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Purpose Roux-en-Y gastric bypass (RYGB) involves alterations of the gastrointestinal tract resulting in altered absorption. Patients with obesity have a higher prevalence of depression, and antidepressants are often prescribed. Alterations caused by RYGB could modify drug bioavailability and cause potential subtherapeutic plasma concentrations, increasing the risk of depressive relapse. The aim of this study was to describe the evolution of trough drug dose-normalized antidepressant plasma concentrations before and after RYGB. Materials and Methods This naturalistic prospective case series considers patients with trough plasma concentrations in a 1-year timeframe before and after RYGB. Only antidepressants prescribed to at least three patients were included in the present study. Results Thirteen patients (n = 12 females, median age 44 years, median BMI before intervention = 41.3 kg/m2) were included. Two patients were treated concurrently with fluoxetine and trazodone; the remaining patients were all treated with antidepressant monotherapy. Therapeutic drug monitoring (TDM) values for duloxetine (n = 3), escitalopram (n = 4), fluoxetine (n = 4), and trazodone (n = 4) before (median 4.7 weeks) and after (median 21.3 weeks) RYGB intervention were analyzed. Compared to preintervention, median [interquartile range] decreases in dose-normalized trough plasma concentrations for duloxetine (33% [− 47; − 23]), escitalopram (43% [− 51; − 31]), fluoxetine (9% [− 20; 0.2]), and trazodone (16% [− 29; 0.3]) were observed. Conclusion This study shows a decrease in plasma antidepressant concentrations following RYGB. TDM before and after RYGB, in addition to close monitoring of psychiatric symptomatology, may help optimize antidepressant treatment after bariatric surgery. These results also highlight the need for prospective studies assessing the clinical evidence available through TDM in these patients. Graphical Abstract

Patients suffering from mental disorders are at high risk of developing cardiovascular diseases, leading to a reduction in life expectancy. Genetic variants can display greater influence on cardiometabolic features in psychiatric cohorts compared to the general population. The difference is possibly due to an intricate interaction between the mental disorder or the medications used to treat it and metabolic regulations. Previous genome wide association studies (GWAS) on antipsychotic-induced weight gain included a low number of participants and/or were restricted to patients taking one specific antipsychotic. We conducted a GWAS of the evolution of body mass index (BMI) during early (i.e., ≤ 6) months of treatment with psychotropic medications inducing metabolic disturbances (i.e., antipsychotics, mood stabilizers and some antidepressants) in 1135 patients from the PsyMetab cohort. Six highly correlated BMI phenotypes (i.e., BMI change and BMI slope after distinct durations of psychotropic treatment) were considered in the analyses. Our results showed that four novel loci were associated with altered BMI upon treatment at genome-wide significance (p −8): rs7736552 (near MAN2A1), rs11074029 (in SLCO3A1), rs117496040 (near DEFB1) and rs7647863 (in IQSEC1). Associations between the four loci and alternative BMI-change phenotypes showed consistent effects. Replication analyses in 1622 UK Biobank participants under psychotropic treatment showed a consistent association between rs7736552 and BMI slope (p = 0.017). These findings provide new insights into metabolic side effects induced by psychotropic drugs and underline the need for future studies to replicate these associations in larger cohorts.

This article provides an overview of the pharmacokinetic drug-drug interactions (DDIs) for agents prescribed for attention-deficit/hyperactivity disorder (ADHD). Polypharmacy in the treatment of patients with ADHD leads to high exposures to DDIs and possibly adverse safety outcomes. We performed a systematic search of DDI reports for ADHD agents in Embase and Medline. We also searched for agents in the pharmacological pipeline, which include (1) mazindol, molindone and viloxazine, which were previously prescribed for other indications; (2) centanafadine and AR-08, never before approved; and (3) two extracts (Polygala tenuifolia extract and the French maritime pine bark extracts). The identified literature included case reports, cross-sectional, cross-over and placebo-controlled studies of patient cohorts and healthy volunteers. The DDIs were classified as follows: ADHD agents acting as perpetrators, i.e., affecting the clearance of co-prescribed agents (victim drugs), or ADHD agents being the victim drugs, being affected by other agents. Ratios for changes in pharmacokinetic parameters before and after the DDI were used as a rough estimate of the extent of the DDI. Alcohol may increase plasma dextroamphetamine concentrations by presystemic effects. Until studies are done to orient clinicians regarding dosing changes, clinicians need to be aware of the potential for cytochrome P450 (CYP) 2D6 inhibitors to increase amphetamine levels, which is equivalent to increasing dosages. Atomoxetine is a wide therapeutic window drug. The CYP2D6 poor metabolizers who do not have CYP2D6 activity had better atomoxetine response, but also an increased risk of adverse effects. CYP2D6 inhibitors have been used to increase atomoxetine response in CYP2D6 extensive metabolizers. Guanfacine is mainly metabolized by CYP3A4, which can be induced and inhibited. The package insert recommends that in guanfacine-treated patients, after adding potent CYP3A4 inducers, the guanfacine dose should be doubled; after adding potent CYP3A4 inhibitors the guanfacine dose should be halved. Based on a phenobarbital case report and our experience with CYP3A4-metabolized antipsychotics, these correction factors may be too low. According to two case reports, carbamazepine is a clinically relevant inducer of methylphenidate (MPH). A case series study suggested that MPH may be associated with important elevations in imipramine concentrations. Due to the absence of or limitations in the data, no comments for clinicians can be provided on the pharmacokinetic DDIs for clonidine, centanafadine, mazindol, molindone, AR-08, P. tenuifolia extract and the French maritime pine bark extracts. According to currently available data, clinicians should not expect that ADHD drugs modify each other's serum concentrations. A summary table for clinicians provides our current recommendations on pharmacokinetic DDIs of ADHD agents based on our literature review and the package inserts; whenever it was possible, we provide information on serum concentrations and dose correction factors. There will be a need to periodically update these recommendations and these correction factors as new knowledge becomes available.

Metabolic syndrome after transplantation is a major concern following solid organ transplantation (SOT). The CREB-regulated transcription co-activator 2 (CRTC2) regulates glucose metabolism. The effect of CRTC2 polymorphisms on new-onset diabetes after transplantation (NODAT) was investigated in a discovery sample of SOT recipients (n1=197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS, n2=1294 and n3=759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (n4=46'186, n5=123'865, n6>100,000) were finally analyzed. In the discovery sample, CRTC2 rs8450-AA genotype was associated with NODAT, fasting blood glucose and body mass index (PcorrectedA was significantly associated with several metabolic abnormalities. CRTC2 rs8450G>A appears to have an important role in the high prevalence of metabolic traits observed in patients with SOT. A weak association with metabolic traits was also observed in the population-based samples.The Pharmacogenomics Journal advance online publication, 8 December 2015; doi:10.1038/tpj.2015.82.

Background Caffeine intake is generally estimated by self-reported consumption, but it remains unclear how well self-report associates with metabolite urinary excretion. We investigated the associations of self-reported consumption of caffeinated drinks with urinary excretion of caffeine and its major metabolites in an adult population. Methods We used data from the population-based Swiss Kidney Project on Genes in Hypertension (SKIPOGH) study. Consumption of caffeinated coffee, decaffeinated coffee and other caffeinated beverages was assessed by self-administered questionnaire. Quantification of caffeine, paraxanthine, theobromine and theophylline was performed by ultra-high performance liquid chromatography tandem mass spectrometry in 24-h urine. Association of reported consumption of caffeinated drinks with urinary caffeine derived metabolites was determined by quantile regression. We then explored the association between urinary metabolite excretion and dichotomized weekly consumption frequency of caffeinated coffee, with Receiver Operator Characteristic (ROC) analysis. Results In the present analysis, we included 598 individuals (52% women, mean age =46 ± 17 years). Self-reported caffeinated coffee intake was positively associated with 24-h urinary excretions of paraxanthine, theophylline and caffeine (p

Cytochrome P4501A2 (CYP1A2) is involved in the metabolism of several drugs and is induced by smoking. We aimed to determine the interindividual change in CYP1A2 activity after smoking cessation and to relate it to CYP1A2 genetic polymorphisms. CYP1A2 activity was determined from the paraxanthine:caffeine ratio in 194 smokers and in 118 of them who had abstained from smoking during a 4-week period. The participants were genotyped for CYP1A2*1F, *1D, and *1C polymorphisms. Smokers had 1.55-fold higher CYP1A2 activity than nonsmokers (P < 0.0001). The individual change in CYP1A2 activity after smoking cessation ranged from 1.0-fold (no change) to a 7.3-fold decrease in activity. In five participants with low initial CYP1A2 activity, an increase was observed after smoking cessation. Before smoking cessation, the following factors were found to influence CYP1A2 activity: CYP1A2*1F (P = 0.005), CYP1A2*1D (P = 0.014), the number of cigarettes/day (P = 0.012), the use of contraceptives (P < 0.001), and -163A/-2467T/-3860G haplotype (P = 0.002). After quitting smoking, only CYP1A2*1F (P = 0.017) and the use of contraceptives (P = 0.05) had an influence. No influence of CYP1A2 polymorphisms on the inducibility of CYP1A2 was observed.

Background and Objective Recent in vitro studies have suggested an important role of cytochrome P450 (CYP) 2B6 and CYP2C19 in methadone metabolism. We aimed to determine the influence of CYP2B6, CYP2C9, and CYP2C19 genetic polymorphism on methadone pharmacokinetics and on the response to treatment. Methods We included 209 patients in methadone maintenance treatment on the basis of their response to treatment and their daily methadone dose. Patients were genotyped for CYP2B6, CYP2C9, and CYP2C19. Steady-state trough and peak (R)-, (S)-, and (R,S)-plasma levels and peak-to-trough plasma level ratios were measured. Results CYP2B6 genotype influences (S)-methadone and, to a lesser extent, (R)-methadone plasma levels, with the median trough (S)-methadone plasma levels being 105, 122, and 209 ng · kg/mL · mg for the noncarriers of allele *6, heterozygous carriers, and homozygous carriers (*6/*6), respectively (P = .0004). CYP2C9 and CYP2C19 genotypes do not influence methadone plasma levels. Lower peak and trough plasma levels of methadone and higher peak-to-trough ratios were measured in patients considered as nonresponders [median (R,S)-methadone trough plasma levels of 183 and 249 ng · kg/mL · mg (P = .0004) and median peak-to-trough ratios of 1.82 and 1.58 for high-dose nonresponders and high-dose responders, respectively (P = .0003)]. Conclusion Although CYP2B6 influences (S)-methadone plasma levels, given that only (R)-methadone contributes to the opioid effect of this drug, a major influence of CYP2B6 genotype on response to treatment is unlikely and has not been shown in this study. Lower plasma levels of methadone in nonresponders, suggesting a higher clearance, and higher peak-to-trough ratios, suggesting a shorter elimination half-life, are in agreement with the usual clinical measures taken for such patients, which are to increase methadone dosages and to split the daily dose into several intakes. Clinical Pharmacology & Therapeutics (2005) 78, 593–604; doi: 10.1016/j.clpt.2005.08.011

A dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment. The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p

BACKGROUND AND OBJECTIVES: Cytochrome P450 (CYP) 3A4 is the main CYP isozyme involved in methadone metabolism. We investigated the influence of grapefruit juice, which contains inhibitors of intestinal CYP3A, on the steady-state pharmacokinetics of methadone. METHODS: For 5 days, 8 patients undergoing methadone maintenance treatment received 200 mL water or grapefruit juice 30 minutes before and again together with their daily dose of methadone. Blood sampling for R-, S-, and R,S-methadone plasma determination was performed over a 24-hour period. CYP3A activity was determined by measuring the plasma 1'-hydroxymidazolam/midazolam ratio. RESULTS: A decrease in the midazolam ratio was measured in all patients after grapefruit juice (mean +/- SD before grapefruit juice, 9.3 +/- 5.9; mean +/- SD after grapefruit juice, 3.9 +/- 1.2; P

Methadone is widely used for the treatment of opioid dependence. Although in most countries the drug is administered as a racemic mixture of (R)- and (S)- methadone, (R)-methadone accounts for most, if not all, of the opioid effects. Methadone can be detected in the blood 15-45 minutes after oral administration, with peak plasma concentration at 2.5-4 hours. Methadone has a mean bioavailability of around 75% (range 36-100%). Methadone is highly bound to plasma proteins, in particular to alpha(1)-acid glycoprotein. Its mean free fraction is around 13%, with a 4-fold interindividual variation. Its volume of distribution is about 4 L/kg (range 2-13 L/kg). The elimination of methadone is mediated by biotransformation, followed by renal and faecal excretion. Total body clearance is about 0.095 L/min, with wide interindividual variation (range 0.02-2 L/min). Plasma concentrations of methadone decrease in a biexponential manner, with a mean value of around 22 hours (range 5-130 hours) for elimination half-life. For the active (R)-enantiomer, mean values of around 40 hours have been determined. Cytochrome P450 (CYP) 3A4 and to a lesser extent 2D6 are probably the main isoforms involved in methadone metabolism. Rifampicin (rifampin), phenobarbital, phenytoin, carbamazepine, nevirapine, and efavirenz decrease methadone blood concentrations, probably by induction of CYP3A4 activity, which can result in severe withdrawal symptoms. Inhibitors of CYP3A4, such as fluconazole, and of CYP2D6, such as paroxetine, increase methadone blood concentrations. There is an up to 17-fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of CYP enzymes accounts for a large part of this variation. Since methadone probably also displays large interindividual variability in its pharmacodynamics, methadone treatment must be individually adapted to each patient. Because of the high morbidity and mortality associated with opioid dependence, it is of major importance that methadone is used at an effective dosage in maintenance treatment: at least 60 mg/day, but typically 80-100 mg/day. Recent studies also show that a subset of patients might benefit from methadone dosages larger than 100 mg/day, many of them because of high clearance. In clinical management, medical evaluation of objective signs and subjective symptoms is sufficient for dosage titration in most patients. However, therapeutic drug monitoring can be useful in particular situations. In the case of non-response trough plasma concentrations of 400 microg/L for (R,S)-methadone or 250 microg/L for (R)-methadone might be used as target values.

This work is to investigate the on-line control of the fermentation by Arthrobacter viscosus. This species of bacteria can secrete penicillin acylase which is a key enzyme in pharmaceutical industry. The growth of more cells during the fermentation will obtain more enzyme. Both the enzyme activity and the cell growth are rather sensitive to the change of pH. Once the pH during a fermentation is not properly controlled, the decay of cells' activity will irreversibly occur. Two peristaltic pumps for supplying acidic and basic solutions, respectively, were connected for the regulation of pH. With superior ability in identification and prediction of dynamic time series, recurrent backpropagation network (RBPN), instead of conventional controllers, was used as the adaptive controller model for the fermentation with dynamic characteristics. Based on a 1-3-1 BPN, a corresponding 4-4-1 RBPN was determined. The deviation of the pH measured at current time from the set point of 7.0, denoted as Δ pH(t), was chosen as the input node of the network controller. The output node of this network controller was the predicted flow rate of the peristaltic pump for next control time interval. Such a model was operated by two phases. During the first phase, the network was set as the process model and trained by a fixed set of on-line acquired data. During the second phase, the network was stopped learning and switched to become a predictor, the predicted control action was hence obtained. The optimum sampling time was determined experimentally. To enhance the effective computation of this network, the number of training data was limited. A moving-window type of supplying training data to the network was applied for the on-line learning. The window size was also determined for each learning. With properly chosen network parameters as well as operation conditions, pH of the fermentation was thus well controlled by the RBPN controller.

Methods: Twenty-two patients receiving (R)-methadone maintenance treatment were switched to a double dose of (R, S)-methadone: blood samples were collected before and after the change, and the concentrations of the enantiomers were measured. In the second period, during racemic methadone treatment, important interindividual variability in the stereoselective disposition of the enantiomers of methadone was measured, with (R)/(S) ratios ranging from 0.63 to 2.40. This point should be taken into account particularly with respect to therapeutic drug monitoring of racemic methadone. Results: A significant decrease P < 0.005 in the mean serum concentration/dose ratios of the active (R)-enantiomer before and after the change was measured (mean 3.97 and 3.33). Conclusion: Although of small amplitude (16%), this decrease confirms previously described adaptive changes in methadone pharmacokinetics during racemic methadone maintenance treatment and may necessitate, in some patients, a dose adjustment.

Concentrations of total (R) + (S) and of the enantiomers (R) and (S) of thioridazine and metabolites were measured in 21 patients who were receiving 100 mg thioridazine for 14 days and who were comedicated with moclobemide (450 mg/day). Two patients were poor metabolizers of dextromethorphan and one was a poor metabolizer of mephenytoin. Cytochrome P450IID6 (CYP2D6) is involved in the formation of thioridazine 2-sulfoxide (2-SO) from thioridazine and also probably partially in the formation of thioridazine 5-sulfoxide (5-SO), but not in the formation of thioridazine 2-sulfone (2-SO2) from thioridazine 2-SO. Significant correlations between the mephenytoin enantiomeric ratio and concentrations of thioridazine and metabolites suggest that cytochrome P450IIC19 could contribute to the biotransformation of thioridazine into yet-unknown metabolites, other than thioridazine 2-SO, thioridazine 2-SO2, or thioridazine 5-SO. An enantioselectivity and a large interindividual variability in the metabolism of thioridazine have been shown: measured (R)/(S) ratios of thioridazine, thioridazine 2-SO fast eluting (FE), thioridazine 2-SO slow eluting (SE), thioridazine 2-SO (FE+SE), thioridazine 2-SO2, thioridazine 5-SO(FE), and thioridazine 5-SO(SE) were (mean +/- SD) 3.48 +/- 0 .93 (range, 2.30 to 5.80), 0.45 +/- 0.22 (range, 0.21 to 1.20), 2.27 +/- 8.1 (range, 6.1 to 40.1), 4.64 +/- 0.68 (range, 2.85 to 5.70), 3.26 +/- 0.58 (range, 2.30 to 4.30), 0.049 +/- 0.019 (range, (0.021 to 0.087), and 67.2 +/- 66.2 (range, 16.8 to 248), respectively. CYP2D6 is apparently involved in the formation of (S)-thioridazine 2-SO(FE), (R)-thioridazine 2-SO(SE), and also probably (S)-thioridazine 5-SO(FE) and (R)-thioridazine 5-SO(SE).

The plasma concentrations of α1-acid glycoprotein (AAG), albumin, triglycerides, cholesterol, and total proteins, as well as the plasma binding of racemic, d-methadone, and 1-methadone were measured in 45 healthy subjects. The AAG phenotypes and the concentrations of AAG variants were also determined. The measured free fractions for racemic, d-methadone, and 1-methadone were, respectively, 12.7% ± 3.3%, 10.0% ± 2.9%, and 14.2% ± 3.2% (mean ± SD). A significant correlation was obtained between the binding ratio (B/F) for dl-methadone and the total AAG concentration (r = 0.724;p < 0.001). A multiple stepwise regression analysis showed that AAG was the main explanatory variable for the binding of the racemate. When concentrations of AAG variants were considered, a significant correlation was obtained between the binding ratio of dl-methadone and orosomucoid2 A concentration (r = 0.715; p < 0.001), a weak correlation between dl-methadone and orosomucoidl S concentration (r = 0.494; p < 0.001), and no correlation between dl-methadone and orosomucoidl F1 concentration (r = 0.049; not significant). Similar findings were obtained with the enantiomers. This study shows the importance of considering not only total AAG but also concentrations of AAG variants when measuring the binding of methadone and possibly of other drugs in plasma. Clinical Pharmacology and Therapeutics (1990) 47, 338–346; doi:10.1038/clpt.1990.37

OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P

In this issue of Critical Care, Megarbane and colleagues present a case report of methadone-induced respiratory depression and conduct a toxicokinetic/toxicodynamic evaluation. An opioid-dependent patient receiving methadone maintenance treatment (daily dose 70 mg) was found unconscious after ingesting 240 mg methadone and 2 mg flunitrazepam. Significant improvement in consciousness was achieved after an intravenous bolus of 0.3 mg naloxone followed by a continuous infusion of naloxone at 0.3 mg/hour. In patients receiving methadone maintenance treatment, an occasional intake of two to four times the usual daily dose of methadone is not an exceptional occurrence. However, few such patients experience episodes of life-threatening respiratory depression. Here, we discuss whether recent pharmacogenetic data could help us to understand interindividual variability in sensitivity to respiratory depression and, ultimately, to predict which patients are most likely to be affected.