Dose-response relationship of sertindole and haloperidol using the pharmacopsychometric triangle.

OBJECTIVE: Renewed insight into dose-related effects of sertindole and haloperidol was sought by re-analysing published data for antipsychotic effect, extrapyramidal effect, and patient wellbeing - i.e., the important pharmacopsychometric triangle domains. METHOD: Selected Positive and Negative Syndrome Scale (PANSS) subscales and the Simpson-Angus scale were tested for validity. Standardized effect sizes [last observation carried forward (LOCF)] at endpoint were calculated. RESULTS: The scales were found to be valid instruments. The PANSS(11) psychotic subscale showed clinically significant effect sizes for all doses of sertindole (12, 20, and 24 mg) and haloperidol (4, 8, and 16 mg). Extrapyramidal effects were evident for all doses of haloperidol, but absent for the lower doses of sertindole. The PANSS(6) depression subscale, a proxy measure of quality of life, showed a clinically significant effect for sertindole 20 mg and no effect for haloperidol. CONCLUSION: This re-analysis confirmed the antipsychotic effect and absence of extrapyramidal effects for sertindole and, in addition, showed a clinically significant antidepressant effect. A profile for bipolar states emerged.

Suicide attempts in a prospective cohort of patients with schizophrenia treated with sertindole or risperidone.

The incidence of suicide attempts (fatal and non-fatal) was analysed in a prospective cohort of patients with schizophrenia randomly assigned to sertindole (4905 patients) or risperidone (4904 patients) in a parallel-group open-label study with blinded classification of outcomes (the sertindole cohort prospective study--SCoP). The total exposure was 6978 and 7975 patient-years in the sertindole and risperidone groups, respectively. Suicide mortality in the study was low (0.21 and 0.28 per 100 patients per year with sertindole and risperidone, respectively). The majority (84%) of suicide attempts occurred within the first year of treatment. Cox's proportional hazards model analysis of the time to the first suicide attempt, reported by treating psychiatrists and blindly reviewed by an independent expert group according to the Columbia Classification Algorithm of Suicide Assessment (both defining suicide attempts by association of suicidal act and intent to die), showed a lower risk of suicide attempt for sertindole-treated patients than for risperidone-treated patients. The effect was statistically significant with both evaluation methods during the first year of randomized treatment (hazard ratios [95% CI]: 0.5 [0.31-0.82], p=0.006; and 0.57 [0.35-0.92], p=0.02, respectively). With classification by an independent safety committee using a broader definition including all incidences of intentional self-harm, also those without clear suicidal intent, the results were not significant. A history of previous suicide attempts was significantly associated with attempted suicides in both treatment groups.

Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP).

OBJECTIVE: To explore whether sertindole increases all-cause mortality or cardiac events requiring hospitalization, compared with risperidone. METHOD: Multinational randomized, open-label, parallel-group study, with blinded classification of outcomes, in 9858 patients with schizophrenia. RESULTS: After 14147 person-years, there was no effect of treatment on overall mortality (sertindole 64, risperidone 61 deaths, Hazard Ratio (HR) = 1.12 (90% CI: 0.83, 1.50)) or cardiac events requiring hospitalization [sertindole 10, risperidone 6, HR = 1.73 (95% CI: 0.63, 4.78)]: Of these, four were considered arrhythmia-related (three sertindole, one risperidone). Cardiac mortality was higher with sertindole (Independent Safety Committee (ISC): 31 vs. 12, HR=2.84 (95% CI: 1.45, 5.55), P = 0.0022; Investigators 17 vs. 8, HR=2.13 (95% CI: 0.91, 4.98), P = 0.081). There was no significant difference in completed suicide, but fewer sertindole recipients attempted suicide (ISC: 68 vs. 78, HR=0.93 (95% CI: 0.66, 1.29), P = 0.65; Investigators: 43 vs. 65, HR=0.67 (95% CI: 0.45, 0.99), P = 0.044). CONCLUSION: Sertindole did not increase all-cause mortality, but cardiac mortality was higher and suicide attempts may be lower with sertindole.

Course of recovery of cognitive impairment in patients with schizophrenia: a randomised double-blind study comparing sertindole and haloperidol.

OBJECTIVE: To compare the impact of sertindole and haloperidol on cognitive function in patients suffering from schizophrenia. METHODS: In a 12 week trial, of the 40 patients randomised to treatment, 34 (17 sertindole and 17 haloperidol) were included in the analysis set. Cognitive sub-processes were investigated with the Reaction Time Decomposition (RTD) method and the Wisconsin Card Sorting Test (WCST), at baseline, Week 4 and Week 12. RESULTS: In executive function, i.e. set shifting tasks, sertindole reversed cognitive deficits significantly more than haloperidol. It was demonstrated that this atypical drug improved cognitive processing independently of motor function. Patients receiving sertindole markedly improved on the RTD task at Week 4 and continued to improve (although at a slower rate) at Week 12, those patients receiving haloperidol showed marked impairment at Week 4 with partial recovery by Week 12. CONCLUSION: The study demonstrated two distinct processes of action on cognition between sertindole and haloperidol and the marked beneficial effects of sertindole, particularly in parameters that are regarded as schizophrenia-related cognitive disturbances.

The validity of the depression rating scales in discriminating between citalopram and placebo in depression recurrence in the maintenance therapy of elderly unipolar patients with major depression.

The World Federation of Societies of Biological Psychiatry guidelines for treatment of unipolar major depression has recommended three depression rating scales for evaluating outcome: The Hamilton Depression Rating Scale (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Bech-Rafaelsen Melancholia Scale (MES). In this study we evaluated the ability of these scales to differentiate between citalopram and placebo in the recurrence prevention of unipolar depression. The study is a psychometric reexamination of a trial on the efficacy of citalopram versus placebo in the maintenance therapy of elderly patients with unipolar depression. Internal validity (the Cronbach coefficient alpha, the Loevinger coefficient of homogeneity, and factor analysis) of the three scales has been examined to evaluate their unidimensionality. In the outcome analysis for depression recurrence, the conventional cutoff scores of the three scales are used. In total, 60 patients received citalopram and 61 patients received placebo in the maintenance phase of 48 weeks. The results showed that the internal validity was higher for MES and MADRS than for HAM-D. Using the MADRS, 67.2 % of the patients on placebo and 31.6 % of the patients on citalopram developed a depression recurrence (ratio 2.12); using HAM-D17, 42.6 % on placebo and 13.3 % on citalopram developed a depression recurrence (ratio 3.20); and using the MES, 34.4 % on placebo and 11.7 % on citalopram developed a depression recurrence (ratio 2.94). The conventional cutoff scores of HAM-D17 and MES for depression recurrence indicated a ratio between citalopram and placebo of around 3, while the conventional cutoff scores of MADRS for depression recurrence indicated a ratio of only around 2. In future trials on the recurrence prevention of unipolar depression, a cutoff score of 25 rather than 22 on the MADRS is recommended.

Citalopram dose-response revisited using an alternative psychometric approach to evaluate clinical effects of four fixed citalopram doses compared to placebo in patients with major depression.

RATIONALE: Among the many problems in interpreting dose-response studies with antidepressants are the psychometric problems in the identification of true antidepressive effect versus true adverse drug effect. OBJECTIVES: This study is a re-examination of a dose-response trial with citalopram in order to examine the explanatory ability of using strict psychometric dimensions to measure the wanted and unwanted drug effects of different doses compared to placebo. METHODS: The antidepressive response was measured after 2 and 6 weeks of therapy with the depression subscales of the HAM-D and on the Montgomery-Asberg Depression Scale (MADRS). The patient-reported Symptom Checklist (SCL) sub-scales for depression and anxiety were also examined. Subjective side-effects were measured on serotonin-specific items of the SCL. Effect size statistics were used to measure the antidepressive effect (an effect size of 0.30 equals a drug superiority over placebo of 15-20%). Side effects were statistically analysed using baseline-adjusted scores of the individual symptoms. RESULTS: The psychometric analysis of the outcome scales showed that the full HAM-D(17), the SCL-56 and the SCL side-effect subscale were multidimensional scales, while the HAM-D and MADRS subscales as well as the SCL-anxiety subscale were most homogeneous, indicating that their total scores are sufficient statistics. When the scales were used as well as the individual serotonin-specific SCL side-effect symptoms, the results showed that after 2 weeks of therapy a clinical response (effect side over 0.30) was only seen for the SCL-anxiety subscale in the citalopram doses of 40 mg and 60 mg daily. After 6 weeks of therapy response to even 10 mg and 20 mg was seen in the HAM-D and MADRS subscales and in the SCL-anxiety subscale, however, with lower effect sizes than found for 40 mg and 60 mg citalopram daily. The dose of 20 mg citalopram induced side-effects comparable with those seen for 40 mg and 60 mg, while 10 mg was not different from placebo. This was further confirmed by the fact that more patients dropped out on 20 mg than on 10 mg citalopram daily, due to adverse events. CONCLUSION: This psychometric re-examination of a citalopram dose-response trial has shown that the pure antidepressive or antianxiety effects can be observed after 6 weeks of therapy even in a dose of 10 mg daily. However, both 10 mg and 20 mg daily had lower effect sizes than 40 mg and 60 mg daily. At a dose level of 20 mg daily, side effects are more pronounced initially than at 10 mg daily; this should be taken into account clinically when evaluating the overall benefit of the drug. For a highly serotonin-specific drug such as citalopram, both wanted and unwanted effects are dose-related.

Predictors of response to pharmacotherapy with citalopram in obsessive-compulsive disorder.

Although serotonin reuptake inhibitors (SRIs) are the medications of choice in the treatment of obsessive-compulsive disorder (OCD), only 50-60% of patients respond to a single trial of any of these agents. Improved knowledge of the predictors of response to treatment may have important clinical implications. Data from a large randomized placebo-controlled trial of citalopram in OCD was analysed using logistic regression to determine predictors of response. Demographic (age, sex), clinical (OCD severity and duration, depression severity, prior treatment) and trial variables (citalopram dose, treatment duration) were included. Subjects with longer duration of OCD, more severe OCD symptoms or previous selective SRI use were less likely to be responders in the citalopram trial. In contrast, subjects who received adequate medication doses for sufficient periods of time in the citalopram trial were more likely to be responders. Despite greater awareness of OCD in recent years, there is evidence that the disorder continues to be underdiagnosed and undertreated. The data here emphasize the crucial importance of early diagnosis and treatment of OCD, and of pharmacotherapy with appropriate dose and duration.

Cardiac safety of citalopram: prospective trials and retrospective analyses.

The selective serotonin reuptake inhibitors (SSRIs) are believed to have a more benign cardiovascular safety profile than do the tricyclic antidepressants. The effects of the SSRI citalopram on cardiac conduction and repolarization have been extensively evaluated, both in prospective studies in volunteers and patients and in retrospective evaluations of all electrocardiographic (ECG) data from all clinical trials conducted from 1978 through 1996 (a total of 40 studies). A randomized, double-blind, placebo-controlled study was conducted in healthy volunteers (N = 23) to assess intraindividual variability of the QTc interval, as well as possible changes during treatment with placebo or citalopram, and its correlation to plasma drug levels. To document any dose-related changes, ECGs were performed at baseline and at the end of study in three randomized, double-blind, placebo- or active-controlled, fixed-dose trials in adult and elderly patients (N = 1,460) with major depression and/or dementia. Finally, more than 6,000 ECGs (N = 1,789 citalopram-treated patients) collected from all clinical trials conducted from 1978 through 1996 were reassessed in a standardized manner to identify any effects of citalopram on ECG parameters. Results of both prospective and retrospective analyses showed that the only effect of citalopram on ECG findings is a small reduction in heart rate (< or = 8 beats per minute). There were no significant effects on PQ, QRS, or QTc intervals, indicating that citalopram has no effect on cardiac conduction and repolarization during short- or long-term treatment.

The optimal dosing regimen for citalopram--a meta-analysis of nine placebo-controlled studies.

Optimal dosing schedules for an antidepressant drug can only be established during clinical studies in depressed patients. The benefits of antidepressant therapy are usually progressive, and thus patients must be maintained on a particular treatment for at least 3-4 weeks to assess the efficacy of different doses. Meta-analysis, a widely accepted statistical technique which allows the combination of the results of multiple studies, was used to assess the efficacy of several doses of citalopram over nine placebo-controlled clinical trials. Statistically significant differences between citalopram and placebo were found at both the 20 and 40 mg dose levels. The minimal effective dose of citalopram was shown to be 20 mg. However, analysis of patient subgroups revealed a tendency for those patients suffering from severe or recurrent depression to achieve better results with a higher dosage (40 mg), while patients experiencing their first period of depression or with less severe depression responded well to the minimally effective dose of 20 mg.

A 24-week study of 20 mg citalopram, 40 mg citalopram, and placebo in the prevention of relapse of major depression.

A total of 147 patients who had responded in a placebo-controlled study to 6 weeks treatment of an episode of DSM-III-R major depression with either 20 mg or 40 mg citalopram were randomized double-blind to continue on the same dose of citalopram or to receive placebo during a 24-week study of the efficacy of citalopram in the prevention of relapse. The citalopram 20 and 40 mg groups showed a significant advantage compared with placebo both in relapses (p < 0.05) and in the survival analysis of time to relapse (p = 0.01 and p = 0.02, respectively). Both 20 and 40 mg citalopram appeared similarly safe and well tolerated with little difference in side effects from placebo. The results demonstrate that citalopram, at a dose of both 20 and 40 mg is effective and well tolerated in continuation treatment to consolidate response. The relapse rate in patients who had responded to placebo during the 6-week acute treatment study, who were continued double-blind with placebo but not included in the efficacy analysis, was similar to the rate in the formal placebo control group, suggesting that patients who respond to placebo in a short treatment course may nonetheless require long-term active treatment to prevent relapse.

Clinical patch test data evaluated by multivariate analysis. Danish Contact Dermatitis Group.

The aim of the present study was to evaluate the influence of individual explanatory factors, such as sex, age, atopy, test time and presence of diseased skin, on clinical patch test results, by application of multivariate statistical analysis. The study population was 2166 consecutive patients patch tested with the standard series of the International Contact Dermatitis Research Group (ICDRG) by members of the Danish Contact Dermatitis Group (DCDG) over a period of 6 months. For the 8 test allergens most often found positive (nickel, fragrance-mix, cobalt, chromate, balsam of Peru, carba-mix, colophony, and formaldehyde), one or more individual factors were of significance for the risk of being sensitized, except for chromate and formaldehyde. It is concluded that patch test results can be compared only after stratification of the material or by multivariate analysis.