Sarah E. Lammertz

Risperidone-induced extrapyramidal side effects: is the need for anticholinergics the consequence of high plasma concentrations?

Antipsychotic drugs can induce various undesirable adverse motor reactions, such as extrapyramidal side effects (EPS). A widely accepted pharmacodynamic mechanism underlying EPS includes an increase in striatal D2-receptor occupancy. However, less is known about the pharmacokinetic background of EPS. The aim of this study was to analyze in-vivo possible pharmacokinetic patterns underlying biperiden-treated EPS in risperidone (RIS)-medicated patients. A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxyrisperidone (9-OH-RIS) of 2293 adult inpatients and outpatients was analyzed. Two groups were compared: a group receiving RIS (n=772) and a group comedicated with biperiden (n=68). Plasma concentrations, dose-adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS, and active moiety (AM) (RIS+9-OH-RIS) as well as ratios of concentrations for metabolite to parent drug (9-OH-RIS/RIS) were computed. We compared the plasma concentrations of the different compounds between the two groups considering the prescription of biperiden as an indirect report of EPS. The daily dosage of RIS did not differ between groups. No differences were detected in case of plasma concentrations and C/D of RIS and active metabolite between the groups. However, plasma concentrations of the AM were significantly higher in the comedicated group (P=0.032) and showed a trend in terms of the active metabolite 9-OH-RIS (P=0.053). Data indicate enhanced AM plasma concentrations of RIS in patients comedicated with biperiden as an EPS treatment. This might underscore an association between higher plasma concentrations of the AM and treatment-requiring EPS.

Body mass index (BMI) but not body weight is associated with changes in the metabolism of risperidone; A pharmacokinetics-based hypothesis.

OBJECTIVE We sought to unravel the influence of body weight and body mass index (BMI), both consistently reported as pharmacokinetic relevant parameters, on metabolism of risperidone in a naturalistic sample. METHODS Conducting non parametrical tests we sought for correlations between plasma concentrations of RIS, 9-OH-RIS and AM and body weight and BMI in patients out of a therapeutic drug monitoring (TDM) database. Further, we stratified patients to three groups based upon BMI values and compared drug concentrations between groups. RESULTS Although body weight failed to correlate with pharmacokinetic parameters, BMI was positively correlated with plasma concentrations of the active metabolite (9-OH-RIS) (rs=0.121, p=0.002) and active moiety (sum of RIS+9-OH-RIS) (rs=0.128, p=0.001) as well as dose adjusted plasma concentrations of the active moiety (rs=0.08, p=0.04). The comparison of pharmacokinetic parameters between different BMI groups yielded lower plasma concentrations of 9-OH-RIS in patients with low BMI (<20kg/m2) and higher plasma concentrations of the active moiety in obese patients (BMI ≥30kg/m2) when compared with the control group (30>BMI≥20kg/m2). By comparing low vs. high BMI patients, the latter group showed higher 9-OH-RIS plasma concentrations. CONCLUSIONS AND LIMITATIONS Considerable alterations in metabolism of risperidone were detected when comparing obese and cachectic patients with the control group in alignment with the positive correlation between BMI values and plasma concentrations of the active metabolite and active moiety as well as dose adjusted plasma concentrations of the active moiety. We suggest changes in CYP2D6 or CYP3A4 activity or differences in P-glycoprotein function in obese patients with greater BMI as a plausible mechanism underlying these alterations.

Reward: From Basic Reinforcers to Anticipation of Social Cues

Reward processing plays a major role in goal-directed behavior and motivation. On the neural level, it is mediated by a complex network of brain structures called the dopaminergic reward system. In the last decade, neuroscientific researchers have become increasingly interested in aspects of social interaction that are experienced as rewarding. Recent neuroimaging studies have provided evidence that the reward system mediates the processing of social stimuli in a manner analogous to nonsocial rewards and thus motivates social behavior. In this context, the neuropeptide oxytocin is assumed to play a key role by activating dopaminergic reward pathways in response to social cues, inducing the rewarding quality of social interactions. Alterations in the dopaminergic reward system have been found in several psychiatric disorders that are accompanied by social interaction and motivation problems, for example autism, attention deficit/hyperactivity disorder, addiction disorders, and schizophrenia.

Pharmacokinetic considerations in the treatment of hypertension in risperidone-medicated patients – thinking of clinically relevant CYP2D6 interactions

Background: Treatment of arterial hypertension in patients with severe mental illnesses often results in polypharmacy, potentially leading to drug-drug interactions. The objective of the study was to analyse the in vivo inhibitory potential of two antihypertensive drugs, amlodipine and metoprolol on CYP2D6 catalysed 9-hydroxylation of risperidone (RIS). Methods: A therapeutic drug monitoring database with plasma concentrations of RIS and 9-hydroxyrisperidone (9-OH-RIS) of 1584 patients was analysed. Three groups were considered; a group of patients receiving RIS without a potentially cytochrome influencing co-medication (control group, R0, n=852), a group co-medicated with amlodipine (RA, n=27) and a group, co-medicated with metoprolol (RM, n=41). Plasma concentrations, concentration-to-dose ratios (C/Ds) of RIS, 9-OH-RIS and the active moiety (AM), as well as the metabolic ratios were computed and compared using the Kruskal-Wallis test, the Mann-Whitney U test and the Jonckheere-Terpstra test to determine the means and different patterns of distribution of plasma concentrations as well as the concentration-to-dose ratios. Results: The median daily dosage of RIS did not differ between the groups (p=0.708). No differences were found in median plasma concentrations of RIS, 9-OH-RIS and AM. However, concentration-to-dose ratios for RIS, 9-OH-RIS and AM were significantly higher in the amlodipine group (p=0.025, p=0.048 and p=0.005). In the metoprolol group, the concentration-to-dose ratio for RIS was significantly higher than in the control group (p=0.017), while the C/D for 9-OH-RIS and AM was not. Conclusions and limitations: Our data show a potential pharmacokinetic interaction, most likely via CYP3A4 between amlodipine and RIS, reflected in significantly different C/Ds for RIS, 9-OH-RIS and AM. Although the interaction did not result in significantly higher plasma levels, changes in C/Ds and their distribution with regard to the median concentrations were observed.

Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment.

Background The combination of anticonvulsant mood stabilizers with antipsychotic drugs may lead to clinically relevant drug-drug interactions. The objective of the study was to identify pharmacokinetic interactions of different mood stabilizers on the metabolism of risperidone (RIS) under natural conditions. Methods A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxy-RIS (9-OH-RIS) of 1,584 adult patients was analyzed. Four groups (n = 1,072) were compared: a control group without a potentially cytochrome interacting comedication (R0, n = 852), a group comedicated with valproate (VPA) (RVPA, n = 153), a group comedicated with lamotrigine (LMT) (RLMT, n = 46), and a group under concomitant medication with carbamazepine (CBZ) (RCBZ, n = 21). Dose-adjusted plasma concentrations (C/D ratio) for RIS, 9-OH-RIS and active moiety (AM) (RIS + 9-OH-RIS), as well as metabolic ratios (RIS/9-OH-RIS) were computed. Results Groups did not differ with regard to the daily dosage (P = 0.46). Differences were detected for the distributions of the C/D ratios for RIS, 9-OH-RIS and AM (P = 0.003, P < 0.001 and P < 0.001, respectively). Differences remained significant after conducting a Bonferroni correction (P = 0.0125). Pairwise comparisons of the concomitant medication groups with the control group revealed significant differences; RIS C/D ratios were significantly higher in the VPA and the LMT group than in the control group (P = 0.013; P = 0.021). However, these differences did not remain significant after Bonferroni correction. In contrast, CBZ-treated patients showed lower dose-adjusted plasma concentrations of 9-OH-RIS (P < 0.001) as well as the AM (P < 0.001) than the control group; this difference survived the Bonferroni correction. Conclusions The data give evidence for pharmacokinetic interactions between RIS and different anticonvulsant mood stabilizers. Carbamazepine decreased serum concentrations of 9-OH-RIS and the AM when compared with the control group. In case of VPA and LMT, findings were less significant; hints for a weak RIS metabolism inhibition by LMT of unclear clinical significance were found.

Lamotrigine in pregnancy - therapeutic drug monitoring in maternal blood, amniotic fluid, and cord blood

This study is the first to measure and correlate lamotrigine concentrations in maternal blood, amniotic fluid, and umbilical cord blood and account for distribution of the drug between these three compartments. Concentrations of lamotrigine were measured in six mother–infant pairs at the time of delivery. Daily doses of lamotrigine ranged between 200 and 650 mg. Daily doses were correlated with maternal serum and umbilical cord blood concentrations, and serum levels were correlated with levels in amniotic fluid. Lamotrigine levels in serum correlated strongly with the lamotrigine levels in amniotic fluid (r=+0.986, P<0.001) and cord blood (r=+0.928, P=0.008). The penetration ratio into amniotic fluid was in a range between 0.31 and 0.75 (mean 0.58, SD 0.17); the penetration ratio into the fetal circulation, calculated on the basis of umbilical cord blood levels, was found to be in a range between 0.48 and 1.27 (mean 0.81, SD 0.28). Lamotrigine concentrations in amniotic fluid provided evidence that maternally administered lamotrigine is accessible to the fetus in a manner not previously appreciated. Furthermore, the penetration ratio into umbilical cord blood calculated here is in line with the largest study carried out so far to explore transplacental transfer.

Effects of alexithymia and empathy on the neural processing of social and monetary rewards

Empathy has been found to affect the neural processing of social and monetary rewards. Alexithymia, a subclinical condition showing a close inverse relationship with empathy is linked to dysfunctions of socio-emotional processing in the brain. Whether alexithymia alters the neural processing of rewards, which is currently unknown. Here, we investigated the influence of both alexithymia and empathy on reward processing using a social incentive delay (SID) task and a monetary incentive delay (MID) task in 45 healthy men undergoing functional magnetic resonance imaging. Controlling for temperament-character dimensions and rejection sensitivity, the relationship of alexithymia and empathy with neural activity in several a priori regions of interest (ROIs) was examined by means of partial correlations, while participants anticipated and received social and monetary rewards. Results were considered significant if they survived Holm–Bonferroni correction for multiple comparisons. Alexithymia modulated neural activity in several ROIs of the emotion and reward network, both during the anticipation of social and monetary rewards and in response to the receipt of monetary rewards. In contrast, empathy did not affect reward anticipation and modulated ROI activity only in response to the receipt of social rewards. These results indicate a significant influence of alexithymia on the processing of social and monetary rewards in the healthy brain.

Duloxetine enters the brain – But why is it not found in the cerebrospinal fluid

BACKGROUND Antidepressants enter the brain to reach their site of action in a different extent. However, there has been no study to date about duloxetines ability to enter the brain and cerebrospinal fluid. Aim of this study was to measure blood and cerebrospinal fluid concentrations of duloxetine and to account for the distribution between the two compartments. METHODS Concentrations of duloxetine were measured in blood serum and cerebrospinal fluid of 19 patients treated with daily doses of 30-120mg. Daily doses were correlated with serum and cerebrospinal fluid concentrations and serum concentrations were correlated with concentrations in cerebrospinal fluid. RESULTS Serum concentrations of duloxetine showed a moderate but significant correlation with the applied daily dose, r=+0.473, p=0.04. Duloxetine concentrations in the cerebrospinal fluid above the designated limit of quantification of 2.0ng/mL were only found in three of the 19 patients. CONCLUSIONS AND LIMITATIONS Contrasting to own preceding studies on venlafaxine, mirtazapine and citalopram with comparably high concentrations in cerebrospinal fluid, the here presented findings indicate that duloxetine shows a very different distribution pattern. Very low concentrations in the cerebrospinal fluid may be due to the fact that the drug crosses the blood-cerebrospinal fluid barrier much worse than other antidepressants do, suggesting a low ability of duloxetine to enter the brain. Alternatively, low drug concentrations may be interpreted in a sense of a missing residence time in cerebrospinal fluid due to active transport mechanisms out of this environment either back into the bloodstream or into the brain.

Measuring citalopram in blood and central nervous system: revealing a distribution pattern that differs from other antidepressants.

The aim of this study was to measure blood and cerebrospinal fluid concentrations of citalopram and its weakly active N-demethylated metabolite desmethylcitalopram to account for the distribution between the two compartments. The findings are discussed in the context with own preceding studies on the distribution pattern of different antidepressants. Concentrations of citalopram were measured in blood serum and cerebrospinal fluid of 18 patients treated with daily doses of 10–40 mg. Daily doses were correlated with serum and cerebrospinal fluid concentrations, and serum concentrations were correlated with concentrations in cerebrospinal fluid. Serum concentrations of citalopram and desmethylcitalopram showed no significant correlation to the daily dose, r=0.164, P=0.515, and r=0.174, P=0.505, respectively, whereas citalopram concentrations in serum and cerebrospinal fluid were highly correlated (r=0.763, P<0.001). The cerebrospinal fluid/serum ratio for citalopram (total=bound+unbound concentration) varied between 0.14 and 0.86 (mean 0.35, SD 0.16). By correcting the mean cerebrospinal fluid/serum ratio for 80% plasma protein binding, cerebrospinal fluid concentrations of citalopram were on average 77% higher than the calculated unbound serum concentration with a ratio of 1.77 (SD 0.81, range 0.68–4.29). Findings indicate a very good ability of citalopram to cross the blood–brain and cerebrospinal fluid barrier. High concentrations of citalopram in the cerebrospinal fluid are indicative of active transport of citalopram into or missing active transport out of the cerebrospinal fluid. The results suggest a high ability of citalopram to enter the brain with sufficiently high drug concentrations at the target sites within the brain, contributing toward clinical efficacy.

Pharmacokinetic considerations in antipsychotic augmentation strategies : How to combine risperidone with low-potency antipsychotics

Objectives: To investigate in vivo the effect of low‐potency antipsychotics on metabolism of risperidone (RIS). Methods: A therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9‐OH‐RIS of 1584 patients was analyzed. Five groups were compared; a risperidone group (n = 842) and four co‐ medication groups; a group co‐medicated with chlorprothixene (n = 67), a group with levomepromazine (n = 32), a group with melperone (n = 46), a group with pipamperone (n = 63) and a group with prothipendyl (n = 24). Plasma concentrations, dose‐adjusted plasma concentrations (C/D) of RIS, 9‐OH‐RIS and active moiety (RIS + 9‐OH‐RIS; AM) as well as the metabolic ratios (9‐OH‐RIS/RIS; MR) were computed. Results: Differences in plasma concentrations were detected for AM and RIS. Pairwise comparisons revealed significant findings; RIS plasma concentrations were higher in co‐medication groups than in monotherapy group. Chlorprothixene‐ and prothipendyl‐ medicated patients demonstrated no other differences. In the levomepromazine and melperone group plasma and C/D concentrations of AM and RIS were higher, while MRs were lower. For pipamperone, differences included higher C/D values of RIS and lower MRs. Conclusions: Alterations of risperidone metabolism suggest pharmacokinetic interactions for levomepromazine and melperone. In the pipamperone‐group, lower MRs as well as higher plasma and C/D levels of RIS suggest potential interactions. Graphical abstract Figure. No caption available. HighlightsCombining low‐potency antipsychotics with 1st or 2nd generation antipsychotics may lead to pharmacokinetic interactions.Levomepromazine and melperone lead to higher blood concentrations of RIS and 9‐OH‐RIS by inhibiting the CYP2D6 activity.Chlorprothixene, prothipendyl and pipamperone are less likely to lead to risperidone metabolism alterations.