Grant N. Ko

Haloperidol and reduced haloperidol concentrations in plasma and red blood cells from chronic schizophrenic patients.

In a double-blind, placebo-controlled study, 15 drug-free chronic schizophrenic inpatients were treated with a fixed dose of haloperidol for 6 weeks. Haloperidol and its metabolite, reduced haloperidol, were measured in plasma and red blood cells after 2, 4, and 6 weeks of treatment. Behavioral change was rated using the Brief Psychiatric Rating Scale (BPRS). Not only the raw concentrations, but also blood compartment sums and ratios of these four drug measurements were tested for their strength of association with behavioral improvement. Positive associations with some BPRS subscales at some time points emerged; however, no significant correlations were found to extend across all time points measured. There was a trend in this cohort for negative symptom improvement to be associated with the ratio of haloperidol to reduced haloperidol in red blood cells. The ratio of haloperidol to reduced haloperidol in plasma was always greater than that in the red blood cells for all patients, reflecting an accumulation of the metabolite in red blood cells.

Effect of valproic acid on behavior and plasma amino acid concentrations in chronic schizophrenic patients

Valproic acid (VPA), or 2-propylpentanoic acid, has an anticonvulsant effect and is used clinically in the treatment of petit mal seizures (Simon and Penry 1975). Although VPA increases brain gamma-aminobutyric acid (GABA) concentrations, the anticonvulsant effect appears to be more closely associated with a reduction in brain concentrations of aspartic acid (Chapman et al. 1982, 1983; Schechter et al. 1978). Based on the inhibitory action of GABA on brain dopamine systems (Waszczak and Waiters 1979), there has recently been considerable interest in the experimental treatment of schizophrenia with GABA agonists or agents that increase brain GABA concentrations. The results of these experiments have generally been equivocal (cf. Garbutt and van Kammen 1983). VPA in particular has been administered to schizophrenic patients in three previous studies. In two of these, patients improved during VPA treatment (Linnoila et al. 1976: Nagao et al. 1979). The third study reported that patients worsened

On the clinical relevance and methods of quantification of plasma concentrations of neuroleptics.

Literature concerning quantification of plasma concentrations of neuroleptics is reviewed with a particular emphasis on the radioreceptor assay. Based on previously published reports and their own data, the authors conclude that further studies on factors influencing the results of the radioreceptor assay are needed prior to its application in the clinic. Furthermore, the original suggestion of using a single standard reference drug for all neuroleptics may be misleading. Rather, known concentrations of each neuroleptic quantified need to be used as standards. (J Clin Psychopharmacol 1985;5:253–262)

The Genain Quadruplets 25 years later: a diagnostic and biochemical followup.

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.

Possible interference by the reduced haloperidol metabolite with the radioimmunoassay and radioreceptor assay of blood haloperidol.

Serum or plasma samples from haloperidol-treated patients were analyzed by high performance liquid chromatography (HPLC) with electrochemical detection, radioimmunoassay (RIA), and radioreceptor assay (RRA). The HPLC assay allows simultaneous quantitation of the reduced alcohol metabolite of haloperidol. The HPLC and RIA haloperidol results correlated fairly well (r = 0.63), while the HPLC reduced haloperidol and the RIA haloperidol had a weak correlation (r = 0.28). The RRA haloperidol results had a fair correlation with those of the HPLC (r = 0.55), but their correlation with the HPLC reduced haloperidol was almost as good (r = 0.52). The RIA tended to give lower and the RRA higher apparent haloperidol concentrations than the HPLC assay. The results indicate that the reduced haloperidol does not interfere with the RIA procedure used in this study, but it may partially account for higher concentrations obtained with the RRA.

ALPHA2 Adrenergic receptors in Alzheimer's disease and schizophrenic cortex frontal

m-CPP. In the second study, we compared the behavioral and neuroendocrine responses across age of 32 normal volunteers who received m-CPP (0.1 mg/kg iv) and found that behavioral but not neuroendocrine responsivity to m-CPP decreases with age. These data may help explain the functional significance of 5-HT abnormalities in Alzheimer’s disease and normal aging. The decrease in behavioral responsivity with age parallels the documented loss of cortical 5-HT, receptors, indicating a possible decline with age in 5-HT system function. Alzheimer patients appear to be more sensitive than age-matched controls to the effects of direct 5-HT receptor agonist stimulation. This increased behavioral responsivity could reflect the widespread disruption in neuronal 5-HT seen in Alzheimer’s disease or the lack of inhibitory drive of a defective cholinergic system on the 5-HT system, producing functionally hyperresponsive 5-HT, receptors. The discrepancy between behavioral and hormonal responses following m-CPP in Alzheimer’s disease might also be consistent with regional loss of some 5-HT receptors, with relative sparing of others.