opc-14857 and Schizophrenia

It has been suggested that a plasma trough concentration of aripiprazole plus its active metabolite, dehydroaripiprazole of 225 ng/mL is a threshold for a good therapeutic response in the treatment of acutely exacerbated patients with schizophrenia. The present study investigated whether or not an optimal dose of aripiprazole could be predicted from these concentrations at week 1.. The subjects were 26 inpatients with schizophrenia, who received aripiprazole once a day for 3 weeks. The daily doses were 12 mg for the first week and 24 mg for the next 2 weeks. No other drugs except biperiden and flunitrazepam were coadministered. Blood samples were taken at weeks 1 and 3 after the treatment. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection.. There was a significant linear relationship between the plasma concentrations of aripiprazole plus dehydroaripiprazole at weeks 1 (x) and 3 (y) (P < 0.001). Regression equation was y = 2.580x + 34.86 (R = 0.698). Based on the equation, a nomogram to estimate an optimal dose of aripiprazole could be constructed.. The present study suggests that an optimal dose of aripiprazole for the treatment of patients with schizophrenia can be predicted from the plasma concentrations of the sum of the 2 compounds at week 1.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Nomograms; Piperazines; Quinolones; Schizophrenia; Time Factors; Treatment Outcome; Young Adult

To assess acute efficacy and safety of 9.75 mg of intramuscular (IM) injections of the atypical antipsychiatric aripiprazole in patients with schizophrenia or bipolar disorder and acute agitation.. Open-label trial of IM injections of aripiprazole and 24-hour monitoring of clinical response in patients with major psychoses and acute agitation. Partial analysis of blood levels of the administered drug to correlate with clinical response.. Acute psychiatric care wards in a single university hospital.. A total of 201 acutely agitated patients (79 with schizophrenia and 122 with bipolar disorder I).. Aripiprazole 9.75 mg IM injection.. We evaluated clinical response using the Excitatory Component of the Positive and Negative Syndrome Scale (PANSS-EC), the Agitation/Calmness Evaluation Scale (ACES), and the Clinical Global Impressions scale (CGI). Assessments were conducted 30, 60, 90, and 120 minutes and 24 hours after the first injection for PANSS-EC and ACES, and 2, 4, 6, and 24 hours for CGI. Response was at least a 40% decrease in PANSS-EC scores. We measured serum aripiprazole and dehydroaripiprazole levels in a subsample. IM aripiprazole significantly improved clinical measures. PANSS-EC improved progressively, starting after 30 minutes. ACES improved after 90 minutes and continued thereafter. Effects were sustained, with steadily decreasing CGI scores, until the 24th hour. Response rate was 83.6% after 2 hours, but with repeat injections, it rose to over 90% with no differences among diagnostic groups. Although there were gender differences in the response to individual PANSS-EC items, the responses were similar overall. Neither clinical monitoring nor patient reporting revealed any side effects. No therapeutic window was identified, and levels did not correlate with any clinical measure.. Aripiprazole was effective and safe in reducing acute agitation in patients with bipolar disorder or schizophrenia. Our results compare favorably to double-blind trials, probably due to higher expectations in trials involving no placebo arm. Absence of side effects could be related to the short observation time.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Female; Hospitals, University; Humans; Injections, Intramuscular; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Psychomotor Agitation; Quinolones; Schizophrenia; Time Factors; Treatment Outcome; Young Adult

The effects of paroxetine coadministration on plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, were studied in 14 Japanese patients with schizophrenia.. The patients had been treated with aripiprazole (24 mg/d in 5 cases, 12 mg/d in 5 cases, and 6 mg/d in 4 cases) for at least 2 weeks. Paroxetine 10 mg/d was coadministered during the first week, and the dose was increased to 20 mg/d during the second week. Blood samples were taken 3 times, before the start of paroxetine and then 1 and 2 weeks after paroxetine coadministration. On the same days, the severity of illness and extrapyramidal adverse effects were evaluated by the clinical global impressions and the Drug-Induced Extra-Pyramidal Symptoms Scale, respectively. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection.. Plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole during coadministration of paroxetine 10 and 20 mg/d were significantly (P < 0.05) higher (1.5-fold and 1.7-fold; 1.4-fold and 1.5-fold) than those before paroxetine coadministration. Those values during coadministration of paroxetine 20 mg/d were also significantly (P < 0.05) higher (1.1-fold and 1.1-fold) than those during coadministration of paroxetine 10 mg/d. Plasma concentrations of dehydroaripiprazole were unchanged throughout the study period. The mean clinical global impression score was significantly (P < 0.05) higher during the paroxetine 10 mg/d than that before coadministration, whereas the Drug-Induced Extra-Pyramidal Symptoms Scale scores remained unchanged during the study.. This study suggests that lower doses (10-20 mg/d) of paroxetine coadministration increase plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole.

Topics: Adult; Aged; Antipsychotic Agents; Aripiprazole; Asian People; Basal Ganglia Diseases; Chromatography, Liquid; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Japan; Male; Mass Spectrometry; Middle Aged; Paroxetine; Piperazines; Psychiatric Status Rating Scales; Quinolones; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Young Adult

Aripiprazole is widely used to treat schizophrenia. Plasma levels of aripiprazole and its active metabolite dehydroaripiprazole and their clinical responses in patients were explored. Forty-five (male/female: 19/26) patients with schizophrenia were treated with aripiprazole after a washout period of at least 3 days. There was no concomitant psychotropic except benzodiazepines for insomnia. The Positive and Negative Syndrome Scale (PANSS) was used to measure the clinical response at baseline and at weeks 2, 4, and 6. Blood was drawn at week 6 to measure the plasma concentrations of aripiprazole and dehydroaripiprazole. Patients with a PANSS score that decreased by more than 20% were defined as responders after 6 weeks of treatment. There was no difference in baseline PANSS scores or the daily dosage used between responders (n = 28) and nonresponders (n = 17) (15.0 ± 5.9 vs 12.9 ± 6.9 mg, respectively; P = 0.203). The responders showed a trend toward a higher plasma concentration of aripiprazole than nonresponders (234.4 ± 156.7 vs 163.5 ± 77.2 ng/mL, respectively; P = 0.117) and a significantly higher plasma concentration of dehydroaripiprazole (101.6 ± 58.0 vs 66.0 ± 48.4, respectively; P = 0.023). Higher plasma concentrations of aripiprazole and its active metabolite dehydroaripiprazole were noted in responders than nonresponders. Compared with Western patients, Oriental patients had higher plasma concentrations of aripiprazole and dehydroaripiprazole at the same dose. We suggest that therapeutic drug monitoring of aripiprazole will help improve the response in clinical practice.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Asian People; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Quinolones; Schizophrenia; Treatment Outcome

A rapid, convenient, precise HPLC method was developed for the simultaneous determination of aripiprazole and its active metabolite dehydroaripiprazole in blood serum. The separation was carried out by RP HPLC on Symmetry C₁₈ column (150 x 4.6 mm; 5 μm). The mobile phase was composed of acetonitrile: water (30 : 70, v/v), pH 3.0 adjusted with o-phosphoric acid. The detection was monitored at 220 nm.

Topics: Acetonitriles; Activation, Metabolic; Antipsychotic Agents; Aripiprazole; Buffers; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Drug Compounding; Drug Monitoring; Humans; Hydrogen-Ion Concentration; Phosphoric Acids; Piperazines; Quinolones; Schizophrenia; Solvents; Water

We studied the effects of various factors, including genetic polymorphisms of the cytochrome P450 (CYP) 2D6, CYP3A5, and ABCB1, age, gender, and smoking habit on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in 89 patients with schizophrenia (46 males, 43 females).. All patients had been receiving fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 56) and 12 mg (n = 33). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection. The CYP2D6 (CYP2D6*5, CYP2D6*10, and CYP2D6*14), CYP3A5 (CYP3A5*3), and ABCB1 (C3435T and G2677T/A) genotypes were identified by PCR analyses.. The mean concentration/dose ratios of aripiprazole and the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with 1 (P < 0.01 and P < 0.01) or 2 (P < 0.001 and P < 0.05) mutated alleles for CYP2D6 than in those without mutated alleles. No differences were found in the values of dehydroaripiprazole among CYP2D6 genotypes. There were no differences in the values of aripiprazole, dehydroaripiprazole, and the sum of the 2 compounds among CYP3A5 or the 2 ABCB1 variants. Multiple regression analyses including these polymorphisms, age, gender, and smoking habit showed that only the number of mutated alleles for CYP2D6 was correlated with mean concentration/dose ratios of aripiprazole [standardized partial correlation coefficients (beta) = 0.420, P < 0.001] and the sum of the 2 compounds (standardized beta = 0.335, P < 0.01).. The findings of this study suggest that CYP2D6 genotypes play an important role in controlling steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects, whereas CYP3A5 and ABCB1 genotypes seemed unlikely to have an impact.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Asian People; ATP Binding Cassette Transporter, Subfamily B; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Male; Middle Aged; Piperazines; Polymorphism, Genetic; Quinolones; Schizophrenia; Young Adult

The CYP2D6*10(*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of approximately 50%. We studied the effects of the *10 allele on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole. The subjects were 63 Japanese patients with schizophrenia who had only the wild-type or *10 alleles. Twenty-seven patients were homozygous for the wild-type allele, 31 were heterozygous, and five were homozygous for the *10 allele. All patients had been receiving the fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 40) and 12 mg (n = 23). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. The mean ± standard deviation values of concentration/dose ratios of aripiprazole in the patients with zero, one, and two *10 alleles were 9.0 ± 2.9, 12.7 ± 4.4, and 19.0 ± 6.8 ng/mL/mg, respectively, and those values for dehydroaripiprazole were 4.9 ± 1.6, 5.9 ± 1.7, and 5.9 ± 1.9 ng/mL/mg, respectively. The respective values for the sum of aripiprazole and dehydroaripiprazole were 13.9 ± 4.3, 18.6 ± 5.9, and 24.6 ± 8.5 ng/mL/mg. The mean concentration/dose ratios of aripiprazole were significantly (P < 0.01 or P < 0.001) different among the three genotype groups. The values for the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with one (P < 0.01) and two (P < 0.001) *10 alleles compared with those with zero *10 alleles. This study suggests that the *10 allele plays an important role in controlling the steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects.

Topics: Alleles; Antipsychotic Agents; Aripiprazole; Asian People; Cytochrome P-450 CYP2D6; Drug Monitoring; Female; Genotype; Humans; Male; Piperazines; Quinolones; Schizophrenia

A sensitive high-performance CZE combining on-column field-amplified sample injection (FASI) has been developed for simultaneous determination of aripiprazole and its active metabolite, dehydroaripiprazole, in human plasma. A sample pretreatment by means of liquid-liquid extraction (LLE) (diethyl ether) with subsequent quantitation by FASI-CZE was used. The separation of aripiprazole and dehydroaripiprazole was performed using a BGE containing 150 mM phosphate buffer (pH 3.5) with 40% methanol and 0.02% PVA as a dynamic coating to reduce interaction of analytes with the capillary wall. Before sample loading, a methanol plug (0.3 psi, 6 s) was injected to permit FASI for stacking. The samples were injected electrokinetically (10 kV, 30 s) to introduce sample cations and the applied voltage was 20 kV with on-column detection at 214 nm. Several parameters affecting the separation and sensitivity of the drug and its active metabolite were studied, including reconstitution solvent, organic modifier, pH and concentration of phosphate buffer. The linear ranges of the method for test drug and its active metabolite, in plasma using amlodipine as an internal standard, were over the range 5.0-100.0 ng/mL. One female volunteer (25 years old) was orally administered a single dose of 10 mg aripiprazole (Abilify, Otsuka) and blood samples were drawn over a 60 h period for pharmacokinetic study. The method was also applied to monitor the concentration of aripiprazole and dehydroaripiprazole in plasma collected after oral administration of 20 or 30 mg aripiprazole (Abilify, Otsuka) daily at steady state in one schizophrenic patient.

Topics: Adult; Amlodipine; Antipsychotic Agents; Aripiprazole; Dose-Response Relationship, Drug; Electrophoresis, Capillary; Female; Humans; Hydrogen-Ion Concentration; Male; Piperazines; Quinolones; Reference Values; Schizophrenia; Solvents

Aripiprazole is a fairly new atypical antipsychotic substance. It acts as a partial D2- and 5-HT1A-agonist and as a 5-HT2A-antagonist. To date, there are few data concerning the dose-serum concentration relationship in children and adolescent psychiatric patients. Also, there are only few data on the influence of age, sex, body mass index, smoking behavior, and comedication on aripiprazole serum concentrations. In 33 consecutively admitted patients of a child and adolescent psychiatric hospital [age (mean +/- standard deviation) 18.7 +/- 1.7 years (range, 13.5-21.6 years)], 117 steady-state serum concentrations (repeated samples from individuals) of aripiprazole and its metabolite dehydroaripiprazole were assessed using high-performance liquid chromatography. The aripiprazole (mean +/- standard deviation) daily dose was 12.9 +/- 6.4 mg (range, 5-30 mg); the aripiprazole serum concentration was 142.0 +/- 122.7 ng/mL (range, 40.0-648.3 ng/mL; interquartile range, 74.0-167.0 ng/mL). The mean dehydroaripiprazole serum concentration was 51.6 +/- 22.3 ng/mL (range, 30.0-111.6 ng/mL; interquartile range, 34.3-62.1 ng/mL). There was a positive correlation between oral dose and serum concentrations of aripiprazole (r = 0.548, P = 0.001) and dehydroaripiprazole (r = 0.740, P < 0.0005). Aripiprazole serum concentrations showed high inter- and intraindividual variability. Intraindividual variability was one- to 9.3-fold (dehydroaripiprazole: one- to 8.6-fold) and maximum interindividual variability 6.4-fold (dehydroaripiprazole: 6.8-fold). No significant influence was detected for age, sex, body mass index, comedication, and smoking on concentration-to-dose aripiprazole serum concentrations. Further studies are required to obtain data on the relationship between serum concentrations and resulting clinical effects.

Topics: Adolescent; Adult; Aging; Antipsychotic Agents; Aripiprazole; Biotransformation; Body Mass Index; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Piperazines; Quinolones; Regression Analysis; Schizophrenia; Sex Characteristics; Young Adult

Aripiprazole is a novel atypical antipsychotic drug with neuroprotective properties. As excessive glutamate release is now considered to be part of the pathophysiology of schizophrenia, the objective of this study was to use an in vitro assay system to investigate the effect of aripiprazole and its human metabolite OPC14857 on the release of endogenous glutamate from isolated nerve terminals (synaptosomes), freshly prepared from rat prefrontal cortex. Both aripiprazole and OPC13857 potently inhibited 4-aminopyridine (4-AP)-evoked glutamate release in a concentration-dependent manner. Inhibition of glutamate release by aripiprazole and OPC13857 was associated with a reduction of 4AP-evoked Na+ influx and depolarization, as well as downstream elevation of cytoplasmic free calcium concentration mediated via N- and P/Q-type voltage-dependent Ca2+ channels (VDCCs). Release induced by direct Ca2+ entry with Ca2+ ionophore (ionomycin) was unaffected by aripiprazole or OPC13857, indicating that the inhibitory effect of aripiprazole or OPC13857 is not due to directly interfering with the release process at some point subsequent to Ca2+ influx. In addition, the dopamine D2 receptor antagonist haloperidol and the 5-HT 1A receptor antagonist WAY100635 all effectively blocked the aripiprazole or OPC13857-mediated inhibition of 4-AP-evoked glutamate release. Moreover, aripiprazole or OPC13857 modulation of 4-AP-evoked glutamate release appears to involve a protein kinase A (PKA) signaling cascade, insofar as pretreatment of synaptosomes with the PKA inhibitor H89 suppressed the inhibitory effect of aripiprazole or OPC13857. Together, these results suggest that aripiprazole and its human metabolite OPC14857 inhibit glutamate release from rat prefrontocortical nerve terminals, likely by the activation of dopamine D2 and 5-HT 1A receptors, which subsequently results in the reduction of nerve terminal excitability and downstream VDCC activation through a signaling cascade involving PKA. These actions of aripiprazole may contribute to its neuroprotective effect in excitotoxic injury.

Topics: Animals; Aripiprazole; Dose-Response Relationship, Drug; Glutamic Acid; Humans; Male; Neuroprotective Agents; Piperazines; Prefrontal Cortex; Presynaptic Terminals; Quinolones; Rats; Rats, Sprague-Dawley; Schizophrenia

Aripiprazole, a novel antipsychotic drug, is metabolized by CYP3A4 and CYP2D6 forming mainly its active metabolite dehydroaripiprazole. In this study, aripiprazole and dehydroaripiprazole serum levels of psychiatric patients were measured and related to dose, comedication, and clinical effects including therapeutic and side effects. Patients were treated with mean doses of 20 +/- 8 mg/day of aripiprazole (median 15 mg, range 7.5-60 mg). Serum levels correlated significantly with the dose (r = 0.419; P < 0.01), with a mean value of aripiprazole of 214 +/- 140 ng/ml. Mean concentrations of the active metabolite dehydroaripiprazole amounted to 40% of the parent compound. Comedication with CYP3A4 and CYP2D6 inducers or inhibitors changed serum levels up to 51%. Improvement was best in patients with a serum level between 150 and 300 ng/ml. No or only mild side effects were detected in patients, with aripiprazole plasma concentrations between 110 and 249 ng/ml. A total of 32% of the patients who received no other antipsychotic drug besides aripiprazole reported side effects; tension being the most frequent one. Since serum levels of aripiprazole and dehydroaripiprazole were highly variable between individuals, and distinct ranges were associated with good therapeutic response and minimal side effects, it seems likely that therapeutic drug monitoring can be helpful to improve the antipsychotic drug therapy.

Topics: Adult; Aged; Antipsychotic Agents; Aripiprazole; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Female; Humans; Male; Middle Aged; Piperazines; Quinolones; Schizophrenia