Unmedicated Individuals Research Articles

Gene Age Gap Estimate (GAGE) for major depressive disorder: a penalized biological age model using gene expression.

Recent associations between Major Depressive Disorder (MDD) and measures of premature aging suggest accelerated biological aging as a potential biomarker for MDD susceptibility or MDD as a risk factor for age-related diseases. Residuals or "gaps" between the predicted biological age and chronological age have been used for statistical inference, such as testing whether an increased age gap is associated with a given disease state. Recently, a gene expression-based model of biological age showed a higher age gap for individuals with MDD compared to healthy controls (HC). In the current study, we propose an approach that simplifies gene selection using a least absolute shrinkage and selection operator (LASSO) penalty to construct an expression-based Gene Age Gap Estimate (GAGE) model. We train a LASSO gene age model on an RNA-Seq study of 78 unmedicated individuals with MDD and 79 HC, resulting in a model with 21 genes. The L-GAGE shows higher biological aging in MDD participants than HC, but the elevation is not statistically significant. However, when we dichotomize chronological age, the interaction between MDD status and age has a significant association with L-GAGE. This effect remains statistically significant even after adjusting for chronological age and sex. Using the 21 age genes, we find a statistically significant elevated biological age in MDD in an independent microarray gene expression dataset. We find functional enrichment of infectious disease and SARS-COV pathways using a broader feature selection of age related genes.

Nuclear factor kappa-B cell (NF-κB), interferon regulatory Factor, and glucocorticoid receptor pathway activation in major depressive Disorder: The role of cytomegalovirus infection

Altered activity of major immunoregulatory pathways has been reported in major depressive disorder (MDD) and is thought to underlie the elevations in circulating inflammatory mediators present in a subgroup of patients. However, the drivers of these changes in gene expression remain unclear. One potential modulator of immune function is viral infection. Here we examined the relationship between cytomegalovirus (CMV), a common herpesvirus, that has been shown to be a pathological cofactor in inflammatory disorders, and activity of key coordinators of the innate inflammatory response in MDD. We used RNAseq to characterize gene expression differences in in 79 unmedicated individuals with MDD and 80 healthy controls (HCs). A well-established bioinformatic strategy was used to quantify transcription control pathway activity based on the relative prevalence of pre-specified transcription factor-binding motifs in the promoters of differentially expressed genes. The main aim was to characterize diagnostic differences in immunoregulatory pathway activity and determine if these were related to CMV serostatus or antibody titer (viral reactivation). Significantly increased activity of interferon regulatory factor 1 (IRF1) and nuclear factor kappa-B cell (NF-κB) pathways was observed in the MDD group compared with HCs. Transcript Origin Analyses using cell-specific reference transcriptomes indicated that the MDD-associated transcriptome changes derived primarily from myeloid lineage immune cells (classical and non-classical monocytes). A more modest MDD-associated upregulation of glucocorticoid receptor (GR) pathway activity was also present. CMV infection/activity across the combined MDD and HC groups was weakly related to GR pathway activation but not to IRF1 and NF-κB activity; the most salient signature of CMV was activation and/or expansion of the CD8+ T-cell population. The elevated MDD-associated NF-κB (but not IRF1) activity was markedly attenuated after controlling for CMV antibody titer or for CD8+ T-cell prevalence. At least some of the NF-κB signal in MDD may be attributable to the cellular immune response to CMV, suggesting that CMV infection may be one of several pathways contributing to inflammation in depression. The pronounced activation of the antiviral IRF-1 pathway in MDD suggests the contribution of viral processes although this specific antiviral effect was not specific to CMV.CMV may indirectly drive interferon responses by impairing T-cell control of other viral infections.

Divergent transcriptomic profiles in depressed individuals with hyper- and hypophagia implicating inflammatory status

BackgroundMajor Depressive Disorder (MDD) is a heterogenous and etiologically complex disease often presenting with divergent appetitive phenotypes including Hyperphagic MDD (characterized by an increased appetite) and Hypophagic MDD (characterized by a decrease in appetite) which are closely related to comorbidities, including cardiometabolic disorders. Hyperphagia is associated with atypical depression, decreased stress-hormone signaling, a pro-inflammatory status, hypersomnia, and poorer clinical outcomes. Yet, our understanding of associated biological correlates of Hyperphagic and Hypophagic MDD remain fragmented. MethodsWe performed an exploratory study on peripheral blood RNA profiling using bulk RNAseq in unmedicated individuals with Hyperphagic and Hypophagic MDD (n = 7 and n = 13, respectively). ResultsAt baseline, we discovered an increased expression of TADA2B in hyperphagic MDD with the significant enrichment of 72 gene ontology pathways mainly related to inflammation. In addition, we used the Maastricht Acute Stress Task to uncover stress-related transcriptomic profiles in Hyper- and Hypophagic MDD and discovered the upregulation of CCDC196 and the downregulation of SPATA33 in hyperphagic MDD. Gene ontology enrichment analysis after stress exposure showed pathways related to ribosomal activity. Limitations: The present findings are tempered primarily by the limited sample size, which requires independent replication of this exploratory study. However, stringent methods controlling for false positive findings mitigate the risk associated with sample size limitations. DiscussionLimitations notwithstanding, findings suggest that hyper- and hypophagic MDD is associated with divergent RNA expression profiles in peripheral blood that are amplified by exposure to a controlled stress test. Our findings in a well-controlled study provide evidence for peripheral markers of a relevant endophenotype of MDD.

Chronic Use of Antihypertensive Medications and Peak Exercise Blood Pressure in Adult Men and Women from the BALL ST Cohort.

To determine if individuals chronically (>1 yr) prescribed antihypertensive medications have a normal BP response to peak exercise compared with unmedicated individuals. Participants included 2555 adults from the Ball State Adult Fitness Longitudinal Lifestyle STudy cohort who performed a peak treadmill exercise test. Participants were divided into groups by sex and antihypertensive medication status. Individuals prescribed antihypertensive medications for >1 yr were included. Exaggerated and blunted SBP within each group was categorized using the Fitness Registry and the Importance of Exercise: A National Database (FRIEND) and absolute criteria as noted by the American Heart Association. The unmedicated group had a greater prevalence ( P < 0.05) of blunted SBP responses, whereas the medicated group had a higher prevalence ( P < 0.05) of exaggerated SBP responses using both the FRIEND and absolute criteria. Peak SBP was higher ( P < 0.01) in medicated compared with unmedicated participants in the overall cohort when controlling for age and sex, but not after controlling for resting SBP ( P = 0.613), risk factors ( P = 0.104), or cardiorespiratory fitness ( P = 0.191). When men and women were assessed independently, peak SBP remained higher in the medicated women after controlling for age and resting SBP ( P = 0.039), but not for men ( P = 0.311). Individuals on beta-blockers had a higher peak SBP even after controlling for age, sex, risk factors, and cardiorespiratory fitness ( P = 0.022). Individuals on antihypertensive medications have a higher peak SBP response to exercise. Given the prognostic value of exaggerated peak SBP, control of exercise BP should be considered in routine BP assessment and in the treatment of hypertension.

Altered Cortical Gyrification Morphology in Nonsucidal Self-injury

IntroductionNonsuicidal self-injury (NSSI) is defined as deliberate and direct damage to one’s body tissues without any suicidal intent. NSSI is now recognized as a major risk factor for suicide and is prevalent among adolescents, with prevalence rates ranging from 7.5% to 46.5%, leading to increased interest in the pathophysiology of NSSI. This study aimed to examine cortical gyrification morphology, a neurobiological index of cortical folding and patterning, among unmedicated individuals with NSSI, which is prevalent in adolescents and young adults.Objectives The main objective of this study is to compare cortical morphological abnormalities between individuals with NSSI and controls in terms of the local gyrification index (LGI), the ratio of the smooth cortical surface area at each vertex to the corresponding sulcal folds. In addition, we hypothesized that the LGI, a stable neurodevelopmental marker of cortical and subcortical circuit intergrity, would correlate with clinical measures in youth with NSSI.Methods A total of 101 individuals with NSSI and 100 age-, gender-, and handedness-matched controls completed self-report questionnaires and structural magnetic resonance imaging (MRI) data were acquired on a 3T Siemens scanner. A surface-based analysis was conducted using the Computational Anatomy Toolbox (CAT12) in Statistical Parametric Mapping (SPM12). Partial correlation analysis was also performed using R software to investigate the association between the LGI values extracted from the region of interest (ROI) and clinical symptoms, including depression, anxiety, emotion dysregulation, and anhedonia in individuals with NSSI.ResultsIndividuals with NSSI showed significantly increased LGI in the right insula sulcus and left superior temporal sulcus (STS), along with decreased LGI in the right calcarine and left superior parietal sulcus (SPS), compared to controls (5000 permutation correction, threshold-free cluster enhancement with a threshold of p &lt; .05). In addition, higher LGI in left STS was correlated with greater scores of the Beck Anxiety Inventory (r = 0.22, p &lt; .05) and of the Impulse Control Difficulties subscale of the Difficulties in Emotion Regulation Scale (r = 0.34, p &lt; .001). Conversely, reduced LGI of the right calcarine was associated with a higher score on the Anhedonia subscale of the Beck Depression Inventory (r = -0.23, p &lt; .05) within individuals with NSSI.ConclusionsThis study identified hypergyria in the right insular and left STS and hypogyria in the right calcarine and left SPS in individuals with NSSI. The former pattern was associated with anxiety and impulse control difficulties, and the latter was with anhedonia. This study is the first to alter distinct neurodevelopmental patterns of local gyrification and their correlations with clinical manifestations in individuals with NSSI.Disclosure of InterestNone Declared

Hippocampal volume changes after (R,S)-ketamine administration in patients with major depressive disorder and healthy volunteers

The hippocampus and amygdala have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). Preclinical models suggest that stress-related changes in these regions can be reversed by antidepressants, including ketamine. Clinical studies have identified reduced volumes in MDD that are thought to be potentiated by early life stress and worsened by repeated depressive episodes. This study used 3T and 7T structural magnetic resonance imaging data to examine longitudinal changes in hippocampal and amygdalar subfield volumes associated with ketamine treatment. Data were drawn from a previous double-blind, placebo-controlled, crossover trial of healthy volunteers (HVs) unmedicated individuals with treatment-resistant depression (TRD) (3T: 18 HV, 26 TRD, 7T: 17 HV, 30 TRD) who were scanned at baseline and twice following either a 40 min IV ketamine (0.5 mg/kg) or saline infusion (acute: 1–2 days, interim: 9–10 days post infusion). No baseline differences were noted between the two groups. At 10 days post-infusion, a slight increase was observed between ketamine and placebo scans in whole left amygdalar volume in individuals with TRD. No other differences were found between individuals with TRD and HVs at either field strength. These findings shed light on the timing of ketamine’s effects on cortical structures.

Impact of stimulant treatment on refractive errors and pupil diameter in attention deficit hyperactivity disorder.

The relationship between attention deficit hyperactivity disorder (ADHD) and visual impairment remains poorly understood, and the impact of visual impairment on the development of ADHD is uncertain. The aim of this study was to investigate the refractive profile and ocular biometric characteristics in patients diagnosed with ADHD and compare them with a control group. Additionally, we aimed to explore the potential influence of sex and medication intake. A cohort of 100 participants, including 50 individuals with ADHD and 50 age- and sex-matched control subjects, was included in this study. Ocular biometric parameters were measured, and refractive error was assessed using cycloplegic and non-cycloplegic autorefraction. Subgroup analyses were performed within the ADHD group based on sex, medication intake and age to investigate potential associations with the ocular findings. We observed no statistically significant differences in axial length, corneal topography parameters or anterior chamber characteristics between ADHD and control subjects. However, subgroup analysis within the ADHD group revealed that the prevalence of ametropia under cycloplegia was significantly higher in unmedicated (69.6%) compared to medicated (37.5%) (X2(2) = 7.320, p = 0.026) participants. Pupil diameter was significantly larger in medicated (3.91 mm) compared to unmedicated (3.58 mm; p = 0.017) individuals. Males had flatter (p = 0.004) and thicker (p = 0.008) corneas than females. Older ADHD participants had higher refractive error (p = 0.008 for non-cycloplegic and p = 0.0.003 for cycloplegic), axial length (p = 0.002) and corneal astigmatism (p = 0.049). Our study provides compelling evidence that individuals diagnosed with ADHD exhibit a similar incidence of refractive errors and ocular parameters compared to normal subjects. Nonetheless, the prevalence of refractive errors appears to be higher in unmedicated ADHD patients, suggesting the potential benefit of stimulant treatment. Additionally, stimulant use is associated with an increase in pupil diameter.

Reduced visual context effects in global motion processing in depression.

Research supports abnormal inhibitory visual motion processing in adults with remitted and current depression, but all studies to date have used paradigms with simple grating stimuli. Global motion processing, where multiple motion signals must be integrated, has not been explored in depression, nor have inhibitory processes within that domain. Depressed participants (n = 46) and healthy controls (n = 28) completed a direction discrimination task featuring a random dot pattern stimulus. Various signal (rightward or leftward dots) to noise (dots with randomly assigned directions) ratios modulated task difficulty. Metrics of global center surround suppression and facilitation were calculated. Accuracy in the baseline condition (i.e., no surrounding annulus) was not significantly different between depressed and healthy participants. Global center surround suppression and facilitation were not significantly different between healthy and depressed participants overall. When limiting the sample to unmedicated individuals, depressed participants (n = 27) showed a reduced global center surround suppression effect compared to controls, and there was no difference in global center surround facilitation. While global motion processing is intact in depression, abnormal center surround suppression effects in depression do extend to global motion stimuli. These alterations may be mitigated by the psychotropic medications taken by some subjects in our depressed sample. Future studies should explore the mechanisms underlying these effects.

Psycho-pharmacomicrobiomics: A Systematic Review and Meta-analysis

BackgroundUnderstanding the interactions between the gut microbiome and psychotropic medications (psycho-pharmacomicrobiomics) could improve treatment stratification strategies in psychiatry. In this systematic review and meta-analysis, we first explored whether psychotropics modify the gut microbiome; second, we investigated whether the gut microbiome affects the efficacy and tolerability of psychotropics. MethodsFollowing PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched (November 2022) for longitudinal and cross-sectional studies that investigated the effect of psychotropics on the gut microbiome. The primary outcome was the difference in diversity metrics (alpha and beta) before and after treatment with psychotropics (longitudinal studies) and in medicated compared with unmedicated individuals (cross-sectional studies). Secondary outcomes included the association between gut microbiome and efficacy and tolerability outcomes. Random effect meta-analyses were conducted on alpha diversity metrics, while beta diversity metrics were pooled using distance data extracted from graphs. Summary statistics included standardized mean difference and Higgins I2 for alpha diversity metrics and F and R values for beta diversity metrics. ResultsNineteen studies were included in our synthesis; 12 investigated antipsychotics and 7 investigated antidepressants. Results showed significant changes in alpha (4 studies; standard mean difference: 0.12; 95% CI: 0.01–0.23; p = .04; I2: 14%) and beta (F = 15.59; R2 = 0.05; p < .001) diversity metrics following treatment with antipsychotics and antidepressants, respectively. Altered gut microbiome composition at baseline was associated with tolerability and efficacy outcomes across studies, including response to antidepressants (2 studies; alpha diversity; standard mean difference: 2.45; 95% CI: 0.50–4.40; p < .001, I2: 0%). ConclusionsTreatment with psychotropic medications is associated with altered gut microbiome composition, and the gut microbiome may in turn influence the efficacy and tolerability of these medications.

Is practice good enough? Retrieval benefits students with ADHD but does not compensate for poor encoding in unmedicated students.

A significant proportion of currently enrolled college students receive support for attention deficit/hyperactivity disorder (ADHD) and these students are often at risk of academic failure. Retrieval practice or self-testing is an effective, accessible, and affordable tool for improving academic performance. Three recent studies found conflicting results with regards to the effectiveness of retrieval practice in this population. The present study compared 36 individuals with ADHD to 36 controls. Participants studied Swahili-English word pairs that varied in difficulty. Half of the pairs were repeatedly studied, and the other half repeatedly tested. On a final test, all participants showed a benefit of retrieval practice relative to restudy and participant status did not moderate the effect. However, unmedicated individuals with ADHD performed worse overall, both during the encoding phase and on the final test, whereas medicated participants were not significantly different from controls. An examination of self-reported encoding strategies found unmedicated participants used fewer deep strategies at encoding, consistent with prior work on ADHD and memory. Although retrieval practice is effective in this group, improved strategy use may be necessary to ensure performance that is fully equivalent to that of students without ADHD.

Decreased gray matter volume in regions associated with affective pain processing in unmedicated individuals with nonsuicidal self-injury

Nonsuicidal self-injury (NSSI) has been consistently associated with a reduced aversion to physical pain. Yet, little research has been done to investigate the brain structures related to pain in individuals with NSSI. This study examined gray matter volume patterns of pain processing regions in participants engaging in NSSI (n = 63) and age-, sex-, and handedness-matched healthy controls (n = 63). Voxel-based morphometry was performed to explore gray matter volume in regions of interest (ROIs) and partial correlation analyses were conducted to identify their associations with the frequency, versatility, duration, functions, and pain intensity of self-injury. As a result, significant volume decreases were found in the right anterior insula, bilateral secondary somatosensory cortex (SII), and left inferior frontal gyrus. Moreover, individuals with smaller anterior insula and SII volume showed a higher likelihood of endorsing affect-regulation and sensation-seeking functions of NSSI, as well as engaging in self-injury with a greater perceived intensity of pain. Our results provide the first empirical evidence that individuals with NSSI may exhibit distinct characteristics in brain regions associated with the affective component of pain processing. These neurobiological changes may be associated with their maladaptive response to noxious and painful NSSI experiences.

Trait- and state-like co-activation pattern dynamics in current and remitted major depressive disorder

BackgroundDistinguishing between trait- and state-like neural alternations in major depressive disorder (MDD) may advance our understanding of this recurring disorder. We aimed to investigate dynamic functional connectivity alternations in unmedicated individuals with current or past MDD using co-activation pattern analyses. MethodsResting-state functional magnetic resonance imaging data were acquired from individuals with first-episode current MDD (cMDD, n = 50), remitted MDD (rMDD, n = 44), and healthy controls (HCs, n = 64). Using a data-driven consensus clustering technique, four whole-brain states of spatial co-activation were identified and associated metrics (dominance, entries, transition frequency) were analyzed with respect to clinical characteristics. ResultsRelative to rMDD and HC, cMDD showed increased dominance and entries of state 1 (primarily involving default mode network (DMN)), and decreased dominance of state 4 (mostly involving frontal-parietal network (FPN)). Among cMDD, state 1 entries correlated positively with trait rumination. Conversely, relative to cMDD and HC, individuals with rMDD were characterized by increased state 4 entries. Relative to HC, both MDD groups showed increased state 4-to-1 (FPN to DMN) transition frequency but reduction in state 3 (spanning visual attention, somatosensory, limbic networks), with the former metric specifically related to trait rumination. LimitationsFurther confirmation with longitudinal studies are required. ConclusionsRegardless of symptoms, MDD was characterized by increased FPN-to-DMN transitions and reduced dominance of a hybrid network. State-related effect emerged in regions critically implicated in repetitive introspection and cognitive control. Asymptomatic individuals with past MDD were uniquely linked to increased FPN entries. Our findings identify trait-like brain network dynamics that might increase vulnerability to future MDD.

Gender-specific anatomical correlations of schizotypy in healthy individuals

IntroductionSchizotypy refers to a continuum of symptoms from subclinical manifestations in the general population to severe symptoms in schizophrenia spectrum disorders. Neuroimaging studies revealed significant relationships between schizotypy and cortical anatomy in the general population. However, it remains unclear whether these structural associations has a gender specificity.ObjectivesThe present study used structural MRI data to investigate the relationship between subclinical schizotypy symptoms and cortical and subcortical morphometric measures in male and female samples of healthy individuals.Methods164 right-handed healthy unmedicated individuals (18.0-34.9 years, 57% females) underwent structural MRI at 3T Philips scanner. T1-weighted images were processed via FreeSurfer 6.0 to quantify cortical thickness for 34 regions-of-interest (ROIs) according to Desikan atlas and volumes for 7 subcortical structures at each hemisphere. Schizotypy levels were assessed using self-report Schizotypal Personality Questionnaire, total schizotypy score and 4 factors scores (Cognitive-perceptual, negative, disorganized and paranoid factors as per Stefanis et al. Schizophr Bull. 2004; 30 335-350) were calculated. Partial correlation analysis (ppcor version 1.1, R version 4.2.1) was used to assess the associations between ROIs cortical thickness and total schizotypy or 4 factors scores including age and sex as covariates. The same analysis was performed for subcortical volumes including intracranial volume as additional covariate.ResultsIn male group we revealed a positive correlation between greater thickness of the left caudal middle frontal gyrus and higher total schizotypy (r=0.42, punc=0.0003, 95% CI [0.21–0.60]) and negative factor of schizotypy (r=0.49, punc&lt;0.0001, 95% CI [0.28–0.65]) (Image). No correlations survived correction for multiple comparisons in female sample. There were no differences in age, caudal middle frontal gyrus thickness, total schizotypy or negative factor of schizotypy scores between male and female subgroups.Image:ConclusionsThe results suggest that the association of dorsolateral prefrontal cortex (DLPFC) and levels of schizotypy is gender specific. We showed that total and negative schizotypy positively correlated with thicker DLPFC in male but not in female sample. The present data are inverse to findings of prefrontal cortical thinning observed in schizophrenia. Such correlations suggest that thicker cortex could be a potential compensatory mechanism or could reflect alterations in trajectory of cortical thickness reductions across the lifespan.The work was supported by RFBR grant 20-013-00748Disclosure of InterestNone Declared

Altered intrinsic brain activity and cognitive impairment in euthymic, unmedicated individuals with bipolar disorder.

Cognitive impairment in euthymic bipolar disorder (BD) contributes to poor functional outcomes. Resting-state magnetic resonance imaging (MRI)may help us understand the neurobiology of cognitive impairment in BD. Here, forty unmedicated euthymic BD patients and thirty-nine healthy controls were recruited, undergoing MRI scans and neuropsychological measures. The amplitude of low-frequency fluctuation (ALFF) and ALFF-based functional connectivity (FC) analysis was employed to explore the potential alterations of neural activity. Voxel-wised correlation was calculated between clinical and cognitive variables and abnormal brain activity. Compared with healthy controls, euthymic BD patients showed worse cognitive performance in Trail Making Test, Digit Span Test, and Stroop Color-Word Test (SCWT). The euthymic BD group had significantly lower ALFF in the left medial frontal gyrus, right middle frontal gyrus, right postcentral gyrus, and left superior frontal gyrus. Furthermore, we found decreased ALFF values in the right middle frontal gyrus that was negatively correlated with cognitive inhibition, (r=-0.43, P=0.015). ALFF-based FC analysis showed that BD group showed significantly decreased FC between the right middle frontal gyrus (seed) and left middle temporal gyrus and left medial frontal gyrus, (Two-tailed, PFWE < 0.05, TFCE corrected). The findings demonstrated that individuals with BD during the euthymic phase exhibited decreased ALFF and hypoconnectivity of key brain areas within the frontoparietal network. These altered spontaneous brain activity in euthymic BD patients may be involved in the pathophysiology mechanism of cognitive deficits.

Systematic Review and Meta-Analysis of Damage Associated Molecular Patterns HMGB1 and S100B in Schizophrenia.

Immune system dysregulation is hypothesised to be central to the aetiopathogenesis of schizophrenia; however, the role of sterile inflammation remains unclear. Damage associated molecular patterns are key initiators of sterile inflammation and are detectable in peripheral blood. A defined systematic search of the Web of Science, PubMed, and Scopus was performed to identify adult case-control studies published between January 1990 and June 2022. Three studies consisting of 242 cases and 83 controls met inclusion for the systematic review and meta-analysis of HMGB1 while twenty-eight studies consisting of 1,544 cases and 1,248 healthy controls were included for S100B. A significant standardised mean difference in peripheral S100B and HMGB1 concentrations was detected between cases and controls. S100B subgroup analysis determined the largest significant effect size for unmedicated individuals diagnosed with schizophrenia. This study provides evidence that peripheral S100B and HMGB1 concentrations are elevated in individuals diagnosed with schizophrenia when compared with healthy controls. These results should be interpreted with caution as significant heterogeneity was present during meta-analysis of S100B in the entire sample and in sub-group analysis. The persistence of significant heterogeneity throughout subgroup analysis indicates that the current diagnostic groupings may be a barrier to understanding human behaviours and emotions.

Differential expression of MDGA1 in major depressive disorder

The identification of gene expression-based biomarkers for major depressive disorder (MDD) continues to be an important challenge. In order to identify candidate biomarkers and mechanisms, we apply statistical and machine learning feature selection to an RNA-Seq gene expression dataset of 78 unmedicated individuals with MDD and 79 healthy controls. We identify 49 genes by LASSO penalized logistic regression and 45 genes at the false discovery rate threshold 0.188. The MDGA1 gene has the lowest P-value (4.9e-5) and is expressed in the developing brain, involved in axon guidance, and associated with related mood disorders in previous studies of bipolar disorder (BD) and schizophrenia (SCZ). The expression of MDGA1 is associated with age and sex, but its association with MDD remains significant when adjusted for covariates. MDGA1 is in a co-expression cluster with another top gene, ATXN7L2 (ataxin 7 like 2), which was associated with MDD in a recent GWAS. The LASSO classification model of MDD includes MDGA1, and the model has a cross-validation accuracy of 79%. Another noteworthy top gene, IRF2BPL, is in a close co-expression cluster with MDGA1 and may be related to microglial inflammatory states in MDD. Future exploration of MDGA1 and its gene interactions may provide insights into mechanisms and heterogeneity of MDD.

Reduced Real-life Affective Well-being and Amygdala Habituation in Unmedicated Community Individuals at Risk for Depression and Anxiety

Early identification of risk for depression and anxiety disorders is important for prevention, but real-life affective well-being and its biological underpinnings in the population remain understudied. Here, we combined methods from epidemiology, psychology, ecological momentary assessment, and functional magnetic resonance imaging to study real-life and neural affective functions in individuals with subclinical anxiety and depression from a population-based cohort of young adults. We examined psychological measures, real-life affective valence, functional magnetic resonance imaging amygdala habituation to negative affective stimuli, and the relevance of neural readouts for daily-life affective function in 132 non-help-seeking community individuals. We compared psychological and ecological momentary assessment measures of 61 unmedicated individuals at clinical risk for depression and anxiety (operationalized as subthreshold depression and anxiety symptoms or a former mood or anxiety disorder) with those of 48 nonrisk individuals and 23 persons with a mood or anxiety disorder. We studied risk-associated functional magnetic resonance imaging signals in subsamples with balanced sociodemographic and image quality parameters (26 nonrisk, 26 at-risk persons). Compared with nonrisk persons, at-risk individuals showed significantly decreased real-life affective valence (p= .038), reduced amygdala habituation (familywise error-corrected p= .024, region of interest corrected), and an intermediate psychological risk profile. Amygdala habituation predicted real-life affective valence in control subjects but not in participants at risk (familywise error-corrected p= .005, region of interest corrected). Our data suggest real-life and neural markers for affective alterations in unmedicated community individuals at risk for depression and anxiety and highlight the significance of amygdala habituation measures for the momentary affective experience in real-world environments.

No influence of mineralocorticoid and glutamatergic NMDA receptor stimulation on spatial learning and memory in individuals with major depression

BackgroundMajor depressive disorder (MDD) is associated with impairments in spatial learning and memory and with altered functioning of central mineralocorticoid receptors (MR) and glutamatergic N-methyl-D-aspartate receptors (NMDA-R). Both receptors are highly expressed in the hippocampus and prefrontal cortex – brain areas that are critical for spatial learning and memory. Here, we examined the effects of separate and combined MR and NMDA-R stimulation on spatial learning and memory in individuals with MDD and healthy controls. MethodsWe used a randomized, double-blind, placebo-controlled between-group study design to examine the effects of separate and combined stimulation of the MR (with 0.4 mg fludrocortisone) and NMDA-R (with 250 mg D-cycloserine) in 116 unmedicated individuals with MDD (mean age: 34.7 ± 13.3 years; 78.4% women) and 116 age-, sex-, and education-matched healthy controls. Participants were randomly assigned to one of four conditions: 1) placebo; 2) MR stimulation; 3) NMDA-R stimulation; and 4) combined MR/NMDA-R stimulation. Three hours after drug administration, spatial learning and memory were assessed using a virtual Morris Water Maze task. ResultsIndividuals with MDD and healthy controls did not differ in spatial learning and memory performance. Neither separate nor combined MR or NMDA-R stimulation altered measures of spatial performance. ConclusionIn this study of relatively young, predominantly female, and unmedicated individuals, we found no effect of MDD and no effect of separate or combined MR and NMDA-R stimulation on spatial learning and memory.

Increased neural responses to negative facial emotions and their relationship with dysfunctional attitudes among unmedicated individuals with major depressive disorder

Increased neural responses to negative facial emotions and their relationship with dysfunctional attitudes among unmedicated individuals with major depressive disorder

P593. Inflammatory Chemokine Levels in Plasma and CSF are Positively Correlated in Unmedicated First Episode Psychosis

Early-life exposure to stress has been postulated to induce systemic changes linked to pro-inflammatory cytokines and activated microglia in psychotic illness. We have reported evidence of peripheral inflammation as indexed by both chemokines (Eotaxin-1, IL-8, CCL-2, MDC, MIP-1B, TARC) and cytokines (TNFa) in unmedicated individuals at clinical high risk and in the first episode of psychosis (FEP). In preliminary data we have reported an association between neurometabolites in the dorsal caudate and inflammatory biomarkers. What is not known is to what degree peripheral inflammatory biomarkers are related to those in the CNS.