Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose-response analysis.

PF-04171327 is a dissociated agonist of the glucocorticoid receptor (DAGR) being developed to retain anti-inflammatory efficacy while reducing unwanted effects. Our aim was to conduct a longitudinal dose-response analysis to identify the DAGR doses with efficacy similar to or greater than prednisone 10 mg once daily (QD). The data included were from a Phase 2, randomized, double-blind, parallel-group study in 323 subjects with active rheumatoid arthritis on a background of methotrexate. Subjects received DAGR 1, 5, 10 or 15 mg, prednisone 5 or 10 mg, or placebo QD for 8 weeks. The Disease Activity Score 28-4 calculated using C-Reactive Protein (DAS28-4 CRP) was the efficacy endpoint utilized in this dose-response model. For DAGR, the maximum effect (Emax) on DAS28-4 CRP was estimated to be -1.2 points (95 % CI -1.7, -0.84), and the evaluated dose range provided 31-87 % of the Emax; for prednisone 5 and 10 mg, the estimated effects were -0.27 (95 % CI -0.55, 0.006) and -0.94 point (95 % CI -1.3, -0.59), respectively. Stochastic simulations indicated that the DAGR 1, 5, 10 and 15 mg have probabilities of 0.9, 29, 54 and 62 %, respectively, to achieve efficacy greater than prednisone 10 mg at week 8. DAGR 9 mg estimated probability was 50 % suggesting that DAGR ≥9 mg QD has an effect on DAS28-4 CRP comparable to or greater than prednisone 10 mg QD. This work informs dose selection for late-stage confirmatory trials.

Relating Spontaneously Reported Extrapyramidal Adverse Events to Movement Disorder Rating Scales.

BACKGROUND: While antipsychotic-induced extrapyramidal symptoms (EPS) and akathisia remain important concerns in the treatment of patients with schizophrenia, the relationship between movement disorder rating scales and spontaneously reported EPS-related adverse events (EPS-AEs) remains unexplored. METHODS: Data from four randomized, placebo- and haloperidol-controlled ziprasidone trials were analyzed to examine the relationship between spontaneously reported EPS-AEs with the Simpson Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS). Categorical summaries were created for each treatment group to show the frequencies of subjects with EPS-AEs in each of the SAS and BARS categories at weeks 1, 3, and 6, and agreement between ratings was quantified by means of weighted kappa (κ). RESULTS: In general, we found greater frequencies of EPS-AEs with increasing severity of the SAS and BARS scores. The EPS-AEs reported with a "none" SAS score ranged from 0 to 22.2%, with a "mild" SAS score from 3.3 to 29.0%, and with a "moderate" SAS score from 0 to 100%. No subjects in any treatment group reported "severe" SAS scores or corresponding EPS-AEs. Agreement between SAS scores and EPS-AEs was poor for ziprasidone and placebo (κ < 0.2) and only slightly better for haloperidol. The EPS-AEs reported with "non questionable" BARS scores ranged from 1.9 to 9.8%, with "mild moderate" BARS scores from 12.8 to 54.6%, and with "marked severe" scores from 0 to 100%. Agreement was modest for ziprasidone and placebo (κ < 0.4) and moderate for haloperidol (κ < 0.6). CONCLUSIONS: These findings may reflect either underreporting of AEs by investigators and subjects or erroneous rating scale evaluations.

Risk for adverse events and discontinuation due to adverse events of ziprasidone monotherapy relative to placebo in the acute treatment of bipolar depression, mania, and schizophrenia.

OBJECTIVE: This study aimed to examine the risk difference (RD) in the discontinuation due to adverse events, akathisia, overall extrapyramidal symptoms (EPS), reported-somnolence, and 7% or greater weight gain between ziprasidone monotherapy and placebo in the acute treatment of bipolar depression (BPD), bipolar mania (BPM), and schizophrenia. METHODS: Pooled data from 9 randomized, double-blind, placebo-controlled, acute studies of ziprasidone in BPD, BPM, and schizophrenia were used. The number needed to treat to harm (NNTH) of ziprasidone relative to placebo was estimated when an RD was statistically significant. RESULTS: The RD in discontinuation due to adverse events or 7% or greater weight gain between ziprasidone and placebo was not significant in all 3 psychiatric conditions. The risk for akathisia with ziprasidone was significantly higher in BPD with an RD of 2.3% (NNTH = 44) and in BPM with an RD of 8.4% (NNTH = 12). Risk for overall EPS with ziprasidone was significantly higher in BPM with an RD of 8.7% (NNTH = 12) and schizophrenia with an RD of 3.3% (NNTH = 30). Risk of reported-somnolence with ziprasidone was also significantly higher in BPD with an RD of 11.8% (NNTH = 8), BPM with an RD of 14.3% (NNTH = 7), and schizophrenia with an RD of 7% (NNTH = 14). Dose-dependent increase in the risk for reported somnolence with ziprasidone was observed in BPD and schizophrenia. CONCLUSIONS: Ziprasidone was associated with significant differential adverse effects relative to placebo in BPM, BPD, and schizophrenia with no significant difference in weight gain in all 3 groups. Self-reported somnolence was increased across the 3 conditions. Subjects with BPM were more vulnerable to EPS than those with BPD or schizophrenia.

Two 6-week, randomized, double-blind, placebo-controlled studies of ziprasidone in outpatients with bipolar I depression: did baseline characteristics impact trial outcome?

Two randomized, double-blind, placebo-controlled, 6-week studies comparing ziprasidone versus placebo for treatment of bipolar depression (BPD) failed to meet their primary study objectives, indicating that either ziprasidone is ineffective in the treatment of BPD or the study failed. Adult outpatients with bipolar I depression with 17-item Hamilton Rating Scale for Depression total score more than 20 at screening and baseline received either ziprasidone 40 to 80 mg/d, 120 to 160 mg/d, or placebo (study 1), or ziprasidone 40 to 160 mg/d or placebo (study 2). Primary efficacy measure in both studies was change from baseline in Montgomery-Åsberg Depression Rating Scale total scores at week 6 (end of the study). Mixed-model repeated-measures methodology was used to analyze the primary efficacy measure in both studies. Secondary efficacy measures in both studies included Hamilton Rating Scale for Depression total score and Clinical Global Impression-Improvement score. Post hoc analyses were conducted for both studies to examine potential reasons for study failure. In both, ziprasidone treatment groups failed to separate statistically from placebo for change from baseline Montgomery-Åsberg Depression Rating Scale score at week 6. Response rates were 49%, 53%, and 46% for placebo, ziprasidone 40 to 80 mg/d, and ziprasidone 120 to 160 mg/d, respectively (study 1), and 51% and 53% for placebo and ziprasidone 40 to 160 mg/d, respectively (study 2). Ziprasidone 40 to 160 mg/d did not show superiority over placebo at week 6 in the treatment of BPD. Post hoc analyses revealed serious inconsistencies in subject rating that may have limited the ability to detect a difference between drug and placebo response. Rating reliability warrants further investigation to improve clinical trial methodology in psychiatry.

Machine Learning and Artificial Intelligence in Pharmaceutical Research and Development: a Review.

Over the past decade, artificial intelligence (AI) and machine learning (ML) have become the breakthrough technology most anticipated to have a transformative effect on pharmaceutical research and development (R&D). This is partially driven by revolutionary advances in computational technology and the parallel dissipation of previous constraints to the collection/processing of large volumes of data. Meanwhile, the cost of bringing new drugs to market and to patients has become prohibitively expensive. Recognizing these headwinds, AI/ML techniques are appealing to the pharmaceutical industry due to their automated nature, predictive capabilities, and the consequent expected increase in efficiency. ML approaches have been used in drug discovery over the past 15-20 years with increasing sophistication. The most recent aspect of drug development where positive disruption from AI/ML is starting to occur, is in clinical trial design, conduct, and analysis. The COVID-19 pandemic may further accelerate utilization of AI/ML in clinical trials due to an increased reliance on digital technology in clinical trial conduct. As we move towards a world where there is a growing integration of AI/ML into R&D, it is critical to get past the related buzz-words and noise. It is equally important to recognize that the scientific method is not obsolete when making inferences about data. Doing so will help in separating hope from hype and lead to informed decision-making on the optimal use of AI/ML in drug development. This manuscript aims to demystify key concepts, present use-cases and finally offer insights and a balanced view on the optimal use of AI/ML methods in R&D.

Methodological challenges in the coding and adjudication of sudden deaths in a large simple trial with observational follow-up: the ziprasidone observational study of cardiac outcomes (ZODIAC).

PURPOSE: The Ziprasidone Observational study of car DIAC Outcomes (ZODIAC), a large simple trial comparing ziprasidone versus olanzapine in real-world use, showed no difference in risk of sudden death. Upon the request of the US Food and Drug Administration, 205 fatal events were readjudicated applying ICD-10 coding rules for sudden death. METHODS: A readjudication committee coded three domains (witness to death, time of symptom onset to death, and most likely cause of death) for use within algorithms consistent with ICD-10 rules. Relative risks (RR) and corresponding 95%CI were calculated for persons randomized to ziprasidone versus olanzapine, comparing 1-year incidence of sudden death, using multiple definitions. RESULTS: Data on symptom onset to death and diagnosis of specific cardiac arrhythmias required by the ICD-10 rules were often lacking. Sensitivity analyses were conducted to explore the impact of cases suggestive of cardiac origin but missing data required by ICD-10 sudden death codes. Overall, the readjudicated data matched the study's initial findings, with no significant difference in 1-year mortality between ziprasidone and olanzapine for sudden death not otherwise specified and sudden cardiac death (R96.0 or R96.1 or I46.1; RR = 1.11, 95%CI 0.45- 2.77). CONCLUSIONS: After outcome readjudication, ZODIAC found no difference in the risk of sudden death among those randomized to ziprasidone versus olanzapine. However, unlike hospital-based studies, fatal events in general population studies often occur outside hospital and often lack the clinical detail needed for the exact determination of symptom onset and event. Epidemiological evaluations of sudden death need to consider the limitations of the available data.

Early improvement on antipsychotic treatment as a predictor of subsequent response in schizophrenia: analyses from ziprasidone clinical studies.

OBJECTIVE: We examine data from short-term placebo-controlled and comparator-controlled clinical trials of ziprasidone in schizophrenia to confirm the predictive capacity of early symptom changes for response. We pose the question of how early is too early to consider "stay or switch" and evaluate the predictive capability of a clinical measure in this regard. METHODS: We presented two separate pooled analyses of (i) two placebo-controlled and (ii) two active comparator (risperidone and olanzapine) randomized trials of ziprasidone in schizophrenia. Relationship between early changes in Positive and Negative Syndrome Scale (PANSS) total, Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression-Improvement (CGI-I) scores and treatment outcome was evaluated. RESULTS: Week 2 improvement was more reliably predictive of subsequent outcome than week 1 improvement using PANSS and BPRS scores with high sensitivity and specificity, whereas CGI-I had much lower specificity. Overall, non-improvement at week 1 or week 2 was highly predictive of non-response using BPRS scores and PANSS but not CGI-I. CONCLUSIONS: These data, independent of antipsychotic used, confirm prior research showing that early improvement in symptoms is predictive of response. There appears to be an important window of time, beyond week 1, during which important clinical decisions to stay or switch medication may be made.

Meta-analysis of relapse prevention antidepressant trials in depressive disorders.

OBJECTIVE: Continuation therapy with antidepressants is recommended for depressed patients who have responded to initial treatment. We quantified its efficacy in preventing relapse of depression in a meta-analysis of 54 double-blind placebo-controlled relapse prevention studies (patient n = 9268). METHOD: Relapse prevention studies in primary depression and depression subtypes were identified in a systematic literature search. The primary efficacy comparison was relapse rates between active and placebo arms calculated as odds ratios (ORs) using Review Manager version 5.0. Effects of patient age, drug class, diagnostic system and duration of therapy on ORs was examined, along with ORs calculated using different statistical methods. RESULTS: Continuation antidepressants produced robust reduction in relapse (OR = 0.35; 95%CI 0.32-0.39). Pooled ORs were not affected by patient age, drug class, depression subtype or treatment duration, and were similar when calculated by different statistical methods. Patients with primary depression diagnosed by earlier diagnostic systems had slightly lower ORs than those diagnosed using DSM criteria. CONCLUSIONS: This meta-analysis emphasizes the importance of continuation treatment following acute response in depressive disorders. The robust findings of relapse prevention designs contrast with acute antidepressant efficacy studies, and may be due to enrichment of the patient population.

An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder.

This randomized, placebo-controlled, double-blind study was the first to evaluate the antidepressant efficacy, safety, and tolerability of an NR2B subunit-selective N-methyl-D-aspartate receptor antagonist, CP-101,606. Subjects had major depression, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and a history of treatment refractoriness to least 1 adequate trial of a selective serotonin reuptake inhibitor. The study had 2 treatment periods. In period 1, subjects first received a 6-week open-label trial of paroxetine and a single-blind, intravenous placebo infusion. Period 1 nonresponders (n = 30) then received a randomized double-blind single infusion of CP-101,606 or placebo plus continued treatment with paroxetine for up to an additional 4 weeks (period 2). Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale. On the prespecified main outcome measure (change from baseline in the Montgomery-Asberg Depression Rating Scale total score at day 5 of period 2), CP-101,606 produced a greater decrease than did placebo (mean difference, 8.6; 80% confidence interval, -12.3 to -4.5) (P < 0.10). Hamilton Depression Rating Scale response rate was 60% for CP-101,606 versus 20% for placebo. Seventy-eight percent of CP-101,606-treated responders maintained response status for at least 1 week after the infusion. CP-101,606 was safe, generally well tolerated, and capable of producing an antidepressant response without also producing a dissociative reaction. Antagonism of the NR2B subtype of the N-methyl-D-aspartate receptor may be a fruitful target for the development of a new antidepressant with more robust effects and a faster onset compared with those currently available and capable of working when existing antidepressants do not.

Completed and attempted suicides among 18,154 subjects with schizophrenia included in a large simple trial.

OBJECTIVE: To characterize subgroups of subjects with schizophrenia from the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) trial who either completed or attempted suicide and those who did not. METHOD: The ZODIAC, conducted between February 2002 and March 2007, was an open-label, randomized, large simple trial of patients with schizophrenia (N = 18,154) followed up for 1 year by unblinded investigators providing usual care in 18 countries; the primary outcome measure was nonsuicide mortality. Every report on a completed or attempted suicide was independently adjudicated using a predefined algorithm. Primary analysis for the current report examined the association between completed or attempted suicides and the baseline variables using descriptive statistics and multivariate logistic regression models. Usage of "hard" or "soft" methods for attempted or completed suicide and distribution of suicide-related events by geographical region were also summarized. RESULTS: Overall incidences of subjects who either completed (35/18,154) or attempted (108/18,154) suicide were low, as were rates per person-time on assigned treatment analysis (0.24 for completed and 0.74 for attempted suicides per 100 person-years of exposure). The highest suicide-related mortality was seen among subjects recently diagnosed with schizophrenia. Among all potential baseline risk factors for completed suicide examined, the variables most associated with completed suicide were history of suicide attempts (OR = 2.6; 95% CI, 1.33-5.12) and usage of antidepressant medication (OR = 3.5; 95% CI, 0.84-14.85). History of > 5 hospitalizations in the past (OR = 2.1; 95% CI, 1.35-3.31) and history of suicide attempts (OR = 5.0; 95% CI, 3.21-7.76) were the variables most associated with attempted suicide among potential baseline risk factors for suicide attempts. CONCLUSIONS: Our results, obtained in a large prospective randomized study, confirm current clinical understanding regarding completed or attempted suicide in schizophrenia and the associated risk factors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00418171.

Changes in weight, plasma lipids, and glucose in adults treated with ziprasidone: a comprehensive analysis of pfizer-initiated clinical trials.

BACKGROUND: Elevated cardiometabolic morbidity and mortality in patients with schizophrenia and bipolar disorder have been attributed to multiple sources, including antipsychotic treatment, which may adversely affect cardiometabolic risk factors. We therefore present here a comprehensive set of analyses of changes in metabolic parameters from ziprasidone clinical trials. METHOD: The comprehensive set of analyses of metabolic changes conducted here was considered post hoc and exploratory. Changes in weight, fasting lipids, and fasting glucose from baseline to study end (last observation carried forward [LOCF]) for adult subjects in Pfizer-sponsored oral monotherapy randomized placebo-controlled ziprasidone clinical trials were analyzed by using an analysis of covariance model. In addition, available weight, fasting lipids, and fasting glucose data from all ziprasidone-treated subjects from all controlled and uncontrolled oral monotherapy studies of ziprasidone (102 studies; N = 12,599) conducted from 1992 to 2009 were analyzed similarly. RESULTS: In short-term randomized controlled trials (RCTs) (duration ≤ 12 weeks), least squares mean ± SD change from baseline to end of study (LOCF) in weight was 0.64 ± 0.12 kg in ziprasidone-treated subjects (n = 1,386) versus -0.02 ± 0.14 kg in placebo-treated subjects (n = 747) (P < .0001); in long-term RCTs (duration > 12 weeks), the corresponding values were -0.96 ± 0.68 kg for ziprasidone (n = 363) and -1.68 ± 0.80 kg for placebo (n = 142) (P = .24). Mean ± SD weight change in ziprasidone-treated subjects from all controlled and uncontrolled studies ranged from 0.2 ± 5.6 kg at 6 weeks (n = 3,156) to 1.7 ± 10.1 kg at 36 months (n = 178). There were no significant differences between the ziprasidone and placebo groups in fasting triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or glucose in the controlled studies, and there were minimal changes in ziprasidone-treated subjects in all controlled and uncontrolled studies. CONCLUSIONS: This comprehensive analysis of data from the ziprasidone clinical trial database demonstrates limited evidence of any clinically significant adverse effects of ziprasidone on weight and consistent evidence of a neutral effect on fasting plasma lipids and glucose.

Adjunctive oral ziprasidone in patients with acute mania treated with lithium or divalproex, part 1: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy and safety of adjunctive ziprasidone in subjects with acute mania treated with lithium or divalproex, with an inadequate response to the mood stabilizer. METHOD: The study enrolled subjects aged 18-65 years who had a primary DSM-IV diagnosis of bipolar I disorder, with the most recent episode manic or mixed, with or without rapid cycling, and a Young Mania Rating Scale (YMRS) score ≥ 18. Subjects were randomized under double-blind conditions to receive ziprasidone, 20 to 40 mg (n = 226) or 60 to 80 mg (n = 232), or placebo (n = 222) twice a day for 3 weeks in addition to their mood stabilizer. The primary efficacy variable was change in YMRS scores from baseline to 3 weeks. Secondary efficacy measures included the Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity of Illness and -Improvement scales, and Global Assessment of Functioning. Computer-administered YMRS was included for quality control and to evaluate study performance. The study was conducted between April 2006 and December 2008. RESULTS: Least-squares mean ± standard error changes in YMRS scores from baseline to week 3 were -10.2 ± 0.80 in the mood stabilizer + ziprasidone 60- to 80-mg group, -11.0 ± 0.80 in the mood stabilizer + ziprasidone 20- to 40-mg group, and -9.5 ± 0.80 in the mood stabilizer + placebo group. Mean treatment differences between adjunctive ziprasidone groups and placebo were not statistically significant on primary or secondary efficacy measures. Ziprasidone was well tolerated. CONCLUSIONS: Adjunctive ziprasidone treatment failed to separate from mood stabilizer (lithium or divalproex) treatment on primary and secondary end points. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00312494.

Adjunctive oral ziprasidone in patients with acute mania treated with lithium or divalproex, part 2: influence of protocol-specific eligibility criteria on signal detection.

OBJECTIVES: High failure rates of randomized controlled trials (RCTs) are well recognized but poorly understood. We report exploratory analyses from an adjunctive ziprasidone double-blind RCT in adults with bipolar I disorder (reported in part 1 of this article). Data collected by computer interviews and by site-based raters were analyzed to examine the impact of eligibility criteria on signal detection. METHOD: Clinical assessments and a remote monitoring system, including a computer-administered Young Mania Rating Scale (YMRS(Comp)) were used to categorize subjects as eligible or ineligible on 3 key protocol-specified eligibility criteria. Data analyses compared treatment efficacy for eligible versus ineligible subgroups. All statistical analyses reported here are exploratory. Criteria were considered "impactful" if the difference between eligible and ineligible subjects on the YMRS change scores was ≥ 1 point. RESULTS: 504 subjects had baseline and ≥ 1 post-randomization computer-administered assessments but only 180 (35.7%) met all 3 eligibility criteria based on computer assessments. There were no statistically significant differences between treatment groups in change from baseline YMRS score on the basis of site-based rater or computer assessments. All criteria tested improved signal detection except the entry criteria excluding subjects with ≥ 25% improvement from screen to baseline. CONCLUSIONS: On the basis of computer assessments, nearly two-thirds of randomized subjects did not meet at least 1 protocol-specified eligibility criterion. These results suggest enrollment of ineligible subjects is likely to contribute to failure of acute efficacy studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00312494.

Ziprasidone and the corrected QT interval: a comprehensive summary of clinical data.

BACKGROUND: Prolongation of the corrected QT interval (QTc) is understood to be a predictor of risk for ventricular arrhythmia; consequently, data on QTc effects of drugs are used by regulatory bodies to evaluate potential safety risks. Clinical pharmacology studies in adults receiving oral ziprasidone demonstrated a dose-dependent mean increase (4.5-19.5 milliseconds [ms]) in QTc over the range of 40-160 mg/d with a small incremental increase (22.5 ms) at 320 mg/d. In a comparative study of ziprasidone versus five antipsychotics, the mean QTc increase at steady state maximum concentration (C(max)) for ziprasidone was 15.9 ms. Accordingly, the effects of ziprasidone on QTc were studied in phase II-IV randomized controlled trials (RCTs). OBJECTIVE: The objective of this study was to provide clinicians and clinical researchers with a comprehensive analysis of QTc changes associated with ziprasidone based on data from Pfizer-sponsored phase II-IV RCTs in schizophrenia or bipolar disorder patients, safety reports and post-marketing surveillance. METHODS: The following analyses of data were conducted to obtain a comprehensive summary of QTc data on ziprasidone: (i) post hoc analyses (using primarily descriptive statistics) of pooled QTc data (Fridericia correction) from more than 40 phase II-IV adult ziprasidone RCTs organized according to the following subgroups: all monotherapy studies in schizophrenia and bipolar disorder, all intramuscular (IM) studies, adjunctive studies in bipolar disorder and fixed-dose oral studies; (ii) post hoc analyses from 36 phase II-IV adult ziprasidone RCTs exploring the relationship between QTc change from baseline and baseline QTc in adults; (iii) post hoc analyses from phase II-IV adult ziprasidone RCTs modelling QTc change as a function of ziprasidone concentration in both adult (17 studies) and paediatric (5 studies) subjects; (iv) cardiac adverse event (AE) reports from all phase II-IV adult ziprasidone RCTs in schizophrenia; (v) a large simple trial entitled Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) in 18 154 subjects with schizophrenia (the only previously reported results included here); and (vi) cardiac-related AEs presented in a ziprasidone post-marketing surveillance report created in 2007. RESULTS: A total of 4306 adults received ziprasidone in placebo- and active-comparator phase II-IV RCTs and had evaluable QTc data. One subject reached a QTc ≥480 ms; 33 (0.8%) had a QTc ≥450 ms. QTc prolongation ≥30 ms was observed in 389 subjects (9.0%); ≥60 ms in 30 (0.7%); and ≥75 ms in 12 (0.3%). In the placebo-controlled studies, mean change in QTc from baseline to end of study was 3.6 (± 20.8) ms in the ziprasidone group; the corresponding QTc change in the pooled placebo group was -0.3 (± 20.6) ms. Data from IM studies, and bipolar studies in which ziprasidone was used adjunctively with lithium, valproate or lamotrigine, demonstrated similar QTc effects. A scatter-plot of QTc prolongation against baseline QTc showed QTc prolongation ≥60 ms exclusively in adult subjects with a baseline QTc ≤400 ms. The final concentration-response analysis model, comprising 2966 data points from 1040 subjects, estimates an increase in QTc of 6 ms for each 100 ng/mL increase in ziprasidone concentration. The large simple trial (ZODIAC) failed to show that ziprasidone is associated with an elevated risk of non-suicidal mortality relative to olanzapine in real-world use. Post-marketing data over a 5-year period did not show a signal of increased cardiac AEs. CONCLUSIONS: These analyses provide the first comprehensive summary of QTc changes associated with ziprasidone based on Pfizer-sponsored phase II-IV RCTs, safety reports and post-marketing surveillance. The results of the analyses of pooled data from phase II-IV RCTs in adults demonstrate a modest mean increase in QTc, infrequent QTc prolongation ≥60 ms (<1.0%) and rare observation of QTc ≥480 ms. These data are consistent with results from ziprasidone clinical pharmacology studies, safety reports and post-marketing surveillance. Taken together, they provide the most comprehensive evidence published to date that ziprasidone appears to be safe when used as indicated in patients with schizophrenia or bipolar disorder.

Switching from quetiapine to ziprasidone: a sixteen-week, open-label, multicenter study evaluating the effectiveness and safety of ziprasidone in outpatient subjects with schizophrenia or schizoaffective disorder.

OBJECTIVE: The objectives of this study were to evaluate the effects of switching from quetiapine to ziprasidone on weight, safety, and effectiveness METHODS: In this study, 241 subjects with schizophrenia or schizo affective disorder who had been treated with quetiapine (≥300 mg/day) for ≥3 months with either suboptimal efficacy or poor tolerability were enrolled in a 16-week, open-label, flexible-dose trial, with a 16-week follow-up (total 32 weeks). Quetiapine was tapered and discontinued over the course of 2 weeks, while ziprasidone was titrated up and dosed at 40-80 mg b.i.d. The primary endpoint was weight change (kg) from baseline at 16 weeks. Secondary endpoints were change in waist/hip circumference, lipid profile, fasting glucose, and glycosylated hemoglobin (HbA1c). Additional secondary endpoints included changes in scores on the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions Improvement and Severity Scales (CGI-I and CGI-S), the Calgary Depression Scale for Schizophrenia (CDSS), the Schizophrenia Cognition Rating Scale (ScoRS), and the Global Assessment of Functioning (GAF). Safety measures included adverse event (AE) reporting and administration of the Abnormal Involuntary Movement Scale (AIMS). RESULTS: At week 16, there was a small but statistically significant decrease in weight, with a mean change from baseline of -0.73 kg (1-sided 95% upper confidence bound=-0.33) using the last observation carried forward [LOCF] approach. There were small mean decreases in levels of total cholesterol, low density lipoprotein (LDL), and triglycerides at week 16, but no change in fasting glucose or HbA1c. At week 16, there were also significant changes indicating improvement in the secondary clinical assessments, including the PANSS scores, CGI-S, CDSS, SCoRS and GAF. There was no change in the AIMS. AEs included insomnia (12.4%), somnolence (13.7%), and nausea (9.1%). CONCLUSION: Subjects switching from quetiapine to ziprasidone showed a small but significant decrease in weight as well as improved lipid profiles, regardless of their metabolic status and disease severity at baseline. Subjects also showed improvement in clinical symptoms and in cognitive functioning. Ziprasidone, with a comparatively neutral metabolic profile relative to other antipsychotics, may be an effective treatment alternative for patients experiencing weight gain or lack of tolerability with quetiapine.

Comparative efficacy of antidepressants in preventing relapse in anxiety disorders - a meta-analysis.

BACKGROUND: We assessed the efficacy of continuation treatment with antidepressants in a meta-analysis of relapse prevention studies in the five principal anxiety disorders, to explore the benefit of continuation treatment in each disorder, and their relative efficacy across these disorders. METHOD: Double-blind placebo-controlled studies with relapse prevention designs in Panic Disorder, Generalized Anxiety Disorder, Social Phobia, Post-Traumatic Stress Disorder and Obsessive-Compulsive Disorder were identified in a systematic literature search. The primary efficacy comparison was relapse rates between active and placebo arms calculated as odds ratios (ORs) using Review Manager version 5.0. Relapse data were also used to calculate relative risk (RR), risk difference (RD) and number needed to treat (NNT). RESULTS: Twenty-two relapse prevention trials were identified for these 5 disorders. Continuation antidepressant treatment produced robust treatment effects for each disorder, however the magnitude varied by indication. The greatest treatment effect was noted for GAD (pooled OR 0.20), whereas the pooled ORs for PD and OCD were for almost 2-fold higher (0.35 and 0.38 respectively). RR, RD and NNT showed similar statistically significant trends. LIMITATIONS: This study cannot identify an optimal duration of therapy. This analysis only examined studies testing monoamine reuptake inhibiting antidepressants, and therefore these results might not be generalizable to other classes of antianxiety agents. CONCLUSIONS: This meta-analysis underscores the importance of continuation treatment following acute response in all 5 anxiety disorders, however the relative efficacy of continuation antidepressant treatment appears to vary by disorder.

A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression.

OBJECTIVE: The corticotropin-releasing hormone (CRH) system is implicated in the pathogenesis of several psychiatric disorders, including major depressive disorder. This study was designed to evaluate the safety and efficacy of CP-316,311, a selective nonpeptide antagonist of corticotropin-releasing hormone type 1 (CRH(1)) receptors, in the treatment of recurrent major depressive disorder. METHOD: Of a total of 167 patients with recurrent major depression who were screened, 123 were randomly assigned to receive 400 mg of CP-316,311 twice daily, or 100 mg of sertraline daily, or placebo in a 6-week fixed-dose, double-blind, double-dummy, parallel-group, placebo- and sertraline-controlled trial. The primary efficacy analysis compared the change in score from baseline to endpoint on the 17-item Hamilton Depression Rating Scale (HAM-D) between the CP-316,311 and placebo groups. A group sequential design was used to support early trial termination based on efficacy or futility at a planned interim analysis. RESULTS: The evaluable data set for the interim analysis included 28 patients in the CP-316,311 group, 31 patients in the placebo group, and 30 patients in the sertraline group. In the interim analysis, the change from baseline in the HAM-D score at the final visit was not significantly different between the CP-316,311 and placebo groups, while change from baseline between the sertraline and placebo groups was significantly different. Given these results, futility was declared for CP-316,311 and the trial was terminated. CONCLUSIONS: Although CP-316,311 was safe and well tolerated in this study population, it failed to demonstrate efficacy in the treatment of major depression.

Effects of steady-state lasofoxifene on CYP2D6- and CYP2E1-mediated metabolism.

BACKGROUND: Lasofoxifene, a selective estrogen receptor modulator, may be coadministered with other drugs, raising the issue of drug-drug interactions. OBJECTIVE: Using a 7-day, open-label, sequential study to determine whether lasofoxifene at steady-state concentration affects cytochrome P450-mediated drug metabolism. METHODS: Lasofoxifene was tested in 18 postmenopausal women with probe drugs for CYP2E1 and CYP2D6. Changes in CYP2E1 metabolism were measured by the formation clearance of 6-hydroxychlorzoxazone (6-OHCLZ; Cl(f,6-OHCLZ)) following a 250 mg dose of chlorzoxazone in the absence (day 1) and presence (day 6) of lasofoxifene. Changes in the dextromethorphan/dextrorphan urine metabolic ratio (MRDX) measured the effect on CYP2D6 metabolism following a 30 mg dose of dextromethorphan in the absence and presence of lasofoxifene (days 2 and 7). RESULTS: Steady-state lasofoxifene did not affect the formation clearance of 6-OHCLZ or the urinary MRDX. For 6-OHCLZ, the lower boundary (87.12%) of the 90% confidence interval for the ratio (day 6/day 1) of Cl(f,6-OHCLZ) was well above the clinically acceptable ratio of 60%. Both the individual and group mean Cl(f,6-OHCLZ) values were comparable in the absence and presence of lasofoxifene. For MRDX, the upper boundary (129.37%) of the 90% confidence interval for the ratio (day 7/day 2) of MRDX was well below the stipulated ratio of 200%. The individual and mean MRDX values were comparable in the absence and presence of lasofoxifene. Lasofoxifene was well tolerated; adverse events were mild and transient. CONCLUSIONS: Lasofoxifene has no effect on CYP2E1- or CYP2D6-mediated drug metabolism and should not affect drugs metabolized by other cytochrome P450 isoenzymes.