Clinical effects of CYP2D6 phenoconversion in patients with psychosis.

BACKGROUND: Pharmacogenetics is considered a promising avenue for improving treatment outcomes, yet evidence arguing for the use of pharmacogenetics in the treatment of psychotic disorders is mixed and clinical usefulness is under debate. Many patients with psychosis use multiple medications, which can alter the metabolic capacity of CYP enzymes, a process called phenoconversion. In clinical studies, treatment outcomes of drugs for psychosis management may have been influenced by phenoconversion. AIM: Here we evaluate the impact and predictive value of CYP2D6 phenoconversion in patients with psychotic disorders under pharmacological treatment. METHOD: Phenoconversion-corrected phenotype was determined by accounting for inhibitor strength. Phenoconversion-corrected and genotype-predicted phenotypes were compared in association with side effects, subjective well-being and symptom severity. RESULTS: Phenoconversion led to a large increase in poor metabolizers (PMs; 17-82, 16% of sample), due to concomitant use of the serotonin reuptake inhibitors fluoxetine and paroxetine. Neither CYP2D6-predicted nor phenoconversion-corrected phenotype was robustly associated with outcome measures. Risperidone, however, was most affected by the CYP2D6 genotype. CONCLUSION: Polypharmacy and phenoconversion were prevalent and accounted for a significant increase in PMs. CYP2D6 may play a limited role in side effects, symptoms and well-being measures. However, due to the high frequency of occurrence, phenoconversion should be considered in future clinical trials.

Unidentified CYP2D6 genotype does not affect pharmacological treatment for patients with first episode psychosis.

BACKGROUND: Research on the pharmacogenetic influence of hepatic CYP450 enzyme 2D6 (CYP2D6) on metabolism of drugs for psychosis and associated outcome has been inconclusive. Some results suggest increased risk of adverse reactions in poor and intermediate metabolizers, while others find no relationship. However, retrospective designs may fail to account for the long-term pharmacological treatment of patients. Previous studies found that clinicians adapted risperidone dose successfully without knowledge of patient CYP2D6 phenotype. AIM: Here, we aimed to replicate the results of those studies in a Dutch cohort of patients with psychosis (N = 418) on pharmacological treatment. METHOD: We compared chlorpromazine-equivalent dose between CYP2D6 metabolizer phenotypes and investigated which factors were associated with dosage. This was repeated in two smaller subsets; patients prescribed pharmacogenetics-actionable drugs according to published guidelines, and risperidone-only as done previously. RESULTS: We found no relationship between chlorpromazine-equivalent dose and phenotype in any sample (complete sample: p = 0.3, actionable-subset: p = 0.82, risperidone-only: p = 0.34). Only clozapine dose was weakly associated with CYP2D6 phenotype (p = 0.03). CONCLUSION: Clinicians were thus not intuitively adapting dose to CYP2D6 activity in this sample, nor was CYP2D6 activity associated with prescribed dose. Although the previous studies could not be replicated, this study may provide support for existing and future pharmacogenetic research.

The Association Between Trajectories of Self-reported Psychotic Experiences and Continuity of Mental Health Care in a Longitudinal Cohort of Adolescents and Young Adults.

BACKGROUND AND HYPOTHESIS: Young people (YP) with psychotic experiences (PE) have an increased risk of developing a psychiatric disorder. Therefore, knowledge on continuity of care from child and adolescent (CAMHS) to adult mental health services (AMHS) in relation to PE is important. Here, we investigated whether the self-reported trajectories of persistent PE were associated with likelihood of transition to AMHS and mental health outcomes. STUDY DESIGN: In this prospective cohort study, interviews and questionnaires were used to assess PE, mental health, and service use in 763 child and adolescent mental health service users reaching their service's upper age limit in 8 European countries. Trajectories of self-reported PE (3 items) from baseline to 24-month follow-up were determined using growth mixture modeling (GMM). Associations were assessed with auxiliary variables and using mixed models. Study results. At baseline, 56.7% of YP reported PE. GMM identified 5 trajectories over 24 months: medium increasing (5.2%), medium stable (11.7%), medium decreasing (6.5%), high decreasing (4.2%), and low stable (72.4%). PE trajectories were not associated with continuity of specialist care or transition to AMHS. Overall, YP with PE reported more mental health problems at baseline. Persistence of PE or an increase was associated with poorer outcomes at follow-up. CONCLUSIONS: PE are common among CAMHS users when reaching the upper age limit of CAMHS. Persistence or an increase of PE was associated with poorer mental health outcomes, poorer prognosis, and impaired functioning, but were less discriminative for continuity of care.

Intracortical myelin across laminae in adult individuals with 47,XXX: a 7 Tesla MRI study.

47,XXX (Triple X syndrome) is a sex chromosome aneuploidy characterized by the presence of a supernumerary X chromosome in affected females and is associated with a variable cognitive, behavioral, and psychiatric phenotype. The effect of a supernumerary X chromosome in affected females on intracortical microstructure is currently unknown. Therefore, we conducted 7 Tesla structural MRI and compared T1 (ms), as a proxy for intracortical myelin (ICM), across laminae of 21 adult women with 47,XXX and 22 age-matched typically developing females using laminar analyses. Relationships between phenotypic traits and T1 values in 47,XXX were also investigated. Adults with 47,XXX showed higher bilateral T1 across supragranular laminae in the banks of the superior temporal sulcus, and in the right inferior temporal gyrus, suggesting decreases of ICM primarily within the temporal cortex in 47,XXX. Higher social functioning in 47,XXX was related to larger inferior temporal gyrus ICM content. Our findings indicate an effect of a supernumerary X chromosome in adult-aged women on ICM across supragranular laminae within the temporal cortex. These findings provide insight into the role of X chromosome dosage on ICM across laminae. Future research is warranted to further explore the functional significance of altered ICM across laminae in 47,XXX.

Possible pathophysiologic roles of neurotransmitter systems in men with lifelong premature ejaculation: a scoping review.

INTRODUCTION: Lifelong premature ejaculation (LPE) is a subtype of premature ejaculation. Genetic research on LPE has primarily focused on neurotransmitters such as serotonin, dopamine, and norepinephrine, whereas LPE treatment studies have focused on drugs such as selective serotonin reuptake inhibitors. However, findings from genetic association and pharmacotherapeutic studies have been inconsistent. OBJECTIVES: To provide a quality overview of neurobiological targets that are potentially associated with LPE by investigating genetic association and pharmacotherapeutic studies. METHODS: This scoping review was conducted per the PRISMA-ScR tool (Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews). Five databases were searched in March 2023 without timeline- or language-related restrictions. RESULTS: After deduplication, 3949 records were obtained for review. Following screening and full-text review with citation tracking, 52 studies were included: 18 genetic and 34 pharmacotherapy studies. Serotonergic targets, such as the serotonin transporter and pre- and postsynaptic serotonergic receptors, were most often associated with LPE in genetic and pharmacotherapeutic studies. Mixed results were found among polymorphisms within genetic studies. This mechanism is in accordance with pharmacotherapeutic studies, as the highest efficacy was found for potent serotonergic antidepressants. Successful treatment was also observed with medication acting on phosphodiesterase-5 enzyme, such as tadalafil and vardenafil. Analyses of other genetic association studies did not yield any further evidence for associated targets. CONCLUSIONS: This review is the first comprehensive scoping review on LPE. We found that serotonergic targets are most often associated with LPE, suggesting that the serotonergic pathway is a predisposing factor in LPE. Furthermore, there is some evidence for phosphodiesterase 5 inhibitors, which should be investigated. Other previously investigated neurobiological targets appear less likely to contribute to LPE. Future studies should focus on multiple targets, ideally in a genome-wide association study design.This review has been registered with the Open Science Framework (doi:10.17605/OSF.IO/JUQSD).

Neurocognitive profiles of 22q11.2 and 16p11.2 deletions and duplications.

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function.

Adaptation and validation of the On Your Own Feet - Transition Experiences Scale evaluating transitions to adult services among adolescent mental health service users in Europe.

PURPOSE: Experiences of young people transitioning from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS) have mostly been investigated qualitatively. This study adapts and validates the On Your Own Feet - Transition Experiences Scale (OYOF-TES) in a sample of CAMHS users in Europe and describes young people's and parents' experiences with transition and end of care at CAMHS. METHODS: The OYOF-TES was adapted to a mental health setting and translated. An End Of Care (OYOF-EOC) version (self- and parent-report) was developed. A total of 457 young people and 383 parents completed an OYOF-TES or OYOF-EOC. Psychometric properties and descriptives are presented. RESULTS: The Cronbach's alphas of the OYOF-TES and OYOF-EOC parent/self-report ranged from 0.92 to 0.94. The two-factor structure was confirmed. The mean overall satisfaction reported by young people was 6.15 (0-10; SD=2.92) for transition and 7.14 (0-10; SD=2.37) for care ending. However, 26.7%-36.4% of young people were unsatisfied. DISCUSSION: The OYOF-TES and OYOF-EOC can be used reliably in mental healthcare settings to capture young people's and parents' transition experiences. The majority of young people and parents was satisfied with the process of transition and care ending, yet a third of young people had negative experiences.

Glucagon-like peptide agonists for weight management in antipsychotic-induced weight gain: A systematic review and meta-analysis.

INTRODUCTION: Managing body weight in patients with antipsychotic-induced weight gain (AIWG) is challenging. Besides lifestyle interventions, pharmacological interventions may contribute to weight loss. This systematic review and meta-analysis evaluated the effect on weight loss and adverse effects of glucagon-like peptide-1 (GLP-1) agonists in patients with AIWG. MATERIALS AND METHODS: Following PRISMA guidelines, we performed a meta-analysis of blinded and open-label randomised controlled trials (RCTs), non-randomised controlled trials and cohort studies that evaluated treatment with GLP-1 in patients with AIWG, regardless of psychiatric diagnosis. PubMed, Embase, PsycINFO and Cochrane Library databases were searched. Primary outcome measures were changes in body weight and BMI. Secondary outcomes were changes in adverse effects and severity of psychopathology due to GLP-1 agonists. RESULTS: Only data for exenatide and liraglutide could be included, that is, five RCTs and one cohort study. For exenatide the mean weight loss was -2.48 kg (95% Confidence Interval (CI) -5.12 to +0.64; p = 0.07), for liraglutide the mean weight loss was -4.70 kg (95% CI -4.85 to -4.56; p < 0.001). The mean change in BMI was -0.82 (95% CI -1.56 to -0.09; p = 0.03) in the exenatide groups and -1.52 (95% CI -1.83 to -1.22; p < 0.001) in the liraglutide groups. Exenatide and liraglutide did not adversely affect psychopathology. The most common adverse events were nausea, vomiting, and diarrhoea. CONCLUSION: The GLP-1 agonists exenatide and liraglutide are promising drugs for inducing weight loss in patients with AIWG. The adverse effects are acceptable, and the addition of GLP-1 does not increase the severity of psychopathology. However, more research is needed.

A Scoping Review of the Effect of EEG Neurofeedback on Pain Complaints in Adults with Chronic Pain.

Background and Aim: Non-pharmacological treatments such as electroencephalogram (EEG) neurofeedback have become more important in multidisciplinary approaches to treat chronic pain. The aim of this scoping review is to identify the literature on the effects of EEG neurofeedback in reducing pain complaints in adult chronic-pain patients and to elaborate on the neurophysiological rationale for using specific frequency bands as targets for EEG neurofeedback. Methods: A pre-registered scoping review was set up and reported following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) extension for Scoping Reviews (PRISMA-ScR). The data were collected by searching for studies published between 1985 and January 2023 in PubMed, EMBASE, and PsycINFO. Results: Thirty-two studies on various types of chronic pain were included. The intervention was well-tolerated. Approximately half of the studies used a protocol that reinforced alpha or sensorimotor rhythms and suppressed theta or beta activity. However, the underlying neurophysiological rationale behind these specific frequency bands remains unclear. Conclusions: There are indications that neurofeedback in patients with chronic pain probably has short-term analgesic effects; however, the long-term effects are less clear. In order to draw more stable conclusions on the effectiveness of neurofeedback in chronic pain, additional research on the neurophysiological mechanisms of targeted frequency bands is definitely worthwhile. Several recommendations for setting up and evaluating the effect of neurofeedback protocols are suggested.