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 (Geodon, Zeldox) is an atypical antipsychotic agent with a unique neurotransmitter receptor-binding profile. The oral formulation is indicated for the treatment of adult patients with schizophrenia and the intramuscular formulation for the control of acute agitation in these patients. In adult patients with schizophrenia or schizoaffective disorder, oral ziprasidone was effective at a dosage of 40-80 mg twice daily in patients experiencing a phase of acute illness, and at a dosage of 20-80 mg twice daily in those with chronic schizophrenia or schizoaffective disorder, including those who were symptomatically stable. Ziprasidone offers the advantage over most other atypical antipsychotic agents of being available in a fast-acting intramuscular formulation for control of acute agitation, thus providing clinicians with the option to safely and effectively transition to longer-term treatment with the oral formulation. Although careful consideration should be given to the propensity for ziprasidone to cause corrected QT (QTc) interval prolongation, albeit at a relatively low incidence, the drug generally has a favourable tolerability profile of low extrapyramidal syndrome (EPS) liability, neutral bodyweight gain, and potentially low propensity for metabolic complications. Thus, ziprasidone is an effective option for the management of patients with schizophrenia or schizoaffective disorder, with the intramuscular formulation providing a useful option for the treatment of acute agitation in these patients.     

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.     

Ziprasidone, a new atypical antipsychotic drug

Although the introduction of antipsychotic drugs in 1954 was a breakthrough in the treatment of patients with schizophrenia, these agents have a number of adverse effects that limit effectiveness and compliance. The atypical antipsychotic drugs provide an improved tolerability profile, particularly in minimizing extrapyramidal side effects; however, they are associated with significant weight gain, which may be related to growing evidence linking the atypical agents with diabetes and hyperlipidemia. Ziprasidone, a new atypical antipsychotic drug, was demonstrated in clinical trials to be more efficacious than placebo and similar in efficacy to haloperidol in the treatment of schizophrenia. Like the existing atypical agents, ziprasidone has a rate of extrapyramidal side effects similar to that of placebo and does not cause significant elevations in prolactin levels. In contrast, ziprasidone has a low propensity for causing weight gain. For patients requiring an antipsychotic drug, ziprasidone represents a new treatment option with a limited adverse effect profile.     

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.     

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。     

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 aripiprazole : a review of its use in the management of agitation in schizophrenia and bipolar I disorder

An intramuscular formulation of the atypical antipsychotic aripiprazole (Abilify) has been developed and is approved in the EU for use in agitation and disturbed behaviour associated with schizophrenia. In the US, it is approved for the treatment of agitation associated with schizophrenia or bipolar I disorder (manic or mixed). In large, well designed trials, intramuscular aripiprazole was an effective and generally well tolerated treatment for agitation associated with schizophrenia, schizoaffective disorder, schizophreniform disorder or bipolar I disorder. Intramuscular aripiprazole was more effective than placebo in these patient populations and was noninferior to intramuscular haloperidol in those with agitation associated with schizophrenia and its related disorders. Aripiprazole is associated with a low risk for extrapyramidal symptoms (EPS), cardiac effects, hyperprolactinaemia, weight gain and other metabolic disturbances. Head-to-head trials comparing intramuscular aripiprazole with other intramuscular atypical antipsychotics are required before the relative position of each of these agents can be fully determined. In the meantime, intramuscular aripiprazole, with its favourable tolerability profile, is a valuable treatment option for agitation in patients with schizophrenia, schizoaffective disorder, schizophreniform disorder or bipolar I disorder.     

Ziprasidone for the treatment of acute manic or mixed episodes associated with bipolar disorder

Ziprasidone, a benzisothiazolyl piperazine-type atypical antipsychotic agent, has a unique receptor-binding profile. A potent antagonist of serotonin 5-HT(2A) and dopamine D(2) receptors, ziprasidone has an affinity for 5-HT(2A) receptors >10-fold higher than its affinity for D(2) receptors.Ziprasidone has been shown to be effective in the treatment of bipolar disorder in patients experiencing manic or mixed episodes. It was significantly more effective than placebo in improving manic symptoms as early as day 2 of treatment in two 3-week placebo-controlled trials as monotherapy. In a 12-week, placebo-controlled trial of patients with acute mania, ziprasidone as monotherapy showed comparable efficacy with, and fewer movement-related adverse events than, haloperidol. It has demonstrated efficacy in two 1-year open-label extension trials, both as monotherapy and in combination with lithium.Ziprasidone has a generally favourable adverse effect profile. In short-term placebo-controlled trials, there were similar discontinuation rates in active treatment and placebo recipients. While twice as many patients treated with ziprasidone compared with placebo discontinued therapy because of adverse events, the number of events was small and adverse effects were generally mild or moderate. The favourable tolerability of ziprasidone has been confirmed in long-term extension studies and its use was not associated with weight gain or dyslipidaemia. Ziprasidone-related movement disorders occurred infrequently.     

Pharmacological management of acute agitation

Acute agitation occurs in a variety of medical and psychiatric conditions, and when severe can result in behavioural dyscontrol. Rapid tranquillisation is the assertive use of medication to calm severely agitated patients quickly, decrease dangerous behaviour and allow treatment of the underlying condition. Intramuscular injections of typical antipsychotics and benzodiazepines, given alone or in combination, have been the treatment of choice over the past few decades.Haloperidol and lorazepam are the most widely used agents for acute agitation, are effective in a wide diagnostic arena and can be used in medically compromised patients. Haloperidol can cause significant extrapyramidal symptoms, and has rarely been associated with cardiac arrhythmia and sudden death. Lorazepam can cause ataxia, sedation and has additive effects with other CNS depressant drugs.Recently, two fast-acting preparations of atypical antipsychotics, intramuscular ziprasidone and intramuscular olanzapine, have been developed for treatment of acute agitation. Intramuscular ziprasidone has shown significant calming effects emerging 30 minutes after administration for acutely agitated patients with schizophrenia and other nonspecific psychotic conditions. Intramuscular ziprasidone is well tolerated and has gained widespread use in psychiatric emergency services since its introduction in 2002. In comparison with other atypical antipsychotics, ziprasidone has a relatively greater propensity to increase the corrected QT (QTc) interval and, therefore, should not be used in patients with known QTc interval-associated conditions. Intramuscular olanzapine has shown faster onset of action, greater efficacy and fewer adverse effects than haloperidol or lorazepam in the treatment of acute agitation associated with schizophrenia, schizoaffective disorder, bipolar mania and dementia. Intramuscular olanzapine has been shown to have distinct calming versus nonspecific sedative effects. The recent reports of adverse events (including eight fatalities) associated with intramuscular olanzapine underscores the need to follow strict prescribing guidelines and avoid simultaneous use with other CNS depressants. Both intramuscular ziprasidone and intramuscular olanzapine have shown ease of transition to same-agent oral therapy once the episode of acute agitation has diminished. No randomised, controlled studies have examined either agent in patients with severe agitation, drug-induced states or significant medical comorbidity. Current clinical experience and one naturalistic study with intramuscular ziprasidone suggest that it is efficacious and can be safely used in such populations. These intramuscular atypical antipsychotics may represent a historical advance in the treatment of acute agitation.     

Ziprasidone in bipolar disorder

Ziprasidone is a second-generation antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania. It has a unique receptor profile that includes high-affinity antagonist activity at 5-hydroxytryptamine (5-HT) 2A, D2, 1D and 2C receptors, a potent agonist activity at 5-HT1A receptors and a relatively high affinity for the 5-HT and noradrenaline transporters. The efficacy of ziprasidone in bipolar mania (current episode, manic or mixed) has been well demonstrated in three placebo-controlled trials. In a three-arm controlled study, ziprasidone was shown to be efficacious in dysphoric mania, whereas haloperidol was comparable to placebo. Open-label treatment for up to 52 weeks supported the sustained efficacy of ziprasidone in bipolar disorder. Combined with lithium, ziprasidone has been shown to be efficacious as an augmenting agent in the acute treatment of mania, with sustained efficacy up to 1 year. Ziprasidone was very well tolerated by patients with bipolar disorder and did not cause increased weight, glucose or lipid levels.     

Long-acting risperidone: a review of its use in schizophrenia

Long-acting risperidone (Risperdal Consta) is a novel, intramuscular formulation of the atypical antipsychotic risperidone, which has shown efficacy in the treatment of patients with schizophrenia.Long-acting risperidone is pharmacokinetically equivalent to and causes less plasma drug concentration fluctuation than the oral formulation. This novel formulation is an aqueous suspension of microspheres comprising risperidone and a biodegradable copolymer. Significant release of risperidone from the microspheres begins 3 weeks after the first injection: thus, administration of another antipsychotic is necessary during this period only. Steady-state plasma concentrations are reached after the fourth injection. Elimination is complete 7-8 weeks after the last injection.Long-acting risperidone 25 or 50mg every 2 weeks demonstrated significantly greater antipsychotic efficacy than placebo and equivalent efficacy to oral risperidone 2-6 mg/day in two randomised, double-blind, double-dummy, 12-week trials of patients with schizophrenia. Additionally, in one of these trials, improvements in health-related quality of life (HRQOL) were superior with long-acting risperidone than placebo. Compared with baseline, improvements in the symptoms of schizophrenia in stable patients were significant with long-acting risperidone 25 or 50mg (12-month trial) and 25, 37.5 or 50mg (12-week trial) every 2 weeks, in two noncomparative, multicentre trials. Patient satisfaction with their medication and patient HRQOL mental health scores improved significantly in the 12-month trial.Long-acting risperidone is generally well tolerated, with a low incidence of injection site pain and an otherwise similar profile of adverse effects to the oral formulation. The overall incidence of extrapyramidal disorders in clinical trials was low (< or= 10%) with similar, yet minimal, changes in extrapyramidal symptom severity between patients treated with long-acting risperidone, oral risperidone or placebo. Tardive dyskinesia was reported in the 12-month trial, in 0.7% of patients. CONCLUSIONS: Long-acting risperidone is effective and generally well tolerated in patients with schizophrenia, including those patients with stable symptoms. Long-acting risperidone is the first atypical antipsychotic available in a formulation which offers a sustained, steady release of drug and is thus an attractive, new option in the treatment of patients with schizophrenia.     

Amisulpride: a review of its use in the management of schizophrenia

Amisulpride (Solian), a substituted benzamide derivative, is a second-generation antipsychotic that preferentially binds to dopamine D2/D3 receptors in limbic rather than striatal structures. High dosages preferentially antagonise postsynaptic D2/D3 receptors, resulting in reduced dopamine transmission, and low dosages preferentially block presynaptic D2/D3 receptors, resulting in enhanced dopamine transmission. Amisulpride (200-1200 mg/day) was at least as effective as haloperidol and as effective as risperidone or olanzapine, in studies of up to 1 year in patients with schizophrenia manifesting predominantly positive symptoms. Amisulpride (50-300 mg/day) was significantly more effective than placebo in studies of up to 6 months in patients manifesting predominantly negative symptoms. Quality of life was also improved significantly more in patients receiving amisulpride than in those receiving haloperidol in 4- and 12-month studies in patients with predominantly mixed symptoms. Amisulpride was generally well tolerated in clinical trials. In patients with predominantly positive symptoms, amisulpride appeared to be better tolerated than haloperidol and was tolerated as well as risperidone and olanzapine. The incidence of extrapyramidal adverse effects with amisulpride was lower than with haloperidol but was generally similar to risperidone or olanzapine. Weight gain with amisulpride was less than that with risperidone or olanzapine and, unlike these agents, amisulpride does not seem to be associated with diabetogenic effects. Plasma prolactin levels are increased during amisulpride therapy and amenorrhoea occurs in about 4% of women. The incidence of adverse events with low dosages of amisulpride (< or = 300 mg/day) in patients with predominantly negative symptoms was similar to that observed with placebo. In conclusion, oral amisulpride (200-1200 mg/day) is at least as effective as haloperidol, and as effective as risperidone or olanzapine, in the treatment of patients with schizophrenia manifesting predominantly positive symptoms. In the treatment of patients manifesting predominantly negative symptoms, low dosages of amisulpride (50-300 mg/day) are significantly more effective than placebo. Amisulpride appears to be better tolerated than haloperidol, causing a lower incidence of extrapyramidal adverse effects and an improved quality of life. Compared with risperidone or olanzapine, amisulpride is more likely to cause hyperprolactinaemia, but has a lower propensity to cause weight gain and does not seem to be associated with diabetogenic effects. Thus, amisulpride is an effective and well tolerated option for the first-line treatment of patients with acute schizophrenia as well as for those requiring long-term maintenance therapy.     

Intramuscular olanzapine: a review of its use in the management of acute agitation

Intramuscular olanzapine (Zyprexa) is a rapid-acting atypical antipsychotic drug that is also indicated for use in patients with agitation associated with schizophrenia or bipolar mania, the focus of this review. Evidence from three well designed trials indicates that this formulation of olanzapine is at least as effective as intramuscular haloperidol or lorazepam in the treatment of patients with acute agitation associated with schizophrenia or bipolar mania, and has a faster onset of action. Although transient reductions in blood pressure and heart rate may occur in some patients administered intramuscular olanzapine, preliminary evidence of a general lack of clinical effect on the corrected QT (QTc) interval and a low incidence of extrapyramidal symptoms (EPS) is promising. The parenteral formulation of olanzapine appears to offer an effective, fast-acting and generally well tolerated alternative in the treatment of this significant behavioural problem.     

The tolerability of intramuscular ziprasidone and haloperidol treatment and the transition to oral therapy

The intramuscular (i.m.) formulation of ziprasidone offers promise as an alternative to conventional i.m. agents for the short-term management of agitated patients with psychosis. This 7-day, randomized, open-label study evaluated the tolerability of ziprasidone i.m. and haloperidol i.m. in hospitalized patients with a psychotic disorder and moderate psychopathology. Patients received three fixed doses of ziprasidone i.m. 5 mg qid (n=69), 10mg qid (currently maximum recommended daily dose in USA; n=71), 20mg qid (n=66), or flexible-dose/ flexible-schedule haloperidol i.m. up to 10 mg bid-qid (n=100) for 3 days. This was followed by oral treatment with the same medication for 4 days. Ziprasidone i.m. was associated with a notably lower burden of movement disorders than haloperidol i.m. (mean 11 mg/day). No bradycardia, sinus pauses, disinhibition, confusion, excessive sedation or respiratory depression was observed with ziprasidone. No safety issues were identified with the coadministration of lorazepam with the i.m. formulations of either agent. All three ziprasidone i.m. doses and haloperidol i.m. maintained control of symptoms and, following the transition to oral treatment, symptoms remained controlled. Ziprasidone i.m. 5,10, and 20 mg qid, given for 3 days were well tolerated. The transition from i.m. to oral ziprasidone was well tolerated with continuing maintenance of symptom control.     

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.     

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

Aripiprazole, a quinolinone derivative, is an atypical antipsychotic drug indicated for the treatment of adult patients with schizophrenia. Aripiprazole 10 or 15 mg once daily is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. Although aripiprazole has only been directly compared with haloperidol and olanzapine in treatment-responsive patients to date, current data generally indicate that aripiprazole has a beneficial profile in terms of a low potential for bodyweight gain. Dosage titration is not necessary and the drug is effective in the first few weeks of treatment. Head-to-head comparative trials with atypical antipsychotic agents are required, as are long-term (> or =1 year) studies, to fully define the position of aripiprazole in relation to other antipsychotic drugs. Aripiprazole is a valuable new therapeutic option in the management of patients with schizophrenia. PHARMACOLOGICAL PROPERTIES: Aripiprazole is a quinolinone derivative with a high affinity for dopamine D2 and D3 receptors, and serotonin 5-HT1A, 5-HT2A and 5-HT2B receptors. The mechanism of action of aripiprazole is not yet known, but evidence suggests that its efficacy in the treatment of the positive and negative symptoms of schizophrenia and its lower propensity for extrapyramidal symptoms (EPS) may be attributable to aripiprazole's partial agonist activity at dopamine D2 receptors. At serotonin 5-HT1A receptors, in vitro studies have shown that aripiprazole acts as a partial agonist whereas at serotonin 5-HT2A receptors aripiprazole is an antagonist. The main active metabolite, dehydro-aripiprazole, has affinity for dopamine D2 receptors and thus has some pharmacological activity similar to that of the parent compound. Aripiprazole is rapidly absorbed after oral administration. The mean time to peak plasma concentration is 3 hours following multiple-dose administration of aripiprazole 10 or 15 mg and the absolute oral bioavailability of the drug is 87%. Steady-state plasma drug concentrations are achieved by 14 days; however, the drug appears to accumulate over this period, since mean peak plasma concentration and mean area under the plasma concentration-time curve values of aripiprazole 10 or 15 mg/day are 4-fold greater on day 14 than on day 1. This accumulation may be expected, since the mean elimination half-life of a single dose of aripiprazole is about 75 hours. Aripiprazole has extensive extravascular distribution and more than 99% of aripiprazole and dehydro-aripiprazole (the main active metabolite of aripiprazole) is bound to plasma protein. Elimination of the drug is primarily hepatic; the cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems transform aripiprazole to dehydro-aripiprazole, with the latter enzyme system subject to genetic polymorphism. Thus, dosage adjustment of aripiprazole is necessary when it is coadministered with CYP3A4 and CYP2D6 inhibitors (since aripiprazole concentration is increased) and with inducers of CYP3A4 (since aripiprazole concentration is decreased). THERAPEUTIC EFFICACY: The efficacy of aripiprazole has been demonstrated in patients with schizophrenia or schizoaffective disorder. In general, significant reductions from baseline in mean Positive and Negative Syndrome Scale total, positive and negative symptom scores, and Clinical Global Impression Severity of Illness scores were observed in patients with acute relapse of chronic schizophrenia or schizoaffective disorder receiving recommended (10 or 15 mg/day) or higher-than-recommended (20 or 30 mg/day) dosages of aripiprazole versus those receiving placebo in three well controlled, short-term trials. No additional therapeutic benefit was observed at the higher-than-recommended dosages. The drug is effective as early as the first or second week of treatment. The efficacy of aripiprazole was maintained for up to 52 weeks. The drug was significantly more effective than placebo in preventing relapse in patients with stable chronic schizophrenia in a 26-week, randomised trial. In a 52-week trial in patients with acute relapse of schizophrenia, the percentage of responders maintaining a response at study end was 77% of aripiprazole versus 73% of haloperidol recipients. Aripiprazole may improve cognitive function. In a nonblind, 26-week trial, patients with chronic schizophrenia receiving aripiprazole 30 mg/day experienced similar (general cognitive function) or better (verbal learning) changes from baseline in the neurocognitive parameters evaluated compared with recipients of olanzapine 10-15 mg/day. TOLERABILITY: Aripiprazole 10-30 mg/day was generally well tolerated. The tolerability profile of aripiprazole was broadly similar to that observed with placebo in a meta-analysis of short-term trials in patients with acute relapse of schizophrenia or schizoaffective disorder and in a 26-week trial in patients with chronic stable schizophrenia. The most frequent treatment-emergent adverse events included insomnia and anxiety, and additionally, headache and agitation (in short-term trials) or akathisia and psychosis (in a 52-week trial). In general, the drug was associated with a placebo-level incidence of EPS and EPS-related adverse events. Significantly fewer aripiprazole recipients experienced EPS-related adverse events than haloperidol recipients in a 52-week trial. Changes in severity of EPS were minimal and usually no different from those observed with placebo. Moreover, there was less severe EPS in the aripiprazole group than the haloperidol group in a long-term trial. Treatment-emergent tardive dyskinesia was reported in only 0.2% of patients receiving aripiprazole (short-term trials), an incidence similar to that seen in placebo recipients (0.2%). Aripiprazole has a low propensity to cause clinically significant bodyweight gain, hyperprolactinaemia or corrected QT interval prolongation in patients with schizophrenia or schizoaffective disorder. In addition, there were no clinically relevant differences in mean changes from baseline in measures of diabetes and dyslipidaemia between the aripiprazole or placebo groups in a 26-week, placebo-controlled trial.     

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.     

Amisulpride: a review of its use in the management of schizophrenia.

Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D2/D3 autoreceptors. At higher doses, amisupride antagonises postsynaptic dopamine D2 and D3 receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission. In patients with acute exacerbations of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. In comparative trials, amisulpride administered within this range (400 to 1200 mg/day) was as effective as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in patients with acute exacerbations of schizophrenia with predominantly positive symptoms. Amisulpride was more effective than haloperidol but equally effective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixol in controlling affective symptoms in these patients. In randomised, double-blind trials involving patients with predominantly negative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more effective than placebo. Amisulpride is effective as maintenance therapy in patients with chronic schizophrenia. Long-term treatment with amisulpride was associated with improvements in quality of life and social functioning. Amisulpride is generally well tolerated. In well-controlled trials, the neurological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. At low dosages of amisulpride (< or =300 mg/day), the incidence of adverse events (including extrapyramidal symptoms) reported with amisulpride was similar to that with placebo. CONCLUSION: In comparative trials, amisulpride 400 to 1200 mg/day showed efficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in patients with acute exacerbations of schizophrenia. Moreover, its effective alleviation of negative and affective symptoms, its lower association with extrapyramidal symptoms and loss of cognitive function than conventional antipsychotics and its long-term efficacy justifies consideration of the use of higher dosages of amisulpride in this group of patients. Consequently, the dosage of amisulpride that is recommended in patients with acute exacerbations of schizophrenia is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with negative symptoms of schizophrenia. Amisulpride is a first-line treatment option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.