Distinct proteomic profiles in prefrontal subareas of elderly major depressive disorder and bipolar disorder patients.

We investigated for the first time the proteomic profiles both in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) of major depressive disorder (MDD) and bipolar disorder (BD) patients. Cryostat sections of DLPFC and ACC of MDD and BD patients with their respective well-matched controls were used for study. Proteins were quantified by tandem mass tag and high-performance liquid chromatography-mass spectrometry system. Gene Ontology terms and functional cluster alteration were analyzed through bioinformatic analysis. Over 3000 proteins were accurately quantified, with more than 100 protein expressions identified as significantly changed in these two brain areas of MDD and BD patients as compared to their respective controls. These include OGDH, SDHA and COX5B in the DLPFC in MDD patients; PFN1, HSP90AA1 and PDCD6IP in the ACC of MDD patients; DBN1, DBNL and MYH9 in the DLPFC in BD patients. Impressively, depending on brain area and distinct diseases, the most notable change we found in the DLPFC of MDD was 'suppressed energy metabolism'; in the ACC of MDD it was 'suppressed tissue remodeling and suppressed immune response'; and in the DLPFC of BD it was differentiated 'suppressed tissue remodeling and suppressed neuronal projection'. In summary, there are distinct proteomic changes in different brain areas of the same mood disorder, and in the same brain area between MDD and BD patients, which strengthens the distinct pathogeneses and thus treatment targets.

Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches.

BACKGROUND: The immune cell compartment of the mammalian brain changes dramatically and peripheral T cells infiltrate the brain parenchyma during normal aging. However, the mechanisms underlying age-related T cell infiltration in the central nervous system remain unclear. RESULTS: Chronic inflammation and peripheral T cell infiltration were observed in the subventricular zone of aged mice. Cell-cell interaction analysis revealed that aged microglia released CCL3 to recruit peripheral CD8+ memory T cells. Moreover, the aged microglia shifted towards a pro-inflammation state and released TNF-α to upregulate the expression of VCAM1 and ICAM1 in brain venous endothelial cells, which promoted the transendothelial migration of peripheral T cells. In vitro experiment reveals that human microglia would also transit to a chemotactic phenotype when treated with CSF from the elderly. CONCLUSIONS: Our research demonstrated that microglia play an important role in the aging process of brain by shifting towards a pro-inflammation and chemotactic state. Aged microglia promote T cell infiltration by releasing chemokines and upregulating adhesion molecules on venous brain endothelial cells.

High concentrations of serum interleukin-6 and interleukin-8 in patients with bipolar disorder.

Immune system dysregulation plays a key role in the physiopathology of bipolar disorder (BD) and major depressive disorder (MDD). However, whether interleukins might be biomarkers to distinguish these 2 affective disorders is unclear. Here, we assessed the differences in serum levels of interleukin 6 (IL-6) and interleukin 8 (IL-8) as well as C-reactive protein (CRP) in patients with MDD and BD. In total, we enrolled 21 MDD patients, 26 BD patients, and 20 healthy controls. We collected a total of 35 samples from BD patients in 3 different phases, depression phase, manic phase, and remission stage, and 27 samples from MDD patients in acute and remission phases. Serum IL-6 and IL-8 levels were assessed with solid phase sandwich ELISA-based quantitative arrays, and CRP levels were determined with an automatic analyzer. Both serum IL-6 and IL-8 levels were elevated in BD patients but not MDD patients. Subgroup analysis indicated elevated serum IL-6 in both the depression and manic phases in BD patients. The serum CRP levels did not change in either BD or MDD patients. However, sex differences in CRP concentrations were observed in healthy controls. Furthermore, there were linear correlations between the CRP levels and Bech-Rafaelsen Mania Rating Scale (BRMS) scores in BD patients. IL-6 and IL-8 levels may serve as biomarkers to differentiate between MDD and BD patients, even when the clinical manifestations are atypical. IL-6 may be used for the differential diagnosis of MDD and depressive episodes in BD.

The changes in, and relationship between, plasma nitric oxide and corticotropin-releasing hormone in patients with major depressive disorder.

There is strong evidence of roles of the hypothalamus-pituitary-adrenal axis and nitric oxide (NO) synthase-NO system in depression, but the relationship between them is unknown. The aim of this study, therefore, was to elucidate whether there is any correlation between NO and corticotropin-releasing hormone (CRH) in major depressive disorder (MDD) patients. In 16 outpatients with MDD and 18 healthy controls, the plasma amino acids citrulline (Cit) and arginine (Arg) were determined by high-performance liquid chromatography, and CRH levels was measured by radioimmunoassay. The Cit/Arg ratio was calculated as an index of NO synthesis. Correlations between NO and CRH were examined with the Spearman test. Before treatment, no significant correlation was observed between the plasma NO level and CRH levels in MDD patients. The plasma NO levels were significantly higher in MDD patients. A significant correlation was found between NO levels and Hamilton Depression Rating Scale (HAMD) scores in MDD patients. The plasma CRH levels were significantly higher in MDD patients than in controls. After monotherapy for 2 months, the NO levels had dramatically declined but were also higher than those in the controls. This study is the first report of the absence of a significant correlation between plasma NO and CRH levels, although both levels are elevated in MDD patients. Furthermore, the strong links between the plasma NO levels and the HAMD scores, as well as the increased NO reduction after remission, suggest that NO plays a key role in depression and may be an indicator of therapeutic success.

Efficacy and tolerability of vilazodone for major depressive disorder: evidence from phase III/IV randomized controlled trials.

Vilazodone is a new molecule approved for major depressive disorder (MDD). This report focuses on the efficacy and tolerability of vilazodone for MDD. MEDLINE, EMBASE, and Cochrane Library were searched. A total of 1,930 patients from four trials were included. A significant improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score was seen as early as week 2 (P<0.01) in vilazodone-treated patients. The results showed a higher rate of MADRS response with vilazodone compared with placebo (P<0.001). There were also greater improvements in the Hamilton Rating Scale for Anxiety as well as the Clinical Global Impressions (severity of illness and improvement of illness) scores from baseline in vilazodone-treated patients compared to placebo patients (P<0.001). Discontinuation rates due to adverse events were higher with vilazodone than placebo (P=0.0002). The most common adverse events of vilazodone were vomiting, nausea, diarrhea, insomnia, somnolence, dizziness, and dry mouth (P<0.05). Treatment-related effects on sexual function were mild compared to placebo in men (P=0.03). In conclusion, 40 mg/day of vilazodone had a rapid onset of response and showed good improvement in anxiety symptoms as well as good tolerability during short-term treatment (8-10 weeks) for MDD. Further studies should focus on the efficacy and tolerability of vilazodone over a longer duration and should utilize active comparators.

Clinical and MRI evaluation of anxiety as the first symptom of sporadic Creutzfeldt-Jakob disease: A case report.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare, transmissible prion disease of the brain, characterized by prominent neurological symptoms and progressive dementia. Early psychiatric manifestations as an initial or sole symptom of sCJD are relatively rare. The current report describes an elderly female patient with sCJD demonstrating anxiety as an initial symptom. The present patient was initially diagnosed with adjustment disorder and anxiety; however, the rapid deterioration of the patient's cognitive and neurological functioning led to a diagnosis of sCJD. Diffusion-weighted magnetic resonance images of the brain supported a diagnosis of sCJD, and it was posited that the abnormalities of gray matter that were observed within the bilateral cingulate cortex may be the pathophysiological basis of the anxiety associated with this case of sCJD. The patient eventually succumbed to inhalational bronchopneumonia 5 months after anxiety onset. The present case report emphasizes the importance of secondary causes of anxiety symptoms in elderly patients, and indicates that brain DWI is a non-invasive and useful examination in the early diagnosis of sCJD.

Olanzapine-valproate combination versus olanzapine or valproate monotherapy in the treatment of bipolar I mania: a randomized controlled study in a Chinese population group.

BACKGROUND: Bipolar disorder (BP) is a mental illness that has a high social burden estimated by disability-adjusted life years. In the present study, we investigated the efficacy of olanzapine-valproate combination therapy versus olanzapine or valproate monotherapy in the treatment of bipolar I mania in a Chinese population group. SUBJECTS AND METHODS: Patients aged 19-58 years who had had an acute manic episode of BP were enrolled in the present study and randomly assigned to receive 600 mg sodium valproate daily (group A), 10 mg olanzapine daily (group B), or a combination of 600 mg olanzapine and 10 mg sodium valproate daily (group C) for 4 weeks. The primary outcome was reduction in Young Mania Rating Scale (YMRS) scores. The secondary outcome was assessed with the Clinical Global Impression - Bipolar (CGI-BP) scale. Adverse reactions, such as weight gain, sleepy, and dizziness were also evaluated. Statistical analysis was carried out on a per-protocol basis. RESULTS: Patients in groups B and C showed significant improvement in YMRS scores compared with those in group A (P<0.01) during weeks 1-4 of treatment. Patients in group C showed significant improvement in YMRS scores compared with those in group B (P<0.01) only after 4 weeks of treatment. Furthermore, after 3-4 weeks of treatment, patients in groups B and C showed significantly greater improvement in CGI-BP scale scores compared with group A (P<0.05), while Group C demonstrated significantly greater improvement in CGI-BP scale scores than group B (P<0.01). No significant difference existed in extrapyramidal reactions among these groups. Adverse reactions, including weight gain, drowsiness, dizziness, and constipation, were stronger in groups B and C than in group A (P<0.05). CONCLUSION: The combination therapy with olanzapine and sodium valproate had higher efficacy than monotherapy in patients with bipolar mania, which provides a crucial insight of the treatment regimen during clinical practice.

Nitric oxide synthase and nitric oxide alterations in chronically stressed rats: a model for nitric oxide in major depressive disorder.

Nitric oxide (NO) and NO synthase-1 (NOS1) are involved in the stress response and in depression. We compared NOS-NO alterations in rats exposed to chronic unpredictable stress (CUS) with alterations in major depressive disorder (MDD) in humans. In the hypothalamus of male CUS rats we determined NOS activity, and in the paraventricular nucleus (PVN) we determined NOS1-immunoreactive (ir) cell densities and co-localization of NOS1 with stress-related neuropeptides corticotropin-releasing hormone (CRH), vasopressin (AVP) or oxytocin (OXT). We measured plasma NO levels and cortisol in male medicine-naïve MDD patients and plasma NO and corticosterone (CORT) in CUS rats. In the CUS rat total NOS activity in the hypothalamus (P=0.018) and NOS1-ir cell density in the PVN were both significantly decreased (P=0.018), while NOS1 staining was mainly expressed in OXT-ir neurons in this nucleus. Interestingly, plasma NO levels were significantly increased both in male CUS rats (P=0.001) and in male MDD patients (P<0.001). Plasma CORT levels were increased in male CUS rats (P=0.001), while male MDD patients did not show a significant change in cortisol levels. In conclusion, the changes in plasma and hypothalamic NOS-NO of CUS rats and MDD were similar. The male CUS rat model may thus help us with our investigation of the mechanism underlying NOS-NO alterations in depression.

Decreased plasma neuroactive amino acids and increased nitric oxide levels in melancholic major depressive disorder.

BACKGROUND: Amino acid neurotransmitters and nitric oxide (NO) are involved in the pathogenesis of major depressive disorder (MDD). Here we want to establish whether changes in their plasma levels may serve as biomarker for the melancholic subtype of this disorder. METHODS: Plasma levels of glutamic acid (Glu), aspartic acid (Asp), glycine (Gly), gamma-aminobutyric acid (GABA), and NO were determined in 27 medicine-naïve melancholic MDD patients and 30 matched controls. Seven of the MDD patients participated also in a follow-up study after 2 months' antidepressant treatment. The relationship between plasma and cerebral-spinal fluid (CSF) levels of these compounds was analyzed in an additional group of 10 non-depressed subjects. RESULTS: The plasma levels of Asp, Gly and GABA were significantly lower whereas the NO levels were significantly higher in melancholic MDD patients, also after 2 months of fluoxetine treatment. In the additional 10 non-depressed subjects, no significant correlation was observed between plasma and CSF levels of these compounds. CONCLUSION: These data give the first indication that decreased plasma levels of Asp, Gly and GABA and increased NO levels may serve as a clinical trait-marker for melancholic MDD. The specificity and selectivity of this putative trait-marker has to be investigated in follow-up studies.

Effects of curcumin on glucose metabolism in the brains of rats subjected to chronic unpredictable stress: a 18 F-FDG micro-PET study.

BACKGROUND: Chronic unpredictable stress (CUS) can cause behavioral and physiological abnormalities that are important to the prediction of symptoms of depression that may be associated with cerebral glucose metabolic abnormalities. Curcumin showed potential antidepressant effects, but whether or not it can reverse cerebral functional abnormalities and so ameliorate depression remains unknown. METHODS: To investigate the effects of curcumin on brain activity in CUS rats, rats were subjected to 3 weeks of CUS and then treated with curcumin orally at a dose of 40 mg/kg/day for one month. 18 F fluorodeoxyglucose (18 F-FDG)-micro positron emission tomography (micro-PET) neuroimaging was used to detect changes in cerebral metabolism. Body weight, sucrose preference, and open field tests were used to record depressive behaviors during CUS and after curcumin treatment. RESULTS: Three weeks of CUS significantly decreased body weight, sucrose preference, sucrose consumption, total distance travelling, and the number of rearing events. It also induced metabolic alterations in several parts of the brain, showing increased glucose metabolism in the right hemisphere. After curcumin treatment for one month, sucrose preference, sucrose consumption, total distance travelling, and the number of rearing events returned to normal levels. Curcumin treatment also induced strong deactivation of the left primary auditory cortex and activation of amygdalohippocampal cortex. CONCLUSION: Curcumin was found to ameliorate the abnormalities in the behavior and brain glucose metabolism caused by CUS, which may account for its antidepressive effects.

[Alterations of plasma aspartic acid, glycine and asparagine levels in patients with major depressive disorder].

OBJECTIVE: To evaluate the changes of plasma levels of the excitatory amino acid neurotransmitter aspartic acid (Asp), inhibitory neurotransmitter glycine (Gly) and asparagine (Asn) in patients with major depressive disorder (MDD). METHODS: Plasma samples were collected from 15 MDD patients (9 males and 6 females, aged 32-64 y) and 14 healthy subjects (7 males and 7 females, aged 30-65 y); and also collected from 7 MDD patients (5 males and 2 females) 2 months after antidepressant treatment. The plasma levels of amino acids were determined by high performance liquid chromatography with fluorescence detection method. RESULTS: Plasma Asp and Gly levels were significantly lower in MDD patients than those in controls (P<0.04). There were positive correlations between plasma levels of Gly and Asp, and between Gly and Asn (P<0.005) in the control group; while in MDD patients, a significant positive correlation was found only between plasma levels of Gly and of Asp (P<0.001). MDD patients did not show significant changes in plasma Asp, Asn and Gly levels after antidepressant treatment compared to those before treatment. CONCLUSION: The reduced plasma Asp and Gly levels may serve as a clinical biomarker for MDD.

Alexithymia and personality disorder functioning styles in paranoid schizophrenia.

OBJECTIVES: Personality disorder functioning styles might contribute to the inconclusive findings about alexithymic features in schizophrenia. We therefore studied the relationship between alexithymia and personality styles in paranoid schizophrenia. METHODS: We administered the Chinese versions of the Toronto Alexithymia Scale (TAS-20), the Parker Personality Measure (PERM), the Positive and Negative Syndrome Scale as well as the Hamilton Anxiety and Depression Scales to 60 paranoid schizophrenia patients and 60 healthy control subjects. RESULTS: Patients scored significantly higher on the Positive and Negative Syndrome Scale, TAS 'difficulty identifying feelings' and 'difficulty describing feelings', Hamilton Depression Scale and most PERM scales. In healthy subjects, difficulty identifying feelings predicted the PERM 'dependent' style, and the Hamilton Anxiety Scale predicted difficulty identifying feelings and difficulty describing feelings. In patients, difficulty identifying feelings nonspecifically predicted all the PERM scales; by contrast, the PERM 'antisocial' style predicted difficulty identifying feelings, the 'avoidant' style predicted difficulty describing feelings, and the 'histrionic' and 'paranoid (-)' styles predicted 'externally oriented thinking'. CONCLUSIONS: Personality disorder functioning styles - instead of anxiety, depression, psychotic symptoms or disease duration - were specifically associated with alexithymia scales in our patients, which sheds light on a cognitive-personological substrate in paranoid schizophrenia on the one hand, and calls for a longitudinal design to discover how premorbid or postacute residual personality styles contribute to the sluggish disorder on the other.