| 1 | J Clin Psychiatry 2001 Oct 62: 812-7 |
|---|---|
| PMID | 11816871 |
| Title | Repeated ingestion of grapefruit juice does not alter clozapine's steady-state plasma levels, effectiveness, and tolerability. |
| Abstract | Grapefruit juice can inhibit the gastrointestinal activity of cytochrome P450 (CYP) 3A4, while its effect on CYP1A2 remains controversial. Several grapefruit juice bioflavonoids also modulate the activity of the drug transporter P-glycoprotein in the gut and in the blood-brain barrier. Both CYP1A2 and CYP3A4 are involved in clozapine metabolism. This study investigated the effects of repeated ingestion of grapefruit juice on multiple-dose pharmacokinetics and pharmacodynamics of clozapine in schizophrenic patients. Clozapine therapy was initiated for fifteen treatment-resistant schizophrenic inpatients (DSM-IV criteria). The doses were individually titrated from day -35 to day -15 and then kept unchanged from day -14 to day 49. Regular-strength grapefruit juice (250 mL) was coadministered b.i.d. with each clozapine dose from day 15 to day 28. Plasma levels of clozapine and its main metabolites (norclozapine and clozapine N-oxide) were obtained, and clinical efficacy and safety assessments were completed prior to juice administration (days 0, 7, and 14), during the coadministration (days 17, 21, and 28), and after cessation of the juice (days 35, 42, and 49). After reaching steady states, plasma concentrations of clozapine and its metabolites and Positive and Negative Syndrome Scale scores were not significantly altered by the effect of grapefruit juice ingestion. The Clinical Global Impressions scale scores, Calgary Depression Scale scores, and side effect profiles (by the Extrapyramidal Symptom Rating Scale, the UKU Side Effect Rating Scale, and thorough examinations including electrocardiography and electroencephalography) also remained constant during the study. Consumption of regular-strength grapefruit juice, 250 mL b.i.d., for 14 days did not significantly impact clozapine metabolism, clinical efficacy, or tolerability. One reason is that enzymes other than CYP3A4 also mediate clozapine disposition. Also, grapefruit juice inhibits CYP3A4 in the gut, but not in the liver. The preliminary results also suggest that clozapine is unlikely to be a P-glycoprotein substrate. Further rigorous studies are necessary to reconfirm these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | J Clin Psychopharmacol 2001 Aug 21: 408-16 |
| PMID | 11476125 |
| Title | An evaluation of risperidone drug interactions. |
| Abstract | Risperidone, an atypical antipsychotic drug, is widely used in the treatment of psychoses associated with schizophrenia, Alzheimer's disease, and other psychiatric disorders. Polypharmacology is a necessary condition for the optimal treatment of many patients with comorbid psychiatric and medical illness. One concern raised by the widespread use of multiple concurrent pharmacotherapies is the potential for drug-drug interactions to adversely affect patient outcome. Accordingly, the biomedical literature was reviewed for reports of drug interactions involving risperidone, and the clinical significance of each report was evaluated. Additionally, the potential for risperidone to participate in drug interactions was evaluated by considering the drug's pharmacokinetic properties. Controlled studies and case reports indicate that risperidone has a low potential for metabolic drug interactions. Drugs that inhibit cytochrome P450 (CYP) 2D6 or induce or inhibit CYP3A4 may alter risperidone plasma concentrations, but the clinical significance of such interactions seems to be minimal. Adherence to a few guidelines for the design of dosage regimens should limit the effect of drug-drug interactions on patient status and contribute to optimal pharmacotherapy with risperidone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Br J Clin Pharmacol 2001 Sep 52: 265-71 |
| PMID | 11560558 |
| Title | Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients. |
| Abstract | This study was carried out to evaluate the influence of CYP2D6 genotype on the steady state plasma concentrations of haloperidol and reduced haloperidol in Korean schizophrenic patients. One hundred and twenty Korean schizophrenic patients treated with various, clinically determined, doses of haloperidol (range 3-60, median 20 mg day-1) during monotherapy were recruited. CYP2D6 genotypes were determined by analysis of the CYP2D6*10 allele using allele-specific PCR and the CYP2D6*5 allele by long-PCR. Steady state plasma concentrations of haloperidol and reduced haloperidol were analysed by h.p.l.c. Twenty-three (19.2%), 60 (50.0%), 1 (0.8%), 33 (27.5%) and 3 patients (2.5%) possessed the CYP2D6 genotypes *1/*1, *1/*10, *1/*5, *10/*10 and *10/*5, respectively. The allele frequencies of CYP2D6*1, *10 and *5 were 44.6%, 53.8% and 1.7%, respectively. Significant relationships between dose and plasma concentrations of haloperidol (linear; r2 = 0.60, P < 0.0001) and reduced haloperidol (quadratic equation; r(2) = 0.67) were observed. Overall, the concentrations normalized for dose (C/D) of haloperidol were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups (one-way ANOVA; P = 0.028). No significant differences between the genotype groups were found with respect to the C/D of reduced haloperidol (P = 0.755). However, in patients with daily doses less than 20 mg, significant differences in the C/D of haloperidol (P = 0.003), but not of reduced haloperidol, were found between the three major genotype groups. In patients with doses higher than 20 mg, no differences were found between the genotype groups for either haloperidol or reduced haloperidol. 68 patients (57%) used benztropine, an antimuscarinic agent. All four patients with a *5 allele (one together with *1 and three with *10) were found to use benztropine. The patients homozygous for the *1 allele seemed to need less benztropine than the patients with one or two mutated alleles (Fisher's exact test; P = 0.036). The dose-corrected steady state plasma concentrations of haloperidol, but not of reduced haloperidol, were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups when doses lower than 20 mg haloperidol were given. No differences were found at higher doses. These results suggest the involvement of CYP2D6 in the metabolism of haloperidol at low doses of haloperidol (< 20 mg daily), while another enzyme, probably CYP3A4, contributes at higher doses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Drug Metabol Drug Interact 2001 -1 18: 263-78 |
| PMID | 11791889 |
| Title | Lack of CYP3A4 inhibition by grapefruit juice and ketoconazole upon clozapine administration in vivo. |
| Abstract | The drug-food and drug-drug interaction between grapefruit juice (GFJ) and ketoconazole (KETO) was evaluated in schizophrenic patients given a single dose of clozapine (CLZ). CLZ is metabolized primarily by CYP isozymes 3A4 and 1A2 to two principal metabolites, desmethylclozapine (DCLZ) and clozapine N-oxide (CNO). GFJ and KETO are well known potent CYP 3A4 inhibitors in the gastrointestinal tract and hepatic isozymes, respectively. Twenty-one schizophrenic patients participated in the co-administration of CLZ 50 mg and GFJ. After a one-week washout, five patients were given double the GFJ (HGFJ) dose for 7 consecutive days. In another group of five patients, ketoconazole (KETO) 400 mg was given for 7 consecutive days. At the end of the 7-day period for both groups, CLZ was coadministered with the HGFJ and KETO groups. CLZ, DCLZ and CNO were assayed by HPLC. GFJ, HGJF and ketoconazole failed to significantly change CLZ disposition. Metabolites DCLZ and CNO concentrations remained unchanged during the study. The only exception was decreased Cmax in DCLZ and CNO concentrations. These results indicate that CYP 3A4 inhibition may not be clinically significant compared to CYP 1A2, as previous studies show a dramatic increase in CLZ plasma concentrations with fluvoxamine (CYP 1A2 inhibitor). The reasons for the lack of drug-food and drug-drug interactions with CLZ and CYP 3A4 inhibitors can be explained by the higher Ki values for gastrointestinal and hepatic CYP 3A4 isozymes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Curr Opin Investig Drugs 2002 Jul 3: 1073-80 |
| PMID | 12186270 |
| Title | New antipsychotic agents for schizophrenia: pharmacokinetics and metabolism update. |
| Abstract | The so-called atypical antipsychotics undergo extensive metabolism, except for amisulpride, which is substantially excreted unchanged. Risperidone is oxidized by CYP2D6/CYP3A4 and iloperidone is reduced by cytosolic enzymes, although CYP1A2, CYP2E1 and CYP3A4 are involved as well. Olanzapine is both conjugated and oxidized (mainly by CYP1A2), while quetiapine and zotepine primarily undergo CYP3A4-mediated oxidation. Ziprasidone pathways include aldehyde oxidase-mediated reduction and CYP3A4-mediated oxidation. The main metabolites of risperidone, zotepine and possibly perospirone and ziprasidone contribute to the parent drug's effect. Information is limited, however, on some promising antipsychotics in the pipeline. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Pharmacogenomics 2002 Mar 3: 201-18 |
| PMID | 11972442 |
| Title | Cytochrome P450 polymorphisms and response to antipsychotic therapy. |
| Abstract | Antipsychotic drugs are used for the treatment of schizophrenia and other related psychotic disorders. The antipsychotics currently available include older or classical compounds and newer or atypical agents. Most antipsychotic drugs are highly lipophilic compounds and undergo extensive metabolism by cytochrome P450 (CYP) enzymes in order to be excreted. There is a wide interindividual variability in the biotransformation of antipsychotic drugs, resulting in pronounced differences in steady-state plasma concentrations and, possibly, in therapeutic and toxic effects, during treatment with fixed doses. Many classical and some newer antipsychotics are metabolized to a significant extent by the polymorphic CYP2D6, which shows large interindividual variation in activity. Other CYPs, especially CYP1A2 and CYP3A4, also contribute to the interindividual variability in the kinetics of antipsychotics and occurrence of drug interactions. No relationship between CYP2D6 genotype or activity and therapeutic effects of classical antipsychotic drugs has been found in the few studies performed. On the other hand, some investigations suggest that poor metabolizers (PMs) of CYP2D6 would be more prone to over-sedation and, possibly, Parkinsonism during treatment with classical antipsychotics, while other studies, mostly retrospective, have been negative or inconclusive. For the newer antipsychotics, such data are lacking. To date, CYP2D6 phenotyping and genotyping appear, therefore, to be clinically useful for dose predicting only in special cases and for a limited number of antipsychotics, while their usefulness in predicting clinical effects must be further explored. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | J Clin Psychopharmacol 2002 Aug 22: 419-23 |
| PMID | 12172343 |
| Title | Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction. |
| Abstract | The effect of fluoxetine on the steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was evaluated in 10 patients with schizophrenia or schizoaffective disorder. Patients stabilized on risperidone (4-6 mg/day) received additional fluoxetine (20 mg/day) to treat concomitant depression. One patient dropped out after 1 week due to the occurrence of akathisia associated with markedly increased plasma risperidone concentrations. In the other subjects, mean plasma concentrations of risperidone increased during fluoxetine administration from 12 +/- 9 ng/mL at baseline to 56 +/- 31 at week 4 (p < 0.001), while the levels of 9-OH-risperidone were not significantly affected. After 4 weeks of combined treatment, the levels of the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) increased by 75% (range, 9-204%, p < 0.01) compared with baseline. The mean plasma risperidone/9-OH-risperidone ratio also increased significantly. During the second week of adjunctive therapy, two patients developed Parkinsonian symptoms, which were controlled with anticholinergic medication. These findings indicate that fluoxetine, a potent inhibitor of the cytochrome P450 enzyme CYP2D6 and a less potent inhibitor of CYP3A4, reduces the clearance of risperidone by inhibiting its 9-hydroxylation or alternative metabolic pathways. This interaction may lead to toxic plasma risperidone concentrations. In addition to careful clinical observation, monitoring plasma risperidone levels may be of value in patients given adjunctive therapy with fluoxetine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Ann Pharmacother 2002 May 36: 839-51 |
| PMID | 11978164 |
| Title | Ziprasidone: the fifth atypical antipsychotic. |
| Abstract | To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of ziprasidone as a treatment for schizophrenia. Information was selected from a MEDLINE search (July 2000-October 2001) of English-language medical literature using ziprasidone as the search term. Manual searches of pertinent journal article references, request for medical information from Pfizer, and access of the Web site of the Food and Drug Administration were also performed. All available published information regarding the pertinent characteristics of ziprasidone were considered for selection. Pharmacology and pharmacokinetic studies were selected to provide a comprehensive description of these characteristics. Clinical investigations were evaluated for design, sample size, diagnosis, duration, and outcome. Data from all investigations were selected by 1 author and reviewed by both authors. Ziprasidone is a benzisothiazolyl piperazine-type atypical antipsychotic that shares the serotonin(2A)/dopamine(2) (5-HT(2A)/D(2)) profile of the available atypical antipsychotics. Ziprasidone has demonstrated in vitro activity as a 5-HT(1A) receptor agonist and as a very weak inhibitor of serotonin and norepinephrine reuptake. These data do not support ziprasidone as being a clinically meaningful inhibitor of serotonin/norepinephrine reuptake. Oral bioavailability of ziprasidone taken with food is approximately 60%, half-life is approximately 6-7 hours, and protein binding is extensive at >99%. Twelve metabolites have been identified, yet only 4 of these are considered to be primary metabolites. Metabolism of ziprasidone by aldehyde oxidase produces its only metabolite with potential pharmacologic activity; CYP3A4 also contributes to the metabolism of ziprasidone. Clinical studies support ziprasidone as efficacious for the treatment of patients with acute exacerbations of schizophrenia or schizoaffective disorder. Daily doses permitted in these clinical trials ranged from 40 to 160 mg, but only doses between 120 and 160 mg/d have been superior to placebo. Future research efforts should be directed toward refractory schizophrenia, cognitive impairment in schizophrenia, affective and anxiety symptoms associated with schizoaffective disorder, and bipolar disorder. Adverse effect characteristics of ziprasidone commonly include headache, nausea, and somnolence; infrequent effects include extrapyramidal symptoms and weight gain. Ziprasidone has been reported to cause an average QTc prolongation of approximately 20 msec; there have only been 2 patients (0.06%) reported by the manufacturer to have a measured QTc interval >500 msec. Ziprasidone is a safe and efficacious atypical antipsychotic for the acute management of schizophrenia. Efficacy data and most safety data for ziprasidone support its use as a first-line treatment for schizophrenia; however, its potential effects on ventricular repolarization relegate it to second-line status in patients with comorbid cardiovascular risks. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Drug Metab. Dispos. 2003 Jan 31: 60-6 |
| PMID | 12485954 |
| Title | Differences in cytochrome P450 forms involved in the metabolism of N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a novel sigma ligand, in human liver and intestine. |
| Abstract | N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100) has been developed to treat subjects with schizophrenia. This drug is mainly excreted in the form of oxidative metabolites. In the present study, identification of p450 forms involved in the metabolism was carried out using human livers and intestinal microsomes (HLM and HIM). Eadie-Hofstee plots for NE-100 disappearance in HLM were biphasic, thus indicating the involvement of at least two p450 forms. The metabolism of NE-100 was mediated with recombinant CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. A significant correlation was observed between activities of NE-100 metabolism and dextromethorphan O-demethylation (a specific activity for CYP2D6) or testosterone 6beta-hydroxylation (a specific activity for CYP3A4) in HLM. The activity of NE-100 metabolism was inhibited by approximately 80% by an anti-CYP2D6 antibody and only by quinidine among the p450-selective inhibitors at a low substrate concentration (0.1 microM). In contrast, with a high substrate concentration (10 microM), the activity was inhibited by an anti-CYP3A4 antibody and by ketoconazole. On the other hand, in HIM, the Eadie-Hofstee plots for NE-100 disappearance were monophasic, and the metabolism was strongly inhibited by an anti-CYP3A4 antibody and by ketoconazole but not by other inhibitors used. These results strongly suggest that NE-100 has different profiles regarding metabolism between liver and intestine. During absorption, NE-100 is mainly metabolized by CYP3A4 in the intestine and thereafter by CYP2D6 in the liver in the presence of therapeutic doses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | CNS Drugs 2003 -1 17: 307-24 |
| PMID | 12665390 |
| Title | Fatalities associated with therapeutic use and overdose of atypical antipsychotics. |
| Abstract | Since 1989, several novel antipsychotic drugs have become available for use including clozapine, risperidone, olanzapine, quetiapine and ziprasidone. These agents represent a substantial improvement in the treatment of schizophrenia and related disorders and are considered to have a favourable adverse effect profile relative to traditional antipsychotics. Nonetheless, in rare cases, people have died as a result of taking atypical antipsychotic drugs at therapeutic and supratherapeutic doses. Toxic doses of atypical antipsychotics are highly variable: some patients have died while taking therapeutic doses and others have survived massive overdoses. Toxicity may be increased by coingestion of other agents, particularly drugs with similar metabolic pathways. Atypical antipsychotics are metabolised predominantly by cytochrome p450 (CYP) isoenzymes, particularly CYP1A2 (clozapine and olanzapine), CYP3A4 (clozapine, quetiapine and ziprasidone) and CYP2D6 (olanzapine and risperidone). Concurrent prescription of other drugs that inhibit these isoenzymes may increase the probability of adverse events in patients taking atypical antipsychotics. Deaths due to atypical antipsychotic toxicity are often related to cardiovascular complications, but pulmonary, neurological, endocrine and gastrointestinal complications have also caused fatalities. Prevention and management of atypical antipsychotic overdose are of increased clinical relevance as prescription of these drugs increases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | J Clin Psychopharmacol 2003 Jun 23: 229-32 |
| PMID | 12826984 |
| Title | Ziprasidone metabolism, aldehyde oxidase, and clinical implications. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Drugs 2004 -1 64: 1715-36 |
| PMID | 15257633 |
| Title | Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. |
| Abstract | Aripiprazole, a quinolinone derivative, is an atypical antipsychotic drug indicated for the treatment of adult patients with schizophrenia. Aripiprazole 10 or 15 mg once daily is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. Although aripiprazole has only been directly compared with haloperidol and olanzapine in treatment-responsive patients to date, current data generally indicate that aripiprazole has a beneficial profile in terms of a low potential for bodyweight gain. Dosage titration is not necessary and the drug is effective in the first few weeks of treatment. Head-to-head comparative trials with atypical antipsychotic agents are required, as are long-term (> or =1 year) studies, to fully define the position of aripiprazole in relation to other antipsychotic drugs. Aripiprazole is a valuable new therapeutic option in the management of patients with schizophrenia. PHARMACOLOGICAL PROPERTIES: Aripiprazole is a quinolinone derivative with a high affinity for dopamine D2 and D3 receptors, and serotonin 5-HT1A, 5-HT2A and 5-HT2B receptors. The mechanism of action of aripiprazole is not yet known, but evidence suggests that its efficacy in the treatment of the positive and negative symptoms of schizophrenia and its lower propensity for extrapyramidal symptoms (EPS) may be attributable to aripiprazole's partial agonist activity at dopamine D2 receptors. At serotonin 5-HT1A receptors, in vitro studies have shown that aripiprazole acts as a partial agonist whereas at serotonin 5-HT2A receptors aripiprazole is an antagonist. The main active metabolite, dehydro-aripiprazole, has affinity for dopamine D2 receptors and thus has some pharmacological activity similar to that of the parent compound. Aripiprazole is rapidly absorbed after oral administration. The mean time to peak plasma concentration is 3 hours following multiple-dose administration of aripiprazole 10 or 15 mg and the absolute oral bioavailability of the drug is 87%. Steady-state plasma drug concentrations are achieved by 14 days; however, the drug appears to accumulate over this period, since mean peak plasma concentration and mean area under the plasma concentration-time curve values of aripiprazole 10 or 15 mg/day are 4-fold greater on day 14 than on day 1. This accumulation may be expected, since the mean elimination half-life of a single dose of aripiprazole is about 75 hours. Aripiprazole has extensive extravascular distribution and more than 99% of aripiprazole and dehydro-aripiprazole (the main active metabolite of aripiprazole) is bound to plasma protein. Elimination of the drug is primarily hepatic; the cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems transform aripiprazole to dehydro-aripiprazole, with the latter enzyme system subject to genetic polymorphism. Thus, dosage adjustment of aripiprazole is necessary when it is coadministered with CYP3A4 and CYP2D6 inhibitors (since aripiprazole concentration is increased) and with inducers of CYP3A4 (since aripiprazole concentration is decreased). THERAPEUTIC EFFICACY: The efficacy of aripiprazole has been demonstrated in patients with schizophrenia or schizoaffective disorder. In general, significant reductions from baseline in mean Positive and Negative Syndrome Scale total, positive and negative symptom scores, and Clinical Global Impression Severity of Illness scores were observed in patients with acute relapse of chronic schizophrenia or schizoaffective disorder receiving recommended (10 or 15 mg/day) or higher-than-recommended (20 or 30 mg/day) dosages of aripiprazole versus those receiving placebo in three well controlled, short-term trials. No additional therapeutic benefit was observed at the higher-than-recommended dosages. The drug is effective as early as the first or second week of treatment. The efficacy of aripiprazole was maintained for up to 52 weeks. The drug was significantly more effective than placebo in preventing relapse in patients with stable chronic schizophrenia in a 26-week, randomised trial. In a 52-week trial in patients with acute relapse of schizophrenia, the percentage of responders maintaining a response at study end was 77% of aripiprazole versus 73% of haloperidol recipients. Aripiprazole may improve cognitive function. In a nonblind, 26-week trial, patients with chronic schizophrenia receiving aripiprazole 30 mg/day experienced similar (general cognitive function) or better (verbal learning) changes from baseline in the neurocognitive parameters evaluated compared with recipients of olanzapine 10-15 mg/day. Aripiprazole 10-30 mg/day was generally well tolerated. The tolerability profile of aripiprazole was broadly similar to that observed with placebo in a meta-analysis of short-term trials in patients with acute relapse of schizophrenia or schizoaffective disorder and in a 26-week trial in patients with chronic stable schizophrenia. The most frequent treatment-emergent adverse events included insomnia and anxiety, and additionally, headache and agitation (in short-term trials) or akathisia and psychosis (in a 52-week trial). In general, the drug was associated with a placebo-level incidence of EPS and EPS-related adverse events. Significantly fewer aripiprazole recipients experienced EPS-related adverse events than haloperidol recipients in a 52-week trial. Changes in severity of EPS were minimal and usually no different from those observed with placebo. Moreover, there was less severe EPS in the aripiprazole group than the haloperidol group in a long-term trial. Treatment-emergent tardive dyskinesia was reported in only 0.2% of patients receiving aripiprazole (short-term trials), an incidence similar to that seen in placebo recipients (0.2%). Aripiprazole has a low propensity to cause clinically significant bodyweight gain, hyperprolactinaemia or corrected QT interval prolongation in patients with schizophrenia or schizoaffective disorder. In addition, there were no clinically relevant differences in mean changes from baseline in measures of diabetes and dyslipidaemia between the aripiprazole or placebo groups in a 26-week, placebo-controlled trial. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Psychiatr Prax 2004 Nov 31 Suppl 1: S142-4 |
| PMID | 15570533 |
| Title | [Risk of QTc prolongation due to combination of ziprasidone and quetiapine]. |
| Abstract | Ziprasidone, a novel antipsychotic agent for the treatment of schizophrenia, undergoes partial metabolism by cytochrome P450 3A4. It is associated with moderate prolongation of QT interval, but no increased risk for ventricular tachyarrhythmia or sudden death was demonstrated. A 70-year-old male was initiated on quetiapine therapy for an acute exacerbation of chronic schizophrenia. The baseline electrocardiogram (ECG) showed a normal QT interval (QTc: 417 ms). In combination therapy of quetiapine and ziprasidone the patient developed suddenly cardiac arrhythmia with extrasystoles and the ECG revealed a prolonged QTc interval of 482 ms. After breaking off treatment with quetiapine and reduction of ziprasidone a normalized QT interval (QTc: 428 ms) was measured. We suppose a potential of pharmacokinetic interaction between quetiapine and ziprasidone because of the same metabolic pathway by CYP3A4. Combining treatment of quetiapine and ziprasidone is therefore contraindicated. In addition we suggest caution using ziprasidone with any potential 3A4 substrate or inhibitor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Schizophr. Res. 2005 Jun 75: 21-6 |
| PMID | 15820320 |
| Title | Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: III. Lack of association of CYP3A4 and CYP2D6 gene polymorphisms. |
| Abstract | Tardive dyskinesia is a severe debilitating movement disorder characterized by choreoathetotic movements developing in one-fifth of the patients with schizophrenia. In this study we have investigated the significance of CYP3A4*1B and CYP2D6*4 polymorphisms in TD susceptibility among chronic schizophrenia patients (n = 335) from north India. Tardive dyskinesia was diagnosed in approximately 29% (96/335) of these patients. No significant association of either of the two SNPs with TD (CYP3A4*1B chi2 = 0. 308, df = 1, p = 0.579; CYP2D6*4 chi2 = 0.006, df = 1, p = 0.935) was observed. However a trend towards increased severity of TD in patients heterozygous for the CYP2D6*4 mutation was observed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Pharmacol. Res. 2005 Dec 52: 497-501 |
| PMID | 16226034 |
| Title | Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia. |
| Abstract | The effect of fluvoxamine on plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was investigated in 11 schizophrenic patients with prevailingly negative or depressive symptoms. Additional fluvoxamine, at the dose of 100 mg/day, was administered for 4 weeks to patients stabilized on risperidone (3-6 mg/day). Mean plasma concentrations of risperidone, 9-OH-risperidone and the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) were not significantly modified following co-administration with fluvoxamine. After 4 weeks, fluvoxamine dosage was increased to 200 mg/day in five patients and then maintained until the end of week 8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the six patients who were still receiving the initial fluvoxamine dose, while concentrations increased slightly but significantly (by a mean 26% over pretreatment; P < 0.05) in the subgroup of five subjects treated with a final dose of 200 mg/day. Fluvoxamine co-administration with risperidone was well tolerated and no patient developed extrapyramidal side effects. These findings indicate that fluvoxamine at dosages up to 100 mg/day is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of fluvoxamine may elevate plasma risperidone levels, presumably as a result of a dose-dependent inhibitory effect of fluvoxamine on CYP2D6-and/or CYP3A4-mediated 9-hydroxylation of risperidone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Pharmacol. Res. 2005 Dec 52: 497-501 |
| PMID | 16226034 |
| Title | Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia. |
| Abstract | The effect of fluvoxamine on plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was investigated in 11 schizophrenic patients with prevailingly negative or depressive symptoms. Additional fluvoxamine, at the dose of 100 mg/day, was administered for 4 weeks to patients stabilized on risperidone (3-6 mg/day). Mean plasma concentrations of risperidone, 9-OH-risperidone and the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) were not significantly modified following co-administration with fluvoxamine. After 4 weeks, fluvoxamine dosage was increased to 200 mg/day in five patients and then maintained until the end of week 8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the six patients who were still receiving the initial fluvoxamine dose, while concentrations increased slightly but significantly (by a mean 26% over pretreatment; P < 0.05) in the subgroup of five subjects treated with a final dose of 200 mg/day. Fluvoxamine co-administration with risperidone was well tolerated and no patient developed extrapyramidal side effects. These findings indicate that fluvoxamine at dosages up to 100 mg/day is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of fluvoxamine may elevate plasma risperidone levels, presumably as a result of a dose-dependent inhibitory effect of fluvoxamine on CYP2D6-and/or CYP3A4-mediated 9-hydroxylation of risperidone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Drug Metab. Dispos. 2005 Jul 33: 879-83 |
| PMID | 15821046 |
| Title | 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. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Feb 32: 520-2 |
| PMID | 18006133 |
| Title | Long-term perospirone treatment with a single dose at bedtime in schizophrenia: relevant to intermittent dopamine D2 receptor antagonism. |
| Abstract | Perospirone, a serotonin 5-HT2A and dopamine D2 receptor antagonist, is metabolized to ID-15036 by CYP3A4 and the elimination half-life (T1/2) for the latter is longer than the former. The active metabolite ID-15036 is an 8-times weaker D2 antagonist than perospirone, although it has a high affinity for 5-HT2A receptor. In this study, we measured the plasma concentrations of perospirone and ID-15036 in the long-term stable schizophrenic patients with a single dose of perospirone at bedtime. The mean level of perospirone at 11-15 h after a last dosing was much lower (0.49 ng/ml) than that of ID-15036 (2.89 ng/ml). These results show that a long-term perospirone monotherapy with a single dose at bedtime is effective for the maintenance treatment of chronic schizophrenia and also suggest the possibility that intermittent D2 receptor blockade may be sufficient for effective relapse prevention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Feb 32: 520-2 |
| PMID | 18006133 |
| Title | Long-term perospirone treatment with a single dose at bedtime in schizophrenia: relevant to intermittent dopamine D2 receptor antagonism. |
| Abstract | Perospirone, a serotonin 5-HT2A and dopamine D2 receptor antagonist, is metabolized to ID-15036 by CYP3A4 and the elimination half-life (T1/2) for the latter is longer than the former. The active metabolite ID-15036 is an 8-times weaker D2 antagonist than perospirone, although it has a high affinity for 5-HT2A receptor. In this study, we measured the plasma concentrations of perospirone and ID-15036 in the long-term stable schizophrenic patients with a single dose of perospirone at bedtime. The mean level of perospirone at 11-15 h after a last dosing was much lower (0.49 ng/ml) than that of ID-15036 (2.89 ng/ml). These results show that a long-term perospirone monotherapy with a single dose at bedtime is effective for the maintenance treatment of chronic schizophrenia and also suggest the possibility that intermittent D2 receptor blockade may be sufficient for effective relapse prevention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Clin Ther 2008 Jul 30: 1251-63 |
| PMID | 18691984 |
| Title | Risk of discontinuation of risperidone after exposure to potentially interacting drugs: a nested case-control study in patients with schizophrenia. |
| Abstract | The cytochrome P450 (CYP) 2D6 and 3A4 isozymes play an important role in the metabolism of risperidone. Concurrent use of drugs that inhibit or induce the action of these enzymes may increase or decrease levels of risperidone, thereby increasing the risk for discontinuation of risperidone or the need for supplemental treatment to control disease symptoms. This study examined the association between exposure to potentially interacting drugs and nonpersistence in a cohort of patients with schizophrenia newly starting treatment with risperidone. The data for this nested case-control study were obtained from the administrative health databases of the Régie de l'Assurance Maladie de Québec. The base cohort included patients aged > or = 15 years who began treatment with risperidone between July 2001 and December 2004. Cases consisted of those who were nonpersistent with risperidone either through drug discontinuation or the addition of/switch to a different atypical antipsychotic; noncases were those who persisted with risperidone through the end of their follow-up period. Exposure to CYP-inhibiting or CYP-inducing medications in the 1-, 3-, and 6-month windows before nonpersistence was compared between cases and noncases. The association between exposure to interacting medications and nonpersistence was analyzed using conditional logistic regression models to account for matching by time on treatment. The base cohort included 20,840 patients, of whom 59.2% were female and 57.7% were aged > or = 65 years. Nonpersistence occurred in 10,913 patients (52.4%) during the study period. Between 40% and 50% of patients were exposed to potential CYP inhibitors, and 6% to 10% were exposed to potential CYP inducers. Exposure to CYP inhibitors over 3 and 6 months was associated with an increase in risk for nonpersistence of approximately 10% (odds ratio [OR] for 3-month exposure = 1.10 [95% CI, 1.06-1.14]; OR for 6-month exposure = 1.11 [95% CI, 1.07-1.15]), whereas exposure to CYP inducers was not associated with a significant change in risk. Exposure to potentially interacting drugs was more likely to lead to nonpersistence while patients were still new to risperidone (ie, in the first month of treatment). For instance, the OR for 6-month exposure to inhibiting drugs was 1.20 (95% CI, 1.04-1.39) in the 1st month of treatment and 1.11 (95% CI, 1.01-1.20) between the 6th and 12th months. In this study, use of medications that are potential inhibitors of CYP2D6 and CYP3A4 appeared to be associated with an increased risk of nonpersistence with risperidone, particularly while patients were still new to treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Pharmacogenet. Genomics 2008 Jul 18: 599-609 |
| PMID | 18551040 |
| Title | Naturalistic pharmacogenetic study of treatment resistance to typical neuroleptics in European-Brazilian schizophrenics. |
| Abstract | This study aimed to explore the influence of variation in DRD2, DRD3, CYP2D6, CYP3A4, and CYP3A5 genes on treatment resistance to typical neuroleptics in a Brazilian sample of patients with schizophrenia. One polymorphism at DRD2 gene, five at DRD3, 24 at CYP2D6, nine at CYP3A4 gene, and one at CYP3A5 gene were genotyped in a sample of 186 patients with schizophrenia. From the nine studied CYP3A4 single nucleotide polymorphisms, only the -392A>G was polymorphic, and significant associations were observed between this single nucleotide polymorphism and efficacy of neuroleptic treatment. Homozygous individuals for the -392A variant [P=0.014, odds ratio (OR)=3.32] were more frequent in the treatment-resistant group, compared with carriers of one copy of the -392G variant. The CYP3A5 low expressor genotype (CYP3A5*3/CYP3A5*3) was found to be associated with refractoriness to neuroleptic treatment (P=0.003, OR=3.16). Among the haplotypes observed in DRD3 gene, the T/A/G/A/C haplotype showed an association with refractoriness to neuroleptics (chi=5.342, P=0.021, OR=1.75). This association showed that carriers of one copy of this haplotype presented intermediate values between noncarriers and homozygous individuals for the haplotype. No association was observed with polymorphisms in DRD2 and CYP2D6 genes. Multiple logistic regression analyses showed that the number of copies of DRD3 T/A/G/A/C haplotype and CYP3A5 low expressor genotype were predictors of refractoriness to neuroleptic after controlling for selected risk factors. CYP3A5*3 individuals carrying at least one copy of the T/A/G/A/C haplotype showed a higher risk to be refractory to neuroleptics than CYP3A5*3 homozygotes+non-T/A/G/A/C carriers (chi=5.533, P=0.019, OR=2.32, 95% confidence interval=1.08-5.02). No significant associations were observed with DRD2 and CYP2D6 polymorphisms. Our results suggest a role for CYP3A5 and DRD3 gene variants on refractoriness to neuroleptic treatment in Brazilians with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Pharmacogenet. Genomics 2008 Jul 18: 599-609 |
| PMID | 18551040 |
| Title | Naturalistic pharmacogenetic study of treatment resistance to typical neuroleptics in European-Brazilian schizophrenics. |
| Abstract | This study aimed to explore the influence of variation in DRD2, DRD3, CYP2D6, CYP3A4, and CYP3A5 genes on treatment resistance to typical neuroleptics in a Brazilian sample of patients with schizophrenia. One polymorphism at DRD2 gene, five at DRD3, 24 at CYP2D6, nine at CYP3A4 gene, and one at CYP3A5 gene were genotyped in a sample of 186 patients with schizophrenia. From the nine studied CYP3A4 single nucleotide polymorphisms, only the -392A>G was polymorphic, and significant associations were observed between this single nucleotide polymorphism and efficacy of neuroleptic treatment. Homozygous individuals for the -392A variant [P=0.014, odds ratio (OR)=3.32] were more frequent in the treatment-resistant group, compared with carriers of one copy of the -392G variant. The CYP3A5 low expressor genotype (CYP3A5*3/CYP3A5*3) was found to be associated with refractoriness to neuroleptic treatment (P=0.003, OR=3.16). Among the haplotypes observed in DRD3 gene, the T/A/G/A/C haplotype showed an association with refractoriness to neuroleptics (chi=5.342, P=0.021, OR=1.75). This association showed that carriers of one copy of this haplotype presented intermediate values between noncarriers and homozygous individuals for the haplotype. No association was observed with polymorphisms in DRD2 and CYP2D6 genes. Multiple logistic regression analyses showed that the number of copies of DRD3 T/A/G/A/C haplotype and CYP3A5 low expressor genotype were predictors of refractoriness to neuroleptic after controlling for selected risk factors. CYP3A5*3 individuals carrying at least one copy of the T/A/G/A/C haplotype showed a higher risk to be refractory to neuroleptics than CYP3A5*3 homozygotes+non-T/A/G/A/C carriers (chi=5.533, P=0.019, OR=2.32, 95% confidence interval=1.08-5.02). No significant associations were observed with DRD2 and CYP2D6 polymorphisms. Our results suggest a role for CYP3A5 and DRD3 gene variants on refractoriness to neuroleptic treatment in Brazilians with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Br J Clin Pharmacol 2009 Oct 68: 574-9 |
| PMID | 19843060 |
| Title | In vitro and in vivo evaluation of the inhibition potential of risperidone toward clozapine biotransformation. |
| Abstract | To study the impact of risperidone (RISP) on clozapine (CLZ) biotransformation in vitro in microsomal fractions containing varying expression of CYP oxidases and in vivo in patients. Human liver microsomes (n= 11) were assessed for expression of CYPs 1A2, 2D6 and 3A4, because these enzymes mediate RISP and CLZ oxidation. Inhibition of CLZ oxidation by RISP was assessed. Plasma CLZ elimination was estimated in patients with schizophrenia who received either CLZ alone or the CLZ-RISP combination (n= 10 per group). (i) The CYP3A4 and CYP1A2 inhibitors ketoconazole and fluvoxamine inhibited CLZ oxidation to varying extents in individual microsomal fractions. (ii) RISP did not inhibit CLZ oxidation, regardless of variations in CYP expression. (iii) RISP co-administration did not impair CLZ clearance. No evidence was found for CYP-mediated inhibitory or pharmacokinetic interactions between RISP and CLZ. Occasional literature reports of such interactions may involve other pathways that participate in CLZ disposition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Ther Drug Monit 2009 Apr 31: 239-46 |
| PMID | 19307938 |
| Title | A high-throughput assay using liquid chromatography-tandem mass spectrometry for simultaneous in vivo phenotyping of 5 major cytochrome p450 enzymes in patients. |
| Abstract | The phenotyping cocktail is a practical approach for phenotyping of cytochrome P450 (CYP) enzymes in vivo. In this study, a liquid chromatography-tandem mass spectrometry method using a dual-extraction approach was developed and validated to quantify 5 selective substrates and their metabolites for the simultaneous phenotyping CYPs 1A2, 2C19, 2C9, 2D6, and 3A4 in patient blood samples. The assay was applied in a pilot study of 11 patients with schizophrenia. Five blood samples were collected before and at 1, 2, 4, and 6 hours after administration of a phenotyping cocktail consisting of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam. The method successfully quantitated the CYP enzyme activities without serious side effects in patients. The ratios of metabolite to parent area under the concentration-time curve values were calculated over the 6-hour postdosage to reflect CYP2D6, CYP3A4, and CYP2C9 activities. The ratios of metabolite to parent plasma concentrations were calculated at 4-hour postdosage for CYP1A2 and at 4- or 6-hour postdose for CYP2C19, respectively. The plasma concentration of midazolam at 4 hours was also estimated as another phenotyping index for CYP3A4 activity. The simultaneous assay of all these analytes in a single matrix (plasma) will increase the feasibility of CYP phenotyping in patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Oct 33: 1200-4 |
| PMID | 19591893 |
| Title | A case-control association study between the CYP3A4 and CYP3A5 genes and schizophrenia in the Chinese Han population. |
| Abstract | In this study, variants of two genes coding for cytochrome P450 enzyme (CYP3A4 and CYP3A5) were analysed in a case-control sample using 398 schizophrenic patients and 391 healthy controls. All subjects were unrelated Han Chinese from Shanghai. No difference was observed on the allelic or genotypic distribution of CYP3A4 and CYP3A5 gene polymorphisms between the groups. However, the two-marker haplotypes covering components CYP3A41G and CYP3A53 were observed to be significantly associated with schizophrenia (corrected global p=0.0009). In addition, we identified one common risk haplotype, G/G (present in 59.5% of the general population). The results suggest that CYP3A4 and CYP3A5 might play a role in genetic susceptibility to schizophrenia. However, confirmatory studies in independent samples are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Oct 33: 1200-4 |
| PMID | 19591893 |
| Title | A case-control association study between the CYP3A4 and CYP3A5 genes and schizophrenia in the Chinese Han population. |
| Abstract | In this study, variants of two genes coding for cytochrome P450 enzyme (CYP3A4 and CYP3A5) were analysed in a case-control sample using 398 schizophrenic patients and 391 healthy controls. All subjects were unrelated Han Chinese from Shanghai. No difference was observed on the allelic or genotypic distribution of CYP3A4 and CYP3A5 gene polymorphisms between the groups. However, the two-marker haplotypes covering components CYP3A41G and CYP3A53 were observed to be significantly associated with schizophrenia (corrected global p=0.0009). In addition, we identified one common risk haplotype, G/G (present in 59.5% of the general population). The results suggest that CYP3A4 and CYP3A5 might play a role in genetic susceptibility to schizophrenia. However, confirmatory studies in independent samples are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Xenobiotica 2010 Nov 40: 721-9 |
| PMID | 20937004 |
| Title | In vitro assessment of metabolic drug?drug interaction potential of AZD2624, neurokinin-3 receptor antagonist, through cytochrome P(450) enzyme identification, inhibition, and induction studies. |
| Abstract | AZD2624 was pharmacologically characterized as a NK3 receptor antagonist intended for treatment of schizophrenia. The metabolic drug-drug interaction potential of AZD2624 was evaluated in in vitro studies. CYP3A4 and CYP3A5 appeared to be the primary enzymes mediating the formation of pharmacologically active ketone metabolite (M1), whereas CYP3A4, CYP3A5, and CYP2C9 appeared to be the enzymes responsible for the formation of the hydroxylated metabolite (M2). The apparent K(m) values were 1.5 and 6.3 µM for the formation of M1 and M2 in human liver microsomes, respectively. AZD2624 exhibited an inhibitory effect on microsomal CYP3A4/5 activities with apparent IC(50) values of 7.1 and 19.8 µM for midazolam and testosterone assays, respectively. No time-dependent inactivation of CYP3A4/5 activity (midazolam 1'-hydroxylation) by AZD2624 was observed. AZD2624 demonstrated weak to no inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. AZD2624 was not an inducer of CYP1A2 or CYP2B6. Although AZD2624-induced CYP3A4 activity in hepatocytes, the potential of AZD2624 to cause inductive drug interactions of this enzyme was low at relevant exposure concentration. Together with targeted low efficacious concentration, the results of this study demonstrated AZD2624 has a relatively low metabolic drug-drug interaction potential towards co-administered drugs. However, metabolism of AZD2624 might be inhibited when co-administrated with potent CYP3A4/5 inhibitors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | J. Psychopharmacol. (Oxford) 2010 Jul 24: 1115-20 |
| PMID | 19395426 |
| Title | Relationship between response to risperidone, plasma concentrations of risperidone and CYP3A4 polymorphisms in schizophrenia patients. |
| Abstract | In this study, we examined the relationships between plasma concentrations of risperidone and 9-hydroxyrisperidone and polymorphisms of CYP3A4. All 130 schizophrenia patients (45 men, 85 women, age 15-60 years) who met DSM-IV criteria were given risperidone for 8 weeks. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS). CYP3A4*1G was found to be associated with the change in total PANSS scores (Kruskal-Wallis test, P = 0.021), which was not significant on adjusting for multiple testing. Our study has, for the first time, conducted a genetic association study of the CYP3A4 gene with risperidone response. Further studies on larger groups and on the effects of the longer term risperidone treatment are needed to confirm these results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Drug Des Devel Ther 2010 -1 4: 187-201 |
| PMID | 20856845 |
| Title | Emerging treatments in the management of schizophrenia - focus on sertindole. |
| Abstract | The antipsychotic treatment of schizophrenia is still marked by poor compliance, and drug discontinuation; the development of more effective and safer drugs still remains a challenge. Sertindole is a second-generation antipsychotic with high affinity for dopamine D(2), serotonin 5-HT(2A), 5-HT(2C), and ?(1)-adrenergic receptors, and low affinity for other receptors. Sertindole undergoes extensive hepatic metabolism by the cytochrome P450 isoenzymes CYP2D6 and CYP3A4 and has an elimination half-life of approximately three days. In controlled clinical trials sertindole was more effective than placebo in reducing positive and negative symptoms, whereas it was as effective as haloperidol and risperidone against the positive symptoms of schizophrenia. The effective dose-range of sertindole is 12-20 mg, administered orally once daily. The most common adverse events are headache, insomnia, rhinitis/nasal congestion, male sexual dysfunction, and moderate weight gain, with few extrapyramidal symptoms and metabolic changes. Sertindole is associated with corrected QT interval prolongation, with subsequent risk of serious arrythmias. Due to cardiovascular safety concerns, sertindole is available as a second-line choice for patients intolerant to at least one other antipsychotic agent. Further clinical studies, mainly direct "head-to-head" comparisons with other second-generation antipsychotic agents, are needed to define the role of sertindole in the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Drugs Today 2010 Aug 46: 567-79 |
| PMID | 20830317 |
| Title | Iloperidone for the treatment of schizophrenia. |
| Abstract | Iloperidone is a recently approved antipsychotic agent indicated for the acute treatment of schizophrenia in adults. Iloperidone is characterized as a serotonin 5-HT(2A) and dopamine D(2) receptor antagonist, which makes its core mechanism of action similar to other second-generation antipsychotic agents. The affinity (or lack thereof) of iloperidone for other receptors (e.g., histamine, muscarinic, ?(1)-adrenoceptors, serotonin) results in a unique side effect and perhaps response profile that may make it an additional option for patients who have previously not tolerated or adequately responded to other available agents. Iloperidone has been studied in over 3,200 patients throughout its development. Its efficacy appears to be similar to haloperidol, risperidone and ziprasidone. It appears to be safe with minimal extrapyramidal side effects, weight gain and prolactin elevation. A cautious dosing and titration schedule is recommended at the initiation of therapy due to the potential for orthostatic hypotension and dizziness. Drug interactions through the CYP3A4 and CYP2D6 enzymes, along with the potential for QT prolongation, may influence its use in certain patients. Genetic studies conducted during drug development may facilitate the clinical use of pharmacogenomic tests to aid clinicians in optimizing the risk-benefit ratio of iloperidone. The purpose of this review is to summarize the chemistry, pharmacology and clinical aspects of iloperidone, with the goals of identifying key scientific and clinical issues for its use, as well as assessing the potential utility of iloperidone for the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Psychiatry Clin. Neurosci. 2011 Feb 65: 3-19 |
| PMID | 21265934 |
| Title | Pharmacogenomics of antipsychotics efficacy for schizophrenia. |
| Abstract | Central nervous system disorders are the third greatest health problem in developed countries, and schizophrenia represents some of the most disabling ailments in young individuals. There is an abuse and/or misuse of antipsychotics, and recent advances in pharmacogenomics pose new challenges for the clinical management of this complex disorder. schizophrenia is a multi-factorial/polygenic complex disorder in which hundreds of different genes are potentially involved, leading to the phenotypic expression of the disease in conjunction with epigenetic and environmental phenomena. Consequently, structural and functional genomic changes induce proteomic and metabolomic defects associated with the disease phenotype. Disease-related genomic profiles and genetic variants in genes involved in drug metabolism are responsible for drug efficacy and safety. About 20% of Caucasians are defective in CYP2D6 enzymes, which participate in the metabolism of 25-30% of central nervous system drugs. Approximately 40% of antipsychotics are substrates of CYP2D6 enzymes, 23% are substrates of CYP3A4, and 18% are substrates of CYP1A2. In order to achieve a mature discipline of pharmacogenomics of schizophrenia it would be effective to accelerate: (i) the education of physicians and the public in the use of genomic screening in daily clinical practice; (ii) the standardization of genetic testing for major categories of drugs; (iii) the validation of pharmacogenomic procedures according to drug category and pathology; (iv) the regulation of ethical, social, and economic issues; and (v) the incorporation of pharmacogenomic procedures of drugs in development and drugs on the market in order to optimize therapeutics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | CNS Neurosci Ther 2011 Oct 17: 541-65 |
| PMID | 20718829 |
| Title | Genomics and pharmacogenomics of schizophrenia. |
| Abstract | schizophrenia (SCZ) is among the most disabling of mental disorders. Several neurobiological hypotheses have been postulated as responsible for SCZ pathogenesis: polygenic/multifactorial genomic defects, intrauterine and perinatal environment-genome interactions, neurodevelopmental defects, dopaminergic, cholinergic, serotonergic, gamma-aminobutiric acid (GABAergic), neuropeptidergic and glutamatergic/N-Methyl-D-Aspartate (NMDA) dysfunctions, seasonal infection, neuroimmune dysfunction, and epigenetic dysregulation. SCZ has a heritability estimated at 60-90%. Genetic studies in SCZ have revealed the presence of chromosome anomalies, copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single nucleotide polymorphisms (SNPs) in microRNA genes, mitochondrial DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. About 10-20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6+CYP2C19+CYP2C9 genes. The pharmacogenomic response of SCZ patients to conventional psychotropic drugs also depends on genetic variants associated with SCZ-related genes. Consequently, the incorporation of pharmacogenomic procedures both to drugs in development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system (CNS) disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Clin Schizophr Relat Psychoses 2011 Jan 4: 251-7 |
| PMID | 21177242 |
| Title | Lurasidone for schizophrenia: a brief review of a new second-generation antipsychotic. |
| Abstract | Lurasidone is a second-generation antipsychotic newly approved by the U.S. Food and Drug Administration for the treatment of schizophrenia. Similar to most other second-generation antipsychotics, lurasidone is a full antagonist at dopamine D2 and serotonin 5HT2A receptors. Efficacy within the dose range of 40-120 mg/d was established in four 6-week, randomized, controlled trials. The recommended starting dose is 40 mg/d and the maximum recommended dose is 80 mg/d. Doses above 80 mg/d do not appear to confer added benefit and may be associated with a dose-related increase in certain adverse reactions such as somnolence and akathisia. Lurasidone is administered once daily with at least 350 calories of food in order to optimize bioavailability. Lurasidone is primarily metabolized in the liver through the CYP3A4 enzyme system, and coadministration with drugs that are strong inhibitors of CYP3A4 (such as ketoconazole) or strong inducers (such as rifampin) are contraindicated. Lurasidone is associated with minimal weight gain and no clinically meaningful alterations in glucose, lipids, or the ECG QT interval. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Prescrire Int 2011 Nov 20: 257-61 |
| PMID | 22066308 |
| Title | Quetiapine. A me-too neuroleptic; no panacea. |
| Abstract | Quetiapine, a so-called atypical neuroleptic, is authorised in the European Union for use in the standard indications of neuroleptics. However, it is the only neuroleptic licensed for the treatment and prevention of depressive episodes in patients with bipolar disorder, and as add-on therapy for depressive episodes inadequately improved by an antidepressant. In patients with schizophrenia, the authors of two meta-analyses, one including 12 trials (3443 patients) and the other 21 trials (4101 patients), concluded that quetiapine was not clearly more effective than other conventional or atypical neuroleptics. In bipolar patients with manic episodes, the results of two trials suggest that quetiapine monotherapy is not more effective than haloperidol or lithium. Two placebo-controlled trials of add-on quetiapine therapy in patients receiving a mood stabiliser (lithium or divalproate sodium) yielded conflicting results. In bipolar patients with a depressive episode, the only available trial, versus placebo and versus paroxetine in 740 patients, failed to provide conclusive evidence. In two trials with controversial designs, in which quetiapine was added to a mood stabiliser in order to prevent new depressive or manic episodes in bipolar patients, quetiapine appeared to be more effective than placebo: about 15% to 20% more patients were stabilised on quetiapine than on placebo. There are no trials to show whether quetiapine is more effective in preventing manic episodes than a neuroleptic. In a trial including 1226 patients in whom quetiapine was effective during a first depressive or manic episode, quetiapine appeared to be more effective than lithium in preventing a depressive episode (relapse rate 8.9% versus 13.5%) but not a manic episode. These comparisons may be biased, however. Two placebo-controlled trials assessed quetiapine add-on therapy in patients in whom an antidepressant was inadequately effective. The conflicting results obtained in these two trials rule out drawing firm conclusions as to the efficacy of quetiapine. Overall, quetiapine has the adverse effect profile common to atypical neuroleptics. However, hypercholesterolaemia is more frequent than with risperidone, and both clinical trials and post-marketing data have shown that quetiapine carries a risk of hypothyroidism. Animal studies suggested a risk of cataracts, but this adverse effect has not yet been confirmed in humans. The risk of sudden cardiovascular death appears similar to that reported with other neuroleptics. A retrospective survey suggests that the consequences of acute overdose are more severe with quetiapine than with other neuroleptics. Quetiapine is metabolised by cytochrome P450 isoenzyme CYP3A4, creating a high risk of pharmacokinetic interactions. In practice, quetiapine has not been shown to provide a therapeutic advantage over other treatments, although additional trials in the prevention of depressive episodes are warranted in selected patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Int Clin Psychopharmacol 2012 Mar 27: 121-4 |
| PMID | 22113252 |
| Title | Interaction of St John's wort (Hypericum perforatum) with clozapine. |
| Abstract | St John's wort (Hypericum perforatum) is notorious for its ability to induce the enzymes of the P450 system. Especially, it induces CYP1A2 and CYP3A4, enzymes that are closely involved in the metabolism of clozapine. We present a patient with schizophrenia, who was stable on a fixed dose with stable plasma level of clozapine, and who deteriorated after she started self-medicating with St John's wort. The reduced plasma clozapine level and the psychiatric condition normalized after the withdrawal of St John's wort. It is possible that, beside the induction of P450-enzymes, the induction of P-glycoprotein by St John's wort aggravated psychiatric deterioration of the patient. Physicians should be alert to patients self-medicating with over-the-counter medicines, especially when these medicines can lower clozapine concentrations below the therapeutic range. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Am J Hosp Palliat Care 2012 Jun 29: 295-301 |
| PMID | 21998445 |
| Title | Role of haloperidol in palliative medicine: an update. |
| Abstract | Haloperidol is a butyrophenone neuroleptic agent characterized as a high-affinity dopamine antagonist, originally used for the treatment of schizophrenia. Awareness of the role dopamine plays in many symptoms in palliative care, such as nausea, vomiting, and delirium, has led to the use of dopamine antagonists such as haloperidol for the treatment of these symptoms in the palliative care setting. Listed as 1 of the 25 important drugs in palliative care, haloperidol can be administered by multiple routes and can be given without dose alteration in the setting of both renal and hepatic insufficiency. Haloperidol is extensively metabolized in the liver, with CYP3A4 the chief cytochrome oxidase responsible for metabolism. This article will review the pharmacology, pharmacokinetics, and current uses of haloperidol in palliative medicine. There will be an examination of the evidence base for the use of haloperidol in palliative medicine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | J Clin Pharm Ther 2012 Apr 37: 221-5 |
| PMID | 21518375 |
| Title | Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers. |
| Abstract | Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mainly metabolized by human cytochrome P450 CYP2D6 and partly by CYP3A4 to 9-hydroxyrisperidone. Ketoconazole is used as a CYP3A4 inhibitor probe for studying drug-drug interactions. We aim to investigate the effect of ketoconazole on the pharmacokinetics of risperidone in healthy male volunteers. An open-label, randomized, two-phase crossover design with a 2-week washout period was performed in 10 healthy male volunteers. The volunteers received a single oral dose of 2mg of risperidone alone or in combination with 200mg of ketoconazole, once daily for 3days. Serial blood samples were collected at specific periods after ingestion of risperidone for a period of 96h. Plasma concentrations of risperidone and 9-hydroxyrisperidone were determined using a validated HPLC-tandem mass spectrometry method. After pretreatment with ketoconazole, the clearance of risperidone decreased significantly by 34·81±5·10% and the T(1/2) of risperidone increased significantly by 28·03±40·60%. The AUC(0-96) and AUC(0-?) of risperidone increased significantly by 66·61± 43·03% and 66·54±39·76%, respectively. The Vd/f of risperidone increased significantly by 39·79±53·59%. However, the C(max) and T(max) of risperidone were not significantly changed, indicating that ketoconazole had minimal effect on the absorption of risperidone. The C(max) , T(max) and T(1/2) of 9-hydroxyrisperidone did not decrease significantly. However, the Cl/f of 9-hydroxyrisperidone increased significantly by 135·07± 124·68%, and the Vd/f of 9-hydroxyrisperidone decreased significantly by 29·47±54·64%. These changes led to a corresponding significant decrease in the AUC(0-96) and AUC(0-?) of 9-hydroxyrisperidone by 47·76±22·39% and 48·49± 20·03%, respectively. Ketoconazole significantly inhibited the metabolism of risperidone through the inhibition of hepatic CYP3A4. our results suggest that besides CYP2D6, CYP3A4 contributes significantly to the metabolism of risperidone. The pharmacokinetics of risperidone was affected by the concomitant administration of ketoconazole. If a CYP3A4 inhibitor is used concomitantly with risperidone, it is necessary for the clinicians to monitor their patients for signs of adverse drug reactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Neuropsychiatr Dis Treat 2012 -1 8: 155-68 |
| PMID | 22570547 |
| Title | Critical appraisal of lurasidone in the management of schizophrenia. |
| Abstract | Lurasidone is a new atypical antipsychotic in the benzoisothiazoles class of chemicals. Like most second-generation antipsychotics it is a full antagonist at dopamine D(2) and serotonin 5-HT(2A) receptors, and is a partial agonist at 5-HT(1A) receptors, a property shared by some but not all older agents. It has much greater affinity for 5-HT(7) subtype receptors than other atypical antipsychotics. Pharmacokinetic studies showed that lurasidone is reasonably rapidly absorbed, with bioavailability appearing to be increased by food. Lurasidone undergoes extensive metabolism to a number of metabolites, some of which retain pharmacological activities. Metabolism is mainly by CYP3A4, resulting in steady-state concentrations that vary between individuals and are potentially affected by strong inducers and inhibitors of this enzyme. Short-term clinical trials have demonstrated the efficacy of lurasidone in acute schizophrenia, with doses of 40 and 80 mg/day giving significant improvements from baseline in the PANSS and BPRS scores. The most common adverse events are nausea, vomiting, akathisia, dizziness, and sedation, with minimal increases in the risk of developing metabolic syndrome. Lurasidone did not raise the risk of QTc interval prolongation, although additional studies are required. Long-term trials are also needed to assess the risk of new-onset diabetes. Ongoing trials in patients with bipolar disorder are being completed but, again, efficacy and safety have been investigated only in a few short-term clinical trials. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | J Clin Pharmacol 2012 Sep 52: 1399-409 |
| PMID | 21903893 |
| Title | Investigation of a possible interaction between quetiapine and armodafinil in patients with schizophrenia: an open-label, multiple-dose study. |
| Abstract | The wakefulness-promoting medication armodafinil (R-modafinil) is being studied as an adjunctive treatment for patients with schizophrenia receiving antipsychotic therapy. This open-label study in 37 adults with schizophrenia evaluated whether a drug-drug interaction occurs between armodafinil (a moderate CYP3A4 inducer) and the atypical antipsychotic quetiapine (primarily metabolized by CYP3A4). Patients were required to be on a stable dose of quetiapine ?300 mg once daily in the evening before enrollment. Steady-state quetiapine pharmacokinetics were determined following daily administration of quetiapine alone in the evening (day 5) and then following concomitant armodafinil administration (titrated to 250 mg) daily in the morning (day 38). In 25 evaluable patients, concomitant armodafinil resulted in a statistically significant decrease in mean AUC(0-24) and C(max) values of quetiapine by 42% and 45%, respectively, versus quetiapine alone. Adverse events occurred more frequently with combination therapy and were consistent with the known profiles of the 2 drugs. No significant changes in mean PANSS negative, positive, and total scores or SANS scores were observed. Although the data do not suggest that the observed decrease in systemic exposure to quetiapine was associated with a change in disease state, patients with schizophrenia should be monitored during combination therapy with quetiapine and armodafinil. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | J Clin Psychopharmacol 2013 Feb 33: 3-10 |
| PMID | 23277250 |
| Title | A thorough QTc study of 3 doses of iloperidone including metabolic inhibition via CYP2D6 and/or CYP3A4 and a comparison to quetiapine and ziprasidone. |
| Abstract | The potential for iloperidone, a D2/5-HT2A antipsychotic, to affect the heart rate-corrected QT interval (QTc) was assessed in the absence and presence of metabolic inhibitors in a randomized, open-label, multicenter study. QT interval prolongation by medications, including both conventional and atypical antipsychotic drugs, can predispose patients to cardiac arrhythmias and result in sudden death. Adults with schizophrenia or schizoaffective disorder and normal electrocardiograms at baseline (N = 188) were randomized 1:1:1:1:1 to iloperidone, 8 mg twice daily (BID), 12 mg BID, 24 mg once daily (QD); quetiapine, 375 mg BID; or ziprasidone, 80 mg BID during period 1 (no metabolic inhibitors present). Iloperidone BID produced mean changes in QTc Fridericia correction (QTcF) interval (8.5-9.0 milliseconds [ms]) similar to those produced by ziprasidone (9.6 ms) and higher than those produced by quetiapine (1.3 ms). Iloperidone, 24 mg QD, produced a mean QTcF change of 15.4 ms. Coadministration of metabolic inhibitors with iloperidone during periods 2 (paroxetine) and 3 (paroxetine and ketoconazole) resulted in greater increases in the QTc interval. Increased QTc was observed in individuals with specific cytochrome P450 2D6 polymorphisms. Up to 10% of patients on iloperidone experienced QTc intervals of 60 ms or longer in the presence of metabolic inhibition and QD dosing. However, no patients experienced QTc changes of clinical concern (QTc ? 500 ms). The most common adverse events with iloperidone were headache, anxiety, and dyspepsia. The only cardiovascular adverse events with iloperidone were non-concentration-dependent tachycardia that was mild in most patients and did not lead to further sequelae. Pharmacogenetics and recommendations are discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Int Rev Psychiatry 2013 Oct 25: 509-33 |
| PMID | 24151799 |
| Title | Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy. |
| Abstract | Adverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Schizophr. Res. 2013 Sep 149: 1-14 |
| PMID | 23870808 |
| Title | CYP450 pharmacogenetic treatment strategies for antipsychotics: a review of the evidence. |
| Abstract | Although a number of first- and second-generation antipsychotics are available, achieving optimal therapeutic response for patients with schizophrenia can be challenging. The presence of polymorphic alleles for cytochrome P (CYP) 450 may result in lack of expression, altered levels of expression, or altered function of CYP450 enzymes. CYP2D6, CYP1A2, and CYP3A4/5 are major enzymes in the metabolism of antipsychotics and polymorphisms of alleles for these proteins are associated with altered plasma levels. Consequently, standard dosing may result in drug plasma concentrations that are subtherapeutic or toxic in some patients. Patient CYP450 genotype testing can predict altered pharmacokinetics, and is currently available and relatively inexpensive. Evidence-based guidelines provide dose recommendations for some antipsychotics. To date few studies have demonstrated a significant association with genotype-guided antipsychotic use and clinical efficacy. However, many studies have been small, retrospective or cohort designs, and many have not been adequately powered. Numerous studies have shown a significant association between genotype and adverse effects, such as CYP2D6 polymorphisms and tardive dyskinesia. This review summarizes evidence for the role of CYP450 genetic variants in the response to antipsychotic medications and the clinical implications of pharmacogenetics in the management of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Front Med 2013 Jun 7: 180-90 |
| PMID | 23606027 |
| Title | Pharmacogenomics can improve antipsychotic treatment in schizophrenia. |
| Abstract | schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population, and heritability of up to 80%. Drug therapy is an important approach to treating the disease. However, the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects. Many studies have indicated that about 30% of the patients exhibit little or no improvements associated with antipsychotics. The response of individual patients who are given the same dose of the same drug varies considerably. In addition, antipsychotic drugs are often accompanied by adverse drug reactions (ADRs), which can cause considerable financial loss in addition to the obvious societal harm. So, it is strongly recommended that personalized medicine should be implemented both to improve drug efficacy and to minimize adverse events and toxicity. There is therefore a need for pharmacogenomic studies into the factors affecting response of schizophrenia patients to antipsychotic drugs to provide informed guidance for clinicians. Individual differences in drug response is due to a combination of many complex factors including ADEM (absorption, distribution, metabolism, excretion) process, transporting, binding with receptor and intracellular signal transduction. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this interindividual variability in antipsychotics response. In addition, epigenetic factors such as methylation of DNA and regulation by miRNA have also been reported to play an important role in the complex interactions between the multiple genes and environmental factors which influence individual drug response phenotypes in patients. In this review, we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolic enzymes (CYP2D6, CYP1A2, CYP3A4, etc.), drug transporters (mainly ABCB1) and neurotransmitter receptors (dopamine receptors and serotonin receptors, etc.). We also discuss the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics and potential clinical applications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Expert Opin Drug Metab Toxicol 2013 Feb 9: 193-206 |
| PMID | 23320989 |
| Title | Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. |
| Abstract | Cariprazine is an atypical antipsychotic in clinical development for the treatment of schizophrenia and bipolar mania/mixed episodes. The purpose of this review is to describe the chemistry, pharmacodynamic profile, pharmacokinetics, and clinical profile of cariprazine. Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist. Doses ? 1.5 mg/d yielded 69 - 75% D2/D3 receptor occupancy as measured in positron emission tomography scans. Mean half-life for cariprazine was 2 - 5 d over a dose range of 1.5 - 12.5 mg. Cariprazine produces two clinically relevant metabolites: desmethyl-cariprazine and didesmethyl-cariprazine, the latter having a longer half-life than cariprazine. Exposure to didesmethyl-cariprazine exceeded that of the parent drug. Cariprazine is metabolized by CYP3A4 and to a lesser extent by CYP2D6. The efficacy and safety of cariprazine have been so far investigated only in a few short-term (unpublished) clinical trials; however, three studies in schizophrenia and three studies in bipolar mania/mixed episodes evidenced a statistically significant therapeutic effect compared to placebo for cariprazine at doses ranging from 1.5 to 12 mg/d. There does not appear to be clinically relevant adverse effects of cariprazine on metabolic variables. Commonly encountered adverse events associated with cariprazine include insomnia, extrapyramidal symptoms, akathisia, sedation, nausea, dizziness, and constipation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Neuropsychiatr Dis Treat 2013 -1 9: 1521-9 |
| PMID | 24143101 |
| Title | Lurasidone as a potential therapy for bipolar disorder. |
| Abstract | Lurasidone is a benzisothiazol derivative and an atypical antipsychotic approved by the US Food and Drug Administration for the acute treatment of adults with schizophrenia (October 2010) and bipolar 1 depression (June 2013). Lurasidone has a strong antagonistic property at the D2, serotonin (5-HT)2A, and 5-HT7 receptors, and partial agonistic property at the 5-HT1A receptor. Lurasidone also has lower binding affinity for the ?2C and 5-HT2C receptor. Lurasidone is rapidly absorbed (time to maximum plasma concentration: 1-3 hours), metabolized mainly by CYP3A4 and eliminated by hepatic metabolism. In two large, well-designed, 6-week trials in adult patients with bipolar 1 depression, lurasidone monotherapy and adjunctive therapy with mood stabilizers were significantly more effective than placebo at improving depressive symptoms assessed using the Montgomery-Åsberg Depression Rating Scale total score. In both trials, lurasidone also reduced the Clinical Global Impression-Bipolar Severity depression score to a greater extent than placebo. In these two trials, discontinuation rates due to adverse events in the lurasidone group were small (<7%) and were not different from those of the placebo group. The most common adverse events in the lurasidone group were headache, nausea, somnolence, and akathisia. The changes in lipid profiles, weight, and parameters of glycemic control were minimal, and these findings were in line with those observed in schizophrenia trials. Further active comparator trials and long-term tolerability and safety data in bipolar patients are required. Lurasidone may be an option for the management of depressive symptoms in patients with bipolar 1 disorder, and it may be considered as a treatment alternative for patients who are at high risk for metabolic abnormalities. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Drug Metab. Dispos. 2013 Dec 41: 2066-75 |
| PMID | 24003250 |
| Title | Heterotropic activation of the midazolam hydroxylase activity of CYP3A by a positive allosteric modulator of mGlu5: in vitro to in vivo translation and potential impact on clinically relevant drug-drug interactions. |
| Abstract | Allosteric modulation of G protein-coupled receptors has gained considerable attention in the drug discovery arena because it opens avenues to achieve greater selectivity over orthosteric ligands. We recently identified a series of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu(5)) for the treatment of schizophrenia that exhibited robust heterotropic activation of CYP3A4 enzymatic activity. The prototypical compound from this series, 5-(4-fluorobenzyl)-2-((3-fluorophenoxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (VU0448187), was found to activate CYP3A4 to >100% of its baseline intrinsic midazolam (MDZ) hydroxylase activity in vitro; activation was CYP3A substrate specific and mGlu(5) PAM dependent. Additional studies revealed the concentration-dependence of CYP3A activation by VU0448187 in multispecies hepatic and intestinal microsomes and hepatocytes, as well as a diminished effect observed in the presence of ketoconazole. Kinetic analyses of the effect of VU0448187 on MDZ metabolism in recombinant P450 or human liver microsomes resulted in a significant increase in V(max) (minimal change in K(m)) and required the presence of cytochrome b5. The atypical kinetics translated in vivo, as rats receiving an intraperitoneal administration of VU0448187 prior to MDZ treatment demonstrated a significant increase in circulating 1- and 4-hydroxy- midazolam (1-OH-MDZ, 4-OH-MDZ) levels compared with rats administered MDZ alone. The discovery of a potent substrate-selective activator of rodent CYP3A with an in vitro to in vivo translation serves to illuminate the impact of increasing intrinsic enzymatic activity of hepatic and extrahepatic CYP3A in rodents, and presents the basis to build models capable of framing the clinical relevance of substrate-dependent heterotropic activation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Expert Opin Drug Saf 2014 Feb 13: 241-6 |
| PMID | 24206391 |
| Title | Safety profile of iloperidone in the treatment of schizophrenia. |
| Abstract | Iloperidone is a novel antipsychotic medication approved for the treatment of schizophrenia in adults with efficacy similar to its class counterparts. The purpose of this article is to describe the safety profile of iloperidone and its clinical implications. A PubMed search was undertaken on May 10, 2013, using the keyword iloperidone. Of the 121 articles that resulted, those with primary sources of information, along with secondary sources with an emphasis on drug safety, were included in this article. Iloperidone was found to have lower extrapyramidal symptom (EPS) and akathisia rates compared to haloperidol and risperidone. Twelve percent of patients experienced clinically significant weight gain, largely during initiation phase of treatment. No other clinically significant metabolic abnormalities were observed. QTc interval was increased by 10 ms, comparable to the effect observed with ziprasidone. QTc prolongation was heightened under inhibition of CYP2D6 and CYP3A4. Orthostatic hypotension was a common effect seen in the first week of treatment. The favorable EPS and akathisia profile of iloperidone makes it an attractive choice for patients whose compliance is limited by these effects. However, the slow titration schedule adapted to reduce orthostasis may limit the use of this agent in an acute setting. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | Bioorg. Med. Chem. 2014 Jul 22: 3515-26 |
| PMID | 24837154 |
| Title | Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability. |
| Abstract | In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure-activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Neuropsychiatr Dis Treat 2014 -1 10: 1605-11 |
| PMID | 25210454 |
| Title | Schizophrenia relapse and the clinical usefulness of once-monthly aripiprazole depot injection. |
| Abstract | Improving medication adherence is critical to improving outcomes in patients with schizophrenia. A long-acting injectable (depot) antipsychotic is one of the most effective methods for improving treatment adherence and decreasing rehospitalization rates in patients with schizophrenia. Until recently, only three second-generation antipsychotics were available in a long-acting injectable formulation (risperidone, paliperidone, and olanzapine). In this respect, the emergence of long-acting aripiprazole injection (ALAI), approved by the US Food and Drug Administration for the treatment of schizophrenia in 2013, is timely. ALAI is a lyophilized powder of aripiprazole, and the aripiprazole molecule is unmodified. The initial and target dosage of ALAI is 400 mg once monthly, but it could be reduced to 300 mg if adverse reactions occur with 400 mg. When first administering ALAI, it is recommended to continue treatment with oral aripiprazole (10-20 mg/day) or another oral antipsychotic for 2 weeks in order to maintain therapeutic antipsychotic concentrations. The primary clearance route for ALAI is hepatic, ie, cytochrome P450 (CYP)2D6 and CYP3A4, so dose adjustment is required in poor CYP2D6 metabolizers. The efficacy of ALAI was demonstrated in three studies. A randomized controlled trial that formed the basis for approval of ALAI in the treatment of schizophrenia showed that ALAI significantly delayed time to impending relapse when compared with placebo (P<0.0001, log-rank test). An open-label, mirror study demonstrated that total psychiatric hospitalization rates were significantly lower after switching from oral antipsychotics to ALAI. Another randomized controlled trial presented in poster form suggested that ALAI 400 mg was comparable with oral aripiprazole 10-30 mg in preventing relapse. ALAI was generally well tolerated during both short-term and long-term studies. Its tolerability profile, including extrapyramidal symptoms and clinically relevant metabolic parameters, was similar to placebo. However, insomnia, headache, anxiety, akathisia, weight gain, injection site pain, and tremor need clinical attention. These studies suggest that ALAI is a viable treatment option for patients with schizophrenia, but direct head-to-head comparisons between ALAI and other long-acting injectable antipsychotics are needed to elucidate its risk-benefit profile. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Ther Drug Monit 2014 Dec 36: 815-8 |
| PMID | 24739668 |
| Title | Lack of correlation between the steady-state plasma concentrations of aripiprazole and haloperidol in Japanese patients with schizophrenia. |
| Abstract | Both aripiprazole and haloperidol have been used in the treatment of schizophrenia, and are metabolized by the cytochrome P450 (CYP) 2D6 and CYP3A4. The authors studied the correlations between the steady-state plasma concentrations (Css) of aripiprazole and its active metabolite, dehydroaripiprazole, and those of haloperidol in 19 Japanese patients with schizophrenia, together with the effects of CYP2D6 genotypes on the steady-state kinetics of these compounds. All the patients received first 24 mg/d of aripiprazole for 3 weeks and later received 6 mg/d of haloperidol for 2 weeks. Blood samplings were performed at least 2 weeks after the initiation of each treatment. The Css values of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection, and those of haloperidol were measured by using an enzyme immunoassay. CYP2D6 genotypes were determined by using polymerase chain reaction analysis. None of the correlations between the Css of aripiprazole (r = 0.286) or the sum of aripiprazole plus dehydroaripiprazole (r = 0.344) and those of haloperidol were significant. The mean Css of aripiprazole was significantly higher (P < 0.05) in the subjects with 1 *10 allele of CYP2D6 (n = 6) than in those with no mutated alleles (n = 13), whereas there were no significant differences in those of haloperidol between the 2 groups. This study suggests that the Css of aripiprazole and that of aripiprazole plus dehydroaripiprazole do not correlate with that of haloperidol in the same individual, because of the greater involvement of CYP2D6 in the metabolism of aripiprazole than in that of haloperidol. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | J Clin Psychiatry 2015 Dec 76: 1633-4 |
| PMID | 26717524 |
| Title | Delayed drug interactions in psychiatry: armodafinil and risperidone as a potential case in point. |
| Abstract | Modafinil or armodafinil (ar/mod) augmentation of antipsychotic medication in schizophrenia patients may be considered with a view to reduce negative symptoms associated with the illness or excessive daytime drowsiness due to any cause. The available data suggest that there is no role for ar/mod in reducing negative symptom burden. A recent pharmacokinetic (PK) study suggested that armodafinil (250 mg/d) reduces key PK parameters of risperidone by about 50%, and key PK parameters of 9-hydroxyrisperidone (paliperidone) by about 20%-30%, probably through induction of CYP3A4. Ar/mod augmentation is therefore best avoided in patients receiving risperidone or paliperidone (and most other atypical antipsychotic drugs, as well, because most atypical antipsychotics are metabolized by enzymes that ar/mod induce). If the ar/mod-antipsychotic drug combination is necessary, for whatever reason, then the dose of the atypical antipsychotic drug may need to be appropriately raised. If this is not done, relapse may occur; because the relapse may postdate the introduction of ar/mod by many months, the causal role of a metabolic drug interaction may not be suspected, and physicians may attribute the relapse to the natural course of the illness. Physicians need to be aware that any agent that induces the metabolism of psychotropic drugs that are used in maintenance therapy may, through lowered psychotropic drug levels, result in a delayed drug interaction that is characterized by illness relapse. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | Int J Risk Saf Med 2015 -1 27 Suppl 1: S23-4 |
| PMID | 26639694 |
| Title | CYP3A4 activity and haloperidol effects in alcohol addicts. |
| Abstract | Haloperidol is one of the most commonly used typical antipsychotics [2]. It has a powerful antipsychotic activity blocking mesolimbic postsynaptic dopamine receptors. Unwanted adverse effects accompany the use of haloperidol. Therefore alcohol abusers' attitudes towards haloperidol are ambiguous and often negative, which sometimes limits it's use in patients with addictive disorders [3]. Cytosolic carbonyl reductase reduces haloperidol to reduced form, which has 10-20% of the activity of the parent molecule. It is further metabolized by CYP3A4 to a tetrahydropyridine and then conjugated by glucuronidation and sulphation. Reduced haloperidol is back-oxidized to haloperidol by CYP3A4 and CYP2D6. Haloperidol is N-dealkylated by CYP3A4 and CYP2D6 to 4-chlorophenyl-4-hydroxypiperidine and p-fluorobenzoyl propionic acid. The correlation between CYP2D6 and CYP3A4 activity and the rate of biotransformation of haloperidol was demonstrated in a number of studies on patients with schizophrenia [1, 2, 5]. At the same time other studies deny or disaffirm this correlation [4]. To estimate the correlation between CYP3A4 isoenzyme activity and the efficacy and safety of haloperidol in patients with alcohol abuse during the exacerbation of the addiction. The study involved 15 men, alcohol abusers, in exacerbation of their addiction, who were hospitalized in Moscow Research and Practical Centre for Narcology of the Departament of Public Health. All 15 patients received haloperidol in tablets and injections. Determination of CYP3A4 activity was performed using high performance liquid chromatography with mass spectrometry (HPLC/ MS) by determination of endogenous substrate of this isoenzyme and its metabolite in urine - the ratio: cortisol/6-beta-hydroxycortisol. We used international psychometric scales to assess efficacy of haloperidol (the scale of determining the severity of addiction of The National Research Center on Addictions of the Ministry of Health Of Russia, Hamilton Anxiety Research Scale (HARS)). The safety of haloperidol was estimated by the UKU Side-Effect Rating Scale. Scales express the clinical picture of the abuse. The higher the score, the more pronounced the addiction is. Calculating the differences in scores of the scales allowed for clinical assessment of haloperidol effects. The larger the difference in scores was, the more pronounced were the changes in clinical picture of abuse, and the higher the efficacy of therapy was assumed. Statistical analysis of the results of the study was performed by non-parametric statistics by the program STATISTICA v10.0 («StatSoft Inc.», USA). The normality of sample distribution was estimated by Shapiro-Wilk's W-test, and the homogeneity of dispersion, that was estimated by Fisher's T-test (in case of comparison of two samples). The differences were evaluated as significant in case of p < 0,05 (statistic power >80%). To determine the correlation between the quantitative characteristics Spearman rank R coefficient was calculated. The value of correlation coefficient r from 0,3 to 0,7 (p < 0,05) indicated positive moderate, but significant correlation between the characteristics, r>0,7 (p < 0,05) - strong and significant correlation, negative value of r indicated inverse correlation. Data analysis demonstrated a correlation between the activity of isoenzyme CYP3A4 and the scores of pathological addiction (r1 = -0,36), HARS (r2 = -0,45), UKU Side-Effect Rating Scale (r3 = -0.15) in the entire group (p < 0.05). In a group of patients, who received the higher doses of haloperidol (more than 7.5 mg per day in tablets or 5 mg per day in injections), the following results were received in the same groups of data: r1 = -0.68, r2 = -0.71, r3 = -0.76 (p < 0.05). The results demonstrate the correlation between CYP3A4 activities and the efficacy and safety of haloperidol in alcohol abusers during the exacerbation of the addiction. The inverse correlation indicates that the higher the activity of CYP3A4 is, the lower the efficacy of haloperidol is. Also it can be assumed that the presence of strong correlation between the activity of CYP3A4 and the efficacy of haloperidol in group of patients, who received higher doses of haloperidol, may indicate that CYP3A4 is involved in haloperidol metabolism when it is used at higher doses. It should be noted that in this research the activity of CYP3A4 was determined using high performance liquid chromatography with mass spectrometry (HPLC/MS) by determination the ratio of cortisol/6-beta-hydroxycortisol for the fist time. To increase the level of our confidence in the results further studies with a larger number of people are necessary. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | Evid Based Complement Alternat Med 2015 -1 2015: 615285 |
| PMID | 25793001 |
| Title | Effects of green tea extracts on the pharmacokinetics of quetiapine in rats. |
| Abstract | Quetiapine is an atypical antipsychotic, used clinically in the treatment of schizophrenia, acute mania in bipolar disorders, and bipolar depression in adults. In this study, the effect of green tea extracts (GTE) on the pharmacokinetics of quetiapine (substrate of CYP3A4) was investigated in rats. Male Wistar albino rats received GTE (175?mg/kg) or saline (control) by oral gavage for 7 days before a single intragastric administration of 25?mg/kg quetiapine. Plasma concentrations of quetiapine were measured up to 12?h after its administration by a validated ultraperformance liquid chromatography-tandem mass spectroscopy. Pretreatment with GTE produced significant reductions in the maximum plasma concentration and area under the curve of quetiapine by 45% and 35%, respectively, compared to quetiapine alone. However, GTE did not produce significant change in elimination half-life and oral clearance of quetiapine. This study concluded that GTE may decrease the bioavailability of quetiapine when coadministered. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | Bioorg. Med. Chem. 2015 Jan 23: 297-313 |
| PMID | 25515954 |
| Title | Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition. |
| Abstract | A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with (11)C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3mg/kg in mice novel object recognition test. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | J Clin Psychopharmacol 2015 Dec 35: 635-44 |
| PMID | 26488675 |
| Title | Fast Versus Slow Strategy of Switching Patients With Schizophrenia to Aripiprazole From Other Antipsychotics. |
| Abstract | This study aimed to compare strategies differing in the speed of switching schizophrenic patients to aripiprazole from other antipsychotic agents, with dual administration for 2 weeks and then tapering off the current antipsychotic in fast (within 1 week) versus slow (within 4 weeks) strategies. This 8-week, open-label, randomized, parallel study assigned patients with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or schizoaffective disorder to either the fast-switching (n = 38) or slow-switching (n = 41) group. Efficacy assessments at 5 time points included Positive and Negative Syndrome Scale and Clinical Global Impression scale. Safety assessments included extrapyramidal symptoms, metabolic profile, serum prolactin level, QTc interval, and adverse events. Drug concentrations and cytochrome P450 CYP2D6 and CYP3A4 genotypes were also measured. The fast- and slow-switching groups were comparable in demographical and clinical features at baseline and dropout rate. In the intention-to-treat analysis using mixed-effects models, there were significant within-group decreases over time in the Positive and Negative Syndrome Scale total scores (P = 0.03) and its subscores except for positive subscores, whereas no between-group differences were found. A reduction in body weight (P = 0.01) and lower levels of total cholesterol (P = 0.03), triglycerides (P = 0.03), and prolactin (P = 0.01) were noted in both groups but no increase in extrapyramidal symptoms or prolongation of QTc. The blood concentrations of aripiprazole in all patients were in a therapeutic range at day 56, with CYP2D6*10 polymorphisms being associated with aripiprazole concentrations. In conclusion, there is no significant difference between the fast- and slow-switching strategy in terms of improvements in clinical symptoms and metabolic profile in this 8-week study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | J Clin Psychopharmacol 2015 Dec 35: 635-44 |
| PMID | 26488675 |
| Title | Fast Versus Slow Strategy of Switching Patients With Schizophrenia to Aripiprazole From Other Antipsychotics. |
| Abstract | This study aimed to compare strategies differing in the speed of switching schizophrenic patients to aripiprazole from other antipsychotic agents, with dual administration for 2 weeks and then tapering off the current antipsychotic in fast (within 1 week) versus slow (within 4 weeks) strategies. This 8-week, open-label, randomized, parallel study assigned patients with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or schizoaffective disorder to either the fast-switching (n = 38) or slow-switching (n = 41) group. Efficacy assessments at 5 time points included Positive and Negative Syndrome Scale and Clinical Global Impression scale. Safety assessments included extrapyramidal symptoms, metabolic profile, serum prolactin level, QTc interval, and adverse events. Drug concentrations and cytochrome P450 CYP2D6 and CYP3A4 genotypes were also measured. The fast- and slow-switching groups were comparable in demographical and clinical features at baseline and dropout rate. In the intention-to-treat analysis using mixed-effects models, there were significant within-group decreases over time in the Positive and Negative Syndrome Scale total scores (P = 0.03) and its subscores except for positive subscores, whereas no between-group differences were found. A reduction in body weight (P = 0.01) and lower levels of total cholesterol (P = 0.03), triglycerides (P = 0.03), and prolactin (P = 0.01) were noted in both groups but no increase in extrapyramidal symptoms or prolongation of QTc. The blood concentrations of aripiprazole in all patients were in a therapeutic range at day 56, with CYP2D6*10 polymorphisms being associated with aripiprazole concentrations. In conclusion, there is no significant difference between the fast- and slow-switching strategy in terms of improvements in clinical symptoms and metabolic profile in this 8-week study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | Clin Drug Investig 2015 Nov 35: 725-33 |
| PMID | 26387027 |
| Title | Evaluation of potential pharmacokinetic drug-drug interaction between armodafinil and risperidone in healthy adults. |
| Abstract | Patients with bipolar I disorder and schizophrenia have an increased risk of obstructive sleep apnea. The effects of armodafinil, a weak cytochrome P450 (CYP) 3A4 inducer, on pharmacokinetics and safety of risperidone, an atypical antipsychotic used to treat major psychiatric illness, were investigated. Healthy subjects received 2 mg risperidone alone and after armodafinil pretreatment (titrated to 250 mg/day). Pharmacokinetic parameters were derived from plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone (formed via CYP2D6 and CYP3A4), collected before and over 4 days after risperidone administration, and from steady-state plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone. Safety and tolerability were assessed. Thirty-six subjects receiving study drug were evaluable for safety; 34 were evaluable for pharmacokinetics. Risperidone maximum plasma concentration (C max) decreased from mean 16.5 ng/mL when given alone to 9.2 ng/mL after armodafinil pretreatment (geometric mean ratio [90 % CI] 0.55 [0.50-0.61]); area under the plasma concentration-time curve from time 0 to infinity (AUC0-?) decreased from 92.3 to 44.5 ng·h/mL (geometric mean ratio [90 % CI] 0.51 [0.46-0.55]). C max and AUC0-? for 9-hydroxyrisperidone were also reduced (geometric mean ratios [90 % CI] 0.81 [0.77-0.85] and 0.73 [0.69-0.77], respectively). Adverse events were consistent with known safety profiles. Consistent with CYP3A4 induction, risperidone and 9-hydroxyrisperidone systemic exposure was reduced in the presence of armodafinil. Concomitant armodafinil and risperidone use may necessitate risperidone dosage adjustment, particularly when starting or stopping coadministration of the two drugs. However, any such decision should be based on patient disease state and clinical status. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |