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.

[Antidepressive agents and suicidal tendencies]. / Antidepressiva und Suizidalität.

In the last 2 years the discussions on the question whether antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) can lead to suicidality, aggression and violence, flared up again. The available data on the problem, which has been discussed since the introduction of this substance group in the late 1980s, is presented in this article. A systematic literature search showed that a scientific consensus exists that the benefits of antidepressant pharmacotherapy in general, and of treatment with SSRIs and selective serotonin/norepinephrine reuptake inhibitors (SSNRIs) in particular, outweigh the risks of their use. This also applies to the treatment of children, adolescents and young adults. The agitation occasionally occurring at the beginning of treatment, which can be experienced as aversive in susceptible patients, can intensify or even trigger suicidal thoughts or impulses. This has to be paid particular attention to especially at the beginning of treatment. It is recommended that the indications for antidepressant pharmacotherapy of children, adolescents and young adults are assessed by a specialist.

[Schizophrenia and other psychotic disorders in DSM-5: summary of the changes compared to DSM-IV]. / Schizophrenie und andere psychotische Störungen im DSM-5 : Zusammenfassung der Änderungen gegenüber DSM-IV.

With the introduction of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) numerous changes in the area of the schizophrenia spectrum and psychotic disorders have been implemented. Establishing a metastructure based on the characteristics of the spectrum of psychopathological disturbances should improve clarity. The classical subtypes of schizophrenia were eliminated and specific psychopathological dimensions for the assessment of disease severity were added. The special role of Schneiderian first rank symptoms was abandoned and a higher delineation towards schizoaffective disorders is made. The nosological status of catatonia is clarified and occurs together with a consistent use of catatonic disturbances over all chapters. The attenuated psychosis syndrome is added as a new condition for further study. The shared psychotic disorder in the sense of a folie à deux is no longer maintained. However, the initial goal to integrate more disorder-specific etiopathogenetic information into the reconceptualization could not be achieved. Contemporaneously to the development process of DSM-5 the National Institute of Mental Health (NIMH) carried out the research domain criteria project (RDoC) attempting to incorporate the current growth in knowledge of genetics, neurocognitive and cognitive sciences in future diagnostic systems. This article gives an overview of the changes that have been made within the revision process from DSM-IV to DSM-5.

[Integrated care for depressive disorders]. / Integrierte Versorgung bei depressiven Störungen.

BACKGROUND: According to the special report of the Advisory Council on the Assessment of Developments in the Health Care Sector, the termination of contracts on integrated care (IC) in accordance with §140a-d of the Social Act V (SGB V) was mostly due to high costs and volume expansion by services providers (physicians). However, there is still limited knowledge about the medical and economic impact of projects of integrated care, as such projects were on the one hand not primarily designed with a scientific evaluation in mind and on the other hand health insurance agencies usually do not evaluate data for scientific reasons. AIM: In Aachen the IC project "Integrated Care in Mental Health" ran between 2006 and 2011. During that time a total of 3,408 patients with depressive disorders were treated across institutional and trans-sectoral borders according to the national clinical practice guidelines and S3 guidelines on unipolar depression. This study was initiated in an attempt to describe and evaluate the clinical success of treatment. RESULTS: This study evaluated the outcome of the clinical treatment provided but due to the lack of available data on the economic impact of the project, the study contribution is limited to non-economic aspects. By comparing various clinical parameters it could be shown that scores in certain patient-reported clinical scales, such as the Hamilton rating scale for depression, and the WHO-5 well-being index as well as on the clinician-reported clinical global impression (CGI) improved in a statistically significant manner over time compared to initial assessments. Due to the lack of data on an appropriate comparison cohort of patients any comparative statements concerning the superiority of the treatment of depressive disorders outside an integrated care project remains hypothetical and preliminary. CONCLUSION: This study revealed the limitations of a naturalistic study in an IC setting and showed that without adequate funding a satisfactory evaluation that fulfills scientific criteria seems to be impossible.

[Basic principles of therapy with neuropsychotropic drugs]. / Grundprinzipien der Therapie mit Neuropsychopharmaka.

This review provides the general principles for a rational therapy with psychotropic drugs. It covers the discussion on the basics of the pharmacokinetics (with consideration of drug metabolism and the importance of genetic polymorphisms), pharmacodynamics (drug-receptor interaction, receptor pharmacology) and the effects of chronic administration of neuropsychotropic drugs on behavior. The reader will thus obtain the basis and stimulation for further study.

Augmentative effects of fluvoxamine on duloxetine plasma levels in depressed patients.

Duloxetine is a potent and selective inhibitor of serotonin and norepinephrine reuptake with weak activity on dopamine reuptake. Enzymes involved in duloxetine metabolism are cytochrome P450 isoenzymes (CYP) CYP1A2 and to a lesser extent CYP2D6 whereas the selective serotonin reuptake inhibitor Fluvoxamine is known to be a potent inhibitor of CYP1A2. Changes in plasma levels of duloxetine revealing pharmacokinetic interactions with fluvoxamine, clinical effects and adverse effects of adding fluvoxamine in thirteen patients with a steady-state duloxetine treatment by intraindividual comparisons were analyzed in this retrospective survey. Patients had been treated with duloxetine under steady-state conditions until fluvoxamine was added. Plasma duloxetine levels were measured at steady state of different daily doses due to lacking experience with the combination of DLX and FLX. Adding 25 mg of fluvoxamine (FLX) per day to a steady-state treatment with 30 mg of duloxetine (DLX) in 8 patients led to an average increase of duloxetine plasma levels that was 3-fold with a magnitude of 50-506%. Our findings indicate that duloxetine plasma levels can be enhanced by a potent CYP1A2 inhibition by FLX and that DLX, even in higher plasma levels, seems to be well tolerated. The use of combined treatments, however, underscores the importance of understanding pharmacokinetic interactions.

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.