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PHARMACOKINETICS AND PHARMACODYNAMICS |
From the Otsuka Maryland Research Institute, Rockville, Maryland (Dr. Mallikaarjun, Dr. Bramer) and Bristol-Myers Squibb, Princeton, New Jersey (Dr. Salazar). Dr. Salazar is a fellow of the American College of Clinical Pharmacology.
Address for reprints: Dr. Suresh Mallikaarjun, Otsuka Maryland Research Institute, 2440 Research Boulevard, Rockville, MD 20850.
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ABSTRACT |
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 TOP ABSTRACT PARTICIPANTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Pharmacokinetics • aripiprazole • healthy volunteers • drug safety
The aim of these two placebo-controlled studies was to evaluate the pharmacokinetics, safety, and tolerability of aripiprazole in healthy male subjects. The first study (Study 1) assessed aripiprazole at doses of 5, 10, 15, and 20 mg/day over 14 days of treatment. Subjects were retained for an additional 6 days after the last dose to determine aripriprazole's apparent elimination half-life. Thus, the total observation period was 20 days. The second study (Study 2) assessed aripiprazole titrated to 30 mg/day over the same time period.
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PARTICIPANTS AND METHODS |
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TOPABSTRACTPARTICIPANTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Inclusion/Exclusion Criteria
Both studies enrolled normal healthy male subjects, ages 18 to 45 years, whose body weight was within 15% of "ideal" according to the Metropolitan Life Insurance table.10 Subjects were excluded if they had any disease or condition that could compromise the evaluation of their hematopoietic, renal, hepatic, endocrine, pulmonary, or central nervous function. Additional exclusion criteria were the following: a positive urine test for drugs of abuse; a history of alcohol abuse, drug abuse, mental illness, or drug allergy; a positive test for hepatitis B or HIV; donation of blood or plasma within the previous 30 days; participation in another investigational drug study within the previous 30 days; treatment with any prescription drug during the previous 2 weeks; or treatment with any over-the-counter drug during the previous 3 days.
Study Design
Both studies were randomized, placebo controlled, and double blind. The pharmacokinetic parameters determined were the following: peak plasma level of aripiprazole over 24 hours (Cmax); time from dosing to Cmax (tmax); area under the plasma concentration-time curve, computed by the trapezoidal method for a given 0- to 24-hour interval (AUC0-24); apparent terminal half-life (t1/2); and apparent systemic clearance (CL/F), defined as dose/AUC0-24 at steady state.
In both studies, safety and tolerability were assessed via evaluation of adverse events, vital signs, electrocardiogram (ECG), electroencephalogram (EEG), and clinical laboratory tests. To evaluate the former, study site staff members questioned the subjects and observed any signs or symptoms of an adverse event (AE) on the day of check-in to the clinical unit (Day 1), prior to dosing, during any procedure, at random intervals, at discontinuation, and prior to leaving the clinical unit at completion of the studies (Day 20). The subjects were also instructed to report any spontaneous signs and symptoms they experienced during the study period. Adverse events were classified according to the COSTART adverse reaction dictionary, with the exception of dizziness or lightheadedness, which was reported using the non-COSTART term postural dizziness. The intensity of any experience was graded according to a 3-point scale (mild, moderate, severe). A serious AE was defined as any event that was fatal, life-threatening (i.e., the subject was at immediate risk of death from the experience as it occurred), or permanently disabling; required inpatient hospitalization; or was a congenital abnormality, cancer, or overdose.
In Study 1, 39 subjects were randomized to receive aripiprazole orally, in tablet form, 5 mg/day (n =6), 10 mg/day (n =8), 15 mg/day (n = 6), or 20 mg/day (n =6) or placebo (n = 13). Subjects received aripiprazole or placebo every morning for 14 days. Subjects remained fasted for 4 hours after taking their medication on Days 1, 8, and 14 and for 30 minutes after taking their medication on all other days. Subjects were housed in a clinical environment throughout treatment and for 6 days after taking their last dose. The total observation period was thus 20 days. Doses were tested in sequential ascending order. In all cases, testing of an increased dose was not initiated until the group receiving the previous lower dose had undertaken at least 5 days of treatment with satisfactory tolerance.
Study 2 evaluated the safety, tolerability, and pharmacokinetics of aripiprazole titrated from 10 to 30 mg/day. Treatments consisted of 10 mg/day for the first 2 days, followed by 20 mg/day for the next 2 days, and then 30 mg/day for the remaining 10 days, given as combinations of 10- and 15-mg tablets and matching placebo tablets. Eleven subjects participated in the study: 7 were randomized to active drug and 4 were randomized to placebo. All doses were taken in the morning, in a fasted state. On Days 1, 10, and 14, subjects remained in a fasted state for 4 hours postdose. On all other days, subjects fasted for approximately 30 minutes postdose. As in Study 1, subjects were housed in a clinical environment throughout treatment and for 6 days after taking their last dose to determine the half-life of aripiprazole, so the total observation period was 20 days.
Blood samples for pharmacokinetic analyses were taken on Days 1, 8, and 14 in Study 1 and Days 1, 10, and 14 in Study 2. On each day, samples were taken predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours postdose. In both studies, trough pharmacokinetic samples were taken on Days 3 through 7 and Days 10 through 13, prior to dosing. Additional samples were collected at 24-hour intervals on Days 15 through 20 to determine the half-life of aripiprazole.
The occurrence and severity of AEs were recorded throughout the study. In Study 1, vital signs were measured 1 day before baseline, at baseline, throughout the treatment period, and on Day 19. A complete physical examination was undertaken at screening or baseline. In Study 2, vital signs were measured 1 day before baseline and on Days 1, 3, 5, 10, 14, and 19. On each day, these vital sign measurements were taken just before collection of the predose pharmacokinetic sample and at 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after collection of the pharmacokinetic sample.
In both studies, ECGs were taken at baseline, at 4 hours postdose on Days 1 and 14, and at the end of the study (Day 20). EEGs were taken at baseline and 4 h after dosing on Day 12 or 13. Urinalysis, plus routine assessment of biochemical and hematological parameters, was undertaken on Days 1 and 4, on Day 15 (postdosing), and prior to discharge on Day 20. Serum prolactin levels were measured at baseline, 4 hours after dosing on Day 14 in Study 1 and before dosing, and 4 and 8 hours after dosing on Days 1 and 14 in Study 2.
Bioanalytical Methods
The samples from both studies were analyzed by Kansas City Analytical Services (Shawnee, KS). Aripiprazole and an internal standard were extracted from plasma using liquid-liquid extraction. This extract was subjected to reverse-phase high-performance liquid chromatography on a 5-µm C-18 column. Aripiprazole was then detected and quantified by ultraviolet absorbance detection at 254 nm. System calibration, in the range 5 to 600 ng/mL, was accomplished for each batch of samples by linear regression of the ratio of the peak height of aripiprazole to that of the added internal standard, OPC-14558.
Pharmacokinetic Methods
For each subject, the plasma concentration-time data were analyzed using a noncompartmental method.11 Values for peak plasma concentrations (Cmax) and time to Cmax (tmax) were taken from the observed data. The terminal half-life (t1/2) was estimated by a log-linear regression of at least three terminal plasma concentrations. The area under the curve from time 0 to 24 hours postdose on Day 1 and Day 14 (AUC0-24) was calculated using a trapezoidal method. The oral clearance at steady state (CL/F) was estimated from the dose administered and the AUC0-24 at steady state. The accumulation index (R) was calculated as the ratio of AUC0-24 on Day 14 to Day 1. Plots of plasma concentration versus time were examined to determine the presence or absence of lag time in the absorption phase. The assessment of whether steady state was reached was performed by linear regression of predose concentrations on Days 11, 12, 13, 14, and 15.
A model-dependent analysis was also performed to estimate a set of pharmacokinetic parameters describing the absorption, distribution, and elimination rates for aripiprazole. This model was based on all plasma concentrations collected during the 20 days of the study, and PC NONLIN was used to fit the data. It was assumed that absorption, distribution, and elimination kinetics of the drug remained constant over 20 days. A two-compartment open model with first-order elimination from a central compartment was selected because a preliminary evaluation showed that larger or smaller numbers of compartments were not appropriate.
It was apparent that the absorption rate of aripiprazole was relatively fast compared to the distribution and elimination rates. Based on this observation, the limits on parameter estimates were set to ensure K (abs) > 
> ß. In so doing, the PC NONLIN program was able to converge for each set of data. Various weighting factors (i.e., 1, 1/C1, and 1/C2) were evaluated for this analysis.
Statistical Methods
The linearity of aripiprazole pharmacokinetics was assessed by examining the AUC0-24,Cmax, and CL/F on Day 14 as a function of the administered dose (5-30 mg) from both studies.
Fisher's exact test was used to compare the incidence of treatment-emergent adverse events between the aripiprazole and placebo groups. In all statistical comparisons, significance was set at the = 0.05 level, and tests were two-tailed.
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RESULTS |
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TOPABSTRACTPARTICIPANTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics
Steady-State Determination
In Study 1, assessment of steady state was undertaken using plasma concentrations determined on Days 11, 12, 13, 14, and 15. All but 4 subjects—2 in the 15-mg group and 2 in the 20-mg group—achieved steady state by Day 14. These 4 subjects achieved plasma concentrations within 90% of steady state by the end of the study, Day 14. In Study 2, all subjects also reached steady state, or plasma levels at 90% of steady state, within 14 days of dosing. The mean plasma concentrations on Day 14 for both studies are shown in Figure 1.
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Noncompartmental Pharmacokinetic Parameters
Table II shows the model-independent pharmacokinetic parameters for subjects taking aripiprazole in both studies. Aripiprazole plasma concentrations were 4 to 6 times higher on Day 14 compared to Day 1 based on the accumulation index. This is consistent with the accumulation of a drug with a half-life of 50 to 75 hours, administered every 24 hours. It was also found that tmax occurred approximately 3 to 5 hours after dosing, and both Cmax and AUC0-24 increased with dose.
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The mean Cmax ranged from 98 to 452 ng/mL, and the mean AUC0-24 ranged from 1633 to 8360 ng•h/mL following multiple oral doses of aripiprazole 5 to 30 mg, respectively. The median tmax for the 5-mg and 30-mg groups was 4 and 3 hours, respectively. There did not appear to be a lag time in the absorption phase, based on the plasma concentrations at 1 hour postdose.
Linearity
Cmax was found to increase in a linear manner over the range 5 to 30 mg/day. Linear regression of the untransformed AUC0-24 and Cmax on Day 14 versus dose (Figure 2) indicated that the 95% confidence interval of the intercept (-1105 to 1700 for the AUC0-24 and -37 to 87 for Cmax) included zero for both parameters. Regression of the log-transformed AUC0-24 and Cmax on Day 14 as a function of log dose12 showed that the confidence interval of the slope included 1, indicating linear pharmacokinetics across the doses studied. Linear regression of CL/F versus dose indicated that the slope was not significantly different from zero (p = 0.29). One subject in the 20-mg group, who had 112% greater AUC and 96% greater Cmax compared to the group mean, appeared to be an outlier and was excluded from the regression analysis.
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Saturation or Induction Effects
If the pharmacokinetics of a drug indicated saturation or induction of metabolism, then the slope of the clearance and the terminal elimination half-life as a function of the dose should be significantly different from zero. The regression of aripiprazole clearance versus dose (p = 0.29) and terminal half-life versus dose (p = 0.36) were not significantly different from zero, indicating that there is no saturation or induction of aripiprazole metabolism over the dose range 5 to 30 mg/day.
Compartmental Analysis
Study 1. The data were fitted to a two-compartment open model with first-order absorption and elimination from the central compartment. Each subject fitted the model reasonably well, based on the examination of residuals, which were random, and the coefficient of determination (r2). Table III shows the mean and SD values for the pharmacokinetic parameters derived from the fitting.
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The absorption half-life of aripiprazole was approximately 1 to 2 hours for all doses. The mean distribution ( half-life) was between 2.1 and 4.5 hours. The elimination phase half-life (ß phase), with mean values between 58.0 and 78.6 hours, generally agreed with the values from the model-independent analysis. The apparent distribution volume (V/F) ranged from 116 L at 5 mg/day to 196 L at 20 mg/day.
Study 2. Plasma data for each subject in Study 2 were also fitted to the same two-compartment open model (Table III). The findings were consistent with those seen in Study 1. The absorption half-life phase, for example, was less than 2 hours. Distribution ( half-life) was also similar to that in the previous study, with a mean of 2.3 hours. The elimination phase half-life (ß phase) had a mean value of 70.5 hours, which is in general agreement with values from the model-independent analysis. The mean apparent distribution volume (V/F) of 132 L agrees with the values obtained in Study 1.
Safety and Tolerability
Of the 39 subjects randomized in Study 1, 38 were included in the analysis of safety and tolerability. One randomized subject received the wrong dose; his data were therefore not included in the analysis. All 11 subjects in Study 2 were included in the safety and tolerability analysis.
In both studies, adverse events were generally mild to moderate. Four adverse events classified as severe were reported in each study. In Study 1, these were three occurrences of postural dizziness (two in the 5-mg group and one in the 10-mg group) and one occurrence of somnolence (15-mg group). In Study 2, these severe events were two incidences of vomiting, one incidence of postural hypotension, and one incidence of asthenia, all with aripiprazole treatment. All of the severe events occurred during Day 1 in each study and subsequently resolved. One of these events (vomiting) led to discontinuation from the study.
There were two withdrawals due to adverse events, one in each study. Both occurred on Day 1. In Study 1, 1 subject in the aripiprazole 20-mg group withdrew due to tachycardia. Other concomitant adverse events included nausea and postural dizziness. In Study 2, 1 subject withdrew after experiencing nausea and vomiting shortly after taking his first dose of aripiprazole. An upper endoscopy revealed distal esophagitis, judged by the investigator to be a preexisting condition unrelated to study medication.
Nausea, postural dizziness, and somnolence were the most commonly reported adverse events in the aripiprazole groups in both studies. These three adverse events accounted for 47% and 38% of all adverse events and for 86% and 89% of adverse events occurring on Day 1 in Study 1 and Study 2, respectively.
Adverse events in subjects taking aripiprazole generally occurred early in the dosing period. Very few, if any, adverse events were present when steady state was reached sometime between Days 11 and 14 of the study. In Study 1, 60% of the adverse events in patients taking aripiprazole were reported on the first day, and 76% were reported during the first 3 days of dosing. This compares with 7.4% of adverse events in the placebo group reported on the first day and 33% reported by Day 3. Similarly, in Study 2, 56% of adverse events in patients taking aripiprazole were reported on the first day of dosing, compared with 3% in the placebo group. The occurrence of an adverse event did not appear to depend on aripiprazole plasma concentrations. A relatively rapid tolerance appeared to be built up to the drug-related side effects.
Akathisia was reported as an adverse event in all four aripiprazole groups in Study 1 and in the aripiprazole treatment group in Study 2. It is difficult, however, to distinguish between true drug-induced akathisia and general restlessness due to confinement in a controlled clinical setting. Such restlessness is exemplified by the fact that akathisia was reported as an adverse event in more than 40% of the placebo group in both studies.
In both studies, postural dizziness was considered to be clinically significant by the investigators. In Study 1, postural dizziness was reported by 3 or 4 subjects in each aripiprazole group compared with 4 subjects in the placebo group. In Study 2, 6 of 7 aripiprazole subjects reported postural dizziness compared with 1 of 4 placebo subjects. In both studies, some subjects receiving aripiprazole were unable to stand for measurement of vital signs due to light-headedness. This affected the reported incidence of orthostatic hypotension (defined as a 
25 mmHg decrease in systolic blood pressure and a 20% increase in heart rate on changing position from supine to standing); as according to protocol, such subjects were conservatively assumed to have orthostatic hypotension. In Study 1, 15 of 26 subjects receiving aripiprazole experienced orthostatic hypotension based on actual vital sign measurements. These values compared with 6 of 12 subjects in the placebo group. Similarly, of the 7 subjects receiving aripiprazole in Study 2, 3 subjects had measured orthostatic hypotension, while a further 3 subjects were conservatively assumed to have orthostatic hypotension. There were no instances of orthostatic hypotension in the placebo group.
Evaluation of other vital signs, clinical chemistry, hematology, and urinalysis revealed no clinically relevant findings in either study. Similarly, prolactin levels were not increased in any of the treatment groups (Figure 3), and there were no clinically relevant changes in EEGs or ECGs—the latter exemplified by the QTc measurements taken on Days 1 and 14 (Table IV).
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DISCUSSION |
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TOPABSTRACTPARTICIPANTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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In both studies, the variability in Cmax and AUC0-24 appeared to rise as the dose of aripiprazole was increased, especially in the 20-mg and 30-mg dose groups. This is not, however, unexpected since the coefficient of variation (%CV) is approximately similar across the pharmacokinetic parameters, except for the 20-mg dose, which had a greater %CV due to the subject who had high plasma concentrations compared to the others in the group.
Studies 1 and 2 both found that the pharmacokinetics of aripiprazole was described by a two-compartment open model with first-order absorption. The pharmacokinetic parameters obtained using this model were similar to those seen using a model-independent analysis. Furthermore, the parameters obtained indicated that the absorption rate of aripiprazole was relatively rapid compared to distribution and elimination rates.
The present data suggest that aripiprazole can be administered on a once-daily basis with few or no significant adverse symptoms. The safety and tolerability profile showed that if adverse events occurred, they tended to be mild to moderate and generally occurred early in the study. The potential for adverse events decreased with continued dosing of aripiprazole, indicating apparent tolerance to adverse events at higher drug-plasma concentrations. In Study 1, for example, more than 75% of adverse events in the aripiprazole groups were reported during the first 3 days of dosing. This improvement in tolerance is clinically important because two of the most frequent adverse events, postural dizziness and nausea, are symptoms that could complicate dosing and tolerability on a day-to-day basis if present for a sustained period.
Differences in the tolerability of antipsychotics between healthy volunteers and patients with schizophrenia are well known.13 The efficacy, as well as favorable safety and tolerability, of aripiprazole in patients with acute exacerbation of schizophrenia or schizoaffective disorder has been established in multiple clinical trials. A meta-analysis of safety data from five short-term (4- or 6-week) clinical studies showed that adverse events occurred at a similar incidence in patients receiving aripiprazole and those receiving placebo.8 For example, the incidence of nausea was similar in the aripiprazole (14%) and placebo (10%) groups. Furthermore, the incidence of nausea with aripiprazole was comparable to that with haloperidol (11%) and risperidone (11%) treatment used as active controls in these studies.
The incidence of orthostatic hypotension was high in both the aripiprazole and placebo groups in Studies 1 and 2. However, this does not reflect the experience from clinical trials involving patients with schizophrenia. A meta-analysis of these clinical trial data showed a low incidence rate for orthostatic hypotension with both aripiprazole treatment (1.9%) and placebo (1.0%).8 Such minor cardiovascular adverse effects from antipsychotic drugs are extremely common.14
More important, there were no clinically meaningful changes in heart rate or other ECG parameters, including PR, QT, QTc, and QRS intervals, at doses up to 30 mg/day. This has been confirmed by safety and tolerability data from clinical studies involving patients with schizophrenia or schizoaffective disorder, which showed a low liability for cardiovascular effects with aripiprazole treatment. Unlike other antipsychotics (e.g., sertindole and ziprasidone) that have been found to elongate the QTc interval, which can lead to a potentially fatal ventricular arrhythmia, aripiprazole did not show a prolongation of QTc.
Assessment of clinical chemistry, hematology, urinalysis, and EEG revealed no clinically significant changes over the course of the studies. Most notably, there were no increases in prolactin levels. Examination of these safety issues is clearly of considerable importance, given that the use of some antipsychotic drugs is greatly limited by safety concerns. Aripiprazole's lack of effect on prolactin levels is also clinically important given the ability of hyperprolactinemia to induce hypogonadism, a condition that can lead to sexual dysfunction and/or galactorrhea, and is potentially linked to osteoporosis, cancer, and heart disease.15 It is well established that currently available antipsychotics, such as haloperidol and risperidone, can increase prolactin levels.15,16
Although a number of hematological issues can also arise with the use of antipsychotics, aripiprazole produced no such clinically significant changes in these studies. Leukopenia and agranulocytosis, for instance, are well reported and dangerous side effects associated with the use of some typical and atypical antipsychotics. These potentially life-threatening phenomena have led to treatment discontinuation and the consequent reemergence of psychiatric symptoms in a number of patients.17 The potential for agranulocytosis with clozapine has, for example, severely restricted the use of this drug.18 Recent case studies have also suggested the possibility that in some patients, leukopenia or agranulocytosis during olanzapine treatment may also be dose related.17
In summary, the results of the two studies indicate that aripiprazole has a predictable pharmacokinetic profile, with linear pharmacokinetics over the 5- to 30-mg/day dose range studied. The reported half-life also supports the use of aripiprazole for once-daily dosing. While both studies involved young, healthy male volunteers, the results provide a firm foundation for further investigations. Aripiprazole was shown to have a good safety and tolerability profile in these studies. This is consistent with the results from subsequent clinical trials in patients with schizophrenia, which have shown that aripiprazole is efficacious and well tolerated, with a low liability for sedation, EPS, weight gain, QTc interval prolongation, or hyperprolactinemia. Areas for such future studies include the pharmacokinetics, safety, and tolerability of aripiprazole in special populations; delineation of aripiprazole's metabolic profile; drug interaction studies based on its metabolic profile; and population pharmacokinetic/pharmacodynamic analysis in patients with schizophrenia and schizoaffective disorder.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTPARTICIPANTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication July 31, 2003; Revised version accepted November 14, 2003.
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REFERENCES |
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TOPABSTRACTPARTICIPANTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, et al: Aripiprazole, a novel antipsychotic, is a high affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 2002;302: 381-389.
2. Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA: The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur J Pharmacol 2002;441: 137-140.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. McQuade R, Burris KD, Jordan S, Tottori K, Kurahashi N, Kikuchi T: Aripiprazole: a dopamine-serotonin system stabilizer. Int J Neuropsychopharm 2002;5(Suppl. 1): S176.
4. Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GC, Zimbroff DL, et al: Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63: 763-771.[Web of Science][Medline] [Order article via Infotrieve]
5. Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali MW, Stock E, et al: Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs. placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 2003;60: 681-690.
6. Pigott TA, Carson WH, Saha AR, Torbeyns A, Stock E, Ingenito GG, for the Aripiprazole Study Group: Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study. J Clin Psychiatry 2003;64: 1048-1056.[Web of Science][Medline] [Order article via Infotrieve]
7. Kasper S, McQuade RD, Saha A, Carson WH, Ali M, Archibald D, et al: Efficacy and safety of aripiprazole versus haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol; in press.
8. Marder SR, McQuade RD, Stock E, Kaplita S, Marcus R, Safferman AZ, et al: Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophrenia Res 2003;61: 123-126.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Tamminga CA: Partial dopamine agonists in the treatment of psychosis. J Neural Transm 2002;109: 411-420.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. MLIC: Metropolitan height and weight tables. Stats Bull Met Life Insurance Co 1983;64: 2-9.
11. Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, et al: Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 1999;20: 612-627.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. Gough K, Hutchinson M, Keene O: Assessment of dose proportionality: report from the Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Joint Working Party. Drug Info J 1995;29: 1039-1048.
13. Cutler NR: Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients. J Clin Psych 2001;62(Suppl. 5): 10-13, discussion 23-24.
14. Buckley NA, Sanders P: Cardiovascular adverse effects of antipsychotic drugs. Drug Safety 2000;23: 215-228.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
15. Dickson RA, Glazer WM: Neuroleptic-induced hyperprolactinemia. Schizophr Res 1999;35: S75-S86.
16. Kleinberg DL, Davis JM, de Coster R, Van Baelen B, Brecher M: Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19: 57-61.[CrossRef][Medline] [Order article via Infotrieve]
17. Kodesh A, Finkel B, Lerner AG, Kretzmer G, Sigal M: Dose-dependent olanzapine-associated leukopenia: three case reports. Int Clin Psychopharmacol 2001;16: 117-119.[Medline] [Order article via Infotrieve]
18. Kluznik JC, Walbek NH, Farnsworth MG, Melstrom K: Clinical effects of a randomized switch of patients from clozaril to generic clozapine. J Clin Psychiatry 2001;62(Suppl. 5): 14-17, discussion 23-24.
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