Individual differences in working memory predict the efficacy of experimenter-manipulated gestures in first-grade children.

Why is instructional gesture ineffective in some contexts? And what is it about learners that predicts whether they will learn from gestures? This between-subjects linear measurement training study compares gesture instruction to two controls-operant action and transient action-in a diverse sample of first-grade students (N = 174, Mage = 7.01 years; Nfemale = 84; Nmale = 90, 10% Latinx-identified; 70% White; 6% Black; 6% Asian; 18% multiple racial categories, Mincome = $59,750, SDincome ≈ $25,000; data collected 03/16-03/19). Results show that instructor-manipulated gestures may be less effective than demonstrative actions in part because they are iterative and do not leave a lasting trace. Verbal working memory, but not spatial, positively predicted an ability to learn from gesture and transient action in children with the lowest context knowledge.

Personalized mood prediction from patterns of behavior collected with smartphones.

Over the last ten years, there has been considerable progress in using digital behavioral phenotypes, captured passively and continuously from smartphones and wearable devices, to infer depressive mood. However, most digital phenotype studies suffer from poor replicability, often fail to detect clinically relevant events, and use measures of depression that are not validated or suitable for collecting large and longitudinal data. Here, we report high-quality longitudinal validated assessments of depressive mood from computerized adaptive testing paired with continuous digital assessments of behavior from smartphone sensors for up to 40 weeks on 183 individuals experiencing mild to severe symptoms of depression. We apply a combination of cubic spline interpolation and idiographic models to generate individualized predictions of future mood from the digital behavioral phenotypes, achieving high prediction accuracy of depression severity up to three weeks in advance (R2 ≥ 80%) and a 65.7% reduction in the prediction error over a baseline model which predicts future mood based on past depression severity alone. Finally, our study verified the feasibility of obtaining high-quality longitudinal assessments of mood from a clinical population and predicting symptom severity weeks in advance using passively collected digital behavioral data. Our results indicate the possibility of expanding the repertoire of patient-specific behavioral measures to enable future psychiatric research.

Exploring Individual Differences: A Case for Measuring Children's Spontaneous Gesture Production as a Predictor of Learning From Gesture Instruction.

Decades of research have established that learners benefit when instruction includes hand gestures. This benefit is seen when learners watch an instructor gesture, as well as when they are taught or encouraged to gesture themselves. However, there is substantial individual variability with respect to this phenomenon-not all individuals benefit equally from gesture instruction. In the current paper, we explore the sources of this variability. First, we review the existing research on individual differences that do or do not predict learning from gesture instruction, including differences that are either context-dependent (linked to the particular task at hand) or context-independent (linked to the learner across multiple tasks). Next, we focus on one understudied measure of individual difference: the learner's own spontaneous gesture rate. We present data showing rates of "non-gesturers" across a number of studies and we provide theoretical motivation for why this is a fruitful area for future research. We end by suggesting ways in which research on individual differences will help gesture researchers to further refine existing theories and develop specific predictions about targeted gesture intervention for all kinds of learners.

Unlocking the Power of Gesture: Using Movement-Based Instruction to Improve First Grade Children's Spatial Unit Misconceptions.

Gestures are hand movements that are produced simultaneously with spoken language and can supplement it by representing semantic information, emphasizing important points, or showing spatial locations and relations. Gestures' specific features make them a promising tool to improve spatial thinking. Yet, there is recent work showing that not all learners benefit equally from gesture instruction and that this may be driven, in part, by children's difficulty understanding what an instructor's gesture is intended to represent. The current study directly compares instruction with gestures to instruction with plastic unit chips (Action) in a linear measurement learning paradigm aimed at teaching children the concept of spatial units. Some children performed only one type of movement, and some children performed both: Action-then-Gesture [AG] or Gesture-then-Action [GA]. Children learned most from the Gesture-then-Action [GA] and Action only [A] training conditions. After controlling for initial differences in learning, the gesture-then-action condition outperformed all three other training conditions on a transfer task. While gesture is cognitively challenging for some learners, that challenge may be desirable-immediately following gesture with a concrete representation to clarify that gesture's meaning is an especially effective way to unlock the power of this spatial tool and lead to deep, generalizable learning.

A Novel and Integrated Digitally Supported System of Care for Depression and Anxiety: Findings From an Open Trial.

BACKGROUND: The global burden of anxiety and depression has created an urgent need for scalable approaches to increase access to evidence-based mental health care. The Screening and Treatment for Anxiety and Depression (STAND) system of care was developed to meet this need through the use of internet-connected devices for assessment and provision of treatment. STAND triages to level of care (monitoring only, digital therapy with coaches, digital therapy assisted by clinicians in training, and clinical care) and then continuously monitors symptoms to adapt level of care. Triaging and adaptation are based on symptom severity and suicide risk scores obtained from computerized adaptive testing administered remotely. OBJECTIVE: This article discusses how the STAND system of care improves upon current clinical paradigms, and presents preliminary data on feasibility, acceptability, and effectiveness of STAND in a sample of US-based university students. METHODS: US-based university students were recruited and enrolled in an open trial of the STAND system of care. Participants were triaged based on initial symptom severity derived from a computerized adaptive test and monitored over 40 weeks on anxiety, depression, and suicide risk to inform treatment adaptation and evaluate preliminary effectiveness. RESULTS: Nearly 5000 students were screened and 516 received care. Depression and anxiety severity scores improved across all tiers (P<.001 in all cases). Suicide risk severity improved in the highest tier (ie, clinical care; P<.001). Acceptability and feasibility were demonstrated. CONCLUSIONS: STAND is a feasible and acceptable model of care that can reach large numbers of individuals. STAND showed preliminary effectiveness on all primary outcome measures. Current directions to improve STAND are described.

Anterior default mode network and posterior insular connectivity is predictive of depressive symptom reduction following serial ketamine infusion.

BACKGROUND: Ketamine is a rapidly-acting antidepressant treatment with robust response rates. Previous studies have reported that serial ketamine therapy modulates resting state functional connectivity in several large-scale networks, though it remains unknown whether variations in brain structure, function, and connectivity impact subsequent treatment success. We used a data-driven approach to determine whether pretreatment multimodal neuroimaging measures predict changes along symptom dimensions of depression following serial ketamine infusion. METHODS: Patients with depression (n = 60) received structural, resting state functional, and diffusion MRI scans before treatment. Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17), the Inventory of Depressive Symptomatology (IDS-C), and the Rumination Response Scale (RRS) before and 24 h after patients received four (0.5 mg/kg) infusions of racemic ketamine over 2 weeks. Nineteen unaffected controls were assessed at similar timepoints. Random forest regression models predicted symptom changes using pretreatment multimodal neuroimaging and demographic measures. RESULTS: Two HDRS-17 subscales, the HDRS-6 and core mood and anhedonia (CMA) symptoms, and the RRS: reflection (RRSR) scale were predicted significantly with 19, 27, and 1% variance explained, respectively. Increased right medial prefrontal cortex/anterior cingulate and posterior insula (PoI) and lower kurtosis of the superior longitudinal fasciculus predicted reduced HDRS-6 and CMA symptoms following treatment. RRSR change was predicted by global connectivity of the left posterior cingulate, left insula, and right superior parietal lobule. CONCLUSIONS: Our findings support that connectivity of the anterior default mode network and PoI may serve as potential biomarkers of antidepressant outcomes for core depressive symptoms.

Enhancing Racial/Ethnic Equity in College Student Mental Health Through Innovative Screening and Treatment.

Although college campuses are diversifying rapidly, students of color remain an underserved and understudied group. Online screening and subsequent allocation to treatment represents a pathway to enhancing equity in college student mental health. The purpose of the current study was to evaluate racial/ethnic differences in mental health problems and treatment enrollment within the context of a largescale screening and treatment research initiative on a diverse college campus. The sample was comprised of n = 2090 college students who completed an online mental health screening survey and were offered either free online or face-to-face treatment based on symptom severity as a part of a research study. A series of ordinal, binomial and multinomial logistic regression models were specified to examine racial/ethnic differences in mental health problems, prior treatment receipt, and enrollment in online and face-to-face treatment through the campus-wide research initiative. Racial/ethnic differences in depression, anxiety and suicidality endorsed in the screening survey were identified. Students of color were less likely to have received prior mental health treatment compared to non-Hispanic white students, but were equally likely to enroll in and initiate online and face-to-face treatment offered through the current research initiative. Rates of enrollment in online therapy were comparable to prior studies. Online screening and treatment may be an effective avenue to reaching underserved students of color with mental health needs on college campuses. Digital mental health tools hold significant promise for bridging gaps in care, but efforts to improve uptake and engagement are needed.

Modulation of the functional connectome in major depressive disorder by ketamine therapy.

BACKGROUND: Subanesthetic ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depression. How single and repeated ketamine treatment modulates the whole-brain functional connectome to affect clinical outcomes remains uncharacterized. METHODS: Data-driven whole brain functional connectivity (FC) analysis was used to identify the functional connections modified by ketamine treatment in patients with major depressive disorder (MDD). MDD patients (N = 61, mean age = 38, 19 women) completed baseline resting-state (RS) functional magnetic resonance imaging and depression symptom scales. Of these patients, n = 48 and n = 51, completed the same assessments 24 h after receiving one and four 0.5 mg/kg intravenous ketamine infusions. Healthy controls (HC) (n = 40, 24 women) completed baseline assessments with no intervention. Analysis of RS FC addressed effects of diagnosis, time, and remitter status. RESULTS: Significant differences (p < 0.05, corrected) in RS FC were observed between HC and MDD at baseline in the somatomotor network and between association and default mode networks. These disruptions in FC in MDD patients trended toward control patterns with ketamine treatment. Furthermore, following serial ketamine infusions, significant decreases in FC were observed between the cerebellum and salience network (SN) (p < 0.05, corrected). Patient remitters showed increased FC between the cerebellum and the striatum prior to treatment that decreased following treatment, whereas non-remitters showed the opposite pattern. CONCLUSION: Results support that ketamine treatment leads to neurofunctional plasticity between distinct neural networks that are shown as disrupted in MDD patients. Cortico-striatal-cerebellar loops that encompass the SN could be a potential biomarker for ketamine treatment.

Ketamine's modulation of cerebro-cerebellar circuitry during response inhibition in major depression.

Patients with major depressive disorder (MDD) exhibit impaired control of cognitive and emotional systems, including deficient response selection and inhibition. Though these deficits are typically attributed to abnormal communication between macro-scale cortical networks, altered communication with the cerebellum also plays an important role. Yet, how the circuitry between the cerebellum and large-scale functional networks impact treatment outcome in MDD is not understood. We thus examined how ketamine, which elicits rapid therapeutic effects in MDD, modulates cerebro-cerebellar circuitry during response-inhibition using a functional imaging NoGo/Go task in MDD patients (N = 46, mean age: 39.2, 38.1% female) receiving four ketamine infusions, and healthy controls (N = 32, mean age:35.2, 71.4% female). We fitted psychophysiological-interaction (PPI) models for a functionally-derived cerebellar-seed and extracted average PPI in three target functional networks, frontoparietal (FPN), sensory-motor (SMN) and salience (SN) networks. Time and remission status were then evaluated for each of the networks and their network-nodes. Follow-up tests examined whether PPI-connectivity differed between patient remitter/non-remitters and controls. Results showed significant decreases in PPI-connectivity after ketamine between the cerebellum and FPN (p < 0.001) and SMN networks (p = 0.008) in remitters only (N = 20). However, ketamine-related changes in PPI-connectivity between the cerebellum and the SN (p = 0.003) did not vary with remitter status. Cerebellar-FPN, -SN PPI values at baseline were also associated with treatment outcome. Using novel methodology to quantify the functional coupling of cerebro-cerebellar circuitry during response-inhibition, our findings highlight that these loops play distinct roles in treatment response and could potentially serve as novel biomarkers for fast-acting antidepressant therapies in MDD.

Interleukin-8 and lower severity of depression in females, but not males, with treatment-resistant depression.

INTRODUCTION: In cross-sectional studies of depressed patients, relationships between depression and levels of IL-8 are inconsistent, and have not been examined in relation to sex. Given identified sex differences in longitudinal data, it is important to evaluate sex-specific cross-sectional relationships between IL-8 and depressive symptoms, which may explain some inconsistency in the extant literature. It is further unknown whether IL-8 levels may relate to specific symptom profiles among depressed patients, with or without regard to sex. METHODS: Among 108 patients with treatment resistant depression (50 females), we evaluated cross-sectional relationships between IL-8 and depression severity, as measured by the Hamilton Depression Rating Scale [HAM-D] Score, and examined sex-specific relationships, as well as relationships with depressive symptom profiles. Other inflammatory markers (IL-6, IL-10, TNF-α, CRP) were also explored in relation to HAM-D. RESULTS: Higher IL-8 was associated with lower total HAM-D score (standardized ß = -0.19, p = 0.049). Sex-specific effects were identified (IL-8 x sex interaction: p = 0.03), in which higher IL-8 related to lower HAM-D score in females (standardized ß = -0.41, p = 0.004, effect size (sr2) = 0.17), but not males (standardized ß = 0.02, p = 0.91). Among a subset of 94 patients (41 females) who had individual HAM-D items available, we evaluated relationships between IL-8 and HAM-D factor subscores. Across sexes, higher IL-8 was associated with lower anxiety/hypochondriasis subscores (standardized ß = -0.31, p = 0.002; sex interaction: p = 0.99). Sex differences were identified for relationships between IL-8 and two other HAM-D factor subscores. CONCLUSIONS: IL-8 may be related to anxiety symptoms across sexes, but may have a sex-specific relationship with other depressive symptoms. Further evaluation of sex-specific relationships between IL-8, depression symptom profiles, treatment response, and potential neurobiological correlates, may inform mechanisms of depression pathophysiology and aid in development of precision medicine strategies.

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

Depression treatment response to ketamine: sex-specific role of interleukin-8, but not other inflammatory markers.

Inflammation plays a role in depression pathophysiology and treatment response, with effects varying by sex and therapeutic modality. Lower levels of interleukin(IL)-8 predict depression response to antidepressant medication and to electroconvulsive therapy (ECT), although ECT effects are specific to females. Whether IL-8 predicts depression response to ketamine and in a sex-specific manner is not known. Here, depressed patients (n = 46; female, n = 17) received open label infusion of ketamine (0.5 mg/kg over 40 min; NCT02165449). Plasma levels of IL-8 were evaluated at baseline and post-treatment. Baseline levels of IL-8 had a trending association with response to ketamine, depending upon sex (responder status × sex interaction: p = 0.096), in which lower baseline levels of IL-8 in females (p = 0.095) but not males (p = 0.96) trended with treatment response. Change in levels of IL-8 from baseline to post-treatment differed significantly by responder status (defined as ≥50% reduction in Hamilton Depression Rating Scale [HAM-D] Score), depending upon sex (responder status × sex × time interaction: F(1,42)=6.68, p = 0.01). In addition, change in IL-8 interacted with sex to predict change in HAM-D score (ß = -0.63, p = 0.003); increasing IL-8 was associated with decreasing HAM-D score in females (p = 0.08) whereas the inverse was found in males (p = 0.02). Other inflammatory markers (IL-6, IL-10, tumor necrosis factor-α, C-reactive protein) were explored with no significant relationships identified. Given these preliminary findings, further evaluation of sex differences in the relationship between IL-8 and treatment response is warranted to elucidate mechanisms of response and aid in the development of personalized approaches to depression treatment.

Individual differences in gesture interpretation predict children's propensity to pick a gesturer as a good informant.

To learn from others, children rely on cues (e.g., familiarity, confidence) to infer who around them will provide useful information. We extended this research to ask whether children will use an informant's inclination to gesture as a marker of whether or not the informant is a good person to learn from. Children (N = 459, ages 4-12 years) watched short videos in which actresses made statements accompanied by meaningful iconic gestures, beat gestures (which act as prosodic markers with speech), or no gestures. After each trial, children were asked "Who do you think would be a good teacher?" (good teacher [experimental] condition) or "Who do you think would be a good friend?" (good friend [control] condition). Results show that children do believe that someone who produces iconic gesture would make a good teacher compared with someone who does not, but this is only later in childhood and only if children have the propensity to see gesture as meaningful. The same effects were not found in the good friend condition, indicating that children's responses are not just about liking an adult who gestures more. These findings have implications for how children attend to and learn from instructional gesture.

Effects of Serial Ketamine Infusions on Corticolimbic Functional Connectivity in Major Depression.

BACKGROUND: Ketamine is a highly effective antidepressant for patients with treatment-resistant major depressive disorder (MDD). Resting-state functional magnetic resonance imaging studies show disruptions of functional connectivity (FC) between limbic regions and resting-state networks (RSNs) in MDD, including the default mode network, central executive network (CEN), and salience network (SN). Here, we investigated whether serial ketamine treatments change FC between limbic structures and RSNs. METHODS: Patients with MDD (n = 44) were scanned at baseline (time 1 [T1]) and 24 hours after the first (T2) and fourth (T3) infusions of ketamine. Healthy control subjects (n = 50) were scanned at baseline, with a subgroup (n = 17) being rescanned at 2 weeks. Limbic regions included the amygdala and hippocampus, and RSNs included the default mode network, CEN, and SN. RESULTS: Ketamine increased right amygdala FC to the right CEN (p = .05), decreased amygdala FC to the left CEN (p = .005) at T2 versus T1 (p = .015), which then increased at T3 versus T2 (p = .002), and decreased left amygdala FC to the SN (p = .016). Decreased left amygdala to SN FC at T2 predicted improvements in anxiety at T3 (p = .006). Ketamine increased right hippocampus FC to the left CEN (p = .001), and this change at T2 predicted decreased anhedonia at T3 (p = .005). CONCLUSIONS: Ketamine modulates FC between limbic regions and RSNs implicated in MDD. Increases in FC between limbic regions and the CEN suggest that ketamine may be involved in restoring top-down control of emotion processing. FC decreases between the left amygdala and SN suggest that ketamine may ameliorate MDD-related dysconnectivity in these circuits. Early FC changes between limbic regions and RSNs may be predictive of clinical improvements.

Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression.

Subanesthetic ketamine is found to induce fast-acting and pronounced antidepressant effects, even in treatment resistant depression (TRD). However, it remains unclear how ketamine modulates neural function at the brain systems-level to regulate emotion and behavior. Here, we examined treatment-related changes in the inhibitory control network after single and repeated ketamine therapy in TRD. Forty-seven TRD patients (mean age = 38, 19 women) and 32 healthy controls (mean age = 35, 18 women) performed a functional magnetic resonance imaging (fMRI) response inhibition task at baseline, and 37 patients completed the fMRI task and symptom scales again 24 h after receiving both one and four 0.5 mg/kg intravenous ketamine infusions. Analyses of fMRI data addressed effects of diagnosis, time, and differences between treatment remitters and non-remitters. Significant decreases in brain activation were observed in the inhibitory control network, including in prefrontal and parietal regions, and visual cortex following serial ketamine treatment, p < 0.05 corrected. Remitters were distinguished from non-remitters by having lower functional activation in the supplementary motor area (SMA) prior to treatment, which normalized towards controls following serial ketamine treatment. Results suggest that ketamine treatment leads to neurofunctional plasticity in executive control networks including the SMA during a response-inhibitory task. SMA changes relate to reductions in depressive symptoms, suggesting modulation of this network play an important role in therapeutic response. In addition, early changes in the SMA network during response inhibition appear predictive of overall treatment outcome, and may serve as a biomarker of treatment response.

Inflammation and depression treatment response to electroconvulsive therapy: Sex-specific role of interleukin-8.

Females suffer from depression at twice the rate of males and have differential neural and emotional responses to inflammation. However, sex-specific evaluation of relationships between inflammation and response to depression treatments are lacking. Some data suggest that interleukin(IL)-8 predicts treatment response to antidepressants and has a relationship with depressive symptom severity. This study examines whether IL-8 predicts treatment response to electroconvulsive therapy (ECT), and whether there are sex specific effects. In 40 depressed patients (22 female), plasma levels of IL-8, as well as other markers of inflammation including IL-6, IL-10, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) were obtained prior to administration of ECT and after completion of the index treatment series. Depression treatment response was defined as ≥ 50% reduction in Hamilton Depression Rating Scale (HAM-D) Score. Baseline levels of IL-8 differed by responder status, depending on sex (group × sex interaction: ß = -0.571, p = 0.04), with female responders having lower levels of IL-8 at baseline as compared to female non-responders [t(20) = 2.37, p = 0.03]. Further, IL-8 levels from baseline to end of treatment differed by responder status, depending on sex (group × sex × time interaction: [F(1,36) = 9.48, p = 0.004]), and change in IL-8 from baseline to end of treatment was negatively correlated with percentage change in HAM-D score in females (ß = -0.458, p = 0.03), but not in males (ß = 0.315, p = 0.20). Other inflammatory markers did not differ in relation to responder status and sex. Further evaluation of sex differences in the relationship between IL-8, depression, and treatment response, across disparate treatment modalities, may inform mechanisms of response and aid in development of personalized medicine strategies.

Modulation of amygdala reactivity following rapidly acting interventions for major depression.

Electroconvulsive therapy (ECT) and ketamine treatment both induce rapidly acting antidepressant effects in patients with major depressive disorder unresponsive to standard treatments, yet their specific impact on emotion processing is unknown. Here, we examined the neural underpinnings of emotion processing within and across patients (N = 44) receiving either ECT (N = 17, mean age: 36.8, 11.0 SD) or repeated subanesthetic (0.5 mg/kg) intravenous ketamine therapy (N = 27, mean age: 37.3, 10.8 SD) using a naturalistic study design. MRI and clinical data were collected before (TP1) and after treatment (TP2); healthy controls (N = 31, mean age: 34.5, 13.5 SD) completed one MRI session (TP1). An fMRI face-matching task probed negative- and positive-valence systems. Whole-brain analysis, comparing neurofunctional changes within and across treatment groups, targeted brain regions involved in emotional facial processing, and included regions-of-interest analysis of amygdala responsivity. Main findings revealed a decrease in amygdalar reactivity after both ECT and ketamine for positive and negative emotional face processing (p < .05 family wise-error (FWE) corrected). Subthreshold changes were observed between treatments within the dorsolateral prefrontal cortex and insula (p < .005, uncorrected). BOLD change for positive faces in the inferior parietal cortex significantly correlated with overall symptom improvement, and BOLD change in frontal regions correlated with anxiety for negative faces, and anhedonia for positive faces (p < .05 FWE corrected). Both serial ketamine and ECT treatment modulate amygdala response, while more subtle treatment-specific changes occur in the larger functional network. Findings point to both common and differential mechanistic upstream systems-level effects relating to fast-acting antidepressant response, and symptoms of anxiety and anhedonia, for the processing of emotionally valenced stimuli.

Single and repeated ketamine treatment induces perfusion changes in sensory and limbic networks in major depressive disorder.

Ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depressive disorder (MDD). Yet, how single and repeated ketamine treatment induces brain systems-level neuroplasticity underlying symptom improvement is unknown. Advanced multiband imaging (MB) pseudo-continuous arterial spin labeling (pCASL) perfusion MRI data was acquired from patients with treatment resistant depression (TRD) (N = 22, mean age=35.2 ± 9.95 SD, 27% female) at baseline, and 24 h after receiving single, and four subanesthetic (0.5 mg/kg) intravenous ketamine infusions. Changes in global and regional CBF were compared across time points, and relationships with overall mood, anhedonia and apathy were examined. Comparisons between patients at baseline and controls (N = 18, mean age=36.11 ± 14.5 SD, 57% female) established normalization of treatment effects. Results showed increased regional CBF in the cingulate and primary and higher-order visual association regions after first ketamine treatment. Baseline CBF in the fusiform, and acute changes in CBF in visual areas were related to symptom improvement after single and repeated ketamine treatment, respectively. In contrast, after serial infusion therapy, decreases in regional CBF were observed in the bilateral hippocampus and right insula with ketamine treatment. Findings demonstrate that neurophysiological changes occurring with single and repeated ketamine treatment follow both a regional and temporal pattern including sensory and limbic regions. Initial changes are observed in the posterior cingulate and precuneus and primary and higher-order visual areas, which relate to clinical responses. However, repeated exposure to ketamine, though not relating to clinical outcome, appears to engage deeper limbic structures and insula. ClinicalTrials.gov: Biomarkers of Fast Acting Therapies in Major Depression, https://clinicaltrials.gov/ct2/show/NCT02165449, NCT02165449.

Time Course of Changes in Peripheral Blood Gene Expression During Medication Treatment for Major Depressive Disorder.

Changes in gene expression (GE) during antidepressant treatment may increase understanding of the action of antidepressant medications and serve as biomarkers of efficacy. GE changes in peripheral blood are desirable because they can be assessed easily on multiple occasions during treatment. We report here on GE changes in 68 individuals who were treated for 8 weeks with either escitalopram alone, or escitalopram followed by bupropion. GE changes were assessed after 1, 2, and 8 weeks of treatment, with significant changes observed in 156, 121, and 585 peripheral blood gene transcripts, respectively. Thirty-one transcript changes were shared between the 1- and 8-week time points (seven upregulated, 24 downregulated). Differences were detected between the escitalopram- and bupropion-treated subjects, although there was no significant association between GE changes and clinical outcome. A subset of 18 genes overlapped with those previously identified as differentially expressed in subjects with MDD compared with healthy control subjects. There was statistically significant overlap between genes differentially expressed in the current and previous studies, with 10 genes overlapping in at least two previous studies. There was no enrichment for genes overexpressed in nervous system cell types, but there was a trend toward enrichment for genes in the WNT/ß-catenin pathway in the anterior thalamus; three genes in this pathway showed differential expression in the present and in three previous studies. Our dataset and other similar studies will provide an important source of information about potential biomarkers of recovery and for potential dysregulation of GE in MDD.