Fear memory regulation by the cAMP signaling pathway as an index of reexperiencing symptoms in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder associated with traumatic memory, yet its etiology remains unclear. Reexperiencing symptoms are specific to PTSD compared to other anxiety-related disorders. Importantly, reexperiencing can be mimicked by retrieval-related events of fear memory in animal models of traumatic memory. Recent studies revealed candidate PTSD-associated genes that were related to the cyclic adenosine monophosphate (cAMP) signaling pathway. Here, we demonstrate the tight linkage between facilitated cAMP signaling and PTSD by analyzing loss- and gain-of-cAMP signaling effects on fear memory in mice and the transcriptomes of fear memory-activated mice and female PTSD patients with reexperiencing symptoms. Pharmacological and optogenetic upregulation or downregulation of cAMP signaling transduction enhanced or impaired, respectively, the retrieval and subsequent maintenance of fear memory in mice. In line with these observations, integrative mouse and human transcriptome analysis revealed the reduced mRNA expression of phosphodiesterase 4B (PDE4B), an enzyme that degrades cAMP, in the peripheral blood of PTSD patients showing more severe reexperiencing symptoms and the mouse hippocampus after fear memory retrieval. Importantly, more severe reexperiencing symptoms and lower PDE4B mRNA levels were correlated with decreased DNA methylation of a locus within PDE4B, suggesting the involvement of methylation in the mechanism of PTSD. These findings raise the possibility that the facilitation of cAMP signaling mediating the downregulation of PDE4B expression enhances traumatic memory, thereby playing a key role in the reexperiencing symptoms of PTSD patients as a functional index of these symptoms.

Blood mRNA expression levels of glucocorticoid receptors and FKBP5 are associated with depressive disorder and altered HPA axis.

BACKGROUND: While depression has been associated with alterations in the hypothalamic-pituitary adrenal (HPA) axis function, there is still controversy regarding the nature and extent of the dysfunction, such as in the debate about hypercortisolism vs. hypocortisolism. It may therefore be necessary to understand whether and how HPA axis function in depression is linked to mRNA expression of key genes regulating this system. METHODS: We studied 163 depressed outpatients, most of whom were chronically ill, and 181 healthy controls. Blood mRNA expression levels of NR3C1 (including GRα, GRß, and GR-P isoforms), FKBP4, and FKBP5 were measured at baseline. HPA axis feedback sensitivity was measured by the dexamethasone (Dex)/corticotropin-releasing hormone (CRH) test. The association between mRNA expression levels and HPA axis feedback sensitivity was examined. RESULTS: Compared to controls, patients showed significantly higher expression of GRα and lower expression of FKBP5, and higher post-Dex cortisol levels, even after controlling for age and sex. FKBP5 expression was significantly positively correlated with cortisol levels in patients, while GRα expression was significantly negatively correlated with cortisol levels in controls. LIMITATIONS: Most patients were taking psychotropic medications. The large number of correlation tests may have caused type I errors. CONCLUSIONS: The tripartite relationship between depression, mRNA expression of GR and FKBP5, and HPA axis function suggests that the altered gene expression affects HPA axis dysregulation and, as a result, impacts the development and/or illness course of depressive disorder. The combination of increased GRα expression and decreased FKBP5 expression may serve as a biomarker for chronic depression.

Blunted diurnal interleukin-6 rhythm is associated with amygdala emotional hyporeactivity and depression: a modulating role of gene-stressor interactions.

Background: The immune system has major roles in the brain and related psychopathology. Disrupted interleukin-6 secretion and aberrant amygdala emotional reactivity are well-documented in stress-related mental disorders. The amygdala regulates psychosocial stress-related interleukin-6 affected by related genes. These led us to comprehensively examine the relationship between interleukin-6, amygdala activity, and stress-related mental symptoms under gene-stressor interactions. Methods: One hundred eight nonclinical participants with various levels of anxiety/depression underwent magnetic resonance imaging scans during an emotional face task for amygdala activity and saliva collection (at 10-time points across 2 days) for the total output and diurnal patterns of interleukin-6. Gene-stressor interactions between rs1800796 (C/G) and rs2228145 (C/A) and stressful life events for the biobehavioral measures were explored. Results: The blunting of interleukin-6 diurnal pattern was associated with hypoactivation of the basolateral amygdala in response to fearful (vs. neutral) faces (t = 3.67, FWE-corrected p = 0.003), and was predominantly observed in individuals with rs1800796 C-allele homozygotes and negative life changes in the past year (F = 19.71, p < 0.001). When considered in a comprehensive model, the diminished diurnal pattern predicted greater depressive symptoms (ß = -0.40), modulated by the amygdala hypoactivity (ß = 0.36) and rs1800796-stressor interactions (ß = -0.41; all p < 0.001). Conclusion: Here we show that the blunted interleukin-6 diurnal rhythm predicts depressive symptoms, modulated by amygdala emotional hyporeactivity and gene-stressor interactions. These findings indicate a potential mechanism underlying vulnerability to depressive disorders, suggesting their early detection, prevention, and treatment through the understanding of immune system dysregulation.

Suicidality in civilian women with PTSD: Possible link to childhood maltreatment, proinflammatory molecules, and their genetic variations.

Background: Posttraumatic stress disorder (PTSD) is a robust risk factor for suicide. Studies have suggested an association between suicide and elevated inflammatory markers, although such evidence in PTSD is scarce. Suicide risk, PTSD, and inflammatory molecules are all shown to be associated with childhood maltreatment and genetic factors. Methods: We examined the association between suicidal ideation/risk and inflammatory markers in 83 civilian women with PTSD, and explored the possible influence of childhood maltreatment and inflammatory genes. Suicidal ideation and risk were assessed using the Beck Depression Inventory-II and the Mini-International Neuropsychiatric Interview. Childhood maltreatment history was assessed with the Childhood Trauma Questionnaire (CTQ). Blood levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and high-sensitivity tumor necrosis factor-α were measured. Genetic polymorphisms of CRP rs2794520 and IL6 rs1800796 were genotyped. Results: Suicidal ideation was significantly positively correlated with hsCRP (p = 0.002) and IL-6 (p = 0.015) levels. Suicide risk weighted score was significantly positively correlated with hsCRP (p = 0.016) levels. The risk alleles of CRP rs2794520 and IL6 rs1800796 leading to increased respective protein levels were dose-dependently associated with higher risk of suicide (p = 0.007 and p = 0.029, respectively). The CTQ total score was significantly correlated with suicidal ideation and risk, but not with inflammatory marker levels. Furthermore, a multivariate regression analysis controlling for PTSD severity and potential confounders revealed that rs2794520 and rs1800796, but not hsCRP or IL-6 levels, significantly predicted suicidal ideation (p < 0.001) and risk (p = 0.007), respectively. Conclusion: Genetic variations within inflammatory genes might be useful in detecting PTSD patients at high risk of suicide.

Analyzing schizophrenia-related phenotypes in mice caused by autoantibodies against NRXN1α in schizophrenia.

The molecular pathological mechanisms underlying schizophrenia remain unclear; however, genomic analysis has identified genes encoding important risk molecules. One such molecule is neurexin 1α (NRXN1α), a presynaptic cell adhesion molecule. In addition, novel autoantibodies that target the nervous system have been found in patients with encephalitis and neurological disorders. Some of these autoantibodies inhibit synaptic antigen molecules. Studies have examined the association between schizophrenia and autoimmunity; however, the pathological data remain unclear. Here, we identified a novel autoantibody against NRXN1α in patients with schizophrenia (n = 2.1%) in a Japanese cohort (n = 387). None of the healthy control participants (n = 362) were positive for anti-NRXN1α autoantibodies. Anti-NRXN1α autoantibodies isolated from patients with schizophrenia inhibited the molecular interaction between NRXN1α and Neuroligin 1 (NLGN1) and between NRXN1α and Neuroligin 2 (NLGN2). Additionally, these autoantibodies reduced the frequency of the miniature excitatory postsynaptic current in the frontal cortex of mice. Administration of anti-NRXN1α autoantibodies from patients with schizophrenia into the cerebrospinal fluid of mice reduced the number of spines/synapses in the frontal cortex and induced schizophrenia-related behaviors such as reduced cognition, impaired pre-pulse inhibition, and reduced social novelty preference. These changes were improved through the removal of anti-NRXN1α autoantibodies from the IgG fraction of patients with schizophrenia. These findings demonstrate that anti-NRXN1α autoantibodies transferred from patients with schizophrenia cause schizophrenia-related pathology in mice. Removal of anti-NRXN1α autoantibodies may be a therapeutic target for a subgroup of patients who are positive for these autoantibodies.

Plasma neuropeptide levels in patients with schizophrenia, bipolar disorder, or major depressive disorder and healthy controls: A multiplex immunoassay study.

AIM: We aimed to compare neuropeptide levels between patients with major psychiatric disorders and healthy controls and examine their association with symptoms and cognitive function. METHODS: The participants were 149 patients with schizophrenia, 115 patients with bipolar disorder (BD), 186 unremitted patients with major depressive disorder (MDD), and 350 healthy controls. Psychiatric (schizophrenic, manic, and depressive) symptoms, sleep state, and cognitive (premorbid intelligence quotient, general cognitive, and memory) functions were evaluated. A multiplex immunoassay kit was used to measure cerebrospinal fluid (CSF) and plasma α-melanocyte-stimulating hormone (MSH), ß-endorphin, neurotensin, oxytocin, and substance P levels. RESULTS: The verification assay revealed that CSF α-MSH, ß-endorphin, neurotensin, oxytocin, and substance P levels were too low to be reliably measured, while plasma α-MSH, ß-endorphin, neurotensin, oxytocin, and substance P levels could be successfully measured. Plasma α-MSH, ß-endorphin, neurotensin, oxytocin, and substance P levels were not significantly different between patients with schizophrenia, BD, or MDD and healthy controls. Plasma α-MSH, ß-endorphin, neurotensin, oxytocin, and substance P levels were not significantly correlated with psychiatric symptom scores in patients with schizophrenia, BD, or MDD and cognitive function scores in patients or healthy controls. CONCLUSION: Our data suggest that plasma neuropeptide levels do not elucidate the involvement of neuropeptides in the pathology of schizophrenia, BD, or MDD.

Haplotype phasing of a bipolar disorder pedigree revealed rare multiple mutations of SPOCD1 gene in the 1p36-35 susceptibility locus.

BACKGROUND: The etiology of bipolar disorder (BD) is poorly understood. Considering the complexity of BD, pedigree-based sequencing studies focusing on haplotypes at specific loci may be practical to discover high-impact risk variants. This study comprehensively examined the haplotype sequence at 1p36-35 BD and recurrent depressive disorder (RDD) susceptibility loci. METHODS: We surveyed BD families in Okinawa, Japan. We performed linkage analysis and determined the phased sequence of the affected haplotype using whole genome sequencing. We filtered rare missense variants on the haplotype. For validation, we conducted a case-control genetic association study on approximately 3000 Japanese subjects. RESULTS: We identified a three-generation multiplex pedigree with BD and RDD. Strikingly, we identified a significant linkage with mood disorders (logarithm of odds [LOD] = 3.61) at 1p36-35, supported in other ancestry studies. Finally, we determined the entire sequence of the 6.4-Mb haplotype shared by all affected subjects. Moreover, we found a rare triplet of missense variants in the SPOCD1 gene on the haplotype. Notably, despite the rare frequency, one heterozygote with multiple SPOCD1 variants was identified in an independent set of 88 BD type I genotyping samples. LIMITATIONS: The 1p36-35 sequence was obtained from only a single pedigree. The replicate sample was small. Short-read sequencing might miss structural variants. A polygenic risk score was not analyzed. CONCLUSION: The 1p36-35 haplotype sequence may be valuable for future BD variant studies. In particular, SPOCD1 is a promising candidate gene and should be validated.

Association of childhood maltreatment history with salivary interleukin-6 diurnal patterns and C-reactive protein in healthy adults.

Childhood maltreatment has been associated with increased inflammation, as indicated by elevated levels of proinflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP). Studies in humans show that secretion of IL-6 follows a clear circadian rhythm, implying that its disturbed rhythm represents an important aspect of dysregulated inflammatory system. However, possible alterations in diurnal secretion patterns of IL-6 associated with childhood maltreatment have not been studied. Here we investigated this association in 116 healthy adults. Diurnal levels of IL-6 were examined using saliva samples collected at 5 times a day across 2 consecutive days. Salivary CRP levels were also determined by averaging measurements at 2 times a day for 2 days. Different types of childhood maltreatment were assessed with the Childhood Trauma Questionnaire (CTQ). CTQ total and emotional abuse scores were significantly correlated with smaller IL-6 diurnal variation as indexed by lower standard deviation across the measurement times (p = 0.024 and p = 0.008, respectively). Individuals with emotional abuse, as defined by a cut-off score of CTQ, showed flatter IL-6 rhythm than those without (p = 0.031). These results, both correlation and group comparison, remained significant after controlling for age, sex, and body mass index. Childhood maltreatment was not associated with total output of IL-6 or CRP. Our findings indicate that childhood trauma can have a long-term negative effect on the circadian rhythm of inflammatory system. The findings are consistent with those of previous studies on adulthood trauma, suggesting that the disrupted IL-6 rhythmicity may be associated with a broad range of trauma-related conditions.

Hypothalamic-pituitary-adrenal axis and renin-angiotensin-aldosterone system in adulthood PTSD and childhood maltreatment history.

Accumulated evidence shows that psychological trauma and posttraumatic stress disorder (PTSD) are associated with dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis. Besides the HPA axis hormones, recent evidence suggests that the renin-angiotensin-aldosterone (RAA) system and genetic factors may be involved in trauma/PTSD as well as in HPA axis regulation. This study attempted to better understand the HPA axis function in relation to PTSD and childhood maltreatment by simultaneously examining RAA system and genetic polymorphisms of candidate genes. Here we studied 69 civilian women with PTSD and 107 healthy control women without DSM-IV-based traumatic experience. Childhood maltreatment history was assessed with the Childhood Trauma Questionnaire. PTSD severity was assessed with the Posttraumatic Diagnostic Scale. Functional disability was assessed with the Sheehan Disability Scale. HPA axis was examined by measuring blood levels of cortisol, adrenocorticotropic hormone, and dehydroepiandrosterone-sulphate (DHEA-S). RAA system was examined by measuring blood renin and aldosterone levels. The FKBP5 rs1360780 and CACNA1C rs1006737 polymorphisms were genotyped. No significant differences were seen between patients and controls in any of the five hormone levels. DHEA-S levels were significantly negatively correlated with overall PTSD severity (p = 0.003) and functional disability (p = 0.008). A two-way analysis of variance with diagnostic groups and genotypes as fixed factors revealed that patients with the rs1006737 A-allele had significantly lower DHEA-S levels than patients with the GG genotype (p = 0.002) and controls with the A-allele (p = 0.006). Childhood maltreatment history was not significantly correlated with any of the five hormone levels. These results were generally unchanged after controlling for the potentially confounding effect of age, depression, and anxiety. Our findings suggest that lower DHEA-S levels could indicate more severe subtype of PTSD, the association of which might be partly modified by the CACNA1C polymorphism.

Childhood maltreatment history and attention bias variability in healthy adult women: role of inflammation and the BDNF Val66Met genotype.

Childhood maltreatment has been associated with greater attention bias to emotional information, but the findings are controversial. Recently, a novel index of attention bias, i.e., attention bias variability (ABV), has been developed to better capture trauma-related attentional dysfunction. However, ABV in relation to childhood trauma has not been studied. Here, we examined the association of childhood maltreatment history with attention bias/ABV in 128 healthy adult women. Different types of childhood maltreatment were assessed with the Childhood Trauma Questionnaire. Attention bias/ABV was measured by the dot-probe task. Possible mechanisms whereby childhood maltreatment affects attention bias/ABV were also explored, focusing on blood proinflammatory markers and the BDNF Val66Met polymorphism. We observed a significant positive correlation between childhood emotional abuse and ABV (P = 0.002). Serum high-sensitivity tumor necrosis factor-α levels were significantly positively correlated with ABV (P < 0.001), but not with childhood maltreatment. Jonckheere-Terpstra trend test showed a significant tendency toward greater ABV with increasing numbers of the BDNF Met alleles (P = 0.021). A two-way analysis of variance further revealed that the genotype-by-emotional abuse interaction for ABV was significant (P = 0.022); individuals with the Val/Met and Met/Met genotypes exhibited even greater ABV when childhood emotional abuse was present. These results indicate that childhood emotional abuse can have a long-term negative impact on emotional attention control. Increased inflammation may be involved in the mechanism of ABV, possibly independently of childhood maltreatment. The BDNF Met allele may dose-dependently increase ABV by interacting with childhood emotional abuse.

Association of CRP genetic variation with symptomatology, cognitive function, and circulating proinflammatory markers in civilian women with PTSD.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with increased inflammation. C-reactive protein (CRP) is a marker of systemic inflammation, and recently, single nucleotide polymorphisms (SNPs) in the CRP gene have been associated with increased blood CRP protein levels and illness severity in PTSD patients. However, the mechanism by which the CRP SNPs are involved in PTSD remains unclear. Here we investigated the association of CRP genetic variation with blood proinflammatory protein levels, symptomatology, and cognitive function, and further explored the moderating effect of childhood maltreatment history, in adult patients with PTSD. METHODS: Fifty-seven Japanese civilian women with PTSD and 73 healthy control women were enrolled. Three SNPs in the CRP gene, namely rs2794520, rs1130864, and rs3093059, were genotyped, and analyses focused on rs2794520 (T/C). Serum levels of high-sensitivity CRP (hsCRP), high-sensitivity tumor necrosis factor-α (hsTNF-α), and interleukin-6 were measured. PTSD symptoms were evaluated by the Posttraumatic Diagnostic Scale. Cognitive function was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status. Childhood maltreatment history was assessed by the Childhood Trauma Questionnaire. RESULTS: Patients with the rs2794520 CC/CT genotype, compared to those with the TT genotype, showed significantly higher levels of hsCRP (p=0.009) and hsTNF-α (p=0.001), more severe PTSD symptoms (p=0.036), and poorer cognitive function (p=0.018). A two-way analysis of variance revealed a significant genotype-by-maltreatment interaction for more severe PTSD avoidance symptom (p=0.012). LIMITATIONS: The relatively small sample size limited our findings. CONCLUSIONS: These findings may provide an insight into the etiology of PTSD from the inflammatory perspective.

Possible associations between plasma fibroblast growth factor 21 levels and cognition in bipolar disorder.

Bipolar disorder (BD) is a mental disorder characterized by extreme changes in mood polarity. It is also characterized by cognitive and metabolic dysfunctions. Fibroblast growth factor 21 (FGF21) is an endocrine protein that has a multifaceted function such as glucose and lipid regulation in the periphery, and neuroprotection and induction of synaptic plasticity in the central nervous system. Previous studies reported inconsistent results concerning peripheral FGF21 levels in patients with BD. In this study, we compared plasma FGF21 levels between 26 patients with BD and 51 healthy controls using a human FGF21 ELISA Kit. There was no significant difference in plasma FGF21 levels between the patients and controls. We found significant positive correlations between plasma FGF21 levels and some cognitive parameters (word association and motor speed). If our results are replicated that higher peripheral FGF21 may be associated with better cognitive performance in patients with BD.

The BDNF Val66Met polymorphism affects negative memory bias in civilian women with PTSD.

Memory abnormalities are considered a core feature of posttraumatic stress disorder (PTSD). Studies attempting to quantify such memory dysfunction in PTSD have reported that individuals with this disorder exhibit selective memory bias toward negative material. The low expression Met allele of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with the aetiology of PTSD and with memory abnormalities. It is therefore possible that the BDNF Val66Met polymorphism can moderate the relationship between PTSD and memory bias. Here we examined this association in 50 civilian women with PTSD and 70 non-trauma-exposed healthy control women. All subjects were genotyped for the BDNF Val66Met (rs6265) polymorphism. Negative memory bias was assessed using a recognition memory task. Patients showed significantly greater negative memory bias compared to controls. In patients, negative memory bias significantly increased with increasing numbers of Met alleles; while no significant relationship was seen in controls. Further pairwise analyses revealed that patients with the Met allele had significantly greater negative memory bias than controls. These results suggest that the relationship between PTSD and negative memory bias can be moderated by the BDNF Val66Met polymorphism. More studies are needed to further clarify the relationship between this polymorphism and memory abnormalities in PTSD.

Proinflammatory status-stratified blood transcriptome profiling of civilian women with PTSD.

Etiology of posttraumatic stress disorder (PTSD) remains largely unknown. Studies have shown that a significant subset of patients with PTSD exhibit increased inflammation, suggesting that the understanding of this disorder could be facilitated by classifying these patients by inflammatory status. Here we performed a microarray-based blood transcriptome analysis on proinflammatory status-stratified Japanese civilian women with PTSD most of whom developed the disorder after experiencing interpersonal violence. By utilizing our previously identified cut-off serum interleukin-6 (IL-6) level that approximately corresponded to the median IL-6 level of our PTSD patients, we classified patients into those with high IL-6 levels and those with normal IL-6 levels (n = 16 for each). Transcriptome profiles of these 2 groups were compared with the profile of 16 age-matched healthy control women. Differentially expressed genes between high IL-6 patients and controls showed significant enrichment in a number of gene ontology terms and pathways primarily involved in immune/inflammatory responses, and their protein-protein interaction network was significantly enriched. In contrast, differentially expressed genes between normal IL-6 patients and controls showed significant enrichment in several gene ontology terms related to ion transport and neural function. The microarray data were confirmed by reverse transcription quantitative PCR. These findings illustrate the heterogeneous molecular mechanisms of PTSD within this relatively homogeneous sample in terms of sex, trauma type, and ethnicity, suggesting that peripheral proinflammatory status such as IL-6 levels could be a useful subtyping marker for this disorder. With further research, it is hoped that our findings will be translated into personalized medicine.

Reduced plasma orexin-A levels in patients with bipolar disorder.

PURPOSE: Orexins are hypothalamic neuropeptides involved in the regulation of sleep, appetite and arousal. An altered orexin system has been implicated in the pathophysiology of psychiatric disorders. This study aimed to examine whether plasma orexin-A levels differ in patients with schizophrenia, major depressive disorder (MDD), or bipolar disorder (BD) compared to in healthy controls. We also examined the possible correlations between plasma orexin-A levels and clinical variables. PATIENTS AND METHODS: All participants were Japanese. The sample consisted of 80 patients with schizophrenia (42 women, 52.5%; mean age 36.8 years), 80 patients with MDD (43 women, 53.8%; 43.7 years), and 40 patients with BD (24 women, 60%; 41.1 years), as well as 80 healthy controls (48 women, 60%; 47.0 years). Plasma orexin-A levels were quantified by an enzyme-linked immunosorbent assay. RESULTS: Mean orexin-A levels were significantly different across the four diagnostic groups (F=4.09; df=3; p=0.007, η2 =0.06). In particular, the patients with BD showed significantly lower orexin-A levels than did the controls. When the median value of the control group (109.8 pg/ml) was set as a cut-off value, subjects whose orexin-A levels were below the cut-off were more common in all psychiatric groups (schizophrenia: 73.8%, x2 =9.56, df=1, p=0.003, OR=2.81, 95% CI: 1.45 to 5.45, d=0.57; MDD: 78.5%, x2 =14.02, df=1, p<0.001, OR=3.65, 95% CI: 1.82 to 7.29, d=0.72; BD: 87.5%, x2 =16.0, df=1, p<0.001, OR=7.00, 95% CI: 2.49 to 19.70, d=1.07). We found no association between plasma orexin-A levels and any clinical symptoms, depression severity, or medication doses. CONCLUSION: Our results suggest that plasma orexin-A levels are reduced in patients with BD.

Altered polyunsaturated fatty acid levels in relation to proinflammatory cytokines, fatty acid desaturase genotype, and diet in bipolar disorder.

Inflammation and altered polyunsaturated fatty acid (PUFA) levels have been implicated in bipolar disorder (BD). A recent genome-wide association study identified a locus in the fatty acid desaturase (FADS) gene cluster conferring susceptibility to BD. In this study, we examined PUFA levels in patients with BD in relation to proinflammatory cytokines, FADS genotype, and dietary habits. We enrolled 83 patients with BD and 217 healthy controls who underwent plasma PUFA measurement. A subsample of 65 patients and 90 controls underwent plasma interleukin (IL)-6 and tumor necrosis factor alpha (TNFα) measurement, and three FADS single nucleotide polymorphisms (SNPs) were genotyped. Information on fish consumption was obtained by a self-reported diet history questionnaire. In comparing PUFA levels between patients and controls, significant differences were found for all 7 PUFAs tested. Specifically, n-3 eicosapentaenoic acid (EPA) level was decreased, and n-6 arachidonic acid level was increased in the patients (p < 0.0001 for both). Plasma IL-6 and TNFα levels were both significantly increased in the patients. Plasma EPA level was negatively correlated with IL-6 and TNFα levels. The FADS genotype, which was associated with increased n-6 PUFA levels, was also associated with marked elevation in TNFα levels. Less frequent fish intake was associated with low EPA and high IL-6 level. Taken together, our results provide strong evidence for altered plasma PUFA and proinflammatory cytokine levels in patients with BD. Furthermore, FADS genotype and fish consumption may contribute not only to altered PUFA levels but also to inflammation in BD.

Integrated profiling of phenotype and blood transcriptome for stress vulnerability and depression.

Etiology of depression and its vulnerability remains elusive. Using a latent profile analysis on dimensional personality traits, we previously identified 3 different phenotypes in the general population, namely stress-resilient, -vulnerable, and -resistant groups. Here we performed microarray-based blood gene expression profiling of these 3 groups (n = 20 for each group) in order to identify genes involved in stress vulnerability as it relates to the risk of depression. Identified differentially expressed genes among the groups were most markedly enriched in ribosome-related pathways. These ribosomal genes, which included ribosomal protein L17 (RPL17) and ribosomal protein L34 (RPL34), were upregulated in relation to the stress vulnerability. Protein-protein interaction and correlational co-expression analyses of the differentially expressed genes/non-coding RNAs consistently showed that functional networks involving ribosomes were affected. The significant upregulation of RPL17 and RPL34 was also observed in depressed patients compared to healthy controls, as confirmed in 2 independent case-control datasets by using pooled microarray data and qPCR experiments (total number of subjects was 122 and 166, respectively). Moreover, the upregulation of RPL17 and RPL34 was most marked in DSM-IV major depressive disorder, followed by in bipolar disorder, and then in schizophrenia, suggesting some diagnostic specificity of these markers as well as their general roles in stress vulnerability. These results suggest that ribosomal genes, particularly RPL17 and RPL34, can play integral roles in stress vulnerability and depression across nonclinical and clinical conditions. This study presents an opportunity to understand how multiple psychological traits and underlying molecular mechanisms interact to render individuals vulnerable to depression.

Plasma amino acid profile in major depressive disorder: Analyses in two independent case-control sample sets.

Some amino acids act as neurotransmitters themselves, or are precursors of neurotransmitters. Previous studies reported inconsistent results regarding their changes in blood in major depressive disorder (MDD), which prompted us to examine plasma levels of amino acids and related molecules in two independent case-control sample sets. In total, 511 subjects were recruited. Sample set A consisted of 164 patients with MDD (147 currently depressed [dMDD]; 17 in remission, DSM-IV) and 217 healthy controls. Sample set B consisted of 65 patients (51 dMDD; 14 in remission) and 65 controls. Plasma amino acid levels were measured using high-performance liquid chromatography for set A and liquid chromatography/mass spectrometry for set B. We further analyzed the relationships between plasma amino acid levels and clinical variables. In sample set A, plasma asparagine, histidine+1-methylhistidine, methionine, phenylalanine, tryptophan, and tyrosine levels were decreased, while plasma glutamate and phosphoethanolamine were elevated in dMDD compared to controls (all P < 0.0005), even after correcting for multiple testing. Plasma leucine levels were associated with "psychic anxiety." In sample set B, glutamate and methionine levels were also altered in the same direction to that in sample set A (both P < 0.05). In the integrative analysis, plasma glutamate and methionine levels were found to be significantly associated with the diagnosis of MDD with small to medium effect sizes (both P < 1.0E-6). In conclusion, several amino acids and related molecules were altered in patients with MDD. Decreased methionine and increased glutamate levels were found consistently in the two sample sets, suggesting their involvement in MDD. Further investigations are warranted on the possible role of amino acids in the pathophysiology of MDD.

Plasma and cerebrospinal fluid G72 protein levels in schizophrenia and major depressive disorder.

G72 is a modulator of D-amino acid oxidase, the enzyme that degrades D-serine, an amino acid that plays a critical role in glutamate neurotransmission, and has been implicated in psychiatric disorders. The aim of this study was to examine whether plasma or cerebrospinal fluid (CSF) G72 protein levels were altered in either schizophrenia or major depressive disorder (MDD) and whether any correlation between G72 levels and disease severity existed. Initially, 27 schizophrenic patients, 26 MDD patients, and 27 healthy controls matched for age, sex, and ethnicity were enrolled. Compared to those of controls, plasma or CSF G72 levels were not significantly different in patients with schizophrenia or MDD. Although we found a significant positive correlation between plasma G72 levels and a positive symptoms score on the positive and negative syndrome scale (PANSS), this was not replicated in the second study (40 schizophrenic patients). CSF G72 levels showed no significant correlation with PANSS scores. In MDD, neither plasma nor CSF G72 levels correlated significantly with depression severity. Since severity of our patients were relatively mild, further investigations in a large number of subjects including drug-free patients, younger patients, and more severely affected patients are warranted.