Plasma Levels of the Cytokines B Cell-Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) in Schizophrenia, Bipolar, and Major Depressive Disorder: A Cross Sectional, Multisite Study.

BACKGROUND: Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. METHODS: We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. RESULTS: Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen's d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10). CONCLUSIONS: These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.

Sex difference in cerebrospinal fluid/blood albumin quotients in patients with schizophreniform and affective psychosis.

BACKGROUND: The importance of cerebrospinal fluid (CSF) diagnostics for psychiatry is growing. The CSF/blood albumin quotient (QAlb) is considered to be a measure of the blood-CSF barrier function. Recently, systematically higher QAlb in males than in females was described in neurological patients. The aim of this study was to investigate whether a sex difference could also be detected in a well-characterized psychiatric cohort. METHODS: The patient cohort comprised 989 patients, including 545 females and 444 males with schizophreniform and affective syndromes who underwent CSF diagnostics, including QAlb measurement. The basic CSF findings and antineuronal autoantibody data of this cohort have already been published. This re-analysis employed analysis of covariance with age correction for QAlb mean values and chi2-testing for the number of increased age-corrected QAlb levels to investigate sex differences in QAlb. RESULTS: The QAlb levels were elevated above reference levels by 18% across all patients, and a comparison between male and female patients revealed a statistically significant sex difference, with increased values in 26% of male patients and a corresponding rate of only 10% in female patients (chi2 = 42.625, p < 0.001). The mean QAlb values were also significantly higher in males (6.52 ± 3.69 × 10-3) than in females (5.23 ± 2.56 × 10-3; F = 52.837, p < 0.001). DISCUSSION: The main finding of this study was a significantly higher QAlb level in male compared to female patients with psychiatric disorders, complementing previously described sex differences in neurological patient cohorts. This result indicates bias from some general factors associated with sex and could be partly explained by sex differences in body height, which is associated with spine length and thus a longer distance for CSF flow within the subarachnoid space down the spine from the occipital area to the lumbar puncture site in males compared to females. Hormonal influences caused by different estrogen levels and other sex-specific factors could also play a relevant role. The significance of the study is limited by its retrospective design, absence of a healthy control group, and unavailability of exact measures of spine length.

A miRNome analysis of drug-free manic psychotic bipolar patients versus healthy controls.

The lifetime presence of psychotic symptoms is associated with more clinical severity, poorer outcome and biological changes in patients affected by bipolar disorder (BD). Epigenetic mechanisms have been evoked to explain the onset of psychotic symptoms in BD as well as the associated biological changes. The main objective of the present study was to evaluate the expression profiles of circulating microRNAs (miRNAs) in drug-free manic psychotic bipolar patients versus healthy controls (HC), to identify possible non-invasive molecular markers of the disorder. 15 drug-free manic psychotic bipolar patients and 9 HC were enrolled and 800 miRNAs expression profile was measured by Nanostring nCounter technology on plasma samples and validated through qPCR. Overall, twelve miRNAs showed a significantly altered expression between the two groups (p < 0.05). Functional annotation of predicted miRNAs targets by MultiMIR R tool showed repression in bipolar patients of genes with a role in neurodevelopment and neurogenesis, and upregulation of genes involved in metabolism regulation. We identified a signature of circulating miRNA characteristic of manic psychotic bipolar patients, suggesting a possible role in neurodevelopment and metabolic processes regulation.

Serum neurofilament light chain is a discriminative biomarker between frontotemporal lobar degeneration and primary psychiatric disorders.

Due to the significant clinical overlap between frontotemporal lobar degeneration (FTLD) spectrum disorders and late-onset primary psychiatric disorders (PPD), diagnostic biomarkers reflecting the different underlying pathophysiologies are urgently needed. Thus far, elevated cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) have been reported in various neurological conditions. Furthermore, recent advancements in ultrasensitive analytical methods (e.g., single molecule array, Simoa) have enabled sensitive and less invasive NfL detection also from blood samples. In this study, we evaluated the potential of serum NfL (sNfL) as a diagnostic tool between FTLD and PPD. We analyzed sNfL levels with Simoa from 125 participants including patients from FTLD (n = 91) and PPD (n = 34) spectra. Our results show that sNfL levels are higher in the FTLD group compared to the PPD group as well as in separate clinical subtypes of FTLD compared to different psychiatric manifestations (i.e., mood or psychotic disorders). At single-subject level, discrimination between FTLD and PPD was possible with 80% sensitivity and 85% specificity (AUC = 0.850, 95% CI 0.776-0.923), and between behavioral variant frontotemporal dementia (bvFTD) and PPD with 79% sensitivity and 85% specificity (AUC = 0.830, 95% CI 0.732-0.908). These findings highlight the potential of sNfL as a discriminating biomarker for FTLD over PPD in patients with wide-ranging behavioral, psychiatric and cognitive symptoms.

HPA axis in psychotic major depression and schizophrenia spectrum disorders: Cortisol, clinical symptomatology, and cognition.

The Hypothalamic Pituitary Adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance, and a potential role of HPA axis genetic variation in cognition. In schizophrenia differential HPA activity has been found, including higher rates of non-suppression to dexamethasone challenge and higher salivary cortisol levels, which have been a premonitory risk factor for conversion to psychosis in adolescents at risk for developing schizophrenia. The present study investigated the simultaneous roles HPA axis activity and clinical symptomatology play in poor cognitive performance. Patients with major depression with psychosis (PMD) or schizophrenia spectrum disorder (SCZ) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, and overnight hourly blood sampling for cortisol. Cognitive performance did not differ between the clinical groups, though they both performed more poorly than the HC's across a variety of cognitive domains. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher evening cortisol levels than did SCZ and HCs. Cortisol and clinical symptoms, as well as age, sex, and antipsychotic use predicted cognitive performance. Diathesis stress models and their links to symptomatology, cognition, and HPA function are discussed.

An association between YKL-40 and type 2 diabetes in psychotic disorders.

OBJECTIVE: This study examines if YKL-40 is increased in individuals with psychotic disorders and if elevated YKL-40 levels at baseline is associated with subsequent development of type 2 diabetes. METHOD: A total of 1383 patients with a diagnosis of schizophrenia or affective psychosis and 799 healthy controls were recruited in the period 2002-2015. Plasma YKL-40 and metabolic risk factors were measured and medication was recorded. Using national registry data, association between baseline risk factors and later development of type 2 diabetes was assessed using Cox proportional hazards models. RESULTS: Plasma YKL-40 was higher in patients vs. healthy controls also after adjusting for metabolic risk factors, with no difference between the schizophrenia and affective psychosis groups. Patients were diagnosed with type 2 diabetes at a significantly younger age. Multivariate Cox regression analyses showed that elevated YKL-40 (hazard ratio (HR) = 5.6, P = 0.001), elevated glucose (HR = 3.6, P = 0.001), and schizophrenia diagnosis (HR = 3.0, P = 0.014) at baseline were associated with subsequent development of type 2 diabetes. CONCLUSIONS: Patients with psychotic disorders have at baseline increased levels of YKL-40 beyond the effect of comorbid type 2 diabetes and metabolic risk factors. Elevated YKL-40 level at baseline is associated with later development of type 2 diabetes.

Peroxisome proliferator-activated receptor gamma co-activator-1 alpha in depression and the response to electroconvulsive therapy.

BACKGROUND: The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), termed the 'master regulator of mitochondrial biogenesis', has been implicated in stress and resilience to stress-induced depressive-like behaviours in animal models. However, there has been no study conducted to date to examine PGC-1α levels in patients with depression or in response to antidepressant treatment. Our aim was to assess PGC-1α mRNA levels in blood from healthy controls and patients with depression pre-/post-electroconvulsive therapy (ECT), and to examine the relationship between blood PGC-1α mRNA levels and clinical symptoms and outcomes with ECT. METHODS: Whole blood PGC-1α mRNA levels were analysed in samples from 67 patients with a major depressive episode and 70 healthy controls, and in patient samples following a course of ECT using quantitative real-time polymerase chain reaction (qRT-PCR). Exploratory subgroup correlational analyses were carried out to determine the relationship between PGC-1α and mood scores. RESULTS: PGC-1α levels were lower in patients with depression compared with healthy controls (p = 0.03). This lower level was predominantly accounted for by patients with psychotic unipolar depression (p = 0.004). ECT did not alter PGC-1α levels in the depressed group as a whole, though exploratory analyses revealed a significant increase in PGC-1α in patients with psychotic unipolar depression post-ECT (p = 0.045). We found no relationship between PGC-1α mRNA levels and depression severity or the clinical response to ECT. CONCLUSIONS: PGC-1α may represent a novel therapeutic target for the treatment of depression, and be a common link between various pathophysiological processes implicated in depression.

Low plasma concentrations of N-methyl-d-aspartate receptor subunits as a possible biomarker for psychosis.

BACKGROUND: N-methyl-d-aspartate receptor (NMDAR) has been largely implicated in the neurobiology of schizophrenia and other psychosis. Aiming to evaluate their potential as peripheral biomarkers for psychosis, we quantified the plasma concentrations of NR1 and NR2 NMDAR subunits of first-episode psychosis patients in their first contact with mental health services due to psychotic symptoms, compared with siblings and matched community-based controls. METHODS: The quantifications of NR1 and NR2 plasma concentrations were performed by ELISA. Data were analysed by nonparametric tests and Receiver Operating Curve (ROC) analysis. RESULTS: We included 166 first-episode psychosis patients (mean age = 30.3 ±â€¯12.2 years; 64% men), with the diagnosis of schizophrenia spectrum (n = 84), bipolar disorder (n = 51) and psychotic depression (n = 31), 76 siblings (mean age = 31.5 ±â€¯11.0 years; 30.3% men) and 166 healthy community-based controls (mean age = 31.4 ±â€¯12.0 years; 63.9% men). NMDAR subunits were significantly lower in patients compared with siblings and controls (p < 0.001), except by NR1 plasma concentrations of bipolar patients compared with siblings and controls. NR1 plasma concentrations lower than 17.65 pg/ml (AUC = 0.621) showed sensitivity of 42.8%, specificity of 84.3%, positive predictive value (PPV) of 73.2% and negative predictive value (NPV) of 59.6%. Individuals with NR2 plasma concentrations lower than 2.92 ng/ml (AUC = 0.801) presented a 10.61-fold increased risk of psychosis, with a sensibility of 71.9%, specificity of 80.6%, PPV of 79.0% and NPV of 73.9%. CONCLUSIONS: This is the first study reporting the measurement and the reduction of NR1 and NR2 NMDAR subunits plasma concentrations in psychiatric disorders. In particular, the NR2 subunit may be a possible plasma biomarker for psychosis.

Serum kynurenic acid is reduced in affective psychosis.

A subgroup of individuals with mood and psychotic disorders shows evidence of inflammation that leads to activation of the kynurenine pathway and the increased production of neuroactive kynurenine metabolites. Depression is hypothesized to be causally associated with an imbalance in the kynurenine pathway, with an increased metabolism down the 3-hydroxykynurenine (3HK) branch of the pathway leading to increased levels of the neurotoxic metabolite, quinolinic acid (QA), which is a putative N-methyl-d-aspartate (NMDA) receptor agonist. In contrast, schizophrenia and psychosis are hypothesized to arise from increased metabolism of the NMDA receptor antagonist, kynurenic acid (KynA), leading to hypofunction of GABAergic interneurons, the disinhibition of pyramidal neurons and striatal hyperdopaminergia. Here we present results that challenge the model of excess KynA production in affective psychosis. After rigorous control of potential confounders and multiple testing we find significant reductions in serum KynA and/or KynA/QA in acutely ill inpatients with major depressive disorder (N=35), bipolar disorder (N=53) and schizoaffective disorder (N=40) versus healthy controls (N=92). No significant difference was found between acutely ill inpatients with schizophrenia (n=21) and healthy controls. Further, a post hoc comparison of patients divided into the categories of non-psychotic affective disorder, affective psychosis and psychotic disorder (non-affective) showed that the greatest decrease in KynA was in the affective psychosis group relative to the other diagnostic groups. Our results are consistent with reports of elevations in proinflammatory cytokines in psychosis, and preclinical work showing that inflammation upregulates the enzyme, kynurenine mono-oxygenase (KMO), which converts kynurenine into 3-hydroxykynurenine and quinolinic acid.

Reduced levels of vasopressin and reduced behavioral modulation of oxytocin in psychotic disorders.

Oxytocin (OT) and arginine vasopressin (AVP) exert robust influence on social affiliation and specific cognitive processes in healthy individuals. Abnormalities in these neuroendocrine systems have been observed in psychotic disorders, but their relation to impairments in behavioral domains that these endocrines modulate is not well understood. We compared abnormalities of OT and AVP serum concentrations in probands with schizophrenia (n = 57), schizoaffective disorder (n = 34), and psychotic bipolar disorder (n = 75); their first-degree relatives without a history of psychosis (n = 61, 43, 91, respectively); and healthy controls (n = 66) and examined their association with emotion processing and cognition. AVP levels were lower in schizophrenia (P = .002) and bipolar probands (P = .03) and in relatives of schizophrenia probands (P = .002) compared with controls. OT levels did not differ between groups. Familiality estimates were robust for OT (h(2) = 0.79, P = 3.97e-15) and AVP (h(2) = 0.78, P = 3.93e-11). Higher levels of OT were associated with better emotion recognition (ß = 0.40, P < .001) and general neuropsychological function (ß = 0.26, P = .04) in healthy controls as expected but not in any proband or relative group. In schizophrenia, higher OT levels were related to greater positive symptom severity. The dissociation of OT levels and behavioral function in all proband and relative groups suggests that risk and illness factors associated with psychotic disorders are not related to reduced OT levels but to a disruption in the ability of physiological levels of OT to modulate social cognition and neuropsychological function. Decreased AVP levels may be a marker of biological vulnerability in schizophrenia because alterations were seen in probands and relatives, and familiality was high.

The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary-adrenal activity in humans with psychotic major depression.

INTRODUCTION: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs). METHODS: Fourteen PMDs, 16 NPMDs, and 19 HCs were admitted to the Stanford University Hospital General Clinical Research Center. Serum cortisol levels were sampled at baseline and every hour from 18:00 to 23:00h, when greatest MR activity is expected, on two consecutive nights. On the second afternoon at 16:00h all subjects were given 0.5mg fludrocortisone. Mean cortisol levels pre- and post-fludrocortisone and percent change in cortisol levels were computed. RESULTS: There were no significant group differences for cortisol at baseline: F(2,47)=.19, p=.83. There were significant group differences for post-fludrocortisone cortisol: F(2,47)=5.13, p=.01, which were significantly higher in PMDs compared to HCs (p=.007), but not compared to NPMDs (p=.18). There were no differences between NPMD's and HC's (p=.61). Also, PMDs had a lower percent change from baseline in cortisol levels at 2200h than NPMDs (p=.01) or HCs (p=.009). CONCLUSIONS: Individuals with psychotic major depression compared to healthy control subjects have diminished feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in response to the mineralocorticoid receptor agonist fludrocortisone. To our knowledge, this is the first study to examine HPA axis response to MR stimulation in major depression (with and without psychosis), and only the third study to demonstrate that exogenously administered fludrocortisone can down-regulate the HPA axis in humans.

Decreased birth weight in psychosis: influence of prenatal exposure to serologically determined influenza and hypoxia.

BACKGROUND: Decreased birth weight (BW) is associated with later psychosis, but the sources of decreased BW for those at risk for psychosis remain unclear. AIM: To determine whether fetal exposure to influenza and/or hypoxia accounts for BW decreases among psychotic cases and controls. METHOD: Subjects were 111 cases diagnosed with schizophrenia or affective psychosis and 333 matched controls from the Collaborative Perinatal Project. Psychiatric diagnoses were ascertained from medical records. Influenza and hypoxia were determined from maternal and cord sera collected at birth. RESULTS: Cases exposed to severe fetal hypoxia or influenza had significantly lower BW compared with unexposed cases and controls, regardless of exposure status. No significant differences in BW were observed among controls based on exposure status. CONCLUSIONS: Decreased BW appears to be a risk factor for psychosis only in the presence of other teratogens. Liability to psychosis likely renders fetuses vulnerable to decreased fetal growth in response to hypoxia and influenza.

Comparing tolerability profile of quetiapine, risperidone, aripiprazole and ziprasidone in schizophrenia and affective disorders: a meta-analysis.

OBJECTIVE: Second-generation antipsychotics (SGAs) are extensively prescribed for psychiatric disorders. Based on clinical observations, schizophrenia (SCZ) and affective disorder (AD) patients can experience different SGA side effects. The expanded use of SGAs in psychiatry suggests a need to investigate whether there is a difference in the incidence and severity of side effects related to diagnosis. METHODS: A comprehensive literature search was conducted to identify studies reporting side effects of four common prescribed SGAs (aripiprazole, quetiapine, risperidone and ziprasidone) in the treatment of SCZ or AD. Randomized controlled trials were included in this study if they administered oral SGAs as a monotherapy, in adult patients. The metabolic and extrapyramidal side effects were collected separately for each group, and then were combined in a meta-analysis. RESULTS: 80 studies were included in the analysis (N = 14,319). Quetiapine treatment induced significantly higher low-density lipoprotein (LDL) and total blood cholesterol mean change in the SCZ group, relative to the AD group. Based on the results, the incidence of extrapyramidal side effects was more frequent in the AD group. Aripiprazole treatment led to significantly more akathisia incidence in the AD group, compared with the SCZ group. CONCLUSION: The results suggest that SCZ patients may be more vulnerable to some SGA-induced metabolic disturbances, in which lifestyle risk factors and possible inherent genetic vulnerabilities may play a role. Most of the studied SGAs caused more movement disorders in AD patients than SCZ. It might be that an antipsychotic induces severity of side effect according to the phenotype.

No correlation between lithium serum levels and psychopathological features during the euthymic interval of patients with recurrent affective disorder.

INTRODUCTION: The aim of this prospective study was to investigate the influence of lithium serum levels on subclinical psychopathological features during the euthymic interval in patients with an affective disorder. METHODS: The study included 54 patients with a recurrent affective disorder undergoing a continuous prophylactic lithium treatment (31 unipolar, 23 bipolar). The observation period lasted for 2 years and included 332 visits. Visits consisted of a detailed interview, a continuous measurement of lithium levels and the collection of validated scales including HAMD, YMRS, CGI, VAMS and the SCL-90R. Several correlations between lithium serum levels and different psychopathological features during the euthymic interval were calculated on an individual patient basis and on a group basis to reveal generally occurring correlations. RESULTS: No generally occurring significant correlations between lithium serum levels and specific psychopathological features were found. Only on a single patient level, 32 significant correlations between lithium level and specific psychopathological features were found, partly indicating a negative and partly indicating a positive influence of higher lithium levels on psychopathological symptoms. Nevertheless, in the group analyses no significant correlations were found. DISCUSSION: Higher lithium levels were not associated with an improved psychopathological status, but they were not associated with a worse status (due to a higher burden of side effects) either. According to the literature there is currently no strong evidence to treat patients with a higher lithium level. It is recommended to start with a lower level and to continue with individual adjustments in accordance to prophylactic efficacy and tolerability.

Measures of glycemic variability and links with psychological functioning.

The goal of this article is to review the recent literature on measures of glycemic variability, links between glycemic variability and psychological functioning, and methods for examining these links. A number of commonly used measures of glycemic variability are reviewed and compared, including recently proposed methods. Frequently used measures of glycemic variability are also discussed in the context of research that uses continuous glucose monitoring for the collection of blood glucose data. The results of previous studies that have examined the link between psychological functioning and glycemic variability within relatively short-term time frames are reviewed. Methods for examining glycemic variability and its link with psychological functioning are discussed so that important research questions can be addressed to aid in understanding the effect of changes in psychological functioning on glycemic variability and vice versa in future research.

Hyperprolactinaemia - a risperidone side-effect.

A 47 year old patient has been treated for psychotic depression for the last 5 years. The illness began manifesting through the symptoms of depressive thoughts, intrapsychic tension, projectivity, derealisation phenomena and pre-psychotic fears. She was treated with a combination of antidepressives, anxiolitics and hypnotics in ambulatory conditions. The therapy applied did not obtain the effects expected due to which an atypical antipsychotic was administered subsequently - risperidone, a 2 mg dose in the evening. After commencing the antipsychotic treatment, the symptoms started to weaken and a steady remission was obtained. Two years after a regular risperidone administration (in combination with fluoxetine, alprazolam and flurazepam) the patient reported some "bleeding" in October 2006. Hormonal blood tests were performed and high prolactin values were registered (2567.0 mIJ/L),due to which a gradual risperidone retractement was indicated. Medicamentous hyperprolactinaemia is a well known side effect of risperidone. A gradual risperidone retractement lead to a lowered and normal prolactin level within a month.

Meta-analysis of the effects of lithium usage on serum creatinine levels.

There is conflicting evidence concerning lithium's effect on renal function. The aim is to clarify whether lithium affects kidney function and at what stage of treatment any effect may occur. Systematic review identified 23 studies split into three groups on which meta-analysis was performed to identify the following: A) lithium's effect on renal function in cross-sectional case-control studies, B) studies of renal function before and after commencement on lithium, C) studies of longer term effect in those already established on lithium therapy. Group A showed a statistically significant increase of 5.7 µmol/L in creatinine in the study population compared with controls. Group B showed a non-statistically significant rise in creatinine (2.9 µmol/L) after a mean follow-up of 86 months. Group C showed a statistically significant increase in creatinine of 7.0 µmol/L over a mean duration of 64 months. An increase in creatinine of an average of 1.6 µmol/L/year on lithium was also identified in this group. Any lithium-associated increase in serum creatinine is quantitatively small and of questionable clinical significance. However, routine renal function monitoring of patients on lithium is essential.

Flow cytometric analysis of T cell subsets in paired samples of cerebrospinal fluid and peripheral blood from patients with neurological and psychiatric disorders.

Recent studies suggest inflammatory mechanisms involved in the pathogenesis of major psychiatric disorders (MPD). T cells play a major role during inflammation, but little is known about T cell subpopulations in the cerebrospinal fluid (CSF). We investigated the frequency of cells positive for the surface markers CD4, CD8, CD25, CD45, CD69, and CD127 in 45 paired cerebrospinal fluid (CSF) and peripheral blood (PB) samples by multiparameter flow cytometry from patients with MPD of the schizophrenic and affective spectrum with normal CSF cell counts and compared them with those from patients with non-inflammatory (NIND), chronic inflammatory (CIND) neurological disorders, and meningitis (MEN). In MEN patients, CD4+ cell frequency in PB, but not in CSF, was significantly increased as compared to CIND and NIND. No difference between patient groups was observed for CD8+. CD4+CD45RO+ double positive cells in PB were significantly lower in CIND than in MEN or NIND. The frequency of CD4+CD25+ cells in PB was significantly higher in MEN than in MPD or CIND. For CSF, the percentage of CD4+CD127(dim) cells was significantly lower in MEN than in MPD. CD4+CD127(dim) in PB and CSF showed overlapping characteristic clusters between MPD and CIND and MEN patients. Overall, the hypothesis of low degree inflammation in a subgroup of MPD is supported. The analysis of lymphocyte subsets in PB and CSF constitutes a novel promising tool to understand underlying pathomechanisms in psychiatric and neurological disorders on an individual case level.

Decreased plasma BDNF level in depressive patients.

BACKGROUND: Recent reports have suggested a pathophysiological role for brain-derived neurotrophic factor (BDNF) in major depressive disorder (MDD). We evaluated plasma levels of BDNF in patients with MDD. METHODS: Plasma BDNF levels were measured in 77 MDD patients and 95 normal controls. The severity of psychiatric symptoms was measured with the Hamilton Depression Rating Scale and the Brief Psychiatric Rating Scale. RESULTS: Plasma BDNF levels were significantly lower in MDD patients than in normal control subjects (p<0.001). Plasma BDNF levels were significantly lower in MDD patients with recurrent episodes than in MDD patients with the first episode or normal controls (p<0.001). Plasma BDNF levels were significantly lower in non-psychotic MDD patients than in psychotic MDD patients or normal controls (p<0.001). Plasma BDNF in suicidal MDD patients were significantly lower than those in non-suicidal MDD patients (p<0.001). LIMITATIONS: We measured only plasma levels of BDNF. However, the cellular sources of BDNF in human plasma are not yet clearly defined. CONCLUSIONS: Our study suggests that there is a decrease in plasma BDNF levels in untreated MDD patients. However, relapsed or recurrent episodes, suicidal behavior, and psychotic features could also affect the plasma levels of BDNF. Further studies are required to understand the source and role of the circulating BDNF in depression.

Hyperlipidemia following treatment with antipsychotic medications.

OBJECTIVE: This study attempted to estimate the relative risk of developing hyperlipidemia after treatment with antipsychotics in relation to no antipsychotic treatment. METHOD: A matched case-control analysis was performed with pharmacy and claims data from California Medicaid (Medi-Cal). Patients were excluded if they were treated for medical disorders or prescribed medications known to increase their risk of hyperlipidemia. Cases were ages 18 to 64 years with schizophrenia, major depression, bipolar disorder, or other affective psychoses and incident hyperlipidemia. Cases were matched to up to six control subjects by age, sex, race, and psychiatric diagnosis. Both groups were prescribed either no antipsychotic medication or had two or more prescriptions for one and only one antipsychotic medication during the 60 days prior to the first indication of hyperlipidemia (cases) or matched index date (controls) in the billing record. Conditional logistic regressions were used to derive odds ratios and 95% confidence intervals (95% CIs) of each antipsychotic medication in relation to no antipsychotic medication. RESULTS: A total of 13,133 incident cases of hyperlipidemia were matched to 72,140 control subjects. As compared with no antipsychotic medication, treatment with clozapine (odds ratio: 1.82, 95% CI: 1.61-2.05), risperidone (odds ratio: 1.53, 95% CI: 1.43-1.64), quetiapine (odds ratio: 1.52, 95% CI: 1.40-1.65), olanzapine (odds ratio: 1.56, 95% CI: 1.47-1.67), ziprasidone (odds ratio: 1.40, 95% CI: 1.19-1.65), and first-generation antipsychotics (odds ratio: 1.26, 95% CI: 1.14-1.39), but not aripiprazole (odds ratio: 1.19, 95% CI: 0.94-1.52) was associated with a significant increase in risk of incident hyperlipidemia. CONCLUSIONS: These findings suggest that most commonly prescribed antipsychotic medications increase the risk of developing hyperlipidemia in patients with schizophrenia or mood disorders.