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Background Endogenous opioid-mediated reward pathways may play a role in the development and maintenance of alcohol dependence. This study tested whether LY2196044, an opioid receptor antagonist, in combination with medical management would reduce drinking in alcohol-dependent patients. Methods This was a multicenter, outpatient, randomized, double-blind, parallel, and placebo-controlled trial with a 16-week treatment period. Patients (N = 375) were alcohol-dependent, treatment-seeking adults. Patients were randomly assigned to once-daily LY2196044 (final doses of 125 or 250 mg/d) or placebo. DNA samples were collected at baseline. At each visit, patients underwent safety assessments, laboratory testing, efficacy measures, and medical management. Blood samples were also obtained for pharmacokinetic testing. The primary measure was the change from baseline in the percent heavy drinking days (HDD). Secondary efficacy measures were percent days abstinent per month and number of drinks per day. Results The treatment difference in change from baseline in % HDD between LY2196044 and placebo was not statistically significant (−43.02 vs. −38.72%, respectively; p = 0.12). There was a trend toward greater change from baseline in the percent days abstinent per month for the LY2196044 group compared with the placebo group (33.49 vs. 28.12%, respectively; p = 0.051). The decrease from baseline for mean number of drinks per day was statistically significantly greater in the LY2196044 group compared with the placebo group (−5.37 vs. −4.66 drinks per day, respectively; p = 0.013). LY2196044-treated patients who were dopamine receptor type 4–variable number tandem repeat L carriers had greater reductions in % HDD (p = 0.0565), increased percent days abstinent (p = 0.0496), and reduced drinks per day (p = 0.0069) than placebo-treated L carriers. The safety profile for LY2196044 appeared similar to that of other opioid antagonists. Conclusions The results from this proof-of-concept clinical trial warrant further evaluation of LY2196044 for the treatment of alcohol dependence.

The origin of modern psychopharmacology can be traced to the discovery of the first clinically efficacious antipsychotic drug, chlorpromazine, in 1952. Following this watershed advance, several additional antipsychotic agents of the same (i.e., phenothiazine) class, as well as others derived from the butyrophenone scaffold (e.g., haloperidol, 1958), were discovered and widely utilized in the treatment of schizophrenia patients. Arvid Carlsson and his colleagues were the first to show that antipsychotics of both the phenothiazine and butyrophenone classes acted via blockade of dopamine (DA) receptors [1]. This hypothesis was further refined over a decade later by observations that all antipsychotic drugs potently block dopamine D2-like receptors [2, 3]. Interest in moving to mechanisms of antipsychotic action other than dopamine D2

Objective To determine the effect of intramuscular (IM) olanzapine in severely agitated patients. Methods This was an open-label multicenter 1-week observational study of IM olanzapine treatment in severely agitated inpatients and psychiatric emergency services with bipolar mania (n = 22) or schizophrenia (n = 52). Mean change from baseline to 2 h post-first injection (LOCF) in agitation was assessed by PANSS-Excited Component (PANSS-EC) (score range: 5–35 points) mean change from baseline to 15, 30, 45, 60, 90, and 120 min post-first injection, and visit-wise mean changes from mixed-model repeated measures analysis of variance. Kaplan–Meier survival curve analyses estimated time to categorical response (rating of ≤3 points each PANSS-EC item). Results Two hours post-injection of olanzapine (mean dose = 9.9 mg), patients exhibited mild calmness and agitation was significantly reduced by 19.2 ± 1.0 points (p

Objective Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available.Method Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine 11, receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed.Results and Conclusion In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction Of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patterns of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some type, of neurodegenerative disorders. Copyright (C) 2001 John Wiley Sons, Ltd.

Our objective was to compare lipid profiles of schizophrenic patients treated with conventional antipsychotics or risperidone to those of patients switched to olanzapine. Our results indicate that in patients switched to olanzapine, fasting serum lipids initially increased then returned to pretreatment levels, and endpoint lipid levels were not significantly different from those in patients remaining on conventional antipsychotics or risperidone.

The aim of this study was to determine the prevalence of osteopenia in schizophrenic patients with hyperprolactinemia and to identify factors influencing bone density. Our results indicate that low bone mineral density was highly prevalent in a chronic psychiatric population treated with prolactin-elevating antipsychotics. Identified risk factors appear to be age and hyperprolactinemia for both females and males.

Although considerable controversy remains as to the etiology and pathophysiology of tardive dyskinesia, epidemiologic evidence is compelling in supporting the role of neuroleptics as a major factor in the development of this syndrome. Current evidence suggests that tardive dyskinesia is a heterogeneous condition in terms of nature of onset, phenomenology, course, and response to specific treatments or pharmacologic probes. The point prevalence of tardive dyskinesia varies widely depending on the nature of the patient population and the criterion utilized to identify a “case.” The incidence of tardive dyskine-sia among relatively young patients of varying diagnoses exposed to neuroleptics appears to be approximately 3–4% per year of cumulative neuroleptic exposure, at least for the first 6 years of such treatment. Age, vulnerability to acute extrapyramidal side effects, and a diagnosis of affective illness appear to be associated with increased risk of tardive dyskinesia development. There is clearly a need to take this aspect into consideration for new drug developments.