We compared the antidepressant efficacy and patient tolerance of two different doses of milnacipran (75 mg and 150 mg daily) in 66 outpatients with major depression, using the 17-item Hamilton Depression Rating Scale (HDRS). Only new patients who had never experienced frank depressive episodes before, or those who had remained free from thymoregulators for more than 1 year without recurrence of depressive symptoms, were recruited. Subjects were randomly selected to receive a daily dose of milnacipran that reached either 75 mg or 150 mg within 2-3 weeks and then remained stable over an 8-week period. The results showed a significant superiority of milnacipran at 150 mg/day over 75 mg/day at the end of the study period in both response (50% or more decrease in total score from baseline, P=0.026) and remission (total HDRS score lower than 7 points, P=0.034). A response was recorded for 56.0% of the patients treated with 75 mg of milnacipran and for 84.6% of those treated with 150 mg after the 8-week study period. No significant difference was seen between the treatment groups for either individual or total incidence of adverse events. Notably, nausea and vomiting occurred most often immediately after the first visit, when subjects in both groups started with a daily dose of 50 mg. We conclude that additional comparisons between different doses of milnacipran should be performed to confirm or deny the linear dose/efficacy relationship observed in the present study.

To better understand antidepressant drug effects on the GABA_A receptor complex (the GABA_A receptor, chloride ionophore and benzodiazepine receptor), we investigated how antidepressants influenced power spectrum changes induced by pentylenetetrazol (PTZ), a chloride ionophore antagonist, in the rat hippocampal electroencephalogram (EEG). In control recording, PTZ (27.5 mg/kg i.p.) increased EEG power at frequencies under 12 Hz up to five times. After rats were pretreated with imipramine, fluoxetine or trazodone for 7 days (10 mg/kg i.p., twice a day), PTZ could not increase EEG power to more than three times the power before injection; this effect was not observed after pretreatment for 3 days. These three antidepressants inhibit serotonin uptake, while two other antidepressants, desipramine and nortriptyline, that inhibit norepinephrine uptake failed to counter the PTZ effect. We concluded that antidepressants with serotonergic effects enhanced the function of the GABA_A receptor complex.

Aim: Memory impairment is a potential major adverse effect of electroconvulsive therapy (ECT). Some reports have suggested that propofol, an intravenous anesthetic widely used for general anesthesia in ECT, can minimize adverse effects on memory and cognitive function following ECT. The relation between propofol blood level during ECT and memory impairment after the procedure is unknown. We aimed to determine the relation between predicted blood level of propofol administered by targetcontrolled infusion during ECT and memory impairment after the procedure.Methods: Thirty-six patients who underwent a total of 260 series of ECT were enrolled as subjects. Anesthesia was induced with intravenous injection of propofol with a target-controlled infusion pump for predicting blood levels. Orientation and memory testing were performed after completion of ECT. In a subsequent analysis, subjects were divided into early memory recovery (n = 195) and late memory recovery (n = 65) groups. Likewise, for orientation testing, subjects were divided into early recovery (n = 193) and late recovery (n = 67) groups. In both groups, predicted blood propofol levels, total propofol dose, and other variables, such as number of ECT treatments, stimulus energy volume, and spike and slow wave time, were determined for comparison.Results: Predicted blood propofol levels and propofol total dose were significantly higher in the early memory recovery group, while no significant differences were observed for the other variables. As for orientation, there were no significant differences between the early and late orientation recovery groups.Conclusions: Our data shows that the predicted blood propofol levels and the total dose influences memory impairment after the ECT.

Using microdialysis, extracellular concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in the striatum of rats. In rats given trazodone, m-chlorophenylpiperazine dihydrochloride, or imipramine, the concentrations of 5-HT were unchanged. 5-HIAA in trazodone- or imipramine-treated rats, however, was respectively, decreased to 80 or 65% of preinjections levels. When the potassium concentration (K⁺) was increased up to 150 mmol/l in the perfusate, the concentrations of 5-HT increased to about ten times the basal levels in the rats given saline. In rats treated with trazodone, K⁺-evoked elevations of 5-HT were less than five times the basal level. Multiple trazodone administrations prolonged the duration of inhibition of 5-HT release. In rats treated with other drugs, the K⁺-evoked 5-HT release was not affected. These observations suggest that trazodone itself might reduce 5-HT neural transmission.

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