Onur N. Karayal

Efficacy and tolerability of switching to ziprasidone from olanzapine, risperidone or haloperidol: an international, multicenter study

To compare the effectiveness of a switch from haloperidol (N=99), olanzapine (N=82), or risperidone (N=104) to 12 weeks of treatment with 80–160 mg/day ziprasidone in patients with stable schizophrenia or schizoaffective disorder. Stable outpatients with persistent symptoms or troublesome side effects were switched using one of three 1-week taper/switch strategies as determined by the investigator. Efficacy was assessed using the Brief Psychiatric Rating Scale score, Clinical Global Impression, Positive and Negative Symptom Scale, Montgomery–Åsberg Depression Rating Scale, and the Global Assessment of Functioning Scale, and tolerability by using standard measures of weight change, extrapyramidal symptoms, and laboratory findings. Suboptimal efficacy was the primary reason for switching. The preferred switch strategy was immediate discontinuation, and the preferred dosing regimen was 120 mg/day. Completer rates were 68, 60, and 86% in the haloperidol, risperidone, and olanzapine pre-switch groups, respectively. At week 12, a switch to ziprasidone resulted in statistically significant improvement from baseline on the Brief Psychiatric Rating Scale score, Clinical Global Impression-Improvement, Positive and Negative Symptom Scale, and Global Assessment of Functioning scales, reduction in extrapyramidal symptoms and a neutral impact on metabolic parameters. Switch from olanzapine and risperidone resulted in weight reduction and from haloperidol in some weight increase. In conclusion, oral ziprasidone of 80–160 mg/day with food was a clinically valuable treatment option for stable patients with schizophrenia or schizoaffective disorder experiencing suboptimal efficacy or poor tolerability with haloperidol, olanzapine, or risperidone.

Metabolic risk factors in first-episode schizophrenia: baseline prevalence and course analysed from the European First-Episode Schizophrenia Trial

Available data on antipsychotic-induced metabolic risks are often constrained by potential confounding effects due to prior antipsychotic treatment. In this study, we assessed the baseline prevalence of metabolic abnormalities and changes following treatment with five commonly-used antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine or ziprasidone) in first-episode, partially antipsychotic-naive patients with schizophrenia in the European first-episode schizophrenia trial (EUFEST). Overall baseline prevalence of metabolic syndrome (MetS) was 6.0%, with similar rates observed in the antipsychotic-naive patients (5.7%, 9/157) and in the other patients with only a brief prior exposure to antipsychotics (6.1%, 20/326). These results are consistent with the MetS prevalence rate estimated in a general population of similar age. Examination of individual risk factors showed 58.5% of subjects had one or more elevated metabolic risks at baseline: 28.5% demonstrated suboptimal HDL; 24.2% hypertension; 17.7% hypertriglyceridemia; 8.2% abdominal obesity; 7.3% hyperglycaemia. Increase in body weight (kg/month) occurred in patients treated with haloperidol (0.62 S.E. 0.11), amisulpride (0.76 S.E. 0.08), olanzapine (0.98 S.E. 0.07) and quetiapine (0.58 S.E. 0.09), which was significantly greater than that in the ziprasidone group (0.18 S.E. 0.10). The incidence rate of new diabetes cases over a 52-wk follow-up period was 0.82% (4/488). More patients experienced worsening rather than improvement of hypertriglyceridemia or hyperglycaemia in all treatment groups. Our findings suggest that in first-episode, partially antipsychotic-naive patients, the baseline prevalence rate of MetS appears to be no higher than that in the general population, but serious underlying individual risk factors nevertheless existed.

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.

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).

Effect of ziprasidone dose on all-cause discontinuation rates in acute schizophrenia and schizoaffective disorder: A post-hoc analysis of 4 fixed-dose randomized clinical trials

BACKGROUND Higher dose ziprasidone has been associated with improved treatment outcomes in patients with schizophrenia or schizoaffective disorder. This study examines the relationship of ziprasidone dose and all-cause discontinuation in randomized clinical trials in patients with an acute exacerbation of schizophrenia or schizoaffective disorder. METHOD Data were analyzed for the first 28 days from 4 pivotal, randomized, double-blind, fixed-dose ziprasidone trials. Patients in these trials had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder where ziprasidone was administered twice daily with food. Data were analyzed to examine the association between ziprasidone dose and all-cause discontinuation due to lack of efficacy, adverse events, or because of other reasons, relative to placebo. Differences in discontinuation were evaluated using Cox proportional hazard models and number needed to treat (NNT). RESULTS All-cause discontinuation for ziprasidone ranged from a low of 26.9% for the 160 mg/d dose group, to 40.9% for the 40 mg/d and 45.5% for the 80 mg/d groups, compared with 49.5% for placebo. The NNTs for avoiding 1 additional all-cause discontinuation compared with placebo were 12 (40 mg/d; n=186), 25 (80 mg/d; n=154), 9 (120 mg/d; n=125), and 4 (160 mg/d; n=104). The 120 mg/d and 160 mg/d groups were the only ziprasidone regimens associated with significantly lower all-cause discontinuation rates versus placebo in both the survival analysis (p=0.031 and <0.0001, respectively) and in examination of the NNT. The 160 mg/d group was associated with lower all-cause discontinuation rates versus lower-dose ziprasidone regimens (p=0.0158 for versus 40 mg/d, p=0.002 for versus 80 mg/d). Efficacy accounted for 51% of all medication discontinuations across ziprasidone groups, compared with 62% for placebo. Findings for overall discontinuation due to lack of efficacy are consistent with results for all-cause discontinuation. CONCLUSIONS Consistent with previous reports, higher doses of ziprasidone (120-160 mg/d, dosed twice daily with meals) are associated with significantly lower all-cause discontinuation rates and more favorable NNTs versus placebo. This was primarily driven by lower rates of discontinuation due to lack of efficacy.

Ziprasidone with adjunctive mood stabilizer in the maintenance treatment of bipolar I disorder: Long-term changes in weight and metabolic profiles

This analysis was conducted to compare the effects of adjunctive ziprasidone or placebo on metabolic parameters among patients receiving maintenance treatment with lithium or valproate. We also tested whether metabolic syndrome (MetS) and other risk factors were associated with baseline characteristics and treatment response. In the stabilization phase (Phase 1), 584 bipolar I disorder (DSM-IV) patients received 2.5-4 months of open label ziprasidone (80-160 mg/d) plus lithium or valproic acid (ZIP+MS). Patients who achieved at least 8 weeks of clinical stability were subsequently randomized into Phase 2 to 6-months of double-blind treatment with ZIP+MS (n=127) vs. placebo+MS (n=113). At baseline of Phase 1, MetS was found in 111 participants (23%). Participants with MetS (vs. non-MetS participants) were more likely to be aged 40 years or older, had significantly more severe manic symptoms, higher abdominal obesity, and higher BMI. Increase in abdominal obesity was associated with lower manic symptom improvement (p<0.05, as assessed by MRS change score) during Phase 1, while symptom improvement differed across racial groups. In the Phase 2 double-blind phase, the ZIP+MS group had similar weight and metabolic profiles compared to the placebo+MS group across visits. These results corroborate existing findings on ziprasidone which exhibits a neutral weight and metabolic profile in the treatment of schizophrenia and bipolar patients. Our findings suggest that MetS is highly prevalent in patients with bipolar disorder, may be associated with greater manic symptom severity, and may predict treatment outcomes.

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.

THAOS: Gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease

BackgroundTransthyretin amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin monomers. Two main forms exist: hereditary and wild-type transthyretin amyloidosis, the former associated with transthyretin gene mutations. There are several disease manifestations; however, gastrointestinal complications are common in the hereditary form. The aim of this study was to explore the prevalence and distribution of gastrointestinal manifestations in transthyretin amyloidosis and to evaluate their impact on the patients’ nutritional status and health-related quality of life (HRQoL).MethodsThe Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with transthyretin amyloidosis and the registry is sponsored by Pfizer Inc. This study presents baseline data from patients enrolled in THAOS as of June 2013. The modified body mass index (mBMI), in which BMI is multiplied with serum albumin, was used to assess the nutritional status and the EQ-5D Index was used to assess HRQoL.ResultsData from 1579 patients with hereditary transthyretin amyloidosis and 160 patients with wild-type transthyretin amyloidosis were analyzed. Sixty-three percent of those with the hereditary form and 15% of those with the wild-type form reported gastrointestinal symptoms at enrollment. Unintentional weight loss and early satiety were the most frequent symptoms, reported by 32% and 26% of those with transthyretin gene mutations, respectively. Early-onset patients (<50 years) reported gastrointestinal complaints more frequently than those with a late onset (p < 0.001) and gastrointestinal symptoms were more common in patients with the V30M mutation than in those with other mutations (p < 0.001). For patients with predominantly cardiac complications, the prevalence of gastrointestinal manifestations was not evidently higher than that expected in the general population. Both upper and lower gastrointestinal symptoms were significant negative predictors of mBMI and the EQ-5D Index Score (p < 0.001 for all).ConclusionsGastrointestinal symptoms were common in patients with hereditary transthyretin amyloidosis and had a significant negative impact on their nutritional status and HRQoL. However, patients with wild-type transthyretin amyloidosis or transthyretin mutations associated with predominantly cardiac complications did not show an increased prevalence of gastrointestinal disturbances.

Clinical, ECG and echocardiographic clues to the diagnosis of TTR-related cardiomyopathy

Background Signs of cardiac transthyretin (TTR) amyloidosis (ATTR) in patients with echocardiographic increase in interventricular septal thickness (IVST) are lacking. Objectives To identify clinical and ECG/echocardiographic signs associated with increased IVST in ATTR. Methods Analysis of patients with baseline echocardiography in the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry (N=1682). Patients were categorised into IVST classes according to the American Society of Echocardiography classification adapted to gender (ie, normal, mild, moderate, severe); then into two combined IVST classes (normal-mild and moderate-severe). Results 425 patients were included: 336 with a TTR mutation (m-TTR) and 89 with wild-type TTR (WT-TTR). 72% were men. Median (25th, 75th centile) age was 62 (45, 72) years. Non-Val30Met and WT-TTR were frequent in moderate (41% and 35%) and severe (50% and 33%) IVST classes. Median IVST was 15 mm (14, 16) (moderate) and 20 mm (18, 22) (severe). In the combined moderate-severe class, 85% of patients were ≥55 years of age; 81% were men; 86% had blood pressure <140 mm Hg; and 77% had increased right ventricle thickness (≥7 mm). Up to 66% of patients had cardiac sparkling. Systolic dysfunction (left ventricular ejection fraction <50%), restrictive pattern and low voltage were less frequent, and observed in 49%, 18% and 33% of patients, respectively. Conclusions Increased IVST, especially in men ≥55 years with normal systolic blood pressure, increase in right ventricle free wall and valve thicknesses, and sparkling, should alert practitioners to the possibility of ATTR. Absence of restrictive pattern and low voltage should not rule out the suspicion. Trial registration number: NCT00628745 (clinicaltrials.gov).

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.

ObjectiveThis 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. MethodsPooled 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. ResultsThe 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. ConclusionsZiprasidone 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.