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)

Ziprasidone (Geodon, Zeldox), a recently approved atypical antipsychotic agent for the treatment of schizophrenia, undergoes extensive metabolism in humans with very little (<5%) of the dose excreted as unchanged drug. Two enzyme systems have been implicated in ziprasidone metabolism: the cytosolic enzyme, aldehyde oxidase, catalyzes the predominant reductive pathway, and cytochrome P4503A4 (CYP3A4) is responsible for two alternative oxidation pathways. The involvement of two competing pathways in ziprasidone metabolism greatly reduces the potential for pharmacokinetic interactions between ziprasidone and other drugs. Because CYP3A4 only mediates one third of ziprasidone metabolism, the likelihood of interactions between ziprasidone and CYP3A4 inhibitors/ substrates is low. Furthermore, aldehyde oxidase activity does not appear to be altered when drugs or xenobiotics are coadministered. Aldehyde oxidase, a molybdenum-containing enzyme, catalyzes the oxidation of N-heterocyclic drugs such as famciclovir and zaleplon, in addition to reducing some agents such as zonisamide. Both reactions can occur simultaneously. Although in vitro inhibitors of aldehyde oxidase have been identified, there are no reported clinical interactions with aldehyde oxidase inhibitors or inducers. There is no evidence of genetic polymorphism in aldehyde oxidase, and thus it not surprising that ziprasidone exposure demonstrates unimodality in humans. Aldehyde oxidase is unrelated to the similarly named enzyme aldehyde dehydrogenase, which is predominantly responsible for the oxidation of acetaldehyde during ethanol metabolism. Consequently, it is unlikely that there would be any pharmacokinetic interaction between ethanol and ziprasidone.
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PMID:Ziprasidone metabolism, aldehyde oxidase, and clinical implications. 1523 43

Choosing among the atypical antipsychotics currently available for the treatment of schizophrenia requires the clinician to evaluate the relative merits of each agent. Ziprasidone is another atypical antipsychotic, currently under consideration for approval to use in clinical practice, whose role is at present unclear. Based upon the information reviewed here, ziprasidone is an agent which possesses the preclinical and clinical attributes which characterize an "atypical" antipsychotic and is an effective antipsychotic medication for the treatment of psychosis. Ziprasidone appears to discriminate from other atypical antipsychotics by its low propensity for weight gain and by the availability of a short-acting intramuscular formulation. Its role in clinical practice will be determined by clinician experience and by additional phase IV clinical trials.
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PMID:Ziprasidone: pharmacology, clinical progress and therapeutic promise. 1284 82

Schizophrenia is a highly complex disorder characterized by a diversity of symptoms, psychotic and nonpsychotic, that most likely arise from heterogeneous neuroanatomical and neurochemical malfunctions. As with all antipsychotic agents, ziprasidone targets the key hypothetical neurochemical disturbance in psychosis-excessive dopamine neurotransmission at dopamine D2 receptors in the mesolimbic pathway of the brain-presumably responsible for the positive symptoms of schizophrenia. Like other atypical antipsychotic agents, ziprasidone is a serotonin-2A (5-HT2A)/dopamine D2 antagonist; however, its in vitro 5-HT2A/D2 receptor affinity ratio is higher than that of the other first-line atypical antipsychotic agents (namely, risperidone, olanzapine, quetiapine, and aripiprazole). Ziprasidone also exhibits potent interaction with 5-HT2C, 5-HT1D, and 5-HT1A receptors in human brain tissue, characteristics that predict heightened negative symptom relief, enhanced modulation of mood, cognitive improvement, and reduced motor dysfunction. Ziprasidone has moderate affinity for serotonin and norepinephrine reuptake sites, predicting antidepressant/anxiolytic activity. On the other hand, ziprasidone's low affinity for alpha1-adrenoceptors, as well as histamine H1 and muscarinic M1 receptors, suggests that patients should experience relatively little orthostatic hypotension, sedation, cognitive disturbance, weight gain, or dysregulation of prolactin levels. Efficacy and tolerability data from trials to date indicate that ziprasidone's clinical activity is consistent with its receptor profile.
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PMID:The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. 1759 32

The appropriate management of schizophrenia and schizoaffective disorder requires effective, safe antipsychotic agents for use across a continuum of treatment, from control of acute psychotic episodes to prevention of relapse. Intramuscular (IM) formulations are the method of choice for administering antipsychotics to schizophrenic patients who require emergency treatment but cannot take oral medication. Atypical antipsychotics are now widely acknowledged as the first-line choice for the management of patients with schizophrenia. However, use of these agents in acutely agitated psychotic patients has been limited by the lack of an IM formulation. Ziprasidone is the first, and currently only, atypical antipsychotic to be available in a rapid-acting IM formulation. This review focuses on studies evaluating the efficacy and tolerability of IM ziprasidone. In agitated psychotic patients, IM ziprasidone reduces agitation as early as 15 minutes after administration, with improvement sustained for > or = 4 hours. In patients with acute psychosis, with or without agitation, IM ziprasidone has been demonstrated to be superior to IM haloperidol in improving overall symptom severity. During the critical IM-to-oral transition, efficacy and tolerability are maintained with ziprasidone. IM ziprasidone represents an important advance over older, conventional IM agents in the treatment of the acutely ill patient with schizophrenia.
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PMID:Intramuscular ziprasidone: moving beyond the conventional in the treatment of acute agitation in schizophrenia. 1472 85

Reducing the risk of relapse and maintaining symptom control are core goals in the long-term treatment of patients with schizophrenia or schizoaffective disorder because symptom control can allow patients and clinicians to focus on functional improvement. The atypical antipsychotic agents have gained widespread acceptance in this setting because they are at least as effective as the conventional antipsychotic agents, may offer an advantage in relapse prevention, and offer safety advantages, primarily a reduced liability for movement disorders. However, there are differences among the atypical agents that may affect both clinician choice and patient adherence to long-term therapy. Ziprasidone has shown long-term antipsychotic efficacy in comparisons with haloperidol, olanzapine, and risperidone, as well as efficacy in patients switched from another antipsychotic agent. This review examines symptom efficacy data for ziprasidone in long-term trials that lasted between 28 and 52 weeks. Antipsychotic medication is the foundation of long-term treatment of schizophrenia. Optimization of treatment for the individual patient requires consideration of symptom control, prevention of relapse, and possible long-term health consequences. Clinical trial data on ziprasidone's long-term efficacy provide a firm basis for selection of this agent.
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PMID:Maintaining symptom control: review of ziprasidone long-term efficacy data. 1472 87

Ziprasidone is an atypical antipsychotic that is approved for the treatment of adults with schizophrenia. To date, only a limited number of studies have been published on the use of ziprasidone for treating neuropsychiatric conditions in children and adolescents. This report describes ziprasidone treatment of two adolescents with severe psychotic illness who had unsuccessful trials of alternative antipsychotic medications. These patients presented with hallucinations and grossly disorganized speech and behavior. Further study is needed to determine if these findings can be generalized.
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PMID:Ziprasidone treatment of two adolescents with psychosis. 1514 1

Many psychiatric illnesses, including chronic schizophrenia, bipolar disorder, and dementia, are characterized by episodes of acute agitation, making administration of oral agents difficult or impossible. Ziprasidone, the first atypical antipsychotic available in both intramuscular (IM) and oral formulations, has demonstrated significant control of acute agitation within 15 minutes, as seen in two 24-hour studies in patients with schizophrenia. Improvement was maintained for > or = 4 hours, and a low incidence of extrapyramidal symptoms, akathisia, and dystonia as well as no excessive sedation were observed Also, two 7-day studies (n = 132 and n = 306) and one 6-week study (n = 567) of sequential IM/oral ziprasidone versus IM/oral haloperidol in patients with psychotic disorders found IM ziprasidone more effective than IM haloperidol within 3 days of IM treatment; both drugs produced further comparable improvements in efficacy parameters after transition to oral therapy. IM ziprasidone was associated with a lower incidence of movement disorders than was haloperidol in all of these studies. Overall, discontinuations were similar for IM ziprasidone and haloperidol in the comparative trials, including the sequential IM/oral studies. However, in the 6-week sequential IM/oral trial, the rate of discontinuation due to adverse events was twice as high among haloperidol vs ziprasidone patients. This report focuses on the pharmacology, clinical efficacy, and tolerability of IM ziprasidone, and provides an overview of the utility of other commonly used antipsychotics in the management of acute psychotic agitation.
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PMID:The utility of intramuscular ziprasidone in the management of acute psychotic agitation. 1551 47

Evidence on the efficacy and safety of atypical antipsychotics in children and adolescents with schizophrenia is limited. The purpose of this review is to assess the published data on the use of atypical antipsychotics in children and adolescents with schizophrenia alone and with comorbid disorders, and to establish benefit-risk guidelines for clinicians.Risperidone, olanzapine and clozapine were found to be effective in the treatment of aggression and mania. Risperidone, and possibly also olanzapine, may be the drugs of choice in children with comorbid tic disorders. Ziprasidone has some monoamine reuptake inhibition properties and may be administered as an augmenting agent in children and adolescents with schizophrenia and comorbid anxiety and mood disorders. Compared with the typical antipsychotics, the atypical drugs seem to be more effective, better tolerated and lead to better patient adherence. Importantly, the atypical antipsychotics have a lower propensity to induce extrapyramidal symptoms and a potential (shown so far only in adults) to improve cognitive function and inhibit suicidal behaviour (especially clozapine). Yet, the adverse effects associated with these agents, especially weight gain, which may also have long-term effects, can lead to non-compliance in the young population. In children and adolescents receiving clozapine, olanzapine and quetiapine (but not ziprasidone, which does not have a pro-appetite effect), particularly those with obesity or a family history of diabetes mellitus, fasting blood glucose and lipid levels must be monitored frequently. Weight gain might be better controlled when the children and their parents are properly informed about this adverse effect and diet is regulated. Another major disadvantage of the atypical antipsychotics, especially risperidone, is their association with hyperprolactinaemia, which can lead to hypogonadism-induced osteoporosis, galactorrhoea, gynaecomastia, irregular menstruation and sexual dysfunction, all seen also with typical antipsychotics. Other atypical antipsychotics, namely olanzapine and ziprasidone, have been reported to be prolactin sparing in adults, but may not be completely devoid of hyperprolactinaemic effects in children and adolescents. Thus, prolactin levels should be assessed routinely in young patients treated with atypical antipsychotics. Further, children and adolescents with hyperprolactinaemia-related effects should be switched to a prolactin-sparing agent, such as quetiapine. All atypical antipsychotics may induce sedation and they are not devoid of extrapyramidal symptoms (especially risperidone). The use of typical antipsychotics has been limited to patients who are resistant to atypical antipsychotics, intolerant to their adverse effects, or require injections or depot preparations. Further double-blind, placebo-controlled trials and long-term safety assessments are needed before definitive conclusions can be reached about the place of atypical antipsychotics in the therapeutic armamentarium of childhood-onset schizophrenia.
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PMID:Benefit-risk assessment of atypical antipsychotics in the treatment of schizophrenia and comorbid disorders in children and adolescents. 1555 47

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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PMID:Ziprasidone: efficacy, tolerability, and emerging data on wide-ranging effectiveness. 1575 29

Ziprasidone (Geodone), a novel atypical antipsychotic agent, is recently approved for the treatment of schizophrenia. It undergoes extensive metabolism in preclinical species and humans after oral administration, and only a very small amount of administered dose is excreted as unchanged drug. In vitro studies using human liver microsomes have shown that the oxidative metabolism of ziprasidone is mediated primarily by CYP3A4. However, coadministration of ziprasidone with ketoconazole, a CYP3A4 inhibitor, showed only a modest increase in its exposure. Therefore, in vitro metabolism of ziprasidone was investigated in hepatic cytosolic fractions to further understand its clearance mechanisms in preclinical species and humans. The major metabolite from incubation of ziprasidone in cytosolic fractions of rat, dog, and human was characterized by liquid chromatography-tandem mass spectrometry and found to be the product of reductive cleavage. Derivatization and hydrogen/deuterium exchange were used to deduce that the addition of two hydrogen atoms had occurred at the benzisothiazole moiety. Further studies to determine the enzyme involved in the formation of this metabolite are currently in progress. The identification of this novel metabolite in cytosol has clarified the clearance mechanism of ziprasidone in humans and preclinical species.
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PMID:Characterization of a novel metabolite intermediate of ziprasidone in hepatic cytosolic fractions of rat, dog, and human by ESI-MS/MS, hydrogen/deuterium exchange, and chemical derivatization. 1582 Oct 46


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