Brian P Brennan | Harvard Medical School (original) (raw)

Papers by Brian P Brennan

Frontiers in Psychiatry

Initial controlled trials of the serotonergic antidepressant fluvoxamine showed promise for treat... more Initial controlled trials of the serotonergic antidepressant fluvoxamine showed promise for treatment of mild to moderate COVID-19 in outpatients, although more recent outpatient data have been less encouraging. Turning to studies of hospitalized patients, a retrospective cohort study by Hoertel and associates in 2021 found a markedly reduced risk of intubation or death among patients hospitalized with COVID-19 who were receiving serotonergic antidepressants at the time of admission vs. those not receiving antidepressants. In an attempt to replicate these latter findings, we performed a similarly designed study of 500 individuals hospitalized with COVID-19 in a large academic hospital system who were taking a serotonergic antidepressant at the time of admission compared with two groups (N = 573 and N = 593) not receiving an antidepressant. In analyses controlling for demographic and clinical variables, we found no significant difference in effect between the antidepressant group and...

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

• Obsessive compulsive disorder (OCD) is characterized by intrusive, distressing thoughts (i.e., ... more • Obsessive compulsive disorder (OCD) is characterized by intrusive, distressing thoughts (i.e., obsessions), as well as repetitive behaviors aimed to reduce distress (i.e., compulsions; APA, 2013). • Response inhibition (RI) is a neuropsychological construct that refers to one’s ability to inhibit a pre-potent motor response. • RI may contribute to the etiology and maintenance of OCD (Abramovitch & Cooperman, 2015), as individuals with OCD demonstrate reduced performance on measures of RI (Abramovitch et al., 2013). • However, research regarding RI and OCD has been largely mixed, which could be due to the notably heterogeneous nature of OCD that has not been consistently accounted for in previous literature. • Aim: To examine the relationship between RI and OCD symptom dimensions in intensive treatment for OCD. • Hypotheses: • RI would be uniquely correlated with concerns about contamination, germs, and dirt, and concerns about symmetry, completeness, and the need for things to be just right at admission and discharge. • RI would significantly predict the severity of these specific symptoms at admission and discharge, when controlling for overall symptom severity.

The American Journal on Addictions, 2010

In a study of performance-enhancing substance use among 231 experienced young male weightlifters,... more In a study of performance-enhancing substance use among 231 experienced young male weightlifters, we found that 27 (12%) reported illicit use of human growth hormone (HGH) or its bioactive derivative, insulin-like growth factor-1 (IGF-I). All of these 27 men also reported use of anabolic-androgenic steroids (AAS) and 22 (81%) met criteria for current or past AAS dependence. Fifteen (56%) also reported current or past dependence on opioids, cocaine, and/or ecstasy. These findings suggest that among young male weightlifters, illicit HGH use has become a common form of substance abuse, frequently associated with both AAS dependence and classical substance dependence.

Ample evidence suggests that response inhibition is impaired in obsessive-‐compulsive disorder (... more Ample evidence suggests that response inhibition is impaired in obsessive-‐compulsive disorder (OCD). This cognitive deficit may be a manifestation of lateral orbitofrontal loop dysfunction, which could itself serve as an endophenotypic marker for OCD and related disorders. Despite such findings, little research to date has evaluated the putative relationship between baseline response inhibition and psychosocial treatment response. Further, few studies have assessed the relationship between symptom cluster severity and treatment outcome. The studies that do exist have produced equivocal results. Finally, there have been fair few studies that have evaluated the variability in response inhibition by symptom subtype. None have looked at implications for treatment. The goal of the current study was to determine whether response inhibition and symptom subtype predicted course of treatment in patients undergoing intensive residential treatment (IRT).

Neuropsychopharmacology, 2015

The anterior cingulate cortex is implicated in the neurobiology of obsessive-compulsive disorder ... more The anterior cingulate cortex is implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, few studies have examined functional and neurochemical abnormalities specifically in the rostral subdivision of the ACC (rACC) in OCD patients. We used functional magnetic resonance imaging (fMRI) during an emotional counting Stroop task and single-voxel J-resolved proton magnetic resonance spectroscopy (1 H-MRS) in the rACC to examine the function and neurochemistry of the rACC in individuals with OCD and comparison individuals without OCD. Between-group differences in rACC activation and glutamine/glutamate ratio (Gln/Glu), Glu, and Gln levels, as well as associations between rACC activation, Gln/Glu, Glu, Gln, behavioral, and clinical measures were examined using linear regression. In a sample of 30 participants with OCD and 29 age-and sex-matched participants without OCD, participants with OCD displayed significantly reduced rACC deactivation compared with those without OCD in response to OCD-specific words versus neutral words on the emotional counting Stroop task. However, Gln/Glu, Glu, and Gln in the rACC did not differ between groups nor was there an association between reduced rACC deactivation and Gln/Glu, Glu, or Gln in the OCD group. Taken together, these findings strengthen the evidence for rACC dysfunction in OCD, but weigh against an underlying association with abnormal rACC glutamatergic neurotransmission.

Journal of Obsessive-Compulsive and Related Disorders, 2015

Objectives-Disgust is a well-established phenomenon with known neurobiological correlates. Howeve... more Objectives-Disgust is a well-established phenomenon with known neurobiological correlates. However, it remains unclear how or whether disgust changes with clinical treatment, because few longitudinal studies have tracked the association of disgust vulnerability and clinical symptoms in patient populations. Methods-We assessed disgust propensity and symptoms of obsessive-compulsive disorder (OCD) in 134 patients receiving intensive residential treatment for OCD. Using linear regression with adjustment for age, sex, and depression severity, we tested the association between change in disgust propensity and change in OCD symptoms from admission to discharge. Results-Change in disgust propensity was significantly associated with improvement in contamination/washing symptoms (β = 0.25 [95% confidence interval: 0.11-0.39]; P = .001). No significant association was found between change in disgust propensity and change in other OCD symptom dimensions. Conclusions-In patients with OCD undergoing intensive residential treatment, disgust propensity appears to improve in parallel with contamination/washing symptoms.

Journal of Clinical Psychopharmacology, 2013

Background-Bipolar disorder may be associated with mitochondrial dysfunction. Therefore, agents t... more Background-Bipolar disorder may be associated with mitochondrial dysfunction. Therefore, agents that enhance mitochondrial functioning may be efficacious in bipolar disorder. We performed a randomized placebo-controlled trial of the mitochondrial enhancers acetyl-L-carnitine (ALCAR) and α-lipoic acid (ALA) in patients with bipolar depression, and assessed markers of cerebral energy metabolism using phosphorus magnetic resonance spectroscopy. Methods-We administered ALCAR (1000-3000 mg daily) plus ALA (600-1800 mg daily) or placebo for 12 weeks to 40 patients with bipolar depression and obtained imaging data at baseline, week 1, and week 12 of treatment in 20 patients using phosphorus 3-dimensional chemical-shift imaging at 4 T. Statistical analysis used random effects mixed models. Results-We found no significant difference between ALCAR/ALA and placebo on change from baseline in the Montgomery-Asberg Depression Rating Scale in both the longitudinal (mean difference [95% confidence interval], −1.4 [−6.2 to 3.4], P = 0.58) and last-observation-carriedforward (−3.2 [−7.2 to 0.9], P = 0.12) analyses. ALCAR/ALA treatment significantly reduced phosphocreatine levels in the parieto-occipital cortex at week 12 (P = 0.002). Reduction in whole brain total nucleoside triphosphate levels from baseline to week 1 was associated with reduction in Montgomery-Asberg Depression Rating Scale scores (P = 0.02) in patients treated with ALCAR/ ALA. However, this was likely a chance finding attributable to multiple statistical comparisons.

Journal of Psychiatric Research, 2014

Background: Intensive residential treatment (IRT) is effective for severe, treatment-resistant ob... more Background: Intensive residential treatment (IRT) is effective for severe, treatment-resistant obsessivecompulsive disorder (OCD). We sought to characterize predictors and course of response to IRT. Methods: Admission, monthly, and discharge data were collected on individuals receiving IRT. We examined the association between baseline characteristics and percent change in OCD symptoms as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) using linear regression. We compared baseline characteristics of IRT responders (!35% reduction in Y-BOCS) versus non-responders, and of patients who did versus those who did not achieve wellness (Y-BOCS 12) using non-parametric tests. To examine the course of OCD severity over time, we used linear mixed-effects models with randomly varying intercepts and slopes. Results: We evaluated 281 individuals admitted to an IRT program. Greater baseline Y-BOCS scores were associated with a significantly greater percent reduction in Y-BOCS scores (b ¼ À1.49 ([95% confidence interval: À2.06 to À0.93]; P < .001)). IRT responders showed significantly greater baseline Y-BOCS scores than non-responders (mean (SD) 28 (5.2) vs. 25.6 (5.8); P ¼ .003) and lower past-year alcohol use scores than non-responders (1.4 (1.9) vs. 2.1 (2.2); P ¼ .01). Participants who achieved wellness displayed lower hoarding factor scores than those who did not (5 (4.6) vs. 9.53 (6.3); P ¼ .03). OCD symptoms declined rapidly over the first month but more slowly over the remaining two months. Conclusions: Higher baseline OCD severity, lower past-year alcohol use, and fewer hoarding symptoms predicted better response to IRT. IRT yielded an initial rapid reduction in OCD symptoms, followed by a slower decline after the first month.

JAMA Psychiatry

IMPORTANCE Large-scale neuroimaging studies have revealed group differences in cortical thickness... more IMPORTANCE 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 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 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:

Translational Psychiatry

No diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Here, we aimed to... more No diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Here, we aimed to identify magnetic resonance imaging (MRI) biomarkers for OCD, using 46 data sets with 2304 OCD patients and 2068 healthy controls from the ENIGMA consortium. We performed machine learning analysis of regional measures of cortical thickness, surface area and subcortical volume and tested classification performance using cross-validation. Classification performance for OCD vs. controls using the complete sample with different classifiers and cross-validation strategies was poor. When models were validated on data from other sites, model performance did not exceed chance-level. In contrast, fair classification performance was achieved when patients were grouped according to their medication status. These results indicate that medication use is associated with substantial differences in brain anatomy that are widely distributed, and indicate that clinical heterogeneity contributes to the po...

Human Brain Mapping

Neuroimaging has played an important part in advancing our understanding of the neurobiology of o... more Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive-compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD

Oxford Medicine Online

Studies using functional neuroimaging have played a critical role in the current understanding of... more Studies using functional neuroimaging have played a critical role in the current understanding of the neurobiology of obsessive-compulsive disorder (OCD). Early studies using positron emission tomography (PET) identified a core cortico-striatal-thalamo-cortical circuit that is dysfunctional in OCD. Subsequent studies using behavioral paradigms in conjunction with functional magnetic resonance imaging (fMRI) have provided additional information about the neural substrates underlying specific psychological processes relevant to OCD. More recently, studies utilizing resting state fMRI have identified abnormal functional connectivity within intrinsic brain networks including the default mode and frontoparietal networks in OCD patients. Although these studies, as a whole, clearly substantiate the model of cortico-striatal-thalamo-cortical circuit dysfunction in OCD and support the continued investigation of neuromodulatory treatments targeting these brain regions, there is also growing e...

Journal of Obsessive-Compulsive and Related Disorders

ABSTRACTObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD),... more ABSTRACTObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders...

Biological Psychiatry

Objective: Lateralized dysfunction has been suggested in Obsessive-Compulsive Disorder (OCD). How... more Objective: Lateralized dysfunction has been suggested in Obsessive-Compulsive Disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of structural brain asymmetry. Here we carried out by far the largest study of brain structural asymmetry in OCD. Method: We studied a collection of 16 pediatric datasets (501 OCD patients and 439 healthy controls), as well as 30 adult datasets (1777 patients and 1654 controls) from the OCD Working Group within the ENIGMA (Enhancing Neuro-Imaging Genetics through Meta-Analysis) consortium. Asymmetries of the volumes of subcortical structures, and of regional cortical thickness and surface area measures, were assessed based on T1-weighted MRI scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in OCD patients. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status. Results: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d =-0.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, and/or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets. Conclusions: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD.

PLOS Biology

Functional MRI (fMRI) studies have traditionally relied on intersubject normalization based on gl... more Functional MRI (fMRI) studies have traditionally relied on intersubject normalization based on global brain morphology, which cannot establish proper functional correspondence between subjects due to substantial intersubject variability in functional organization. Here, we reliably identified a set of discrete, homologous functional regions in individuals to improve intersubject alignment of fMRI data. These functional regions demonstrated marked intersubject variability in size, position, and connectivity. We found that previously reported intersubject variability in functional connectivity maps could be partially explained by variability in size and position of the functional regions. Importantly, individual differences in network topography are associated with individual differences in task-evoked activations, suggesting that these individually specified regions may serve as the "localizer" to improve the alignment of task-fMRI data. We demonstrated that aligning task-fMRI data using the regions derived from resting state fMRI may lead to increased statistical power of task-fMRI analyses. In addition, resting state functional connectivity among these homologous regions is able to capture the idiosyncrasies of subjects and better predict fluid intelligence (gF) than connectivity measures derived from group-level brain atlases. Critically, we showed that not only the connectivity but also the size and position of functional regions are related to human behavior. Collectively, these findings suggest that identifying homologous functional regions across individuals can benefit a wide range of studies in the investigation of connectivity, task activation, and brain-behavior associations.