Adjunctive therapy with pregabalin in generalized anxiety disorder patients with partial response to SSRI or SNRI treatment.

This study evaluated the efficacy of adjunctive pregabalin versus placebo for treatment of patients with generalized anxiety disorder (GAD) who had not optimally responded to previous or prospective monotherapies. This was a phase 3, randomized, double-blind, placebo-controlled study. Patients diagnosed with GAD who had a historical and current lack of response to pharmacotherapy [Hamilton Anxiety Rating Scale (HAM-A) of ≥ 22 at screening] were randomized to adjunctive treatment with either pregabalin (150-600 mg/day) or placebo. The primary outcome measure was the change in HAM-A total scores after 8 weeks of combination treatment. Adverse events were regularly monitored. Randomized patients (N=356) were treated with pregabalin (n=180) or placebo (n=176). Mean baseline HAM-A scores were 20.7 and 21.4, respectively. After treatment, the mean change in HAM-A was significantly greater for pregabalin compared with placebo (-7.6 vs. -6.4, respectively; P<0.05). HAM-A responder rates (≥ 50% reduction) were significantly higher for pregabalin (47.5%) versus placebo (35.2%; P=0.0145). The time-to-sustained response favored pregabalin over placebo (P=0.014). Adverse events were consistent with previous studies and discontinuations were infrequent for pregabalin (4.4%) and placebo (2.3%). The study was discontinued early after an interim analysis. The results indicate that adjunctive pregabalin is an efficacious therapy for patients with GAD who experience an inadequate response to established treatments.

Effects of high-dose ziprasidone and haloperidol on the QTc interval after intramuscular administration: a randomized, single-blind, parallel-group study in patients with schizophrenia or schizoaffective disorder.

BACKGROUND: Antipsychotic agents have been associated with a prolonged QT interval. Data on the effects of ziprasidone and haloperidol on the QTc interval are lacking. OBJECTIVE: This study aimed to characterize the effects of 2 high-dose intramuscular injections of ziprasidone and haloperidol on the QTc interval at T(max). METHODS: This randomized, single-blind study enrolled patients with schizophrenia or schizoaffective disorder in whom long-term antipsychotic therapy was indicated. Patients were randomized to receive 2 high-dose intramuscular injections of ziprasidone (20 and 30 mg) or haloperidol (7.5 and 10 mg) separated by 4 hours. The primary outcome measure was the mean change from baseline in QTc at the T(max) of each injection. Each dose administration was followed by serial ECG and blood sampling for pharmacokinetic determinations. Twelve-lead ECG data were obtained immediately before and at predetermined times after injections. ECG tracings were read by a blinded central reader. Blood samples were obtained immediately before and after injections. Point estimates and 95% CIs for mean QTc and changes from baseline in QTc were estimated. No between-group hypothesis tests were conducted. For the assessments of tolerability and safety profile, patients underwent physical examination, including measurement of vital signs, clinical laboratory evaluation, and monitoring for adverse events (AEs) using spontaneous reporting. RESULTS: A total of 59 patients were assigned to treatment, and 58 received study medication (ziprasidone, 31 patients; haloperidol, 27; age range, 21-72 years; 79% male). After the first injection, mean (95% CI) changes from baseline were 4.6 msec (0.4-8.9) with ziprasidone (n = 25) and 6.0 msec (1.4-10.5) with haloperidol (n = 24). After the second injection, these values were 12.8 msec (6.7-18.8) and 14.7 msec (10.2-19.2), respectively. Mild and transient changes in heart rate and blood pressure were observed with both treatments. None of the patients had a QTc interval >480 msec. Two patients in the ziprasidone group experienced QTc prolongation >450 msec (457 and 454 msec) and QTc changes that exceeded 60 msec (62 and 76 msec) relative to the time-matched baseline values. With haloperidol, QTc interval values were <450 msec with no changes >60 msec. Treatment-emergent AEs were reported in 29 of 31 patients (93.5%) in the ziprasidone group and 25 of 27 patients (92.6%) in the haloperidol group; most events were of mild or moderate severity. Frequently reported AEs were somnolence (90.3% and 81.5%, respectively), dizziness (22.6% and 7.4%), anxiety (16.1% and 7.4%), extrapyramidal symptoms (6.5% and 33.3%), agitation (6.5% and 18.5%), and insomnia (0% and 14.8%). CONCLUSIONS: In this study of the effects of high-dose ziprasidone and haloperidol in patients with schizophrenic disorder, none of the patients had a QTc interval >480 msec, and changes from baseline QTc interval were clinically modest with both drugs. Both drugs were generally well tolerated.

Effects of Oral Ziprasidone and Oral Haloperidol on QTc interval in patients with Schizophrenia or Schizoaffective disorder.

STUDY OBJECTIVE: To characterize the effect of oral ziprasidone and haloperidol on the corrected QT (QTc) interval under steady-state conditions. Design. Prospective, randomized, open-label, parallel-group study. SETTING: Inpatient clinical research facility. Patients Fifty-nine adults (age range 25-59 yrs) with schizophrenia or schizoaffective disorder who had no clinically significant abnormality on electrocardiogram (ECG) at screening. Intervention. During period 1 (days -10 to -4), antipsychotic and anticholinergic drugs were tapered. On the first day (day -3) of period 2, the drugs were discontinued, and placebo was given for the next 3 days (days -2 to 0). On the last day (day 0) of period 2, serial baseline ECGs were collected. During period 3 (days 1-16), patients received escalating oral doses of ziprasidone and haloperidol to reach steady state. Period 4 (days 17-19) allowed for study drug washout and initiation of outpatient antipsychotic therapy; safety assessments were also performed during this period. MEASUREMENTS AND RESULTS: At each steady-state dose level, three ECGs and a serum or plasma sample were collected at the predicted time of peak exposure to the administered drug. Point estimates and 95% confidence intervals (CIs) were determined for the mean QTc interval at baseline and for the mean change from baseline in QTc at each steady-state dose level. Mean changes from baseline in the QTc interval (msec) for ziprasidone were 4.5 (95% CI 1.9-7.1), 19.5 (95% CI 15.5-23.4), and 22.5 (95% CI 15.7- 29.4) for steady-state doses of 40, 160, and 320 mg/day, respectively; for haloperidol, -1.2 (95% CI -4.1-1.7), 6.6 (95% CI 1.6-11.7), and 7.2 (95% CI 1.4-13.1) for steady-state doses of 2.5, 15, and 30 mg/day. Although no patient in either treatment group experienced a QTc interval of 450 msec or greater, the QTc interval increased 30 msec or more in 11 and 17 ziprasidone-treated patients at 160 and 320 mg/day, respectively, and in 3 and 5 haloperidol-treated patients at 15 and 30 mg/day, respectively. Most treatment-emergent adverse drug reactions were mild in intensity, and none were severe. CONCLUSION: The QTc interval in ziprasidone- and haloperidol-treated patients increased with dose. Treatment with high doses of ziprasidone or haloperidol did not result in any patient experiencing a QTc interval of 450 msec or greater.

The effect of food on the absorption of oral ziprasidone.

Oral ziprasidone bioavailability is increased when taken with food. Here we describe two pharmacokinetic studies to quantify the impact of food on ziprasidone absorption in healthy volunteers. The first, an open-label, six-way crossover study, investigated ziprasidone absorption in eight healthy men. Subjects received oral ziprasidone (20, 40, and 80 mg) after an 8-hour fast or immediately following a US Food and Drug Administration standard meal (50% fat). In this study, area under the serum concentration- time curve (AUC) was greater in fed than in fasting states at each dose (20 mg, +48%; 40 mg, +87%; 80 mg, +101%). Under fasting conditions, increases in AUC and maximum drug concentration (Cmax) were less than dose-proportional; under fed conditions, they were dose-proportional. The second, an open-label, randomized, three-way crossover study, explored the impact of dietary fat on ziprasidone absorption in 14 healthy subjects. Subjects received ziprasidone (40 mg) under three conditions: fasting, with a high-fat meal (60% fat), and with a moderate-fat (30% fat) meal. AUC and Cmax under fed conditions increased by 104% and 84% (60%-fat meal) and 79% and 98% (30%-fat meal) , respectively, relative to the fasting state. There was no clear difference in ziprasidone bioavailability between the fed groups, suggesting that meal fat content is not a major determinant of bioavailability. Less pharmacokinetic variability was observed in the fed state, suggesting more consistent absorption of ziprasidone. These results demonstrate that administration of ziprasidone with food is crucial to ensure optimal, reliable dose-dependent bioavailability and thus predictable symptom control and tolerability.

Single-dose pharmacokinetics and safety of ziprasidone in children and adolescents.

OBJECTIVE: The purpose of this study was to provide single-dose pharmacokinetic, safety, and tolerability data for ziprasidone in youths with tic disorder, for comparison to adult studies to discern whether ziprasidone pediatric dosing could be modeled from adult data. METHOD: A single-dose, open-label study of ziprasidone was conducted in youths (ages 7-16 years) with Tourette's disorder or chronic tic disorder. Dosing of ziprasidone oral suspension (40 mg/mL) was weight adjusted: >60 kg, 20 mg (group 1, n = 8); 31 to 60 kg, 10 mg (group 2, n = 8); and 16 to 30 kg, 5 mg (group 3, n = 8). Patients were assessed for serum ziprasidone concentration, safety, tolerability, and electrocardiogram pre- and postdose. RESULTS: Twenty-four patients were evaluated for safety and tolerability, and 23 were evaluated for pharmacokinetics. Regression analysis of AUC(0-infinity) and Cmax values versus weight-normalized dose showed linear, dose-related changes in ziprasidone exposure. Ziprasidone was well tolerated with frequent, although transient, somnolence. No clinically significant change from baseline was observed in Bazett's or Fridericia's corrected QT(c) interval, and change in QT(c) interval was not related to serum ziprasidone concentration. CONCLUSIONS: Oral ziprasidone exhibited linear pharmacokinetics and dose-related exposure in youths with Tourette's disorder or chronic tic disorder, which are comparable to adult data. A single dose of ziprasidone was well tolerated without clinically significant effects on electrocardiograms collected around the time of maximum serum concentration.

Pharmacokinetics, safety, and tolerability of intramuscular ziprasidone in healthy volunteers.

Little has been published regarding the pharmacokinetics of the intramuscular (IM) formulation of Ziprasidone. The authors report results from 2 early phase I studies in healthy volunteers: a trial of single 5-, 10-, or 20-mg IM doses of ziprasidone in 24 subjects and an open-label 3-way crossover trial of 5-mg intravenous (IV), 5-mg IM, and 20-mg oral ziprasidone in 12 subjects. Absorption of IM ziprasidone was rapid (Tmax < 1 hour). The IM pharmacokinetic profile was consistent between studies and linear, with dose-related increases in exposure observed. The mean IM elimination t(1/2) was short and approximately 2.5 hours. The mean bioavailability for the 5-mg IM ziprasidone dose was approximately 100%. Adverse events were generally mild to moderate, and no subjects were discontinued from the study. No significant effects on renal function or other laboratory values were noted. These results support the use of IM ziprasidone in treating acutely agitated patients with schizophrenia.

A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition.

Many drugs have been associated with QTc prolongation and, in some cases, this is augmented by concomitant administration with metabolic inhibitors. The effects of 6 antipsychotics on the QTc interval at and around the time of estimated peak plasma/serum concentrations in the absence and presence of metabolic inhibition were characterized in a prospective, randomized study in which patients with psychotic disorders reached steady-state on either haloperidol 15 mg/d (n = 27), thioridazine 300 mg/d (n = 30), ziprasidone 160 mg/d (n = 31), quetiapine 750 mg/d (n = 27), olanzapine 20 mg/d (n = 24), or risperidone 6-8 mg/d increased to 16 mg/d (n = 25/20). Electrocardiograms (ECGs) were done at estimated Cmax at steady-state on both antipsychotic monotherapy and after concomitant administration of appropriate cytochrome P-450 (CYP450) inhibitor(s). Mean QTc intervals did not exceed 500 milliseconds in any patient taking any of the antipsychotics studied, in the absence or presence of metabolic inhibition. The mean QTc interval change was greatest in the thioridazine group, both in the presence and absence of metabolic inhibition. The presence of metabolic inhibition did not significantly augment QTc prolongation associated with any agent. Each of the antipsychotics studied was associated with measurable QTc prolongation at steady-state peak plasma concentrations, which was not augmented by metabolic inhibition. The theoretical risk of cardiotoxicity associated with QTc prolongation should be balanced against the substantial clinical benefits associated with atypical antipsychotics and the likelihood of other toxicities.

Pharmacodynamics of ziprasidone in children and adolescents: impact on dopamine transmission.

OBJECTIVE: Ziprasidone is an atypical antipsychotic with a high ratio of 5-HT(2A) to D(2) receptor antagonism. It is also an agonist at 5-HT(1A), which has been shown in rats to increase dopamine in prefrontal cortex. The objective of this study was to probe the dopamine agonist and antagonist pharmacodynamic properties of ziprasidone in youth. METHOD: A single-dose, open-label study was conducted in 24 youths, 7 to 16 years of age, with Tourette syndrome or chronic tic disorder. Ziprasidone oral suspension (40 mg/mL) was given to achieve 0.2 to 0.3 mg/kg. Patients were subsequently assessed for serum ziprasidone, serum prolactin, and eye blink rates. RESULTS: Serum ziprasidone peaked 4 hours postdose. Prolactin (baseline mean 7.2 ng/mL, 95% confidence interval [CI] 5.2-9.2) peaked at 4 hours (mean 27.5 ng/mL, 95% CI 22.6-32.3). Eyeblink rates per 5 minutes (baseline mean 60, 95% CI 42-79) peaked at 6 hours (mean 74, 95% CI 52-96). CONCLUSIONS: Ziprasidone acutely blocks dopamine transmission, as indicated by increased prolactin levels, and, in a delayed fashion, appears to stimulate dopaminergic transmission, as indicated by the increase in spontaneous eye blinks. The mechanism of dopaminergic stimulation is presumed to be indirect, via 5-HT(1A) agonism.

Ziprasidone metabolism, aldehyde oxidase, and clinical implications.

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.

The anxiolytic effect of the novel antipsychotic ziprasidone compared with diazepam in subjects anxious before dental surgery.

The novel atypical antipsychotic ziprasidone has a pharmacologic profile notable for potent agonism of serotonin (5-HT)1A receptors, antagonism at 5-HT1D receptors, and reuptake inhibition of norepinephrine. 5-HT1A receptor agonism, in particular, suggests anxiolytic activity, and ziprasidone has shown preliminary efficacy in treating the symptoms of anxiety associated with psychotic disorders. In this study, the anxiolytic efficacy of ziprasidone was evaluated in nonpsychotic subjects who were anxious before undergoing minor dental surgery. We compared a single oral dose of 20 mg ziprasidone (N = 30) with that of 10 mg diazepam (N = 30) and placebo (N = 30) in a randomized, parallel-group, double-blind study. The peak anxiolytic effect of ziprasidone compared with that of placebo was similar to that of diazepam but had a later onset. At 3 hours postdose, the anxiolytic effect of ziprasidone was significantly greater than that of placebo (p < 0.05) and somewhat greater than that of diazepam. Diazepam showed a significantly greater anxiolytic effect than placebo at 1 hour (p < 0.05) but not at 3 hours. The sedative effect of ziprasidone was never greater than that of placebo, whereas that of diazepam was significantly greater than that of placebo 1 to 1.5 hours postdose. Ziprasidone was generally well tolerated. Only one patient reported treatment-related adverse events (nausea and vomiting) and, unlike diazepam, ziprasidone did not cause reductions in blood pressure. Dystonia, extrapyramidal syndrome, akathisia, and postural hypotension were not seen with ziprasidone. Thus, ziprasidone may possess anxiolytic effects in addition to its antipsychotic properties.