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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 scoresor = 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.

The purpose of this study was to compare, from the payor perspective, the clinical and economic outcomes of olanzapine to those of haloperidol for the treatment of schizophrenia.Clinical, quality-of-life and resource utilisation data were prospectively collected for US-residing patients with schizophrenia who were participating in a multicentre, randomised, double-blind clinical trial comparing olanzapine and haloperidol. Direct medical costs were estimated by assigning standardised prices (1995 values) to the resource utilisation data.817 patients with schizophrenia who had a baseline Brief Psychiatric Rating Scale score (BPRS)or = 18 (items scored 0 to 6) and/or were no longer tolerating current antipsychotic therapy.Olanzapine 5 to 20 mg/day (n = 551) or haloperidol 5 to 20 mg/day (n = 266) for 6 weeks. Patients showing a predefined level of clinical response entered a 46-week maintenance phase.After acute treatment, BPRS-based clinical improvements were seen in 38 and 27% of olanzapine and haloperidol patients, respectively (p = 0.002). Clinically important improvements on the Quality of Life Scale were achieved during acute treatment in 33% of olanzapine recipients and 25% of haloperidol recipients (p = 0.094). Olanzapine treatment in the acute phase led to significantly lower inpatient ($US5125 vs $US5795, p = 0.038) and outpatient ($US663 vs $US692, p = 0.001) costs, resulting in a significant overall reduction in mean total medical costs of $US388 (p = 0.033). This significant reduction in total costs was found despite olanzapine mean medication costs being significantly greater than haloperidol medication costs ($US326 vs $US15, p0.001). No significant differences in clinical improvement were observed in the maintenance phase. Maintenance phase olanzapine mean total medical costs were $US636 lower than haloperidol total costs (p = 0.128). Although olanzapine medication costs were significantly higher than haloperidol medication costs ($US3461 vs $US95, p0.001), this difference was offset by significantly lower inpatient ($US8322 vs $US10,662, p = 0.044) and outpatient ($US3810 vs $US5473, p = 0.038) costs.In this study, olanzapine treatment was more effective than haloperidol in producing clinical response in the acute phase. In addition, olanzapine treatment led to reductions in inpatient and outpatient costs that more than offset olanzapine's higher medication costs relative to haloperidol.

Olanzapine is a potential new "atypical" antipsychotic agent. This double-blind, acute phase study compared two doses of olanzapine [1 mg/day (Olz1.0); 10 mg/day (Olz10.0)] with placebo in the treatment of 152 patients who met the DSM-III-R criteria for schizophrenia and had a Brief Psychiatric Rating Scale (BPRS)-total score (items scored 0-6)or = 24. In overall symptomatology improvement [BPRS-total score and Positive and Negative Syndrome Scale (PANSS)-total score], Olz10.0 was statistically significantly superior to placebo. In positive symptom improvement (PANSS-positive score, BPRS-positive score), Olz10.0 was statistically significantly superior to placebo. In negative symptom improvement (PANSS-negative score), Olz10.0 was statistically superior to placebo. Olz 1.0 was clinically comparable to placebo in all efficacy comparisons. The only adverse event to show an overall statistically significant incidence difference was anorexia (reported for 10% of placebo-treated and 0% of Olz10.0-treated patients). The Olz10.0-treated patients improved over baseline with respect to parkinsonian and akathisia symptoms, and these changes were comparable with those observed with placebo. There were no dystonias associated with Olz10.0 treatment. At endpoint, the incidence of patients with elevated prolactin values did not differ statistically significantly between placebo-treated and Olz10.0-treated patients. Olanzapine appears to be not only safe and effective, but a promising atypical antipsychotic candidate.

Olanzapine is a potential new "atypical" antipsychotic agent. The double-blind acute phase of this study compared three dosage ranges of olanzapine (5 +/- 2.5 mg/day [Olz-L], 10 +/- 2.5 mg/day [Olz-M], 15 +/- 2.5 mg/day [Olz-H]) to a dosage range of haloperidol (15 +/- 5 mg/day [Hal]) and to placebo in the treatment of 335 patients who met the DSM-III-R criteria for schizophrenia. In overall symptomatology improvement (Brief Psychiatric Rating Scale [BPRS]-total), Olz-M, Olz-H, and Hal were significantly superior to placebo. In positive symptom improvement (BPRS-positive), Olz-M, Olz-H, and Hal were comparable and significantly superior to placebo. In negative symptom improvement (Scale for the Assessment of Negative Symptoms [SANS]-composite), Olz-L and Olz-H were significantly superior to placebo and Olz-H was also significantly superior to Hal. The most common treatment-emergent adverse events included somnolence, agitation, asthenia, and nervousness. No acute dystonia was observed with olanzapine. Treatment-emergent parkinsonism occurred with Olz-H at approximately one-third the rate of Hal, and akathisia occurred with Olz-H at approximately one-half the rate of Hal. Prolactin elevations associated with olanzapine were not significantly greater than those observed with placebo and were also significantly less than those seen with haloperidol.

A peripheral model for the central 5-HT neuron is the characterization of platelet imipramine binding. We studied an outpatient major depressive cohort who fulfilled Research Diagnostic Criteria for agitation. After a 1-week placebo lead-in, subjects were blindly randomized to either imipramine (IMI) of fluoxetine (FLU) during an 8-week, double-blind study period. Thirty-three subjects (15 IMI, 18 FLU) provided both baseline and endpoint samples for the platelet [3H]-IMI assay. Depression efficacy was comparable across the two treatments, whereas FLU was significantly more effective in reducing secondary anxiolysis (p = .023). Discontinuations due to an adverse event were significantly more frequent with IMI than FLU (p < .01). Baseline affinity (KD) was mildly predictive of change in the HAMD (r = -.22; p = .07). Whereas baseline to endpoint density (Bmax) changes (Δ) were similar for IMI (183 ± 329 fmol/mg) and FLU (196 ± 402 fmol/mg), a statistically significant treatment difference in ΔKD emerged (IMI -0.005 ± 0.010 pmol/ml versus FLU 0.08 ± 0.013 at p = .004). Moreover, the changes in KD and HAMD17 trended to a positive correlation among only the FLU-treated subjects (4 = 0.406, p = .095). The Clinical effects of 5-HT-based selective antidepressant may be reflected by dynamic changes in the platelet 5-HT uptake apparatus. These data suggest that the baseline confirmational status of the [3H]-IMI:5-HT transporter may reflect a "capacity" for a treatment response.

To examine whether harsh winter weather is associated with depressive symptoms, 45 healthy subjects from Minnesota were compared to 42 subjects from California near the end of the winter season. No differences in the prevalence of depressive symptoms were found between the two groups.