Publications by authors named "Katherine E Burdick"

123 Publications

Association between visceral adipose tissue and major depressive disorder across the lifespan: a Scoping Review.

Bipolar Disord 2021 Sep 22. Epub 2021 Sep 22.

Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Objectives: Increasing evidence supports a bidirectional relationship between major depressive disorder (MDD) and obesity, but the role of visceral adipose tissue (VAT) as a measure of obesity in relation to MDD is not well understood. Here we review literature investigating the link between MDD and VAT in terms of biomarkers, sex differences, and aging.

Methods: PubMed, EMBASE, PsycINFO, and CINAHL searches were conducted on December 11, 2020. No date or language limits were imposed. Major concepts searched were Depressive Disorder linked with Adipose Tissue, White, Hypothalmo-Hypophyseal System, and Pituitary-Adrenal System in addition to keywords. A final set of 32 items meeting criteria for inclusion.

Results: Converging biological evidence suggests a significant bidirectional relationship between VAT and MDD across the lifespan. In adulthood, greater VAT was associated with increased risk for depression, especially in vulnerable groups such as individuals who are overweight/obese, postmenopausal women, and individuals with comorbid medical or psychiatric illness. In older adults, sarcopenia had an impact on the relationship between abnormal VAT and risk of depression. Additionally, sex differences emerged as a potential factor affecting the strength of the association between VAT and depression.

Conclusions: Elucidating the pathophysiological mechanisms associated with increased rates of depression in obese individuals will be crucial for developing specific treatment strategies that seek to improve outcomes in individuals with comorbid depression and obesity. Moreover, identifying age- and sex-specific risk factors may contribute to a more personalized medicine approach, thereby improving the quality of clinical care.
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http://dx.doi.org/10.1111/bdi.13130DOI Listing
September 2021

Age moderates the relationship between affective response inhibition and bipolar disorder in adults.

J Affect Disord 2021 Aug 24;295:298-304. Epub 2021 Aug 24.

Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Background: Patients with bipolar disorder (BD) often have impairments in neurocognition, including affective processing and affective response inhibition. While studies suggest that cognitive control in general may decline with age in BD, less is known about age-related changes in response inhibition to emotionally salient information.

Methods: 258 participants with BD and 54 healthy controls, ages 18-70, completed the Cambridge Neuropsychological Test Automated Battery (CANTAB) Affective Go/No-Go task to assess affective response inhibition to positive and negative valenced stimuli. We examined the relationship between BD and affective response inhibition (number of commission and omission errors and reaction time), as well as a potential moderating effect of age, using mixed effects linear regression models.

Results: The BD group made more omission and commission errors overall than the control group (p < 0.018). We observed a significant 3-way group-by-age-by-valence interaction for reaction time (p = 0.006). Within BD, a slower reaction time to negative than positive stimuli was found in middle and older age groups (p < 0.012), but not in the younger age group. No significant moderating effect of age was observed within the control group.

Conclusions: These cross-sectional findings indicate that compared with healthy controls, individuals with BD display differential and age-related effects in inhibition to emotionally salient information that is valence-dependent. The observed pattern of a switch in bias from negative to positive stimuli with age in BD may aid in our understanding of the progression of neurocognitive changes with aging in BD, as well as inform targeted treatments for cognitive symptoms.
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http://dx.doi.org/10.1016/j.jad.2021.08.019DOI Listing
August 2021

Cognitive heterogeneity is a key predictor of differential functional outcome in patients with bipolar disorder.

Eur Neuropsychopharmacol 2021 Jul 10;53:4-6. Epub 2021 Jul 10.

Mood and Psychosis Research Program, Department of Psychiatry, Brigham and Women's Hospital, Boston, MA USA; Department of Psychiatry, Harvard Medical School, Boston, MA USA.

Bipolar disorder (BD) is a complex illness with variability at the level of symptom presentation, clinical course, cognitive capacity, and everyday function. Cognition is a key predictor of functional disability in BD, however, much remains unknown about the development and presentation of cognitive dysfunction in BD. Studies have shown that 30-50% of affectively stable people with BD are indistinguishable from healthy individuals in terms of cognitive presentation. In contrast, many people with BD have moderate to severe cognitive deficits, in some cases on par with what is typically observed in schizophrenia (SZ). Recent research efforts have aimed to parse this cognitive heterogeneity using unsupervised statistical techniques, resulting in more homogeneous subgroups. This method has provided new insights into the clinical and biological predictors of a potentially - neuroprogressive - declinin - gcognitive course in BD. Future studies that include detailed longitudinal follow-up in large BD cohorts hold promise for guiding the development of novel treatments that reach beyond the primary affective symptoms and target functionally relevant outcomes to promote full recovery.
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http://dx.doi.org/10.1016/j.euroneuro.2021.06.008DOI Listing
July 2021

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

Neuropsychopharmacology 2021 09 25;46(10):1788-1801. Epub 2021 May 25.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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.
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http://dx.doi.org/10.1038/s41386-021-01023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357785PMC
September 2021

Defining Heterogeneous Cognitive Trajectories in Bipolar Disorder: A Perspective.

Harv Rev Psychiatry 2021 Jul-Aug 01;29(4):298-302

From Harvard Medical School; Mood and Psychosis Research Program, Department of Psychiatry, Brigham and Women's Hospital, Boston, MA.

Abstract: Bipolar disorder (BD) is a highly disabling mental illness that affects approximately 1% of the global population. Cognitive capacity is a strong predictor of "everyday" functional outcome in BD and should thus be considered a key treatment target. Interventions to improve cognition have been largely unsuccessful, likely due to the substantial heterogeneity inherent to the illness. It is known that 40%-60% of people with BD have cognitive impairment, yet impairment is not "one size fits all"; in fact, the literature supports discrete cognitive subtypes in BD (e.g., intact, globally impaired, and selectively impaired). Gaining a better understanding of these cognitive subtypes, their longitudinal trajectories, and their biological underpinnings will be essential for improving patient outcomes. The prevailing hypothesis for the development of cognitive impairment in BD postulates a stepwise cumulative effect of repeated mood episodes causing wear-and-tear on the brain. However, a paucity of data supports this idea at the group level. We propose that studying heterogeneity longitudinally will allow for clearer delineation of the natural history of cognitive trajectories in BD. In sum, parsing heterogeneity in BD will allow us to identify causal mechanisms and optimize treatment at the level of the individual.
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http://dx.doi.org/10.1097/HRP.0000000000000297DOI Listing
May 2021

Pramipexole to Improve Cognition in Bipolar Disorder: A Randomized Controlled Trial.

J Clin Psychopharmacol 2021 Jul-Aug 01;41(4):421-427

Brigham and Women's Hospital, Mood and Psychosis Research Program, Boston.

Background: Adults with bipolar disorder (BD) often experience neurocognitive impairment that negatively impacts functioning and quality of life. Previous trials have found that dopamine agonist agents improve cognition in healthy volunteers and that adults with BD who have stable mood and mild cognitive deficits may also benefit. We hypothesized that pramipexole, a dopamine agonist, would improve neurocognitive function in patients with BD.

Methods: We recruited 60 adults (aged 18-65 years) with a diagnosis of BD I or II for an 8-week, double-blind, placebo-controlled trial (NCT02397837). All had stable mood and clinically significant neurocognitive impairment at baseline. Participants were randomized to receive pramipexole (n = 31) or a placebo (n = 29), dose was initiated at 0.125 mg 2 times a day and increased to a target of 4.5 mg/d.

Results: At trial end, the primary outcome, MATRICS Consensus Cognitive Battery composite score, had not improved more in the pramipexole group (mean [SD] = 1.15 [5.4]) than in the placebo group (mean [SD] = 4.12 [5.2], Cohen's d = 0.56, P = 0.049), and mixed models, controlling for symptoms, showed no association between treatment group and MATRICS Consensus Cognitive Battery scores. No serious adverse events were reported.

Conclusions: These results suggest that pramipexole is not an efficacious cognitive enhancement agent in BD, even in a sample enriched for characteristics that were associated with a beneficial response in prior work. There are distinct cognitive subgroups among adults with BD and may be related differences in neurobiology that affect response to pramipexole. Additional research to better understand the onset and nature of the cognitive deficits in people with BD will be an important step toward a more personalized approach to treatment.
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http://dx.doi.org/10.1097/JCP.0000000000001407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238822PMC
May 2021

The impact of COVID-19 on cognition in severe cases highlights the need for comprehensive neuropsychological evaluations in all survivors.

Neuropsychopharmacology 2021 Mar 22. Epub 2021 Mar 22.

Mood and Psychosis Research Program, Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41386-021-00995-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983959PMC
March 2021

Recognising the relevance of cognitive dysfunction in the clinical management of bipolar disorder.

Bipolar Disord 2021 06 2;23(4):414-415. Epub 2021 Mar 2.

Department of Psychiatry, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1111/bdi.13063DOI Listing
June 2021

Recognising the relevance of cognitive dysfunction in the clinical management of bipolar disorder.

Bipolar Disord 2021 06 2;23(4):414-415. Epub 2021 Mar 2.

Department of Psychiatry, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1111/bdi.13063DOI Listing
June 2021

Brain morphology does not clearly map to cognition in individuals on the bipolar-schizophrenia-spectrum: a cross-diagnostic study of cognitive subgroups.

J Affect Disord 2021 02 13;281:776-785. Epub 2020 Nov 13.

Centre for Mental Health, Faculty of Health, Arts and Design, School of Health Sciences, Swinburne University, Melbourne, Australia; Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health. Electronic address:

Background: Characterisation of brain morphological features common to cognitively similar individuals with bipolar disorder (BD) and schizophrenia spectrum disorders (SSD) may be key to understanding their shared neurobiological deficits. In the current study we examined whether three previously characterised cross-diagnostic cognitive subgroups differed among themselves and in comparison to healthy controls across measures of brain morphology.

Method: T1-weighted structural magnetic resonance imaging scans were obtained for 143 individuals; 65 healthy controls and 78 patients (SSD, n = 40; BD I, n = 38) classified into three cross-diagnostic cognitive subgroups: Globally Impaired (n = 24), Selectively Impaired (n = 32), and Superior/Near-Normal (n = 22). Cognitive subgroups were compared to each other and healthy controls on three separate analyses investigating (1) global, (2) regional, and (3) vertex-wise comparisons of brain volume, thickness, and surface area.

Results: No significant subgroup differences were evident in global measures of brain morphology. In region of interest analyses, the Selectively Impaired subgroup had greater right accumbens volume than those Superior/Near-Normal subgroup and healthy controls, and the Superior/Near-Normal subgroup had reduced volume of the left entorhinal region compared to all other groups. In vertex-wise comparisons, the Globally Impaired subgroup had greater right precentral volume than the Selectively Impaired subgroup, and thicker cortex in the postcentral region relative to the Superior/Near-Normal subgroup.

Limitations: Exploration of medication effects was limited in our data.

Conclusions: Although some differences were evident in this sample, generally cross-diagnostic cognitive subgroups of individuals with SSD and BD did not appear to be clearly distinguished by patterns in brain morphology.
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http://dx.doi.org/10.1016/j.jad.2020.11.064DOI Listing
February 2021

Macro and micro sleep architecture and cognitive performance in older adults.

Nat Hum Behav 2021 01 16;5(1):123-145. Epub 2020 Nov 16.

Harvard Medical School, Boston, MA, USA.

We sought to determine which facets of sleep neurophysiology were most strongly linked to cognitive performance in 3,819 older adults from two independent cohorts, using whole-night electroencephalography. From over 150 objective sleep metrics, we identified 23 that predicted cognitive performance, and processing speed in particular, with effects that were broadly independent of gross changes in sleep quality and quantity. These metrics included rapid eye movement duration, features of the electroencephalography power spectra derived from multivariate analysis, and spindle and slow oscillation morphology and coupling. These metrics were further embedded within broader associative networks linking sleep with aging and cardiometabolic disease: individuals who, compared with similarly aged peers, had better cognitive performance tended to have profiles of sleep metrics more often seen in younger, healthier individuals. Taken together, our results point to multiple facets of sleep neurophysiology that track coherently with underlying, age-dependent determinants of cognitive and physical health trajectories in older adults.
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http://dx.doi.org/10.1038/s41562-020-00964-yDOI Listing
January 2021

NSI-189 phosphate, a novel neurogenic compound, selectively benefits moderately depressed patients: A post-hoc analysis of a phase 2 study of major depressive disorder.

Ann Clin Psychiatry 2020 08;32(3):182-196

Background: NSI-189 phosphate (NSI-189) is a novel neurogenic molecule with pleiotropic properties, including antidepressant, procognitive, synaptoplastic, and neurotrophic activities demonstrated in preclinical studies. Its antidepressant activity is monoamine-independent. NSI-189 was previously tested in patients with recurrent major depressive disorder in an inpatient setting.

Methods: This study involved 220 patients randomized to an NSI-189 40-mg dose, NSI-189 80-mg dose, or placebo daily for 12 weeks. The study utilized the sequential parallel comparison design, in which the drug effect was tested in 2 separate stages of 6 weeks each. Herein, post-hoc analyses of the data are presented.

Results: NSI-189's antidepressant effect increased when the participants' initial baseline depression severity was dichotomized along a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 30. The NSI-189 80-mg dose showed significant benefit over placebo when utilizing the MADRS-6 (P = .046) in the subgroup of patients who were moderately depressed (MADRS < 30) but was not significant in patients who were severely depressed (MADRS ≥30). More pronounced procognitive effects were also observed in the moderate subgroup relative to the severe subgroup or the whole study group, in which 11/36 (31%), 5/36 (14%), or 7/36 (19%) of CogScreen variables significantly improved, respectively.

Conclusions: These results suggest that NSI-189 is effective as a safe adjunctive therapy, with most compelling antidepressant and procognitive benefits noted in patients with moderate depression.
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August 2020

A molecular approach to treating cognition in schizophrenia by calcium channel blockade: An open-label pilot study of the calcium-channel antagonist isradipine.

Schizophr Res Cogn 2020 Sep 18;21:100180. Epub 2020 May 18.

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Cognitive impairment is a prominent and difficult to treat symptom in schizophrenia (SZ), which is directly related to functional disability. A variant in the gene coding for the alpha 1C subunit of L-type voltage gated calcium channel (CACNA1C) has been shown to negatively affect several neurocognitive domains. We conducted a 4-week, open label, pilot study of isradipine, a calcium channel blocker, to determine its feasibility, safety, and efficacy in improving cognition in SZ patients. Ten adults with stable SZ were started on a flexible dose of isradipine 5 mg/day (up to 10 mg/day) for 4 weeks. Weekly in-person visits tracked side effects and symptoms while neurocognition and functional capacity were assessed at baseline and week 4. There were no serious adverse events reported. Newly emergent side effects were dizziness (1 new incidence at week 4); difficulty sleeping (2 new incidences at week 4); and decreased energy (3 new incidences at week 4). 1 patient discontinued medication and was withdrawn. Treatment did not exacerbate clinical symptoms. Although power is limited, results indicate no clear benefit on neurocognition but a positive effect (baseline mean = 6.8 ± 1.3 to week 4 mean = 7.9 ± 1.1; t = 2.91, p = 0.017) on functional capacity was noted. This open label, pilot study provides preliminary evidence that isradipine is a relatively safe medication when used adjunctively in SZ patients. This study suggests that isradipine offers no clear cognitive and only minimal functional benefit; however, additional studies may be warranted in symptomatic patients, or those with specific CACNA1C genotypes.
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http://dx.doi.org/10.1016/j.scog.2020.100180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235642PMC
September 2020

The association between lithium use and neurocognitive performance in patients with bipolar disorder.

Neuropsychopharmacology 2020 09 29;45(10):1743-1749. Epub 2020 Apr 29.

NORMENT, Division of Psychiatry, Haukeland University Hospital and Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1-5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p < 0.001], CVLT trials 1-5 [F = 29.81; p < 0.001], CVLT delayed recall [F = 15.27; p < 0.001], and TMT-B [F = 6.64, p = 0.012] was detected. The cross-sectional and longitudinal (on a subset of 88 patients) investigations suggest that lithium may be beneficial to neurocognitive functioning in patients with BD and that at the very least it does not seem to significantly impair cognition when used therapeutically.
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http://dx.doi.org/10.1038/s41386-020-0683-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419515PMC
September 2020

Cognitive validation of cross-diagnostic cognitive subgroups on the schizophrenia-bipolar spectrum.

J Affect Disord 2020 04 25;266:710-721. Epub 2020 Jan 25.

Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Melbourne, Australia; Centre for Mental Health, Faculty of Health, Arts and Design, School of Health Sciences, Swinburne University, Melbourne, Australia. Electronic address:

Background: Cognitive heterogeneity in schizophrenia spectrum disorders (SSD) and bipolar disorder (BD) has been explored using clustering analyses. However, the resulting subgroups have not been cognitively validated beyond measures used as clustering variables themselves. We compared the emergent cross-diagnostic subgroups of SSD and BD patients on measures used to classify them, and also across a range of alternative cognitive measures assessing some of the same constructs.

Method: Domain scores from the Matrics Consensus Cognitive Battery were used in a cross-diagnostic clustering analysis of 86 patients with SSD (n = 45) and BD (n = 41). The emergent subgroups were then compared to each other and healthy controls (n = 76) on these and alternative measures of these domains, as well as on premorbid IQ, global cognition and a proxy of cognitive decline.

Results: A three-cluster solution was most appropriate, with subgroups labelled as Globally Impaired, Selectively Impaired, and Superior/Near-Normal relative to controls. With the exception of processing speed performance, the subgroups were generally differentiated on the cognitive domain scores used as clustering variables. Differences in cognitive performance among these subgroups were not always statistically significant when compared on the alternative cognitive measures. There was evidence of global cognitive impairment and putative cognitive decline in the two cognitively impaired subgroups.

Limitations: For clustering analysis, sample size was relatively small.

Conclusions: The overall pattern of findings tentatively suggest that emergent cross-diagnostic cognitive subgroups are not artefacts of the measures used to define them, but may represent the outcome of different cognitive trajectories.
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http://dx.doi.org/10.1016/j.jad.2020.01.123DOI Listing
April 2020

Entering the debate: Cognitive enhancement therapy for mood disorders: A new paradigm?

Bipolar Disord 2020 05 27;22(3):305-306. Epub 2020 Jan 27.

Melbourne Neuropsychiatry Centre, Melbourne, Australia.

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http://dx.doi.org/10.1111/bdi.12889DOI Listing
May 2020

The buildup of an urge in obsessive-compulsive disorder: Behavioral and neuroimaging correlates.

Hum Brain Mapp 2020 04 9;41(6):1611-1625. Epub 2020 Jan 9.

Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, New York.

Obsessive-compulsive disorder (OCD) is highly heterogeneous. While obsessions often involve fear of harm, many patients report uncomfortable sensations and/or urges that drive repetitive behaviors in the absence of a specific fear. Prior work suggests that urges in OCD may be similar to everyday "urges-for-action" (UFA) such as the urge to blink, swallow, or scratch, but very little work has investigated the pathophysiology underlying urges in OCD. In the current study, we used an urge-to-blink approach to model sensory-based urges that could be experimentally elicited and compared across patients and controls using the same task stimuli. OCD patients and controls suppressed eye blinking over a period of 60 s, alternating with free blinking blocks, while brain activity was measured using functional magnetic resonance imaging. OCD patients showed significantly increased activation in several regions during the early phase of eyeblink suppression (first 30 s), including mid-cingulate, insula, striatum, parietal cortex, and occipital cortex, with lingering group differences in parietal and occipital regions during late eyeblink suppression (last 30 s). There were no differences in brain activation during free blinking blocks, and no conditions where OCD patients showed reduced activation compared to controls. In an exploratory analysis of blink counts performed in a subset of subjects, OCD patients were less successful than controls in suppressing blinks. These data indicate that OCD patients exhibit altered brain function and behavior when experiencing and suppressing the urge to blink, raising the possibility that the disorder is associated with a general abnormality in the UFA system that could ultimately be targeted by future treatments.
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http://dx.doi.org/10.1002/hbm.24898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082184PMC
April 2020

Cognitive Control Network Homogeneity and Executive Functions in Late-Life Depression.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 02 7;5(2):213-221. Epub 2019 Nov 7.

Department of Psychiatry, Joan & Sanford I. Weill Medical College of Cornell University, New York. Electronic address:

Background: Late-life depression is characterized by network abnormalities, especially within the cognitive control network. We used alternative functional connectivity approaches, regional homogeneity (ReHo) and network homogeneity, to investigate late-life depression functional homogeneity. We examined the association between cognitive control network homogeneity and executive functions.

Methods: Resting-state functional magnetic resonance imaging data were analyzed for 33 older adults with depression and 43 healthy control subjects. ReHo was performed as the correlation between each voxel and the 27 neighbor voxels. Network homogeneity was calculated as global brain connectivity restricted to 7 networks. T-maps were generated for group comparisons. We measured cognitive performance and executive functions with the Dementia Rating Scale, Trail-Making Test (A and B), Stroop Color Word Test, and Digit Span Test.

Results: Older adults with depression showed increased ReHo in the bilateral dorsal anterior cingulate cortex (dACC) and the right middle temporal gyrus, with no significant findings for network homogeneity. Hierarchical linear regression models showed that higher ReHo in the dACC predicted better performance on Trail-Making Test B (p < .001; R = .49), Digit Span Backward (p < .05; R = .23), and Digit Span Total (p < .05; R = .23). Used as a seed, the dACC cluster of higher ReHo showed lower functional connectivity with bilateral precuneus.

Conclusions: Higher ReHo within the dACC and right middle temporal gyrus distinguish older adults with depression from control subjects. The correlations with executive function performance support increased ReHo in the dACC as a meaningful measure of the organization of the cognitive control network and a potential compensatory mechanism. Lower functional connectivity between the dACC and the precuneus in late-life depression suggests that clusters of increased ReHo may be functionally segregated.
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http://dx.doi.org/10.1016/j.bpsc.2019.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010539PMC
February 2020

Patient interest in mental health mobile app interventions: Demographic and symptom-level differences.

J Affect Disord 2020 02 14;263:216-220. Epub 2019 Nov 14.

Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA.

Background: Mobile app interventions for mental health conditions (MH apps) are an accessible and effective but underutilized treatment option. Learning which patients are most interested in MH apps is important for informing stakeholders where to position these treatments within the healthcare landscape. This study examined the relationship between patient characteristics and interest in MH apps.

Methods: A demographically-balanced sample of 400 patients diagnosed with depression, anxiety and/or post-traumatic stress disorder were identified from VA corporate data warehouse records. These individuals were mailed an information packet explaining the study and the study survey for those who opted to participate. The survey contained questions on demographics, symptom severity and interest in MH apps. 149 participants returned completed surveys.

Results: Level of interest in MH apps was consistent across race, sex and education level. Patients reporting no interest in MH apps had less severe symptoms and were older than patients reporting some or high interest.

Limitations: Participants were Veterans in one geographic region; our sample size was not large enough to evaluate more fine-grained demographic differences; replication would be required to better understand generalizability of findings.

Conclusions: Findings suggest interest in MH apps may be more similar across demographic groups than previously thought. This stands in juxtaposition to interest in clinic-based services, for which men and minorities have traditionally reported less interest and show lower utilization. Findings also counter prevailing notions that MH apps will be best received by less symptomatic patients. Implications for integrating MH apps into care are discussed.
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http://dx.doi.org/10.1016/j.jad.2019.11.083DOI Listing
February 2020

Affective cognition in bipolar disorder: A systematic review by the ISBD targeting cognition task force.

Bipolar Disord 2019 12 16;21(8):686-719. Epub 2019 Oct 16.

Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.

Background: Impairments in affective cognition are part of the neurocognitive profile and possible treatment targets in bipolar disorder (BD), but the findings are heterogeneous. The International Society of Bipolar Disorder (ISBD) Targeting Cognition Task Force conducted a systematic review to (i) identify the most consistent findings in affective cognition in BD, and (ii) provide suggestions for affective cognitive domains for future study and meta-analyses.

Methods: The review included original studies reporting behavioral measures of affective cognition in BD patients vs controls following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement. Searches were conducted on PubMed/MEDLINE, EMBASE, and PsychInfo from inception until November 2018.

Results: A total of 106 articles were included (of which nine included data for several affective domains); 41 studies assessed emotional face processing; 23 studies investigated reactivity to emotional words and images; 3 investigated explicit emotion regulation; 17 assessed implicit emotion regulation; 31 assessed reward processing and affective decision making. In general, findings were inconsistent. The most consistent findings were trait-related difficulties in facial emotion recognition and implicit emotion regulation, and impairments in reward processing and affective decision making during mood episodes. Studies using eye-tracking and facial emotion analysis revealed subtle trait-related abnormalities in emotional reactivity.

Conclusion: The ISBD Task Force recommends facial expression recognition, implicit emotion regulation, and reward processing as domains for future research and meta-analyses. An important step to aid comparability between studies in the field would be to reach consensus on an affective cognition test battery for BD.
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http://dx.doi.org/10.1111/bdi.12834DOI Listing
December 2019

Current understandings of the trajectory and emerging correlates of cognitive impairment in bipolar disorder: An overview of evidence.

Bipolar Disord 2020 02 29;22(1):13-27. Epub 2019 Aug 29.

Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, University of Valencia, CIBERSAM, Valencia, Spain.

Objectives: Cognitive dysfunction affects a significant proportion of people with bipolar disorder (BD), but the cause, trajectory and correlates of such dysfunction remains unclear. Increased understanding of these factors is required to progress treatment development for this symptom dimension.

Methods: This paper provides a critical overview of the literature concerning the trajectories and emerging correlates of cognitive functioning in BD. It is a narrative review in which we provide a qualitative synthesis of current evidence concerning clinical, molecular, neural and lifestyle correlates of cognitive impairment in BD across the lifespan (in premorbid, prodromal, early onset, post-onset, elderly cohorts).

Results: There is emerging evidence of empirical links between cognitive impairment and an increased inflammatory state, brain structural abnormalities and reduced neuroprotection in BD. However, evidence regarding the progressive nature of cognitive impairment is mixed, since consensus between different cross-sectional data is lacking and does not align to the outcomes of the limited longitudinal studies available. Increased recognition of cognitive heterogeneity in BD may help to explain some inconsistencies in the extant literature.

Conclusions: Large, longitudinally focussed studies of cognition and its covariation alongside biological and lifestyle factors are required to better define cognitive trajectories in BD, and eventually pave the way for the application of a precision medicine approach for individual patients in clinical practice.
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http://dx.doi.org/10.1111/bdi.12821DOI Listing
February 2020

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Am J Hum Genet 2019 08;105(2):334-350

Centre for Epidemiology, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester M139PL, United Kingdom; School of Healthcare Sciences, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.
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http://dx.doi.org/10.1016/j.ajhg.2019.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699140PMC
August 2019

Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Nat Commun 2019 May 1;10(1):2068. Epub 2019 May 1.

Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, 00014, Finland.

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.
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http://dx.doi.org/10.1038/s41467-019-10160-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494826PMC
May 2019

Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases.

Biol Psychiatry 2019 07 20;86(2):110-119. Epub 2018 Dec 20.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood.

Methods: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis.

Results: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden.

Conclusions: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
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http://dx.doi.org/10.1016/j.biopsych.2018.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586545PMC
July 2019

Adoption of Mobile Apps for Depression and Anxiety: Cross-Sectional Survey Study on Patient Interest and Barriers to Engagement.

JMIR Ment Health 2019 Jan 25;6(1):e11334. Epub 2019 Jan 25.

Center for Healthcare Organization and Implementation Research, VA Boston Healthcare System, Boston, MA, United States.

Background: Emerging research suggests that mobile apps can be used to effectively treat common mental illnesses like depression and anxiety. Despite promising efficacy results and ease of access to these interventions, adoption of mobile health (mHealth; mobile device-delivered) interventions for mental illness has been limited. More insight into patients' perspectives on mHealth interventions is required to create effective implementation strategies and to adapt existing interventions to facilitate higher rates of adoption.

Objective: The aim of this study was to examine, from the patient perspective, current use and factors that may impact the use of mHealth interventions for mental illness.

Methods: This was a cross-sectional survey study of veterans who had attended an appointment at a single Veterans Health Administration facility in early 2016 that was associated with one of the following mental health concerns: unipolar depression, any anxiety disorder, or posttraumatic stress disorder. We used the Veteran Affairs Corporate Data Warehouse to create subsets of eligible participants demographically stratified by gender (male or female) and minority status (white or nonwhite). From each subset, 100 participants were selected at random and mailed a paper survey with items addressing the demographics, overall health, mental health, technology ownership or use, interest in mobile app interventions for mental illness, reasons for use or nonuse, and interest in specific features of mobile apps for mental illness.

Results: Of the 400 potential participants, 149 (37.3%, 149/400) completed and returned a survey. Most participants (79.9%, 119/149) reported that they owned a smart device and that they use apps in general (71.1%, 106/149). Most participants (73.1%, 87/149) reported interest in using an app for mental illness, but only 10.7% (16/149) had done so. Paired samples t tests indicated that ratings of interest in using an app recommended by a clinician were significantly greater than general interest ratings and even greater when the recommending clinician was a specialty mental health provider. The most frequent concerns related to using an app for mental illness were lacking proof of efficacy (71.8%, 107/149), concerns about data privacy (59.1%, 88/149), and not knowing where to find such an app (51.0%, 76/149). Participants expressed interest in a number of app features with particularly high-interest ratings for context-sensitive apps (85.2%, 127/149), and apps focused on the following areas: increasing exercise (75.8%, 113/149), improving sleep (73.2%, 109/149), changing negative thinking (70.5%, 105/149), and increasing involvement in activities (67.1%, 100/149).

Conclusions: Most respondents had access to devices to use mobile apps for mental illness, already used apps for other purposes, and were interested in mobile apps for mental illness. Key factors that may improve adoption include provider endorsement, greater publicity of efficacious apps, and clear messaging about efficacy and privacy of information. Finally, multifaceted apps that address a range of concerns, from sleep to negative thought patterns, may be best received.
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http://dx.doi.org/10.2196/11334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367667PMC
January 2019

Adoption of Mobile Apps for Depression and Anxiety: Cross-Sectional Survey Study on Patient Interest and Barriers to Engagement.

JMIR Ment Health 2019 Jan 25;6(1):e11334. Epub 2019 Jan 25.

Center for Healthcare Organization and Implementation Research, VA Boston Healthcare System, Boston, MA, United States.

Background: Emerging research suggests that mobile apps can be used to effectively treat common mental illnesses like depression and anxiety. Despite promising efficacy results and ease of access to these interventions, adoption of mobile health (mHealth; mobile device-delivered) interventions for mental illness has been limited. More insight into patients' perspectives on mHealth interventions is required to create effective implementation strategies and to adapt existing interventions to facilitate higher rates of adoption.

Objective: The aim of this study was to examine, from the patient perspective, current use and factors that may impact the use of mHealth interventions for mental illness.

Methods: This was a cross-sectional survey study of veterans who had attended an appointment at a single Veterans Health Administration facility in early 2016 that was associated with one of the following mental health concerns: unipolar depression, any anxiety disorder, or posttraumatic stress disorder. We used the Veteran Affairs Corporate Data Warehouse to create subsets of eligible participants demographically stratified by gender (male or female) and minority status (white or nonwhite). From each subset, 100 participants were selected at random and mailed a paper survey with items addressing the demographics, overall health, mental health, technology ownership or use, interest in mobile app interventions for mental illness, reasons for use or nonuse, and interest in specific features of mobile apps for mental illness.

Results: Of the 400 potential participants, 149 (37.3%, 149/400) completed and returned a survey. Most participants (79.9%, 119/149) reported that they owned a smart device and that they use apps in general (71.1%, 106/149). Most participants (73.1%, 87/149) reported interest in using an app for mental illness, but only 10.7% (16/149) had done so. Paired samples t tests indicated that ratings of interest in using an app recommended by a clinician were significantly greater than general interest ratings and even greater when the recommending clinician was a specialty mental health provider. The most frequent concerns related to using an app for mental illness were lacking proof of efficacy (71.8%, 107/149), concerns about data privacy (59.1%, 88/149), and not knowing where to find such an app (51.0%, 76/149). Participants expressed interest in a number of app features with particularly high-interest ratings for context-sensitive apps (85.2%, 127/149), and apps focused on the following areas: increasing exercise (75.8%, 113/149), improving sleep (73.2%, 109/149), changing negative thinking (70.5%, 105/149), and increasing involvement in activities (67.1%, 100/149).

Conclusions: Most respondents had access to devices to use mobile apps for mental illness, already used apps for other purposes, and were interested in mobile apps for mental illness. Key factors that may improve adoption include provider endorsement, greater publicity of efficacious apps, and clear messaging about efficacy and privacy of information. Finally, multifaceted apps that address a range of concerns, from sleep to negative thought patterns, may be best received.
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http://dx.doi.org/10.2196/11334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367667PMC
January 2019

Premorbid adjustment trajectories in schizophrenia and bipolar disorder: A transdiagnostic cluster analysis.

Psychiatry Res 2019 02 31;272:655-662. Epub 2018 Dec 31.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; VISN 2 Mental Illness Research, Education, and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA; Brigham and Women's Hospital, Boston, MA, USA. Electronic address:

Despite the overlap between schizophrenia and bipolar disorder, neurodevelopmental abnormalities are thought to be associated primarily with schizophrenia. Transdiagnostic and empirical identification of subgroups based on premorbid adjustment (PMA) may enhance understanding of illness trajectories. 160 patients with bipolar I or II disorder (BD; n = 104) or schizophrenia or schizoaffective disorder (SZ; n = 56) were assessed on PMA course from childhood to late adolescence and current symptoms and functioning. A hierarchical cluster analysis was performed using social and academic PMA scores, resulting in three optimal clusters. Cluster 1 (n = 28 SZ, 65 BD) had normal social and academic PMA, the most education, and mildest current symptoms. Cluster 2 (n = 15 SZ, 24 BD) had normal social PMA but an impaired-declining academic course and had a greater proportion of males than Cluster 1. Cluster 3 (n = 13 SZ, 15 BD) had an impaired-stable social PMA and an impaired-declining academic course and the most severe current negative symptoms and childhood trauma. The proportions of SZ and BD diagnoses, current neurocognition, and functioning did not differ between clusters. These findings suggest shared neurodevelopmental abnormalities between SZ and BD, with subgroups exhibiting distinct PMA trajectories that cut across disorders.
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http://dx.doi.org/10.1016/j.psychres.2018.12.169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441475PMC
February 2019

Functional neural mechanisms of sensory phenomena in obsessive-compulsive disorder.

J Psychiatr Res 2019 02 21;109:68-75. Epub 2018 Nov 21.

Department of Psychiatry, New York University School of Medicine, New York, NY, USA; Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA. Electronic address:

Sensory phenomena (SP) are aversive or uncomfortable sensations that accompany and/or drive repetitive behaviors in obsessive-compulsive disorder (OCD). Although SP are associated with significant distress and may respond less well to standard treatments than harm-related obsessions, little is known about their underlying neurobiology. The present study used functional magnetic resonance imaging (fMRI) to measure brain functioning related to severity of SP during a "body-focused" videos task designed to elicit activation in sensorimotor brain regions. Regression analysis examined the relationship between severity of SP and activation during task using permutation analysis, cluster-level corrected for multiple comparisons (family-wise error rate p < 0.05). The distribution of SP severity was not significantly different from normal, with both high- and low-severity scores represented in the OCD sample. Severity of SP was not correlated with other clinical symptoms in OCD including general anxiety, depression, or harm avoidance. When viewing body-focused videos, patients with greater severity of SP showed increased activity in the mid-posterior insula, a relationship that remained significant when controlling for other clinical symptoms, medication status, and comorbidities. At uncorrected thresholds, SP severity was also positively related to somatosensory, mid orbitofrontal, and lateral prefrontal cortical activity. These data suggest that SP in OCD are dissociable from other symptoms in the disorder and related to hyperactivation of the insula. Future work examining neural mechanisms of SP across different disorders (tics, trichotillomania) as well as with other imaging modalities will be needed to further understand the neurobiology of these impairing symptoms.
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http://dx.doi.org/10.1016/j.jpsychires.2018.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347462PMC
February 2019
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