Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.

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.

[Therapeutic drug monitoring in psychiatry. A brief summary of the new consensus paper by the task force on TDM of the AGNP]. / Therapeutisches Drug-Monitoring in der Psychiatrie. Kurze Zusammenfassung des neuen Konsensuspapiers der Arbeitsgruppe TDM der AGNP.

In October 2011 the Task Force Therapeutic Drug Monitoring of the Association for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update (Pharmacopsychiatry 2011, 44: 195-235) of the first version of the consensus paper on therapeutic drug monitoring (TDM) published in 2004. This article summarizes the essential statements to make them accessible to a wider readership in German speaking countries.

AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint eff ort.

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

Olanzapine and breast-feeding: changes of plasma concentrations of olanzapine in a breast-fed infant over a period of 5 months.

We here report on a psychotic mother and her breast-fed infant who was treated with olanzapine. Consecutively olanzapine concentrations in the milk and plasma of the mother and in the infant were measured with tandem mass spectroscopy over a period of five month. The results show a relatively high plasma level in the infant aged four month, probably referring to an immature hepatic transformation system, especially CYP1A2. In the following four months plasma levels of olanzapine decreased to very low, even undetectable concentrations in the infant. The infant developed normally and showed no side effects during the treatment period.

Value and actuality of the prescription information for therapeutic drug monitoring of psychopharmaceuticals: a comparison with the medico-scientific evidence.

Therapeutic drug monitoring (TDM) of psychopharmaceuticals, i.e., the assay of plasma concentrations, is a practical therapeutic application of pharmacokinetic principles in psychiatry. The prescription information (summary of product characteristics, SPC) is provided by pharmaceutical companies according to the requirements of regulatory authorities. The present study investigated the degree of agreement of German SPCs for 48 psychopharmaceuticals with the existing medico-scientific evidence in the area of TDM. For this aim, an empirical summary score of SPC content related to TDM (SPCC (TDM)) was calculated and compared with the level of recommendation of TDM (LOR) of the AGNP-TDM expert group consensus guidelines. Considerable disagreement was found between the information on TDM in SPCs and existing medico-scientific evidence, e.g., in the case of antidepressant and antipsychotic drugs. Even for well studied compounds, such as amitriptyline and clozapine, insufficient information on TDM is included in German SPCs. Small differences existed in the TDM-related information in SPCs of generic drugs with, however, much variance between Germany, Austria and Switzerland. Generally, it must be concluded that deficits exist in the preparation of German SPCs for psychopharmaceutical drugs with respect to empirical pharmacokinetic data, i.e., TDM-relevant information. It is recommended that SPCs of psychopharmaceuticals should be improved in terms of TDM-related information and that target plasma concentrations be adjusted according to the guidelines of the AGNP-TDM expert group. A higher level of good pharmacokinetic practice may be thus achieved.

[Therapeutic drug monitoring (TDM) of psychotropic drugs: a consensus guideline of the AGNP-TDM group]. / Le dosage plasmatique des médicaments psychotropes a des fins thérapeutiques: recommandations du groupe d'experts AGNP-TDM.

In psychiatry, therapeutic drug monitoring (TDM) is an established procedure for most psychotropic drugs. However, as its use in everyday clinical practice is far from optimal, the AGNP-TDM group has worked out consensus guidelines to assist psychiatrists and laboratories involved in drug analysis. Based on a thorough analysis of available literature, 5 levels of recommendation were defined with regard to TDM of psychoactive drugs, from 1) (strongly recommended) to 5) (not recommended). A list of indications for TDM, alone or in combination with pharmacogenetic tests is presented. Instructions are given with regard to preparation of TDM, analytical procedures, reporting and interpretation of results and the use of information for patient treatment. Using the consensus guideline will help to ensure optimal clinical benefit of TDM.

The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry.

Therapeutic Drug Monitoring (TDM) is a valid tool to optimise pharmacotherapy. It enables the clinician to adjust the dosage of drugs according to the characteristics of the individual patient. In psychiatry, TDM is an established procedure for lithium, some antidepressants and antipsychotics. In spite of its obvious advantages, however, the use of TDM in everyday clinical practice is far from optimal. The interdisciplinary TDM group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has therefore worked out consensus guidelines to assist psychiatrists and laboratories involved in psychotropic drug analysis to optimise the use of TDM of psychotropic drugs. Five research-based levels of recommendation were defined with regard to routine monitoring of plasma concentrations for dose titration of 65 psychoactive drugs: (1) strongly recommended, (2) recommended, (3) useful, (4) probably useful and (5) not recommended. A second approach defined indications to use TDM, e. g. control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic particularity concerning the drug metabolism, children, adolescents and elderly patients. Indications for TDM are relevant for all drugs either with or without validated therapeutic ranges. When studies on therapeutic ranges are lacking, target ranges should be plasma concentrations that are normally observed at therapeutic doses of the drug. Therapeutic ranges of plasma concentrations that are considered to be optimal for treatment are proposed for those drugs, for which the evaluation of the literature demonstrated strong evidence. Moreover, situations are defined when pharmacogenetic (phenotyping or genotyping) tests are informative in addition to TDM. Finally, practical instructions are given how to use TDM. They consider preparation of TDM, analytical procedures, reporting and interpretation of results and the use of information for patient treatment. Using the consensus guideline will help to ensure optimal clinical benefit of TDM in psychiatry.

Therapeutic monitoring of psychotropic drugs: an outline of the AGNP-TDM expert group consensus guideline.

TDM of psychotropic drugs is widely used, but there is little consensus regarding its optimal use in the clinical context. This prompted a multidisciplinary group comprised of clinical biochemists, clinical pharmacologists, and psychiatrists of the AGNP (Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie) to provide a consensus guideline. This will allow clinical psychiatrists, practitioners, and laboratory directors involved in psychopharmacotherapy to optimize TDM of antidepressants, antipsychotics, and opioid substituents. Recommendations are also given on the combined use of TDM and pharmacogenetic tests.

Intravenous drug injection habits: drug users' self-reports versus researchers' perception.

The present study was designed to obtain human data on the speed of intravenous (i.v.) injection of cocaine, heroin, and morphine as well as on the rate of onset of their subjective effects and their duration in order to improve the accuracy of animal and human experimental models of i.v. drug abuse. To that end, a questionnaire was submitted both to clients of a substitution therapy outpatient clinic and to members of the drug abuse research community. It was found that i.v. drug abusers injected cocaine, heroin, or morphine much faster and also experienced the drug effects much faster than assumed by the drug abuse researchers. The time course of the reemergence of craving was also greatly misjudged by the researchers. On the other hand, the i.v. drug users' self-reports were internally consistent and corresponded well to data obtained in several different human behavioral laboratories. Interestingly, more than half of the i.v. drug users reported that injection speed was not important when injecting cocaine (57%), heroin (72%) or morphine (73%) under conditions that guarantee a maximum effect, suggesting that the rate of the rise in the brain concentration of a drug of abuse is less important for its reinforcing effect and, thus, for its abuse liability, than previously assumed, at least within the time frame of an i.v. drug injection.

Intravenous administration of ecstasy (3,4-methylendioxymethamphetamine) enhances cortical and striatal acetylcholine release in vivo.

The effect of intravenous administration of 3,4-methylendioxymethamphetamine (MDMA), in a range of doses (0.32-3.2 mg/kg) that have been shown to maintain self-administration behaviour in rats, on in vivo acetylcholine release from rat prefrontal cortex and dorsal striatum was studied by means of microdialysis with vertical concentric probes. Intravenous administration of MDMA dose-dependently increased basal acetylcholine release from the prefrontal cortex to 57+/-21%, 98+/-20%, 102+/-7% and 141+/-14% above baseline, at doses of 0.32, 0.64, 1.0 and 3.2 mg/kg, respectively. MDMA also stimulated striatal acetylcholine release at the dose of 3.2 mg/kg i.v. (the maximal increase being 32+/-3% above baseline) while at the dose of 1 mg/kg i.v., MDMA failed to affect basal acetylcholine output. Administration of MDMA also dose-dependently stimulated behaviour. The results of the present study show that MDMA affects measures of central cholinergic neurotransmission in vivo and suggest that at least some of the psychomotor stimulant actions of MDMA might be positively coupled with an increase in prefrontal cortical and striatal acetylcholine release.

Reinforcing effects of MDMA ("ecstasy") in drug-naive and cocaine-trained rats.

3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is one of the most prevalent illegal drugs of abuse among European adolescents, a population not generally experienced with respect to "hard" drugs such as cocaine. We, therefore, determined the reinforcing effect of intravenously self-administered MDMA in a fixed ratio 1 time-out 150 s schedule of reinforcement in rats that were truly drug naive and compared it to cocaine-trained rats. The reinforcing effect of MDMA [0.032-10 mg/(kg.injection)] did not differ between drug-naive rats and cocaine-trained ones. MDMA sensitized the animals to its own rate-increasing effect but not to that of cocaine. When MDMA was tested after cocaine, there was no carryover of cocaine's reinforcing effect to that of MDMA, suggesting that MDMA and cocaine produce distinct interoceptive stimuli in rats.

Lack of reinforcing effect of the benzodiazepine and tricyclic antidepressant combination of diazepam and dothiepin.

Fixed combinations of a tricyclic antidepressant (TCA) with a benzodiazepine (BZD) for the treatment of depressive syndromes enjoy remarkable acceptance among patients and prescribing physicians. In order to investigate if the widespread use of one such fixed TCA-BZD combination might be due to its high positive reinforcing effect, we tested each drug alone and in combination in an operant conditioning paradigm (fixed ratio 1 time-out 150 s) of intravenous self-administration in rats and compared their reinforcing effects to that of cocaine. Diazepam proved to be of only moderate reinforcing strength. Dothiepin alone was ineffective as a reinforcer but essentially abolished the reinforcing effect of diazepam when given in combination with it. These data indicate that the widespread acceptance of the fixed diazepam-dothiepin combination by the therapeutic community is not due to an increase in the positive reinforcing effect of diazepam by dothiepin but that, in contrast, addition of dothiepin might even decrease diazepam's moderately positive reinforcing effect.

Alterations within the endogenous opioid system in mice with targeted deletion of the neutral endopeptidase ('enkephalinase') gene.

The biological inactivation of enkephalins by neutral endopeptidase (enkephalinase, NEP, EC3.4.24.11) represents a major mechanism for the termination of enkephalinergic signalling in brain. A pharmacological blockade of NEP-activity enhances extracellular enkephalin concentrations and induces opioid-dependent analgesia. Recently, knockout mice lacking the enzyme NEP have been developed [Lu et al., J. Exp. Med. 1995;181:2271-2275]. The present study investigates the functional consequences and biochemical compensatory strategies of a systemic elimination of NEP activity in these knockout mice. Using biochemical and behavioural tests we found that the lack of NEP activity in brain is not compensated by enhanced activities of alternative enkephalin-degrading enzymes. Also no change in enkephalin biosynthesis was detectable by in situ methods quantifying striatal proenkephalin-mRNA levels in NEP-deficient mice compared with wildtype. Only a 21% reduction of mu receptor density in crude brain homogenates of NEP knockout mice was observed, while delta- and kappa-opioid receptor densities were unchanged. This receptor downregulation was also confirmed functionally in the hot-plate paradigm. NEP knockouts developed normally, but showed enhanced aggressive behaviour in the resident-intruder paradigm, and altered locomotor activity as assessed in the photobeam system. Thus, although NEP plays a substantial role in enkephalinergic neurotransmission, the biochemical adaptations within the opioid system of NEP-deficient mice are of only modest nature.

Neutral endopeptidase and alcohol consumption, experiments in neutral endopeptidase-deficient mice.

Alcohol consumption was investigated in mice which were rendered deficient in the peptide-degrading enzyme neutral endopeptidase (EC 3.4.24.11) (NEP-/-) by gene targeting and compared to alcohol consumption in corresponding wild type mice (NEP+/+). Mice were offered a free choice to drink tap water or 10% alcohol. The NEP-/- mice consumed significantly more alcohol ( approximately 42%) than the NEP+/+ mice, whereas no significant differences were observed in the total fluid consumption. The daily food consumption of alcohol naive NEP-/- animals was elevated ( approximately 29%). Furthermore, the activities of peptidases closely related to neutral endopeptidase were analysed ex vivo in several brain regions from NEP-/- and NEP+/+ mice not treated with alcohol. There was no obvious compensation for the total loss of neutral endopeptidase by the functionally related peptidases angiotensin-converting enzyme and aminopeptidase N. In vitro, the degradation of exogenously applied [Leu(5)]enkephalin was not reduced in membrane preparations of those brain regions assayed in NEP-/- mice. A small reduction in [Leu(5)]enkephalin degradation was detected in striatal membrane preparations of NEP-/- mice, if aminopeptidase N was additionally blocked by bestatin or amastatin.

In vivo estimates of efficacy at 5-HT1A receptors: effects of EEDQ on the ability of agonists to produce lower-lip retraction in rats.

RATIONALE: Maximal responses are often used as a measure of intrinsic activity or efficacy, but cannot be directly equated to efficacy. Using irreversible antagonists, estimates of efficacy can be obtained that may be less dependent on specific conditions. OBJECTIVES: To characterize the intrinsic activity of serotonin (5-HT)1A agonists by examining the effects of an irreversible antagonist on their ability to produce 5-HT1A receptor-mediated responses. METHODS: The effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the ability of 5-HT1A agonists to produce lower-lip retraction (LLR) in rats were studied. RESULTS: In the absence of EEDQ, each 5-HT1A agonist produced full effects, the rank order of potency being: S 14506 > 8-OH-DPAT > buspirone > ipsapirone. EEDQ decreased the number of 5-HT1A binding sites and shifted the dose-response curves (DRCs) of each agonist either to the right or, at higher EEDQ doses, to the right and downward. The manner in which these shifts occurred, however, differed among the compounds. For each agonist, all DRCs obtained after different doses of EEDQ were fitted to models proposed by Furchgott and Black and Leff, and the results indicated the following rank order of efficacy: ipsapirone < buspirone approximately 8-OH-DPAT < S 14506. 5-HT1A agonist-induced LLR appears to be mediated by 5-HT1A receptors, because the 5-HT1A antagonist, WAY 100635, shifted the agonist DRCs to the right in a parallel and dose-related manner, with pA2 values ranging from 7.8 to 8.1. Moreover, pretreatment with WAY 100635 protected against the antagonist activity of EEDQ. CONCLUSIONS: The results suggest that the effects of EEDQ on the ability of 5-HT1A agonists to produce LLR in rats may be useful to obtain estimates of their apparent efficacy at 5-HT1A receptors.

Signal transduction efficacy of the highly potent mu opioid agonist 14-methoxymetopon.

In search of a truly high-efficacy (i.e., tau > 100) mu opioid analgesic, we determined the efficacy (tau) and apparent in vivo affinity (KA) of the high-potency alkoxymorphinan 14-methoxymetopon. However, in the present study, 14-methoxymetopon's efficacy proved to be only 1.5-fold higher than that of morphine (tau, 19 vs. 12). KA values were 2,900 nmol/kg for 14-methoxymetopon and 46,000 nmol/kg for morphine (Ki for [3H]DAMGO binding, 0.33 vs 3.4 nmol/l). Thus, the 24-fold higher potency of methoxymetopon could be fully accounted for by its 16-fold higher apparent in vivo affinity and its only 1.5-fold higher efficacy. Furthermore, the 10-fold higher affinity of 14-methoxymetopon for the mu opioid receptor - as previously determined in radioligand binding assays - was confirmed in the present behavioral tests of thermal antinociception.

MDMA ('ecstasy') enhances basal acetylcholine release in brain slices of the rat striatum.

The pharmacological basis of acute (+/-)-MDMA (3, 4-methylenedioxymethamphetamine) intoxication still awaits full characterization. According to present knowledge, MDMA enhances the release of serotonin and dopamine in striatal slices and interacts with different types of receptors such as 5-HT2 (5-hydroxytryptamine or serotonin), M1 and M2 muscarinic acetylcholine (ACh), and histamine H1 receptors. Currently, no information is available about the influence of (+/-)-MDMA on striatal cholinergic neurotransmission. In the present study, we used the in vitro perfusion technique to investigate the effect of (+/-)-MDMA on ACh release in rat striatal slices. Perfusions with (+/-)-MDMA (10-300 microM) resulted in a dose-dependent increase of spontaneous ACh release (EC50 approximately 30 microM). The effect was reversible and Ca++- and tetrodotoxin-sensitive. To determine the neurochemical pathways underlying this response, we perfused with (+/-)-MDMA in the presence of various inhibitors of neurotransmitter receptors. Blockade of glutamate or muscarinic ACh receptors as well as 5-HT1, 5-HT2, 5-HT3C or dopamine D2 receptors did not modulate (+/-)-MDMA-induced ACh release. However, the presence of histamine H1 receptor antagonists in the perfusion medium abolished (+/-)-MDMA-induced ACh release. The present data clearly demonstrate that (+/-)-MDMA enhances the activity of striatal cholinergic neurons and suggest an involvement of histamine H1 receptors. The effect is not mediated by glutamate and does not involve the activation of receptors of dopamine D2, 5-HT1, 5-HT2, 5-HT3C or muscarinic ACh. Considering the relatively high affinity of (+/-)-MDMA for the H1 histamine receptor (Ki 6 microM), a direct activation of this type of receptor might represent a plausible mechanism for (+/-)-MDMA-induced ACh release.