Modified-release (MR) zolpidem was developed to maintain effective plasma concentrations during the 3- to 6-hour post-dosage interval, corresponding to the middle portion of the typical sleep interval. Modified-release zolpidem (12.5 mg), standard immediate-release (IR) zolpidem (10 mg), and placebo were compared in a double-blind, single-dose, 3-way crossover daytime study of healthy volunteers (n = 70 completers). Effect areas for electroencephalographic beta amplitude during 0 to 8 hours and 3 to 6 hours after dosage were greater for MR compared to IR (P < .001). The digit-symbol substitution test and sedation rating scales behaved similarly. MR and IR did not differ in effects at 8 hours post-dosage nor in halflife or clearance. Time of peak plasma concentration (tmax) was significantly longer for MR (2.4 vs 2.0 hours, P < .004), and dose-normalized peak plasma concentration (Cmax) was lower (12.2 vs 14.0 ng/mL/mg, P < .001). MR zolpidem also had greater area under the plasma concentration curve (AUC) during the 3- to 6-hour interval (P < .001). Thus, MR zolpidem produces sustained plasma levels compared to IR, with resulting enhancement of pharmacodynamic effects in the 3- to 6-hour post-dosage interval.
This study examined whether patients with major depressive disorder manifest deficits in intelligence during affective episodes and following clinical improvement. WAIS-R scores were contrasted in 100 patients in an episode of major depression with 50 normal controls, matched to the patient sample in terms of demographic variables and estimates of premorbid IQ. The groups were equivalent in verbal IQ, but, in line with previous studies, the depressed patients had a pronounced deficit in performance IQ. A patient subsample was administered the WAIS-R under unlimited time conditions to determine whether the time constraints of performance IQ subtests contributed to the magnitude of the verbal-performance IQ discrepancy. This discrepancy was only slightly reduced with untimed scoring. Subgroups of depressed patients were retested with the WAIS-R within one week (n = 26) or two months (n = 33) following treatment with electroconvulsive therapy. In both subsamples, IQ scores were improved at posttreatment testing relative to pretreatment, but with little change in the verbal-performance IQ discrepancy. These and related findings suggested that a performance IQ deficit is characteristic of depressed patients regardless of affective state.
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