Donepezil HCl (E2020) maintains functional brain activity in patients with Alzheimer disease: results of a 24-week, double-blind, placebo-controlled study.

OBJECTIVE: The authors evaluated the effects of donepezil (10 mg/day) versus placebo on brain glucose metabolism. METHODS: This was a randomized, double-blind, parallel-group, 24-week pilot study in 28 patients with mild-to-moderate Alzheimer disease (AD). Functional brain activity was quantified by measuring average glucose metabolism in an axial brain slice and regional brain glucose metabolism using positron emission tomography. RESULTS: At Week 24, relative to the pons metabolic rate, mean brain glucose metabolism in an axial slice at the level of the striatum was maintained within 0.5% of mean baseline levels for donepezil-treated patients, whereas it declined by an average of 10.4% in placebo-treated patients. This observation was confirmed by an analysis of differences in the mean slopes of glucose metabolism in the striatal slice in donepezil- and placebo-treated patients during the 24-week period. Significant treatment differences at Week 24 favoring donepezil for the mean percentage change from baseline in regional brain glucose metabolism were observed in four predefined regions of interest: the right parietal lobe 1, left temporal lobe 2, right frontal lobe 2, and left frontal lobe 2. CONCLUSION: Placebo-treated patients with AD show a decline in functional brain activity, relative to the pons, in several regions, and treatment with donepezil may slow this decline.

Clozapine-induced EEG abnormalities and clinical response to clozapine.

The authors hypothesized that patients who develop gross EEG abnormalities during clozapine treatment would have a less favorable outcome than patients who did not develop abnormal EEGs. The clinical EEGs and the Brief Psychiatric Rating Scale (BPRS) scores of 12 patients with schizophrenia and 4 patients with schizoaffective disorder were compared before and during treatment with clozapine. Eight patients developed significant EEG abnormalities on clozapine; 1 showed worsening of an abnormal pre-clozapine EEG; none of these subjects had clinical seizures. BPRS scores improved significantly in the group of patients who developed abnormal EEGs but not in the group who did not. Findings are consistent with previous reports of a high incidence of clozapine-induced EEG abnormalities and a positive association between these abnormalities and clinical improvement.

Natural killer cell activity in schizophrenia and schizoaffective disorder: a pilot study.

Natural killer cell activity was prospectively studied in 15 patients with chronic schizophrenia and in seven patients with schizoaffective disorder, depressed type. These patients were compared to individually matched normal controls. No mean differences in natural killer cell activity between the patient groups and their controls were observed.

Limbic-hypothalamic-pituitary-adrenal axis activity and ventricular-to-brain ratio studies in affective illness and schizophrenia.

Some investigators have speculated that structural brain alterations observed in some psychiatric patients might be related to increased limbic-hypothalamic-pituitary-adrenal axis (LHPA) activity. To explore this hypothesis, we prospectively studied 166 research volunteers (19 patients with research diagnostic criteria (RDC) major depression, 9 patients with RDC bipolar depression, 45 patients with RDC schizophrenia, and 94 RDC normal controls), examining the relationship between magnetic resonance image-determined ventricular-to-brain ratio (VBR) and indices of LHPA axis function (cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF), CSF adrenocorticotropic hormone (ACTH), and 24-hour urinary-free cortisol secretion). We observed no significant differences in mean VBR among the three patient groups and the normal control volunteers. Of the indices of LHPA activity, only CSF CRF concentrations distinguished the four subject groups, with CSF CRF being significantly elevated in the more severely depressed major depression patients. Indices of LHPA activity were not significantly correlated with VBR in any of the three patient groups or in the normal volunteers. These preliminary results suggest that VBR is not highly associated with alterations in LHPA activity, at least as determined cross-sectionally. Further longitudinal studies with reference to diagnostic subtypes, severity, symptom profiles, and more specific neuroanatomic regions may allow the elucidation of possible relationships between LHPA pathology and structural brain alterations.

Lateral ventricle-brain ratio and balance between CSF HVA and 5-HIAA in schizophrenia.

OBJECTIVE: Lateral ventricle enlargement in schizophrenia has been positively correlated with poor premorbid competence, negative symptoms, and poor treatment response and negatively correlated with concentrations of homovanillic acid (HVA), a dopaminergic metabolite. The authors provide further evidence of a reciprocal relationship between lateral ventricle size and dopaminergic activity in schizophrenia. METHOD: They assessed the relationship between lateral ventricle enlargement (ventricle-brain ratio, VBR) and CSF neurotransmitter metabolite concentrations (HVA and 5-hydroxyindoleacetic acid [5-HIAA]) in 45 patients with schizophrenia, 28 with affective disorders (19 patients with major depression and nine with bipolar disorder), and 91 normal comparison subjects. RESULTS: No group mean differences were significant. Although individual correlations of VBR with HVA and 5-HIAA were not statistically significant, the ratio of HVA to 5-HIAA was significantly correlated with VBR in the patients with schizophrenia, a finding consistent with dopaminergic-serotonergic balance hypotheses. CONCLUSIONS: These data suggest that it is the balance between HVA and 5-HIAA rather than their absolute levels which is associated with brain morphology and that this relationship between brain chemistry and morphology may be characteristic of the normal range of functioning for these systems. In other words, independent of whether brain morphology and chemistry differentiate psychopathological from nonpsychopathological states, there may be an orderly relationship between lateral ventricle size and the balance between HVA and 5-HIAA balance that is especially prominent in schizophrenia.