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We have investigated proton magnetic resonance spectra of the basal ganglia in 41 medication-free outpatients with major depression, prior to starting an 8-week standardized trial of open-label fluoxetine, and 22 matched comparison subjects. Upon completing the trial, depressed subjects were classified as treatment responders (n = 18) or nonresponders (n = 23), based on changes in the Hamilton Depression Rating Scale. Depressed subjects had a lower area ratio of the choline resonance to the creatine resonance (Cho/Cr) than comparison subjects. This statistically significant difference between the depressed subjects and comparison subjects was more pronounced in the treatment responders than in the nonresponders. There were no differences in the relative volumes of gray matter or white matter in the voxel used for proton spectroscopy in depressed subjects relative to comparison subjects. These results are consistent with an alteration in the metabolism of cytosolic choline compounds in the basal ganglia of depressed subjects and, in particular, those who are responsive to fluoxetine.

Concentrations of the neuroleptics haloperidol, bromperidol, fluphenazine, chlorpromazine and its metabolites nor-1- and nor-2-chlorpromazine, thioridazine and its metabolites mesoridazine, sulforidazine, and northioridazine, and promazine were estimated in serum and brain of rats by high performance liquid chromatography (HPLC) with electrochemical detection following 5 days of chronic administration of drug at typical doses (haloperidol, bromperidol, and fluphenazine 1 mg/kg/day; chlorpromazine, promazine, and thioridazine 25 mg/kg/day). The observed ratio of brain-to-serum concentration of drug varied widely (0.18-62.5) among neuroleptics studied. High potency agents had more favorable brain-to-blood distribution than low potency agents, and a strong correlation (r = 0.734, p < 0.05) was observed between the brain-to-serum ratios of the neuroleptics and standard clinical doses of drug. This finding suggests that drug distribution is a significant determinant of clinical potency. For most neuroleptics, including drugs with high (fluphenazine, haloperidol) and low potency (thioridazine) such as dopamine D2 antagonists, concentration of drug in the brain was similar. If the results are applicable to patients, they suggest that the degree of dopamine D2 blockade achieved during treatment may vary by drug. Chlorpromazine and promazine were notable for producing high concentrations of drug in the brain at typical doses, suggesting that optimal doses might be lower than those in common use. These results may be important in designing and interpreting studies of the effects of neuroleptic drugs in animals and patients.

An abnormality of membranes, possibly representing an increase in internal membranes, has been reported in fluorescence spectroscopic and electron microscopic studies of platelets of patients with Alzheimer's-type dementia (AD). To further define this abnormality, the cholesterol and phospholipid content of platelet and erythrocyte membranes was determined and compared for patients with AD and matched control subjects. No significant differences in either cholesterol or phospholipid, per se, were observed in comparing platelets from subjects in the two study groups. However, the ratio of cholesterol to phospholipid was significantly lower (p less than 0.01) in the platelets of patients with AD (9.37 +/- 1.11) than in the platelets of control subjects (10.20 +/- 1.04). Furthermore, the cholesterol to phospholipid ratio correlated significantly (rs = 0.53, p less than 0.01) with a separately determined measure of platelet membrane characteristics, the steady-state anisotropy of DPH (diphenylhexatriene). No differences were observed between the study groups for any of the same parameters measured in erythrocytes, which lack internal membranes. The findings suggest that there is no general abnormality of membrane lipids in Alzheimer's-type dementia. Rather, because normal internal membranes are reported to be low in their cholesterol to phospholipid ratio and in anisotropy of DPH, the results of these studies, together with the results of studies employing electron microscopy, suggest that platelets of patients with AD have an increase in internal membranes. Such membranes, while present in excess, may be normal in composition.