Causal relationship between resting-state networks and depression: a bidirectional two-sample mendelian randomization study.

BACKGROUND: Cerebral resting-state networks were suggested to be strongly associated with depressive disorders. However, the causal relationship between cerebral networks and depressive disorders remains controversial. In this study, we aimed to investigate the effect of resting-state networks on depressive disorders using a bidirectional Mendelian randomization (MR) design. METHODS: Updated summary-level genome-wide association study (GWAS) data correlated with resting-state networks were obtained from a meta-analysis of European-descent GWAS from the Complex Trait Genetics Lab. Depression-related GWAS data were obtained from the FinnGen study involving participants with European ancestry. Resting-state functional magnetic resonance imaging and multiband diffusion imaging of the brain were performed to measure functional and structural connectivity in seven well-known networks. Inverse-variance weighting was used as the primary estimate, whereas the MR-Pleiotropy RESidual Sum and Outliers (PRESSO), MR-Egger, and weighted median were used to detect heterogeneity, sensitivity, and pleiotropy. RESULTS: In total, 20,928 functional and 20,573 structural connectivity data as well as depression-related GWAS data from 48,847 patients and 225,483 controls were analyzed. Evidence for a causal effect of the structural limbic network on depressive disorders was found in the inverse variance-weighted limbic network (odds ratio, [Formula: see text]; 95% confidence interval, [Formula: see text]; [Formula: see text]), whereas the causal effect of depressive disorders on SC LN was not found(OR=1.0025; CI,1.0005-1.0046; P=0.012). No significant associations between functional connectivity of the resting-state networks and depressive disorders were found in this MR study. CONCLUSIONS: These results suggest that genetically determined structural connectivity of the limbic network has a causal effect on depressive disorders and may play a critical role in its neuropathology.

A preliminary composite of blood-based biomarkers to distinguish major depressive disorder and bipolar disorder in adolescents and adults.

BACKGROUND: Since diagnosis of mood disorder heavily depends on signs and symptoms, emerging researches have been studying biomarkers with the attempt to improve diagnostic accuracy, but none of the findings have been broadly accepted. The purpose of the present study was to construct a preliminary diagnostic model to distinguish major depressive disorder (MDD) and bipolar disorder (BD) using potential commonly tested blood biomarkers. METHODS: Information of 721 inpatients with an ICD-10 diagnosis of MDD or BD were collected from the electronic medical record system. Variables in the nomogram were selected by best subset selection method after a prior univariable screening, and then constructed using logistic regression with inclusion of the psychotropic medication use. The discrimination, calibration and internal validation of the nomogram were evaluated by the receiver operating characteristic curve (ROC), the calibration curve, cross validation and subset validation method. RESULTS: The nomogram consisted of five variables, including age, eosinophil count, plasma concentrations of prolactin, total cholesterol, and low-density lipoprotein cholesterol. The model could discriminate between MDD and BD with an area under the ROC curve (AUC) of 0.858, with a sensitivity of 0.716 and a specificity of 0.890. CONCLUSION: The comprehensive nomogram constructed by the present study can be convenient to distinguish MDD and BD since the incorporating variables were common indicators in clinical practice. It could help avoid misdiagnoses and improve prognosis of the patients.

A study of brain glucose metabolism in obsessive-compulsive disorder patients.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic neural psychological condition. Its pathogenesis is not yet completely understood. This current research used fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging to examine the changes in brain glucose metabolism in patients with OCD during the course of treatment, and analyzed its relationship with clinical efficacy. METHODS: A total of 23 patients with OCD were enrolled and divided into case group 1, consisting of patients who received no drug treatment or those who recently stopped drug treatment for more than five half-life periods (OCD1 group, N=10), and case group 2, consisting of patients who were receiving drug treatment before enrollment (OCD2 group, N=13). Ten healthy volunteers were selected as controls. All patients and healthy controls were subjected to head PET-computed tomography (CT) examination. Seven patients in case group 2 underwent scanning again after 3 months of drug treatment, namely, case group 3 (OCD3 group, N=7). Statistical Parametric Mapping (SPM) 8 software was used to analyze the PET-CT results. RESULTS: OCD patients had abnormally enhanced glucose metabolism in the medium orbito-frontal region of the brain, and abnormally reduced glucose metabolism in brain areas including the insula, caudate nucleus, and middle temporal gyrus. No changes in brain glucose metabolism related to curative effect was found. CONCLUSIONS: In OCD patients, abnormal brain function may not only be limited to the usual cortico-striato-thalamo-cortical (CSTC) loop model, but may involve a wide range of brain regions simultaneously.

Intervention methods for improving reduced heart rate variability in patients with major depressive disorder: A systematic review and meta-analysis.

INTRODUCTION: Several studies have demonstrated that patients with major depressive disorder (MDD) commonly show reductions in heart rate variability (HRV) parameters. Thus, interventions for the improvement of low HRV may be advantageous in treating MDD. This systematic review and meta-analysis aimed to explore the improvement effects of current clinical treatments on low HRV in patients with MDD. METHODS: Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the PubMed, EMBASE, PsycINFO, and CNKI databases were searched for relevant literature. Interventional studies of patients with confirmed MDD, which included baseline and post-intervention data and at least one HRV parameter as an outcome indicator, were included for meta-analysis. RESULTS: Twenty-one studies were included in the review. Several studies affirmed the role of psychotherapy in improving low HRV in patients with MDD showing a significant increase in high-frequency and low-frequency power after psychotherapy in the meta-analysis. However, both pharmacotherapy studies and physiotherapy studies included in the meta-analysis showed significant heterogeneity. LIMITATIONS: The main limitation of this study was the relatively small samples for the meta-analysis, and more high-quality randomized controlled trials in this field are wanted. CONCLUSIONS: Psychotherapy was effective for improving low HRV in patients with MDD. However, the effect of pharmacotherapy or physical therapy on low HRV in MDD remains unclear. Regarding research methods, it is necessary to formulate and standardize operational guidelines for future HRV measurements.

The effect of SSRIs on Semen quality: A systematic review and meta-analysis.

Selective serotonin reuptake inhibitors (SSRIs) are widely used for a variety of diseases, and their impact on semen quality is unclear. We performed a systematic search in PubMed and Embase, and after a strict screening, we included 4 studies with a total of 222 male participants. In result, SSRIs reduced normal sperm morphology (95% CI [-16.29, -3.77], p = 0.002), sperm concentration (95%CI [-43.88, -4.18], p = 0.02), sperm motility (95%CI [-23.46, -0.47], p = 0.04) and sperm DNA fragmentation index (DFI) (95% CI [6.66,21.93], p = 0.0002), without a statistically significant effect on semen volume (95%CI [-0.75,0.65], p = 0.89). Moreover, the impact on both sperm morphology and sperm concentration were observed within the 3-month period of SSRIs use. In general, our meta-analysis showed that SSRIs have a negative effect on semen quality. More larger, randomized, well-controlled clinical studies should be conducted to support our conclusion.

Impaired robust interhemispheric function integration of depressive brain from REST-meta-MDD database in China.

BACKGROUND: Recently, functional homotopy (FH) architecture, defined as robust functional connectivity (FC) between homotopic regions, has been frequently reported to be altered in MDD patients (MDDs) but with divergent locations. METHODS: In this study, we obtained resting-state functional magnetic resonance imaging (R-fMRI) data from 1004 MDDs (mean age, 33.88 years; age range, 18-60 years) and 898 matched healthy controls (HCs) from an aggregated dataset from 20 centers in China. We focused on interhemispheric function integration in MDDs and its correlation with clinical characteristics using voxel-mirrored homotopic connectivity (VMHC) devised to inquire about FH patterns. RESULTS: As compared with HCs, MDDs showed decreased VMHC in visual, motor, somatosensory, limbic, angular gyrus, and cerebellum, particularly in posterior cingulate gyrus/precuneus (PCC/PCu) (false discovery rate [FDR] q < 0.002, z = -7.07). Further analysis observed that the reduction in SMG and insula was more prominent with age, of which SMG reflected such age-related change in males instead of females. Besides, the reduction in MTG was found to be a male-special abnormal pattern in MDDs. VMHC alterations were markedly related to episode type and illness severity. The higher Hamilton Depression Rating Scale score, the more apparent VMHC reduction in the primary visual cortex. First-episode MDDs revealed stronger VMHC reduction in PCu relative to recurrent MDDs. CONCLUSIONS: We confirmed a significant VMHC reduction in MDDs in broad areas, especially in PCC/PCu. This reduction was affected by gender, age, episode type, and illness severity. These findings suggest that the depressive brain tends to disconnect information exchange across hemispheres.

Correlations Between Working Memory Impairment and Neurometabolites of the Prefrontal Cortex in Drug-Naive Obsessive-Compulsive Disorder.

PURPOSE: This study aimed to investigate the mechanism of working memory (WM) impairment in drug-naive obsessive-compulsive disorder (OCD) by using neuropsychological tests and proton magnetic resonance spectroscopy (1H-MRS). PATIENTS AND METHODS: A total of 55 patients with drug-naive OCD and 55 healthy controls (HCs) were recruited for this study. The working memory (WM) was evaluated using the digit span test (DST), visual space memory test (VSMT), and the 2-back task and stroop color word test (SCWT). The bilateral metabolite levels of the prefrontal cortex (PFC) were evaluated by 1H-MRS, then determined the ratios of N-acetyl aspartate (NAA), choline-containing compounds (Cho), and myo-inositol (MI) to creatine (Cr). The independent sample t-test was used to analyse the differences in WM performance and neurometabolite ratios. Multivariate linear regression analysis was performed to screen the influential factors of WM, with an introduction level of 0.05 and a rejection level of 0.10. RESULTS: 1) Patients with OCD performed significantly worse on DST (score), VSMT (score), 2-back task (accuracy rate), SCWT (execution time) when compared with HCs. 2) NAA/Cr and Cho/Cr in the left PFC (lPFC) and MI/Cr ratios in the bilateral PFC of OCD patients were significantly lower when compared to HCs. 3) For OCD patients, the NAA/Cr ratio in the lPFC was negatively correlated with the score of DST (forwards), the Cho/Cr ratio in the lPFC was positively correlated with the accuracy rate of 2-back task, and the MI/Cr ratio in the right PFC (rPFC) was positively correlated with the score of DST (forwards) and the accuracy rate of VSMT. We also found that the compulsive symptoms showed a positive correlation with MI/Cr ratio of the rPFC. CONCLUSION: Drug-naive OCD patients have demonstrated WM impairments, including phonological loop, visual-spatial sketchpad and central executive system, and the WM impairments might be associated with hypometabolism in the PFC, especially the lPFC.

Distinct behavioral traits and associated brain regions in mouse models for obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a mental disease with heterogeneous behavioral phenotypes, including repetitive behaviors, anxiety, and impairments in cognitive functions. The brain regions related to the behavioral heterogeneity, however, are unknown. METHODS: We systematically examined the behavioral phenotypes of three OCD mouse models induced by pharmacological reagents [RU24969, 8-hydroxy-DPAT hydrobromide (8-OH-DPAT), and 1-(3-chlorophenyl) piperazine hydrochloride-99% (MCPP)], and compared the activated brain regions in each model, respectively. RESULTS: We found that the mouse models presented distinct OCD-like behavioral traits. RU24969-treated mice exhibited repetitive circling, anxiety, and impairments in recognition memory. 8-OH-DPAT-treated mice exhibited excessive spray-induced grooming as well as impairments in recognition memory. MCPP-treated mice showed only excessive self-grooming. To determine the brain regions related to these distinct behavioral traits, we examined c-fos expression to indicate the neuronal activation in the brain. Our results showed that RU24969-treated mice exhibited increased c-fos expression in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), prelimbic cortex (PrL), infralimbic cortex (IL), nucleus accumbens (NAc), hypothalamus, bed nucleus of the stria terminalis, lateral division, intermediate part (BSTLD), and interstitial nucleus of the posterior limb of the anterior commissure, lateral part (IPACL), whereas in 8-OH-DPAT-treated mice showed increased c-fos expression in the ACC, PrL, IL, OFC, NAc shell, and hypothalamus. By contrast, MCPP did not induce higher c-fos expression in the cortex than control groups. CONCLUSION: Our results indicate that different OCD mouse models exhibited distinct behavioral traits, which may be mediated by the activation of different brain regions.

The characteristic of cognitive impairments in patients with bipolar II depression and its association with N-acetyl aspartate of the prefrontal white matter.

BACKGROUND: Cognitive deficit is acknowledged as a core feature of clinical manifestations of bipolar disorder (BD). However, the underlying mechanism of cognitive impairment in bipolar II depression has remained uncertain. We aim to determine the association of cognitive impairments with biochemical metabolism using proton magnetic resonance spectroscopy (1H-MRS) and a battery of neuropsychological testing. METHODS: The current study was designed to assess four cognitive domains in a sample of 110 patients with bipolar II depression and 110 healthy controls, using a battery of 6 cognitive tests, including the Digit Symbol Substitution Test (DSST), Wisconsin Cart Sorting Test (WCST), Trail Making Test Part B (TMT-B), Digit Span Test (DST), TMT-part A (TMT-A) and Verbal Fluency Test (VFT). Metabolite levels were obtained in the following brain regions of interest: bilateral prefrontal white matter (PWM), bilateral anterior cingulate cortex (ACC), bilateral lenticular nucleus (LN), and bilateral thalamus. N-acetyl aspartate (NAA)/creatine (Cr) and choline-containing compounds (Cho)/Cr ratios are analyzed. RESULTS: Patients with bipolar II depression performed significantly worse on DSST (score), TMT (completion time), DSB (score), and VFT (valid word number) when compared with healthy controls. In the bilateral PWM, NAA/Cr ratios in the PWM were significantly reduced (bilaterally) than those in healthy controls. Correlation analysis was conducted with data from patients with bipolar II depression, we found that the NAA/Cr ratio of the left PWM was positively correlated with the score of DS and DSB, and the NAA/Cr ratio of the right PWM was negatively correlated with the completion time of TMT-B. CONCLUSIONS: Our findings suggested that psychomotor speed, executive function, working memory, and verbal fluency are impaired in patients with BD II depression. Hypoactivity NAA/Cr in bilateral PWM may be associated with BD II depression's pathophysiology and results in cognitive dysfunction.

Dysregulated plasma levels of miRNA-132 and miRNA-134 in patients with obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a severe, chronic, disabling neuropsychiatric disorder, the pathophysiology of which has yet to be fully understood. In this study, we aimed to detect the levels of miRNA-132 and miRNA-134 in the plasma of patients with OCD and to analyze the factors influencing OCD. METHODS: The levels of miRNA-132 and miRNA-134 in peripheral blood of 30 patients with OCD and 32 normal controls were detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Patients were assessed using clinical scales, including the Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). RESULTS: The plasma levels of miRNA-132 and miRNA 134 in the OCD group were significantly higher than those in the control group (P<0.05). There was no significant correlation between the plasma levels of miR-132 and miR-134 in the OCD group and general demographic (gender, age, and education level) and clinical characteristics (duration of disease, HAMA, HAMD, and Y-BOCS scores). CONCLUSIONS: Patients with OCD have abnormal plasma levels of miRNA-132 and miRNA-134, which may influence the number of dendrites in the cerebral cortex and formation of synapses. Therefore, miRNA-132 and miRNA-134 plasma levels should be considered as potential biomarkers for OCD detection.

Neurocognitive dysfunction and regional cerebral blood flow in medically naïve patients with obsessive-compulsive disorder.

Previous research characterizes obsessive compulsive disorder (OCD) as a complex neurobehavioral disorder that may have multiple etiologies ( den Braber et al., 2008 ). This study analyzed neurocognitive function and change in regional cerebral blood flow (rCBF) to characterize OCD. Neurocognitive function and rCBF were examined in medically naïve patients with OCD and contrasted with controls. Results of this study indicated that the neurocognitive functions impaired in OCD are memory, attention, and executive function, which are primarily associated with the frontal and occipital lobes. Dysfunction in the basal ganglia and occipital lobes were associated with OCD and may be an etiological factor in the disorder.

Pharmacotherapy response and regional cerebral blood flow characteristics in patients with obsessive-compulsive disorder.

OBJECTIVE: To analyze the correlation between the pharmacotherapy response and the characteristics of the pre-treatment regional cerebral blood flow (rCBF) in patients with obsessive-compulsive disorder (OCD). METHODS: Single-photon emission-computed tomography (SPECT) was used to determine the pre-treatment rCBF in 30 OCD patients and 30 normal controls. Based on their clinical remission response, the subjects were divided into two groups: selective serotonin reuptake inhibitors (SSRIs) and SSRIs plus quetiapine. The subjects with clinical remission response were identified after treatment for a period of 24 weeks, and the rCBF imaging data were processed using statistical parametric mapping (SPM) software with two-sample Z-tests. RESULTS: Nineteen OCD patients who achieved clinical remission were included in the study. Increased rCBF in forebrain regions, including the frontal lobe, cingulate gyrus, hypothalamus, and basal ganglia, was found in 11 responders to SSRIs compared to normal control patients. The eight SSRI plus quetiapine responders exhibited a decrease in rCBF within posterior brain regions, including the parietal lobe, cerebellar vermis, and occipital lobe, and an increase in rCBF in the frontal lobe, thalamus, basal ganglia, and cerebellum tonsil compared to normal control patients. CONCLUSIONS: The characteristics of increased rCBF in forebrain regions and decreased rCBF in posterior brain regions before treatment of OCD patients was a potentially predictor of treatment response to guide treatment options.

Valproate (VPA)-associated hyperammonemic encephalopathy independent of elevated serum VPA levels: 21 cases in China from May 2000 to May 2012.

Valproate (VPA) is a medication that is widely used in the treatment of neurological and psychiatric disorders, such as epilepsy and bipolar disorder. Valproate-induced hyperammonemic encephalopathy (VHE) is a rare central nervous system adverse effect of this medication that is characterized by impaired consciousness, which can range from drowsiness to coma; increased seizure frequency; acute cognitive symptoms; and gastrointestinal symptoms. In this manuscript, we report a single case and also review previous cases of VHE (n=20) in Chinese patients to identify risk factors for VHE. Increasing clinicians' awareness of VHE during concomitant VPA therapy is of utmost importance. Serum ammonia level is a useful and important diagnostic test. The discontinuation of VPA is currently the mainstay of treatment for VHE.

[Change characteristics of regional cerebral blood flow and curative efficacy in patients with obsessive-compulsive disorder].

OBJECTIVE: To explore the change characteristics of regional cerebral blood flow (rCBF) and its correlation with curative efficacy in patients with obsessive-compulsive disorder (OCD). METHODS: The images of rCBF and computed tomography (CT) were acquired from 30 OCD and 30 normal controls by single photon emission computed tomography (SPECT) and CT. The tomographic data of rCBF were normalized, smoothed and statistically processed with the statistical parametric mapping (SPM) software with two-sample Z-test. And the OCD grade was evaluated with the Y-BOCS at pre- and post-medication. RESULTS: The abnormal results of CT were not found. The SPM Z-test showed that the sections of higher rCBF in the OCD patients were predominantly located in basal ganglia and occipital lobe compared with the normal controls (P < 0.001). The scores of Y-BOCS in 30 patients were markedly lower at post-medication than those at pre-medication (24 ± 7 vs 11 ± 6, P < 0.001). At post-medication, the scores of Y-BOCS with higher rCBF in basal ganglia and occipital lobe were higher than those in basal ganglia or occipital lobe (P < 0.05). CONCLUSION: The OCD patients have higher rCBF in basal ganglia and occipital lobe. The curative efficacy of OCD with higher rCBF in basal ganglia and occipital lobe is worse than that in basal ganglia or occipital lobe.

Serum uric acid levels and the clinical characteristics of depression.

OBJECTIVE: This study was designed to investigate the correlation between serum uric acid (UA) levels and the clinical characteristics of depression. DESIGN AND METHODS: The serum UA levels were measured in 124 patients with depression, 660 patients with different types of other mental disorders (OMD) and 42 healthy subjects. Clinical characteristics of depression and OMD were also investigated. RESULTS: Depressive patients (271.97 ± 77.50 µmol/L) had significantly lower UA levels than those with delirium, dementia, amnesia and other cognitive disorders (339.95 ± 141.74 µmol/L, P=0.004), substances related disorders (359.61 ± 125.02 µmol/L, P=0.022), schizophrenia (341.03 ± 106.84 µmol/L, P=0.000), schizoaffective disorder (336.78 ± 155.49 µmol/L, P=0.024), bipolar disorder (323.04 ± 108.70 µmol/L, P=0.008) and the healthy control group (315.76 ± 87.50 µmol/L, P=0.012). We also found that the UA levels of depressive patients normalised after a five week treatment with antidepressants. CONCLUSION: Our data suggested that a lowered UA level is another characteristic of depression.