Low-fat oxidation may be a factor in obesity among men with schizophrenia.

OBJECTIVE: Obesity associated with atypical antipsychotic medications is an important clinical issue for people with schizophrenia. The purpose of this project was to determine whether there were any differences in resting energy expenditure (REE) and respiratory quotient (RQ) between men with schizophrenia and controls. METHOD: Thirty-one men with schizophrenia were individually matched for age and relative body weight with healthy, sedentary controls. Deuterium dilution was used to determine total body water and subsequently fat-free mass (FFM). Indirect calorimetry using a Deltatrac metabolic cart was used to determine REE and RQ. RESULTS: When corrected for FFM, there was no significant difference in REE between the groups. However, fasting RQ was significantly higher in the men with schizophrenia than the controls. CONCLUSION: Men with schizophrenia oxidised proportionally less fat and more carbohydrate under resting conditions than healthy controls. These differences in substrate utilisation at rest may be an important consideration in obesity in this clinical group.

Neuropsychological, neurological and symptom correlates of impaired olfactory identification in schizophrenia.

Impaired olfactory identification has been reported in samples of schizophrenic patients. Little is known about the associations between these impairments and neuropsychological deficits, neurological deficits and olfaction-related symptoms. Forty-six subjects (37 men and 9 women) with schizophrenia were examined with the University of Pennsylvania Smell Identification Test (UPSIT), a selection of neuropsychological tests and standardised neurological and symptom evaluations. Eighty-five per cent of the subjects scored below the published norms' 10th percentile on the UPSIT. Stepwise multiple regression found that WAIS-R Information score and Wisconsin Card Sort Test Failure to Maintain Set score (WCST-FMS) were the only significant predictors of the UPSIT percentile scores, accounting for 41% of the variance. Neurological signs did not contribute to the prediction of impaired olfactory identification. Although 26% of subjects reported olfactory hallucinations, there was no association between this symptom and olfactory impairment. The results suggest that general knowledge or general intelligence may have some influence on olfactory identification in subjects with schizophrenia; however, olfactory identification deficit could not be explained by gross impairments of sustained attention, memory or conceptual ability.

Chirality of reduced haloperidol in humans.

In vitro, cytosolic human ketone reductases catalyse the stereospecific (i.e. >99%) formation of S(-) reduced haloperidol (RHP) from haloperidol (HP). Whether this situation is reflected in patients taking the drug is unknown. In this study in nine patients taking HP, only 73.2+/-18.2% of the RHP excreted in urine was the S(-) enantiomer. Thus, enzymes other than cytosolic ketone reductases must be responsible for the formation of the minor enantiomer.

Two pyridinium metabolites of haloperidol are present in the brain of patients at post-mortem.

We have shown in patients taking the antipsychotic drug haloperidol (HP) that two pyridinium metabolites (HPP+ and RHPP+) are present in blood and urine in nM concentrations. These metabolites are structurally analogous to MPP+, the neurotoxic metabolite of the well-known parkinsonian-producing protoxin, MPTP. In this study we measured the concentrations of HPP+ and RHPP+ in seven regions of the brain (putamen, substantia nigra, globus pallidus, caudate, hippocampus, cerebellum and occipital cortex) obtained at post-mortem from three patients who were taking HP before death. Blood, urine, and bile from one patient were analysed as well. HPP+ was present in all regions (except for substantia nigra in one patient and globus pallidus in another); the amount/g ranged from 1.6-8.3 pMol but there was no preferential sequestration of the metabolite in dopaminergic regions. Similarly, RHPP+ was present relatively uniformly in all regions; the amount/g ranged from 1.1-7.6 pMol. The concentrations of HPP+ and RHPP+ in one patient were 24 and 13 nM in blood, 660 and 230 nM in urine, and 13.0 and 1.4 microM in bile, respectively. The presence of these pyridinums in brain adds another important piece of information to the case that, at least for HP, metabolite-induced neurotoxicity could contribute to the extrapyramidal side-effects in patients receiving long-term therapy.

Quantitative analysis of two pyridinium metabolites of haloperidol in patients with schizophrenia.

OBJECTIVE: A pyridinium metabolite (HPP+) of the neuroleptic drug haloperidol has been identified in rats and in the urine of patients. The purpose of this study was to measure the steady-state blood and plasma concentrations and daily urinary excretion of HPP+ in patients treated with haloperidol. METHODS: HPP+ was measured by HPLC with fluorescence detection. The chromatograms also revealed the presence of a previously unknown pyridinium species, which was identified in urine by liquid chromatography/mass spectrometry/mass spectrometry as 4-(4-chlorophenyl)-1-4-(4-fluorophenyl)-4-hydroxybutylpyridinium (RHPP+). Concentrations of RHPP+ were then measured by HPLC. RESULTS: The steady-state concentrations of HPP+ or RHPP+ in blood and plasma from 34 patients were virtually identical. The plasma concentrations of each metabolite were related to the daily dose of haloperidol and to its plasma concentrations. Nonlinearity in the elimination of RHPP+ was suggested by the increase in the ratio between RHPP+ and HPP+ plasma concentrations with dose or steady-state concentrations of haloperidol. The concentrations of RHPP+ in plasma and urine generally exceeded those of HPP+; the ratio between them in plasma ranged from 0.9 to 14.1. The daily urinary excretion of HPP+ and RHPP+ accounted for 0.40% +/- 0.18% and 2.3% +/- 1.4% of the haloperidol dose, respectively. The renal clearance of each species was 4.5 +/- 2.5 and 11.3 +/- 5.3 L/hr, respectively. CONCLUSIONS: The presence of these pyridinium species in humans raises the concern that they may be neurotoxic in a manner similar to the dopaminergic pro-neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Nonlinear relationship between circulating concentrations of reduced haloperidol and haloperidol: evaluation of possible mechanisms.

In patients taking haloperidol (HP), circulating concentrations of reduced haloperidol (RHP increase disproportionately to the dose or concentration of the parent drug. In the current study, we tested the hypothesis that the nonlinearity is due to preferential saturation of the reoxidation of RHP to HP, and two factors that could amplify the nonlinearity-concentration-dependent binding of RHP by plasma proteins, or by red blood cells. In 25 patients with schizophrenia who were taking HP, the unbound fraction of HP (0.085 +/- 0.016) and RHP (0.244 +/- 0.026) in plasma, and the blood:plasma ratio for each compound were independent of their concentration. Thus, saturable binding of RHP to plasma proteins or red blood cells can be excluded. HP reductase and RHP oxidase activity were measured in human liver cytosol and microsomal fractions, respectively. Because ketone reductase-catalysed formation of RHP is stereospecific, we examined each enantiomer of RHP separately. The Vmax for the oxidation of the S(-) and R(+) RHP enantiomers in four livers was 0.23 +/- 0.15 and 0.60 +/- 0.32 mumol/g protein per min (mean +/- SD), respectively. The Km was 110 +/- 40 and 70 +/- 10 microM, respectively. In contrast, HP reductase activity displayed greater capacity and was not saturable. The rate of production of RHP at a HP concentration of 122 microM (the limit of HP solubility) in the same livers was 2.6 +/- 0.7 mumol/g protein per min. Despite the observed nonlinearity between the enzymatic pathways in vitro, RHP concentrations in vivo are 2-3 orders of magnitude lower than the Km for oxidation of each enantiomer of RHP.(ABSTRACT TRUNCATED AT 250 WORDS)

Mianserin-induced up-regulation of serotonin receptors on normal human platelets in vivo.

The antidepressant, mianserin, is a serotonin receptor (5-HT2) antagonist and produces down-regulation of 5-HT2 and 5-HT1c receptors in the cerebral cortex of rats. In preparation for testing the validity of platelets as a model system for changes in 5-HT2 receptors during antidepressant drug treatment, mianserin (40 mg daily), was given to five human volunteers for five days, and platelets were collected on days 0, 1, 6, and 8. 5-HT2 receptor affinity and density were measured by specific binding of 125I-LSD, with and without an excess of spiperone. 5-HT uptake site affinity and density were determined by 3H-paroxetine binding, with and without an excess of fluoxetine. Platelet serotonin content was measured using high pressure liquid chromatography and electrochemical detention. Platelet 5-HT2 receptor density was increased and the ligand affinity was decreased during mianserin administration. In contrast, platelet 5-HT content was not altered significantly by mianserin administration, nor was platelet uptake site density and ligand affinity.

Placebo-controlled, double-blind study of the effects of proglumide in the treatment of schizophrenia.

A double-blind, placebo-controlled, randomized study was performed to determine whether proglumide added to ongoing neuroleptic medication was efficacious in the treatment of 32 patients with persistent positive and negative schizophrenic symptoms. Patients treated with both proglumide and placebo showed a significant improvement over the 8 weeks of the study, but no significant difference between the patients taking proglumide and those taking placebo could be demonstrated. In addition, proglumide had no effect on plasma homovanillic acid concentrations or neuroleptic drug activity. The results suggest that, at least for the dose of proglumide used in this study (15 mg/day), the addition of this particular cholecystokinin antagonist does not potentiate the antipsychotic efficacy of neuroleptic medication in patients with persistent schizophrenic symptoms.

Determination of haloperidol and reduced haloperidol in the plasma and blood of patients on depot haloperidol.

We developed a sensitive HPLC assay to measure haloperidol (HA) and its metabolite, reduced haloperidol (RH), in plasma and whole blood. The conditions under which HA might be converted to RH during collection and analysis of blood were examined. Provided the blood was kept at 0 degrees C, erythrocyte ketone reductase activity was insignificant. The solid phase extraction method did not generate RH. We studied ten patients taking 25-400 mg/month of HA decanoate and one patient for 4 weeks after the daily oral dose of 120 mg HA was ceased. In the patients on depot HA, the plasma and blood concentrations of HA were not significantly different (P greater than 0.1). For the first time, RH was detected in plasma patients on depot drug, but only in three cases. In contrast, RH was present in the blood of eight of these patients. The accumulation of RH in red blood cells was also evident in the patient on oral HA, in whom the mean ratio of RH concentrations in whole blood to plasma was 3.6 +/- 1.1. Plasma concentrations of HA correlated highly with total neuroleptic activity measured by a radioreceptor assay. Compared to plasma, analysis of concentrations of HA and RH in blood has the advantages of greater sensitivity, of using smaller volumes of blood and of avoiding the efflux of HA and RH during separation of plasma and red cells.

Effects of nifedipine on psychosis and tardive dyskinesia in schizophrenic patients.

In an open label study, two fixed doses of nifedipine (30 mg and 60 mg daily) were added to the usual antipsychotic drug treatments of 10 patients suffering from chronic schizophrenia. While no patient experienced significant improvements, statistically significant falls in Brief Psychiatric Rating Scales scores were observed. A significant reduction in Abnormal Involuntary Movement Scale scores was observed in those patients with tardive dyskinesia. After the addition of nifedipine, four of the 10 patients showed large increases in plasma neuroleptic activity (radioreceptor assay) that decreased to baseline levels within two weeks. The possibility that this represents competitive inhibition and subsequent induction of the liver metabolism of the antipsychotic drugs is discussed. Adverse effects encountered are also discussed.

Dopaminergic supersensitivity and vomiting among schizophrenic patients.

The prevalence of vomiting among schizophrenic inpatients was determined over a 6-week period; 8 of 19 patients (42%) experienced at least one episode of vomiting and 3 (16%) experienced 4 episodes. A hypothesis that this may be a dopaminergic supersensitivity phenomenon is proposed, but no association with tardive dyskinesia, another putative supersensitivity phenomena, could be demonstrated. The authors suggest that vomiting among schizophrenic patients is usually underestimated and may at times be a serious clinical problem.

Two cases of papillary carcinoma of the thyroid associated with psychosis and violence.

Two cases are described in which serious violent acts occurred during the course of a psychotic illness and in which papillary carcinoma of the thyroid was later diagnosed. Several possible explanations are examined, including a suggestion that neuroendocrine changes reportedly associated with violence may have allowed existing thyroid cancers to grow so as to become clinically apparent.