Michael Paulzen

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017

Authors C. Hiemke1, 2, N. Bergemann3, H. W. Clement4, A. Conca5, J. Deckert6, K. Domschke7, G. Eckermann8, K. Egberts9, M. Gerlach9, C. Greiner10, G. Gründer11, E. Haen12, U. Havemann-Reinecke13, G. Hefner14, R. Helmer15, G. Janssen16, E. Jaquenoud17, G. Laux18, T. Messer19, R. Mössner20, M. J. Müller21, M. Paulzen11, B. Pfuhlmann22, P. Riederer6, A. Saria23, B. Schoppek24, G. Schoretsanitis25, M. Schwarz26, M. Silva Gracia12, B. Stegmann12, W. Steimer27, J. C. Stingl10, M. Uhr28, S. Ulrich29, S. Unterecker6, R. Waschgler30, G. Zernig23, 31, G. Zurek32, P. Baumann33

Therapeutic plasma concentrations of antidepressants and antipsychotics: lessons from PET imaging.

Therapeutic Drug Monitoring (TDM) of psychotropic drugs is strongly depending on the validity of recommended therapeutic plasma concentration reference ranges. Rational pharmacotherapy is based on the assumption that plasma concentrations are directly related to target occupancy by the respective drug. Here we show that positron emission tomography (PET) of molecular drug targets in the brain (neuroreceptors and transporters) allows for establishment of these relationships, thereby providing guidance for TDM services. Associations between brain target occupancy, plasma concentrations, and clinical effects and adverse reactions will be discussed for the most commonly used antidepressant and antipsychotic drugs.

Cariprazine, a new, orally active dopamine D2/3 receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression

Cariprazine is a novel drug with partial agonist activity at dopamine D2/3 receptors and six- to eightfold higher affinity for human dopamine D3 over D2 receptors. Results from several placebo-controlled Phase II/III trials in patients with a The Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of schizophrenia or bipolar I disorder suggest that cariprazine is superior to placebo with respect to antipsychotic and antimanic activity. Reports concerning safety and tolerability of cariprazine are mainly favorable, although the rates of treatment-associated adverse events, which most commonly included akathisia and extrapyramidal symptom, are rather high. However, only minor alterations of clinical laboratory values, prolactin concentrations and ECG parameters are reported in cariprazine-treated patients. A new drug application to the U.S. F DA for cariprazine for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar I disorder was submitted in November 2012. A more precise assessment of the clinical properties of this new drug will require additional studies, aimed to compare and contrast cariprazine with other antipsychotic agents.

Opiate-Induced Dopamine Release Is Modulated by Severity of Alcohol Dependence: An [18F]Fallypride Positron Emission Tomography Study

BACKGROUND Preclinical data implicate the reinforcing effects of alcohol to be mediated by interaction between the opioid and dopamine systems of the brain. Specifically, alcohol-induced release of β-endorphins stimulates μ-opioid receptors (MORs), which is believed to cause dopamine release in the brain reward system. Individual differences in opioid or dopamine neurotransmission have been suggested to be responsible for enhanced liability to abuse alcohol. In the present study, a single dose of the MOR agonist remifentanil was administered in detoxified alcohol-dependent patients and healthy control subjects to mimic the β-endorphin-releasing properties of ethanol and to assess the effects of direct MOR stimulation on dopamine release in the mesolimbic reward system. METHODS Availability of D(2/3) receptors was assessed before and after single-dose administration of the MOR agonist remifentanil in 11 detoxified alcohol-dependent patients and 11 healthy control subjects with positron emission tomography with the radiotracer [(18)F]fallypride. Severity of dependence as assessed with the Alcohol Use Disorders Identification Test was compared with remifentanil-induced percentage change in [(18)F]fallypride binding (Δ%BP(ND)). RESULTS The [(18)F]fallypride binding potentials (BP(ND)s) were significantly reduced in the ventral striatum, dorsal putamen, and amygdala after remifentanil application in both patients and control subjects. In the patient group, ventral striatum Δ%BP(ND) was correlated with the Alcohol Use Disorders Identification Test score. CONCLUSIONS The data provide evidence for a MOR-mediated interaction between the opioid and the dopamine system, supporting the assumption that one way by which alcohol unfolds its rewarding effects is via a MOR-(γ-aminobutyric acid)-dopamine pathway. No difference in dopamine release was found between patients and control subjects, but evidence for a patient-specific association between sensitivity to MOR stimulation and severity of alcohol dependence was found.

Drug interaction can lead to undetectable serum concentrations of quetiapine in the presence of carbamazepine.

To the Editor: Quetiapine and carbamazepine are frequently used as mood stabilizers in the pharmacological therapy for bipolar affective and schizoaffective disorders. It is not uncommon that patients receive a combination of both. In the treatment of epilepsy, the 2 drugs are sometimes coadministered when psychotic symptoms are present. Significant interaction of both substances has been reported in some patients but has not found broad attention in clinical routine yet. Carbamazepine and phenytoin are potent inductors of the cytochrome P450 isoform 3A4 (CYP3A4) enzyme, which is mainly responsible for the metabolism of quetiapine. Because of an accelerated elimination, low quetiapine serum concentrations were described in patients receiving carbamazepine. Here we report 3 examples showing that at least in some patients, quetiapine serum levels can be completely extinguished in the presence of carbamazepine. This combination of drugs should therefore either be avoided or only be applied when therapeutic drug monitoring is available. A 44-year-old woman with a 25year-long history of a schizoaffective disorder was admitted to our hospital because of an exacerbation of psychotic symptoms mainly consisting of agitation, nervousness, and permanent stimulus satiation. She had been treated with 8 mg/d of risperidone as antipsychotic, 600 mg of carbamazepine as mood stabilizer, and 10 mg of zolpidem. We decided to replace risperidone by quetiapine considering that a higher dosage might be necessary in the presence of carbamazepine. Seven days after reaching the target dose of 700 mg/d of quetiapine, the substance was not detectable in the serum of the patient, although she had taken the medication under strict observance of the nurses (test sensitivity, 25 Hg/L). We continued to administer a daily dose of 700 mg of quetiapine for another week, but again found no quetiapine in the serum. Clinically, the psychopathological condition of the patient remained unchanged. This led us to change the pharmacological therapy. We stopped to administer risperidone, carbamazepine, and zolpidem, and switched to lithium without changing the quetiapine dosage. Under this new therapeutic regimen, we noticed a steady increase of the quetiapine serum concentration (Fig. 1). In the following weeks, the patient clinically improved significantly and was finally able to be discharged from our ward. Two other patients had been treated with carbamazepine for many years because of epilepsy (400 and 800 mg, blood concentrations in therapeutic range). In the first case, 600 mg of quetiapine was added when psychotic depression occurred. In the second case, behavioral disturbances in alcohol dementia were treated with 700 mg of the drug. Although quetiapine was administered under careful ward for more than 2 weeks in both patients, measurable serum levels of quetiapine could also not be detected. Quetiapine has 2 major metabolic pathways, including sulfoxidation and oxidation. The sulfoxide metabolite involves CYP3A4. The enzyme also plays an important role in the metabolism of carbamazepine. We assume that an induction of CYP3A4 was responsible for the negative serum levels of quetiapine. Because zolpidem in our first example is indeed a substrate of CYP3A4 but not an inductor, and risperidone is neither a substrate nor an inductor, carbamazepine is regarded as the most likely cause. In summary, we would like to report that carbamazepine can completely extinguish quetiapine serum concentrations despite high dosages. This effect has enormous clinical relevance because patients might take medication for years without any advantage. In cases when the 2 drugs need to be combined, therapeutic drug monitoring is essential.

Amisulpride-induced hyperprolactinaemia is not reversed by addition of aripiprazole

Hyperprolactinaemia is a well-recognized neuroendocrine response to antipsychotics (Grunder et al., 1999). Both typical and ‘atypical’ antipsychotics have the potential to elevate serum prolactin levels due to their dopamine D2 receptor antagonism (Turrone et al., 2002) ‘Atypical’ antipsychotics with higher dopamine D2 receptor affinities such as risperidone (David et al., 2000) are associated with more pronounced elevation of serum prolactin than those with intermediate or lower affinity such as olanzapine, clozapine, and quetiapine (David et al., 2000). Substituted benzamide antipsychotics such as amisulpride belong to the class of drugs with the strongest potency for prolactin elevation. On the other hand, the partial agonist antipsychotic, aripiprazole, has been shown to lower serum prolactin below placebo levels when it is used as a single agent (Keck et al., 2003).

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.

Venlafaxine and O-Desmethylvenlafaxine Concentrations in Plasma and Cerebrospinal Fluid

OBJECTIVE To investigate whether drug concentrations of venlafaxine and its metabolite O-desmethylvenlafaxine in plasma can be considered as a surrogate marker of concentrations in brain/cerebrospinal fluid (CSF). METHOD For therapeutic drug monitoring purposes, plasma and CSF concentrations of venlafaxine and O-desmethylvenlafaxine were measured between November 2011 and August 2013 in 16 depressive inpatients (ICD-10 diagnoses) who were treated with daily doses of venlafaxine extended release (dose range, 75-225 mg). Daily doses were correlated with plasma and CSF levels. The correlation between venlafaxine, O-desmethylvenlafaxine, and the active moiety (AM) in plasma and CSF was calculated. RESULTS Venlafaxine in plasma (P = .005) and CSF (P = .023) correlated significantly with the daily dose, while O-desmethylvenlafaxine and the active moiety (AM = venlafaxine + O-desmethylvenlafaxine) did not. The correlation between venlafaxine, O-desmethylvenlafaxine, and the AM in plasma and CSF was highly significant (P < .001). The calculated CSF/plasma ratio was 0.74 for venlafaxine, 0.88 for O-desmethylvenlafaxine, and 0.84 for the AM. CONCLUSIONS Venlafaxine and O-desmethylvenlafaxine were found to penetrate well into CSF in patients, which indicated good availability of the drug in the brain, although the findings on CSF concentrations do not allow calculation of concentrations at the target structure within the brain. CSF/plasma ratios for venlafaxine and its metabolite were high probably due to low plasma protein binding. The poor correlation of dose to concentrations in body fluids and the highly significant correlation of plasma to CSF concentrations indicate that plasma concentration is a much better marker of drug concentration in brain than the dose.

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.

Plasma levels and cerebrospinal fluid penetration by duloxetine in a patient with a non-fatal overdose during a suicide attempt

Duloxetine is a potent and selective inhibitor of serotonin and norepinephrine reuptake with weak activity on dopamine reuptake (Wong et al. 1993). Daily doses of 60 mg are effective in the acute treatment of major depression. Duloxetine is extensively metabolized by cytochrome P450 isoenzymes (CYP) 1A2 and to a lesser extent 2D6 (Lobo et al. 2008) to numerous non-active metabolites. Maximum plasma concentration occurs after 6 h, steady-state within 3 d and the mean terminal half-life is 12 h. Fatal outcomes have been reported for acute overdoses as low as 1000 mg, and symptoms of duloxetine overdose are well described. However, information about plasma levels of duloxetine and corresponding cerebrospinal fluid (CSF) levels providing information about its CSF penetration is lacking. We therefore report …