David G. Daniel

Ziprasidone 80 mg/day and 160 mg/day in the Acute Exacerbation of Schizophrenia and Schizoaffective Disorder: A 6-Week Placebo-Controlled Trial

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 ≥ 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.

The Brief Negative Symptom Scale: Psychometric Properties

The participants in the NIMH-MATRICS Consensus Development Conference on Negative Symptoms recommended that an instrument be developed that measured blunted affect, alogia, asociality, anhedonia, and avolition. The Brief Negative Symptom Scale (BNSS) is a 13-item instrument designed for clinical trials and other studies that measures these 5 domains. The interrater, test-retest, and internal consistency of the instrument were strong, with respective intraclass correlation coefficients of 0.93 for the BNSS total score and values of 0.89-0.95 for individual subscales. Comparisons with positive symptoms and other negative symptom instruments supported the discriminant and concurrent validity of the instrument.

Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia.

This double-blind, randomized, multicenter study investigated the use of divalproex with an antipsychotic agent in patients hospitalized for acute exacerbation of schizophrenia. Patients (n=249) who met DSM-IV criteria for schizophrenia were randomly assigned to receive olanzapine monotherapy, risperidone monotherapy, divalproex plus olanzapine, or divalproex plus risperidone for 28 days. Divalproex was initiated at 15 mg/kg/day and titrated over 12 days to a maximum dosage of 30 mg/kg/day. Olanzapine and risperidone, were, respectively, initiated at 5 and 2 mg/day and were titrated over the first 6 days to respective target fixed daily dosages of 15 and 6 mg/day. Improvements from baseline were observed at all evaluation points throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups, with statistically significant treatment differences favoring combination therapy as soon as day 3 for Positive and Negative Syndrome Scale (PANSS) total score, derived Brief Psychiatric Rating Scale (BPRSd) total score, as well as PANSS and BPRSd subscales. These findings were confirmed in post hoc repeated-measures analyses of variance in which treatment differences favoring combination therapy were observed for PANSS total (p=0.020) and PANSS positive scale scores (p=0.002). Both combination therapy and antipsychotic monotherapy were well tolerated. Treatment with divalproex in combination with an atypical antipsychotic agent resulted in earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia. Further evaluation is warranted to confirm these findings.

From clinical research to clinical practice: A 4-year review of ziprasidone

Ziprasidone is a second-generation antipsychotic that received Food and Drug Administration approval in February 2001. It has a unique receptor profile that includes high-affinity antagonist activity at dopamine D2 receptors, inverse agonist activity at serotonin (5-HT)2A receptors, agonist activity at 5-HTlA receptors, and a relatively high affinity for the serotonin and norepinephrine transporters. The 5-HTIA affinity, together with the inhibitory effect on mono-amine reuptake, may underlie the hypothesized beneficial effects on comorbid affective and cognitive abnormalities in schizophrenia and schizoaffective disorder. The short-term efficacy of ziprasidone for core positive symptoms of schizophrenia appears to be comparable to other conventional and atypical antipsychotics. The short-term efficacy of ziprasidone in acute mania has been established based on two 3-week, double-blind, placebo-controlled trials.Open-label treatment for up to 52 weeks confirms the sustained efficacy and safety of ziprasidone in bipolar disorder. Maintenance studies in schizophrenia and schizoaffective disorder indicate that long-term ziprasidone therapy is effective in preventing relapse, while maintaining cognitive and psychosocial benefits. The safety database suggests that the overall cardiovascular and cerebrovascular risk associated with ziprasidone is lower than with other atypicals, with notably lower risk of drug-related increases in weight, glucose, or lipids. The data also suggest a modestly increased risk of QTc prolongation that is not dose related or linked to torsades de pointes. Switching to ziprasidone from other atypicals appears to improve both clinical symptoms and metabolic parameters, though more studies are needed to fully characterize these benefits. This monograph summarizes the efficacy, tolerability, and safety of oral ziprasidone in the treatment of schizophrenia, schizoaffective disorder, and bipolar mania.

Methodological Issues in Negative Symptom Trials

Individuals from academia, the pharmaceutical industry, and the US Food and Drug Administration used a workshop format to discuss important methodological issues in the design of trials of pharmacological agents for improving negative symptoms in schizophrenia. The issues addressed included the need for a coprimary functional measure for registration trials; the characteristics of individuals who should enter negative symptom trials; the optimal duration for a proof-of-concept or registration trial; the optimal design of a study of a broad-spectrum agent that treats both positive and negative symptoms or a co-medication that is added to an antipsychotic; the relative strengths and weaknesses of available instruments for measuring negative symptoms; the definition of clinically meaningful improvement for these trials; and whether drugs can be approved for a subdomain of negative symptoms.

Divalproex ER Combined with Olanzapine or Risperidone for Treatment of Acute Exacerbations of Schizophrenia

The objective of this study was to evaluate the efficacy and safety of divalproex sodium extended release (divalproex ER) vs placebo in combination with olanzapine or risperidone for the treatment of acute exacerbations of schizophrenia. In this 12-week, randomized, double-blind, parallel-group, multi-center trial, a total of 402 patients were randomized and treated; 103 received olanzapine/placebo, 99 received olanzapine/divalproex ER, 101 received risperidone/placebo, and 99 received risperidone/divalproex ER. Divalproex ER was initiated on day 1 at 20 mg/kg per day q AM and was titrated to clinical effect on days 3, 7, and 10, not to exceed a maximum dosage of 35 mg/kg per day. Olanzapine and risperidone were initiated at 5 and 2 mg/day q PM, respectively, increased to 10 and 4 mg/day on day 3, and increased to fixed target doses of 15 and 6 mg/day on day 6. No significant treatment difference was demonstrated between the combination therapy and antipsychotic monotherapy groups on the primary efficacy variable of the mean change from baseline to day 14 last observation carried forward on the Positive and Negative Syndrome Scale (PANSS) total score, although antipsychotic monotherapy did demonstrate superiority to combination therapy on the PANSS Negative subscale at several time points. Combination therapy also failed to show an advantage over antipsychotic monotherapy at day 84 on the PANSS total score. Most adverse events observed in the study were mild to moderate in severity, and the overall number of adverse events did not differ significantly between the combination therapy groups and their corresponding antipsychotic monotherapy group.

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), 10 mg qid (currently maximum recommended daily dose in USA; n=71), 20 mg 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.

Issues in Selection of Instruments to Measure Negative Symptoms

Guidance for selection of instruments for measurement of negative symptoms is rapidly evolving. As there are continuing advances in the description of negative symptoms, new instruments are under development, and new data on the performance of instruments emerge from clinical trials. The Scale for Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANSS), the Marder Negative Factor and the Negative Symptom Assessment-16 (NSA-16) are considered to be reliable and valid measures for negative symptom trials but differ with respect to their domain coverage, use of informants, integration of global scores, administration time and comprehensiveness of their structured interviews. In response to the 2005 NIMH-MATRICS consensus statement, work groups are field testing and refining two new measures, the Clinical Assessment Interview for Negative Symptoms (CAINS) and the Brief Negative Symptom Scale (BNSS). Both address the five currently recognized domains of negative symptoms, differentiate appetitive from consummatory aspects of anhedonia and address desire for social relationships. Thus far, both have exhibited promising psychometric properties.

A Double-Blind, Randomized Study Comparing the Efficacy and Safety of Sertindole and Risperidone in Patients With Treatment-Resistant Schizophrenia

OBJECTIVE The comparative efficacy of second-generation antipsychotics has yet to be fully elucidated in patients with treatment-resistant schizophrenia. The objective of this study was to examine the efficacy and safety of sertindole, compared to risperidone, in this patient population. METHOD In this multicenter, phase 3, randomized, double-blind, parallel-group study, only patients with DSM-IV schizophrenia who had failed an adequate antipsychotic treatment within the previous 6 months and who had not responded positively to haloperidol during screening were eligible for enrollment. The primary efficacy variable was change in Positive and Negative Syndrome Scale (PANSS) from baseline to final assessment. Weekly assessments included the PANSS, the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), and the Clinical Global Impressions (CGI) scale. The study was conducted between June 1996 and April 1998. RESULTS Of the 321 patients randomly assigned to double-blind treatment, 217 patients completed the study (sertindole, n/n = 142/216 [66%]; risperidone, n/n = 75/105 [71%]). The main reason for withdrawal in both groups was ineffective therapy. The between-group difference in PANSS total score was not statistically significant and both groups showed improvement, with mean changes of -18.6 in the sertindole group and -20.9 in the risperidone group based on observed cases and -12.0 and -19.0, respectively, based on the last-observation-carried-forward method for inputing missing data. There were no statistically significant differences between the groups in any of the secondary end points: PANSS positive and negative subscales, CGI scores, BPRS total scores and positive symptom subscale scores, and SANS total scores. Patients reported similar levels of adverse events and treatment-emergent adverse events (TEAEs), except for extrapyramidal syndrome-related TEAEs, which were more common in the risperidone-treated group. Prolongation of the QTc interval was observed significantly more frequently with sertindole treatment. CONCLUSIONS Sertindole and risperidone are effective and well-tolerated in patients with treatment-resistant schizophrenia. Sertindole offers an alternative treatment option for refractory patients in Europe given its good EPS profile, favorable metabolic profile, and comparable efficacy to risperidone.

Ziprasidone: comprehensive overview and clinical use of a novel antipsychotic

Ziprasidone (5-[2-(4-(1,2,-benzisothiazol-3-yl) piperazin-l-yl] ethyl]-6 -chloro indolin-2-one hydrochloride hydrate) is a novel antipsychotic with a pattern of receptor occupancy and preclinical attributes predictive of broad therapeutic efficacy and a favourable tolerability profile in the treatment of psychotic illness. Clinical trials indicate that ziprasidone is effective against positive, negative and affective symptoms in schizophrenia and schizoaffective disorder with minimal motor, cognitive, weight gain, prolactin related, or anticholinergic side effects. In addition, an im. formulation appears to be rapidly effective with significantly less motor side effect liability than haloperidol.