Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Retrospective pilot study for analysis of antidepressant serum concentrations of citalopram and venlafaxine during inflammation.

INTRODUCTION: Inflammation-mediated changes in drug metabolism may increase drug levels in blood and lead to intoxications. The objective of this study was to find out whether elevated serum levels of C-reactive protein (CRP) are associated with increased serum concentrations of the antidepressants citalopram and venlafaxine. METHODS: Therapeutic drug monitoring request forms of psychiatric patients were screened retrospectively. The serum concentrations in relation to the daily doses [(C/D) (ng/ml/mg)] and the metabolic ratios (metabolite/drug) were compared intraindividually under normal (<5 mg/l) and pathological (>5 mg/l) condition by the Wilcoxon signed-rank test. RESULTS: Elevated levels of CRP were not associated with a significant (P>0.05) increase in C/D for citalopram (2.4 ng/ml/mg vs. 2.85 ng/ml/mg, N=15) or in C/D for the active moiety of venlafaxine (1.76 ng/ml/mg vs. 1.68 ng/ml/mg, N=39), compared with normal CRP serum levels. No significant difference in the metabolic ratio was observed in both groups. DISCUSSION: There was no major effect of inflammation on the metabolism of citalopram and venlafaxine. Because of the broad therapeutic indices of these 2 drugs, the drugs seem to be a good choice for the treatment of depression, even if an infection occurs.

SLC6A2 and SLC6A4 variants interact with venlafaxine serum concentrations to influence therapy outcome.

OBJECTIVE: The effects of genetic variants in genes encoding the target structures of antidepressants on the therapeutic efficacy of antidepressant drugs have been investigated with unconclusive results. One possible confounding factor in most studies was the fact that drug serum concentrations had not been determined. METHODS: Within a clinical setting, 56 inpatients suffering from depressive episodes in the context of either major depressive disorder or bipolar affective disorder were studied. Response to venlafaxine was assessed after 4 weeks of treatment and correlated to serum concentration and functional variants in genes encoding the norepinephrine (SLC6A2; rs28386840) and the serotonin transporter (SLC6A4; [5-HTTLPR], rs25531). Symptom change was evaluated using the Clinical Global Impression-Improvement (CGI-I) scale. RESULTS: No association between therapeutic response, venlafaxine serum concentration (active moiety) and rs28386840 was found. In carriers of the high expressing SLC6A4 genotype (lAlA-), a poor response to venlafaxine was found significantly more often. In subsamples stratified for serum concentration this held true for patients with serum concentrations between 201 and 400 ng/mL (n=21), while in patients with sub- (≤ 200 ng/mL; n=12) and supra-recommended (> 400 ng/mL; n=23) concentrations, no significant differences were observed. DISCUSSION: The observed association is consistent with findings of some previous studies, whereas others showed differing results highlighting the need for further investigations.

Effects of gender and age on serum concentrations of antidepressants under naturalistic conditions.

Therapeutic drug monitoring (TDM) data of antidepressant drugs are often evaluated using homogeneous samples of selected individuals without psychiatric or somatic comorbidity. These data may have limitations in transferability to everyday clinical practice. Hence, studies under naturalistic conditions are important to clarify the full clinical relevance of TDM of antidepressants. TDM analyses were retrospectively evaluated for a 3-year period from 2008 to 2010. The influence of gender and age on dose-corrected serum concentrations of antidepressants was examined in a standard clinical setting. 693 TDM analyses of amitriptyline and nortriptyline (AMI + NOR), 160 of citalopram (CIT), 152 of clomipramine and N-clomipramine (CLO + N-CLO), 272 of doxepine and N-doxepine (DOX + N-DOX), 359 of escitalopram (ESC), 198 of fluoxetine and N-fluoxetine (FLU + N-FLU), 92 of maprotiline (MAP), 888 of mirtazapine (MIR), and 77 of sertraline (SER) remained in the sample. Females had significantly higher dose-corrected serum concentrations of AMI + NOR (32 %), CIT (29 %), DOX + N-DOX (29 %), and MIR (20 %), and patients older than 60 years had significantly higher dose-corrected serum concentrations of AMI + NOR (21 %), CIT (40 %), DOX + N-DOX (48 %), MAP (46 %), MIR (24 %), and SER (67 %). Comparing the two extreme groups, females >60 years showed a remarkably higher dose-corrected serum concentration of AMI + NOR (52 %), CIT (78 %), DOX + N-DOX (86 %), and MIR (41 %) in contrast to males ≤60 years. Gender and age have a significant influence on the serum concentrations of different antidepressant drugs, and additive effects must be considered. TDM is recommended to reduce the risk of adverse effects due to supratherapeutic serum levels, also in a naturalistic clinical setting.

Correlation of QTc interval prolongation and serum level of citalopram after intoxication--a case report.

Citalopram (CIT) is a widely used antidepressant which acts by a selective serotonin reuptake inhibition. It is considered to be safer than tricyclic antidepressants at therapeutic levels, but also with respect to intoxications. We report the case of a 46-year-old woman, who ingested in suicidal intention 1400 mg CIT. During the following inpatient treatment repeatedly ECGs and determinations of the serum level of CIT were performed. Initially the patient's serum level of CIT was 1231 ng/mL and QTc interval was 541.60 ms. It took 12 days until the serum level of CIT fell below the upper threshold of the recommended therapeutic range (130 ng/mL). The QTc interval on the sixth day after the intoxication for the first time was below 500 ms. The QTc interval correlated significantly with the serum level of CIT after intoxication (r=0.943; p<0.005). Although CIT is estimated as a safe antidepressant regarding serious adverse effects, toxic doses can lead to potentially hazardous ECG changes which according to our findings correlate strongly with the serum level of the drug.

The effect of age, sex, smoking and co-medication on serum levels of venlafaxine and O-desmethylvenlafaxine under naturalistic conditions.

INTRODUCTION: Venlafaxine (VEN) is a modern antidepressant which exerts both serotonin and norepinephrine reuptake inhibition. In this study we examined the influence of age, sex, smoking, and co-medication on serum levels of VEN and its metabolite O-desmethylvenlafaxine (ODVEN) in patients treated with VEN under naturalistic conditions. METHODS: We retrospectively evaluated 478 TDM analyses of VEN requested in the Pychiatric University Hospitals of Mainz, Regensburg, and Würzburg. The determination of serum levels was performed by virtually identical chromatographic methods in the TDM laboratories of the participating hospitals. RESULTS: Serum levels varied widely on each dose level. Women had about 30% higher dose-corrected serum levels of VEN and ODVEN than men (p<0.01), and patients older than 60 years showed about 46% higher levels of both compounds than younger ones (p<0.01). In smokers, mean serum levels of ODVEN were 21% lower than in non-smokers. Combining these variables a considerable increase of the differences between the subgroups was found indicating an additive effect. ANOVA over the 8 different groups was significant for ODVEN (p<0.01) and sum (p<0.01), but not for VEN (n.s.). Co-medication with other psychotropic drugs was associated with a decreasing ODVEN/VEN ratio indicating a reduced metabolism in patients receiving polypharmacy. DISCUSSION: These findings show that TDM is useful to identify factors affecting the pharmacokinetic properties of VEN. It is concluded that sex, age and smoking should be considered for optimal dosing of patients with VEN.

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants.

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

Therapeutic drug monitoring of tricyclic antidepressants in everyday clinical practice.

Data about therapeutic drug monitoring (TDM) of psychotropic medications are often obtained from samples of highly selected individuals, who may not be representative for the average psychiatric patient. These data therefore may have limitations with regard to their transferability to everyday clinical practice. Therefore studies under naturalistic conditions are important to clarify the full clinical relevance of TDM. We retrospectively evaluated all TDM-analyses of the tricyclic antidepressants (TCA) amitriptyline and clomipramine during a 12-month period in an unselected sample of patients in a standard clinical setting. We especially examined the relationship between serum levels on one hand and clinical response and adverse effects on the other hand. In patients with amitriptyline, responders showed a significantly higher serum level than non-responders, whereas in patients with clomipramine a serum level within the recommended therapeutic range was associated with clinical response. We also found significantly higher serum concentrations in patients with adverse effects compared to patients without adverse effects in the clomipramine group. No such relationship could be shown in patients treated with amitriptyline. Our results suggest that therapeutic ranges in naturalistic settings in some ways differ from those obtained in controlled clinical settings and that TDM studies in everyday clinical practice are necessary and beneficial.

Antidepressant effects of augmentative transcranial magnetic stimulation: randomised multicentre trial.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a new treatment option for depression. Previous studies were performed with low sample sizes in single centres and reported heterogeneous results. AIMS: To investigate the efficacy of rTMS as augmentative treatment in depression. METHOD: In a randomised, double-blind, sham-controlled multicentre trial 127 patients with moderate to severe depressive episodes were randomly assigned to real or sham stimulation for 3 weeks in addition to simultaneously initiated antidepressant medication. RESULTS: We found no difference in the responder rates of the real and the sham treatment groups (31% in each) or in the decrease of the scores on the depression rating scales. CONCLUSIONS: The data do not support previous reports from smaller samples indicating an augmenting or accelerating antidepressant effect of rTMS. Further exploration of the possible efficacy of other stimulation protocols or within selected sub-populations of patients is necessary.