Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serotonin-dopamine antagonists (SDAs) offer the possibility of improved treatment of schizophrenia compared with conventional neuroleptics and have superior safety profiles. Clinical trial data have so far been published for only three SDAs to date, namely, risperidone, sertindole, and olanzapine. Of these, extensive data are available only for risperidone, showing that at doses of 4 to 16 mg/day, it is superior to haloperidol at 10 to 20 mg/day. Furthermore, risperidone, 6 and 16 mg/day, significantly improved negative/symptoms, whereas 20 mg/day of haloperidol was ineffective. Risperidone also appears to cause fewer extrapyrimidal symptoms (EPS) than haloperidol, 10 or 20 mg/day. Similar advantages of risperidone over perphenazine have also been found. A clinical trial of sertindole showed that, at 20 mg/day, it was equivalent to haloperidol, 16 mg/day, and caused fewer EPS. Olanzapine, a chemical derivative of clozapine, has also been shown to be superior to haloperidol (10 to 20 mg/day) at doses of 7.5 to 17.5 mg/day. In addition, at doses of 12.5 to 17.5 mg/day, olanzapine was found to have a significantly superior effect on negative symptoms over haloperidol, 10 to 20 mg/day. Doses of up to 17.5 mg/day of olanzapine also caused fewer EPS than haloperidol, 10 to 20 mg/day. There was no evidence of any leukopenia in patients treated with olanzapine in this small study (N = 335). The low EPS liability of these SDAs, combined with their efficacy, suggests that SDAs should become the mainstay of treatment for schizophrenia.
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PMID:Clinical efficacy of serotonin-dopamine antagonists relative to classic neuroleptics. 753 85

Although neuroleptic drugs have proven value in the management of patients with schizophrenia, the existing drugs are far from ideal. The pharmacological profile of olanzapine (LY 170053, Lilly) in animal models suggests that it may be an effective antipsychotic drug in humans, with the potential for a reduced incidence of desirable extra-pyramidal side effects, compared to existing neuroleptics. The results of this first investigation of olanzapine in schizophrenic patients indicate that it has efficacy as an antipsychotic compound, relieving positive and negative features of schizophrenia. Olanzapine appears to have an acceptable degree of overall tolerability, and may be associated with a low incidence of extrapyramidal tract symptoms. It does not appear to be free of adverse effects on liver function.
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PMID:First clinical experience with olanzapine (LY 170053): results of an open-label safety and dose-ranging study in patients with schizophrenia. 874 45

Compared to typical antipsychotic drugs, clozapine produces a unique pattern of Fos-like immunoreactive neurons in the rat forebrain. It has been proposed, therefore, that this approach may be useful in identifying other agents with clozapine's therapeutic profile. In the present study, we examined the ability of olanzapine to increase the number of Fos-like immunoreactive neurons in the striatum, nucleus accumbens, lateral septal nucleus, and prefrontal cortex. Olanzapine (5, 10 mg/kg) produced dose-dependent increases in the number of Fos-positive neurons in the nucleus accumbens and lateral septal nucleus, important components of the limbic system that may mediate some of the therapeutic actions of neuroleptics. Olanzapine also produced dose-dependent increases in the number of Fos-positive neurons in the dorsolateral striatum, an effect that correlates with the ability of neuroleptics to produce extrapyramidal side-effects. The effects of olanzapine on regional c-fos expression are not therefore identical to clozapine, which is without effect in the dorsolateral striatum. However, olanzapine-induced increases in the dorsolateral striatum were considerably smaller than those generated in the nucleus accumbens suggesting that at low, potentially therapeutic doses olanzapine may not generate significant extrapyramidal side effects. Olanzapine also increased the number of Fos-positive neurons in medical prefrontal cortex, an action unique to clozapine and a few other atypical antipsychotics. These findings are consistent with the hypothesis that olanzapine is an atypical antipsychotic in the sense that it does not produce significant extrapyramidal side-effects at low therapeutic doses. However, extrapyramidal side-effects at higher doses can be predicted by these results. Finally, olanzapine's actions in the medial prefrontal cortex may be predictive of a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Additional clinical experience with olanzapine and other new antipsychotics is required to test the validity of these hypotheses.
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PMID:Effects of olanzapine on regional C-Fos expression in rat forebrain. 882 33

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.
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PMID:Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. 2654 64

Prepulse inhibition (PPI) of the startle reflex provides an operational measure of sensorimotor gating. Deficits in PPI are observed in schizophrenia patients and can be modelled in animals by administration of noncompetitive NMDA antagonists such as phencyclidine (PCP) or dizocilpine (MK-801). Previous studies indicate that the atypical antipsychotic clozapine restores PPI in PCP-treated animals while the typical antipsychotic haloperidol does not. Olanzapine (LY170053) is a novel putative atypical antipsychotic that shares many pharmacological and behavioral properties with clozapine. The present study assessed the ability of olanzapine (0, 1.25, 2.5, 5.0 or 10.0 mg/kg) to antagonize deficits in PPI produced by PCP (1.5 mg/kg) and dizocilpine (0.1 mg/kg). At the two highest doses, olanzapine significantly increased PPI in PCP- and dizocilpine-treated animals without affecting PPI or baseline startle reactivity by itself. These results support the notion that olanzapine is functionally similar to clozapine and may have utility as an atypical antipsychotic agent.
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PMID:Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine. 884 37

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.
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PMID:Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. 893 12

Advances in our understanding of schizophrenia have led to a new generation of antipsychotic agents. These medications not only demonstrate reduced extrapyramidal symptoms but also possess pharmacologic profiles that can be especially advantageous in treating the negative symptoms of schizophrenia. The pharmacokinetics of many of the newer agents are compared and contrasted with typical neuroleptics. Changes in the pharmacokinetics and dosage of the newer agents are also reviewed. A particular emphasis is placed on the metabolism of the newer agents and their potential for drug-drug pharmacokinetic interactions. Clozapine, the archetypal atypical agent, has a complex pharmacokinetic profile with extremely large interpatient variability and many well-documented drug-drug interactions. Thus, clozapine presents special challenges in dose optimization and requires vigilant clinical monitoring for cardiovascular, neurologic, and hematologic adverse effects. Olanzapine demonstrates a very low potential for drug-drug interactions; it requires extremely high inhibitory concentrations at cytrochrome P450 (CYP) systems, typically 30-fold above the usual concentrations observed at steady-state oral high-dose therapy. The metabolic pathways of olanzapine include N-glucuronidation, reducing its overall sensitivity to drugs that might induce or inhibit its own metabolism via CYP or flavin-containing monooxygenase (FMO) systems. Plasma olanzapine concentrations at steady state typically demonstrate only a fourfold to fivefold variability among patients at a standard dose of medications. Sertindole and risperidone demonstrate polymorphic metabolism characteristics mirroring the CYP 2D6 phenotype. The inhibitory potentials of sertindole at CYP 2D6 and CYP 3A are modest and not likely to be of clinical significance. However, in those patients taking CYP 2D6 inhibitors or in those who are genotypic poor metabolizers, concentrations achieved by sertindole and its metabolites might result in moderate inhibition of CYP 3A.
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PMID:Pharmacokinetics and drug interactions: update for new antipsychotics. 937 97

Olanzapine is a thienobenzodiazepine derivative which displays efficacy in patients with schizophrenia and related psychoses. It has structural and pharmacological properties resembling those of the atypical antipsychotic clozapine and an improved tolerability profile compared with the classical antipsychotic haloperidol. In several large, well controlled trials in patients with schizophrenia or related psychoses, olanzapine generally 5 to 20 mg/day was at least as effective as haloperidol (5 to 20mg) and more so than placebo, as assessed by overall rating scales for psychoses. Olanzapine improved negative symptoms to a greater extent than haloperidol in 2 of 3 comparative trials, including the largest trial. Efficacy of olanzapine has a rapid onset (within 1 to 2 weeks). Its clinical benefits appear to be maintained for treatment periods of up to 1 year, as shown by analysis of the extension phase of several trials demonstrating decreased probability of hospitalisation over this period compared with haloperidol. Preliminary data suggest the drug may also improve quality of life. Olanzapine was associated with significantly fewer adverse movement disorders (e.g. akathisia, dystonia, hypertonia, extrapyramidal symptoms) than haloperidol. There have been no reports of agranulocytosis (as occurs with clozapine) or any other haemotoxicity attributed to olanzapine, and the drug has shown minimal effect on prolactin levels. Transient increases in levels of hepatic transaminases seem to be clinically important. The only events recorded more frequently during olanzapine than during haloperidol therapy were weight gain, dry mouth and increased appetite. Although the antipsychotic activity of olanzapine has been well demonstrated. Its efficacy in refractory schizophrenia and its place relative to other atypical antipsychotics remain to be determined. Nevertheless, if the long term tolerability profile of olanzapine is confirmed, the drug should provide a valuable therapeutic alternative in the management of schizophrenia and related psychoses.
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PMID:Olanzapine. A review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses. 902 46

New, so-called atypical antipsychotic medications will no doubt supplant the traditional, or "typical," antipsychotic medications, just as the new generation of antidepressant agents has replaced the older tricyclic drugs. At issue with most of the new drugs is not acute efficacy, but long-term tolerability. Side effects must be minimized to enhance compliance and prevent relapse. It appears that many of the new antipsychotic drugs have fewer or less troublesome side effects than the older agents. In addition, the "atypical" antipsychotic agents hold promise for treating refractory schizophrenia. At present, only clozapine, with its risks for agranulocytosis and seizures, is clearly established as a treatment for refractory illness. Risperidone may be an alternative for treatment-resistant schizophrenia, but this has not yet been clearly proved. Olanzapine has recently been introduced. Sertindole should be available soon, and quetiapine and ziprasidone should quickly follow. Safety, efficacy, and cost will guide their use. None of these newer agents have been compared head-to-head with clozapine. More research is needed to place these new drugs into clinical perspective.
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PMID:New antipsychotic medications: what advantages do they offer? 904 36

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.
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PMID:Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. 916


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