A significant percentage of psychiatric patients who are treated with antipsychotics are treated with more than one antipsychotic drug in the clinic. Thus, it is advantageous to use a rapid and reliable assay that is suitable for determination of multiple antipsychotic drugs in plasma in a single run. A simple and sensitive HPLC-UV method was developed and validated for simultaneous quantification of olanzapine, haloperidol, chlorpromazine, ziprasidone, risperidone and its active metabolite 9-hydroxyrisperidone in rat plasma using imipramine as an internal standard (I.S.). The analytes were extracted from rat plasma using a single step liquid–liquid acid solution back extraction technique with wash procedure, which provided the very clear baseline for blank plasma extraction. The compounds were separated on an Agilent Eclipse XDB C8 (150 mm × 4.6 mm i.d., 5 μm) column using a mobile phase of acetonitrile/30 mM ammonium acetate including 0.05% triethylamine (pH 5.86 adjusted with acetic acid) with gradient elution. All of the analytes were monitored using UV detection. The method was validated and the linearity, lower limit of quantitation (LLOQ), precision, accuracy, recoveries, selectivity and stability were determined. The LLOQ was 2.0 ng/ml and correlation coefficient (R2) values for the linear range of 2.0–500.0 ng/ml were 0.998 or greater for all the analytes. The precision and accuracy for intra-day and inter-day were better than 7.44%. The recovery was above 74.8% for all of the analytes. This validated method has been successfully used to quantify the plasma concentration of the analytes for pharmacological and toxicological studies following chronic treatment with antipsychotic drugs in the rat.

There are various procedures to account for missing values in clinical trials. Mixed Model and Last Observation Carried Forward (LOCF) analyses are commonly employed methods. We compared the two methods by reanalysing Positive and Negative Syndrome Scale (PANSS) scores from the European First Episode in Schizophrenia Trial (EUFEST). While the predefined Mixed Model analysis detected no differences between PANSS total score changes in first episode patients treated with haloperidol, amisulpride, quetiapine, olanzapine or ziprasidone over the course of a one year treatment trial, a LOCF analysis revealed significant differences in favor of the new generation antipsychotics over haloperidol. Implications for clinical trial design and the interpretation of such studies are discussed.

The ZEISIG study (Ziprasidone Experience in Schizophrenia in Germany/Austria) investigated the effectiveness of ziprasidone as measured by discontinuation rates and mean changes of the BPRS total. Secondary objectives included quality of life, subjective well-being, tolerability, and safety.Two hundred and seventy-six subjects with schizophrenia and schizoaffective disorder were treated within an open-label, 12-week, prospective, flexible-dose observational trial of ziprasidone (40–160 mg/day). Baseline and outcome assessments mainly included Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions Scale (CGI), Short-Form 12 (SF-12), and Subjective Well-being under Neuroleptic treatment (SWN-K).Study discontinuation due to any cause was evident in 58% of subjects, most of them within the first 4 weeks after study initiation. In study completers, ziprasidone was associated with improvements in BPRS total (44.8 to 33.6; p < 0.001), CGI, SF-12, and SWN-K total scores (80.5 to 89.5). Ziprasidone was related to reduction of weight, fasting glucose, and serum lipids. No cardiovascular adverse event or significant increase of the QTc interval was observed.Approximately 60% of subjects discontinued ziprasidone prematurely, probably related to an initial and overall underdose. The present study confirmed previous tolerability and safety data of ziprasidone as well as results of its effectiveness. Independent from reason to switch, previous antipsychotic class, and severity of illness at baseline, the recommended starting dose of 80 mg/day as well as the maximum treatment dose of 160 mg/day may not be sufficient for a selected subgroup of patients.