agents in the treatment of GAD. Additional studies will be needed to further assess the toxicological and clinical profile of LY354740/LY544344.

Atomoxetine treatment of adults with ADHD and comorbid alcohol use disorders.

OBJECTIVE: Adults with attention-deficit/hyperactivity disorder (ADHD) have higher rates of alcohol and drug use disorders than adults without ADHD. The study aim was to determine if atomoxetine was superior to placebo in improving ADHD and alcohol use in recently abstinent adults with ADHD and comorbid alcohol use disorder. METHODS: Adults with DSM-IV diagnoses of ADHD and alcohol abuse and/or dependence were abstinent from alcohol at least 4 days (maximum 30 days) before study randomization. Participants received atomoxetine (25-100mg daily) or placebo for 12 weeks. ADHD symptoms were assessed using ADHD Investigator Symptom Rating Scale (AISRS) total score. Time-to-relapse to heavy alcohol use was analyzed using a 2-sided log-rank test based on Kaplan-Meier estimates and cumulative heavy drinking events over time were evaluated post hoc with recurrent-event analysis. RESULTS: Subjects received atomoxetine (n=72) or placebo (n=75) and 80 subjects completed the 12-week double-blind period (n=32 and 48, respectively). ADHD symptoms were significantly improved in the atomoxetine cohort compared to placebo (AISRS total score mean [S.D.], atomoxetine: -13.63 [11.35], P<.001; placebo: -8.31 [11.44], P<.001, difference: P=.007; effect size=0.48). No significant differences between treatment groups occurred in time-to-relapse of heavy drinking (P=.93). However, cumulative heavy drinking days were reduced 26% in atomoxetine-treated subjects versus placebo (event ratio=0.74, P=.023). There were no serious adverse events or specific drug-drug reactions related to current alcohol use. CONCLUSIONS: This 3-month, double-blind, placebo-controlled study of atomoxetine in adults with ADHD and comorbid alcohol use disorder demonstrates clinically significant ADHD improvement, and inconsistent effects on drinking behavior.

Duloxetine versus placebo for the treatment of women with stress predominant urinary incontinence in Taiwan: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: This manuscript compares the efficacy and safety of duloxetine with placebo in Taiwanese women with SUI. METHODS: Taiwanese women with SUI were were randomly assigned to placebo (n = 61) or duloxetine 80 mg/day (n = 60) in this double-blind, 8-week, placebo-controlled study. Outcome variables included: incontinence episode frequency (IEF), Incontinence Quality of Life questionnaire (I-QOL) scores, and Patient Global Impression of Improvement rating (PGI-I). RESULTS: Decrease in IEF was significantly greater in duloxetine-treated than placebo-treated women (69.98% vs 42.56%, P < .001). No treatment differences in I-QOL scores were significant. There were significant differences in PGI-I rating. Treatment-emergent adverse events (TEAEs) were experienced by more duloxetine-treated than placebo-treated women (80.0% vs 44.3%; P < .001). Discontinuations due to adverse events were significantly greater for duloxetine-treated than placebo-treated women (26.7% vs 6.6%; P = .003). CONCLUSION: Data provide evidence for the safety and efficacy of duloxetine for the treatment for Taiwanese women with SUI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00475358.

Functional outcomes in the treatment of adults with ADHD.

OBJECTIVE: ADHD is associated with significant functional impairment in adults. The present study examined functional outcomes following 6-month double-blind treatment with either atomoxetine or placebo. METHOD: Patients were 410 adults (58.5% male) with DSM-IV-defined ADHD. They were randomly assigned to receive either atomoxetine 40 mg/day to 80 mg/day (n = 271) or placebo (n = 139). The primary functional outcome measure was the Endicott Work Productivity Scale (EWPS), and the secondary measure was the Adult ADHD Quality of Life (AAQoL). Patients were seen for four visits in 6 months. RESULTS: At 6 months, both groups had nonsignificantly different improvements in EWPS total scores. Atomoxetine-treated patients showed significantly greater improvement than placebo-treated patients on the AAQoL after controlling for baseline severity of ADHD. Both treatment groups had low 6-month study completion rates. CONCLUSION: Following 6-month treatment with atomoxetine, adults with ADHD showed significantly greater improvement in functioning on disease-specific measures of quality of life than patients treated with placebo.

Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects.

RATIONALE: Some of the behavioral consequences of deficits in N-methyl-D-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry. OBJECTIVE: This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects. METHODS: Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions. RESULTS: Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion. CONCLUSIONS: These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.

Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans.

RATIONALE: LY354740, a structural analogue of glutamate that shows specificity at the mGluR2/3 receptor, has anxiolytic effects in animal models. OBJECTIVE: This study investigated the anxiolytic effects of LY354740 in humans using the fear-potentiated startle reflex methodology. METHODS: Subjects were given either placebo (n=16), 20 mg LY354740 (n=15), or 200 mg LY354740 (n=13). The fear-potentiated startle tests examined startle potentiation to shock anticipation and to darkness. RESULTS: Consistent with previous results, startle was increased by threat of shock and by darkness. LY354740 did not affect baseline startle. Correspondingly, subjects did not report LY354740 to be sedative. LY354740 significantly reduced the increase in startle magnitude during shock anticipation, but not during darkness. Subjective reports of state anxiety and negative affectivity during the fear-potentiated startle tests were also reduced in a dose-dependent manner by LY354740. CONCLUSIONS: These results suggest that LY354740 has an anxiolytic profile in humans without being sedative.

Bioavailability Study of Nizatidine When Administered in Food.

A single-center, open-label, four-way crossover study was performed in 22 healthy adult subjects to determine the relative effect and significance of certain foods on the bioavailability of nizatidine. Results indicate that administration of nizatidine mixed with apple sauce, cranberry juice, or vegetable juice reduces the bioavailability approximately 30--40% relative to administration of a nizatidine capsule with water. The reduction of bioavailability appears to be primarily due to reduced extent of absorption. The mechanism of this effect was not investigated.

Moxonidine versus placebo as an aid in smoking cessation.

This study assessed the effects of moxonidine as an aid in smoking cessation in 166 heavily addicted smokers who were motivated to quit smoking completely. Recruitment was via advertisement. Patients were randomly allocated to receive double-blind placebo or moxonidine (0.1 mg once or twice daily) for 6 weeks. Brief counseling was provided. An encouragement letter was sent prior to the quit date. Success was defined as not smoking any cigarettes during weeks 3 - 6, an expired carbon monoxide level of < 10 ppm, and a plasma cotinine level of < 25 ng/ml. The study failed to demonstrate a statistically significant effect for moxonidine on either nicotine withdrawal symptoms or smoking cessation. Reported side effects were not different with moxonidine than with placebo, however. Copyright 2000 John Wiley & Sons, Ltd.

Atomoxetine for the treatment of attention-deficit/hyperactivity disorder and oppositional defiant disorder.

OBJECTIVE: In this study we examined the effectiveness of atomoxetine for the treatment of oppositional defiant disorder comorbid with attention-deficit/hyperactivity disorder. METHODS: Patients were aged 6 to 12 years and met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnostic criteria for attention-deficit/hyperactivity disorder with a Swanson, Nolan, and Pelham Rating Scale-Revised attention-deficit/hyperactivity disorder subscale score above age and gender norms; Clinical Global Impressions-Severity Scale score of > or = 4; and Swanson, Nolan, and Pelham Rating Scale-Revised oppositional defiant disorder subscale score of > or = 15. Patients were randomly assigned in a 2:1 ratio to receive 1.2 mg/kg per day of atomoxetine (n = 156) or placebo (n = 70) for 8 weeks. Treatment effect on oppositional defiant disorder and attention-deficit/hyperactivity disorder symptoms was measured by using the investigator-rated Swanson, Nolan, and Pelham Rating Scale-Revised. RESULTS: Repeated-measures analysis demonstrated a statistically significant difference favoring atomoxetine over placebo in the reduction of Swanson, Nolan, and Pelham Rating Scale-Revised oppositional defiant disorder total scores. There were significant pairwise treatment differences at weeks 2 and 5 but not at week 8 postbaseline. A last-observation-carried-forward analysis showed Swanson, Nolan, and Pelham Rating Scale-Revised scores at endpoint for the atomoxetine and placebo groups were significantly different for attention-deficit/hyperactivity disorder symptoms but not for oppositional defiant disorder symptoms. Atomoxetine was superior to placebo in a last-observation-carried-forward analysis of Clinical Global Impression-Improvement and Clinical Global Impression-Severity scores. CONCLUSIONS: This study confirms previous findings that patients with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder show statistically and clinically significant improvement in attention-deficit/hyperactivity disorder symptoms and global clinical functioning when treated with atomoxetine. It remains uncertain, however, whether atomoxetine exerts a specific and enduring effect on oppositional defiant disorder symptoms.

Atomoxetine versus methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial.

OBJECTIVE: To (i) test whether atomoxetine is non-inferior to methylphenidate in treating symptoms of attention deficit hyperactivity disorder (ADHD) in paediatric patients; and (ii) determine the tolerability of the two drugs. METHOD: This double-blind study was conducted in 6- to 16-year-old outpatients with ADHD (DSM-IV) in China, Korea and Mexico (January-October 2004). Patients were randomly assigned to once-daily atomoxetine (0.8-1.8 mg kg(-1) day(-1); n = 164) or twice-daily methylphenidate (0.2-0.6 mg kg(-1) day(-1); n = 166) for approximately 8 weeks. Primary efficacy assessment was the comparison of response rates (> or =40% reduction from baseline to end point in total score) on the Attention Deficit Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and -Scored. Tolerability measures included, but were not limited to, the assessment of treatment-emergent adverse events (TEAEs) and weight. RESULTS: Atomoxetine was non-inferior to methylphenidate in improving ADHD symptoms based on response rates (atomoxetine, 77.4%; methylphenidate, 81.5%; one-sided 95% lower confidence limit = -11.7%, p = 0.404). Treatment-emergent adverse effects experienced significantly more frequently in the atomoxetine group, compared with the methylphenidate group, included anorexia (37.2% vs. 25.3%; p = 0.024), nausea (20.1% vs. 10.2%; p = 0.014), somnolence (26.2% vs. 3.6%; p <0.001), dizziness (15.2% vs. 7.2%; p = 0.024) and vomiting (11.6% vs. 3.6%; p = 0.007), most of which were of mild or moderate severity. Atomoxetine-treated patients experienced a small but significantly greater mean weight loss from baseline to end point than methylphenidate-treated patients (-1.2 kg vs. -0.4 kg; p <0.001). CONCLUSIONS: This study suggests that atomoxetine is non-inferior to methylphenidate in the improvement of ADHD symptoms in paediatric outpatients. Although both of the drugs were well tolerated, atomoxetine was associated with a higher incidence of TEAEs than methylphenidate.

Long-term atomoxetine treatment in adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: To determine the efficacy and safety of atomoxetine in adolescent subjects treated for attention-deficit/hyperactivity disorder (ADHD) for up to 2 years. STUDY DESIGN: Data from 13 atomoxetine studies (6 double-blind, 7 open-label) were pooled for subjects age 12 to 18 with ADHD as defined by the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders IV. RESULTS: Of the 601 atomoxetine-treated subjects in this meta-analysis, 537 (89.4%) completed 3 months of acute treatment. A total of 259 subjects (48.4%) are continuing atomoxetine treatment; 219 of these subjects have completed at least 2 years of treatment. The mean dose of atomoxetine at endpoint was 1.41 mg/kg/day. Mean ADHD Rating Scale IV, parent version, investigator-administered and -scored total scores showed significant improvement (P < .001) over the first 3 months. Symptoms remained improved up to 24 months without dosage escalation. During the 2-year treatment period, 99 (16.5%) subjects discontinued treatment due to lack of effectiveness, and 31 (5.2%) subjects discontinued treatment due to adverse events. No clinically significant abnormalities in height, weight, blood pressure, pulse, mean laboratory values, or electrocardiography parameters were found. CONCLUSIONS: Two-year data from this ongoing study indicate that atomoxetine maintains efficacy among adolescents with ADHD, with no evidence of drug tolerance and no new or unexpected safety concerns.

The cost of treating anxiety: the medical and demographic correlates that impact total medical costs.

The purpose of this retrospective, multivariate analysis is to examine how medical conditions and demographic characteristics affect the costs of treating individuals diagnosed with anxiety. Data from MarketScan Databases [The MEDSTAT Group, 2000] were used to identify individuals with new episodes of anxiety. Multivariate analysis was used, with the dependent variable being the log of total medical costs. This analysis controlled for demographic characteristics, medical comorbidities, anxiety diagnosis, and prior resource utilization. A smearing estimate is used to calculate the total medical costs for patients with any anxiety disorder. The mean estimated total medical cost for individuals diagnosed with any anxiety disorder was $6,475. The multivariate model indicates that controlling for demographics and other disease states, generalized anxiety disorder (GAD), panic disorders, and posttraumatic stress disorder (PTSD) are associated with a $2,138, $1,603, and $3,940 increase, respectively, in the total medical cost (P < .0001). The incremental impact of depression, other anxiety disorders, and prior mental health diagnoses on the total medical costs were $1,945, $1,900, and $1,515, respectively (P < .0001). Individuals with the highest costs, and therefore the greatest need for intervention, are anxious patients with depression, individuals diagnosed with PTSD or GAD, and individuals diagnosed with both anxiety and a comorbid medical condition such as an acute myocardial infarction or diabetes.

LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress.

Metabotropic glutamate (mGlu) receptors, which include mGlu1-8 receptors, are a heterogeneous family of G-protein coupled receptors (GPCRs) that function to modulate neuronal excitation and plasticity via pre-synaptic, post-synaptic and glial mechanisms. Agonists for group II mGlu receptors (mGlu2 and mGlu3), such as LY354740, have been shown to suppress enhanced glutamatergic excitations in brain synapses known to be involved in the expression of fear/anxiety in animals and humans. Systemic administration of LY354740 increases open-arm time in the elevated plus maze in mice under conditions of moderate to severe stress, blocks the expression but not development of fear-potentiated startle in rats, prevents lactate-induced panic-like responses in panic-prone rats, and attenuates certain physiological, behavioral, and neurochemical consequences of acute stress in rodents. In these preclinical models, LY354740 does not produce the side-effects (e.g. sedation) that are associated with other anxiolytic agents such as benzodiazepines. Early clinical results with LY354740 have demonstrated safety and efficacy in a human anxiety model (panic provocation induced by CO2 challenge). Collectively, these data indicate mGlu2/3 receptor agonists such as LY354740 represent a promising new approach for treatment of anxiety and stress-related disorders in humans.