A five-year follow-up study of antioxidants, oxidative stress and polyunsaturated fatty acids in schizophrenia.

OBJECTIVE: Oxidative stress and dysregulated antioxidant defence may be involved in the pathophysiology of schizophrenia. In the present study, we investigated changes in antioxidants and oxidative stress from an acute to a later stable phase. We hypothesised that the levels of oxidative markers are increased in schizophrenia compared with healthy controls; change from the acute to the stable phase; and are associated with the levels of membrane polyunsaturated fatty acids (PUFAs) and symptom severity. METHODS: Fifty-five patients with schizophrenia spectrum disorders, assessed during an acute phase and 5 years later during a stable phase, and 51 healthy controls were included. We measured antioxidants (α-tocopherol, uric acid, albumin and bilirubin), markers of oxidative stress (F2-isoprostane and reactive oxygen metabolites) and membrane fatty acids. Antioxidants and oxidative stress markers were compared in schizophrenia versus healthy controls, adjusting for differences in sex, age and smoking, and changes over time. Associations between symptoms and PUFA were also investigated. RESULTS: In the acute phase, α-tocopherol was significantly higher (p < 0.001), while albumin was lower (p < 0.001) compared with the stable phase. Changes in α-tocopherol were associated with PUFA levels in the acute phase. In the stable phase, schizophrenia patients had higher uric acid (p = 0.009) and lower bilirubin (p = 0.046) than healthy controls. CRP was higher in patients in the stable phase (p < 0.001), and there was no significant change from the acute phase. CONCLUSION: The present findings of change in antioxidant levels in the acute versus stable phase of schizophrenia the present findings suggest that redox regulation is dynamic and changes during different phases of the disorder.

Age Impacts Olanzapine Exposure Differently During Use of Oral Versus Long-Acting Injectable Formulations: An Observational Study Including 8,288 Patients.

PURPOSE: Olanzapine is a commonly prescribed antipsychotic available as oral and long-acting injectable (LAI) formulations. Data are lacking on the use and safety of olanzapine-LAI in older patients. The aim of this study was to investigate the effect of increasing age on olanzapine exposure during oral versus LAI administration in a real-life setting. METHODS: This observational study was based on routine therapeutic drug monitoring data collected during 2005-2017. As a measure of exposure, absolute concentrations and concentration/dose ratios of olanzapine were defined as outcome variables. Linear mixed-model analyzes were used to allow for inclusion of multiple samples per patient and adjustment for covariate effects. RESULTS: Olanzapine concentrations and doses from 8,288 patients (21,378 measurements) were included. The number of patients on oral treatment was 7,893 (42%, 50 years or older), while 395 were using olanzapine-LAI (27%, 50 years or older). In contrast to oral use, where the dose-adjusted concentration of olanzapine increased significantly for patients 50 years or older (P < 0.001), increasing age had no effect on olanzapine concentration following LAI administration (P = 0.550). The effects of smoking habits and gender were equal in oral and olanzapine-LAI users. CONCLUSION: While the dose-adjusted systemic exposure of olanzapine increases by age after oral administration, these novel findings from a large patient population show that systemic exposure of olanzapine-LAI is unaffected by age, probably due to the lacking influence of age-related changes in gastrointestinal absorption and/or presystemic metabolism. From a pharmacokinetic point of view, it is therefore no reason to restrict the use of olanzapine-LAI in older patients requiring long-term treatment.

Correlates of major medication side effects interfering with daily performance: results from a cross-sectional cohort study of older psychiatric patients.

BACKGROUND: Polypharmacy is common among older persons who are also vulnerable to side effects. We aimed to characterize patients who on admission to a geriatric psychiatric hospital had major medication side effects interfering with daily performance. METHODS: Cross-sectional cohort study of patients consecutively admitted to a geriatric psychiatric hospital from 2006, 06 December to 2008, 24 October. The UKU side effect rating scale was performed, and patients were divided into those with no/minor side effects versus those with major side effects. Blood levels of 56 psychotropic drugs and 27 safety laboratory tests were measured upon admission. RESULTS: Of 206 patients included in the analysis, 70 (34%) had major side effects related to drug treatment. The most frequent side effects were asthenia (31%), reduced salivation (31%), concentration difficulties (28%), memory impairment (24%), and orthostatic dizziness (18%). The significant characteristics predicting major side effects were female gender (OR = 2.4, 95% confidence interval (CI) = 1.1-5.5), main diagnosis of affective disorder (OR = 4.3, 95% CI = 1.5-12.3), unreported use of psychotropic medications (OR = 2.0, 95% CI = 1.0-4.1), a higher number of reported psychotropic medications (OR = 1.7, 95% CI = 1.2-2.3), a higher number of reported medications for somatic disorders (OR = 1.2, 95% CI = 1.1-1.5), and a higher score on the Charlson comorbidity index (OR = 1.2, 95% CI = 1.0-1.4) (r 2 = 0.238, p < 0.001). CONCLUSIONS: Clinicians should be especially aware of side effects related to drug treatment in geriatric psychiatric female patients with a high use of psychotropic and other medications and somatic comorbidity. Unreported use of psychotropic medications was also related to the risk for side effects, and clinicians should make an effort to ascertain all medications taken by geriatric psychiatric patients.

Psychotropic medication in geriatric psychiatric patients: use and unreported use in relation to serum concentrations.

PURPOSE: The aim of this observational study was to describe the type, number, and serum concentration levels of psychotropic drugs in elderly patients, on admission to a geriatric psychiatric inpatient unit. We further wanted to investigate the use and unreported use of psychotropic drugs by analyzing for a broad spectrum of drugs in the serum samples. METHODS: A total of 236 patients were included. Drug use, patient characteristics, and diagnoses were recorded, and serum analysis was performed for a total of 56 psychotropic drugs in 233 of the patients. RESULTS: Nine out of ten patients (88%) used one or more psychotropic drugs on admission to hospital; the mean use was 2.8 (95% confidence interval (CI) 2.6-2.9) drugs. In 25 patients (11%), drugs reported used were not detected in serum. Unreported use of drugs (serum analysis revealing one or more drugs not reported) was found in 100 patients (43%). This was more common in younger patients. Psychotropic polypharmacy (use of three or more psychotropic drugs) was found in 109 patients (47%). Patients with a main diagnosis of affective disorder used the most psychotropic drugs. CONCLUSIONS: Psychotropic drugs are commonly used among geriatric psychiatric patients on admission to hospital. Psychotropic polypharmacy is a major concern among these patients. There was considerable unreported use of drugs within this population, and a low threshold for a broader serum analysis for psychotropic drugs appears indicated.

Bimodal distribution of polyunsaturated fatty acids in schizophrenia suggests two endophenotypes of the disorder.

BACKGROUND: There is conflicting evidence of whether polyunsaturated fatty acids (PUFA) in red blood cells are bimodally distributed in schizophrenia. The purpose of this study was to examine the distribution of PUFA, as well as its links to plausible causal factors. METHODS: A 16-week cohort study and a case-control study as part of a randomized controlled trial. Ninety-nine patients with DSM-IV schizophrenia, schizoaffective disorder, or schizophreniform disorder, aged 18 to 39, were consecutively included at admission to psychiatric departments of nine Norwegian hospitals. Fatty acids were measured in 97 of these patients and in 20 healthy control subjects. The primary outcome measure was the bimodality test statistic T, assessed by a χ(2) test of the likelihood of one or two normal distributions of PUFA. RESULTS: At baseline, levels of polyunsaturated fatty acids were highly significantly bimodally distributed among patients. One third of patients constituted a group (low PUFA) who had PUFA levels at one fifth (p < .001) of those in high PUFA patients and healthy control subjects, which did not differ. Bimodality was mainly accounted for by docosahexaenoic acid and arachidonic acid. Bimodality was confirmed after 16 weeks. α-tocopherol was a robust predictor of PUFA at both occasions. Desaturase and elongase indexes differed between PUFA groups. Smoking, gender, antipsychotic medication, and dietary factors did not explain the bimodal distribution. CONCLUSIONS: Red blood cell PUFA were bimodally distributed among acutely ill patients with schizophrenia and schizoaffective disorder. Endogenous deficiencies of redox regulation or synthesis of long-chain PUFA in the low PUFA group may explain our findings.

The effect of ethinylestradiol-containing contraceptives on the serum concentration of olanzapine and N-desmethyl olanzapine.

AIM: To investigate the potential interaction between olanzapine, a CYP1A2 substrate, and ethinylestradiol-containing contraceptives (ECC). METHODS: The study was carried out at a routine therapeutic drug monitoring service. To identify patients who were co-administered ECC or other contraceptives, a questionnaire was sent to the physician who ordered serum monitoring of olanzapine for women aged 18-40 years during an 18 month period. The physicians were asked to provide information about contraceptive use and smoking habits. When questionnaires were returned by the physicians, the respective serum concentration data were included in the analysis. Patients were stratified into users of ECC, progestogen-based contraceptives (PBC) or no contraceptives. Dose-adjusted serum concentrations of olanzapine and the metabolite N-desmethyl olanzapine were compared between the subgroups. RESULTS: A total of 149 patients were included in the study (10 ECC users and 10 PBC users). In users of ECC, we found no differences in serum concentrations of olanzapine, but significantly lower concentrations of the CYP1A2-mediated metabolite N-desmethyl olanzapine compared with users of PBC (P = 0.019) and non-contraceptive users (P = 0.012). CONCLUSION: The present study confirms that ECC exhibit CYP1A2-inhibitory properties in terms of significantly lower exposure of N-desmethyl olanzapine. However, the inhibition does not provide clinically relevant changes in serum concentrations of olanzapine.

The effect of variable cigarette consumption on the interaction with clozapine and olanzapine.

OBJECTIVE: Cigarette smoking has been shown in several studies to induce the metabolism of the cytochrome P4501A2 (CYP1A2) substrates clozapine and olanzapine. The aim of the present study was to investigate the dose-dependent effect of cigarette smoking on serum concentrations of these drugs in a naturalistic setting. METHODS: In 73 schizophrenic patients recruited from psychiatric nursing homes, patient characteristics, smoking habits, drug dosing and serum concentrations of clozapine (n=33) and olanzapine (n=40) were registered. Concentration to dose (C/D) ratios of clozapine and olanzapine in non-smokers and subgroups of smokers were compared. RESULTS: Fifty-nine patients (80%) were smokers and these were stratified into the following groups according to smoking habits: 1-6 (n=0), 7-12 (n=13), 13-19 (n=18) and >or=20 (n=28) cigarettes daily. While the mean ratio was twice as high in non-smokers compared to smokers for both drugs (p<0.01), the C/D ratios of clozapine and olanzapine were not significantly different between the subgroups of smokers (p >0.15). Absolute serum concentrations were also higher in non-smokers compared to smokers: 50% for clozapine (p=0.058) and 67% for olanzapine (p<0.01). CONCLUSION: A daily consumption of 7-12 cigarettes is probably sufficient for maximum induction of clozapine and olanzapine metabolism. A 50% lower starting dose of both drugs in non-smokers seems rational to avoid side effects.

Stereospecific determination of citalopram and desmethylcitalopram by capillary electrophoresis and liquid-phase microextraction.

A chiral capillary electrophoresis (CE) system allowing simultaneous enantiomer determination of citalopram (CIT) and its pharmacologically active metabolite desmethylcitalopram (DCIT) was developed. Excellent chiral separation was obtained using 1% sulfated-beta-cyclodextrin (S-beta-CD) as chiral selector in combination with 12% ACN in 25 mM phosphate pH 2.5. Samples were prepared by liquid-phase microextraction (LPME) based on a rodlike porous polypropylene hollow fibre. CIT and DCIT were extracted from 1 ml plasma made alkaline with NaOH, into dodecyl acetate impregnated in the pores of a hollow fibre, and into 20 mM phosphate pH 2.75, inside the hollow fibre. The acceptor solution was directly compatible with the CE system. Efficient sample clean-up was seen, and the recoveries were 46 and 29% for the enantiomers of CIT and DCIT, respectively, corresponding to 31 and 19 times enrichment. The limit of quantification (S/N=10) was <11.2 ng/ml, intra-day precision was <12.8% RSD, and inter-day precision was <14.5% RSD, for all enantiomers. The validated method was successfully applied to simultaneous determination of enantiomer concentrations of CIT and DCIT in plasma samples from nine patients treated with racemic citalopram. The results confirm LPME-CE as a suitable and promising tool for enantiomeric determination of chiral drugs and metabolites in biological matrices.