Interaction between HTR2A rs3125 and negative life events in suicide attempts among patients with major depressive disorder: a cross-sectional study.

BACKGROUND: Both genetic and environmental factors play crucial roles in the development of major depressive disorder (MDD) and suicide attempts (SA). However, the interaction between both items remains unknown. This study aims to explore the interactions between the genetic variants of the serotonin 2 A receptor (HTR2A) and the nitric oxide synthase 1 (NOS1) and environmental factors in patients who experience MDD and SA. METHODS: A total of 334 patients with MDD and a history of SA (MDD-SA) were recruited alongside 518 patients with MDD with no history of SA (MDD-NSA), and 716 healthy controls (HC). The demographic data and clinical characteristics were collected. Sequenom mass spectrometry was used to detect eight tag-single nucleotide polymorphisms (tagSNPs) in HTR2A (rs1328683, rs17068986, and rs3125) and NOS1 (rs1123425, rs2682826, rs3741476, rs527590, and rs7959232). Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-environment interactions. RESULTS: Four tagSNPs (rs17068986, rs3125, rs527590, and rs7959232) exhibited significant differences between the three groups. However, these differences were not significant between the MDD-SA and MDD-NSA groups after Bonferroni correction. A logistic regression analysis revealed that negative life events (OR = 1.495, 95%CI: 1.071-2.087, P = 0.018), self-guilt (OR = 2.263, 95%CI: 1.515-3.379, P < 0.001), and negative cognition (OR = 2.252, 95%CI: 1.264-4.013, P = 0.006) were all independently associated with SA in patients with MDD. Furthermore, GMDR analysis indicated a significant interaction between HTR2A rs3125 and negative life events. Negative life events in conjunction with the HTR2A rs3125 CG + GG genotype were associated with a higher SA risk in patients with MDD when compared to the absence of negative life events in conjunction with the CC genotype (OR = 2.547, 95% CI: 1.264-5.131, P = 0.009). CONCLUSION: Several risk factors and a potential interaction between HTR2A rs3125 and negative life events were identified in patients with SA and MDD. The observed interaction likely modulates the risk of MDD and SA, shedding light on the pathogenesis of SA in patients with MDD.

Decreased left amygdala functional connectivity by cognitive-coping therapy in obsessive-compulsive disorder.

It is of great clinical importance to explore more efficacious treatments for OCD. Recently, cognitive-coping therapy (CCT), mainly focusing on recognizing and coping with a fear of negative events, has been reported as an efficacious psychotherapy. However, the underlying neurophysiological mechanism remains unknown. This study of 79 OCD patients collected Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and resting-state functional magnetic resonance imaging (rs-fMRI) scans before and after four weeks of CCT, pharmacotherapy plus CCT (pCCT), or pharmacotherapy. Amygdala seed-based functional connectivity (FC) analysis was performed. Compared post- to pretreatment, pCCT-treated patients showed decreased left amygdala (LA) FC with the right anterior cingulate gyrus (cluster 1) and with the left paracentral lobule/the parietal lobe (cluster 2), while CCT-treated patients showed decreased LA-FC with the left middle occipital gyrus/the left superior parietal/left inferior parietal (cluster 3). The z-values of LA-FC with the three clusters were significantly lower after pCCT or CCT than pretreatment in comparisons of covert vs. overt and of non-remission vs. remission patients, except the z-value of cluster 2 in covert OCD. CCT and pCCT significantly reduced the Y-BOCS score. The reduction in the Y-BOCS score was positively correlated with the z-value of cluster 1. Our findings demonstrate that both pCCT and CCT with large effect sizes lowered LA-FC, indicating that FCs were involved in OCD. Additionally, decreased LA-FC with the anterior cingulate cortex (ACC) or paracentral/parietal cortex may be a marker for pCCT response or a marker for distinguishing OCD subtypes. Decreased LA-FC with the parietal region may be a common pathway of pCCT and CCT. Trial registration: ChiCTR-IPC-15005969.

Effects of short-term cognitive-coping therapy on resting-state brain function in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) tends to be treatment refractory. Recently, cognitive-coping therapy (CCT) for OCD is reported to be an efficacious psychotherapy. However, the underlying neurophysiological mechanism remains unknown. Here, the effects of CCT on OCD and the resting-state brain function were investigated. METHODS: Fifty-nine OCD patients underwent CCT, pharmacotherapy plus CCT (pCCT), or pharmacotherapy. Before and after a 4-week treatment, Yale-Brown obsessive-compulsive scale (Y-BOCS) was evaluated and resting-state functional magnetic resonance imaging (rs-fMRI) was scanned. RESULTS: Compared with the baseline, significant reduction of Y-BOCS scores was found after four-week treatment (p < .001) in groups of CCT and pCCT, not in pharmacotherapy. Post-treatment Y-BOCS scores of CCT group and pCCT group were not different, but significantly lower than that of pharmacotherapy group (p < .001). Compared with pretreatment, two clusters of brain regions with significant change in amplitude of low-frequency fluctuation (ALFF) were obtained in those who treated with CCT and pCCT, but not in those who received pharmacotherapy. The ALFF in cluster 1 (insula, putamen, and postcentral gyrus in left cerebrum) was decreased, while the ALFF in cluster 2 (occipital medial gyrus, occipital inferior gyrus, and lingual gyrus in right hemisphere) was increased after treatment (corrected p < .05). The changes of ALFF were correlated with the reduction of Y-BOCS score and were greater in remission than in nonremission. The reduction of the fear of negative events was correlated to the changes of ALFF of clusters and the reduction of Y-BOCS score. CONCLUSIONS: The effectiveness of CCT for OCD was related to the alteration of resting-state brain function-the brain plasticity. TRIAL REGISTRATION: ChiCTR-IPC-15005969.

Association between T-182C, G1287A polymorphism in NET gene and suicidality in major depressive disorder in Chinese patients.

Objective: Previous studies have implicated norepinephrine transporter gene (NET) polymorphisms in the etiology of major depressive disorder (MDD). A functional NET T-182C polymorphism (rs2242446) in the promoter region and a synonymous polymorphisms G1287A in the exon 9 (rs5569) were associated with MDD in different populations. However, few studies have focused on the relationship between these polymorphisms and MDD patients with suicidality. The objective of the present study was to examine whether the two polymorphisms are associated with MDD patients with suicidality in the Han Chinese population. Methods: Two hundred and sixty-three suicidal depressed patients and 241 non-suicidal depressed patients who met DSM-IV criteria for MDD were recruited from our hospital. Three hundred and three unrelated, age- and sex-matched healthy control subjects participated in this case-control study. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton rating scale for depression (HAMD). Genotypes of T-182C polymorphism (rs2242446) and G1287A (rs5569) were screened by polymerase chain reaction. Results: No statistical significant differences between patients and controls were found for any of the analysed polymorphisms, either in the genotype or allele distribution. Conclusions: Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of MDD with suicidality. However, the results must be verified in larger samples and different ethnicities.

Effectiveness of cognitive-coping therapy and alteration of resting-state brain function in obsessive-compulsive disorder.

BACKGROUND: Cognitive-coping therapy (CCT), integrating cognitive theory with stress-coping theory, is an efficacious therapy for obsessive-compulsive disorder (OCD). However, the potential brain mediation for the effectiveness remains unclear. We sought to investigate differences of resting-state brain function between OCD and healthy controls and if such differences would be changed by a four-week CCT. PATIENTS AND METHODS: Thirty-one OCD patients were recruited and randomized into CCT (n=15) and pharmacotherapy plus CCT (pCCT, n=16) groups, together with 25 age-, gender- and education-matched healthy controls. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was scored to evaluate the severity in symptoms. Resting-state functional magnetic resonance imaging was scanned pre- and post-treatment. RESULTS: For patients, Y-BOCS scores were reduced during four-week treatment for CCT and pCCT (P<0.001), but no group difference was observed. No differences in amplitude of low-frequency fluctuation (ALFF) values were found between CCT and pCCT either pre- or post-treatment. Compared to controls, ALFF in OCD patients was higher in the left hippocampus, parahippocampus, and temporal lobes, but lower in the right orbitofrontal cortex, rectus, bilateral calcarine, cuneus, lingual, occipital, left parietal, postcentral, precentral, and parietal (corrected P<0.05). The ALFF in those regions was not significantly correlated to the severity of OCD symptoms. After a 4-week treatment, the ALFF differences between OCD patients and controls disappeared. LIMITATIONS: The pharmacotherapy group was not included since OCD patients generally do not respond to pharmacotherapy in four weeks. CONCLUSIONS: Our data indicated that resting-state brain function was different between OCD and controls; such differences disappeared after OCD symptoms were relieved.

Cognitive-coping therapy for obsessive-compulsive disorder: a randomized controlled trial.

Pharmacotherapy and cognitive-behavioral therapy (CBT) are widely used to treat obsessive-compulsive disorder (OCD). These treatments have helped many patients with OCD, but there still is room for improvement. Recently, a promising psychotherapy for OCD, cognitive-coping therapy (CCT), has been developed. Pharmacotherapy plus CCT (PCCT) demonstrates higher efficacy in a shorter period of time and lower relapses than pharmacotherapy or pharmacotherapy plus CBT. In this randomized controlled trial, we investigated the efficacy of CCT for OCD treatment. One hundred and forty-five OCD patients were randomly assigned into two groups: pharmacotherapy (N = 72) and PCCT (N = 73). In each group, drug-resistant (DR) and non-drug-resistant (NDR) OCD were further analyzed to examine the efficacy of CCT. Some clinical features and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) were blindly assessed pre-treatment and post-treatment at week 1, 2, 3, 4, and 12. The Y-BOCS scores were significantly lower in PCCT than in the pharmacotherapy group at any post-treatment time-point (P < 0.001). Compared with pre-treatment, the Y-BOCS scores were significantly reduced at any time-point (P < 0.001) in PCCT group, but only at week 12 (P < 0.001) in the pharmacotherapy group. In the PCCT group, there were no differences between DR and NDR groups' Y-BOCS scores at any post-treatment time-point. The response rates and remission rates were higher in PCCT than in the pharmacotherapy group. Three variables, the number of weeks of treatment, insight, and disregarding of obsessions, were significantly correlated with the Y-BOCS score. Therefore, CCT might be a potential treatment for OCD.

The relationship between single nucleotide polymorphisms in 5-HT2A signal transduction-related genes and the response efficacy to selective serotonin reuptake inhibitor treatments in Chinese patients with major depressive disorder.

OBJECTIVE: To explore the possible relationship between six single nucleotide polymorphisms (SNPs) (rs6311 and rs6305 of 5-HT2A, rs5443 of Gß3, rs2230739 of ACDY9, rs1549870 of PDE1A and rs255163 of CREB1, which are all related with 5-HT2A the signal transduction pathway) and the response efficacy to selective serotonin reuptake inhibitor (SSRI) treatments in major depressive disorder (MDD) Chinese. METHODS: This study included 194 depressed patients to investigate the influence of 6 polymorphisms in 5-HT2A signal transduction-related genes on the efficacy of SSRIs assessed over 1 year. The efficacies of SSRIs on 194 MDD patients were evaluated in an 8-week open-trial study. Over 1 year, a follow-up study was completed for 174 of them to observe the long-term efficacy of SSRIs. The optimal-scaling regression analysis was used for testing the relationship between the different genotypes of five SNPs and the efficacy in MDD. RESULTS: It showed that the patients with rs5443TT and rs2230739GG have a relatively good efficacy in response to short-term SSRIs. We also found that good efficacy appeared in depressed patients with rs2230739GG in response to long-term SSRIs. CONCLUSIONS: It suggested that different genotypes of rs5443 and rs2230739 might influence the signal transduction pathways of second message and affect therapeutic efficacy.

[M cell in vitro model and its application in oral delivery of macromolecular drugs].

The oral administration of bioactive macromolecular drugs such as proteins, peptides and nucleic acids represents unprecedented challenges from the drug delivery point of view. One key consideration is how to overcome the gastrointestinal tract absorption barrier. Recent studies suggest that microfold cell (M cell), a kind of specialized antigen-sampling epithelial cell which is characterized by a high endocytic rate and low degradation ability, may play an important role in macromolecule oral absorption. The development of an in vitro M cell coculture system and its modified models greatly advanced the study of M cells and the development of oral delivery system for macromolecular drugs. The special structure, function and formation characteristics, and biomarkers of M cell are summarized in this review. The applications of in vitro M cell models in developing oral delivery system ofbioactive macromolecular drugs are discussed.

[The mRNA expression levels of IL-1beta, TNF-alpha and tyrosine hydroxylase in peripheral blood of paranoid schizophrenic patients].

AIM: To investigate the gene expression levels of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and tyrosine hydroxylase (TH) in peripheral blood of paranoid schizophrenic patients, and explore the neuroimmunological mechanism of paranoid schizophrenia. METHODS: The mRNA expression levels of IL-1beta, TNF-alpha and TH in the peripheral blood of 39 paranoid schizophrenic patients and 30 normal controls were measured with RT-PCR and semi-quantitative technique. RESULTS: The mRNA expression levels of IL-1beta, TNF-alpha and TH was higher in paranoid schizophrenic patients than those in normal controls (P<0.01). The correlation between the gene expression levels of IL-1beta and TH was found in normal controls (r=0.666, P<0.01), not in paranoid schizophrenic patients (P>0.05); and the correlation between the gene expression levels of IL-1beta and TNF-alpha was significant in all groups (r=0.847 for normal controls and 0.942 for patients, P<0.01, respectively). CONCLUSION: Pro-inflammation cytokines and catecholamines have been demonstrated to be overexpressed in the peripheral blood of paranoid schizophrenic patients. And the correlation between catecholamines and pro-inflammation cytokines, which exists in the controls, is broken in paranoid schizophrenic patients.