Faculty Bibliography
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91
Affective and somatic symptom clusters in depression and their relationship to treatment outcomes in the STAR*D sample
BACKGROUND:The heterogenous nature of depression continues to stymie efforts to identify biomarkers or predict treatment response. Efforts leveraging large datasets to define more uniform subtypes of depression or subgroups of depressed patients have considered only small subsets of symptoms. We aimed to understand how inclusion of more diverse complaints would impact data-emergent symptom and patient clusters. METHODS:We applied principal components analysis to baseline IDS data from 1491 STAR-D patients with major depressive disorder to derive naturally co-occurring symptom subsets before utilizing k-means clustering to divide patients into groups based on standardized residuals of each symptom subset score. We evaluated the clinical utility of our approach by comparing how cluster membership impacted response to citalopram. RESULTS:PCA identified nine naturally co-occurring symptom clusters: core affective symptoms, appetite/weight loss, anxiety, somatic symptoms, insomnia, negative intrusive thoughts, leaden paralysis/mood quality, diurnal mood variation, and irritability. Cluster analysis identified two patient groups, differing significantly in 7 of 9 clusters. Patients distinguished by the prominence of somatic vs. core affective symptoms exhibited greater reduction in depression severity with citalopram treatment. LIMITATIONS/CONCLUSIONS:Results depend not only on raw data, but also parameter selection, and interpretation. Replication is indicated. CONCLUSIONS:Findings are consistent with previous reports linking somatic symptoms and treatment resistance and demonstrating that SSRIs are most effective in treating affective symptoms. A novel distinction between physical somatic symptoms and psychic anxiety highlights the utility of assessing a broad spectrum of symptoms when exploring heterogeneity in depression and the need for treatments targeting physical somatic symptoms specifically.
PMID: 34952119
ISSN: 1573-2517
CID: 5109172
Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia
Increased levels of peripheral cytokines have been previously associated with depression in preclinical and clinical research. Although the precise nature of peripheral immune dysfunction in depression remains unclear, evidence from animal studies points towards a dysregulated response of peripheral leukocytes as a risk factor for stress susceptibility. This study examined dynamic release of inflammatory blood factors from peripheral blood mononuclear cells (PBMC) in depressed patients and associations with neural and behavioral measures of reward processing. Thirty unmedicated patients meeting criteria for unipolar depressive disorder and 21 healthy control volunteers were enrolled. PBMCs were isolated from whole blood and stimulated ex vivo with lipopolysaccharide (LPS). Olink multiplex assay was used to analyze a large panel of inflammatory proteins. Participants completed functional magnetic resonance imaging with an incentive flanker task to probe neural responses to reward anticipation, as well as clinical measures of anhedonia and pleasure including the Temporal Experience of Pleasure Scale (TEPS) and the Snaith-Hamilton Pleasure Scale (SHAPS). LPS stimulation revealed larger increases in immune factors in depressed compared to healthy subjects using an aggregate immune score (t49 = 2.83, p = 0.007). Higher peripheral immune score was associated with reduced neural responses to reward anticipation within the ventral striatum (VS) (r = -0.39, p = 0.01), and with reduced anticipation of pleasure as measured with the TEPS anticipatory sub-score (r = -0.318, p = 0.023). Our study provides new evidence suggesting that dynamic hyper-reactivity of peripheral leukocytes in depressed patients is associated with blunted activation of the brain reward system and lower subjective anticipation of pleasure.
PMID: 34741019
ISSN: 2158-3188
CID: 5038592
Toward a neurocircuit-based taxonomy to guide treatment of obsessive-compulsive disorder
An important challenge in mental health research is to translate findings from cognitive neuroscience and neuroimaging research into effective treatments that target the neurobiological alterations involved in psychiatric symptoms. To address this challenge, in this review we propose a heuristic neurocircuit-based taxonomy to guide the treatment of obsessive-compulsive disorder (OCD). We do this by integrating information from several sources. First, we provide case vignettes in which patients with OCD describe their symptoms and discuss different clinical profiles in the phenotypic expression of the condition. Second, we link variations in these clinical profiles to underlying neurocircuit dysfunctions, drawing on findings from neuropsychological and neuroimaging studies in OCD. Third, we consider behavioral, pharmacological, and neuromodulatory treatments that could target those specific neurocircuit dysfunctions. Finally, we suggest methods of testing this neurocircuit-based taxonomy as well as important limitations to this approach that should be considered in future research.
PMCID:8260628
PMID: 33414496
ISSN: 1476-5578
CID: 5154212
Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial
OBJECTIVE/UNASSIGNED:Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. METHODS/UNASSIGNED:Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Ã…sberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. RESULTS/UNASSIGNED:The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. CONCLUSIONS/UNASSIGNED:The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.
PMID: 33653118
ISSN: 1535-7228
CID: 4877972
White matter microstructure and its relation to clinical features of obsessive-compulsive disorder: findings from the ENIGMA OCD Working Group
Microstructural alterations in cortico-subcortical connections are thought to be present in obsessive-compulsive disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Here we investigated microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. We analyzed diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA OCD Working Group, in a cross-sectional case-control magnetic resonance study. We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen's d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. Adult OCD patients showed significant FA reduction in the sagittal stratum (d = -0.21, z = -3.21, p = 0.001) and posterior thalamic radiation (d = -0.26, z = -4.57, p < 0.0001). In the sagittal stratum, lower FA was associated with a younger age of onset (z = 2.71, p = 0.006), longer duration of illness (z = -2.086, p = 0.036), and a higher percentage of medicated patients in the cohorts studied (z = -1.98, p = 0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to controls. Our findings of microstructural alterations in projection and association fibers to posterior brain regions in OCD are consistent with models emphasizing deficits in connectivity as an important feature of this disorder.
PMCID:7969744
PMID: 33731673
ISSN: 2158-3188
CID: 5545062
Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders
Importance/UNASSIGNED:Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. Objective/UNASSIGNED:To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. Design, Setting, and Participants/UNASSIGNED:Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244. Main Outcomes and Measures/UNASSIGNED:Interregional profiles of group difference in cortical thickness between cases and controls. Results/UNASSIGNED:A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders. Conclusions and Relevance/UNASSIGNED:In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
PMCID:7450410
PMID: 32857118
ISSN: 2168-6238
CID: 4650132
Neural Mechanisms of Symptom Dimensions During Provocation in Obsessive-Compulsive Disorder [Meeting Abstract]
ISI:000645683800868
ISSN: 0006-3223
CID: 5309822
Interoception and Obsessive-Compulsive Disorder: A Review of Current Evidence and Future Directions
Disrupted interoceptive processes are present in a range of psychiatric conditions, and there is a small but growing body of research on the role of interoception in obsessive-compulsive disorder (OCD). In this review, we outline dimensions of interoception and review current literature on the processing of internal bodily sensations within OCD. Investigations in OCD utilizing objective measures of interoception are limited and results mixed, however, the subjective experience of internal bodily sensations appears to be atypical and relate to specific patterns of symptom dimensions. Further, neuroimaging investigations suggest that interoception is related to core features of OCD, particularly sensory phenomena and disgust. Interoception is discussed in the context of treatment by presenting an overview of existing interventions and suggesting how modifications aimed at better targeting interoceptive processes could serve to optimize outcomes. Interoception represents a promising direction for multi-method research in OCD, which we expect, will prove useful for improving current interventions and identifying new treatment targets.
PMCID:8424053
PMID: 34512412
ISSN: 1664-0640
CID: 4998522
Insula Functional Connectivity During Urge Suppression in Obsessive-Compulsive Disorder [Meeting Abstract]
ISI:000645683800577
ISSN: 0006-3223
CID: 5309812
Urges-For-Action in OCD: Blink Suppression Failure Relates to Clinical Heterogeneity [Meeting Abstract]
ISI:000645683800317
ISSN: 0006-3223
CID: 5309802
