Ziprasidone: efficacy, tolerability, and emerging data on wide-ranging effectiveness.
ABSTRACT Ziprasidone is the fifth atypical antipsychotic to become available in the US market. This compound is a serotonin-dopamine-receptor antagonist, with greater affinity for the 5-HT(2A) receptor than the dopamine D2 receptor. Similar to aripiprazole, this compound also has agonist activity at the serotonin 5-HT(1A) receptor. This affinity has the potential to have particularly beneficial effects on cognitive and affective abnormalities in schizophrenia. Oral and short-acting intramuscular formulations are available. This compound has recently been approved for the treatment of acute mania as well as for schizophrenia. Ziprasidone is associated with low weight gain and a low potential to change lipid and glucose levels. Long-term tolerability data have indicated that initial concerns regarding QTc (corrected cardiac output) prolongation are not a major issue. Recent data have indicated that this compound has short-term antipsychotic efficacy that is equivalent to other members of the class, also with evidence of cognitive enhancement. Finally, longer term data has indicated that ziprasidone is successful in the prevention of relapse and has sustained cognitive benefits. Several issues remain to be addressed, including the efficacy of once-daily dosing, the need to take the medication with food, and the correct dosing strategy.
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ABSTRACT: Treatment with second-generation antipsychotics (SGAs) has been associated with weight gain and the development of diabetes mellitus, although the mechanisms are unknown. We tested the hypothesis that SGAs exert direct cellular effects on insulin action and substrate metabolism in adipocytes. We utilized two cultured cell models including 3T3-L1 adipocytes and primary cultured rat adipocytes, and tested for effects of SGAs risperidone (RISP), clozapine (CLZ), olanzapine (OLZ), and quetiapine (QUE), together with conventional antipsychotic drugs butyrophenone (BUTY), and trifluoperazine (TFP), over a wide concentration range from 1 to 500 microM. The effects of antipsychotic drugs on basal and insulin-stimulated rates of glucose transport were studied at 3 h, 15 h, and 3 days. Both CLZ and OLZ (but not RISP) at doses as low as 5 microM were able to significantly decrease the maximal insulin-stimulated glucose transport rate by approximately 40% in 3T3-L1 cells, whereas CLZ and RISP reduced insulin-stimulated glucose transport rates in primary cultured rat adipocytes by approximately 50-70%. Conventional drugs (BUTY and TFP) did not affect glucose transport rates. Regarding intracellular glucose metabolism, both SGAs (OLZ, QUE, RISP) and conventional drugs (BUTY and TFP) increased basal and/or insulin-stimulated glucose oxidation rates, whereas rates of lipogenesis were increased by CLZ, OLZ, QUE, and BUTY. Finally, rates of lipolysis in response to isoproterenol were reduced by the SGAs (CLZ, OLZ, QUE, RISP), but not by BUTY or TFP. These experiments demonstrate that antipsychotic drugs can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. However, only SGAs were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. Thus, SGAs directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. These effects of SGAs on adipocytes could explain, in part, the association of SGAs with weight gain and diabetes.Neuropsychopharmacology 05/2007; 32(4):765-72. DOI:10.1038/sj.npp.1301142 · 7.83 Impact Factor
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ABSTRACT: Delusional disorder is an uncommon mental illness with an estimated prevalence of 0.03%. Its low prevalence has likely contributed to the paucity of research interest in this area, leading to substantial gaps in knowledge concerning its treatment and management. In the absence of a robust literature, most clinicians rely on their experience and guidelines for treating schizophrenia when treating patients with delusional disorder. This article reviews the available literature that is specific to the treatment of delusional disorder. In addition, it focuses on specific forensic and medicolegal aspects of managing patients with delusional disorder.Behavioral Sciences & the Law 05/2006; 24(3):351-67. DOI:10.1002/bsl.683 · 0.96 Impact Factor
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ABSTRACT: As cognitive impairments are related to deficits in everyday functioning in schizophrenia, treatment of these impairments may have the potential to reduce these functional deficits. To determine if treatments truly reduce cognitive impairment, it is important to discriminate direct cognitive effects of treatment from generalized treatment benefits on the multiple clinical dimensions of schizophrenia. Thus, this study used a database from an existing clinical trial and examined the relationships between changes in clinical symptoms and cognitive deficits with several different strategies. Two hundred and seventy stable but symptomatic outpatients with schizophrenia entered a study where they were switched from previous treatment to open-label ziprasidone. The present data are from the 6-month endpoint (n=184). Patients were examined at baseline and the 6-month endpoint with ratings of clinical symptoms based on the Positive and Negative Syndrome Scale (PANSS) and a neuropsychological (NP) assessment battery including aspects of cognitive functioning known to be related to functional outcome in schizophrenia. Changes on the individual PANSS items and NP test scores were examined with two separate principal components analyses, revealing four dimensions of clinical change (psychosis, negative symptoms, affective symptoms, and agitation) and two dimensions of NP improvement. Pearson correlations between changes in the (1) factors derived from the analyses, (2) individual NP items based the four clinical dimensions of change, and (3) the 30 PANSS items and the two NP dimensions of change suggested minimal relationships (largest r=0.15). This sample was selected because previous findings suggested that clinical and NP symptoms of schizophrenia significantly improved from baseline after a switch to ziprasidone treatment. While four dimensions of change in clinical symptoms and two dimensions of cognitive improvements were identified, clinical changes, regardless of how they were defined, were not related to NP improvements.Psychopharmacology 09/2006; 187(3):356-63. DOI:10.1007/s00213-006-0432-1 · 3.99 Impact Factor