Measuring psychotherapeutic processes in the context of psychedelic experiences: Validation of the General Change Mechanisms Questionnaire (GCMQ).

BACKGROUND: Therapeutic and salutogenic effects of psychedelic drugs have been attributed to psychotherapeutic or psychotherapy-like processes that can unfold during the acute psychedelic experience and beyond. Currently, there are no psychometric instruments available to comprehensively assess psychotherapeutic processes (as conceptualized by empirical psychotherapy research) in the context of psychedelic experiences. AIMS: We report the initial validation of the General Change Mechanisms Questionnaire (GCMQ), a self-report instrument designed to measure five empirically established general change mechanisms (GCMs) of psychotherapy-(1) resource activation, (2) therapeutic relationship, (3) problem actuation, (4) clarification, and (5) mastery-in the context of psychedelic experiences. METHODS: An online survey in a sample of 1153 English-speaking and 714 German-speaking psychedelic users was conducted to evaluate simultaneously developed English- and German-language versions of the GCMQ. RESULTS: The theory-based factor structure was confirmed. The five GCMQ scales showed good internal consistency. Evidence for convergent validity with external measures was obtained. Significant associations with different settings and with therapeutic, hedonic, and escapist use motives confirmed the hypothesized context dependence of GCM-related psychedelic experiences. Indicating potential therapeutic effects, the association between cumulative stressful life events and well-being was significantly moderated by resource activation, clarification, and mastery. Factor mixture modeling revealed five distinct profiles of GCM-related psychedelic experiences. CONCLUSION: Initial testing indicates that the GCMQ is a valid and reliable instrument that can be used in future clinical and nonclinical psychedelic research. The five identified profiles of GCM-related experiences may be relevant to clinical uses of psychedelics and psychedelic harm reduction.

Update Lessons from PET Imaging Part II: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antidepressants.

BACKGROUND: Compared with antipsychotics, the relationship between antidepressant blood (plasma or serum) concentrations and target engagement is less well-established. METHODS: We have discussed the literature on the relationship between plasma concentrations of antidepressant drugs and their target occupancy. Antidepressants reviewed in this work are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, duloxetine, milnacipran, tricyclic antidepressants (amitriptyline, nortriptyline, and clomipramine), bupropion, tranylcypromine, moclobemide, and vortioxetine. Four electronic databases were systematically searched. RESULTS: We included 32 articles published 1996-2022. A strong relationship between serotonin transporter (SERT) occupancy and drug concentration is well established for selective serotonin reuptake inhibitors. Lower limits of recommended therapeutic reference ranges largely corroborate with the findings from positron emission tomography studies (80% SERT occupancy). Only a few novel studies have investigated alternative targets, that is, norepinephrine transporters (NETs), dopamine transporters (DATs), or monoamine oxidase A (MAO-A). For certain classes of drugs, positron emission tomography study data are inconclusive. Low DAT occupancy after bupropion treatment speculates its discussed mechanism of action. For MAO inhibitors, a correlation between drug concentration and MAO-A occupancy could not be established. CONCLUSIONS: Neuroimaging studies are critical in TDM-guided therapy for certain antidepressants, whereas for bupropion and MAO inhibitors, the available evidence offers no further insight. Evidence for selective serotonin reuptake inhibitors is strong and justifies a titration toward suggested ranges. For SNRIs, duloxetine, and venlafaxine, NETs are sufficiently occupied, well above the SERT efficacy threshold. For these drugs, a titration toward higher concentrations (within the recommended range) should be considered in case of no response at lower concentrations.

Update Lessons from Positron Emission Tomography Imaging Part I: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antipsychotics.

BACKGROUND: Positron emission tomography (PET) and single photon emission tomography (SPECT) of molecular drug targets (neuroreceptors and transporters) provide essential information for therapeutic drug monitoring-guided antipsychotic drug therapy. The optimal therapeutic windows for D 2 antagonists and partial agonists, as well as their proposed target ranges, are discussed based on an up-to-date literature search. METHODS: This part I of II presents an overview of molecular neuroimaging studies in humans and primates involving the target engagement of amisulpride, haloperidol, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, cariprazine, and ziprasidone. The systemic review particularly focused on dopamine D 2 -like and 5-HT 2A receptors. Target concentration ranges were estimated based on receptor occupancy ranges that relate to clinical effects or side effects (ie, extrapyramidal side effects). In addition, findings for other relevant receptor systems were included to further enrich the discussion. RESULTS: The reported reference ranges for aripiprazole and clozapine align closely with findings from PET studies. Conversely, for haloperidol, risperidone, and olanzapine, the PET studies indicate that a lowering of the previously published upper limits would be necessary to decrease the risk of extrapyramidal side effect. CONCLUSIONS: Molecular neuroimaging studies serve as a strong tool for defining target ranges for antipsychotic drug treatment and directing therapeutic drug monitoring.

Treatment with psychedelics is psychotherapy: beyond reductionism.

Treatment of psychiatric disorders with psychedelic substances represents one of the most promising current treatment approaches in psychiatry. Since its inception in the 1950s, therapy with psychedelics has been conceptualised as psychedelic-assisted psychotherapy-ie, a form of psychotherapy that uses the profound biological effects of this class of substances as a catalyst for changing thinking, emotions, and behaviour. In this view, the psychotherapy component of the treatment is considered as being of the utmost importance for both the safety and efficacy of the therapy. This conceptualisation has been challenged by the idea that the latest clinical studies suggest that the potential therapeutic effects of psychedelics must be attributed solely to the substance itself, with no role for psychotherapy. Here, accompaniment by therapists is understood as mere psychological support, to maintain the safety of the substance administration. In this Personal View, we contrast these two views and argue that the characterisation of treatment with psychedelics as a biological intervention (with psychological support as a purely safety-related component) represents an outdated and reductionistic dualism that has dominated psychiatric treatment and research for far too long. This discussion has important implications for the study and the regulation of these compounds.

Therapeutic Reference Range for Olanzapine in Schizophrenia: Systematic Review on Blood Concentrations, Clinical Effects, and Dopamine Receptor Occupancy.

Objective: Aiming at revising the therapeutic reference range for olanzapine, the present study highlights the association between blood olanzapine levels, clinical effects, and dopamine D2-receptor occupancy for oral and long-acting injectable (LAI) formulations.Data Sources: Databases were systematically searched for randomized controlled trials (RCTs) and uncontrolled trials concerning blood olanzapine levels in relation to clinical outcomes or D2-receptor occupancy using MEDLINE (PubMed), Web of Science, PsycINFO, and Cochrane Library (March 2021, updated in December 2021). We excluded articles not written in English or German and non-human data. Search terms included olanzapine, blood level, drug monitoring, PET, and SPECT.Study Selection: The process of study selection followed a previously published protocol and PRISMA guidelines. A total of 2,824 articles were identified through database search and 1 article via reference list check. Thirty-four studies were suitable for qualitative synthesis, and 13 studies were included in the quantitative analysis.Data Extraction: Reviewers performed data extraction and quality assessment of the included studies independently following the review protocol.Results: Evidence for a relationship between blood olanzapine level and efficacy/side effects (constipation) is considered low (Level C). In total, 3 studies of moderate quality consistently showed therapeutic thresholds of around 20 ng/mL for olanzapine 12 hours post-dose. This threshold is in line with findings from positron emission tomography (PET) studies that suggest optimal drug efficacy (65%-80% D2-receptor occupancy) between 17 and 44 ng/mL.Conclusions: We suggest a therapeutic reference range of 20-40 ng/mL for olanzapine oral and LAI formulations. In this range, optimal treatment response is expected in patients with schizophrenia and schizophrenia spectrum disorders. Side effects, especially weight gain, may already occur at therapeutic levels. However, higher plasma concentrations are in general well tolerated and should not necessarily require a dose reduction in case of good response and tolerance.

Low Escitalopram Concentrations in Patients with Depression predict Treatment Failure: A Naturalistic Retrospective Study.

INTRODUCTION: Cross sectional therapeutic drug monitoring (TDM) data mining introduces new opportunities for the investigation of medication treatment effects to find optimal therapeutic windows. Medication discontinuation has been proven useful as an objective surrogate marker to assess treatment failure. This study aimed to investigate the treatment effects of escitalopram and pharmacokinetic influences on blood levels using retrospectively assessed data from a TDM database. METHODS: Data was collected from 134 patients longitudinally treated with escitalopram for whom TDM was requested to guide drug therapy. Escitalopram metabolism was estimated by the log-transformed dose-corrected concentrations and compared within subpopulations differing in age, gender, renal function, smoking status, body mass index, and comedication. RESULTS: Patients with a depressive episode who were treated with escitalopram and discontinued the treatment within the hospital stay showed lower serum concentrations compared to patients who continued escitalopram treatment with a concentration of 15 ng/mL separating both groups. Variability was high between individuals and factors influencing blood levels, including dose, sex, and age. Comedication that inhibits cytochrome P450 (CYP) 2C19 isoenzymes were further found to influence escitalopram pharmacokinetics independent of dose, age or sex. DISCUSSION: Medication switch is a valuable objective surrogate marker to assess treatment effects under real-world conditions. Of note, treatment discontinuation is not always a cause of insufficient response but may also be related to other factors such as medication side effects. TDM might not only be useful in addressing these issues but titrating drug concentrations into the currently recommended reference range for escitalopram will also increase response in non-responders and avoid treatment failure in underdosed patients.

Functional connectivity signatures of NMDAR dysfunction in schizophrenia-integrating findings from imaging genetics and pharmaco-fMRI.

Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry.

Molecular Imaging Studies of Alcohol Use Disorder.

Alcohol use disorder (AUD) is a serious public health problem in many countries, bringing a gamut of health risks and impairments to individuals and a great burden to society. Despite the prevalence of a disease model of AUD, the current pharmacopeia does not present reliable treatments for AUD; approved treatments are confined to a narrow spectrum of medications engaging inhibitory γ-aminobutyric acid (GABA) neurotransmission and possibly excitatory N-methyl-D-aspartate (NMDA) receptors, and opioid receptor antagonists. Molecular imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can open a window into the living brain and has provided diverse insights into the pathology of AUD. In this narrative review, we summarize the state of molecular imaging findings on the pharmacological action of ethanol and the neuropathological changes associated with AUD. Laboratory and preclinical imaging results highlight the interactions between ethanol and GABA A-type receptors (GABAAR), but the interpretation of such results is complicated by subtype specificity. An abundance of studies with the glucose metabolism tracer fluorodeoxyglucose (FDG) concur in showing cerebral hypometabolism after ethanol challenge, but there is relatively little data on long-term changes in AUD. Alcohol toxicity evokes neuroinflammation, which can be tracked using PET with ligands for the microglial marker translocator protein (TSPO). Several PET studies show reversible increases in TSPO binding in AUD individuals, and preclinical results suggest that opioid-antagonists can rescue from these inflammatory responses. There are numerous PET/SPECT studies showing changes in dopaminergic markers, generally consistent with an impairment in dopamine synthesis and release among AUD patients, as seen in a number of other addictions; this may reflect the composite of an underlying deficiency in reward mechanisms that predisposes to AUD, in conjunction with acquired alterations in dopamine signaling. There is little evidence for altered serotonin markers in AUD, but studies with opioid receptor ligands suggest a specific up-regulation of the µ-opioid receptor subtype. Considerable heterogeneity in drinking patterns, gender differences, and the variable contributions of genetics and pre-existing vulnerability traits present great challenges for charting the landscape of molecular imaging in AUD.

[Psychedelics in Psychiatry - Development and Current State in Germany]. / Psychedelika in der Psychiatrie ­ Entwicklungen und die Stellung in Deutschland.

Clinical research on the therapeutic efficacy of psychedelics is currently experiencing a renaissance. Available scientific evidence on their efficacy in various psychiatric conditions, as well as their legally approved use in some countries of the world, show the possibility of their future application in clinical practice also in Germany. The field is facing substantial challenges that have to be addressed, such as defining and setting a suitable clinical frame. This manuscript deals with the historical background of the clinical application of psychedelics, as well as the psycho-phenomenology, modes of action, possible indications and aspects of safety. The current research status in Germany and the organization of professional societies are discussed in a historical and international context and attention is drawn to unresolved critical issues in the field.

[Attitudes of Mental Health Experts Towards Psilocybin]. / Einstellungen von Expertinnen und Experten für psychische Gesundheit gegenüber Psilocybin.

OBJECTIVE: In recent years, studies investigating the use of psilocybin to treat mental disorders have shown promising results. In this context, this online survey investigated attitudes of trained psychiatrists and psychotherapists towards psilocybin and psilocybin-assisted therapies. MATERIALS AND METHODS: A total of 530 valid responses from individuals with suitable job profiles were collected in this online survey. Statistical analysis was used to identify relevant predictors of attitude measures. RESULTS: The opinions of experts in the treatment of mental disorders with psilocybin and psilocybin-assisted therapies varied widely, and the level of knowledge of the participants to some extent was low. A large number of participants considered treatment of mental disorders with psilocybin to be promising and treatment of depression with psilocybin was seen as promising by the majority of the participants. The results of this study suggest that a higher level of knowledge about psilocybin is associated with more optimistic views about its use in a therapeutic setting. Having additional scientific information led in some cases to more optimistic attitudes towards psilocybin and the use of psilocybin in the treatment of mental disorders. CONCLUSION: If the scientific and public discourse on psilocybin continues to grow in the future, changes in the attitudes of psychotherapists and psychiatrists can be expected.

Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy.

Introduction: A titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11-21 ng/ml) that are expected under the approved dose range (10-20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy. Methods: Following our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram. Results: Of 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C). Conclusion: Based on our findings, we propose a target range of 20-40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram's reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873].

Therapeutic Reference Range for Aripiprazole in Schizophrenia Revised: a Systematic Review and Metaanalysis.

RATIONALE: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. OBJECTIVES: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. METHODS: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. RESULTS: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. CONCLUSIONS: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers.

Molecular Imaging of Dopamine Partial Agonists in Humans: Implications for Clinical Practice.

Positron emission tomography (PET) has been used since the late 1980s for the assessment of relationships between occupancy of D2/3 receptors by antipsychotic drugs in the human brain and the clinical effects and side effects of these compounds in patients. It is now well established for most D2/3 antagonists, both of the first and the second generation, that the ideal occupancy of their target receptors is between approximately 65 and 80%. If the occupancy is below 65%, the probability of treatment response is reduced, if the occupancy is higher than 80%, the risk for extrapyramidal side-effects increases substantially. However, partial agonist antipsychotics behave different from these rules. It has been shown for all three available drugs of this class (aripiprazole, brexpiprazole, cariprazine) that, due to their special pharmacology, a very high target engagement (>90%) not only is not harmful but represents a prerequisite for antipsychotic efficacy. The available PET studies for these drugs are reviewed in this work. It is demonstrated that optimal plasma levels for partial agonist antipsychotics can be derived from these studies, which can guide individual treatment in routine patient care.

The negative impact of vitamin D on antipsychotic drug exposure may counteract its potential benefits in schizophrenia.

AIMS: Patients with schizophrenia frequently show insufficient vitamin D levels, which are associated with somatic comorbidity and may contribute to psychopathology. For many reasons, vitamin D supplementation may be indicated for this patient cohort. However, there is growing evidence for a vitamin D-mediated increase of drug metabolism by induction of cytochrome P450 (CYP) 3A4. Hence, this study aimed to assess vitamin D's impact on both antipsychotic drug concentrations and psychopathology in a non-interventional manner. METHODS: Totals of 107 serum concentrations of different antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine and risperidone), 80 serum concentrations of vitamin D and psychopathological assessments were obtained from 80 patients with schizophrenia. The impact of Vitamin D on antipsychotic drug concentrations and symptomatology was assessed using a generalized linear model, path and correlation analyses. RESULTS: We observed a negative relationship between vitamin D and dose-adjusted antipsychotic drug concentrations, which was particularly pronounced for drugs which are predominantly metabolized via CYP3A4 (i.e., aripiprazole and quetiapine). A path analysis suggested a relieving effect of vitamin D on symptomatology which was, however, counteracted by its negative impact on antipsychotic drug levels. Finally, patients with vitamin D levels above the median exhibited a significantly higher proportion of therapeutically insufficient dose-normalized drug concentrations of aripiprazole and quetiapine. CONCLUSION: Despite vitamin D's potential benefits on physical and mental health, clinicians should be aware of its negative impact on blood concentrations of antipsychotics metabolized by CYP3A4 in patients with schizophrenia. Therefore, when considering its supplementation, therapeutic drug monitoring should be applied to guide dose adjustment.

Amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia in Germany (COMBINE): a double-blind randomised controlled trial.

BACKGROUND: Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy. METHODS: A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20. FINDINGS: Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29·6 [SD 14·5]) than in the olanzapine plus placebo group (-24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment). INTERPRETATION: The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered. FUNDING: German Federal Ministry of Education and Research.

Is Therapeutic Drug Monitoring Relevant for Antidepressant Drug Therapy? Implications From a Systematic Review and Meta-Analysis With Focus on Moderating Factors.

Inter-individual differences in antidepressant drug concentrations attained in blood may limit the efficacy of pharmacological treatment of depressive disorders. Therapeutic drug monitoring (TDM) enables to determine drug concentrations in blood and adjust antidepressant dosage accordingly. However, research on the underlying assumption of TDM, association between concentration and clinical effect, has yielded ambiguous results for antidepressants. It has been proposed that this ambiguity may be caused by methodological shortcomings in studies investigating the concentration-effect relationship. Guidelines recommend the use of TDM in antidepressant treatment as expert opinion. This reflects the lack of research, particularly systematic reviews and meta-analyses of randomized controlled trials, on the relationship between concentration and effect as well as on the benefits of the use of TDM in clinical practice. In this study, a systematic review and meta-analysis of randomized controlled trials has been performed to investigate the relationship between antidepressant concentration, efficacy, and side effects. It is the first meta-analytical approach to this subject and additionally considers methodological properties of primary studies as moderators of effect in quantitative analysis. Our results identified methodological shortcomings, namely the use of a flexible dose design and the exclusion of concentrations in lower- or subtherapeutic ranges, which significantly moderate the relationship between antidepressant concentration and efficacy. Such shortcomings obscure the evidence base of using TDM in clinical practice to guide antidepressant drug therapy. Further research should consider these findings to determine the relationship between concentration and efficacy and safety of antidepressant treatments, especially for newer antidepressants. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=246149, identifier: CRD42021246149.

[Are psychedelics fast acting antidepressant agents?] / Sind Psychedelika schnell wirksame Antidepressiva?

BACKGROUND: Psychedelics, such as psilocybin represent one of the most promising current therapeutic approaches in psychiatry. OBJECTIVE: Psychedelics seem to have not only potent antidepressant effects. Do they also work particularly quickly, i.e. within one day? MATERIAL AND METHODS: The available literature on clinical studies of psychedelics in depressive syndromes is presented both from the period up to the prohibition of these substances in the late 1960s as well as after the resumption of research in the 2000s. One focus is the speed of onset of antidepressant action. RESULTS: Only the clinical studies published since 2016 that meet modern methodological standards have also systematically examined the speed of the antidepressant onset of action. The published studies, which were almost exclusively carried out with psilocybin, so far show small sample sizes (the total number of patients with depression treated in published clinical studies is < 200) and some of them have methodological weaknesses; however, they suggest a pronounced and very rapid onset of action within one day for depression, treatment-resistant depression and depression in the context of life-threatening cancer. CONCLUSION: The available studies indicate a potent, rapid onset and in many cases long-lasting antidepressant effect over several months. The currently conducted studies with three-digit patient numbers will provide final information about the potential of psilocybin for depression.

Prefrontal and striatal dopamine D2/D3 receptors correlate with fMRI BOLD activation during stopping.

D2-like dopamine receptors in animals and humans have been shown to be linked to impulsive behaviors that are highly relevant for several psychiatric disorders. Here, we investigate the relationship between the fronto-striatal D2/D3 dopamine receptor availability and response inhibition in a selected population of healthy OPRM1 G-allele carriers. Twenty-two participants successively underwent blood-oxygen level dependent functional magnetic resonance imaging (fMRI) while performing a stop-signal task and a separate positron emission tomography (PET) scan. Striatal and extrastriatal D2/D3 dopamine receptor availability was measured using the radiotracer [18F]fallypride. Caudate D2/D3 dopamine receptor availability positively correlated with stopping-related fronto-striatal fMRI activation. In addition, right prefrontal D2/D3 dopamine receptor availability correlated positively with stopping-related striatal fMRI BOLD signal. Our study partially replicates previous findings on correlations between striatal D2/D3 dopamine receptor availability and response inhibition in a population selected for its genetic determination of dopamine response to alcohol and as a modulator of impulse control via the endogenous opioid system. We confirm the important role of D2/D3 dopamine receptor availability in the fronto-striatal neural circuit for response inhibition. Moreover, we extend previous findings suggesting that dopamine receptor availability in the right inferior frontal cortex, a crucial region of the stopping network, is also strongly associated with stopping-related striatal fMRI activity in healthy OPRM1 G-allele carriers.

Effects of body weight, smoking status, and sex on plasma concentrations of once-monthly paliperidone palmitate.

OBJECTIVES: Knowledge about the impact of body composition features on pharmacokinetics of newer long-acting injectable antipsychotics is limited. METHODS: We analyzed steady-state plasma concentrations of paliperidone in different body mass index (BMI), age, sex, and smoking status patient subgroups treated with once-monthly paliperidone palmitate (PP1M). Paliperidone plasma concentrations and dose-adjusted-plasma concentrations (C/D) from a therapeutic drug monitoring (TDM) database of PP1M-treated patients were compared among normal BMI, overweight, and obese patients as well as between females vs. males, elderly vs. non-elderly, and smokers vs. non-smokers using non-parametric tests. RESULTS: In a total of 183 PP1M-treated patients, we found highly variable paliperidone plasma concentrations between individuals but no significant effect of PP1M dose or dosing intervals (p> 0.05). C/D ratios were similar in 54 obese, 82 overweight, and 47 normal BMI patients (p> 0.05). Females had 13.7% higher C/D ratios compared to males, yet this difference was not significant (p> 0.05). No differences were found between elderly vs. non-elderly patients or for smokers vs. non-smokers (p> 0.05). CONCLUSION: Our findings suggest that age, sex, smoking, or body weight may not substantially affect pharmacokinetic indices of PP1M. The high interindividual variation of plasma concentrations implies that TDM may be helpful to enhance PP1M efficacy and tolerability.