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.

Neurobiology of early life adversity: A systematic review of meta-analyses towards an integrative account of its neurobiological trajectories to mental disorders.

Adverse childhood experiences (ACEs) may leave long-lasting neurobiological scars, increasing the risk of developing mental disorders in later life. However, no review has comprehensively integrated existing evidence across the fields: hypothalamic-pituitary-adrenal axis, immune/inflammatory system, neuroimaging, and genetics/epigenetics. We thus systematically reviewed previous meta-analyses towards an integrative account of ACE-related neurobiological alterations. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, a total of 27 meta-analyses until October 2021 were identified. This review found that individuals with ACEs possess blunted cortisol response to psychosocial stressors, low-grade inflammation evinced by increased C-reactive protein levels, exaggerated amygdalar response to emotionally negative information, and diminished hippocampal gray matter volume. Importantly, these alterations were consistently observed in those with and without psychiatric diagnosis. These findings were integrated and discussed in a schematic model of ACE-related neurobiological alterations. Future longitudinal research based on multidisciplinary approach is imperative for ACE-related mental disorders' prevention and treatment.

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.

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.

Performance on the Wechsler Adult Intelligence Scale (WAIS) in Japanese patients with bipolar and major depressive disorders in euthymic and depressed states.

AIM: This study aimed to examine the cognitive performance of patients with bipolar disorder (BD) stratified by illness phase compared to that of patients with major depressive disorder (MDD) and healthy controls. METHODS: Participants were 139 patients with BD (55 euthymic and 84 depressed), 311 patients with MDD (88 euthymic and 223 depressed), and 386 healthy controls who underwent the Wechsler Adult Intelligence Scale-Revised or the Third Edition. They were non-elderly Japanese individuals with normal estimated premorbid intelligence quotient (IQ; >90), group-matched for age, sex, and premorbid IQ. RESULTS: The depressed BD group showed significantly lower scores on verbal IQ, performance IQ, full-scale IQ, and three group indexes of perceptual organization, working memory, and processing speed when compared with healthy controls (all P < 0.001). All IQs and working memory index were also significantly lower than those of the depressed MDD group. The depressed MDD group scored significantly lower than controls in performance IQ (P < 0.001), full-scale IQ, and only in the index of processing speed (P < 0.001). The euthymic BD group scored significantly lower than controls in performance IQ (P = 0.004), whereas the euthymic MDD group scored significantly lower than controls only in processing speed (P = 0.030). CONCLUSION: Patients with BD appear to have global and more intense cognitive impairments in depressed states compared with those with MDD whose impairments seem to be apparent only in processing speed in the Wechsler Adult Intelligence Scale. Attenuated impairments appear to exist in euthymic states of both patients.

Enhanced Echo Intensity of Skeletal Muscle Is Associated With Exercise Intolerance in Patients With Heart Failure.

BACKGROUND: Skeletal muscle is quantitatively and qualitatively impaired in patients with heart failure (HF), which is closely linked to lowered exercise capacity. Ultrasonography (US) for skeletal muscle has emerged as a useful, noninvasive tool to evaluate muscle quality and quantity. Here we investigated whether muscle quality based on US-derived echo intensity (EI) is associated with exercise capacity in patients with HF. METHODS AND RESULTS: Fifty-eight patients with HF (61 ± 12 years) and 28 control subjects (58 ± 14 years) were studied. The quadriceps femoris echo intensity (QEI) was significantly higher and the quadriceps femoris muscle thickness (QMT) was significantly lower in the patients with HF than the controls (88.3 ± 13.4 vs 81.1 ± 7.5, P= .010; 5.21 ± 1.10 vs 6.54 ±1.34 cm, P< .001, respectively). By univariate analysis, QEI was significantly correlated with age, peak oxygen uptake (VO2), and New York Heart Association class in the HF group. A multivariable analysis revealed that the QEI was independently associated with peak VO2 after adjustment for age, gender, body mass index, and QMT: ß-coefficient = -11.80, 95%CI (-20.73, -2.86), P= .011. CONCLUSION: Enhanced EI in skeletal muscle was independently associated with lowered exercise capacity in HF. The measurement of EI is low-cost, easily accessible, and suitable for assessment of HF-related alterations in skeletal muscle quality.

Serum Brain-Derived Neurotrophic Factor Levels Are Associated with Skeletal Muscle Function but Not with Muscle Mass in Patients with Heart Failure.

Heart failure (HF) is associated with aberrant skeletal muscle impairments, which are closely linked to the severity of HF. A low level of brain-derived neurotrophic factor (BDNF), a myokine produced in the skeletal muscle, is known to be involved in reduced exercise capacity and poor prognosis in HF. However, little is known about the factors or conditions of skeletal muscle associated with BDNF levels. We investigated the association between serum BDNF levels and the skeletal muscle mass and function in HF patients (n = 60, 63 ± 13 years) and age-matched controls (n = 29, 61 ± 16 years). The serum BDNF level was significantly lower in the HF patients compared to the controls (24.9 ± 0.9 versus 28.6 ± 1.3, P = 0.021). In a univariate analysis, BDNF was significantly correlated with the peak oxygen uptake, estimated glomerular filtration rate, 10-m gait speed, and muscle strength, but not with the body mass index or lean mass in the HF group. A multiple linear regression analysis revealed that BDNF was independently associated with muscle strength (ß-coefficient = 2.80, 95%CI: 1.89-11.8, P = 0.008). Serum BDNF levels were associated with exercise capacity and skeletal muscle function, but not with muscle mass. These novel findings may suggest that BDNF production is controlled by muscle function and activity and consequently regulates exercise capacity, highlighting the importance of adequate training regarding skeletal muscle in HF patients.

Genome-wide quantitative trait loci mapping of the human cerebrospinal fluid proteome.

Cerebrospinal fluid (CSF) is virtually the only one accessible source of proteins derived from the central nervous system (CNS) of living humans and possibly reflects the pathophysiology of a variety of neuropsychiatric diseases. However, little is known regarding the genetic basis of variation in protein levels of human CSF. We examined CSF levels of 1,126 proteins in 133 subjects and performed a genome-wide association analysis of 514,227 single nucleotide polymorphisms (SNPs) to detect protein quantitative trait loci (pQTLs). To be conservative, Spearman's correlation was used to identify an association between genotypes of SNPs and protein levels. A total of 421 cis and 25 trans SNP-protein pairs were significantly correlated at a false discovery rate (FDR) of less than 0.01 (nominal P < 7.66 × 10-9). Cis-only analysis revealed additional 580 SNP-protein pairs with FDR < 0.01 (nominal P < 2.13 × 10-5). pQTL SNPs were more likely, compared to non-pQTL SNPs, to be a disease/trait-associated variants identified by previous genome-wide association studies. The present findings suggest that genetic variations play an important role in the regulation of protein expression in the CNS. The obtained database may serve as a valuable resource to understand the genetic bases for CNS protein expression pattern in humans.

The relationship between the Wechsler Memory Scale-Revised scores and whole-brain structure in patients with schizophrenia and healthy individuals.

INTRODUCTION: The Wechsler Memory Scale (WMS) is a standardised battery for assessing memory functions. We aimed to investigate the relationship between all WMS scores, including subtests, and whole-brain structure in a relatively large sample. METHODS: Participants were 93 patients with schizophrenia and 117 healthy individuals, all right-handed and of Japanese ethnicity, and matched for age and sex. Their memory functions were assessed using the WMS-Revised (WMS-R). Their grey and white matter structure was analyzed using voxel-based morphometry and diffusion tensor imaging. RESULTS: Verbal memory score correlated positively with volumes of the left parahippocampal gyrus and hippocampus, while general memory score correlated positively with volumes of the left parahippocampal and fusiform gyri and hippocampus (p < 0.05, corrected), while there was no correlation with white matter fractional anisotropy values in healthy individuals. No correlation was observed between any WMS-R score and grey or white matter structure in patients. CONCLUSIONS: Using whole-brain structural magnetic resonance imaging, we found several significant correlations between WMS-R scores and grey matter volume in the brains of healthy individuals, while no correlation was found in those of patients with schizophrenia.

Inflammation and post-traumatic stress disorder.

While post-traumatic stress disorder (PTSD) is currently diagnosed based solely on classic psychological and behavioral symptoms, a growing body of evidence has highlighted a link between this disorder and alterations in the immune and inflammatory systems. Epidemiological studies have demonstrated that PTSD is associated with significantly increased rates of physical comorbidities in which immune dysregulation is involved, such as metabolic syndrome, atherosclerotic cardiovascular disease, and autoimmune diseases. In line with this, a number of blood biomarker studies have reported that compared to healthy controls, individuals with PTSD exhibit significantly elevated levels of proinflammatory markers, such as interleukin-1ß, interleukin-6, tumor necrosis factor-α, and C-reactive protein. Moreover, various lines of animal and human research have suggested that inflammation is not only associated with PTSD but also can play an important role in its pathogenesis and pathophysiology. In this review, we first summarize evidence suggestive of increased inflammation in PTSD. We then examine findings that suggest possible mechanisms of inflammation in this disorder in terms of two different but interrelated perspectives: putative causes of increased proinflammatory activities and potential consequences that inflammation generates. Given that there is currently a dearth of treatment options for PTSD, possibilities of new therapeutic approaches using pharmacological and non-pharmacological treatments/interventions that have anti-inflammatory effects are also discussed. Despite the increasing attention given to the inflammatory pathology of PTSD, there remains much to be elucidated, including more detailed mechanisms of inflammation, potential usefulness of inflammatory biomarkers as diagnostic and prognostic markers, and efficacy of novel treatment strategies targeting inflammation.

Increased cerebrospinal fluid complement C5 levels in major depressive disorder and schizophrenia.

Inflammation has been implicated in a variety of psychiatric disorders. We aimed to determine whether levels of complement C5 protein in the cerebrospinal fluid (CSF), which may reflect activation of the complement system in the brain, are altered in patients with major psychiatric disorders. Additionally, we examined possible associations of CSF C5 levels with clinical variables. Subjects comprised 89 patients with major depressive disorder (MDD), 66 patients with bipolar disorder (BPD), 96 patients with schizophrenia, and 117 healthy controls, matched for age, sex, and ethnicity (Japanese). Diagnosis was made according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria. CSF C5 levels were measured by enzyme-linked immunosorbent assay. CSF C5 levels were significantly increased in the patients with MDD (p < 0.001) and in the patients with schizophrenia (p = 0.001), compared with the healthy controls. The rate of individuals with an "abnormally high C5 level" (i.e., above the 95th percentile value of the control subjects) was significantly increased in all psychiatric groups, relative to the control group (all p < 0.01). Older age, male sex, and greater body mass index tended to associate with higher C5 levels. There was a significantly positive correlation between C5 levels and chlorpromazine-equivalent dose in the patients with schizophrenia. Thus, we found, for the first time, elevated C5 levels in the CSF of patients with major psychiatric disorders. Our results suggest that the activated complement system may contribute to neurological pathogenesis in a portion of patients with major psychiatric disorders.

Development of Japanese version of King's Stigma Scale and its short version: Psychometric properties of a self-stigma measure.

AIM: The study aimed to develop two Japanese versions of King's Stigma Scale, a full version (KSS-J-1) and a short version (KSS-J-2), through psychometric property testing. METHODS: The sample included 112 people with mental illness. We tested the constructs of the scales using both confirmatory and exploratory factor analyses. Internal consistency and test-retest reliability were tested. We examined convergent validity with self-esteem or perceived stigma, and different group validity, using the Kessler Psychological Distress Scale (K6). RESULTS: Whereas a relatively weak model fit (comparative fit index = 0.66, Tucker-Lewis index = 0.63, root mean square error of approximation = 0.097) of KSS-J-1 (full version: 28 items) was found, KSS-J-2 (short version: 17 items), produced by exploratory factor analysis, had a moderate model fit (comparative fit index = 0.90, Tucker-Lewis index = 0.89, root mean square error of approximation = 0.063). High internal consistency (KSS-J-1, ω = 0.82-0.89; KSS-J-2, ω = 0.86-0.89) and moderate test-retest reliability (KSS-J-1, interclass correlation = 0.56-0.88; KSS-J-2, interclass correlation = 0.45-0.85) were reported. Some subscales and the entire scale of KSS-J-1 were significantly correlated with self-esteem and perceived stigma. Conversely, only two subscales in KSS-J-2 were significantly correlated with self-esteem. The scores of each subscale and the entire score for both KSS-J-1 and KSS-J-2 in the high psychological distress group were higher than the low group (KSS-J-1, d = 0.61-0.83; KSS-J-2, d = 0.47-0.70), except for the Discrimination subscale in KSS-J-2. CONCLUSION: Both Japanese versions of King's Stigma Scale can be utilized depending on their intended use.

Correlation of reduced social communicational and interactional skills with regional grey matter volumes in schizophrenia patients.

OBJECTIVE: Recent studies have detected similarities between autism spectrum disorder and schizophrenia. We investigated structural abnormalities associated with autistic-like traits in patients with schizophrenia by voxel-based morphometry. METHODS: Patients with schizophrenia and healthy subjects were evaluated by the adult version of the social responsiveness scale (SRS-A), which is sensitive to autistic traits and symptoms even under subthreshold conditions, and magnetic resonance imaging. RESULTS: There were significant decreases in the anterior cingulate cortex, bilateral hippocampi, cerebellums, and right insula of patients with schizophrenia, compared with healthy subjects. We found significant negative correlations of the social communication and interaction (SCI) score, a subscale of SRS-A, with grey matter volume in the left posterior superior temporal region of schizophrenia patients. When subscales of SCI were examined separately in schizophrenic patients, negative correlations were observed between the social cognition score and the volumes of the left posterior superior temporal region, and between social motivation and the posterior cingulate cortex. CONCLUSION: We found significant negative correlation between the SCI score and the grey matter volume in the left posterior superior temporal region of schizophrenia patients. This area was the region affected in previous studies of autistic spectrum disorders. Further, this area was associated with the theory of mind. Schizophrenia patients not necessarily show the impairment of SCI, nor this correlated region was not always the point with schizophrenia-specific change. However, we reveal the relationship between the left posterior superior temporal gyrus and the severity of the SCI in schizophrenia by using with SRS-A.

Association of body mass index-related single nucleotide polymorphisms with psychiatric disease and memory performance in a Japanese population.

OBJECTIVE: Obesity is a risk factor for psychiatric diseases. Recently, a number of single nucleotide polymorphisms (SNPs) have been shown to be related to body mass index (BMI). In this study, we investigated the association of BMI-related SNPs with psychiatric diseases and one of their endophenotypes, memory performance, in a Japanese population. METHODS: The subjects were 1624 patients with one of three psychiatric diseases (799 patients with major depressive disorder, 594 with schizophrenia, and 231 with bipolar disorder) and 1189 healthy controls. Memory performance was assessed using the Wechsler Memory Scale - Revised (WMS-R). Genomic DNA was prepared from venous blood and used to genotype 23 BMI-related SNPs using the TaqMan 5'-exonuclease allelic discrimination assay. We then analysed the relationships between the SNPs and psychiatric disease and various subscales of the WMS-R. RESULTS: Three SNPs (rs11142387, rs12597579, and rs6548238) showed significant differences in the genotype or allele frequency between patients with any psychiatric diseases and controls. Furthermore, six SNPs (rs11142387, rs12597579, rs2815752, rs2074356, rs4776970, and rs2287019) showed significant differences in at least one subscale of the WMS-R depending on the genotypes of the healthy controls. Interestingly, rs11142387 near the Kruppel-like factor 9 (KLF9) was significantly associated with psychiatric disease and poor memory function. CONCLUSIONS: We identified three and six BMI-related SNPs associated with psychiatric disease and memory performance, respectively. In particular, carrying the A allele of rs11142387 near KLF9 was found to be associated with psychiatric disease and poor memory performance, which warrants further investigations.

Effects of ankyrin 3 gene risk variants on brain structures in patients with bipolar disorder and healthy subjects.

AIM: The intronic single-nucleotide polymorphism rs10994336 of the ankyrin 3 gene (ANK3 ) is one of the genome-wide supported risk variants for bipolar disorder (BD), and the T-allele of rs10761482 is also reported to have relevance to BD. We investigated the effect of ANK3 rs10761482 genetic variation on brain structure. METHODS: Subjects were 43 BD patients and 229 healthy volunteers. We evaluated the effects of ANK3 rs10761482 genetic variation on diagnosis, and of the genotype-by-diagnosis interaction on the brain structure and the degree of age-related brain atrophy on magnetic resonance imaging data evaluated by voxel-based morphometry. RESULTS: BD patients showed significantly lower fractional anisotropy value in the bilateral parietal regions, left fronto-occipital fasciculus, and corpus callosum, compared to healthy subjects. Further, we found considerable decreases of fractional anisotropy in the forceps minor in non-T-allele BD patients compared with the T-carrier patient group. We also found significant lessening of age-related brain atrophy in the T-allele carrier groups compared with the non-T-allele carrier groups in the area around the cerebrospinal space, cingulate cortices, and cerebellum. CONCLUSION: Our results suggest the influence of the ANK3 on age-related brain atrophy. The ankyrin 3 genotype may be associated with pathogenesis of age-related neurodegeneration, and, in part, of BD.

Biochemical markers subtyping major depressive disorder.

The pathophysiology of major depressive disorder (MDD) remains elusive, and there is no established biochemical marker used in the daily clinical setting. This situation may result in part from the heterogeneity of MDD, which might include heterogeneous subgroups with different biological mechanisms. In this review, we discuss three promising biological systems/markers to potentially subtype MDD: the dopamine system, the hypothalamic-pituitary-adrenal axis, and chronic inflammatory markers. Several lines of evidence suggest that a facet of MDD is a dopamine agonist-responsive subtype. Focusing on the hypothalamic-pituitary-adrenal axis, depressive spectrum disorders show hypercortisolism to hypocortisolism, which could be detected by hormonal challenge tests, such as the dexamethasone/corticotrophin-releasing hormone test. Finally, accumulating evidence suggests that at least some MDD patients show characteristics similar to those of chronic inflammatory diseases, including neuroinflammatory markers and reduced tryptophan due to the increased activation of the tryptophan-kynurenine pathway. Future studies should examine the inter-relations between these systems/markers to subtype and integrate the pathophysiology of MDD.

Personality in remitted major depressive disorder with single and recurrent episodes assessed with the Temperament and Character Inventory.

AIM: Previous studies consistently reported increased harm avoidance (HA) assessed with the Temperament and Character Inventory (TCI) in patients with major depressive disorder (MDD). However, such findings may have been related with depression severity and number of depressive episodes. The aims of the present study were twofold: to examine TCI personality profile in remitted MDD (DSM-IV) patients and to compare TCI personality between MDD patients with single episode (SGL-MDD) and those with recurrent episodes (REC-MDD) in order to elucidate personality profile associated with recurrence. METHODS: TCI was administered to 86 outpatients with remitted SGL-MDD (12 male and 17 female patients; mean age 43.2 ± 12.1 years) and REC-MDD (26 male and 31 female patients; 40.3 ± 11.6 years), and 529 healthy controls (225 men and 304 women; 43.4 ± 15.5 years), matched for age, sex and education years. Logistic regression analyses were performed in which single/recurrent episodes of depression were the dependent variable and age, sex, age of onset, family history of psychiatric disease and TCI scores were entered as possible predictors. RESULTS: The remitted MDD patients had significantly higher scores on HA (P < 0.001) and lower scores on self-directedness (P < 0.001), compared with the controls. HA (P = 0.03), its subscore, fatigability (P = 0.03), and family history of psychiatric disease were found to be positive predictors for recurrence. CONCLUSION: There are differences in personality profile between remitted MDD patients and controls, and between remitted REC-MDD and SGL-MDD patients, suggesting that they are trait markers. HA and fatigability might be useful to assess risk for recurrence of depression.

White matter abnormalities in major depressive disorder with melancholic and atypical features: A diffusion tensor imaging study.

AIM: The DSM-IV recognizes some subtypes of major depressive disorder (MDD). It is known that the effectiveness of antidepressants differs among the MDD subtypes, and thus the differentiation of the subtypes is important. However, little is known as to structural brain changes in MDD with atypical features (aMDD) in comparison with MDD with melancholic features (mMDD), which prompted us to examine possible differences in white matter integrity assessed with diffusion tensor imaging (DTI) between these two subtypes. METHODS: Subjects were 21 patients with mMDD, 24 with aMDD, and 37 age- and sex-matched healthy volunteers whose DTI data were obtained by 1.5 tesla magnetic resonance imaging. We compared fractional anisotropy and mean diffusivity value derived from DTI data on a voxel-by-voxel basis among the two diagnostic groups and healthy subjects. RESULTS: There were significant decreases of fractional anisotropy and increases of mean diffusivity in patients with MDD compared with healthy subjects in the corpus callosum, inferior fronto-occipital fasciculus, and left superior longitudinal fasciculus. However, we detected no significant difference in any brain region between mMDD and aMDD. CONCLUSION: Our results suggest that patients with MDD had reduced white matter integrity in some regions; however, there was no major difference between aMDD and mMDD.

Effect of L-theanine on glutamatergic function in patients with schizophrenia.

OBJECTIVES: Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. Previous studies suggested that L-theanine affects the glutamatergic neurotransmission and ameliorates symptoms in patients with schizophrenia. The aims of the present study were twofold: to examine the possible effects of L-theanine on symptoms in chronic schizophrenia patients and to evaluate the changes in chemical mediators, including glutamate + glutamine (Glx), in the brain by using 1H magnetic resonance spectroscopy (MRS). METHOD: The subjects were 17 patients with schizophrenia and 22 age- and sex-matched healthy subjects. L-theanine (250 mg/day) was added to the patients' ongoing antipsychotic treatment for 8 weeks. The outcome measures were the Positive and Negative Syndrome Scale (PANSS), Pittsburgh Sleep Quality Index scores and MRS results. RESULTS: There were significant improvements in the PANSS positive scale and sleep quality after the L-theanine treatment. As for MRS, we found no significant differences in Glx levels before and after the 8 week L-theanine treatment. However, significant correlations were observed between baseline density of Glx and change in Glx density by l-theanine. CONCLUSIONS: Our results suggest that L-theanine is effective in ameliorating positive symptoms and sleep quality in schizophrenia. The MRS findings suggest that L-theanine stabilises the glutamatergic concentration in the brain, which is a possible mechanism underlying the therapeutic effect.

Effect of L-theanine on sensorimotor gating in healthy human subjects.

AIM: l-Theanine (N-ethyl-l-glutamine) is an amino acid uniquely found in green tea. Growing evidence has suggested the possible effects of l-theanine on cognition. Previously, we found that l-theanine attenuates MK-801-induced deficit in prepulse inhibition (PPI) in mice. In this study, we examined the effect of l-theanine in increasing the PPI in healthy humans. METHODS: The subjects were 14 healthy adults who underwent PPI testing as a measure of sensorimotor gating 90 min after an oral intake of l-theanine (0, 200, 400, or 600 mg). PPI tests were done by examiners who were blind to the dose. RESULTS: The administration of 200 mg of l-theanine and that of 400 mg, but not 600 mg, significantly increased the % PPI compared to the baseline (0 mg). There was no significant relation between the dose of l-theanine and the startle magnitude or the habituation of startle response. The plasma concentrations of l-theanine correlated with the dose of l-theanine. CONCLUSION: The observed effect with 200-400 mg of l-theanine on PPI suggested that l-theanine at a particular dose range increases sensorimotor gating in humans.