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The purpose of this study was to compare the accuracy of clinical methods to estimate body fat (%BF) in people who take weight-inducing atypical antipsychotic medications. Forty-seven people (35 males, 12 females) with previously diagnosed psychotic illness who had been taking atypical antipsychotic medications for more than 6 months took part in this study. Percentage body fat was estimated using bioelectrical impedance analysis (BIA) and anthropometry from previously published prediction equations and compared with that measured using the deuterium dilution technique which served as the criterion measure. Bland-Altman analyses were used to assess the agreement between measures. In the males, %BF determined using BIA with the Lukaski equation was the only clinical method with mean differences that were not significant from criterion values. While in the females, %BF determined from BMI was the only method that was significantly different from the criterion values. All of the methods of estimating %BF except Watson equations provided consistent estimates across the weight range. Therefore, this study suggests that in a group of people who predominantly had schizophrenia and were taking atypical antipsychotic medications, BIA using the equation of Lukaski was the best indicator of %BF, although on an individual basis the accuracy was poor. BMI underestimated %BF to a greater significant extent than BIA. The use of BIA rather than BMI may provide a better indicator of adiposity in people who take weight inducing antipsychotic medications. [ABSTRACT FROM AUTHOR]

Background: Persons with mental disorders are at a higher risk than the general population for the subsequent development of certain medical conditions., Methods: We used a population-based cohort from Danish national registries that included data on more than 5.9 million persons born in Denmark from 1900 through 2015 and followed them from 2000 through 2016, for a total of 83.9 million person-years. We assessed 10 broad types of mental disorders and 9 broad categories of medical conditions (which encompassed 31 specific conditions). We used Cox regression models to calculate overall hazard ratios and time-dependent hazard ratios for pairs of mental disorders and medical conditions, after adjustment for age, sex, calendar time, and previous mental disorders. Absolute risks were estimated with the use of competing-risks survival analyses., Results: A total of 698,874 of 5,940,299 persons (11.8%) were identified as having a mental disorder. The median age of the total population was 32.1 years at entry into the cohort and 48.7 years at the time of the last follow-up. Persons with a mental disorder had a higher risk than those without such disorders with respect to 76 of 90 pairs of mental disorders and medical conditions. The median hazard ratio for an association between a mental disorder and a medical condition was 1.37. The lowest hazard ratio was 0.82 for organic mental disorders and the broad category of cancer (95% confidence interval [CI], 0.80 to 0.84), and the highest was 3.62 for eating disorders and urogenital conditions (95% CI, 3.11 to 4.22). Several specific pairs showed a reduced risk (e.g., schizophrenia and musculoskeletal conditions). Risks varied according to the time since the diagnosis of a mental disorder. The absolute risk of a medical condition within 15 years after a mental disorder was diagnosed varied from 0.6% for a urogenital condition among persons with a developmental disorder to 54.1% for a circulatory disorder among those with an organic mental disorder., Conclusions: Most mental disorders were associated with an increased risk of a subsequent medical condition; hazard ratios ranged from 0.82 to 3.62 and varied according to the time since the diagnosis of the mental disorder. (Funded by the Danish National Research Foundation and others; COMO-GMC ClinicalTrials.gov number, NCT03847753.)., (Copyright © 2020 Massachusetts Medical Society.)

Objective: Because comorbidity between mental and physical disorders is commonly found in patients, it would be expected that this pattern would also be reflected at the family level. During a recent population-based survey of common mental disorders, respondents were asked about the presence of selected mental and physical disorders in their relatives. The aim of this research was to describe the within-family co-occurrence of selected common physical and mental disorders in a population-based sample., Methods: Subjects were drawn from the Australian National Survey of Mental Health and Wellbeing 2007. A modified version of the World Mental Health Survey Initiative of the Composite International Diagnostic Interview (WMH-CIDI 3.0, henceforth CIDI) was used to identify lifetime-ever common psychiatric disorders (anxiety disorders, depression, drug or alcohol disorders). The respondents were asked if any of their relatives had one of a list of psychiatric (anxiety, bipolar disorder, depression, drug or alcohol problem, schizophrenia) or general physical disorders (cancer, heart problems, intellectual disability, memory problems). We examined the relationship between the variables of interest using logistic regression, adjusting for potential confounding factors., Results: Compared to otherwise-well respondents, those who had a CIDI diagnosis of major depressive disorders, anxiety disorders, or drug or alcohol abuse/dependence were significantly more likely to have first-degree relatives with (a) the same diagnosis as the respondent, (b) other mental disorders not identified in the respondent, and (c) a broad range of general physical conditions., Conclusions: Individuals with common mental disorders report greater familial co-occurrence for a range of mental and physical disorders. When eliciting family histories, clinicians should remain mindful that both mental and physical disorders can co-occur within families.

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.

Body mass index (BMI) is commonly used as an indicator of obesity, although in both clinical and research settings the use of bioelectric impedance analysis (BIA) is commonplace. The purpose of this study was to examine the relationship between BMI, BIA and percentage body fat to determine whether either is a superior indicator of obesity in men with schizophrenia. The reference method of deuterium dilution was used to measure total body water and, subsequently, percentage body fat in 31 men with schizophrenia. Comparisons with the classification of body fat using BMI and BIA were made. The correlation between percentage body fat and BMI was 0.64 whereas the correlation between percentage body fat and BIA was 0.90. The sensitivity and specificity in distinguishing between obese and overweight participants was 0.55 and 0.80 for BMI and 0.86 and 0.75 for BIA. BIA proved to be a better indicator of obesity than BMI. BMI misclassified a large proportion of men with schizophrenia as overweight when they had excess adiposity of sufficient magnitude to be considered as obese. Because of the widespread use of BMI as an indicator of obesity among people with schizophrenia, the level of obesity among men with schizophrenia may be in excess of that previously indicated.

Background: Benchmarking of performance indicators in the mental health field is gaining currency in Australia as a strategy for improving service quality., Aim: To engage mental health service providers in the collection and evaluation of performance data., Methods: Three separate rounds of data collection involving high secure, extended treatment, and medium secure services were carried out between 2003 and 2005. Twenty-five core indicators were identified and these were used to assess service inputs, processes, outputs and outcomes., Results: Differences in casemix, clinical practice and local business rules gave rise to variation in service performance. The benchmarking exercise led to the implementation of quality improvement initiatives., Conclusions: It is possible and useful to collect and evaluate performance data for mental health services. While services appear similar enough to benchmark, information related to both casemix and service characteristics needs to be included in benchmarking data to understand the factors that produce differences in service performance.

Objective: The management of atypical antipsychotic-induced weight gain is a significant challenge for people with mental illness. Fundamental research into energy metabolism in people taking atypical antipsychotic medication has been neglected. The current study of men with schizophrenia taking clozapine aimed to measure total energy expenditure (TEE) and energy expended on physical activity--activity energy expenditure (AEE) and to consider the clinical implications of the findings., Method: The well-established reference method of doubly labelled water (DLW) was used to measure TEE and AEE in men with schizophrenia who had been taking clozapine for more than 6 months. Resting energy expenditure was determined using indirect calorimetry., Results: The TEE was 2511+/-606 kcal day-1 which was significantly different to World Health Organization recommendations (more than 20% lower). The Physical activity level (PAL) was 1.39+/-0.27 confirming the sedentary nature of people with schizophrenia who take clozapine., Conclusions: The findings support the need for weight management strategies for people with schizophrenia who take clozapine to focus on the enhancement of energy expenditure by increasing physical activity and reducing inactivity or sedentary behaviours, rather than relying primarily on strategies to reduce energy intake.

Resting energy expenditure (REE) is lower than predicted in persons taking atypical antipsychotic medication, and weight management is a significant clinical challenge for some of them. However, to date there have been no published guidelines to assist clinicians in choosing appropriate prediction equations to estimate energy expenditure in persons taking atypical antipsychotic medications. The objectives of this study were to measure REE in a group of men taking the atypical antipsychotic clozapine and to determine whether REE can be accurately predicted for this population using previously published regression equations. REE was measured using indirect calorimetry via a ventilated hood on eight men who had completed at least 6 months of treatment with clozapine. Comparisons between measured REE and predicted REE using five different equations were undertaken. The commonly-used Harris-Benedict and Schofield equations systematically overestimated REE. Predictions of REE from other equations were too variable for clinical use. When estimating energy requirements as part of a weight-management program in men who have been taking clozapine for 6 months, predictions of REE from the equations of Harris-Benedict and Schofield should be reduced by 280 kcal/day.

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.

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.

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.

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.

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)

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.

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.

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.

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.

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 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.