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A study examines prevalence of substance use by addicts admitted to Swiss psychiatric hospital. Urine drug screening is done to detect the drug.

Background Cardiovascular diseases and dyslipidemia represent a major health issue in psychiatry. Many psychotropic drugs can induce a rapid and substantial increase of blood lipid levels. Objective This study aimed to determine the potential predictive power of an early change of blood lipid levels during psychotropic treatment on long-term change and on dyslipidemia development. Methods Data were obtained from a prospective study including 181 psychiatric patients with metabolic parameters monitored during the first year of treatment and with adherence ascertained. Blood lipid levels (ie, total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non–high-density lipoprotein cholesterol [non-HDL-C], and fasting triglycerides [TGs]) were measured at baseline and after 1, 3, and/or 12 months of treatment. Results Receiver-operating characteristic analyses indicated that early (ie, after 1 month of psychotropic treatment) increases (≥5%) for TC, LDL-C, TG, and non-HDL-C and decrease (≥5%) for HDL-C were the best predictors for clinically relevant modifications of blood lipid levels after 3 months of treatment (≥30% TC, ≥40% LDL-C, ≥45% TG, ≥55% non-HDL-C increase, and ≥20% HDL-C decrease; sensitivity 70%–100%, specificity 53%–72%). Predictive powers of these models were confirmed by fitting longitudinal multivariate models in the same cohort ( P ≤ .03) as well as in a replication cohort (n = 79; P ≤ .003). Survival models showed significantly higher incidences of new onset dyslipidemia (TC, LDL-C, and non-HDL-C hypercholesterolemia, HDL-C hypocholesterolemia, and hypertriglyceridemia) for patients with early changes of blood lipid levels compared to others ( P ≤ .01). Conclusion Early modifications of blood lipid levels following prescription of psychotropic drugs inducing dyslipidemia should therefore raise questions on clinical strategies to control long-term dyslipidemia. [ABSTRACT FROM AUTHOR]

Abstract: A Le Fort I osteotomy is widely used to correct dentofacial deformity because it is a safe and reliable surgical method. Although rare, various complications have been reported in relation to pterygomaxillary separation. Cranial nerve damage is one of the serious complications that can occur after Le Fort I osteotomy. In this report, a 19-year-old man with unilateral cleft lip and palate underwent surgery to correct maxillary hypoplasia, asymmetry and mandibular prognathism. After the Le Fort I maxillary osteotomy, the patient showed multiple cranial nerve damage; an impairment of outward movement of the eye (abducens nerve), decreased vision (optic nerve), and paraesthesia of the frontal and upper cheek area (ophthalmic and maxillary nerve). The damage to the cranial nerve was related to an unexpected sphenoid bone fracture and subsequent trauma in the cavernous sinus during the pterygomaxillary osteotomy. [Copyright &y& Elsevier]

Highlights: [•] Typical antipsychotic drugs were quantified in human plasma by UHPLC–MS/MS. [•] Sample preparation was performed by simple protein precipitation. [•] Stable isotope-labeled IS were used to compensate for the global method variability. [•] Good validation performances were obtained according to international guidelines. [•] This method is successfully used in our laboratory for routine TDM. [ABSTRACT FROM AUTHOR]

Abstract: A highly sensitive ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC–MS/MS) method was developed for the quantification of buprenorphine and its major metabolite norbuprenorphine in human plasma. In order to speed up the process and decrease costs, sample preparation was performed by simple protein precipitation with acetonitrile. To the best of our knowledge, this is the first application of this extraction technique for the quantification of buprenorphine in plasma. Matrix effects were strongly reduced and selectivity increased by using an efficient chromatographic separation on a sub-2μm column (Acquity UPLC BEH C18 1.7μm, 2.1×50mm) in 5min with a gradient of ammonium formate 20mM pH 3.05 and acetonitrile as mobile phase at a flow rate of 0.4ml/min. Detection was made using a tandem quadrupole mass spectrometer operating in positive electrospray ionization mode, using multiple reaction monitoring. The procedure was fully validated according to the latest Food and Drug Administration guidelines and the Société Française des Sciences et Techniques Pharmaceutiques. Very good results were obtained by using a stable isotope-labeled internal standard for each analyte, to compensate for the variability due to the extraction and ionization steps. The method was very sensitive with lower limits of quantification of 0.1ng/ml for buprenorphine and 0.25ng/ml for norbuprenorphine. The upper limit of quantification was 250ng/ml for both drugs. Trueness (98.4–113.7%), repeatability (1.9–7.7%), intermediate precision (2.6–7.9%) and internal standard-normalized matrix effects (94–101%) were in accordance with international recommendations. The procedure was successfully used to quantify plasma samples from patients included in a clinical pharmacogenetic study and can be transferred for routine therapeutic drug monitoring in clinical laboratories without further development. [Copyright &y& Elsevier]

Abstract: Early improvement of depression severity is considered an important therapeutic goal, predictive of later remission. The present study aimed at testing the hypothesis that plasma concentration might influence the time course of response to paroxetine. Eighty-four patients with a severe depressive episode started paroxetine 20 mg/day, with a possible dose adjustment to 30 mg/day after 2 weeks. Severity of depression (Montgomery–Åsberg Depression Rating Scale) was assessed at weeks 0, 2 and 4 for all patients, and every 2 weeks thereafter until discontinuation. Median duration on paroxetine was 6 weeks (range 4–18 weeks). Plasma concentration was measured at steady-state after 2 weeks at 20 mg/day. In a first stage, pattern analysis led to distinguish patients with non-response, non-persistent response, early persistent response (obtained at week 2) and delayed persistent response (week 4 or later). Comparison of patients with (n =29, 34.5%) and without persistent response (n =55, 65.5%) did not reveal any significant difference, whereas focus on patients with persistent response indicated that shorter time to response was significantly associated with shorter duration of current episode (r S =0.54, p =0.003) and higher plasma level (r S =−0.47, p =0.011). In a second stage, a sigmoid mixed effects model was developed that adequately fitted depression severity versus time profiles among patients with persistent response (n =157 data for 29 patients). Estimated median time to response was 3.2 weeks (range 0.9–6.6). Higher paroxetine concentration, younger age and shorter episode duration were confirmed as significant determinants of a shorter time to response (likelihood ratio tests, p <0.005). The present study supports the hypothesis that higher paroxetine concentration might contribute to hasten relief of depressive symptoms in severely depressed patients. [Copyright &y& Elsevier]

Abstract: Abnormalities of the glutamatergic system in schizophrenia have been identified in numerous studies, but little is known about the role of glutamate transporters and their messenger RNA (mRNA) expression. In addition, the abundances of the two major isoforms of human excitatory amino acid transporter 2 (EAAT2) or its rat ortholog, glutamate transporter 1, have never been compared in a quantitative manner. Using quantitative reverse transcription–polymerase chain reaction, we established that the expression of the EAAT1, EAAT2a, EAAT2b, and EAAT3 transcripts was not different in the dorsolateral prefrontal and primary visual cortices of persons with schizophrenia relative to matched controls. EAAT2a expression was about 25-fold and 10-fold higher than EAAT2b in human and rat brain, respectively. The data provided no evidence of an effect of antipsychotic medications on the mRNA expression of the glutamate transporters. However, because most of the schizophrenic subjects in the cohort had been treated with antipsychotics for many years, it is still possible that changes in transporter expression were masked by medication effects. [Copyright &y& Elsevier]

Genetic factors associated with Body Mass Index (BMI) have been widely studied over the last decade. We examined whether genetic variants previously associated with BMI in the general population are associated with cardiometabolic parameter worsening in the psychiatric population receiving psychotropic drugs, a high-risk group for metabolic disturbances. Classification And Regression Trees (CARTs) were used as a tool capable of describing hierarchical associations, to pinpoint genetic variants best predicting worsening of cardiometabolic parameters (i.e total, HDL and LDL-cholesterol, triglycerides, body mass index, waist circumference, fasting glucose, and blood pressure) following prescription of psychotropic drugs inducing weight gain in a discovery sample of 357 Caucasian patients. Significant findings were tested for replication in a second Caucasian psychiatric sample (n = 140). SH2B1 rs3888190C > A was significantly associated with LDL levels in the discovery and in the replication sample, with A-allele carriers having 0.2 mmol/l (p = 0.005) and 0.36 mmol/l (p = 0.007) higher LDL levels compared to others, respectively. G-allele carriers of RABEP1 rs1000940A > G had lower fasting glucose levels compared to others in both samples (− 0.16 mmol/l; p < 0.001 and − 0.77 mmol/l; p = 0.03 respectively). The present study is the first to observe such associations in human subjects, which may in part be explained by a high risk towards dyslipidemia and diabetes in psychiatric patients receiving psychotropic treatments compared to population-based individuals. These results may therefore give new insight into the etiology of LDL-cholesterol and glucose regulation in psychiatric patients under psychotropic drug therapy. [ABSTRACT FROM AUTHOR]

A bioanalytical method by high performance liquid chromatography coupled to electrospray mass spectrometry (HPLC-ESI–MS), adapted from a previously published method in plasma, was validated in breast milk for the simultaneous quantification of all antidepressants belonging to the class of selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) and their major metabolites (desmethylcitalopram and norfluoxetine). Milk samples (250 μl) first underwent protein precipitation followed by solid-phase extraction on a reversed phase/cation exchange sorbent. Analytes were thereafter separated on a XBridge C18 column (2.1 mm × 100 mm; 3.5 μm) using a mobile phase composed of ammonium acetate buffer (pH 8.1; 50 mM) and acetonitrile in gradient mode. Detection was performed by a single quadrupole mass spectrometer running in selected ion monitoring in positive ionization mode. Method validation covered a wide concentration range of 2–500 ng/ml for citalopram, desmethylcitalopram and paroxetine, 5–500 ng/ml for sertraline, and 2–1000 ng/ml for fluoxetine, norfluoxetine and fluvoxamine. Validation performances such as trueness (90.3–111.6%), repeatability (0.8–9.3%) and intermediate precision (0.9-9.5%) were in agreement with criteria from international guidelines and matrix effects for the analyte/internal standard ratios ranged from 92% to 110% (relative standard deviation <15%). Accuracy profiles (total error of trueness and precision) were lying within the limits of ±30% accepted in bioanalysis. Finally, the method was successfully applied to patient samples collected in a clinical pharmacokinetic study of nursing mothers taking an antidepressant treatment. [ABSTRACT FROM AUTHOR]

A high performance liquid chromatography (HPLC) tandem mass spectrometry (MS/MS) method was developed for the simultaneous, stereoselective quantification of the antidepressant citalopram and its active metabolite desmethylcitalopram in human plasma and breast milk. Sample preparation was performed by a two-step approach, including generic protein precipitation with acetonitrile followed by solid phase extraction. Enantiospecific separation of analytes was achieved on a Phenomenex ® Lux Cellulose-2 column (4.6 mm × 150 mm; 5 μm), using reversed phase chromatography conditions characterized by a gradient elution of ammonium acetate buffer (pH 9.0; 20 mM) and acetonitrile at a flow rate of 0.6 ml/min. The compounds were detected by a tandem quadrupole mass spectrometer equipped with an electrospray ionization source and operating in multiple reaction monitoring mode. The method was fully validated in both biological fluids over a large concentration range of 0.1–100 ng/ml for S-(+)- and R-(−)-citalopram, and 0.3–100 ng/ml for S-(+)- and R-(−)-desmethylcitalopram. Trueness (90.0–113.3% and 97.1–103.6%), repeatability (0.9–15.9% and 0.9–8.4%) and intermediate precision (1.3–17.8% and 0.9–9.6%) in plasma and breast milk, respectively, meet international guidelines for method validation. Internal standard-normalized matrix effects ranged between 99 and 101% and 98–105%, respectively. The accuracy profiles (total error of trueness and precision) were mostly within the acceptance limits for biological samples defined as ±30%. The method was successfully applied to patient samples in a clinical trial setting. [ABSTRACT FROM AUTHOR]

Abstract: A previously developed high performance liquid chromatography mass spectrometry (HPLC–MS) procedure for the simultaneous determination of antidementia drugs, including donepezil, galantamine, memantine, rivastigmine and its metabolite NAP 226-90, was transferred to an ultra performance liquid chromatography system coupled to a tandem mass spectrometer (UPLC–MS/MS). The drugs and their internal standards ([2H7]-donepezil, [13C,2H3]-galantamine, [13C2,2H6]-memantine, [2H6]-rivastigmine) were extracted from 250μL human plasma by protein precipitation with acetonitrile. Chromatographic separation was achieved on a reverse phase column (BEH C18 2.1mm×50mm; 1.7μm) with a gradient elution of an ammonium acetate buffer at pH 9.3 and acetonitrile at a flow rate of 0.4mL/min and an overall run time of 4.5min. The analytes were detected on a tandem quadrupole mass spectrometer operated in positive electrospray ionization mode, and quantification was performed using multiple reaction monitoring. The method was validated according to the recommendations of international guidelines over a calibration range of 1–300ng/mL for donepezil, galantamine and memantine, and 0.2–50ng/mL for rivastimgine and NAP 226-90. The trueness (86–108%), repeatability (0.8–8.3%), intermediate precision (2.3–10.9%) and selectivity of the method were found to be satisfactory. Matrix effects variability was inferior to 15% for the analytes and inferior to 5% after correction by internal standards. A method comparison was performed with patients’ samples showing similar results between the HPLC–MS and UPLC–MS/MS procedures. Thus, this validated UPLC–MS/MS method allows to reduce the required amount of plasma, to use a simplified sample preparation, and to obtain a higher sensitivity and specificity with a much shortened run-time. [Copyright &y& Elsevier]

Abstract: Purpose: To describe the weight gain-related side-effects of psychotropic drugs and their consequences on metabolic complications (hypercholesterolemia, obesity) in a Swiss cohort of psychiatric patients. Method: This cross-sectional observational study was performed in an out-patient psychiatric division with patients having received for more than 3 months the following drugs: clozapine, olanzapine, quetiapine, risperidone, lithium, and/or valproate. Clinical measures and lifestyle information (smoking behaviour, physical activity) were recorded. Results: 196 inclusions were completed. Weight gain (≥10% of initial weight) following drug treatment was reported in 47% of these patients. Prevalence of obesity (BMI ≥ 30), hypercholesterolemia (≥6.2 mmol/L) and low HDL-cholesterol (<1.0 mmol/L in men, <1.3 mmol/L in women) were present in 38%, 21%, and 27% of patients, respectively. A higher standardised dose, an increase of appetite following medication introduction, the type of medication (clozapine or olanzapine > quetiapine or risperidone > lithium or valproate), and the gender were shown to be significantly associated with evolution of BMI. Conclusion: High prevalence of obesity and hypercholesterolemia was found in an out-patient psychiatric population and confirms drug-induced weight gain complications during long-term treatment. The results support the recently published recommendations of monitoring of metabolic side-effects during treatment with atypical antipsychotics. Moreover, the weight gain predictors found in the present study could help to highlight patients with special health care management requirement. [Copyright &y& Elsevier]

Abstract: A simple and sensitive LC–MS method was developed and validated for the simultaneous quantification of aripiprazole (ARI), atomoxetine (ATO), duloxetine (DUL), clozapine (CLO), olanzapine (OLA), sertindole (STN), venlafaxine (VEN) and their active metabolites dehydroaripiprazole (DARI), norclozapine (NCLO), dehydrosertindole (DSTN) and O-desmethylvenlafaxine (OVEN) in human plasma. The above mentioned compounds and the internal standard (remoxipride) were extracted from 0.5mL plasma by solid-phase extraction (mix mode support). The analytical separation was carried out on a reverse phase liquid chromatography at basic pH (pH 8.1) in gradient mode. All analytes were monitored by MS detection in the single ion monitoring mode and the method was validated covering the corresponding therapeutic range: 2–200ng/mL for DUL, OLA, and STN, 4–200ng/mL for DSTN, 5–1000ng/mL for ARI, DARI and finally 2–1000ng/mL for ATO, CLO, NCLO, VEN, OVEN. For all investigated compounds, good performance in terms of recoveries, selectivity, stability, repeatability, intermediate precision, trueness and accuracy, was obtained. Real patient plasma samples were then successfully analysed. [Copyright &y& Elsevier]

Abstract: Background: Genetic variations of the dopamine and opioid receptors could influence the response to methadone maintenance treatment (MMT). Methods: We included 238 MMT patients according to their response to treatment and methadone dosing, along with 217 subjects without substance dependence. All were genotyped for polymorphisms of the dopamine D1, D2, µ-opioid and δ-opioid receptor genes. Results: The polymorphisms of the µ-opioid (118A>G), δ-opioid (921T>C), dopamine D1 (DdeI) and D2 (TaqI A) receptor genes were not associated with response to MMT and methadone dosing, whereas an association was found with the dopamine D2 receptor (DRD2) 957C>T polymorphism. The 957CC carriers were more frequently non-responders to treatment (OR=2.4; p =0.02) and presented a fourfold shorter period of negative urine screening (p =0.02). No significant differences in allele frequencies were observed between the MMT patients and the control group, suggesting no association of the analyzed polymorphisms with opioid dependence. Conclusions: These results suggest that DRD2 genotype may contribute to the understanding of the interindividual variability to the response to MMT. [Copyright &y& Elsevier]

Abstract: The antipsychotic drug clotiapine (Entumine®) has been marketed for more than 35 years, however there is little published data on the therapeutic and toxic concentrations of this drug. To fill this gap, two rapid and sensitive methods were developed for the determination of clotiapine (2-chloro-11-(4-methyl-1-piperazinyl)dibenzo-[b,f][1,4]-thiazepine), in human plasma and post-mortem blood and tissue samples. After simple liquid–liquid extraction at pH 9.5 with n-hexane/dichloromethane (85/15, v/v), clotiapine was quantitated by HPLC-DAD and by GC-NPD. The calibration curve was linear between 10 and 1000μg/L. The limit of detection (LOD) and the limit of quantification (LOQ) were found to be 2 and 6μg/L for the GC-NPD method and 5 and 15μg/L for the HPLC-method, respectively. These methods were applied to 12 plasma samples from patients treated with clotiapine, to seven autopsy cases and to one case of driving under the influence of drugs (DUID). Concentrations ranged for the clotiapine-treated patients between 6 and 155μg/L (mean 46μg/L), and for the autopsy cases between 22 and 341μg/L (mean 123μg/L). [Copyright &y& Elsevier]

Abstract: The effect of aging on steady-state plasma concentrations of citalopram (CIT) and desmethylcitalopram (DCIT) was investigated in 128 depressive patients treated with 10–80 mg/day CIT. They were separated into three groups, with age up to 64 years (mean age±S.D.: 47±12 years; n =48), between 65 and 79 years (72±1 years; n =57), and from 80 years or older (84±1 years; n =23). Body mass index (BMI), renal and hepatic functions were similar in the three groups. A large interindividual variability of plasma levels of CIT (16-fold) and DCIT (12-fold) was measured for a given dose. The mean plasma levels of CIT corrected for a 20 mg daily dose were 55% higher in the very elderly (>=80 years) patients (65±30 ng/ml; p &#60;0.001) and 38% higher in the elderly (65–79 years) patients (58±24 ng/ml; p &#60;0.001) when compared to the adult patients (42±17 ng/ml). DCIT mean plasma level was 38% higher (p &#60;0.05) in the group of very elderly patients (22±10 ng/ml) when compared to the adult patients (16±9 ng/ml). As a consequence, the mean plasma concentration of CIT+DCIT was 48% higher in the very elderly patients (86±36 ng/ml; p &#60;0.001) and 33% higher in the elderly patients (77±28 ng/ml; p &#60;0.001) when compared to the adult patients (58±21 ng/ml). Age correlated significantly with CIT (r=0.43, p &#60;0.001), DCIT (r=0.28, p &#60;0.01), and CIT+DCIT plasma levels (r=0.44, p &#60;0.001), and thus accounts for 18% of the variability of CIT plasma levels, with no influence of gender. The recommended dose reduction of CIT in elderly patients seems therefore justified. [Copyright &y& Elsevier]

We examined in vivo the influence of cytochrome P4503A4 (CYP3A4) activity, measured by the 30 min plasma 1'OH-midazolam/midazolam ratio after oral administration of 7.5 mg midazolam, on the methadone steady-state trough plasma concentrations in a group of 32 patients in methadone maintenance treatment. Patients were grouped as receiving 'low' (up to 99 mg/day, n = 10), 'high' (100-199 mg/day, n = 11) and 'very high' (> or = 200 mg/day, n = 11) doses of methadone, and the CYP3A4 metabolic activity was compared between the three groups. (S)-methadone and (R,S)-methadone, but not (R)-methadone, concentrations to dose ratios significantly correlated with the midazolam ratios (r(2) = -0.17, P = 0.018; r(2) = -0.14, P = 0.032; r(2) = -0.10, P = 0.083, respectively), with a 76% higher CYP3A4 activity in the very high-dose group as compared with the low-dose group. Significant differences in the CYP3A4 activity were calculated between the three groups (P = 0.0036), and group-to-group comparisons, using the Bonferroni correction, showed a significant difference between the low-dose and the very high-dose group (P = 0.0039), between the high-dose and the very high-dose group (P = 0.0064), but not between the low-dose and the high-dose group (P = 0.070). The higher CYP3A4 activity measured in patients receiving very high methadone doses could contribute to the need for higher doses in some patients, due to an increased metabolic clearance. This, however, must be confirmed by a prospective study. [ABSTRACT FROM AUTHOR]