Influence of Large-Scale Brain State Dynamics on the Evoked Response to Brain Stimulation.

Understanding how spontaneous brain activity influences the response to neurostimulation is crucial for the development of neurotherapeutics and brain-computer interfaces. Localized brain activity is suggested to influence the response to neurostimulation, but whether fast-fluctuating (i.e., tens of milliseconds) large-scale brain dynamics also have any such influence is unknown. By stimulating the prefrontal cortex using combined transcranial magnetic stimulation (TMS) and electroencephalography, we examined how dynamic global brain state patterns, as defined by microstates, influence the magnitude of the evoked brain response. TMS applied during what resembled the canonical Microstate C was found to induce a greater evoked response for up to 80 ms compared with other microstates. This effect was found in a repeated experimental session, was absent during sham stimulation, and was replicated in an independent dataset. Ultimately, ongoing and fast-fluctuating global brain states, as probed by microstates, may be associated with intrinsic fluctuations in connectivity and excitation-inhibition balance and influence the neurostimulation outcome. We suggest that the fast-fluctuating global brain states be considered when developing any related paradigms.

Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study.

INTRODUCTION: Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19, CYP2D6, CYP3A4, and ABCB1, and its effect on these outcomes. METHODS: The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects. RESULTS: Eleven cis-SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain (q=0.027) and serum concentrations of ESCadj (q<0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESCadj concentrations. CITs did not indicate that these effects were epigenetically mediated. DISCUSSION: These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored.

A Subtype Perspective on Cognitive Trajectories in Healthy Aging.

Cognitive aging is a complex and dynamic process characterized by changes due to genetics and environmental factors, including lifestyle choices and environmental exposure, which contribute to the heterogeneity observed in cognitive outcomes. This heterogeneity is particularly pronounced among older adults, with some individuals maintaining stable cognitive function while others experience complex, non-linear changes, making it difficult to identify meaningful decline accurately. Current research methods range from population-level modeling to individual-specific assessments. In this work, we review these methodologies and propose that population subtyping should be considered as a viable alternative. This approach relies on early individual-specific detection methods that can lead to an improved understanding of changes in individual cognitive trajectories. The improved understanding of cognitive trajectories through population subtyping can lead to the identification of meaningful changes and the determination of timely, effective interventions. This approach can aid in informing policy decisions and in developing targeted interventions that promote cognitive health, ultimately contributing to a more personalized understanding of the aging process within society and reducing the burden on healthcare systems.

Contrasting MEG effects of anodal and cathodal high-definition TDCS on sensorimotor activity during voluntary finger movements.

Introduction: Protocols for noninvasive brain stimulation (NIBS) are generally categorized as "excitatory" or "inhibitory" based on their ability to produce short-term modulation of motor-evoked potentials (MEPs) in peripheral muscles, when applied to motor cortex. Anodal and cathodal stimulation are widely considered excitatory and inhibitory, respectively, on this basis. However, it is poorly understood whether such polarity-dependent changes apply for neural signals generated during task performance, at rest, or in response to sensory stimulation. Methods: To characterize such changes, we measured spontaneous and movement-related neural activity with magnetoencephalography (MEG) before and after high-definition transcranial direct-current stimulation (HD-TDCS) of the left motor cortex (M1), while participants performed simple finger movements with the left and right hands. Results: Anodal HD-TDCS (excitatory) decreased the movement-related cortical fields (MRCF) localized to left M1 during contralateral right finger movements while cathodal HD-TDCS (inhibitory), increased them. In contrast, oscillatory signatures of voluntary motor output were not differentially affected by the two stimulation protocols, and tended to decrease in magnitude over the course of the experiment regardless. Spontaneous resting state oscillations were not affected either. Discussion: MRCFs are thought to reflect reafferent proprioceptive input to motor cortex following movements. Thus, these results suggest that processing of incoming sensory information may be affected by TDCS in a polarity-dependent manner that is opposite that seen for MEPs-increases in cortical excitability as defined by MEPs may correspond to reduced responses to afferent input, and vice-versa.

Influence of CYP2C19, CYP2D6, and ABCB1 Gene Variants and Serum Levels of Escitalopram and Aripiprazole on Treatment-Emergent Sexual Dysfunction: A Canadian Biomarker Integration Network in Depression 1 (CAN-BIND 1) Study.

OBJECTIVES: Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19 and CYP2D6, and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample. METHODS: A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0-8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n = 91), while responders continued ESC (i.e., ESC-Only, n = 80) from weeks 8-16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0-8 and 8-16, using repeated measures mixed-effects models. RESULTS: In ESC-Only, CYP2C19 intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8-16, relative to CYP2C19 normal metabolizers (NMs) who showed a decline, F(2,54) = 8.00, p < 0.001, q = 0.048. Specifically, CYP2C19 IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF (r = -0.42, p = 0.004, q = 0.034) and SS (r = -0.43, p = 0.003, q = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction (r = -0.39, p = 0.009, q = 0.052). CONCLUSIONS: CYP2C19 metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19 may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.

Transcranial Magnetic Stimulation-Electroencephalography for Biomarker Discovery in Psychiatry.

Current diagnosis and treatment of psychiatric illnesses are still based on behavioral observations and self-reports, commonly leading to prolonged untreated illness. Biological markers (biomarkers) may offer an opportunity to revolutionize clinical psychiatry practice by helping provide faster and potentially more effective therapies. Transcranial magnetic stimulation concurrent with electroencephalography (TMS-EEG) is a noninvasive brain mapping methodology that can assess the functions and dynamics of specific brain circuitries in awake humans and aid in biomarker discovery. This article provides an overview of TMS-EEG-based biomarkers that may hold potential in psychiatry. The methodological readiness of the TMS-EEG approach and steps in the validation of TMS-EEG biomarkers for clinical utility are discussed. Biomarker discovery with TMS-EEG is in the early stages, and several validation steps are still required before clinical implementations are realized. Thus far, TMS-EEG predictors of response to magnetic brain stimulation treatments in particular have shown promise for translation to clinical practice. Larger-scale studies can confirm validation followed by biomarker-informed trials to assess added value compared to existing practice.

Baseline markers of cortical excitation and inhibition predict response to theta burst stimulation treatment for youth depression.

Theta burst stimulation (TBS), a specific form of repetitive transcranial magnetic stimulation (TMS), is a promising treatment for youth with Major Depressive Disorder (MDD) who do not respond to conventional therapies. However, given the variable response to TBS, a greater understanding of how baseline features relate to clinical response is needed to identify which patients are most likely to benefit from this treatment. In the current study, we sought to determine if baseline neurophysiology, specifically cortical excitation and/or inhibition, is associated with antidepressant response to TBS. In two independent open-label clinical trials, youth (aged 16-24 years old) with MDD underwent bilateral dorsolateral prefrontal cortex (DLPFC) TBS treatment. Clinical trial one and two consisted of 10 and 20 daily sessions of bilateral DLPFC TBS, respectively. At baseline, single-pulse TMS combined with electroencephalography was used to assess the neurophysiology of 4 cortical sites: bilateral DLPFC and inferior parietal lobule. Measures of cortical excitation and inhibition were indexed by TMS-evoked potentials (i.e., P30, N45, P60, N100, and P200). Depression severity was measured before, during and after treatment completion using the Hamilton Rating Scale for Depression-17. In both clinical trials, the baseline left DLPFC N45 and P60, which are believed to reflect inhibitory and excitatory mechanisms respectively, were predictors of clinical response. Specifically, greater (i.e., more negative) N45 and smaller P60 baseline values were associated with greater treatment response to TBS. Accordingly, cortical excitation and inhibition circuitry of the left DLPFC may have value as a TBS treatment response biomarker for youth with MDD.Clinical trial 1 registration number: NCT02472470 (June 15, 2015).Clinical trial 2 registration number: NCT03708172 (October 17, 2018).

Developing an Electroencephalography-Based Model for Predicting Response to Antidepressant Medication.

Importance: Untreated depression is a growing public health concern, with patients often facing a prolonged trial-and-error process in search of effective treatment. Developing a predictive model for treatment response in clinical practice remains challenging. Objective: To establish a model based on electroencephalography (EEG) to predict response to 2 distinct selective serotonin reuptake inhibitor (SSRI) medications. Design, Setting, and Participants: This prognostic study developed a predictive model using EEG data collected between 2011 and 2017 from 2 independent cohorts of participants with depression: 1 from the first Canadian Biomarker Integration Network in Depression (CAN-BIND) group and the other from the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) consortium. Eligible participants included those aged 18 to 65 years who had a diagnosis of major depressive disorder. Data were analyzed from January to December 2022. Exposures: In an open-label trial, CAN-BIND participants received an 8-week treatment regimen of escitalopram treatment (10-20 mg), and EMBARC participants were randomized in a double-blind trial to receive an 8-week sertraline (50-200 mg) treatment or placebo treatment. Main Outcomes and Measures: The model's performance was estimated using balanced accuracy, specificity, and sensitivity metrics. The model used data from the CAN-BIND cohort for internal validation, and data from the treatment group of the EMBARC cohort for external validation. At week 8, response to treatment was defined as a 50% or greater reduction in the primary, clinician-rated scale of depression severity. Results: The CAN-BIND cohort included 125 participants (mean [SD] age, 36.4 [13.0] years; 78 [62.4%] women), and the EMBARC sertraline treatment group included 105 participants (mean [SD] age, 38.4 [13.8] years; 72 [68.6%] women). The model achieved a balanced accuracy of 64.2% (95% CI, 55.8%-72.6%), sensitivity of 66.1% (95% CI, 53.7%-78.5%), and specificity of 62.3% (95% CI, 50.1%-73.8%) during internal validation with CAN-BIND. During external validation with EMBARC, the model achieved a balanced accuracy of 63.7% (95% CI, 54.5%-72.8%), sensitivity of 58.8% (95% CI, 45.3%-72.3%), and specificity of 68.5% (95% CI, 56.1%-80.9%). Additionally, the balanced accuracy for the EMBARC placebo group (118 participants) was 48.7% (95% CI, 39.3%-58.0%), the sensitivity was 50.0% (95% CI, 35.2%-64.8%), and the specificity was 47.3% (95% CI, 35.9%-58.7%), suggesting the model's specificity in predicting SSRIs treatment response. Conclusions and Relevance: In this prognostic study, an EEG-based model was developed and validated in 2 independent cohorts. The model showed promising accuracy in predicting treatment response to 2 distinct SSRIs, suggesting potential applications for personalized depression treatment.

SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants.

Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, SNORD90, was elevated following treatment response. When we increased Snord90 levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 (NRG3) as one of the targets of SNORD90, which we show is regulated through the accumulation of N6-methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission.

Resting-state EEG delta and alpha power predict response to cognitive behavioral therapy in depression: a Canadian biomarker integration network for depression study.

Cognitive behavioral therapy (CBT) is often recommended as a first-line treatment in depression. However, access to CBT remains limited, and up to 50% of patients do not benefit from this therapy. Identifying biomarkers that can predict which patients will respond to CBT may assist in designing optimal treatment allocation strategies. In a Canadian Biomarker Integration Network for Depression (CAN-BIND) study, forty-one adults with depression were recruited to undergo a 16-week course of CBT with thirty having resting-state electroencephalography (EEG) recorded at baseline and week 2 of therapy. Successful clinical response to CBT was defined as a 50% or greater reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to post-treatment completion. EEG relative power spectral measures were analyzed at baseline, week 2, and as early changes from baseline to week 2. At baseline, lower relative delta (0.5-4 Hz) power was observed in responders. This difference was predictive of successful clinical response to CBT. Furthermore, responders exhibited an early increase in relative delta power and a decrease in relative alpha (8-12 Hz) power compared to non-responders. These changes were also found to be good predictors of response to the therapy. These findings showed the potential utility of resting-state EEG in predicting CBT outcomes. They also further reinforce the promise of an EEG-based clinical decision-making tool to support treatment decisions for each patient.

TMS combined with EEG: Recommendations and open issues for data collection and analysis.

Transcranial magnetic stimulation (TMS) evokes neuronal activity in the targeted cortex and connected brain regions. The evoked brain response can be measured with electroencephalography (EEG). TMS combined with simultaneous EEG (TMS-EEG) is widely used for studying cortical reactivity and connectivity at high spatiotemporal resolution. Methodologically, the combination of TMS with EEG is challenging, and there are many open questions in the field. Different TMS-EEG equipment and approaches for data collection and analysis are used. The lack of standardization may affect reproducibility and limit the comparability of results produced in different research laboratories. In addition, there is controversy about the extent to which auditory and somatosensory inputs contribute to transcranially evoked EEG. This review provides a guide for researchers who wish to use TMS-EEG to study the reactivity of the human cortex. A worldwide panel of experts working on TMS-EEG covered all aspects that should be considered in TMS-EEG experiments, providing methodological recommendations (when possible) for effective TMS-EEG recordings and analysis. The panel identified and discussed the challenges of the technique, particularly regarding recording procedures, artifact correction, analysis, and interpretation of the transcranial evoked potentials (TEPs). Therefore, this work offers an extensive overview of TMS-EEG methodology and thus may promote standardization of experimental and computational procedures across groups.

ABCB1 Gene Variants and Antidepressant Treatment Outcomes: A Systematic Review and Meta-Analysis Including Results from the CAN-BIND-1 Study.

The P-glycoprotein efflux pump, encoded by the ABCB1 gene, has been shown to alter concentrations of various antidepressants in the brain. In this study, we conducted a systematic review and meta-analysis to investigate the association between six ABCB1 single-nucleotide polymorphisms (SNPs; rs1045642, rs2032582, rs1128503, rs2032583, rs2235015, and rs2235040) and antidepressant treatment outcomes in individuals with major depressive disorder (MDD), including new data from the Canadian Biomarker and Integration Network for Depression (CAN-BIND-1) cohort. For the CAN-BIND-1 sample, we applied regression models to investigate the association between ABCB1 SNPs and antidepressant treatment response, remission, tolerability, and antidepressant serum levels. For the meta-analysis, we systematically summarized pharmacogenetic evidence of the association between ABCB1 SNPs and antidepressant treatment outcomes. Studies were included in the meta-analysis if they investigated at least one ABCB1 SNP in individuals with MDD treated with at least one antidepressant. We did not find a significant association between ABCB1 SNPs and antidepressant treatment outcomes in the CAN-BIND-1 sample. A total of 39 studies were included in the systematic review. In the meta-analysis, we observed a significant association between rs1128503 and treatment response (T vs. C-allele, odds ratio = 1.30, 95% confidence interval = 1.15-1.48, P value (adjusted) = 0.024, n = 2,526). We did not find associations among the six SNPs and treatment remission nor tolerability. Our findings provide limited evidence for an association between common ABCB1 SNPs and antidepressant outcomes, which do not support the implementation of ABCB1 genotyping to inform antidepressant treatment at this time. Future research, especially on rs1128503, is recommended.

Response Inhibition and Predicting Response to Pharmacological and Cognitive Behavioral Therapy Treatments for Major Depressive Disorder: A Canadian Biomarker Integration Network for Depression Study.

BACKGROUND: Major depressive disorder (MDD) is associated with various cognitive impairments, including response inhibition. Deficits in response inhibition may also underlie poor antidepressant treatment response. Recent studies revealed that the neurobiological correlates of response inhibition can predict response to pharmacological treatments. However, the generalizability of this finding to first-line nonpharmacological treatments, particularly cognitive behavioral therapy, remains to be investigated. METHODS: Data from two independent treatment protocols were combined, one in which 65 patients with MDD underwent treatment with escitalopram, and the other in which 41 patients with MDD underwent a course of cognitive behavioral therapy. A total of 25 healthy control subjects were also recruited. Neural correlates of response inhibition were captured by participants completing a Go/NoGo task during electroencephalography recording. Response inhibition-related measures of interest included the amplitudes of the N2 and P3 event-related potentials. RESULTS: Pretreatment P3 amplitude, which has been linked to both the motor and cognitive aspects of response inhibition, was a significant predictor of change in depressive symptoms following escitalopram and cognitive behavioral therapy treatment. A greater pretreatment P3 amplitude was associated with a greater reduction in depressive severity. In addition, the pretreatment P3 amplitude was found to be significantly greater at baseline in remitters than in nonremitters and healthy control subjects. CONCLUSIONS: The integrity of response inhibition may be critical for a successful course of pharmacological or psychological treatment for MDD. Electrophysiological correlates of response inhibition may have utility as a general prognostic marker of treatment response in MDD. Future studies may investigate the benefit of preceding first-line treatments with interventions that improve response inhibition in MDD.

Prediction of depression treatment outcome from multimodal data: a CAN-BIND-1 report.

BACKGROUND: Prediction of treatment outcomes is a key step in improving the treatment of major depressive disorder (MDD). The Canadian Biomarker Integration Network in Depression (CAN-BIND) aims to predict antidepressant treatment outcomes through analyses of clinical assessment, neuroimaging, and blood biomarkers. METHODS: In the CAN-BIND-1 dataset of 192 adults with MDD and outcomes of treatment with escitalopram, we applied machine learning models in a nested cross-validation framework. Across 210 analyses, we examined combinations of predictive variables from three modalities, measured at baseline and after 2 weeks of treatment, and five machine learning methods with and without feature selection. To optimize the predictors-to-observations ratio, we followed a tiered approach with 134 and 1152 variables in tier 1 and tier 2 respectively. RESULTS: A combination of baseline tier 1 clinical, neuroimaging, and molecular variables predicted response with a mean balanced accuracy of 0.57 (best model mean 0.62) compared to 0.54 (best model mean 0.61) in single modality models. Adding week 2 predictors improved the prediction of response to a mean balanced accuracy of 0.59 (best model mean 0.66). Adding tier 2 features did not improve prediction. CONCLUSIONS: A combination of clinical, neuroimaging, and molecular data improves the prediction of treatment outcomes over single modality measurement. The addition of measurements from the early stages of treatment adds precision. Present results are limited by lack of external validation. To achieve clinically meaningful prediction, the multimodal measurement should be scaled up to larger samples and the robustness of prediction tested in an external validation dataset.

Does cognitive aging follow an orchid and dandelion phenomenon?

Cognitive reserve reflects the brain's intrinsic adaptive capacity against the neurodegenerative effects of aging. The maintenance or enhancement of the brain's cognitive reserve plays a crucial role in mitigating the severity of pathologies associated with aging. A new movement, social prescribing, which focuses on prescribing lifestyle activities as a treatment for patients, is growing in popularity as a solution against aging pathologies. However, few studies have demonstrated a clear impact of lifestyle activities on individual cognitive health, outside of floor and ceiling effects. Understanding who benefits from which lifestyle factors remains unclear. Here, we investigated the potential effects of lifestyle activities on individuals' cognitive health from more than 3,530 older adults using a stratification method and advanced analysis technique. Our stratification methods allowed us to observe a new result: older adults who had relatively average cognitive scores were not impacted by lifestyle factors. By comparison, older adults with very high or very low cognitive scores were highly impacted by lifestyle factors. These findings expand the orchid and dandelion theory to the aging field, regarding the biological sensitivity of individuals to harmful and protective environmental effects. Our discoveries demonstrate the role of individual differences in the aging process and its importance for social prescribing programs.

Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study.

Cytochrome P450 drug-metabolizing enzymes may contribute to interindividual differences in antidepressant outcomes. We investigated the effects of CYP2C19 and CYP2D6 gene variants on response, tolerability, and serum concentrations. Patients (N = 178) were treated with escitalopram (ESC) from weeks 0-8 (Phase I), and at week 8, either continued ESC if they were responders or were augmented with aripiprazole (ARI) if they were non-responders (<50% reduction in Montgomery-Åsberg Depression Rating Scale from baseline) for weeks 8-16 (Phase II). Our results showed that amongst patients on ESC-Only, CYP2C19 intermediate and poor metabolizers (IM + PMs), with reduced or null enzyme function, trended towards significantly lower symptom improvement during Phase II compared to normal metabolizers (NMs), which was not observed in ESC + ARI. We further showed that CYP2D6 NMs and IM + PMs had a higher likelihood of reporting a treatment-related central nervous system side effect in ESC-Only and ESC + ARI, respectively. The differences in the findings between ESC-Only and ESC + ARI may be due to the altered pharmacokinetics of ESC by ARI coadministration in ESC + ARI. We provided evidence for this postulation when we showed that in ESC-Only, CYP2C19 and CYP2D6 IM + PMs demonstrated significantly higher ESC concentrations at Weeks 10 and 16 compared to NMs. In contrast, ESC + ARI showed an association with CYP2C19 but not with CYP2D6 metabolizer group. Instead, ESC + ARI showed an association between CYP2D6 metabolizer group and ARI metabolite-to-drug ratio suggesting potential competition between ESC and ARI for CYP2D6. Our findings suggest that dosing based on CYP2C19 and CYP2D6 genotyping could improve safety and outcome in patients on ESC monotherapy.

Identification of Endocannabinoid Predictors of Treatment Outcomes in Major Depressive Disorder: A Secondary Analysis of the First Canadian Biomarker Integration Network in Depression (CAN-BIND 1) Study.

INTRODUCTION: An increasing number of studies are examining the link between the endocannabinoidome and major depressive disorder (MDD). We conducted an exploratory analysis of this system to identify potential markers of treatment outcomes. METHODS: The dataset of the Canadian Biomarker Integration Network in Depression-1 study, consisting of 180 patients with MDD treated for eight weeks with escitalopram followed by eight weeks with escitalopram alone or augmented with aripiprazole was analyzed. Association between response Montgomery-Asberg Depression Rating Scale (MADRS; score reduction≥50%) or remission (MADRS score≤10) at weeks 8 and 16 and single nucleotide polymorphisms (SNPs), methylation, and mRNA levels of 33 endocannabinoid markers were examined. A standard genome-wide association studies protocol was used for identifying SNPs, and logistic regression was used to assess methylation and mRNA levels. RESULTS: Lower methylation of CpG islands of the diacylglycerol lipase alpha gene (DAGLA) was associated with non-remission at week 16 (DAGLA; OR=0.337, p<0.003, q=0.050). Methylation of DAGLA was correlated with improvement in Clinical Global Impression (p=0.026), Quick Inventory of Depressive Symptomatology (p=0.010), and Snaith-Hamilton Pleasure scales (p=0.028). We did not find any association between SNPs or mRNA levels and treatment outcomes. DISCUSSION: Methylation of DAGLA is a promising candidate as a marker of treatment outcomes for MDD and needs to be explored further.

Identification and verification of a 'true' TMS evoked potential in TMS-EEG.

The concurrent combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) can unveil functional neural mechanisms with applications in basic and clinical research. In particular, TMS-evoked potentials (TEPs) potentially allow studying excitability and connectivity of the cortex in a causal manner that is not easily or non-invasively attainable with other neuroimaging techniques. The TEP waveform is obtained by isolating the EEG responses phase-locked to the time of TMS application. The intended component in a TEP waveform is the cortical activation by the TMS-induced electric current, free of instrumental and physiological artifact sources. This artifact-free cortical activation can be referred to as 'true' TEP. However, due to many unwanted auxiliary effects of TMS, the interpretation of 'true' TEPs has not been free of controversy. This paper reviews the most recent understandings of 'true' TEPs and their application. In the first part of the paper, TEP components are defined according to recommended methodologies. In the second part, the verification of 'true' TEP is discussed along with its sensitivity to brain-state, age, and disease. The various proposed origins of TEP components are then presented in the context of existing literature. Throughout the paper, lessons learned from the past TMS-EEG studies are highlighted to guide the identification and interpretation of 'true' TEPs in future studies.

Transcranial magnetic stimulation in the treatment of adolescent depression: a systematic review and meta-analysis of aggregated and individual-patient data from uncontrolled studies.

Transcranial magnetic stimulation (TMS) is a non-invasive treatment for adolescent major depressive disorder (MDD). Existing evidence on the efficacy of TMS in adolescent MDD awaits quantitative synthesis. A systematic literature search was conducted, and data from eligible studies were synthesized using random-effects models. Treatment-covariate interactions were examined in exploratory analyses of individual-patient data (IPD). Systematic search of the literature yielded 1264 hits, of which 10 individual studies (2 randomized trials) were included for quantitative synthesis of mainly uncontrolled studies. Individual patient data (IPD) were available from five trials (all uncontrolled studies). Quantitative synthesis of aggregated data revealed a statistically significant negative overall standardized mean change (pooled SMCC = 2.04, 95% CI [1.46; 2.61], SE = 0.29, p < .001), as well as a significant overall treatment response rate (Transformed Proportion = 41.30%, 95% CI [31.03; 51.57], SE = 0.05; p < 0.001), considering data from baseline to post-treatment. Exploratory IPD analyses suggests TMS might be more effective in younger individuals and individuals with more severe depression, and efficacy might be enhanced with certain treatment modality settings, including higher number of TMS sessions, longer treatment durations, and unilateral and not bilateral stimulation. Existing studies exhibit methodological shortcomings, including small-study effects and lack of control group, blinding, and randomization-compromising the credibility of the present results. To date, two randomized controlled trials on TMS in adolescent depression have been published, and the only large-scale randomized trial suggests TMS is not more effective than sham stimulation. Future large-scale, randomized, and sham-controlled trials are warranted. Future trials should ensure appropriate selection of patients for TMS treatment and guide precision medicine approaches for stimulation protocols.