Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

Auditory P50 Sensory Gating Alterations in Major Depressive Disorder and their Relationship to Clinical Symptoms.

Cognitive deficits in depression are pervasive and include impairments in attention and higher-order functions but the degree to which low-level sensory processes are affected is unclear. The present work examined event-related potential (P50 and N100) features of auditory sensory gating (i.e., the ability to inhibit P50/N100 responses to redundant stimuli) and their relationship to depressive symptoms, including ruminations and dysfunctional attitudes. In 18 patients with major depressive disorder (MDD) and 18 healthy volunteers, auditory sensory gating was measured using a paired-stimulus paradigm yielding ratio (rP50, rN100) and difference (dP50, dN100) gating indices, which reflected amplitude reductions from first (S1) to second (S2) stimulus. Patients with MDD exhibited diminished rP50 and dP50 gating scores and delayed S1-N100 latencies compared to healthy volunteers. These measures were positively associated with ruminative thoughts, negative attitudes and degree of depression. Study findings implicate aberrant sensory processing in depressed patients that is related to severity of maladaptive thinking.

One size does not fit all: notable individual variation in brain activity correlates of antidepressant treatment response.

Introduction: To date, no robust electroencephalography (EEG) markers of antidepressant treatment response have been identified. Variable findings may arise from the use of group analyses, which neglect individual variation. Using a combination of group and single-participant analyses, we explored individual variability in EEG characteristics of treatment response. Methods: Resting-state EEG data and Montgomery-Åsberg Depression Rating Scale (MADRS) symptom scores were collected from 43 patients with depression before, at 1 and 12 weeks of pharmacotherapy. Partial least squares (PLS) was used to: 1) identify group differences in EEG connectivity (weighted phase lag index) and complexity (multiscale entropy) between eventual medication responders and non-responders, and 2) determine whether group patterns could be identified in individual patients. Results: Responders showed decreased alpha and increased beta connectivity, and early, widespread decreases in complexity over treatment. Non-responders showed an opposite connectivity pattern, and later, spatially confined decreases in complexity. Thus, as in previous studies, our group analyses identified significant differences between groups of patients with different treatment outcomes. These group-level EEG characteristics were only identified in ~40-60% of individual patients, as assessed quantitatively by correlating the spatiotemporal brain patterns between groups and individual results, and by independent raters through visualization. Discussion: Our single-participant analyses suggest that substantial individual variation exists, and needs to be considered when investigating characteristics of antidepressant treatment response for potential clinical applicability. Clinical trial registration: https://clinicaltrials.gov, identifier NCT00519428.

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.

Under pressure-exploring partner changes, physiological responses and telomere dynamics in northern gannets across varying breeding conditions.

Background: Life history theory predicts trade-offs between reproduction and survival in species like the northern gannet (Morus bassanus). During breeding, demanding foraging conditions lead them to expand their foraging range and diversify their diet, increasing the risk of reproductive failure. Changing partners may enhance breeding success but lead to more physiological costs. Methods: To investigate the physiological costs of reproduction upon partner changes, we measured and compared 21 biomarkers related to telomere dynamics, oxidative stress, inflammation, hematology, nutritional status, and muscle damage. We used a longitudinal approach with gannets (n = 38) over three contrasting years (2017, 2018 and 2019). Results: Our results suggest that annual breeding conditions exert a greater influence on physiological changes than partnership status. Individuals that changed partner experienced greater short-term stress than retained partners. This transient increase in stress was marked by short-term increases in oxidative lipid damage, lower antioxidant capacity, signs of inflammation, and greater weight loss than individuals that retained partners. During favorable conditions, individuals that changed mates had stabilized telomere length, decreased antioxidant capacity, glucose concentration, and muscle damage, along with increased oxygen transport capacity. Conversely, unfavorable breeding conditions led to increased telomere attrition, stabilized antioxidant capacity, decreased inflammation susceptibility, diminished oxygen transport capacity, and increased muscle damage. In the cases where partners were retained, distinct physiological changes were observed depending on the year's conditions, yet the telomere dynamics remained consistent across both partnership status categories. During the favorable year, there was an increase in unsaturated fatty acids and oxygen transport capacity in the blood, coupled with a reduction in inflammation potential and protein catabolism. In contrast, during the unfavorable year in the retained mates, we observed an increase in oxidative DNA damage, antioxidant capacity, weight loss, but a decrease in inflammation susceptibility as observed in changed mates. Discussion: Our study shows that behavioral flexibility such as mate switching can help seabirds cope with the challenges of food scarcity during reproduction, but these coping strategies may have a negative impact on physiological status at the individual level. In addition, the marked reduction in telomere length observed during harsh conditions, coupled with the stabilization of telomere length in favorable conditions, highlights the long-term physiological impact of annual breeding conditions on seabirds. These findings underscore the effect on their potential survival and fitness, emphasizing that the influence of annual breeding conditions is greater than that of partnership status.

Ketamine promptly normalizes excess norepinephrine and enhances dopamine neuronal activity in Wistar Kyoto rats.

Ketamine acts primarily by blocking the N-methyl-D-aspartate (NMDA) receptor at the phencyclidine site. The rapid antidepressant properties of ketamine were demonstrated in the clinic and several behavioral models of depression in rodents. We hypothesized that the normalization of abnormal activity of monoamine neurons in Wistar Kyoto (WKY) rats contributes to the rapid antidepressant effects of ketamine. A single administration of ketamine (10 mg/kg, i. p) or saline was administered to anesthetized WKY rats before in vivo electrophysiological recordings of dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus (LC) norepinephrine (NE) and ventral tegmental area (VTA) dopamine (DA) neuronal activity. Pyramidal neurons from the medial prefrontal cortex (mPFC) were also recorded before and after a ketamine injection. In the VTA, ketamine elicited a significant increase in the population activity of DA neurons. This enhancement was consistent with findings in other depression-like models in which such a decreased population activity was observed. In the LC, ketamine normalized increased NE neuron burst activity found in WKY rats. In the DRN, ketamine did not significantly reverse 5-HT neuronal activity in WKY rats, which is dampened compared to Wistar rats. Ketamine did not significantly alter the neuronal activity of mPFC pyramidal neurons. These findings demonstrate that ketamine normalized NE neuronal activity and enhanced DA neuronal activity in WKY rats, which may contribute to its rapid antidepressant effect.

Wistar Kyoto rats exhibit decreased serotonin neuronal firing and increased norepinephrine burst activity but dampened hippocampal α2-adrenoceptor sensitivity.

BACKGROUND: Wistar Kyoto (WKY) rats manifest abnormalities in the function of monoamine receptors and transporters, as well as levels of these neurotransmitters in the brain. The present study assessed alterations in the firing activity of serotonin (5-hydroxytryptamine [5-HT]), norepinephrine (NE), and dopamine (DA) neurons, as well as the activity of 5-HT and NE receptors and transporters in the hippocampus. METHODS: In vivo electrophysiological recordings were conducted in male WKY and Wistar rats. Extracellular single-unit recordings of 5-HT, NE, and DA neurons were performed. Recordings of pyramidal neurons were conducted in the medial prefrontal cortex (mPFC) and the hippocampus, where direct application of 5-HT and NE by iontophoresis was also carried out. RESULTS: The mean firing rate of 5-HT neurons was significantly decreased in WKY compared to Wistar rats. The burst activity of NE neurons was significantly increased in WKY, while their mean firing activity was not changed. There was no alteration in the firing, burst, and population activity of DA neurons in WKY animals. In the hippocampus, a decrease in sensitivity of α2-adrenoceptors, but not 5-HT receptors, was observed. There was, however, no change in the activity of 5-HT and NE transporters. The firing activity of mPFC pyramidal neurons was similar in WKY versus Wistar rats. CONCLUSION: In WKY rats, there was a decrease in the firing activity of 5-HT neurons. There was also an enhanced burst activity of NE neurons, accompanied by a reduction in sensitivity of the α2-adrenoceptor in the hippocampus, inferring a decrease in NE transmission.

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.

Northern shrimp from multiple origins show similar sensitivity to global change drivers, but different cellular energetic capacity.

Species with a wide distribution can experience significant regional variation in environmental conditions, to which they can acclimatize or adapt. Consequently, the geographic origin of an organism can influence its responses to environmental changes, and therefore its sensitivity to combined global change drivers. This study aimed at determining the physiological responses of the northern shrimp, Pandalus borealis, at different levels of biological organization and from four different geographic origins, exposed to elevated temperature and low pH to define its sensitivity to future ocean warming and acidification. Shrimp sampled within the northwest Atlantic were exposed for 30 days to combinations of three temperature (2, 6 or 10°C) and two pH levels (7.75 or 7.40). Survival, metabolic rates, whole-organism aerobic performance and cellular energetic capacity were assessed at the end of the exposure. Our results show that shrimp survival was negatively affected by temperature above 6°C and low pH, regardless of their origin. Additionally, shrimp from different origins show overall similar whole-organism performances: aerobic scope increasing with increasing temperature and decreasing with decreasing pH. Finally, the stability of aerobic metabolism appears to be related to cellular adjustments specific to shrimp origin. Our results show that the level of intraspecific variation differs among levels of biological organization: different cellular capacities lead to similar individual performances. Thus, the sensitivity of the northern shrimp to ocean warming and acidification is overall comparable among origins. Nonetheless, shrimp vulnerability to predicted global change scenarios for 2100 could differ among origins owing to different regional environmental conditions.

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.

Solving the conundrum of intra-specific variation in metabolic rate: A multidisciplinary conceptual and methodological toolkit: New technical developments are opening the door to an understanding of why metabolic rate varies among individual animals of a species: New technical developments are opening the door to an understanding of why metabolic rate varies among individual animals of a species.

Researchers from diverse disciplines, including organismal and cellular physiology, sports science, human nutrition, evolution and ecology, have sought to understand the causes and consequences of the surprising variation in metabolic rate found among and within individual animals of the same species. Research in this area has been hampered by differences in approach, terminology and methodology, and the context in which measurements are made. Recent advances provide important opportunities to identify and address the key questions in the field. By bringing together researchers from different areas of biology and biomedicine, we describe and evaluate these developments and the insights they could yield, highlighting the need for more standardisation across disciplines. We conclude with a list of important questions that can now be addressed by developing a common conceptual and methodological toolkit for studies on metabolic variation in animals.

Thermal modulation of mitochondrial function is affected by environmental nickel in rainbow trout (Oncorhynchus mykiss).

In this study, we investigated the combined effects of temperature and nickel (Ni) contamination on liver mitochondria electron transport system (ETS) enzymes, citrate synthase (CS), phospholipid fatty acid composition and lipid peroxidation in rainbow trout (Oncorhynchus mykiss). Juvenile trout were acclimated for two weeks to two different temperatures (5˚C and 15˚C) and exposed to nickel (Ni; 520 µg/L) for three weeks. Using ratios of ETS enzymes and CS activities, our data suggest that Ni and an elevated temperature acted synergistically to induce a higher capacity for reduction status of the ETS. The response of phospholipid fatty acid profiles to thermal variation was also altered under nickel exposure. In control conditions, the proportion of saturated fatty acids (SFA) was higher at 15˚C than at 5˚C, while the opposite was observed for monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA). However, in nickel contaminated fish, the proportion of SFA was higher at 5˚C than at 15˚C, while PUFA and MUFA followed the opposite direction. A higher PUFA ratio is associated with higher vulnerability to lipid peroxidation. Thiobarbituric Acid Reactive Substances (TBARS) content was higher when the PUFA were in higher proportions, except for Ni-exposed, warm-acclimated fish, in which we reported the lowest level of TBARS but the highest proportion of PUFA. We suspect that the interaction of nickel and temperature on lipid peroxidation is due to their synergistic effects on aerobic energy metabolism, as supported by the decrease in the activity of complex IV of the ETS enzyme activity in those fish, or on antioxidant enzymes and pathways. Overall, our study demonstrates that Ni exposure in heat-challenged fish can lead to the remodelling of the mitochondrial phenotype and potentially stimulate alternative antioxidant mechanisms.

Free-Water Diffusion Magnetic Resonance Imaging Differentiates Suicidal Ideation From Suicide Attempt in Treatment-Resistant Depression.

BACKGROUND: Suicide attempt is highly prevalent in treatment-resistant depression (TRD); however, the neurobiological profile of suicidal ideation versus suicide attempt is unclear. Neuroimaging methods including diffusion magnetic resonance imaging-based free-water imaging may identify neural correlates underlying suicidal ideation and attempts in individuals with TRD. METHODS: Diffusion magnetic resonance imaging data were obtained from 64 male and female participants (mean age 44.5 ± 14.2 years), including 39 patients with TRD (n = 21 and lifetime history of suicidal ideation but no attempts [SI group]; n = 18 with lifetime history of suicide attempt [SA group]), and 25 age- and sex-matched healthy control participants. Depression and suicidal ideation severity were examined using clinician-rated and self-report measures. Whole-brain neuroimaging analysis was conducted using tract-based spatial statistics via FSL to identify differences in white matter microstructure in the SI versus SA groups and in patients versus control participants. RESULTS: Free-water imaging revealed elevated axial diffusivity and extracellular free water in fronto-thalamo-limbic white matter tracts of the SA group compared with the SI group. In a separate comparison, patients with TRD had widespread reductions in fractional anisotropy and axial diffusivity, as well as elevated radial diffusivity compared with control participants (thresholded p < .05, familywise error corrected). CONCLUSIONS: A unique neural signature consisting of elevated axial diffusivity and free water was identified in patients with TRD and suicide attempt history. Findings of reduced fractional anisotropy, axial diffusivity, and elevated radial diffusivity in patients versus control participants are consistent with previously published studies. Multimodal and prospective investigations are recommended to better understand biological correlates of suicide attempt in TRD.

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.

The longest-lived metazoan, Arctica islandica, exhibits high mitochondrial H2O2 removal capacities.

A greater capacity of endogenous matrix antioxidants has recently been hypothesized to characterize mitochondria of long-lived species, curbing bursts of reactive oxygen species (ROS) generated in this organelle. Evidence for this has been obtained from studies comparing the long-lived naked mole rat to laboratory mice. We tested this hypothesis by comparing the longest-lived metazoan, the marine bivalve Arctica islandica (MLSP = 507 y), with shorter-lived and evolutionarily related species. We used a recently developed fluorescent technique to assess mantle and gill tissue mitochondria's capacity to consume hydrogen peroxide (H2O2) in multiple physiological states ex vivo. Depending on the type of respiratory substrate provided, mitochondria of Arctica islandica could consume between 3 and 14 times more H2O2 than shorter-lived species. These findings support the contention that a greater capacity for the elimination of ROS characterizes long-lived species, a novel property of mitochondria thus far demonstrated in two key biogerontological models from distant evolutionary lineages.

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.

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.

International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators.

Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; ß*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; ß*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630.