IMPORTANCE Genome-wide association studies (GWASs) indicate that single-nucleotide polymorphisms in the CACNA1C and ANK3 genes increase the risk for bipolar disorder (BD). The genes influence ...neuronal firing by modulating calcium and sodium channel functions, respectively. Both genes modulate γ-aminobutyric acid–transmitting interneuron function and can thus affect brain regional activation and interregional connectivity. OBJECTIVE To determine whether the genetic risk for BD associated with 2 GWAS-supported risk single-nucleotide polymorphisms at CACNA1C rs1006737 and ANK3 rs10994336 is mediated through changes in regional activation and interregional connectivity of the facial affect–processing network. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional functional magnetic resonance imaging study at a research institute of 41 euthymic patients with BD and 46 healthy participants, all of British white descent. MAIN OUTCOMES AND MEASURES Blood oxygen level–dependent signal and effective connectivity measures during the facial affect–processing task. RESULTS In healthy carriers, both genetic risk variants were independently associated with increased regional engagement throughout the facial affect–processing network and increased effective connectivity between the visual and ventral prefrontal cortical regions. In contrast, BD carriers of either genetic risk variant exhibited pronounced reduction in ventral prefrontal cortical activation and visual-prefrontal effective connectivity. CONCLUSIONS AND RELEVANCE Our data demonstrate that the effect of CACNA1C rs1006737 and ANK3 rs10994336 (or genetic variants in linkage disequilibrium) on the brain converges on the neural circuitry involved in affect processing and provides a mechanism linking BD to genome-wide genetic risk variants.
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.
OBJECTIVE: Previous studies suggest that the dopamine agonist pramipexole may possess antidepressant properties. The authors conducted a preliminary randomized, placebo-controlled trial to determine ...the safety and antidepressant efficacy of pramipexole in treatment-resistant bipolar depression. METHOD: Twenty-two depressed outpatients with DSM-IV nonpsychotic bipolar disorder were randomly assigned to receive placebo or flexibly dosed pramipexole (mean maximum dose=1.7 mg day, SD=1.3) added to existing mood stabilizers for 6 weeks. The primary outcome measure was response, defined as improvement in Hamilton Depression Rating Scale score of 50% or more over the baseline score; secondary analyses involved changes in Clinical Global Impression (CGI) severity scores. RESULTS: More patients given pramipexole (10 83% of 12) than patients given placebo (six 60% of 10) completed the study. Eight (67%) of 12 patients taking pramipexole and two (20%) of 10 taking placebo had an improvement of at least 50% in their Hamilton depression scale scores. The mean percentage of improvement from baseline Hamilton depression scale scores was greater for patients taking pramipexole (48%) than for those taking placebo (21%). Mean improvements in CGI severity were also greater with pramipexole than placebo. No patients discontinued the study because of adverse events except for one patient who became hypomanic while taking pramipexole. CONCLUSIONS: Pramipexole was a safe and effective antidepressant among patients with bipolar depression. Larger randomized, controlled trials are needed to affirm these initial observations.
Background Age-related differences in white matter tract microstructure have been well established across the life span. In the present cross-sectional study, we examined whether these differences ...are associated with neurocognitive performance from childhood to late adulthood. Methods Diffusion tensor imaging was performed in 296 healthy subjects aged 8 to 68 years (mean = 29.6, SD = 14.6). The corpus callosum, two projection tracts, and five association tracts were traced using probabilistic tractography. A neurocognitive test battery was used to assess speed of processing, attention, spatial working memory, verbal functioning, visual learning, and executive functioning. Linear mediation models were used to examine whether differences in white matter tract fractional anisotropy (FA) were associated with neurocognitive performance, independent of the effect of age. Results From childhood to early adulthood, higher FA of the cingulum bundle and inferior frontooccipital fasciculus (IFOF) was associated with higher executive functioning and global cognitive functioning, respectively, independent of the effect of age. When adjusting for speed of processing, FA of the IFOF was no longer associated with performance in the other cognitive domains with the exception of visual learning. From early adulthood to late adulthood, white matter tract FA was not associated with cognitive performance independent of the age effect. Conclusions The cingulum bundle may play a critical role in protracted maturation of executive functioning. The IFOF may play a key role in maturation of visual learning and may act as a central “hub” in global cognitive maturation by subserving maturation of processing speed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objectives
Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate ...and compare the influence of key factors on community function in multiple cohorts of well‐characterized samples of individuals with BD.
Methods
Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived “higher versus lower function” as the dependent variable and selected clinical and demographic variables as predictors.
Results
We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning.
Conclusions
The bipolar clinical research community is poised to work together to characterize the multi‐dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large‐scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Purpose of Review
Symptoms of depression and cognitive dysfunction are commonly reported in mastocytosis. The aims of this review paper are to summarize the current literature on cognitive ...dysfunction and depressive symptoms, elucidate some of the mechanistic pathways underlying depressive symptoms in mastocytosis, identify gaps in the literature, and offer guidance for future research in this area
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Recent Findings
The study of cognition and depression in mastocytosis is in its infancy and the methodological flaws of the current literature limit interpretability. There is preliminary evidence that some individuals with mastocytosis might experience mild deficits in memory. On average, depression symptom scores fell within the mild to moderate or sub-syndromal range. Regrettably, only one study utilized a standardized diagnostic instrument to assess major depressive disorder. The authors’ tendency to inaccurately equate depressive symptoms with a diagnosis of major depressive disorder presents a notable issue.
Summary
The prevalence of cognitive deficits and depression appears to be similar to other chronic illnesses. Future work needs to better characterize cognition and characterize “depression” in this population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine displays rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the potential for adverse ...neurocognitive effects in this population has not received adequate study. The current study was designed to investigate the delayed neurocognitive impact of ketamine in TRD and examine baseline antidepressant response predictors in the context of a randomized controlled trial. In the current study, 62 patients (mean age = 46.2 ± 12.2) with TRD free of concomitant antidepressant medication underwent neurocognitive assessments using components of the MATRICS Consensus Cognitive Battery (MCCB) before and after a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg). Participants were randomized to ketamine or midazolam in a 2:1 fashion under double-blind conditions and underwent depression symptom assessments at 24, 48, 72 h, and 7 days post treatment using the Montgomery-Asberg Depression Rating Scale (MADRS). Post-treatment neurocognitive assessment was conducted once at 7 days. Neurocognitive performance improved following the treatment regardless of treatment condition. There was no differential effect of treatment on neurocognitive performance and no association with antidepressant response. Slower processing speed at baseline uniquely predicted greater improvement in depression at 24 h following ketamine (t = 2.3, p = 0.027), while controlling for age, depression severity, and performance on other neurocognitive domains. In the current study, we found that ketamine was devoid of adverse neurocognitive effects at 7 days post treatment and that slower baseline processing speed was associated with greater antidepressant response. Future studies are required to further define the neurocognitive profile of ketamine in clinical samples and to identify clinically useful response moderators.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To compare neuropsychological performance in people at clinical high risk for psychosis (CHR), healthy controls (HCs), or subjects with first-episode psychosis (FEP).
Systematic PubMed/MEDLINE search ...through January 2014, without language restrictions, using search terms prodrome OR clinical high-risk OR ultra-high risk AND cognition OR individual test names.
Studies reporting neuropsychological data in CHR versus a HC or FEP groups or comparing CHR subjects who converted to psychosis (CHR-P) with CHR subjects who did not convert to psychosis (CHR-NP).
Two authors independently extracted and compared neurocognitive test data.
A meta-analysis was performed on 60 neuropsychological tests from 9 domains in 32 studies with 21 nonoverlapping samples (CHR = 1,684 patients, HC = 986, FEP = 405). Compared to HCs, people with CHR performed significantly worse in 7 of 9 domains (Hedges g effect size 95% confidence limit = -0.17 -0.30, -0.04 attention/vigilance to -0.42 -0.64, -0.20 verbal learning, speed of processing and -0.43 -0.68, -0.18 social cognition), except reasoning/problem solving and working memory (which separated in longitudinal studies). California Verbal Learning Test (-0.65 -0.84, -0.46) and Digit Symbol Test (-0.63 -0.86, -0.40) separated groups the most. Compared to FEP subjects, people with CHR performed significantly better in 5 of 6 domains (from 0.29 0.03, 0.56 speed of processing to 0.39 0.17, 0.62 attention/vigilance, verbal learning and -0.40 0.18, 0.64 working memory), except reasoning/problem solving. CHR-P and CHR-NP performed significantly worse than HC (except visual learning, working memory in CHR-NP). Compared to CHR-NP, CHR-P performed significantly worse in 6 of 8 domains (from -0.24 -0.44, -0.03 attention/vigilance to -0.49 -0.76, -0.22 verbal learning and -0.54 -0.80, -0.27 visual learning), without differences in reasoning/problem solving and working memory. Three individual tests (Rey-Osterrieth Complex Figure Test, Verbal Fluency Test/Controlled Oral Word Association Test, and California Verbal Learning Test) discriminated the best between CHR-P and CHR-NP (-0.49 -0.82, -0.16, -0.45 -0.86, -0.03, and -0.40 -0.80, -0.00, respectively).
CHR has mild to moderate globally distributed neuropsychological performance deficits that lie between FEP and HCs. Neuropsychological performance deficits are greater in CHR-P than in CHR-NP, but they overlap, reducing their current utility for risk stratification.
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