Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Controlled Trial.

Objective: To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants.Methods: In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD (DSM-5) were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35).Results: For the ITT analysis (n = 227), mean CFB was 15.1 (SD 11.3) for esmethadone (n = 113) and 12.9 (SD 10.4) for placebo (n = 114), with a mean difference (MD) of 2.3, which was not statistically significant (P = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% (P = .076), and response rates were 39.8% and 27.2% (P = .044) with esmethadone and placebo, respectively. For the PP analysis (n = 198), mean CFB was 15.6 (SD 11.2) for esmethadone (n = 101) and 12.5 (SD 9.9) for placebo (n = 97), with an MD of 3.1 (P = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; P = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; P = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups.Conclusions: The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies.Trial Registration: ClinicalTrials.gov identifier: NCT04688164.

Drug-Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism.

BACKGROUND AND OBJECTIVE: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is the opioid inactive dextro-isomer of racemic methadone. Esmethadone is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker with higher affinity for GluN2D subtypes. Esmethadone showed robust, rapid, and sustained antidepressant effects in patients with major depressive disorder (MDD) with inadequate response to ongoing serotonergic antidepressant treatment. METHODS: Here we described the results of in vitro and phase 1 clinical trials aimed at investigating the esmethadone metabolism and possible drug-drug interactions. RESULTS: Esmethadone is primarily metabolized to EDDP (2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine) by multiple enzymes, including CYP3A4/5 and CYP2B6. In vitro studies showed that esmethadone inhibits CYP2D6 with IC50 of 9.6 µM and is an inducer of CYP3A4/5. The clinical relevance of the inhibition of CYP2D6 and the induction of CYP3A4 were investigated by co-administering esmethadone and dextromethorphan (a substrate for CYP2D6) or midazolam (a substrate for CYP3A4) in healthy volunteers. The administration of esmethadone at the dosage of 75 mg (which is the loading dose administered to patients in MDD clinical trials) significantly increased the exposure (AUC) of both dextromethorphan and its metabolite dextrorphan by 2.71 and 3.11-fold, respectively. Esmethadone did not modify the pharmacokinetic profile of midazolam, while it increased Cmax and AUC of its metabolite 1'-hydroxymidazolam by 2.4- and 3.8-fold, respectively. A second study evaluated the effect of the CYP3A4 inhibitor cobicistat on the pharmacokinetics of esmethadone. Cobicistat slightly increase (+32%) the total exposure (AUC0-inf) of esmethadone. CONCLUSIONS: In summary, esmethadone demonstrated a negligible effect on CYP3A4 induction and its metabolism was not meaningfully affected by strong CYP3A4 inhibitors while it increased exposure of CYP2D6-metabolized drugs.

The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users.

Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (Emax) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p < 0.001) lower Drug Liking VAS Emax compared with the positive control. Results were consistent for all secondary endpoints in both studies. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS Emax (p < 0.05). In the Ketamine Study, Drug Liking VAS Emax scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p < 0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses.

Esmethadone-HCl (REL-1017): a promising rapid antidepressant.

This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders.

Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI).

Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion), an oral N-methyl-D-aspartate (NMDA) receptor antagonist and σ1 receptor agonist, in the treatment of major depressive disorder (MDD).Methods: This double-blind, phase 3 trial, was conducted between June 2019 and December 2019. Patients with a DSM-5 diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg-105 mg tablet) or placebo, orally (once daily for days 1-3, twice daily thereafter) for 6 weeks. The primary endpoint was the change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Other efficacy endpoints and variables included MADRS changes from baseline at week 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (≥ 50% reduction in MADRS score from baseline), clinician- and patient-rated global assessments, Quick Inventory of Depressive Symptomatology-Self-Rated, Sheehan Disability Scale, and quality of life measures.Results: A total of 327 patients were randomized: 163 patients to dextromethorphan-bupropion and 164 patients to placebo. Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. The least-squares mean change from baseline to week 6 in MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least-squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36; P = .002). Dextromethorphan-bupropion was superior to placebo for MADRS improvement at all time points including week 1 (P = .007) and week 2 (P < .001). Remission was achieved by 39.5% of patients with dextromethorphan-bupropion versus 17.3% with placebo (treatment difference, 22.2; 95% CI, 11.7 to 32.7; P < .001), and clinical response by 54.0% versus 34.0%, respectively (treatment difference, 20.0%; 95% CI, 8.4%, 31.6%; P < .001), at week 6. Results for most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all time points (eg, CGI-S least-squares mean difference at week 6, -0.48; 95% CI, -0.48 to -0.79; P = .002). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.Conclusions: In this phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation and was generally well tolerated.Trial Registration: ClinicalTrials.gov Identifier: NCT04019704.

Agitation in Alzheimer's disease: Novel outcome measures reflecting the International Psychogeriatric Association (IPA) agitation criteria.

INTRODUCTION: The 2017 European Union-North American Clinical Trials in Alzheimer's Disease Task Force recommended development of clinician-rated primary outcome measures for Alzheimer's disease (AD) agitation trials, incorporating International Psychogeriatric Association (IPA) criteria. METHODS: In a modified Delphi process, Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory-Clinician (NPI-C) items were mapped to IPA agitation domains generating novel instruments, CMAI-IPA and NPI-C-IPA. Validation in the Agitation and Aggression AD Cohort (A3C) assessed minimal clinically important differences (MCIDs), change sensitivity, and predictive validity. RESULTS: MCID was -17 (odds ratio [OR] = 14.9, 95% confidence interval [CI] = 6.8-32.6) for CMAI; -5 (OR = 9.3, 95% CI = 4.0-21.2) for CMAI-IPA; -3 (OR = 11.9, 95% CI = 4.1-34.8) for NPI-C-A+A; and -5 (OR = 7.8, 95% CI = 3.4-17.9) for NPI-C-IPA at 3 months. Areas under the curve suggested no scale better predicted global clinician ratings. Sensitivity to change for all measures was high. CONCLUSION: Internal consistency and reliability analyses demonstrated better accuracy for the NPI-C-IPA than for the CMAI-IPA and can be used for agitation clinical trial inclusion, and for response to intervention.

Efficacy and Safety of Lumateperone for Treatment of Schizophrenia: A Randomized Clinical Trial.

Importance: Individuals living with schizophrenia are affected by cardiometabolic, endocrine, and motor adverse effects of current antipsychotic medications. Lumateperone is a serotonin, dopamine, and glutamate modulator with the potential to treat schizophrenia with few adverse effects. Objective: To examine the efficacy and safety of lumateperone for the short-term treatment of schizophrenia. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled, phase 3 clinical trial was conducted from November 13, 2014, to July 20, 2015, with data analyses performed from August 13 to September 15, 2015. Patients with schizophrenia who were aged 18 to 60 years and were experiencing an acute exacerbation of psychosis were enrolled from 12 clinical sites in the United States. Interventions: Patients were randomized 1:1:1 (150 patients in each arm) to receive lumateperone tosylate, 60 mg; lumateperone tosylate, 40 mg (equivalent to 42 or 28 mg, respectively, of the active moiety lumateperone); or placebo once daily for 4 weeks. Main Outcomes and Measures: The prespecified primary efficacy end point was mean change from baseline to day 28 in the Positive and Negative Syndrome Scale (PANSS) total score vs placebo. The key secondary efficacy measure was the Clinical Global Impression-Severity of Illness (CGI-S) score. The PANSS subscale scores, social function, safety, and tolerability were also assessed. Results: The study comprised 450 patients (mean [SD] age, 42.4 [10.2] years; 346 [77.1%] male; mean [SD] baseline PANSS score, 89.8 [10.3]; mean [SD] baseline CGI-S score, 4.8 [0.6]). In the prespecified modified intent-to-treat efficacy analysis (n = 435), 42 mg of lumateperone met the primary and key secondary efficacy objectives, demonstrating a statistically significant improvement vs placebo from baseline to day 28 on the PANSS total score (least-squares mean difference [LSMD], -4.2; 95% CI, -7.8 to -0.6; P = .02; effect size [ES], -0.3) and the CGI-S (LSMD, -0.3; 95% CI, -0.5 to -0.1; P = .003; ES, -0.4). For 28 mg of lumateperone, the LSMD from baseline to day 28 was -2.6 (95% CI, -6.2 to 1.1; P = .16; ES, -0.2) on the PANSS total score and -0.2 (95% CI, -0.5 to 0.0; P = .02; ES, -0.3) on the CGI-S. Both lumateperone doses were well tolerated without clinically significant treatment-emergent motor adverse effects or changes in cardiometabolic or endocrine factors vs placebo. Conclusions and Relevance: Lumateperone demonstrated efficacy for improving the symptoms of schizophrenia and had a favorable safety profile. Trial Registration: ClinicalTrials.gov identifier: NCT02282761.

Examining the reliability and validity of the Clinical Assessment Interview for Negative Symptoms within the Management of Schizophrenia in Clinical Practice (MOSAIC) multisite national study.

The current study sought to expand on prior reports of the validity and reliability of the CAINS (CAINS) by examining its performance across diverse non-academic clinical settings as employed by raters not affiliated with the scale's developers and across a longer test-retest follow-up period. The properties of the CAINS were examined within the Management of Schizophrenia in Clinical Practice (MOSAIC) schizophrenia registry. A total of 501 participants with a schizophrenia spectrum diagnosis who were receiving usual care were recruited across 15 national Patient Assessment Centers and evaluated with the CAINS, other negative symptom measures, and assessments of functioning, quality of life and cognition. Temporal stability of negative symptoms was assessed across a 3-month follow-up. Results replicated the two-factor structure of the CAINS reflecting Motivation and Pleasure and expression symptoms. The CAINS scales exhibited high internal consistency and temporal stability. Convergent validity was supported by significant correlations between the CAINS subscales with other negative symptom measures. Additionally, the CAINS was significantly correlated with functioning and quality of life. Discriminant validity was demonstrated by small to moderate associations between the CAINS and positive symptoms, depression, and cognition (and these associations were comparable to those found with other negative symptom scales). Findings suggest that the CAINS is a reliable and valid tool for measuring negative symptoms in schizophrenia across diverse clinical samples and settings.

The Management of Schizophrenia in Clinical Practice (MOSAIC) Registry: a focus on patients, caregivers, illness severity, functional status, disease burden and healthcare utilization.

BACKGROUND: The Management of Schizophrenia in Clinical Practice (MOSAIC), a disease-based registry of schizophrenia, was initiated in December 2012 to address important gaps in our understanding of the impact and burden of schizophrenia and to provide insight into the current status of schizophrenia care in the US. Recruitment began in December 2012 with ongoing assessment continuing through May 2014. METHODS: Participants were recruited from a network of 15 centralized Patient Assessment Centers supporting proximal care sites. Broad entry criteria included patients diagnosed with schizophrenia, schizophreniform or schizoaffective disorder, presenting within the normal course of care, in usual treatment settings, aged ≥18years and able to read and speak English. RESULTS: By May 2014, 550 participants (65.8% male, 59.8% White, 64.4% single, mean age 42.9years), were enrolled. The majority had a diagnosis of schizophrenia (62.0%). Mean illness duration at entry was 15.0years. Common comorbidities at entry were high lipid levels (26.9%), hypertension (23.1%) and type II diabetes (13%). Participants were categorized by baseline overall Clinical Global Impression-Schizophrenia Severity Score as minimally (9.1%), mildly (25.3%), moderately (39.9%), markedly (22.3%) and severely (3.4%) ill. Most commonly used second generation antipsychotics at entry were risperidone (17.8%), clozapine (16.5%), olanzapine (14.0%), aripiprazole (13.6%) and quetiapine (5.6%). CONCLUSIONS: No large-scale patient registry has been conducted in the US to longitudinally follow patients with schizophrenia and describe symptom attributes, support network, care access and disease burden. These data provide important epidemiological, clinical and outcome insights into the burden of schizophrenia in the US.

The humanistic and economic burden of providing care for a patient with schizophrenia.

BACKGROUND: Schizophrenia is a debilitating disorder that often requires the affected individual to receive part- or full-time care from a caregiver. AIMS: The purpose of this study was to examine the humanistic and economic burden of caring for an individual with Schizophrenia with regard to the measures of quality of life (QoL), work productivity, healthcare resource use and estimated economic costs. METHODS: Data for this study came from the 2012 US National Health and Wellness Survey (NHWS; n = 71,149). Specifically, this analysis focused on those individuals in the survey who indicated that they were currently the primary caregiver for an individual with Schizophrenia (C-SCZ; n = 174). These individuals were matched via two separate 1:2 propensity score matches with both caregivers of other disorders (C-Other; n = 294) and non-caregivers (Non-C; n = 294) on significant covariates. Individuals were then compared across the outcomes of QoL, work productivity, healthcare resource use and estimated economic costs. RESULTS: C-SCZ respondents had worse outcomes on all outcomes measured than C-Other respondents and Non-C respondents even when controlling for significant differences between the groups on sociodemographic characteristics. However, due to the small sample sizes, these comparisons were only significant in most cases for the C-SCZ to Non-C comparisons. CONCLUSION: Results indicate that caregivers of those with Schizophrenia experience a heightened humanistic and economic burden, especially relative to the burden experienced by non-caregivers. The fact that Schizophrenia not only affects the individual but also those who care for that individual is underscored by these results.

Determinants of different aspects of everyday outcome in schizophrenia: The roles of negative symptoms, cognition, and functional capacity.

Cognition, negative symptoms, and depression are potential predictors of disability in schizophrenia. We present analyses of pooled data from four separate studies (all n>169; total n=821) that assessed differential aspects of disability and their potential determinants. We hypothesized that negative symptoms would predict social outcomes, but not vocational functioning or everyday activities and that cognition and functional capacity would predict vocational functioning and everyday activities but not social outcomes. The samples were rated by clinician informants for their everyday functioning in domains of social and vocational outcomes, and everyday activities, examined with assessments of cognition and functional capacity, rated clinically with the Positive and Negative Syndrome Scale (PANSS) and self-reporting depression. We computed a model that tested the hypotheses described above and compared it to a model that predicted that negative symptoms, depression, cognition, and functional capacity had equivalent influences on all aspects of everyday functioning. The former, specific relationship model fit the data adequately and we subsequently confirmed a similar fit within all four samples. Analyses of the relative goodness of fit suggested that this specific model fit the data better than the more general, equivalent influence predictor model. We suggest that treatments aimed at cognition may not affect social functioning as much as other aspects of disability, a finding consistent with earlier research on the treatment of cognitive deficits in schizophrenia, while negative symptoms predicted social functioning. These relationships are central features of schizophrenia and treatment efforts should be aimed accordingly.

Defining therapeutic benefit for people with schizophrenia: focus on negative symptoms.

Schizophrenia is a complex, heterogeneous, multidimensional disorder within which negative symptoms are a significant and disabling feature. Whilst there is no established treatment for these symptoms, some pharmacological and psychosocial interventions have shown promise and this is an active area of research. Despite the effort to identify effective interventions, as yet there is no broadly accepted definition of therapeutic success. This article reviews concepts of clinical relevance and reports on a consensus conference whose goal was to apply these concepts to the treatment of negative symptoms. A number of key issues were identified and discussed including: assessment of specific negative symptom domains; defining response and remission for negative symptoms; assessment of functional outcomes; measurement of outcomes within clinical trials; and the assessment of duration/persistence of a response. The group reached a definition of therapeutic success using an achieved threshold of function that persisted over time. Recommendations were agreed upon with respect to: assessment of negative symptom domains of apathy-avolition and deficit of expression symptoms; thresholds for response and remission of negative symptoms based on level of symptomatology; assessing multiple domains of function including social occupation, activities of daily living, and socialization; the need for clinical trial data to include rate of change over time and converging sources of evidence; use of clinician, patient and caregiver perspectives to assess success; and the need for establishing criteria for the persistence of therapeutic benefit. A consensus statement and associated research criteria are offered as an initial step towards developing broad agreement regarding outcomes of negative symptoms treatment.

Characterizing relapse prevention in bipolar disorder with adjunctive ziprasidone: clinical and methodological implications.

BACKGROUND: Ziprasidone, adjunctive to either lithium or valproate, has previously been shown to be associated with a significantly lower risk of relapse in bipolar disorder compared with lithium or valproate treatment alone. METHODS: This placebo-controlled outpatient trial with ziprasidone adjunctive to lithium or valproate or lithium and valproate alone, for subjects with a recent or current manic or mixed episode of bipolar I disorder, comprised a 2.5- to 4-month, open-label stabilization period, followed by a 6-month, double-blind maintenance period. These post hoc analyses characterize the relapse outcomes by dose, relapse types and timing as well as all-reason discontinuations during the maintenance period. RESULTS: Time to relapse and all-reason discontinuation were both statistically significant in favor of the ziprasidone 120mg/day group compared with placebo (p=0.004 and 0.001, respectively) during the 6-month double-blind period. There was no difference in time to relapse in the 80 and 160mg/day dose groups compared with placebo (p=0.16 and 0.40, respectively) and, likewise, for time to all-reason discontinuation (p=0.20 for both doses). The majority of relapses in each group occurred prior to week 8, and most were depressive in nature. LIMITATIONS: The primary study was not designed to compare relapse rates by dose groups. CONCLUSIONS: These analyses confirm the effectiveness of ziprasidone (80-160mg/day) in preventing relapses in subjects with bipolar disorder, with the 120mg/day dosage appearing to have the highest relapse prevention rate.

Achieving and sustaining remission in bipolar I disorder with ziprasidone : a post hoc analysis of a 24-week, double-blind, placebo-controlled study.

BACKGROUND AND OBJECTIVE: A number of operational definitions have been proposed to describe outcomes in bipolar disorders; the criteria used to define terms such as recurrence, relapse, response, remission and recovery have varied both in observational studies and in clinical trials. We carried out a post hoc analysis of rates of symptomatic point remission and sustained remission using four different remission criteria that had been evaluated in a previously published 24-week, double-blind, placebo-controlled study. METHODS: After stabilization for 8 consecutive weeks on open-label ziprasidone plus lithium or valproate, stabilized subjects were randomized to two groups, ziprasidone with lithium or valproate (ziprasidone group), or placebo with lithium or valproate (placebo group) for 16 weeks. Four remission criteria included (i) Mania Rating Scale (MRS) score ≤7, (ii) MRS ≤7 + Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤10, (iii) MRS ≤7 + Clinical Global Impression-Improvement (CGI-I) = 1, (iv) MRS score ≤7 + MADRS score ≤10 + CGI-I score = 1. We examined the percentages of subjects in each treatment group achieving symptomatic point (i.e. at each visit) and sustained (i.e. for ≥8 weeks) remission during the double-blind phase. RESULTS: At week 24, symptomatic point remission based on the above two more stringent criteria was achieved by 48.0 and 24.4% of the ziprasidone group versus 36.9 and 18.0% of placebo recipients, respectively (p = 0.04 and 0.14). Sustained remission rates at 24 weeks were 42.5 and 18.1% for ziprasidone, respectively (vs 33.3 and 14.4% for placebo, p = 0.04 and 0.21, respectively). CONCLUSION: This analysis indicates that ziprasidone plus lithium or valproate treatment showed modest to moderate remission rates at week 24 based on four different remission criteria in terms of symptomatic and sustained remission, despite the stringent criteria. Our findings indicate that ziprasidone may be effective in achieving sustained remission in bipolar I disorder and propose that a better understanding regarding the definition of remission in bipolar disorders should be required in clinical practice since our results showed different remission rates with different remission criteria.

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.

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.

Clinical Global Impression of Improvement (CGI-I) as a valid proxy measure for remission in schizophrenia: analyses of ziprasidone clinical study data.

OBJECTIVE: To determine the degree to which a proxy measure of remission in schizophrenia correlates with the criteria identified by the Remission in Schizophrenia Working Group, and how well early treatment response to ziprasidone predicts remission. METHODS: Data from 10 ziprasidone studies were analyzed to determine rates of remission achieved with ziprasidone using a remission definition of Clinical Global Impression of Improvement (CGI-I) of 1, and compared with rates of remission achieved using the remission working group criteria. Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) scores were then investigated as predictors of remission. RESULTS: A CGI-I score of 1 correlated with the remission criteria developed by the remission working group. In the combined ziprasidone arms, BPRS scores at Weeks 1, 3, and 4 successfully predicted PANSS remission (p<0.01) and BPRS remission (p<0.0001) at study endpoint (44-196weeks). PANSS scores (at Weeks 1, 3, and 4) successfully predicted PANSS remission (p<0.01) at study endpoint. PANSS scores at Week 3 successfully predicted BPRS remission (p=0.02) at study endpoint. A CGI-I score of 1 or 2 at Week 1 also successfully predicted remission in schizophrenia. CONCLUSION: The findings show a correlation between clinical and research scales (remission working group criteria) for the assessment of remission in schizophrenia. This proxy measure for the assessment of remission should be easy to apply in a clinical setting and facilitates the prediction of remission in schizophrenia.

Findings of a U.S. national cardiometabolic screening program among 10,084 psychiatric outpatients.

OBJECTIVE: A national cardiometabolic screening program for patients in a variety of public mental health facilities, group practices, and community behavioral health clinics was funded by Pfizer Inc. between 2005 and 2008. METHODS: A one-day, voluntary metabolic health fair in the United States offered patients attending public mental health clinics free cardiometabolic screening and same-day feedback to physicians from a biometrics testing third party that was compliant with the Health Insurance Portability and Accountability Act. RESULTS: This analysis included 10,084 patients at 219 sites; 2,739 patients (27%) reported having fasted for over eight hours. Schizophrenia or bipolar disorder was self-reported by 6,233 (62%) study participants. In the overall sample, the mean waist circumference was 41.1 inches for men and 40.4 inches for women; 27% were overweight (body mass index [BMI] 25.0-29.9 kg/m(2)), 52% were obese (BMI >or=30.0 kg/m(2)), 51% had elevated triglycerides (>or=150 mg/dl), and 51% were hypertensive (>or=130/85 mm Hg). In the fasting sample, 52% had metabolic syndrome, 35% had elevated total cholesterol (>or=200 mg/dl), 59% had low levels of high-density lipoprotein cholesterol (<40 mg/dl for men or <50 mg/dl for women), 45% had elevated triglycerides (>or=150 mg/dl), and 33% had elevated fasting glucose (>or=100 mg/dl). Among the 1,359 fasting patients with metabolic syndrome, 60% were not receiving any treatment. Among fasting patients who reported treatment for specific metabolic syndrome components, 33%, 65%, 71%, and 69% continued to have elevated total cholesterol, low levels of high-density lipoprotein, high blood pressure, and elevated glucose levels, respectively. CONCLUSIONS: The prevalence of metabolic syndrome and cardiometabolic risk factors, such as overweight, hypertension, dyslipidemia, and glucose abnormalities, was substantial and frequently untreated in this U.S. national mental health clinic screening program.

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.