Sheela Kolluri

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-Åsberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale. On the prespecified main outcome measure (change from baseline in the Montgomery-Åsberg 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.

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.

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

Abstract 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.

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.

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

AbstractBackground: 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 40–160mg/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 (Cmax) 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 activecomparator 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 scatterplot 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 100ng/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 ≥60ms (<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.

A Confidence Interval for the Maximal Mean QT Interval Change Caused by Drug Effect

A statistical problem of primary interest in a thorough QT/QTc study is that of deciding if a drug is noninferior to placebo in terms of QT/QTc prolongation. A standard way of approaching this problem is to construct a 90% two-sided (or a 95% one-sided) confidence interval, using the t distribution, at each time point in the study for the difference in mean QTc between drug and placebo and to conclude that the drug is noninferior to placebo if the upper end points of all of these confidence intervals is less than a prespecified constant, such as 10 ms. Under standard normality assumptions, this procedure corresponds to both an intersection-union test and the likelihood ratio test of size .05. It is not without its drawbacks, however. It is conservative in that the probability of a type I error may be smaller than the intended level .05. It is also biased, which means that the power function, for some values of parameters in the alternative space, takes values less than .05. The May 12, 2005, draft of the International Conference on Harmonisation E14 guidance states: “a negative ‘thorough QT/QTc study’ is one in which the upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect of the drug on the QTc interval excludes 10 ms.” In this article, we show how an approximate confidence interval can be constructed for the largest difference in population mean QT/QTc between drug and placebo. The interval is approximate in the sense that, as sample sizes increase, the asymptotic probability of coverage is at least as large as intended. The results of simulations on a proposed one-sided 95% confidence interval are provided and discussed. Situations in which this interval works well, and does not work well, are delineated.

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 Impres sions 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. (Journal of Psychiatric Practice 2011;17:100–109).

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.

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; Clf,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 Clf,6-OHCLZ was well above the clinically acceptable ratio of 60%. Both the individual and group mean Clf,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.

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

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.