The development of study exit criteria for evaluating antimanic compounds.

BACKGROUND: There is increasing interest on the part of investigators and the public at large in finding ways to study and improve treatments for the seriously mentally ill without exposing such individuals to unnecessary risks. One group of particular interest in this regard are patients suffering from acute mania. We set out to define "exit" criteria or novel clinical endpoints that might help to assess the efficacy of antimanic compounds. We sought a method that would be safer, more economical, and less sensitive to nonspecific factors in the clinical environment while still allowing unambiguous assessment of efficacy. METHOD: From a pool of subjects being screened for or already participating in intervention studies, we retrospectively identified 76 admissions of patients with a manic or mixed episode according to DSM-IV. We fit a mixed-effects regression model to all available data obtained using the Bech-Rafaelsen Mania Scale from admission to day 28 of treatment. Using the estimated model coefficients, we obtained empirical Bayes (EB) estimates of each subject's trend coefficients based on (1) all available data and (2) data through day 11 of treatment for mania. RESULTS: We found a high correlation (r = .67) between EB estimates of final response at day 28 and actual day 28 scores on the Bech-Rafaelsen scale based on scores through day 11. When subjects were categorized as full, partial, or nonresponders according to their final Bech-Rafaelsen score, we were able to show that only 2 of the 23 predicted nonresponders became full responders, 27 of the 31 predicted full responders became full responders, and 16 of the 22 predicted partial responders became partial or full responders. CONCLUSION: We conclude on the basis of this chart review study that it should be possible to define exit criteria for trials assessing the efficacy of antimanic compounds on the basis of relatively short duration exposure to experimental treatment.

Savoxepine: striatal dopamine-D2 receptor occupancy in human volunteers measured using positron emission tomography (PET).

The extent and duration of striatal dopamine-D2 receptor occupancy by savoxepine in humans has been studied using positron emission tomography with [11C]-raclopride, in order to investigate why the anticipated favourable ratio between its extrapyramidal and antipsychotic effects was not achieved in practice. After 0.25 mg savoxepine, striatal D2 receptor occupancy peaked at 50-60% after 24-36 h and disappeared within 6 days. After doses of 0.1 mg to 0.5 mg, D2 receptor occupancy in the putamen and caudate nucleus increased from 20 to 70% 3-7 h after administration and amounted to 40 to 75% at the peak time (20-29 h). This suggests that cumulative D2 receptor blockade would occur if equal or increasing doses of savoxepine were given repeatedly. Extrapyramidal adverse-effects would be likely to occur under such circumstances. An adequate test of the theory that preference for hippocampal dopamine D2 receptors with afford a good therapeutic ratio requires an alternative dosing regimen.

[Comparative study of changes in electroencephalographic and rheoencephalographic recordings with advancing age (author's transl)]. / Etude comparative electroencéphalographique et rhéoencéphalographique dans le vieillissement.

The correlation between the frequency index of the left parietotemporal E.E.G., and cerebral blood flow determined by rheoencephalography, was studied in 20 normal children (aged 8 to 13 years), 24 normal adults (18 to 45 years), 15 normal elderly subjects (78 to 95 years), and 37 patients with pathological disorders. A significant correlation was found in each group between the E.E.G. frequency index and blood flow rate. The occupation times correlating with the flow were: rapid rhythms in children, alpha rhythms (negative correlation) in normal adults, slow rhythms (negative correlations) in elderly subjects, and slow rhythms (negative correlation) in patients with pathological disorders.

[Influence of the computed tomography in brain disorders. Retrospective study of 10,000 investigations (author's transl)]. / La place de l'examen tomodensitométrique en pathologie cérébrale. Etude rétrospective de 10 000 dossiers.

On the basis of 10,000 examinations conducted over a period of 4 years and 7 weeks (1974-1979), the authors quantify the influence of computed tomography on neuroradiological diagnostic procedures. Findings during operation, at autopsy, or from follow-up over a sufficiently long period, are used to compare the diagnoses established after computed tomography with those suggested by other investigational methods. The regular increases in pathological observations demonstrates the increasingly precise selection of patients orientated towards the scanner. Computed tomography significantly reduces the frequency of invasive neuroradiological explorations, with both medical and socio-economic consequences. Computed tomography is greatly superior to morphological scintigraphic investigations.