Psilocybin desynchronizes the human brain.

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion.

Bupropion is used for treating depression, obesity, and seasonal affective disorder, and for smoking cessation. Bupropion is commonly prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability, and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active, and allelic variation in cytochrome P450 (CYP) 2B6 affects clinical hydroxylation of single-dose bupropion. Genetic effects on stereoselective disposition of steady-state bupropion are not known. In this preplanned secondary analysis of a prospective, randomized, double-blinded, crossover study which compared brand and generic bupropion XL 300 mg drug products, we measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations. This investigation evaluated the influence of genetic polymorphisms in CYP2B6, CYP2C19, and P450 oxidoreductase on the disposition of Valeant Pharmaceuticals Wellbutrin brand bupropion in 67 participants with major depressive disorder. We found that hydroxylation of both bupropion enantiomers was lower in carriers of the CYP2B6*6 allele and in carriers of the CYP2B6 516G>T variant, with correspondingly greater bupropion and lesser hydroxybupropion plasma concentrations. Hydroxylation was 25-50% lower in CYP2B6*6 carriers and one-third to one-half less in 516T carriers. Hydroxylation of the bupropion enantiomers was comparably affected by CYP2B6 variants. CYP2C19 polymorphisms did not influence bupropion plasma concentrations or hydroxybupropion formation but did influence the minor pathway of 4'-hydroxylation of bupropion and primary metabolites. P450 oxidoreductase variants did not influence bupropion disposition. Results show that CYP2B6 genetic variants affect steady-state metabolism and bioactivation of Valeant brand bupropion, which may influence therapeutic outcomes. SIGNIFICANCE STATEMENT: Bupropion, used for depression, obesity, and smoking cessation, undergoes metabolic bioactivation, with incompletely elucidated interindividual variability. We evaluated cytochrome P450 (CYP) 2B6, CYP2C19 and P450 oxidoreductase genetic variants and steady-state bupropion and metabolite enantiomers disposition. Both enantiomers hydroxylation was lower in CYP2B6*6 and CYP2B6 516G>T carriers, with greater bupropion and lesser hydroxybupropion plasma concentrations. CYP2C19 polymorphisms did not affect bupropion or hydroxybupropion but did influence minor 4'-hydroxylation of bupropion and primary metabolites. CYP2B6 variants affect steady-state bupropion bioactivation, which may influence therapeutic outcomes.

A Culturally Adapted Perioperative Mental Health Intervention for Older Black Surgical Patients.

OBJECTIVES: Perioperative mental health of older Black surgical patients is associated with poor surgical outcomes; however, evidence-based perioperative interventions are lacking. Our two study objectives included: first, examine factors affecting perioperative care experiences of older Black surgical patients with mental health problems, and second, ascertain design and implementation requirements for a culturally-adapted perioperative mental health intervention. DESIGN SETTING AND PARTICIPANTS: We conducted six focus groups with older Black patients (n = 15; ≥50 years; surgery within the past 5 years and/or interest in mental health research; history of distress, anxiety, or depression coping with surgery/hospitalization/) from a large academic medical center. We engaged study partners, including interventionists and community members, to gather insights on intervention and implementation needs. We followed a hybrid inductive-deductive thematic approach using open coding and the National Institute on Minority Health and Health Disparities Research Framework. RESULTS: Patients reported that their psychological well-being and long-term mental health outcomes were not appropriately considered during perioperative care. Perceived stressors included interpersonal and structural barriers to using mental healthcare services, clinician treatment biases and ageism in care, and lack of healthcare professional connections/resources. Patients utilized various coping strategies, including talk therapy, faith/spirituality, and family and friends. CONCLUSION: This study offers valuable insights into the experiences of older Black surgical patients and the critical elements for developing a personalized perioperative mental health intervention to support their well-being before, during, and after surgery. Our findings demonstrated a need for a patient-centered and culturally adapted intervention targeting the individual/behavioral and interpersonal levels. Informed by the cultural adaptation framework, we propose a multi-component intervention that integrates psychological and pharmacological components.

Alcohol and substance use in older adults with treatment-resistant depression.

INTRODUCTION: Alcohol and substance use are increasing in older adults, many of whom have depression, and treatment in this context may be more hazardous. We assessed alcohol and other substance use patterns in older adults with treatment-resistant depression (TRD). We examined patient characteristics associated with higher alcohol consumption and examined the moderating effect of alcohol on the association between clinical variables and falls during antidepressant treatment. METHODS: This secondary and exploratory analysis used baseline clinical data and data on falls during treatment from a large randomized antidepressant trial in older adults with TRD (the OPTIMUM trial). Multivariable ordinal logistic regression was used to identify variables associated with higher alcohol use. An interaction model was used to evaluate the moderating effect of alcohol on falls during treatment. RESULTS: Of 687 participants, 51% acknowledged using alcohol: 10% were hazardous drinkers (AUDIT-10 score ≥5) and 41% were low-risk drinkers (score 1-4). Benzodiazepine use was seen in 24% of all participants and in 21% of drinkers. Use of other substances (mostly cannabis) was associated with alcohol consumption: it was seen in 5%, 9%, and 15% of abstainers, low-risk drinkers, and hazardous drinkers, respectively. Unexpectedly, use of other substances predicted increased risk of falls during antidepressant treatment only in abstainers. CONCLUSIONS: One-half of older adults with TRD in this study acknowledged using alcohol. Use of alcohol concurrent with benzodiazepine and other substances was common. Risks-such as falls-of using alcohol and other substances during antidepressant treatment needs further study.

Brain-Hazardous Medications and Potential Subadequate Antidepressant Dosing in Older Surgical Patients Receiving Home Antidepressants: An Observational Study of a Large US Health System.

BACKGROUND: Older surgical patients with depression often experience poor postoperative outcomes. Poor outcomes may stem from brain-hazardous medications and subadequate antidepressant dosing. METHODS: This was a retrospective, observational cohort study covering the period between January 1, 2021 and December 31, 2021. Patients ≥60 years of age who underwent inpatient surgery and had an overnight stay at an integrated academic health care system comprising 14 hospitals were eligible. We analyzed the prevalence of home central nervous system (CNS)-active potentially inappropriate medication (PIM) and potential subadequate antidepressant dosing in older surgical patients receiving home antidepressants. Univariable and multivariable regression models were used to identify factors associated with home CNS-active PIM prescribing and potential subadequate antidepressant dosing. Additionally, outcomes were compared among patients receiving and not receiving CNS-active PIMs and patients receiving and not receiving subadequate antidepressant dosing. RESULTS: A total of 8031 patients were included in this study (47% female, mean age = 70 years) of whom 2087 (26%) were prescribed antidepressants. Roughly one-half (49%, 95% confidence interval [CI], 46.5-50.1) of patients receiving home antidepressants were also receiving ≥1 CNS-active PIM and 29% (95% CI, 27.0-29.3) were receiving a potential subadequate dose. Factors associated with an increased likelihood of receiving a home CNS-active PIM included female sex (adjusted odds ratio [aOR], 1.46), anxiety (aOR, 2.43), asthma or chronic obstructive pulmonary disease (aOR, 1.39), and serotonin-norepinephrine reuptake inhibitor use (aOR, 1.54). Patients aged ≥75 years (aOR, 1.57), black race (aOR, 1.48) and those with congestive heart failure (aOR, 1.33) were more likely to be prescribed a potential subadequate antidepressant dose. Patients receiving potential subadequate antidepressant doses were discharged home less often (64% vs 73%), had a longer hospital length of stay (9 days vs 7 days), and a higher mortality rate (18% vs 10%) compared to patients receiving adequate home antidepressant doses (P-value for all <0.01). No differences in these outcomes were found among patients receiving home antidepressants with or without CNS-active PIMs. CONCLUSIONS: Older surgical patients receiving antidepressants are frequently prescribed brain-hazardous medications and potentially subadequate antidepressant doses. Those receiving subadequate antidepressant doses may be at risk for worse postoperative outcomes compared to patients receiving adequate doses. The role of preoperative medication optimization to improve outcomes for older surgical patients should be evaluated.

An investigation of the potential clinical utility of critical slowing down as an early warning sign for recurrence of depression.

BACKGROUND AND OBJECTIVES: Much of the burden of depressive illness is due to relapses that occur after treatment into remission. Prediction of an individual's imminent depressive relapse could lead to just-in-time interventions to prevent relapse, reducing depression's substantial burden of disability, costs, and suicide risk. Increasingly strong relationships in the form of autocorrelations between depressive symptoms, a signal of a phenomenon described as critical slowing down (CSD), have been proposed as a means of predicting relapse. METHODS: In the current study, four participants in remission from depression, one of whom relapsed, responded to daily smartphone surveys with depression symptoms. We used p-technique factor analysis to identify depression factors from over 100 survey responses. We then tested for the presence of CSD using time-varying vector autoregression and detrended fluctuation analysis. RESULTS: We found evidence that CSD provided an early warning sign for depression in the participant who relapsed, but we also detected false positive indications of CSD in participants who did not relapse. Results from time-varying vector autoregression and detrended fluctuation analysis were not in agreement. LIMITATIONS: Limitations include use of secondary data and a small number of participants with daily responding to a subset of depression symptoms. CONCLUSIONS: CSD provides a compelling framework for predicting depressive relapse and future research should focus on improving detection of early warning signs reliably. Improving early detection methods for depression is clinically significant, as it would allow for the development of just-in-time interventions.

Sertraline modulates hippocampal plasticity and learning via sigma 1 receptors, cellular stress and neurosteroids.

In addition to modulating serotonin transport, selective serotonin reuptake inhibitors (SSRIs) have multiple other effects that may contribute to clinical effects, and some of these latter actions prompt repurposing of SSRIs for non-psychiatric indications. We recently observed that the SSRIs fluvoxamine and fluoxetine prevent the acute adverse effects of pro-inflammatory stimulation on long-term potentiation (LTP) in the CA1 hippocampal region. Sertraline showed markedly different effects, acutely inhibiting LTP at a low micromolar concentration through inverse agonism of sigma 1 receptors (S1Rs). In the present studies, we pursued mechanisms contributing to sertraline modulation of LTP in rat hippocampal slices. We found that sertraline partially inhibits synaptic responses mediated by N-methyl-D-aspartate receptors (NMDARs) via effects on NMDARs that express GluN2B subunits. A selective S1R antagonist (NE-100), but not an S1R agonist (PRE-084) blocked effects on NMDARs, despite the fact that both S1R ligands were previously shown to prevent LTP inhibition. Both NE-100 and PRE-084, however, prevented adverse effects of sertraline on one-trial learning. Because of the important role that S1Rs play in modulating endoplasmic reticulum stress, we examined whether inhibitors of cellular stress alter effects of sertraline. We found that two stress inhibitors, ISRIB and quercetin, prevented LTP inhibition, as did inhibitors of the synthesis of endogenous neurosteroids, which are homeostatic regulators of cellular stress. These studies highlight complex effects of sertraline, S1Rs and neurosteroids on hippocampal function and have relevance for understanding therapeutic and adverse drug actions.

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression.

In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine.

Relationship between Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores in older adults with major depressive disorder: An analysis of the OPTIMUM clinical trial.

BACKGROUND: The Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) are commonly used scales to measure depression severity in older adults. METHODS: We utilized data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) clinical trial to produce conversion tables relating PHQ-9 and MADRS total scores. We split the sample into training (N = 555) and validation samples (N = 187). Equipercentile linking was performed on the training sample to produce conversion tables for PHQ-9 and MADRS. We compared the original and estimated scores in the validation sample with Bland-Altman analysis. We compared the depression severity level using the original and estimated scores with Chi-square tests. RESULTS: The Bland-Altman analysis confirmed that differences between the original and estimated scores for at least 95 % of the sample fit within 1.96 standard deviations of the mean difference. Chi-square tests showed a significant difference in the proportion of participants at each depression severity category determined using the original and estimated scores. LIMITATIONS: The conversion tables should be used with caution when comparing depression severity at the individual level. CONCLUSIONS: Our conversion tables relating PHQ-9 and MADRS scores can be used to compare treatment outcomes using aggregate data in studies that only used one of these scales.

Propofol enhancement of slow wave sleep to target the nexus of geriatric depression and cognitive dysfunction: protocol for a phase I open label trial.

INTRODUCTION: Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has been supported by a recent small case series. METHODS AND ANALYSIS: SWIPED (Slow Wave Induction by Propofol to Eliminate Depression) phase I is an ongoing open-label, single-arm trial that assesses the safety and feasibility of using propofol to enhance SWS in older adults with LL-TRD. The study is enrolling 15 English-speaking adults over age 60 with LL-TRD. Participants will receive two propofol infusions 2-6 days apart. Propofol infusions are individually titrated to maximise the expression of EEG slow waves. Preinfusion and postinfusion sleep architecture are evaluated through at-home overnight EEG recordings acquired using a wireless headband equipped with dry electrodes. Sleep EEG recordings are scored manually. Key EEG measures include sleep slow wave activity, SWS duration and delta sleep ratio. Longitudinal changes in depression, suicidality and anhedonia are assessed. Assessments are performed prior to the first infusion and up to 10 weeks after the second infusion. Cognitive ability is assessed at enrolment and approximately 3 weeks after the second infusion. ETHICS AND DISSEMINATION: The study was approved by the Washington University Human Research Protection Office. Recruitment began in November 2022. Dissemination plans include presentations at scientific conferences, peer-reviewed publications and mass media. Positive results will lead to a larger phase II randomised placebo-controlled trial. TRIAL REGISTRATION NUMBER: NCT04680910.

Intraindividual variability in post-stroke cognition and its relationship with activities of daily living and social functioning: an ecological momentary assessment approach.

INTRODUCTION: Ecological momentary assessment (EMA) is a methodological approach to studying intraindividual variation over time. This study aimed to use EMA to determine the variability of cognition in individuals with chronic stroke, identify the latent classes of cognitive variability, and examine any differences in daily activities, social functioning, and neuropsychological performance between these latent classes. METHODS: Participants (N = 202) with mild-to-moderate stroke and over 3-month post-stroke completed a study protocol, including smartphone-based EMA and two lab visits. Participants responded to five EMA surveys daily for 14 days to assess cognition. They completed patient-reported measures and neuropsychological assessments during lab visits. Using latent class analysis, we derived four indicators to quantify cognitive variability and identified latent classes among participants. We used ANOVA and Chi-square to test differences between these latent classes in daily activities, social functioning, and neuropsychological performance. RESULTS: The latent class analysis converged on a three-class model. The moderate and high variability classes demonstrated significantly greater problems in daily activities and social functioning than the low class. They had significantly higher proportions of participants with problems in daily activities and social functioning than the low class. Neuropsychological performance was not statistically different between the three classes, although a trend approaching statistically significant difference was observed in working memory and executive function domains. DISCUSSION: EMA could capture intraindividual cognitive variability in stroke survivors. It offers a new approach to understanding the impact and mechanism of post-stroke cognitive problems in daily life and identifying individuals benefiting from self-regulation interventions.

Sex differences in plasma proteomic markers in late-life depression.

Previous studies have shown significant sex-specific differences in major depressive disorder (MDD) in multiple biological parameters. Most studies focused on young and middle-aged adults, and there is a paucity of information about sex-specific biological differences in older adults with depression (aka, late-life depression (LLD)). To address this gap, this study aimed to evaluate sex-specific biological abnormalities in a large group of individuals with LLD using an untargeted proteomic analysis. We quantified 344 plasma proteins using a multiplex assay in 430 individuals with LLD and 140 healthy comparisons (HC) (age range between 60 and 85 years old for both groups). Sixty-six signaling proteins were differentially expressed in LLD (both sexes). Thirty-three proteins were uniquely associated with LLD in females, while six proteins were uniquely associated with LLD in males. The main biological processes affected by these proteins in females were related to immunoinflammatory control. In contrast, despite the smaller number of associated proteins, males showed dysregulations in a broader range of biological pathways, including immune regulation pathways, cell cycle control, and metabolic control. Sex has a significant impact on biomarker changes in LLD. Despite some overlap in differentially expressed biomarkers, males and females show different patterns of biomarkers changes, and males with LLD exhibit abnormalities in a larger set of biological processes compared to females. Our findings can provide novel targets for sex-specific interventions in LLD.

Perioperative mental health intervention for depression and anxiety symptoms in older adults study protocol: design and methods for three linked randomised controlled trials.

INTRODUCTION: Preoperative anxiety and depression symptoms among older surgical patients are associated with poor postoperative outcomes, yet evidence-based interventions for anxiety and depression have not been applied within this setting. We present a protocol for randomised controlled trials (RCTs) in three surgical cohorts: cardiac, oncological and orthopaedic, investigating whether a perioperative mental health intervention, with psychological and pharmacological components, reduces perioperative symptoms of depression and anxiety in older surgical patients. METHODS AND ANALYSIS: Adults ≥60 years undergoing cardiac, orthopaedic or oncological surgery will be enrolled in one of three-linked type 1 hybrid effectiveness/implementation RCTs that will be conducted in tandem with similar methods. In each trial, 100 participants will be randomised to a remotely delivered perioperative behavioural treatment incorporating principles of behavioural activation, compassion and care coordination, and medication optimisation, or enhanced usual care with mental health-related resources for this population. The primary outcome is change in depression and anxiety symptoms assessed with the Patient Health Questionnaire-Anxiety Depression Scale from baseline to 3 months post surgery. Other outcomes include quality of life, delirium, length of stay, falls, rehospitalisation, pain and implementation outcomes, including study and intervention reach, acceptability, feasibility and appropriateness, and patient experience with the intervention. ETHICS AND DISSEMINATION: The trials have received ethics approval from the Washington University School of Medicine Institutional Review Board. Informed consent is required for participation in the trials. The results will be submitted for publication in peer-reviewed journals, presented at clinical research conferences and disseminated via the Center for Perioperative Mental Health website. TRIAL REGISTRATION NUMBERS: NCT05575128, NCT05685511, NCT05697835, pre-results.