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.

Venlafaxine's therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis.

INTRODUCTION: The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet. OBJECTIVES: We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression. METHODS: Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal. RESULTS: High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75-225 mg/day). The population-based concentration ranges (25-75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225-450 ng/ml for the AM and (ii) 144-302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140-600 ng/ml. CONCLUSION: VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN's dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.

Concentrations of escitalopram in blood of patients treated in a naturalistic setting: focus on patients with alcohol and benzodiazepine use disorder.

The selective serotonin reuptake inhibitor escitalopram (ESC) is indicated for the treatment of major depressive disorder (MDD) and of generalized anxiety disorder (GAD). Monitoring of blood levels (BLs) is strongly indicated due to ESC's high interindividual pharmacokinetic variability. The aim of this study was to analyse clinical efficacy and pharmacokinetic influences on ESC BLs, in patients with depressive disorder alone and with comorbid alcohol or benzodiazepine use disorder. Data were collected from patients treated under naturalistic conditions for whom Therapeutic Drug Monitoring (TDM) was requested to guide antidepressant drug therapy and analysed retrospectively. Particular emphasis was given to patients with alcohol or benzodiazepine use disorder. Responders according to the clinical global impression (CGI) scale were compared with nonresponders for their ESC blood level (BL). The patient sample included 344 patients from 16 psychiatric hospitals in Germany. Influencing factors that could explain 22% of ESC BLs were dose, sex and age. Variability was high between individuals, and doses up to 40 mg were common in real-world settings. Patients treated with ESC monotherapy who responded showed a trend towards higher BLs compared to nonresponders with a concentration of 15 ng/mL separating both groups. Pathological changes in liver function (indicated by elevated GGT in combination with an AST/ALT ratio ≥ 1) resulted in higher dose-corrected ESC concentrations. Influencing factors that could explain 22% of ESC blood levels were dose, sex, and age. Our findings confirm the currently recommended lower threshold level and support the need for standard TDM analyses in everyday clinical practice. The ICD 10 diagnosis alcohol dependence alone does not lead to pharmacokinetic changes in the metabolism of ESC, but altered liver function does.

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.

Assessment of Psychosocial Functioning in a Large Cohort of Patients with Schizophrenia.

BACKGROUND: This study addresses the question of whether psychosocial functioning measured by the Personal and Social Performance (PSP) Scale is related to various psychopathological measures in a cohort of patients with schizophrenia. METHODS: The 'Neuroleptic Strategy Study' (NeSSy) performed at 14 German hospitals between 2010 and 2013 compared two treatment strategies instead of individual drugs. Secondary end-points were the two PSP scales as well as measures of quality of life (SF-36) and the Positive and Negative Syndrome Scale (PANSS). RESULTS: 149 patients were randomised. There was no difference between the two treatment strategies (first-generation versus second-generation antipsychotics) with regard to the PSP. There were differences in doctors' assessments regarding psychosocial functioning compared with patients' own assessments. Furthermore, there were relationships between the PSP and quality of life, level of skills (ICF), and severity of disease (PANSS), level of sexual activities and poor well-being under antipsychotic medication but not with cognitive changes. CONCLUSIONS: The findings on psychosocial functioning of patients with schizophrenia related to severity and skill level could be confirmed. Further findings were the correlation between psychosocial functioning and quality of life, well-being under treatment, and sexuality what emphasizes the substantial importance of a reduced psychosocial functioning.

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.

[Rank of outcome parameters in the treatment of depression : Results of a Delphi panel survey]. / Präferenz von Zielparametern bei der Behandlung der Depression : Ergebnisse einer Delphi-Panel-Erhebung.

BACKGROUND: In the context of new drug benefit assessments a list of outcome parameter are evaluated. Currently it is unclear, how different outcome parameters are weighed in the overall assessment. OBJECTIVES: The objective of the survey is to rank relevant outcome parameters in the treatment of depression, which may be considered in benefit the assessment of new antidepressants. MATERIALS AND METHODS: In 2015 a Delphi panel survey with 30 general practitioners and specialists in Germany was performed regarding the benefit assessment of antidepressants. On the basis of two fictive casuistics (patients with depressive disorders) the physicians weighed a range of relevant outcome parameters regarding efficacy, quality of life, safety and tolerability according to their relevance to clinical practice. RESULTS: Regarding efficacy, response, remission and recovery were rated as the most important outcomes. Regarding quality of life, handling of the daily household activities and mental performance were rated as most important. Suicidality was rated as the most important outcome regarding safety and tolerability. CONCLUSIONS: Individual outcome parameters were rated differently by the physicians regarding their relevance to clinical practice. The results indicate that outcome parameters should be weighed differently when assessing the overall benefit of new antidepressants.

Neural correlates of naturalistic social cognition: brain-behavior relationships in healthy adults.

Being able to infer the thoughts, feelings and intentions of those around us is indispensable in order to function in a social world. Despite growing interest in social cognition and its neural underpinnings, the factors that contribute to successful mental state attribution remain unclear. Current knowledge is limited because the most widely used tasks suffer from two main constraints: (i) They fail to capture individual variability due to ceiling effects and (ii) they use highly simplistic, often artificial stimuli inapt to mirror real-world socio-cognitive demands. In the present study, we address these problems by employing complex depictions of naturalistic social interactions that vary in both valence (positive vs negative) and ambiguity (high vs low). Thirty-eight healthy participants (20 female) made mental state judgments while brain responses were obtained using functional magnetic resonance imaging (fMRI). Accuracy varied based on valence and ambiguity conditions and women were more accurate than men with highly ambiguous social stimuli. Activity of the orbitofrontal cortex predicted performance in the high ambiguity condition. The results shed light on subtle differences in mentalizing abilities and associated neural activity.

Association of Common Polymorphisms in the Nicotinic Acetylcholine Receptor Alpha4 Subunit Gene with an Electrophysiological Endophenotype in a Large Population-Based Sample.

Variation in genes coding for nicotinic acetylcholine receptor (nAChR) subunits affect cognitive processes and may contribute to the genetic architecture of neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in the CHRNA4 gene that codes for the alpha4 subunit of alpha4/beta2-containing receptors have previously been implicated in aspects of (mostly visual) attention and smoking-related behavioral measures. Here we investigated the effects of six synonymous but functional CHRNA4 exon 5 SNPs on the N100 event-related potential (ERP), an electrophysiological endophenotype elicited by a standard auditory oddball. A total of N = 1,705 subjects randomly selected from the general population were studied with electroencephalography (EEG) as part of the German Multicenter Study on nicotine addiction. Two of the six variants, rs1044396 and neighboring rs1044397, were significantly associated with N100 amplitude. This effect was pronounced in females where we also observed an effect on reaction time. Sequencing of the complete exon 5 region in the population sample excluded the existence of additional/functional variants that may be responsible for the observed effects. This is the first large-scale population-based study investigation the effects of CHRNA4 SNPs on brain activity measures related to stimulus processing and attention. Our results provide further evidence that common synonymous CHRNA4 exon 5 SNPs affect cognitive processes and suggest that they also play a role in the auditory system. As N100 amplitude reduction is considered a schizophrenia-related endophenotype the SNPs studied here may also be associated with schizophrenia outcome measures.

[Significance of the German Act on the Reform of the Market for Medicinal Products for psychopharmacotherapy]. / Bedeutung des Arzneimittelmarktneuordnungsgesetzes für die Psychopharmakotherapie.

The German Act on the Reform of the Market for Medicinal Products (AMNOG) will lead to rapid disappearance of many new psychotropic drugs from the market in Germany over the next few years or their not being introduced in the first place. This article lists the reasons and discusses possible solutions. In the long term, the AMNOG could not only lead to an improvement of psychopharmacology but also contribute to the development of psychiatry as a whole, especially if its standards become an international reference.

[Neuroenhancement]. / Neuroenhancement.

BACKGROUND: Cognitive enhancement or neuroenhancement describes the increase in cognitive performance in humans by means of psychotropic drugs or brain stimulation methods, such as transcranial magnetic stimulation (TMS). PROBLEM: This article discusses the potential of pharmacological cognitive enhancement with some of the most common drugs. METHODS: A selective literature search was performed taking into account the most important groups of substances (i.e. caffeine, nicotine, stimulants including modafinil, and acetylcholine esterase inhibitors) for which studies on the pharmacological elevation of cognitive performance in healthy subjects are available. RESULTS: The extent of the effects that can be pharmacologically achieved is essentially genetically determined. Some of the best-characterized polymorphisms are described here. Pharmacological enhancement of cognitive performance is currently possible with all of the compounds described here and caffeine and nicotine are used by millions of people without the explicit intention of most consumers of cognitive enhancement. DISCUSSION: Clinical neuroscientists are required to share their expertise to a greater extent in the social discourse on cognitive enhancement in the future in order to influence opinion-forming and decision-making processes.

[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.

[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.

Dopamine-modulated aversive emotion processing fails in alcohol-dependent patients.

Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task; high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielberger's state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol-dependent patients.

[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.