Effects of intermittent theta-burst transcranial magnetic stimulation on cognition and hippocampal volumes in bipolar depression.

INTRODUCTION: Repetitive transcranial magnetic stimulation (TMS) is increasingly used to treat neurocognitive symptoms in mood disorders. Intermittent theta burst stimulation (iTBS) is a brief version of TMS that may preferentially target cognitive functions. This study evaluated whether iTBS leads to cognitive improvements and associated increased hippocampal volumes in bipolar depression. METHODS: In a two-site double-blind randomised sham controlled trial (NCT02749006), 16 patients received active iTBS to the Left Dorsolateral Prefrontal Cortex (DLPF) and 15 patients received sham stimulation across four weeks. A composite neuropsychological score and declarative memory scores served as the cognitive outcomes. Hippocampal volumes were derived from T1 weighted MRI scans using the longitudinal ComBat method to harmonise data across sites. RESULTS: No significant improvements were observed in any cognitive variables in the active relative to the sham group; however, there was a trend for increased left hippocampal volume in the former. Left hippocampal volume increases were associated with improvements in nonverbal memory in the active group. CONCLUSIONS: Although cognitive improvements were not associated with iTBS, the finding that hippocampal volume increases were associated with memory improvement suggests there may be some level of prefrontal-temporal neuroplasticity that could support cognitive change in future studies of iTBS in bipolar disorder.

Metacognitive knowledge and experience across multiple cognitive domains in euthymic bipolar disorder.

BACKGROUND: Metacognitive knowledge (MK; general awareness of cognitive functioning) and metacognitive experience (ME; awareness of cognitive performance on a specific cognitive task) represent two facets of metacognition that are critical for daily functioning, but are understudied in bipolar disorder. This study was conducted to evaluate MK and ME across multiple cognitive domains in individuals diagnosed with bipolar disorder and unaffected volunteers, and to investigate the association between metacognition and quality of life (QoL). METHODS: Fifty-seven euthymic participants with bipolar disorder and 55 demographically similar unaffected volunteers provided prediction and postdiction ratings of cognitive task performance across multiple cognitive domains. Self-ratings were compared to objective task performance, and indices of MK and ME accuracy were generated and compared between groups. Participants rated QoL on the Quality of Life in Bipolar Disorder Scale (QoL.BD). RESULTS: Metacognitive inaccuracies in both MK and ME were observed in participants with bipolar disorder, but only in select cognitive domains. Furthermore, most metacognitive inaccuracies involved underestimation of cognitive ability. Metacognitive indices were minimally associated with medication variables and mood symptoms, but several indices were related to QoL. CONCLUSIONS: Individuals with bipolar disorder demonstrate inaccuracies in rating their cognitive functioning and in rating their online cognitive task performance, but only on select cognitive functions. The tendency to underestimate performance may reflect a negative information processing bias characteristic of mood disorders. Metacognitive variables were also predictive of QoL, indicating that further understanding of cognitive self-appraisals in persons with bipolar disorder has significant clinical relevance.

Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: a randomised, open-label, pilot study.

BACKGROUND: Cognitive impairment is present in euthymic patients with bipolar disorder and correlates with impairments in everyday functioning. We aimed to examine the efficacy of lurasidone adjunctive therapy compared with treatment as usual (TAU) in improving cognition. METHODS: For this randomised, open-label, pilot study, we recruited patients aged 19-65 years with euthymic bipolar I disorder from the Mood Disorder Centre in UBC Hospital (Vancouver, Canada). We included patients who were taking lithium, or valproate, or an atypical antipsychotic, or a combination of these for mood stabilisation and who showed reduced cognitive functioning (SD≤ -0·25 relative to demographics-corrected norms) on either the Trail Making Test-B or the California Verbal Learning Test-II. Patients were randomly assigned using a randomised block design with a block size of four to TAU or lurasidone adjunctive therapy (20-80 mg/day) for 6 weeks. A research coordinator masked to group allocation administered the International Society for Bipolar Disorders Battery for Assessment of Neurocognition (ISBD-BANC) at baseline and at endpoint. The primary outcome was change in global cognition score, which consisted of the mean demographics-corrected t-score value of the several ISBD-BANC measures, analysed in all patients who completed both tests. This trial is registered on ClinicalTrials.gov, number NCT02147379. FINDINGS: Between July 2, 2014, and Oct 19, 2015, 34 patients were randomly allocated to lurasidone adjunctive therapy (17 patients) or TAU (17 patients). Two patients from each group did not complete the study. The mean lurasidone dose was 48·24 (SD 15·90) mg/day. Lurasidone adjunctive therapy was more effective than TAU in improving the primary efficacy measure of ISBD-BANC global cognition score (mean difference 2·92 [95% CI 0·27-5·57]; time × treatment interaction F=5·09; p=0·032). The between-group effect size (0·82) on baseline versus study-end difference scores in the ISBD global cognition score was of moderate to large magnitude. The magnitude of benefit with lurasidone adjunctive therapy in improving global cognition (effect size 0·46) was greater compared with the improvement observed in the TAU group (0·04). Adverse events were reported by nine (60%) patients in the luradisone group and two (13%) in the TAU group. INTERPRETATION: Our results provide some preliminary evidence for the efficacy of lurasidone in improving cognition in euthymic patients with bipolar I disorder. The strengths of this study were the characterisation of the sample and use of tests sensitive to cognitive impairment in bipolar disorder. Its limitations were the sample size and inability to completely control for other medication use. Larger double-blind trials are warranted to investigate this further. FUNDING: Sumitomo Dainippon Pharma.

Trajectories of body mass index change in first episode of mania: 3-year data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM).

BACKGROUND: Overweight/obesity is common in patients with bipolar disorder (BD). However, little is known about longitudinal trends in body mass index (BMI) in patients with BD. Furthermore, most studies on the association between BMI and clinical outcomes are restricted by retrospective and cross-sectional designs. This study uses prospectively-gathered data from a first episode mania (FEM) cohort to examine the trajectories of BMI change and analyze their association with clinical outcomes during a 3-year period. METHODS: A total of 110 FEM patients receiving maintenance treatment and 57 healthy subjects were included. The comparisons of BMI trajectories were examined using linear mixed-effects models. The effects of BMI on time to any mood episode were assessed by Cox proportional-hazards models. RESULTS: The estimated mean BMI in FEM patients significantly increased from 24.0kg/m2 to 25.4kg/m2 within 6 months. FEM patients had a significant BMI increase trend over the entire 3 years follow-up, which was not observed in the control group. No significant difference in BMI trajectory between patient subgroups (baseline normal-weight vs. overweight/obese; male vs. female) was observed. BMI increase predicted an increased risk of recurrence during follow-up visits (HR=1.50, 95% CI: 1.06-2.13; p=0.02). LIMITATIONS: Naturalistic design does not allow the accurate assessments of the impact of pharmacologic treatments on BMI. CONCLUSIONS: FEM patients showed a significantly increased BMI trajectory compared to healthy subjects. Furthermore, BMI increase is independently associated with an increased risk of recurrence to a new mood episode during 3-year follow-up. Thus, weight control prevention is needed in the early course of BD.

Agathobaculum butyriciproducens gen. nov. sp. nov., a strict anaerobic, butyrate-producing gut bacterium isolated from human faeces and reclassification of Eubacterium desmolans as Agathobaculum desmolans comb. nov.

A novel bacterial strain, SR79T, was isolated from a Korean faecal sample and characterized using a polyphasic approach. SR79T was found to be a strictly anaerobic, Gram-stain-positive, non-spore-forming, non-motile, catalase- and oxidase-negative short rod with no flagella. SR79T grew optimally at 37 °C in the presence of 0.5 % (w/v) NaCl at pH 7. The NaCl range for growth was 0-1 % (w/v). The isolate produced butyric acid (>18 mM) as a major end product. A phylogenetic analysis based on 16S rRNA gene sequences revealed that the most closely related type strains were Eubacteriumdesmolans ATCC 43058T and Butyricicoccus pullicaecorum 25-3T (96.4 and 96.0 % similarity, respectively). The DNA G+C content was determined to be 52.9 mol%. The major cellular fatty acids (>10 %) were C16 : 0, C18 : 1cis-9, C19 : 1 cyc 9,10 and C14 : 0. Meso-diaminopimelic acid was present in the cell wall peptidoglycan and the cell wall hydrolysates contained ribose, glucose and galactose. The 16S rRNA gene sequence similarity, phylogenetic analysis, chemotaxonomic and phenotypic characteristics allowed differentiation of SR79T, which represents a novel species of a new genus within the family Ruminococcaceae, for which the name Agathobaculum butyriciproducens gen. nov. sp. nov. is proposed. The type strain is SR79T (=KCTC 15532T=DSM 100391T). Based on the results of this study, it is also proposed to transfer Eubacteriumdesmolans to this new genus, as Agathobaculum desmolans comb. nov. The type strain of Agathobaculum desmolans is ATCC 43058T (=CCUG 27818T).

Whole genome sequencing of "Faecalibaculum rodentium" ALO17, isolated from C57BL/6J laboratory mouse feces.

BACKGROUND: Intestinal microorganisms affect host physiology, including ageing. Given the difficulty in controlling for human studies of the gut microbiome, mouse models provide an alternative avenue to study such relationships. In this study, we report on the complete genome of "Faecalibaculum rodentium" ALO17, a bacterium that was isolated from the faeces of a 9-month-old female C57BL/6J mouse. This strain will be utilized in future in vivo studies detailing the relationships between the gut microbiome and ageing. RESULTS: The whole genome sequence of "F. rodentium" ALO17 was obtained using single-molecule, real-time (SMRT) technique on a PacBio instrument. The assembled genome consisted of 2,542,486 base pairs of double-stranded DNA with a GC content of 54.0 % and no plasmids. The genome was predicted to contain 2794 open reading frames, 55 tRNA genes, and 38 rRNA genes. The 16S rRNA gene of ALO17 was 86.9 % similar to that of Allobaculum stercoricanis DSM 13633(T), and the average overall nucleotide identity between strains ALO17 and DSM 13633(T) was 66.8 %. After confirming the phylogenetic relationship between "F. rodentium" ALO17 and A. stercoricanis DSM 13633(T), their whole genome sequences were compared, revealing that "F. rodentium" ALO17 contains more fermentation-related genes than A. stercoricanis DSM 13633(T). Furthermore, "F. rodentium" ALO17 produces higher levels of lactic acid than A. stercoricanis DSM 13633(T) as determined by high-performance liquid chromatography. CONCLUSION: The availability of the "F. rodentium" ALO17 whole genome sequence will enhance studies concerning the gut microbiota and host physiology, especially when investigating the molecular relationships between gut microbiota and ageing.

Faecalibaculum rodentium gen. nov., sp. nov., isolated from the faeces of a laboratory mouse.

A novel strictly anaerobic strain, ALO17(T), was isolated from mouse faeces and found to produce lactic acid as a major metabolic end product. The isolate was observed to be Gram-stain positive, non-motile, non-spore forming small rods, oxidase and catalase negative, and to form cream-coloured colonies on DSM 104 agar plates. The NaCl range for growth was determined to be 0-2 % (w/v). The isolate was found to grow optimally at 37 °C, with 0.5 % (w/v) NaCl and at pH 7. The cell wall hydrolysates were found to contain ribose as a major sugar. The genomic DNA G+C content was determined to be 52.3 mol%. A phylogenetic analysis of the 16S rRNA gene sequence revealed that Holdemanella biformis DSM 3989(T), Faecalicoccus pleomorphus ATCC 29734(T), Faecalitalea cylindroides ATCC 27803(T), and Allobaculum stercoricanis DSM 13633(T) are closely related to the isolate (87.4, 87.3, 86.9 and 86.9 % sequence similarity), respectively. The major cellular fatty acids (>10 %) of the isolate were identified as C18:1 cis 9 FAME (36.9 %), C16:0 FAME (33.7 %) and C18:0 FAME (13.2 %). In contrast to the tested reference strains, C20:0 FAME (4.0 %) was detected only in strain ALO17(T) whilst C16:0 DMA was absent. The isolate also differed in its substrate oxidation profiles from the reference strains by being positive for D-melibiose and stachyose but negative for N-acetyl-D-galactosamine and 3-methyl-D-glucose. On the basis of polyphasic taxonomic evidence from this study, the isolate is concluded to belong to a novel genus within the family Erysipelothricaceae. We propose the name Faecalibaculum rodentium gen. nov., sp. nov. to accommodate strain ALO17(T) (=KCTC 15484(T) = JCM 30274(T)) as the type strain.