A pilot study of intramuscular ziprasidone in the short-term treatment of patients with acute exacerbation of schizophrenia

Ziprasidone is a novel antipsychotic which, in oral formulation, has been shown to be effective and well tolerated in the treatment of acute psychosis. This pilot study examined the efficacy and tolerability of the intramuscular (IM) formulation and the transition from IM to oral ziprasidone in patients with acute schizophrenia. The study design was an open, prospective, 5-day treatment trial of IM ziprasidone followed by oral dosing in 12 patients with acute exacerbation of schizophrenia. Various doses (2.5, 5, 10, or 20 mg) up to 60 mg/day total were administered over 3 days, followed by transition to oral ziprasidone on Days 4-5. All patients completed the study. Mean improvements between baseline and Day 3 were observed in Brief Psychiatric Rating Scale (47.8 to 28.9) and Clinical Global Impression of Severity (6.1 to 5.3), and improvements were maintained on Days 4 and 5. No extrapyramidal syndrome, acute dystonia, or serious adverse events were reported. In these patients, IM ziprasidone 20-60 mg/day reduced psychomotor agitation and other symptoms of psychosis. The transition from IM to oral ziprasidone was well tolerated. Copyright 2000 John Wiley & Sons, Ltd.     

Spotlight on ziprasidone in schizophrenia and schizoaffective disorder

Ziprasidone is a novel antipsychotic agent with a pharmacological profile distinct from that of other currently available novel or classical antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative and affective symptoms of schizophrenia with a favourable tolerability profile, including a low propensity to induce extrapyramidal adverse effects. The drug has been administered orally to >300 patients with an acute exacerbation of schizophrenia or schizoaffective disorder in published 4- to 6-week randomised, double-blind trials. When given twice daily at dosages of between 80 and 160 mg/day, ziprasidone produced significantly greater improvements in overall symptomatology than placebo. In the largest study, ziprasidone 80 or 160 mg/day was also significantly more effective than placebo in reducing negative symptoms and, at 160 mg/day, was significantly more effective than placebo in improving depressive symptoms in patients with associated clinically significant depression. Data from a 4-week trial indicate that ziprasidone 160 mg/day has similar efficacy to haloperidol 15 mg/day. Ziprasidone 40 to 160 mg/day was more effective than placebo with respect to prevention of impending relapse and improvement of negative symptoms in 294 stable patients with chronic schizophrenia who were treated for up to 1 year. In addition, significantly more ziprasidone than haloperidol recipients achieved a negative symptom response in a 28-week study involving 301 stable patients with chronic or subchronic schizophrenia. In general, oral ziprasidone is well tolerated with an overall incidence of adverse events similar to placebo. Importantly, the drug has a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. Ziprasidone is associated with slight prolongation of the QTc interval; the clinical significance of this is not yet clear. The drug does not appear to be associated with sustained elevation of plasma prolactin levels. Preliminary data indicate that long-term oral ziprasidone treatment is well tolerated. Ziprasidone is the only novel antipsychotic currently available in a rapid-acting intramuscular formulation. Short-term treatment with intramuscular ziprasidone was effective and well tolerated in patients with acute agitation associated with psychosis. In addition, intramuscular ziprasidone reduced agitation scores by a significantly greater extent than haloperidol in a study involving patients with acute agitation associated with psychosis. CONCLUSIONS: Ziprasidone is a promising new antipsychotic that has shown significant efficacy in the oral treatment of patients with schizophrenia or schizoaffective disorder. The drug is well tolerated with a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. In addition, intramuscular ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.     

Ziprasidone: a review of its use in schizophrenia and schizoaffective disorder

Ziprasidone is a novel antipsychotic agent with a pharmacological profile distinct from that of other currently available novel or classical antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative and affective symptoms of schizophrenia with a favourable tolerability profile, including a low propensity to induce extrapyramidal adverse effects. The drug has been administered orally to >300 patients with an acute exacerbation of schizophrenia or schizoaffective disorder in published 4- to 6-week randomised, double-blind trials. When given twice daily, at dosages of between 80 and 160 mg/day, ziprasidone produced significantly greater improvements in overall symptomatology than placebo. In the largest study, ziprasidone 80 or 160 mg/day was also significantly more effective than placebo in reducing negative symptoms and, at 160 mg/day, was significantly more effective than placebo in improving depressive symptoms in patients with associated clinically significant depression. Data from a 4-week trial indicate that ziprasidone 160 mg/day has similar efficacy to haloperidol 15 mg/day. Ziprasidone 40 to 160 mg/day was more effective than placebo with respect to prevention of impending relapse and improvement of negative symptoms in 294 stable patients with chronic schizophrenia who were treated for up to 1 year. In addition, significantly more ziprasidone than haloperidol recipients achieved a negative symptom response in a 28-week study involving 301 stable patients with chronic or subchronic schizophrenia. In general, oral ziprasidone is well tolerated with an overall incidence of adverse events similar to placebo. Importantly, the drug has a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. Ziprasidone is associated with slight prolongation of the QTc interval; the clinical significance of this is not yet clear. The drug does not appear to be associated with sustained elevation of plasma prolactin concentrations. Preliminary data indicate that long-term oral ziprasidone treatment is well tolerated. Ziprasidone is the only novel antipsychotic currently available in a rapid-acting intramuscular formulation. Short-term treatment with intramuscular ziprasidone was effective and well tolerated in patients with acute agitation associated with psychosis. In addition, intramuscular ziprasidone reduced agitation scores by a significantly greater extent than haloperidol in a study involving patients with acute agitation associated with psychosis. CONCLUSIONS: Ziprasidone is a promising new antipsychotic that has shown significant efficacy in the oral treatment of patients with schizophrenia or schizoaffective disorder. The drug is well tolerated with a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. In addition, intramuscular ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.     

A 1-year,double-blind,placebo-controlled trial of ziprasidone 40, 80 and 160 mg/day in chronic schizophrenia: the Ziprasidone Extended Use in Schizophrenia (ZEUS) study

We evaluated relapse in patients with stable, chronic schizophrenia over a 1-year period; inpatients were randomized to ziprasidone 40 mg/day (n = 72), 80 mg/day (n = 68), 160 mg/day (n = 67) or placebo (n = 71). The probability of relapse (Kaplan-Meier) at 1 year was significantly lower in the ziprasidone 40, 80, and 160 mg/day groups (43%, 35% and 36%, respectively) compared to placebo (77%; P = 0.002, P < 0.001 and P < 0.001, respectively). In those patients who remained on treatment for at least 6 months, only 9% subsequently relapsed on ziprasidone compared to 42% on placebo (P = 0.001). All three doses of ziprasidone were significantly superior to placebo on Positive and Negative Syndrome Scale (PANSS) efficacy variables (all P < 0.05). Ziprasidone was associated with a significantly greater mean improvement in the PANSS negative symptom subscale compared to placebo (P < 0.05). Discontinuation due to adverse events was similar with ziprasidone and placebo. Ziprasidone treatment was indistinguishable from placebo in assessments of movement disorders and was not associated with weight gain or cardiovascular abnormalities. These results demonstrate that ziprasidone was effective in reducing the frequency of relapse and was associated with long-term improvement in negative symptoms. Ziprasidone was well tolerated in this population of patients with chronic, stable schizophrenia.     

Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group.

In this double-blind study, patients with an acute exacerbation of schizophrenia or schizoaffective disorder were randomized to receive either ziprasidone 80 mg/day (n = 106) or 160 mg/day (n = 104) or placebo (n = 92), for 6 weeks. Both doses of ziprasidone were statistically significantly more effective than placebo in improving the PANSS total, BPRS total, BPRS core items, CGI-S, and PANSS negative subscale scores (p < .05). Ziprasidone 160 mg/day significantly improved depressive symptoms in patients with clinically significant depression at baseline (MADRS > or = 14, over-all mean 23.5) (p < .05) as compared with placebo. The percentage of patients experiencing adverse events was similar in each treatment group, and resultant discontinuation was rare. The most frequent adverse events associated with ziprasidone were generally mild dyspepsia, nausea, dizziness, and transient somnolence. Ziprasidone was shown to have a very low liability for inducing movement disorders and weight gain. The results indicate that ziprasidone is effective and well tolerated in the treatment of the positive, negative, and depressive symptoms of an acute exacerbation of schizophrenia or schizoaffective disorder.     

Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with psychosis: a double-blind, randomized trial

RATIONALE: Intramuscular (IM) conventional antipsychotics and/or benzodiazepines are effective in the short-term treatment of acutely agitated psychotic patients but may be associated with adverse effects. A short-acting IM formulation of the novel antipsychotic, ziprasidone, which may offer advantages over conventional agents, has been developed. OBJECTIVE: To compare ziprasidone IM 2 mg (n=38) and 20 mg (n=41) in the acute control and short-term management of agitated psychotic patients. METHODS: A prospective, randomized, double-blind, 24-h study assessed efficacy using the Behavioral Activity Rating Scale (BARS) and the PANSS. The BARS is a validated rating scale for the assessment of treatment response in acute agitation associated with psychosis. Following the initial dose, three more doses could be given 4 h apart if needed during the 24-h period. RESULTS: The mean BARS score had decreased 15 min after the first 20 mg IM dose and was statistically significantly lower than the 2 mg group at 30 min post-dose. The improvement with the 20 mg dose increased until 2 h, and was maintained until at least 4 h post-dose (P<0.001). Two hours after the first injection, almost all of the patients receiving ziprasidone 20 mg were BARS responders compared with just one-third of those receiving 2 mg ziprasidone (P<0.001). The calming effect of ziprasidone was also evident by the significant reduction in PANSS agitation items (P<0.05) and CGI-severity at 4 h (P=0.008). Both ziprasidone doses were very well tolerated. Ziprasidone IM 20 mg was not associated with EPS, dystonia, akathisia, respiratory depression or with excessive sedation. CONCLUSIONS: Ziprasidone IM 20 mg substantially and significantly reduced the symptoms of acute agitation in patients with psychotic disorders. Ziprasidone 20 mg IM was very well tolerated and produced no dystonia or akathisia.     

Ziprasidone and amisulpride effectively treat negative symptoms of schizophrenia: results of a 12-week, double-blind study

We compared the efficacy of ziprasidone and amisulpride in the treatment of negative symptoms and overall psychopathology in subjects who had chronic schizophrenia with predominantly negative symptoms. This multicentre, 12-week, double-blind study randomly assigned subjects with predominantly negative-symptom schizophrenia [i.e. Positive and Negative Syndrome Scale (PANSS) Negative Subscale score >or=6 points greater than Positive Subscale score] to ziprasidone (40-80 mg b.i.d.; n=60) or amisulpride (50-100 mg b.i.d.; n=63). The primary efficacy variable was the change from baseline in PANSS Negative Subscale score. Secondary efficacy variables included change in scores for PANSS Total, Global Assessment of Functioning, Brief Psychiatric Rating Scale derived from PANSS Total and Core, Clinical Global Impression (CGI)-Severity and CGI-Improvement. For the change in PANSS Negative Subscale score, a ratio to assess the equivalence of the treatment groups was calculated from the least squares mean changes from baseline, with equivalence claimed if the lower limit of the 95% confidence interval of the ratio exceeded 0.60. Mean daily dose, adjusted for differential numbers of subjects and differential days between visits, was 118.0 mg for ziprasidone and 144.7 mg for amisulpride. Mean PANSS Negative Subscale scores improved over the 12-week treatment period for intent-to-treat subjects, evaluable subjects (subjects with >or=4 weeks of double-blind treatment and no protocol deviations) and completers in both treatment groups. Ziprasidone demonstrated efficacy comparable to amisulpride in improving negative symptoms and global psychopathology. The groups demonstrated comparable improvements in secondary efficacy variables. Both agents were generally well tolerated, with comparably low incidences of movement disorders. In subjects with negative symptom-prominent schizophrenia, ziprasidone in mean daily doses of 118 mg was equivalent to amisulpride in mean daily doses of 148 mg in ameliorating negative symptoms and comparable in improving overall psychopathology and global illness severity.     

Efficacy and tolerability of ziprasidone in patients with treatment-resistant schizophrenia

This multicentre, parallel-group study compared the efficacy and tolerability of ziprasidone and chlorpromazine in treatment-resistant schizophrenia (at least three treatment periods of at least 6 weeks each with two or more antipsychotic agents during the past 5 years without significant response) that was unresponsive to 6 weeks of open-label haloperidol (相似文献   

齐拉西酮与氟哌啶醇治疗精神分裂症随机双盲双模拟多中心对照研究

目的:评价齐拉西酮治疗精神分裂症的疗效及安全性。方法:将235例精神分裂症病人随机分为齐拉西酮组(118例)和氟哌啶醇组(117例),齐拉西酮和氟哌啶醇最低日剂量分别定为40 mg·d~(-1)和8 mg·d~(-1),最高日剂量分别限定为160 mg·d~(-1)和20 mg·d~(-1),每日分2次服用。进行为期6 wk的多中心双盲双模拟对照研究。采用阳性和阴性症状量表(PANSS)、临床总体印象量表(CGI)、不良反应量表(TESS)及有关实验室检查评价疗效和安全性。结果:治疗结束时,2组PANSS评分较入组时均显著减低(P＜0．05);PANSS减分率——齐拉西酮组为(64±s 19)%,氟哌啶醇组为(67±24)%;临床总有效率——齐拉西酮组为81．1%,氟哌啶醇组为80．2%;2组疗效差异无显著意义。不良反应的发生率2组间比较差异无显著意义,但心电图的异常率氟哌啶醇组明显高于齐拉西酮组,差异有显著意义(P＜0．05)。结论:齐拉西酮治疗精神分裂症的疗效与氟哌啶醇相似,对心电图的影响比氟哌啶醇轻而少,是一种有效、安全的抗精神病药物。     

齐拉西酮注射液治疗精神分裂症激越症状的研究

目的本研究应用氟哌啶醇注射液作为对照,评价齐拉西酮注射液治疗精神分裂症激越患者的疗效、安全性和耐受性。方法连续入组急性精神分裂症患者,按照1：1的比例随机分配到齐拉西酮注射液治疗组（试验组）和氟哌啶醇注射液治疗组（对照组）,对患者进行筛选访视、基线访视,以及肌注治疗第一剂药后的2、4、24、48h和72h的访视。采用简明精神评定量表（BPRS）评价主要疗效,Simpson-Angus量表评定药物的锥体外系反应。结果两组均纳入受试者30例。药物治疗72h后与基线比较,试验组BPRS总分减分平均为12.55±6.88,对照组BPRS总分减分平均为15.60±5.94。两组主要疗效指标差异无统计学意义（P=0.110）。试验组未见锥体外系不良反应,Simpson-Angus量表评分在治疗前后差异无统计学意义（P=0.16）;对照组出现锥体外系不良反应,治疗前后差异有统计学意义（P=0.02）。结论甲磺酸齐拉西酮注射液能够快速有效控制精神分裂症急性激越症状,疗效与氟哌啶醇注射液相当,不良反应轻微,安全性、耐受性好,值得临床推广应用。     

The atypical antipsychotic ziprasidone,but not haloperidol,improves phencyclidine-induced cognitive deficits in a reversal learning task in the rat

The glutamate/N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) has been shown to induce both positive and negative symptoms of schizophrenia, as well as cognitive deficits, thus providing a relatively valid model of psychosis. Isolation rearing from weaning in the rat has been proposed as a non-pharmacological model of psychosis. The aim of the present study was to explore the validity of a combination of these techniques to model cognitive dysfunction associated with schizophrenia. The present study evaluates the effects of the novel antipsychotic ziprasidone and the typical antipsychotic haloperidol in their ability to reverse the cognitive deficit induced by PCP in isolation reared rats and social controls. Rats housed in social isolation (n = 25) or in groups of five (n = 25) from weaning were food deprived and trained to respond for food in an operant reversal learning paradigm. PCP at 1.0 and 1.5 mg/kg (intraperitoneally, i.p.) significantly and selectively impaired reversal task performance in both groups of rats. This impairment was not significantly improved following the coadministration of haloperidol (0.05 mg/kg, i.p.). Higher haloperidol doses (0.1 and 0.25 mg/kg, i.p.) were found to impair task performance, with the social animals being more sensitive than isolation-reared animals. In contrast, ziprasidone (2.5 mg/kg, i.p.) reversed the impairment caused by PCP. This was significant in social animals, while in isolates there was a non-significant enhancement in performance of the reversal task with ziprasidone compared to PCP alone. Thus, PCP produced a selective reversal learning deficit in rats, which was ameliorated following treatment with ziprasidone but not haloperidol. Rearing conditions did not influence performance of the test or the deficit produced by PCP.     

Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial

BACKGROUND: In an earlier 21-day, placebo-controlled trial, ziprasidone was efficacious in improving symptoms of mania and was well tolerated. To confirm these results, a similarly designed 21-day trial was conducted. METHODS: Inpatients with bipolar I disorder, manic or mixed, were randomized to ziprasidone (40 to 80 mg BID) or placebo. Efficacy rating scales were derived from the Schedule for Affective Disorders and Schizophrenia-Change Bipolar Scale (SADS-CB). SADS-CB-derived Mania Rating Scale (MRS) total score was the primary efficacy parameter. Secondary SADS-CB-derived efficacy parameters included Manic Syndrome and Behavior and Ideation Subscales, Hamilton Depression Rating Scale (HAM-D), and the Montgomery Asberg Depression Rating Scale (MADRS). The Clinical Global Impression-Severity Scale (CGI-S), the Global Assessment of Functioning (GAF), and the Positive and Negative Syndrome Scale (PANSS) were also assessed. RESULTS: Sixty-five placebo and 137 ziprasidone patients were evaluable for efficacy. Baseline-to-endpoint mean changes in MRS scores were -11.1 for ziprasidone and -5.6 for placebo (all patients, last observation carried forward [LOCF]; P < 0.01). Ziprasidone produced significantly greater improvements in Manic Syndrome (P < or = 0.01) and Behavior and Ideation Subscales (P < or = 0.001), CGI-S score, (P < or = 0.001), PANSS Total (P < or = 0.01) and Positive Subscale (P < or = 0.001) scores, and GAF (P < or = 0.001). With ziprasidone, significant improvements were observed from Day 2 onward for MRS and CGI-S at all time points except Day 4 for MRS. Treatment-related discontinuations due to adverse events were 5.8% for ziprasidone and 1.5% for placebo (P = 0.20). CONCLUSIONS: Ziprasidone was well tolerated, rapidly efficacious, and superior to placebo in improving symptoms and global illness severity in these inpatients with acute bipolar mania, both manic and mixed episodes.     

Ziprasidone for schizophrenia and bipolar disorder: a review of the clinical trials

Ziprasidone is a newer "atypical" or "second-generation" antipsychotic. Oral ziprasidone (ziprasidone hydrochloride) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia, and acute manic or mixed episodes associated with bipolar disorder (with or without psychotic features). Ziprasidone intramuscular (ziprasidone mesylate) is FDA-approved for acute agitation in patients with schizophrenia. Oral ziprasidone appears efficacious, and has been shown to have some limited clinical advantages over chlorpromazine and haloperidol in ameliorating negative symptoms of schizophrenia. In Phase 2 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia, ziprasidone did not match the clinical performance of olanzapine and risperidone, appearing closer in overall effectiveness to quetiapine. The rate of dose titration and the dose achieved may have an important bearing on ziprasidone's efficacy profile. In studies of usage for acute agitation in individuals with schizophrenia, intramuscular ziprasidone has been shown to be efficacious and relatively well tolerated. Regarding tolerability, ziprasidone, has important advantages in that it is not associated with clinically significant weight gain or adverse changes in cholesterol, triglycerides, or glycemic control, and patients may experience moderate improvement in these measures when switching to ziprasidone from a different antipsychotic agent. It also lacks significant persistent effects on prolactin levels, is not anticholinergic, and only infrequently causes extrapyramidal side effects or postural hypotension, although it can be associated with somnolence. This tolerability profile may be quite valuable in the treatment of some patients. Ziprasidone may prolong the electrocardiogram (ECG) QTc interval (QT interval corrected for heart rate by a standard algorithm), but after 5 years' clinical availability ziprasidone (by itself) does not appear to pose a substantial clinical problem in this regard. Therefore, ziprasidone may be considered a first-line drug option in the treatment of schizophrenia or manic episodes, but, in view of the differences among antipsychotic medications, drug selection should be guided by the patient's individual characteristics and situation.     

齐哌西酮与氟哌啶醇治疗精神分裂症的疗效和安全性比较

目的：验证齐哌西酮治疗精神分裂症的疗效及安全性。方法：采用随机、双盲、双模拟、平行对照研究。治疗d 1～4,试验组每日早餐后服齐哌西酮20 mg及氟哌啶醇安慰剂1片,对照组每日早餐后服氟哌啶醇2 mg及齐哌西酮安慰剂1片；治疗d 5～42,试验组每日早、晚餐后服齐哌西酮20 mg及氟哌啶醇安慰剂1片,对照组每日早、晚餐后服氟哌啶醇2 mg及齐哌西酮安慰剂1片。疗程6 wk。结果：完成6 wk治疗的精神分裂症病人共57例,其中试验组(齐哌西酮组)29例,对照组(氟哌啶醇组)28例。治疗结束时,2组PANSS和BPRS评分较入组时均显著减低(P＜0.05)；PANSS总减分率：齐哌西酮组为(66±s 28)%,氟哌啶醇组为(66±26)%；临床总有效率：齐哌西酮组66%,氟哌啶醇组71%,2组疗效差异无显著意义(P＞0.05)。2组的不良反应发生率差异无显著意义,齐哌西酮组失眠的发生率显著高于氟哌啶醇组(P＜0.05)。结论：国产齐哌西酮治疗精神分裂症有明显疗效,未见明显不良反应。     

The behavioral effects of acute and chronic JL 13, a putative antipsychotic, in Cebus non-human primates

RATIONALE: Neuroleptic or antipsychotic drugs are the mainstay of treating acute and chronic psychosis. However, their efficacy is offset by a wide array of side effects, especially extrapyramidal syndromes (EPS). In an attempt to develop novel antipsychotic agents, several animal models have been developed to characterize the profile of new chemical entities. OBJECTIVE: To evaluate the behavioral characteristics of JL 13, a potentially unique antipsychotic agent, three separate studies across a wide dose range in Cebus monkeys were conducted and compared with two studies of oral and parenteral haloperidol. METHODS: Twelve Cebus monkeys were tested with single i.m. doses of JL 13 (0.1-2.5 mg/kg), single p.o. doses (1.0-50.0 mg/kg), and 35 days of continuous p.o. (up to 25 mg/kg) treatments and were blindly evaluated. The same twelve monkeys were also tested with haloperidol i.m. (0.01-0.25 mg/kg) and nine of the monkeys also received haloperidol p.o. (0.1-5.0 mg/kg). Behaviors scored included sedation/arousal, locomotor activity, EPS of parkinsonism and dystonia, as well as reactivity. RESULTS: JL 13 produced mild to moderate and dose-related increased sedation and decreased locomotor activity. Minimal decreases in eye blinking rates were also noted as a consequence of sedation. Mild dystonia and parkinsonian symptoms of slow movement developed at the highest dose tested of 50 mg/kg p.o. in only 6 of 12 monkeys. This is 50 times higher than oral doses of haloperidol that would be needed to produce similar EPS effects. Dose-related EPS of dystonia and bradykinesia occurred in relation to decreased locomotor activity and reactivity to stimuli with haloperidol i.m. and p.o., which are features characteristically seen with traditional neuroleptics. CONCLUSIONS: The behavioral effects of JL 13 in non-human primates suggest this compound is well tolerated and may have a favorable antipsychotic benefit/risk ratio in the clinic, especially if antipsychotic efficacy occurs at doses well below those that can cause EPS.     

A 6-month prospective, observational, naturalistic, uncontrolled study to evaluate the effectiveness and tolerability of oral ziprasidone in patients with schizophrenia.

This multicenter, uncontrolled, naturalistic study evaluated the effectiveness and tolerability of 6 months of treatment with ziprasidone in 1266 patients with a diagnosis of schizophrenia. The percentage of responders (at least 30% reduction in PANSS total score) in the primary analysis sample (n=1022) was 47.3% (95% CI 44.2-50.4) at the end of the study. Patients showed a significant and clinically relevant reduction in the PANSS total, positive, negative and general psychopathology subscales scores (effect size of 1.60, 1.83, 0.62 and 1.40 respectively). Overall, 453 (35.8%) patients withdrew from the study; 9.3% withdrew owing to adverse events. Ziprasidone doses greater than 120 mg/day were associated with a lower risk of discontinuation for any cause (OR 0.46, 95% CI 0.33-0.65) Ziprasidone was well tolerated. Most common side effects were: insomnia, somnolence and nervousness. The effectiveness and tolerability of ziprasidone in clinical practice are consistent to those previously shown in the more restricted and homogeneous populations of clinical trials.     

Ziprasidone in the short-term treatment of patients with schizoaffective disorder: results from two double- blind, placebo-controlled, multicenter studies

This study assessed the efficacy of ziprasidone for the treatment of schizoaffective disorder. Data were taken from subsets of patients with schizoaffective disorder, derived from two separate double-blind, placebo-controlled, parallel-group, multicenter studies. A total of 115 hospitalized patients with an acute episode of schizoaffective disorder were randomly assigned to receive either fixed oral doses of ziprasidone 40 mg/day (N = 16), 80 mg/day (N = 18), 120 mg/day (N = 22), 160 mg/day (N = 25), or placebo (N = 34) for 4 to 6 weeks. Mean baseline-to-endpoint changes in Brief Psychiatric Rating Scale (BPRS) total, BPRS Core, Clinical Global Impressions Severity scale (CGI-S), BPRS Depressive, BPRS Manic, and Montgomery-Asberg Depression Rating Scale total scores were compared between the placebo and ziprasidone groups. Neurological (Simpson-Angus, Barnes Akathisia, Abnormal Involuntary Movement Scale [AIMS]) and other side effects were also assessed. Significant dose-related improvements on all primary efficacy variables (BPRS total, BPRS Core, CGI-S) and for BPRS Manic items were observed with ziprasidone treatment in a combined analysis of data from both studies (p < or = 0.01). Ziprasidone 160 mg/day was significantly more effective than placebo in improving mean BPRS total, BPRS Core, BPRS Manic, and CGI-S scores (p < 0.05). At 120 mg/day, ziprasidone was significantly more effective than placebo in improving mean CGI-S scores (p < 0.05). The incidence of individual adverse events was generally low in all treatment groups and was not dose-related. In addition, no significant differences were observed between baseline-to-endpoint mean changes in Simpson-Angus and AIMS scores with placebo or ziprasidone 40 to 160 mg/day. These results suggest that ziprasidone may have efficacy in the treatment of affective as well as psychotic symptoms of schizoaffective disorder, with a low side-effect burden.     

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

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

The effects of ziprasidone on steady‐state lithium levels and renal clearance of lithium

Aims   To assess the potential of ziprasidone to alter the renal clearance and steady‐state serum levels of lithium.
Methods  Healthy subjects who had stable serum lithium levels during the first 7 days of treatment with lithium 900 mg day^{− 1}, given as two divided daily doses, were randomized to receive concomitant treatment with either ziprasidone, 40 mg day^{− 1}, given as two divided daily doses, on days 9–11 followed by 80 mg day^{− 1}, given as two divided daily doses on days 12–15 ( n  = 12), or placebo twice daily ( n  = 13). Ziprasidone or placebo was administered 2 h before each dose of lithium.
Results   Ziprasidone administration was associated with a 0.07 mmol l^{− 1} (13%) mean increase in steady‐state serum lithium levels compared with a mean increase of 0.06 mmol l^{− 1} (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h^{− 1} (5%) in the ziprasidone group and by 0.14 l h^{− 1} (9%) in the placebo group. None of these differences between the two groups was statistically or clinically significant.
Conclusions   Ziprasidone does not alter steady‐state serum lithium concentrations or renal clearance of lithium.     

Dose reduction of high-dose first-generation antipsychotics or switch to ziprasidone in long-stay patients with schizophrenia: A 1-year double-blind randomized clinical trial

Long-stay patients with severe schizophrenia are frequently treated with high doses of first-generation antipsychotics (FGA). Dose reduction or switching to ziprasidone may reduce the severity of negative symptoms and side effects.We investigated in a randomized double-blind trial whether a dose-reduction strategy to achieve an adequate dose of a FGA (5 mg/day haloperidol equivalents, n = 24) or switching to ziprasidone (160 mg/day, n = 24) in treatment resistant patients would decrease negative symptoms after 1 year of treatment. We found that negative symptoms did not change significantly in either condition. Positive symptoms, excited symptoms, and emotional distress worsened over time with ziprasidone, resulting in a significant difference between conditions in favour of FGA dose reduction. Relapse and treatment failure, defined as a prolonged or repeated relapse, occurred more often with ziprasidone than with FGA (45.8% versus 20.8%, and 25.0% versus 16.7%, respectively). Treatment with ziprasidone was superior for extrapyramidal symptoms.Our study establishes that lowering high FGA doses to an equivalent of 5 mg/day haloperidol or switching to ziprasidone is feasible in the vast majority of patients but does not improve negative or other symptoms. Neither FGA dose reduction nor switching to ziprasidone is an adequate alternative to clozapine for long-stay patients with severe treatment resistant schizophrenia.