Sex differences in the association of plasma cytokines and neurocognition in first-episode major depressive disorder.

BACKGROUND: Peripheral cytokines were found to be involved in the pathophysiology of neurocognition in individuals with major depressive disorder (MDD). However, whether there are sex differences in this association between cytokines and cognition in MDD remains unknown. Our aim is to examine sex differences in the relationship between plasma cytokines and cognition in MDD. METHOD: One hundred and twenty-seven first episode drug naïve patients with MDD and sixty healthy controls (HCs) were recruited for present study. The MATRICS Consensus Cognitive Battery was administered to measure the cognition. Plasma concentrations of nineteen cytokines were measured using high sensitivity multiplex bead-based assays. RESULTS: Both female and male patients with MDD had significant cognitive impairment in verbal learning and visual learning and had higher levels of a range of cytokines than HCs (all p < 0.05). Female patients performed worse in trail making (F = 4.442, p = 0.018) and had higher concentration of interleukin (IL)-4 (F = 7.775, p = 0.006) than males. In female MDD, a significant positive association between category frequency and level of IL-4 was observed (B = 8.040, p = 0.031). However, this association was not present in male MDD or HCs (p > 0.05). LIMITATION: Present study used a cross-sectional design. CONCLUSION: Female MDD patients had worse trail making performance and higher level of IL-4 than males. The elevated IL-4 in female MDD was positively associated with category fluency, suggesting that IL-4 may be involved in the pathophysiology related to specific cognitive domain in female MDD patients.

Aberrant Dynamic Functional Connectivity of Posterior Cingulate Cortex Subregions in Major Depressive Disorder With Suicidal Ideation.

Accumulating evidence indicates the presence of structural and functional abnormalities of the posterior cingulate cortex (PCC) in patients with major depressive disorder (MDD) with suicidal ideation (SI). Nevertheless, the subregional-level dynamic functional connectivity (dFC) of the PCC has not been investigated in MDD with SI. We therefore sought to investigate the presence of aberrant dFC variability in PCC subregions in MDD patients with SI. We analyzed resting-state functional magnetic resonance imaging (fMRI) data from 31 unmedicated MDD patients with SI (SI group), 56 unmedicated MDD patients without SI (NSI group), and 48 matched healthy control (HC) subjects. The sliding-window method was applied to characterize the whole-brain dFC of each PCC subregion [the ventral PCC (vPCC) and dorsal PCC (dPCC)]. In addition, we evaluated associations between clinical variables and the aberrant dFC variability of those brain regions showing significant between-group differences. Compared with HCS, the SI and the NSI groups exhibited higher dFC variability between the left dPCC and left fusiform gyrus and between the right vPCC and left inferior frontal gyrus (IFG). The SI group showed higher dFC variability between the left vPCC and left IFG than the NSI group. Furthermore, the dFC variability between the left vPCC and left IFG was positively correlated with Scale for Suicidal Ideation (SSI) score in patients with MDD (i.e., the SI and NSI groups). Our results indicate that aberrant dFC variability between the vPCC and IFG might provide a neural-network explanation for SI and may provide a potential target for future therapeutic interventions in MDD patients with SI.

The association between overweight/obesity and poor cognitive function is mediated by inflammation in patients with major depressive disorder.

BACKGROUND: Cognitive dysfunction is a common and core feature of major depressive disorder (MDD). Evidences exerted a potentially harmful role of obesity and higher peripheral levels of inflammation in cognitive function, but few studies have explored whether markers of peripheral inflammation might mediate the association between overweight/obesity and deficits in cognitive function. Our study aimed to examine the cognitive function in MDD patients and clarify the effects of overweight/obesity and inflammatory cytokines on cognitive dysfunction in this population. METHOD: We used a cross-sectional design in this study. A total of 265 patients with MDD were enrolled and divided into underweight, normal weight and overweight/obese groups. The MATRICS Consensus Cognitive Battery (MCCB) was administered to measure the cognition. Plasma levels of nineteen cytokines were measured using high sensitivity multiplex bead-based assays. RESULTS: We found overweight/obese MDD patients associated with higher plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-8, and macrophage inflammatory protein (MIP)-1ß and worse performance in speed of processing and working memory. The mediation analysis found higher levels of IL-8 (direct: ß = -0.591 (95 % Confidence Interval (CI): -1.0 to -0.2), P = 0.002; indirect: ß = 0.060 (95 % CI.: 0.0-0.2), P = 0.032) and TNF-α (direct: ß = -0.589 (95 % CI.: -1.0 to -0.2), P = 0.002; indirect: ß = 0.059 (95 % CI.: 0.1-0.2), P = 0.037) were associated with more deficits in speed of processing, and partially mediated the relationship between body mass index and speed of processing. CONCLUSION: Our results suggest that elevated inflammation might be one biological mechanism underlying the link between higher body mass and deficits in processing speed in patients with MDD.

Early improvement as a predictor of final remission in patients with treatment-resistant depression receiving electroconvulsive therapy with ketofol anesthesia.

OBJECTIVE: To examine whether early symptom improvement can predict eventual remission following electroconvulsive therapy (ECT) with ketamine plus propofol (ketofol) anesthesia in patients with treatment-resistant depression (TRD). METHODS: Thirty Han Chinese subjects suffering from TRD were administered ketofol anesthesia during ECT. Remission was defined as a score of ≤7 on the 17-item Hamilton Depression Rating Scale (HAMD-17). Receiver operating characteristic (ROC) curves were applied to identify the number of ECT sessions (i.e., 1, 2, 3, or 4 ECT sessions) that had the best discriminative capacity for eventual remission. The best definition of early improvement to predict final remission was determined by using the Youden index. RESULTS: Of the 30 patients with TRD, 16 (53.3%) and 30 (100%) were classified as remitters and responders, respectively. A 45% reduction in the HAMD-17 score after 3 ECT sessions was the optimum definition of early improvement in the prediction of eventual remission, with relatively good sensitivity (88%) and specificity (93%). Patients with than without early improvement had a greater possibility of achieving favorable ECT outcomes. CONCLUSION: Final remission of TRD following ECT with ketofol anesthesia appeared to be predicted by early improvement, as indicated by a 45% reduction in HAMD-17 score after 3 ECT sessions.

Predictors of 4-week antidepressant outcome in patients with first-episode major depressive disorder: An ROC curve analysis.

BACKGROUND: Pretreatment characteristics of patients, symptom and function could be associated with antidepressant treatment outcome, but its predictive ability is not adequate. Our study aimed to identify predictors of acute antidepressant efficacy in patients with first-episode Major Depressive Disorder (MDD). METHODS: 187 patients with first-episode MDD were included and assessed clinical symptoms, cognitive function and global functioning using the 17-item Hamilton Depression Inventory (HAMD-17), MATRICS Consensus Cognitive Battery (MCCB) and Global Assessment of Functioning (GAF). Participants received treatment with a SSRI (escitalopram or venlafaxine) for 4 weeks. Logistic regression was used to analyze the association between patients' characteristics, symptom profiles, cognitive performance, and global functioning and the antidepressant outcome at the end of 4 weeks, and ROC curve analysis was performed for predictive accuracy with area under the receiver operating curve (AUC). RESULTS: Antidepressant improvement, response and remission rate at week 4 was 87.7%, 64.7% and 42.8%, respectively. The combination of pretreatment clinical profiles, speed of processing and global functioning showed moderate discrimination of acute improvement, response and remission with AUCs of 0.863, 0.812 and 0.734, respectively. LIMITATIONS: The major limitation of the present study is the study did not combine pharmacogenomics from the perspective of antidepressant drug metabolism. CONCLUSION: Aside from the baseline clinical symptoms, cognitive function and global functioning could be predictors of acute treatment outcome in first episode MDD using escitalopram or venlafaxine. This relatively simple application based on clinical symptoms and function seems to be cost-effective method to identify individuals who are more likely to respond to antidepressant treatment.

Repetitive transcranial magnetic stimulation for cognitive function in adults with bipolar disorder: A pilot study.

BACKGROUND: Cognitive deficits are prevalent in bipolar disorder and are a significant contributor to negative patient-reported outcomes. Herein we conducted a pilot study of repetitive transcranial magnetic stimulation (rTMS) to improve cognitive function in adults with bipolar disorder. METHODS: The study was a triple-blinded, randomized, placebo-control trial. Participants (aged 18 to 60) with a diagnosis of DSM-5-defined bipolar disorder (I or II) were recruited and randomized (N=36) to receive either a sham treatment (n=20) or an active rTMS treatment (n=16). Patients completed the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) at baseline and 1-2 weeks after the rTMS intervention. RESULTS: A significant group by time interaction was observed in the Hopkins Verbal Learning Test-Revised (HVLT-R), (F (1, 34) = 17.0, p < 0.001, partial η2 = 0.33). Post-hoc analysis revealed that although both groups did not significantly differ at baseline (p = 0.58), patients in the active rTMS group significantly improved following neurostimulation (p = 0.02) for HVLT-R. Moreover, within-subject analysis indicated that the active rTMS group significantly improved in score from pre-treatment to post-treatment (p < 0.001), while the sham group did not improve (p = 0.94) for HVLT-R. No significant differences were seen in the other cognitive measures. LIMITATIONS: The study was conducted in a small sample . CONCLUSION: This pilot study, which was intended to establish feasibility, suggests that rTMS may offer benefit in select domains of cognitive functioning in bipolar disorder. None of the measures across subdomains revealed a dyscognitive effect.

Abnormal Degree Centrality Associated With Cognitive Dysfunctions in Early Bipolar Disorder.

Delayed diagnosis of bipolar disorder (BD) is common. However, diagnostic validity may be enhanced using reliable neurobiological markers for BD. Degree centrality (DC) is one such potential marker that enables researchers to visualize neuronal network abnormalities in the early stages of some neuropsychiatric disorders. In the present study, we measured resting-state DC abnormalities and cognitive deficits in order to identify early neurobiological markers for BD. We recruited 23 patients with BD who had recently experienced manic episodes (duration of illness <2 years) and 46 matched healthy controls. Our findings indicated that patients with BD exhibited DC abnormalities in frontal areas, temporal areas, the right postcentral gyrus, and the posterior lobe of the cerebellum. Moreover, correlation analysis revealed that psychomotor speed indicators were associated with DC in the superior temporal and inferior temporal gyri, while attention indicators were associated with DC in the inferior temporal gyrus, in patients with early BD. Our findings suggest that DC abnormalities in neural emotion regulation circuits are present in patients with early BD, and that correlations between attention/psychomotor speed deficits and temporal DC abnormalities may represent early markers of BD.

Depression recognition according to heart rate variability using Bayesian Networks.

BACKGROUND: Doctors mainly use scale tests and subjective judgment in the clinical diagnosis of depression. Researches have demonstrated that depression is associated with the dysfunction of the autonomic nervous system (ANS), where its modulation can be evaluated by heart rate variability (HRV). Depression patients have lower HRV than healthy subjects. Therefore, HRV may be used to distinguish depression patients from healthy people. METHODS: HRV signals were collected from 76 female subjects composed of 38 depression patients and 38 healthy people. Time domain, frequency domain, and non-linear features were extracted from the HRV signals of these subjects, who were subjected to the Ewing test as an ANS stimulus. Then, these multiple features were input into Bayesian networks, served as a classifier, to distinguish depression patients from healthy people. Hence, accuracy, sensitivity, and specificity were calculated to evaluate the performance of the classifier. RESULTS: Recognition results indicate 86.4% accuracy, 89.5% sensitivity, and 84.2% specificity. The individuals subjected to the Ewing test showed better recognition results than those at individual test states (resting state, deep breathing state, Valsalva state, and standing state) of the Ewing test. The root mean square of successive differences (RMSSD) of the HRV exhibits a significant relevance with recognition. CONCLUSION: Bayesian networks can be applied to the recognition of depression patients from healthy people and the recognition results demonstrate the significant association between depression and HRV. The Ewing test is a good ANS stimulus for acquiring the difference of HRV between depression patients and healthy people to recognize depression. The RMSSD of the HRV is important in recognition and may be a significant index in distinguishing depression patients from healthy people.

Heart rate variability in patients with major depression disorder during a clinical autonomic test.

Major depression disorder (MDD) patients express dysfunction autonomic nervous system (ANS) and reduced heart rate variability (HRV). However, previous researches mainly focused on examining resting state without considering a series of stimulation tests of ANS between MDD patients and healthy people. For this purpose, 40 healthy people and 40 MDD patients participated and finished 10min clinical autonomic test-Ewing test. Parameters of HRV such as time domain, frequency domain, and nonlinear dynamical parameters were calculated. Most of HRV parameters during Ewing test of MDD patients are lower than healthy people, and inversely, the ratio of low frequency to high frequency is higher when standing up. In addition, heart rate of healthy people in deep breathing and Valsalva test states are higher than that in resting state, nonlinear dynamical parameter (RCMSE1) of healthy people in standing up state is higher than that in Valsalva test state. The experimental results suggest that parasympathetic nervous system of MDD patients is influenced by mental state and become dysfunction under long-term depression, it cannot exert normal physiological functions when it is activated. Sympathetic activity increases on MDD patients, and this enhancement is more obvious which expresses higher complexity of HRV time series.

Methionine sulfoxide reductase A (MsrA) associated with bipolar I disorder and executive functions in A Han Chinese population.

BACKGROUND: The oxidative stress hypothesis proposed to explain bipolar I disorder (BD I) pathogenesis has gained growing attention based on its association with cognitive impairment. The aim of the present study was to explore the association of the methionine sulfoxide reductase A (MsrA) gene with BD I as well as executive functions of BD I patients. METHODS: A total of 44 tagging single-nucleotide polymorphisms within the MsrA gene were selected to analyze gene association with BD I in 375 BD I patients and 475 controls in a Han Chinese population. The association of MsrA haplotypes with executive functions was analyzed in 157 clinically stable BD I patients and 210 controls. RESULTS: Allele frequencies of the rs4840463 polymorphism were significantly different between BD I patients and controls, and between patients with psychotic symptoms and controls. BD I patients performed more poorly in 11 of the 13 neurocognitive measurements compared with controls. Three MsrA haplotypes showed significant associations with different executive functions. LIMITATIONS: The limited sample size requires a cautious conclusion, and further comprehensive approaches are needed to explore the mechanism of MsrA's effect on BD I. CONCLUSIONS: The rs4840463 polymorphism in the MsrA gene may be associated with the increased risk of BD I in a Chinese population. The association of MsrA haplotypes with executive functions indicated that MsrA is associated with executive function defects in BD I patients.

Association study of dopamine receptor genes polymorphism with cognitive functions in bipolar I disorder patients.

OBJECTIVE: To determine the correlation among the polymorphisms of dopamine receptor genes, cognitive function of Bipolar disorder (BD) patients, and BD. METHODS: Twenty-three Single Nucleotide Polymorphisms (SNPs) of dopamine receptor genes were genotyped using Illumina GoldenGate genotyping assay in 375 patients with bipolar I disorder (BD-I) (patients group) and 475 healthy controls (control group). Cognitive function tests were performed in 158 patients who were clinically stable and 307 healthy controls who were matched with the patients in age, sex, and education. RESULTS: The allele frequencies of rs3758653 in the promoter region of the DRD4 gene were significantly different between patients group and control group (χ(2)=9.386, Corrected P=0.046). This significant difference was also observed between BD-I patients with psychotic symptoms and healthy controls (χ(2)=9.27, Corrected P=0.049). Patients with BD-I performed significantly worse than healthy controls in all cognitive domains (p<0.01) except TMTA errors and illegal time. Significant interactions between polymorphisms of rs5326 in DRD1 gene and phenotype (affected or unaffected with BD-I) were found in non-perseverative errors (ß=3.20 and Corrected P=0.0034) on the Wisconsin Card Sorting Test (WCST). The allele of this SNP denoted the positive effect on the WCST non-perseverative errors in BD-I patients group (ß=2.80 and Corrected P=0.017). The genotypic association analyses also supported the findings (F=4.24 and P=0.007), but this effect was not found in controls. LIMITATIONS: The sample size was relatively small and the SNP coverage was limited, making it very important to be cautious when drawing a conclusion. CONCLUSIONS: DRD4 gene may play an important role in psychotic symptomatology rather than in unique diagnosis, BD, for example. A genetic association exists between DRD1 gene and impaired cognition in BD.

Association analysis of genes in serotonin pathway with attention and executive function in patients with bipolar affective disorder.

BACKGROUND: The reason why it is difficult to identify susceptibility genes attributed to bipolar disorder (BPD) is the phenotypic heterogeneity. The use of endophenotypes has been advocated as one possible strategy to discovery cause variants of BPD. METHODS: A total of 164 patients with BPD and 164 matched controls were employed in the present research. Fifty-two single nucleotide polymorphisms (SNPs) within the genes in serotonin pathway were selected for genotyping using the GoldenGate genotyping assay. All participants completed three neurocognitive tests including the tower of Hanoi (TOH), the Wisconsin card sorting test (WCST) and Trail making tests (TMTA and TMTB-M). RESULTS: Patients with BPD demonstrated a wide range of deficits in mental activities of attention and speed of information processing, and executive function. Significant interactions between rs2760347 in 5HTR2A gene and diagnosis were found for the executive time of TOH, with ß=11.82 and P=0.002 (adjusted P=0.03 after Bonferroni correction). CONCLUSIONS: Cognitive impairments existing in BPD may be particularly notable in certain domains of attention and executive function, and 5HTR2A gene may be involved in modulating executive function of BP-I patients.

[Association study of LIS1 and TSNAX genes with bipolar disorder in Chinese Han population].

OBJECTIVE: To assess the association of neural development-related genes LIS1and TSNAX with bipolar disorder in a Chinese Han population. METHODS: Three hundred and eight five patients (including 188 males and 197 females) from Guangzhou Brain Hospital with bipolar disorder meeting the Diagnostic and Statistic Manual of Bipolar Disorder (BDI) (Fourth Edition) criteria and 475 healthy controls from the local community were recruited. Ten single nucleotide polymorphisms (SNPs) of the LIS1 and TSNAX genes were genotyped by GoldenGate genotyping assay on an Illumina Beadstation 500 machine. Association analyses of SNPs and haplotypes were performed with Plink 1.07 software. RESULTS: Analysis of the total sample has failed to find any association of SNP or haplotype of the two genes with BDI (P> 0.05). When patients were divided into subgroups with or without psychotic symptom, no significant association of the two genes was found with psychotic BDI or non-psychotic BDI (P> 0.05). No significant association was found between any SNP and haplotype of two genes and female BDI or male BDI, nor were significant association found between age of onset and LIS1 and TSNAX gene polymorphisms. CONCLUSION: Our results indicated that LIS1 and TSNAX genes are not associated with susceptibility to bipolar I disorder in Chinese Han population.

Association of the 3' region of the neuregulin 1 gene with bipolar I disorder in the Chinese Han population.

BACKGROUND: Based on the function of neuregulin 1 (NRG1) in neurodevelopment, susceptibility to bipolar disorder presumably involves this gene. The 3' region of NRG1 contains the majority of the coding exons, and transcripts from this region encode 8 of the 9 known NRG1 isoforms; therefore, this region is likely to be predominant versus the 5' region in terms of their relative contributions to NRG1 function. We investigated the association between the 3' region of the NRG1 gene and bipolar I disorder (BPI) in the Chinese Han population and performed further analyses depending on the presence or absence of psychotic features. METHODS: A total of 385 BPI patients and 475 healthy controls were recruited for this study. Thirty tag single nucleotide polymorphisms (SNPs) across the 3' region of the NRG1 gene were genotyped for allelic and haplotypic associations with BPI and subgroups with psychotic features (BPI-P) or without psychotic features (BPI-NP). RESULTS: Individual marker analysis showed that 2 SNPs (rs12547858 and rs6468121) in this region were significantly associated with BPI. Moreover, subgroup analyses showed significant but marginal associations of rs6468121 with BPI-P and rs3757933 with BPI-NP. Haplotype analyses showed that 6 haplotypes were associated with BPI only. LIMITATIONS: The sample size was relatively small. The investigated tag SNPs only represented 83% of the information on the targeted region. There might be a retrospective bias in the subgroup analyses. CONCLUSION: The results suggest that the 3' region of the NRG1 gene plays a role in BPI susceptibility in the Chinese Han population. In addition, the preliminary results show that BPI with psychotic features and BPI without psychotic features may constitute different sub-phenotypes; however, this finding should be confirmed in a larger population sample.

Genes in the serotonin pathway are associated with bipolar affective disorder in a Han Chinese population.

Serotonin plays an important role in mood regulation, but the involvement of serotonin pathway genes in the development of bipolar I disorder (BP-I), a mood disorder, is not clear. We selected 21 single-nucleotide polymorphisms (SNPs) within the HTR2A gene, 8 within the SLC6A4 gene and 23 within the TPH2 gene for genotyping using the GoldenGate genotyping assay. A total of 375 patients with BP-I and 475 normal controls were recruited. Two out of 21 SNPs (rs1475196 and rs9567747) in the HTR2A gene and 1/23 SNPs (rs17110566) in the TPH2 gene were significantly associated with BP-I, both genotype-wise and allele-wise. Furthermore, a specific haplotype in the HTR2A gene showed a significant association with BP-I. Our results indicate that the HTR2A and TPH2 genes in the serotonin pathway play important roles in susceptibility to BP-I.