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.

Breakthrough manic episodes are the rule in bipolar disorders; valproate and olanzapine are considered first-line treatments for manic episodes, nevertheless the two drugs have only been compared in monotherapy studies. In our study we compared the efficacy and safety of valproate and olanzapine added to lithium in the treatment of patients experiencing breakthrough manic episodes while on lithium monotherapy.Patients with bipolar I or II disorder (SCID-I), in treatment with lithium since at least one year, experiencing a manic or hypomanic relapse were randomly assigned to an open-label add-on therapy with valproate (500–1500 mg/day) or olanzapine (7.5–15.0 mg/day) for 8 weeks. The primary efficacy measure was the Young Mania Rating Scale (YMRS) total.Twenty-one patients were randomized to receive the add-on therapy with valproate (n = 9) or olanzapine (n = 12). Both groups showed a significant baseline to endpoint reduction in YMRS total and Clinical Global Impressions-Severity (CGI-S) scores (p < 0.001). At endpoint, the mean reduction of YMRS total or CGI-S scores, as well as response or remission rates, was not significantly different between the groups. However, compared with patients in the valproate add-on group, patients treated with olanzapine add-on showed significantly greater reductions in the YMRS total and CGI-S mean scores at weeks 1 through 4 (p < 0.05). The rate and profile of adverse events were numerically similar in the two groups.Open-label design and limited sample size.Both add-on therapies were efficacious in treating patients with manic or hypomanic relapse, however the olanzapine group showed an earlier response to treatment. These findings can help clinicians in understanding the value of adding other treatments to lithium in patients experiencing a manic or hypomanic relapse.

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.

In case reports of patients with bipolar disorder, atypical antipsychotic drugs are often associated with an exacerbation of manic symptoms. To determine whether the atypical antipsychotic drug ziprasidone is associated with an exacerbation of manic symptoms or a worsening of depressive symptoms when used to treat bipolar mania, we analyzed data pooled from 2 similarly designed randomized, placebo-controlled trials of ziprasidone monotherapy in the treatment of bipolar mania (ziprasidone: n=268, placebo: n=131). Exacerbation of mania was defined as CGI-S ≥ 5 and HAM-D increase from baseline to endpoint ≤ 25%, and worsening of depression was defined as HAM-D at endpoint ≥ 15 and HAM-D change from baseline to endpoint ≥ 20%. A significantly smaller proportion of subjects experienced an exacerbation of mania in the ziprasidone group than in the placebo group (6.7% vs 17.6%, P < 0.001). An analysis of dysphoric/nondysphoric and psychotic/nonpsychotic subpopulations showed significantly smaller proportions of ziprasidone subjects with an exacerbation of mania than placebo subjects in all 4 subsets (P < 0.05). The proportion of subjects experiencing a worsening of depression was smaller in the ziprasidone group than in the placebo group (1.9% vs 4.6%, n.s.). These results strongly suggest that ziprasidone causes neither exacerbation of mania nor worsening of depression in patients with acute bipolar mania. Future research will address this issue in patients with bipolar depression.

The Bayer-Activities of Daily Living Scale (B-ADL) is a 25-item, informant-rated questionnaire which was developed as a brief and internationally applicable instrument for assessing functional disabilities. The scale's target group are elderly patients suffering from mild to moderate dementia or cognitive impairment. To investigate the reliability and validity of different language versions, the B-ADL was administered in the UK, Germany, and Spain to a total of 1,433 subjects with a wide range of cognitive decline. The results from the three country samples were very similar, with internal consistency being above 0.98 (Cronbach alpha). A factor analysis revealed that a one-factor solution accounted for most of the variance. The B-ADL total score significantly increased between adjacent Global Deterioration Scale (GDS) stages 1 to 5. A second factor analysis entering additional variables (GDS stage, Mini-Mental State Examination or MMSE subscores, age, years of education, gender, and country) revealed that all B-ADL items loaded on the same factor, 'dementia severity', and that they were not related to age, education, gender, or country. In the identification of subjects with clinically manifest dementia symptoms (GDS stages 4 and 5), the B-ADL proved to be as efficient as the MMSE in the UK and German samples and superior to the MMSE in the Spanish sample.Copyright (C) 2001 S. Karger AG, Basel.