Faculty Bibliography

Computed tomographic scans of 30 chronic schizophrenic patients and 26 matched medical controls were blindly assessed for ventricular brain ratio, cortical atrophy, third-ventricle diameter, and cerebellar atrophy. Schizophrenic patients had significantly larger third ventricles than the medical controls. There was no difference in the other brain morphologic variables. Phenomenology, drug response, CSF levels of 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, and a wide variety of clinical variables did not correlate with any measure of brain morphology. Clinicopathologic correlates of brain morphology may be limited to those patients with significant atrophy

beta-Carboline-3-carboxylic acid ethyl ester (beta-CCE) binds with high affinity to brain benzodiazepine receptors and has potent behavioral and physiologic effects in primates. Dose-related increases in behavioral agitation, plasma cortisol level, BP, and heart rate were observed after administration of doses between 50 and 500 micrograms/kg of beta-CCE to rhesus monkeys. All of these effects were blocked by pretreatment with diazepam. Pretreatment with clonidine hydrochloride and propranolol hydrochloride, both of which have been reported to have anxiolytic actions in man, attenuated only selective aspects of the response to beta-CCE. The behavioral, endocrine, and physiologic effects of low doses of beta-CCE in monkeys are similar to those observed in anxious patients or normal subjects under anxiety-provoking or stressful situations. Administration of benzodiazepine receptor active antagonists such as beta-CCE to primates may, therefore, provide a valid and reproducible model of human anxiety that could be used to investigate specific biologic aspects of anxiety disorders.

Concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in the lumbar CSF were measured in a group of suicidal schizophrenic patients and in a matched group of nonsuicidal schizophrenic patients. The suicidal group had a significantly lower level. This finding is consistent with reports of low levels of CSF 5-HIAA in suicidal patients with other psychiatric diagnoses and suggests that low CSF 5-HIAA may be a generalized marker of aggressive behavior against the self and others.

Large doses (960 to 3200 mg/day) of propranolol were taken by eight patients with chronic schizophrenia in a double-blind therapeutic trial. To investigate the effects of such treatment on central monoaminergic processes, samples of cerebrospinal fluid (CSF) were drawn before starting the study and after 31 to 63 days (means = 49 days) on propranolol. Concentrations in CSF of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA), the principal metabolites of norepinephrine, serotonin, and dopamine, were determined by HPLC with electrochemical detection. The level of HVA did not change. CSF 5-HIAA levels decreased an average of 34%, which indicates reduced turnover of serotonin in the central nervous system (CNS). There was a strong correlation between duration of treatment with propranolol and change in CSF 5-HIAA levels. The concentration of MHPG in CSF increased an average of 39%; this could have resulted from increased turnover of CNS norepinephrine as a consequence of the blockade of central beta-adrenoceptors or of altered metabolism and clearance of peripheral MHPG. Psychotic symptoms of the patients, as indicated by the 3-day average score on the Bunney-Hamburg scale, were not affected by treatment.

The ethyl ester of beta-carboline-3-carboxylic acid (beta-CCE) has a high affinity for benzodiazepine receptors and can antagonize some of the pharmacologic actions of benzodiazepines in rodents. Administration of beta-CCE (2.5 mg/kg) to chair-adapted, male rhesus monkeys (7-9 kg) elicited a behavioral syndrome characterized by extreme agitation, head and body turning, distress vocalization and other behaviors which might be termed 'anxious'. Concomitant increases in plasma cortisol, epinephrine, norepinephrine, heart rate, and mean arterial blood pressure were observed. Pretreatment of animals with the benzodiazepine receptor antagonist Ro 15-1788 (5 mg/kg) antagonized the behavioral, endocrine, and somatic changes produced by beta-CCE, but did not elicit any significant changes in these parameters when administered alone. Thus, administration of beta-CCE to primates may be a reliable and reproducible model of human anxiety and, as much, may prove valuable for studying the postulated role of 'stress' or 'anxiety' in a variety of human disorders. In toto, these results strongly suggest that benzodiazepine receptors not only mediate the pharmacologic actions of benzodiazepines, but may also subserve both the affective and physiologic expression of anxiety.

A biological and clinical followup of the Genain Quadruplets was initiated as a multilaboratory collaborative effort at the National Institute of Mental Health (NIMH). The quadruplets are 51-year-old monozygotic women previously studied with a battery of psychological and physiological tests 25 years ago at the NIMH. The present article (the first of a series of three) details the clinical history and course of the schizophrenic illness in each of the quadruplets and describes the biochemical measures determined. The findings of elevated urinary phenylethylamine excretion, decreased plasma dopamine-beta-hydroxylase activity, and increased alpha-adrenergic receptor concentrations in all quadruplets warrant further genetic studies

Eight neuroleptic-resistant schizophrenic patients were treated with ceruletide diethylamine, a cholecystokininlike peptide, in a placebo-controlled, double-blind, cross-over study. Ceruletide or placebo was administered intramuscularly twice a day for four consecutive days while patients received a constant dose of fluphenazine hydrochloride. Cholecystokinin octapeptide was also administered to four different schizophrenic patients in a double-blind, cross-over study. Cholecystokinin or placebo was administered as a slow intravenous infusion daily for four days. There were no changes in either the positive or negative symptoms of schizophrenia between the periods of placebo, ceruletide, or cholecystokinin administration. Furthermore, there was no tendency for the patients' conditions to either improve or worsen during the course of ceruletide or cholecystokinin treatment. In contrast to previous reports from uncontrolled studies, cholecystokininlike peptides appear to be devoid of antipsychotic properties when administered parenterally