Decreased levels of serum brain-derived neurotrophic factor in drug-naïve first-episode schizophrenia: relationship to clinical phenotypes

Objective

There is accumulating evidence that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of patients with schizophrenia. Clinical studies show reductions in BDNF in schizophrenic patients treated with first generation antipsychotics or second generation antipsychotics. However, there have been few systematic studies to examine the relationship between BDNF levels and psychopathology in first-episode and drug-naïve patients with schizophrenia.

Materials and methods

Serum BDNF levels were determined using enzyme-linked-immunosorbent assay (ELISA) in the serum of 88 never-medicated first-episode and 90 healthy controls subjects matched for age and gender. The schizophrenia symptomatology and the depressive symptoms were assessed by the positive and negative syndrome scale (PANSS) and the Hamilton rating (HAMD) scale for depression.

Results

The results showed that BDNF levels were significantly lower in first-episode patients with schizophrenia than in healthy control subjects (9.0?±?4.2 ng/ml vs 12.1?±?2.2 ng/ml; F?=?37.6; df?=?1, 176; p?<?0.0001). A significant positive correlation between BDNF levels and PANSS positive subscore was observed (r?=?0.29; df?=?88; p?=?0.008). Furthermore, higher BDNF levels were observed in patients with paranoid subtype of schizophrenia. However, no significant correlation between BDNF and HAMD total score was found.

Conclusion

Low BDNF levels at the onset of psychosis suggest that it may contribute to the pathogenesis of schizophrenia and perhaps, could be a candidate biological marker for positive symptoms.     

Anterior Cingulate Glutamate Levels Related to Clinical Status Following Treatment in First-Episode Schizophrenia

Many patients with schizophrenia show a limited symptomatic response to treatment with dopaminergic antipsychotics. This may reflect the additional involvement of non-dopaminergic neurochemical dysfunction in the pathophysiology of the disorder. We tested the hypothesis that brain glutamate levels would differ between patients with first-episode psychosis who were symptomatic compared with those with minimal symptoms following antipsychotic treatment. Proton magnetic resonance spectroscopy (1H-MRS) spectra were acquired at 3 Tesla in the anterior cingulate cortex and left thalamus in 15 patients with first-episode psychosis in symptomatic remission, and 17 patients with first-episode psychosis who were still symptomatic following at least one course of antipsychotic treatment. Metabolite levels were estimated in ratio to creatine (Cr) using LCModel. Levels of glutamate/Cr in the anterior cingulate cortex were significantly higher in patients who were still symptomatic than in those in remission (T(30)=3.02; P=0.005). Across the entire sample, higher levels of glutamate/Cr in the anterior cingulate cortex were associated with a greater severity of negative symptoms (r=0.42; P=0.017) and a lower level of global functioning (r=−0.47; P=0.007). These findings suggest that clinical status following antipsychotic treatment in schizophrenia is linked to glutamate dysfunction. Treatment with compounds acting on the glutamatergic system might therefore be beneficial in patients who respond poorly to dopaminergic antipsychotics.     

Functional asymmetry of thalamocortical networks in subjects at ultra-high risk for psychosis and first-episode schizophrenia

Disrupted functional asymmetry has been implicated in schizophrenia. However, it remains unknown whether disrupted functional asymmetry originates from intra-hemispheric and/or inter-hemispheric functional connectivity (FC) in the patients, and whether it starts at very early stage of psychosis. Seventy-six patients with first-episode, drug-naive schizophrenia, 74 subjects at ultra-high risk for psychosis (UHR), and 71 healthy controls underwent resting-state functional magnetic resonance imaging. The ‘Parameter of asymmetry’ (PAS) metric was calculated and support vector machine (SVM) classification analysis was applied to analyze the data. Compared with healthy controls, patients exhibited decreased PAS in the left thalamus/pallidum, right hippocampus/parahippocampus, right inferior frontal gyrus/insula, right thalamus, and left inferior parietal lobule, and increased PAS in the left calcarine, right superior occipital gyrus/middle occipital gyrus, and right precentral gyrus/postcentral gyrus. By contrast, UHR subjects showed decreased PAS in the left thalamus relative to healthy controls. A negative correlation was observed between decreased PAS in the right hippocampus/parahippocampus and Brief Visuospatial Memory Test-Revised (BVMT-R) scores in the patients (r = −0.364, p = 0.002). Moreover, the PAS values in the left thalamus could discriminate the patients/UHR subjects from the controls with acceptable sensitivities (68.42%/81.08%). First-episode patients and UHR subjects shared decreased PAS in the left thalamus. This observed pattern of functional asymmetry highlights the involvement of the thalamus in the pathophysiology of psychosis and may also be applied as a very early marker for psychosis.     

Serotonin 1A receptor gene is associated with Japanese methamphetamine-induced psychosis patients

Background

Several investigations have reported associations the serotonin 1A (5-HT1A) receptor to schizophrenia and psychotic disorders, making 5-HT1A receptor gene (HTR1A) an adequate candidate gene for the pathophysiology of schizophrenia and methamphetamine (METH)-induced psychosis. Huang and colleagues reported that rs6295 in HTR1A was associated with schizophrenia. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. It may indicate that METH-induced psychosis and schizophrenia have common susceptibility genes. In support of this hypothesis, we reported that the V-act murine thymoma viral oncogene homologue 1 (AKT1) gene was associated with METH-induced psychosis and schizophrenia in the Japanese population. Furthermore, we conducted an analysis of the association of HTR1A with METH-induced psychosis.

Method

Using one functional SNP (rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients.

Results

Rs878567 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this significance remained after Bonferroni correction. In addition, we detected an association between rs6295 and rs878567 in HTR1A and METH-induced psychosis patients in the haplotype-wise analysis. Although we detected an association between rs6295 and METH-induced psychosis patients, this significance disappeared after Bonferroni correction.

Conclusion

HTR1A may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population. However, because we did not perform a mutation scan of HTR1A, a replication study using a larger sample may be required for conclusive results.     

Effects of Blocking D2/D3 Receptors on Mismatch Negativity and P3a Amplitude of Initially Antipsychotic Na?ve,First Episode Schizophrenia Patients

Background:

Reduced mismatch negativity and P3a amplitude have been suggested to be among the core deficits in schizophrenia since the late 1970s. Blockade of dopamine D2 receptors play an important role in the treatment of schizophrenia. In addition, there is some evidence indicating that deficits in mismatch negativity and P3a amplitude are related to increased dopaminergic activity. This is the first study investigating the effect of amisulpride, a potent D2-antagonist, on mismatch negativity and P3a amplitude in a large group of antipsychotic-naïve, first-episode schizophrenia patients.

Methods:

Fifty-one antipsychotic-naïve, first-episode schizophrenia patients were tested in a mismatch negativity paradigm at baseline and after 6 weeks of treatment with amisulpride. We further examined 48 age- and gender-matched controls in this paradigm.

Results:

At baseline, the patients showed significantly reduced P3a amplitude compared with healthy controls, but no differences in mismatch negativity. Although the treatment with amisulpride significantly improved the patients’ psychopathological (PANSS) and functional (GAF) scores, it did not influence their mismatch negativity amplitude, while also their reduced P3a amplitude persisted.

Conclusion:

Our findings show that antipsychotic naïve, first-episode patients with schizophrenia have normal mismatch negativity yet reduced P3a amplitude compared with healthy controls. In spite of the fact that the 6-week amisulpride treatment improved the patients both clinically and functionally, it had no effect on either mismatch negativity or P3a amplitude. This suggests that even though there is a dopaminergic involvement in global functioning and symptomatology in schizophrenia, there is no such involvement in these particular measures of early information processing.     

Increased methylation at an unexplored glucocorticoid responsive element within exon 1D of NR3C1 gene is related to anxious-depressive disorders and decreased hippocampal connectivity

Among the major psychiatric disorders, anxious-depressive disorders stand out as one of the more prevalent and more frequently associated with hypothalamic-pituitary-adrenal (HPA) axis abnormalities. Methylation at the exon 1_F of the glucocorticoid receptor gene NR3C1 has been associated with both early stress exposure and risk for developing a psychiatric disorder; however, other NR3C1 promoter regions have been underexplored. Exon 1_D emerges as a suggestive new target in stress-related disorders epigenetically sensitive to early adversity. After assessment of 48 monozygotic twin pairs (n=96 subjects) informative for lifetime history of anxious-depressive disorders, they were classified as concordant, discordant or healthy in function of whether both, one or neither twin in each pair had a lifetime diagnosis of anxious-depressive disorders. DNA for epigenetic analysis was extracted from peripheral blood. Exon 1_F and exon 1_D CpG-specific methylation was analysed by means of pyrosequencing technology. Functional magnetic resonance imaging was available for 54 subjects (n=27 twin pairs). Exon 1_D CpG-specific methylation within a glucocorticoid responsive element (GRE) was correlated with familial burden of anxious-depressive disorders (r=0.35, z=2.26, p=0.02). Right hippocampal connectivity was significantly associated with CpG-specific GRE methylation (β=?2.33, t=?2.85, p=0.01). Exon 1_F was uniformly hypomethylated across all subgroups of the present sample. GRE hypermethylation at exon 1_D of the NR3C1 gene in monozygotic twins concordant for anxious-depressive disorders suggests this region plays a role in increasing vulnerability to psychosocial stress, partly mediated by altered hippocampal connectivity.     

Predictors of antipsychotic-induced weight gain in first-episode psychosis: conclusions from a randomized, double-blind, controlled prospective study of olanzapine, risperidone, and haloperidol

BACKGROUND: Antipsychotic-induced weight gain is one of the most distressing adverse effects being observed in recent times. Most studies have been limited by several confounders. AIM: To evaluate the predictors of antipsychotic-induced weight gain in drug-naive patients with first-episode psychosis treated with olanzapine, risperidone, or haloperidol and compare them with a healthy matched control group. METHODS: Newly diagnosed patients with first-episode schizophrenia treated with antipsychotic medication-olanzapine, risperidone, or haloperidol-and matched healthy controls were followed for 6 weeks. Body mass index (BMI), waist circumference, and weight changes and proportions of subjects with more than 7% weight gain were calculated. The predictors of weight gain were explored. RESULTS: Ninety-nine patients with first-episode schizophrenia and 51 healthy controls were examined. Waist circumference (r = -0.25; P < 0.01) and weight (r = -0.24; P < 0.01) at baseline in addition to the disease process (P < 0.001) as well as antipsychotic use (P < 0.001) were associated with greater increases in weight and BMI. Olanzapine (77%) had greater clinically significant weight gain as compared with risperidone (63%) and haloperidol (22%). Lower BMI at baseline and a diagnosis of undifferentiated schizophrenia were associated with antipsychotic-induced weight gain. CONCLUSIONS: The results confirm clinically significant and substantial weight gain induced by antipsychotic treatment in drug-naive patients with first-episode schizophrenia and identify several risk factors for weight gain such as lower BMI scores, use of olanzapine, and a diagnosis of undifferentiated schizophrenia.     

Abnormal Resting State fMRI Activity Predicts Processing Speed Deficits in First-Episode Psychosis

Little is known regarding the neuropsychological significance of resting state functional magnetic resonance imaging (rs-fMRI) activity early in the course of psychosis. Moreover, no studies have used different approaches for analysis of rs-fMRI activity and examined gray matter thickness in the same cohort. In this study, 41 patients experiencing a first-episode of psychosis (including N=17 who were antipsychotic drug-naive at the time of scanning) and 41 individually age- and sex-matched healthy volunteers completed rs-fMRI and structural MRI exams and neuropsychological assessments. We computed correlation matrices for 266 regions-of-interest across the brain to assess global connectivity. In addition, independent component analysis (ICA) was used to assess group differences in the expression of rs-fMRI activity within 20 predefined publicly available templates. Patients demonstrated lower overall rs-fMRI global connectivity compared with healthy volunteers without associated group differences in gray matter thickness assessed within the same regions-of-interest used in this analysis. Similarly, ICA revealed worse rs-fMRI expression scores across all 20 networks in patients compared with healthy volunteers, with posthoc analyses revealing significant (p<0.05; corrected) abnormalities within the caudate nucleus and planum temporale. Worse processing speed correlated significantly with overall lower global connectivity using the region-of-interest approach and lower expression scores within the planum temporale using ICA. Our findings implicate dysfunction in rs-fMRI activity in first-episode psychosis prior to extensive antipsychotic treatment using different analytic approaches (in the absence of concomitant gray matter structural differences) that predict processing speed.     

单磷酸阿糖腺苷联合布地奈德治疗小儿毛细支气管炎的临床研究

目的探讨单磷酸阿糖腺苷联合布地奈德治疗小儿毛细支气管炎的临床疗效。方法选取2014年9月—2016年9月沈阳医学院附属中心医院儿科收治的毛细支气管炎患者151例,随机分成对照组(75例)和治疗组(76例)。对照组雾化吸入吸入用布地奈德混悬液,0.5 mg加入生理盐水3 m L,1次/d,10 min/次。治疗组在对照组的基础上静脉滴注注射用单磷酸阿糖腺苷,0.1 g加入5%葡萄糖溶液100 m L中,1次/d。所有患者均治疗1周。观察两组患者临床效果,对比两组治疗前后症状消失时间、住院时间、炎性指标以及不良反应情况。结果治疗后,对照组和治疗组总有效率分别为84.00%和96.05%,两组总有效率比较差异具有统计学意义(P0.05)。治疗后,治疗组患儿的退热时间、湿啰音消失时间、喘息消失时间和咳嗽消失时间以及住院时间均明显短于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组患儿肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)以及IL-8指标均明显降低(P0.05);且治疗组的降低程度明显优于对照组,两组比较差异有统计学意义(P0.05)。结论单磷酸阿糖腺苷联合布地奈德治疗小儿毛细支气管炎,在临床症状消失时间、住院时间以及炎症因子水平改善方面上均优于单独使用布地奈德治疗,具有一定的临床推广应用价值。     

No Association Between GRM3 and Japanese Methamphetamine-Induced Psychosis

Several investigations have suggested that abnormalities in glutamate neural transmission play a role in the pathophysiology of psychiatric disorders, including schizophrenia. The metabotropic glutamate 3 receptor (mGluR3) gene was reported to be associated with schizophrenia, and paranoid type schizophrenia has symptoms that are similar to those of methamphetamine-induced psychosis. This suggests that mGluR3 gene (GRM3) is a good candidate gene for the pathogenesis of methamphetamine-induced psychosis. To evaluate the association between GRM3 and methamphetamine-induced psychosis, we conducted a case-control study of Japanese samples (181 methamphetamine-induced psychosis and 232 controls).

Methods:

We selected one functional SNP (rs6465084), reported to be associated with prefrontal brain functioning, for an association analysis. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA).

Results:

We did not detect an association between rs6465084 in GRM3 and Japanese methamphetamine-induced psychosis.

Conclusion:

Our findings suggest that rs6465084 in GRM3 does not play a major role in the pathophysiology of methamphetamine-induced psychosis in the Japanese population. However, because we did not perform an association analysis based on linkage disequilibrium (LD) or a mutation scan of GRM3, a replication study using a larger sample and based on LD may be required for conclusive results.     

Association between corneal temperature and mental status of treatment-resistant schizophrenia inpatients

IntroductionPreliminary point-prevalent data suggest that drug-free schizophrenia patients may exhibit increased body/corneal temperature, that antipsychotic drugs (APDs) may decrease body/core temperature and that patients' mental status might be associated with their body/corneal temperature. Hence, we hypothesized that treatment-resistant psychotic APD-treated schizophrenia patients' mental status may correlate with their corneal temperature during a continuous 6-week period.MethodsCorneal temperature of 12 treatment-resistant schizophrenia inpatients and 16 healthy volunteers was evaluated 2–3 times a week during 6 consecutive weeks using a flir thermal imaging camera.ResultsA significant and substantial correlation was found between inpatients' mean weekly Positive and Negative Syndrome Scale (PANSS)'s total scores and their mean weekly corneal temperature during the 6-week study period (r = 0.82; n = 6 weeks; p = 0.043). There was no significant difference in mean 6-week corneal temperature between the patient group and the healthy subjects (34.25 ± 0.64 °C vs. 34.39 ± 0.69 °C, respectively; t = 1.127, df = 131, p = 0.26).ConclusionsThis study indicates that treatment-resistant overtly psychotic schizophrenia inpatients' mental status (as assessed by the PANSS) correlates with their corneal temperature. The relevance of these phenomena to the pathophysiology of schizophrenia, the biological mechanism underlying corneal temperature alterations and the possible role of temperature-modulating drugs (neuroleptics or non-neuroleptics) on schizophrenic psychosis merits further large-scale investigation in both medicated- and drug-free schizophrenia patients compared to matched controls.     

Density of striatal D2 receptors in untreated first-episode psychosis: An I-IBZM SPECT study

There is as yet no definite prognostic marker to determine whether a first-episode psychosis will become schizophrenia or not. The aim of the present study is to address whether the mechanism of sensitization of the subcortical dopaminergic pathway - yielding to an increase of the postsynaptic D2 receptors - may serve as a prognostic marker of clinical outcome in drug naïve patients with a first-episode psychosis, by means of a prospective and multicentric study with untreated first-episode psychosis patients (n = 37). 123I-IBZM SPECT was performed at the time of the inclusion in the study, before antipsychotic medication was initiated. One year later, patients were assessed again so as to determine their diagnosis. There was a significant group effect at baseline in D2 Striatal/Frontal (S/F) ratios (F = 10.2, p < 0.001). Bonferroni posthoc comparisons attested significant differences between diagnosis (p = 0.006), and between schizophrenia and control groups (p < 0.001) but no differences between non-schizophrenia and control groups (p = 0.9). The logistic regression model showed that D2R binding (p = 0.02) and PAS (Premorbid Adjustment Scale) adulthood score (p = 0.03) were predictive of the final diagnosis (schizophrenia/non-schizophrenia; Nagelkerke R² = 0.59; X² = 11.08, p = 0.001). These findings replicate previous results on the usefulness of D2R binding as an objective prognostic parameter, together with the evaluation of premorbid adjustment, of the evolution of first-episode psychosis. In this regard, the results may provide a new view in the approach of early and personalized treatment in the debut of a psychosis.     

Probing GABA Receptor Function in Schizophrenia with Iomazenil

Several lines of evidence from post-mortem, brain imaging, and genetic studies in schizophrenia patients suggest that Gamma-amino butyric acid (GABA) deficits may contribute to the pathophysiology of schizophrenia. Pharmacological induction of a transient GABA-deficit state has been shown to enhance vulnerability of healthy subjects to the psychotomimetic effects of various drugs. Exacerbating or creating a GABA deficit was hypothesized to induce or unmask psychosis in schizophrenia patients, but not in healthy controls. To test this hypothesis, a transient GABA deficit was pharmacologically induced in schizophrenia patients and healthy controls using iomazenil, an antagonist and partial inverse agonist of the benzodiazepine receptor. In a double-blind, randomized, placebo-controlled study, clinically stable chronic schizophrenia patients (n=13) received iomazenil (3.7 μg administered intravenously over 10 min). Psychosis was measured using the Brief Psychiatric Rating Scale and perceptual alterations were measured using the Clinician Administered Dissociative Symptoms Scale before and after iomazenil administration. These data were compared with the effects of iomazenil in healthy subjects (n=20). Iomazenil produced increases in psychotic symptoms and perceptual alterations in schizophrenia patients, but not in healthy controls. The greater vulnerability of schizophrenia patients to the effects of iomazenil relative to controls provides further support for the GABA-deficit hypothesis of schizophrenia.     

Quetiapine in patients with comorbid schizophrenia-spectrum and substance use disorders: an open-label trial

ABSTRACT

Background: Preliminary evidence suggests that clozapine relieves the craving for psychoactive substances in schizophrenia patients. Quetiapine shares crucial pharmacological properties with clozapine. Promising results have been described with quetiapine therapy in patients with psychosis and substance use disorder.

Methods: Based on Diagnostic and Statistical Manual of Mental Disorders – fourth edition (DSM‐IV) criteria, patients were diagnosed with comorbid schizophrenia-spectrum and substance use disorders. Patients were switched to quetiapine for a 12‐week open-label trial. Craving, quantities used, days of consumption, and severity of substance abuse were assessed every 3 weeks. Alcohol and Drug Use Scales were administered on baseline and end-point. Psychiatric symptoms, depressive symptoms, extrapyramidal symptoms, and cognition were also assessed at baseline, week 6 and week 12.

Results: Twenty-four schizophrenia-spectrum patients were included in the last observation carried forward (LOCF) analyses, responding to one or more of the following substance use disorders: cannabis (15 patients), alcohol (10 patients), and other psychoactive substances (nine patients). Overall, severity of substance abuse improved during the study. Less weekly days were spent on drugs of abuse. A decrease in the weekly Canadian dollars spent on psychoactive substances was also observed. Cognition, psychiatric, depressive, and extrapyramidal symptoms also significantly improved (?p < 0.05).

Conclusions: In this open-label, uncontrolled trial, significant improvements were noted in substance abuse, psychiatric symptoms, extrapyramidal symptoms, and cognition during quetiapine therapy. The study suffered from three main limitations: (1) the open-label design of the study; (2) the patients’ poor compliance; and (3) the small sample size involved. Controlled studies on the use of quetiapine in dual diagnosis schizophrenia are warranted to confirm that the effects are drug-related.     

Delayed preattentional functioning in early psychosis patients with cannabis use

Rationale

Cannabis use is prevalent among the early psychosis (EP) population. The event-related potentials, mismatch negativity (MMN) and P3a are reduced in EP. Cannabinoids have been shown to modulate N-methyl-D-aspartate receptors which are involved in MMN generation.

Objectives

This study is the first to investigate the effects of cannabis use on MMN/P3a in EP.

Methods

EP was defined as a history of psychosis or psychotic symptoms with no progression to date to chronic schizophrenia. Twenty-two EP patients with cannabis use (EP?+?CANN), 22 non-cannabis-using EP patients (EP-CANN) and 21 healthy controls participated in this study. MMN/P3a was elicited using a two-tone, auditory paradigm with 8% duration deviants.

Results

As expected, EP-CANN showed marked reductions in MMN/P3a amplitudes compared to controls. However, EP?+?CANN showed evidence of a different pattern of neurophysiological expression of MMN/P3a compared to non-using patients, most notably in terms of delayed frontal MMN/P3a latencies.

Conclusions

This study provides further evidence that MMN/P3a deficits are present during early psychosis and suggests that this biomarker may have utility in differentiating substance- from non-substance-related psychoses.     

FKBP5 Genotype-Dependent DNA Methylation and mRNA Regulation After Psychosocial Stress in Remitted Depression and Healthy Controls

Background:

Polymorphisms in the FK506 binding protein 5 (FKBP5) gene have been shown to influence glucocorticoid receptor sensitivity, stress response regulation, and depression risk in traumatized subjects, with most consistent findings reported for the functional variant rs1360780. In the present study, we investigated whether the FKBP5 polymorphism rs1360780 and lifetime history of major depression are associated with DNA methylation and FKBP5 gene expression after psychosocial stress.

Methods:

A total of 116 individuals with a positive (n = 61) and negative (n = 55) lifetime history of major depression participated in the Trier Social Stress Test. We assessed plasma cortisol concentrations, FKBP5 mRNA expression, and CpG methylation of FKBP5 intron 7 in peripheral blood cells.

Results:

Genotype-dependent plasma cortisol response to psychosocial stress exposure was observed in healthy controls, with the highest and longest-lasting cortisol increase in subjects with the TT genotype of the FKBP5 polymorphism rs1360780, and healthy controls carrying the T risk allele responded with a blunted FKBP5 mRNA expression after psychosocial stress. No genotype effects could be found in remitted depression.

Conclusions:

The FKBP5 rs1360780 polymorphism is associated with plasma cortisol and FKBP5 mRNA expression after psychosocial stress in healthy controls but not in remitted depression. Preliminary results of the DNA methylation analysis suggest that epigenetic modifications could be involved.     

Is treatment-resistance in unipolar melancholic depression characterized by decreased serotonin2A receptors in the dorsal prefrontal – Anterior cingulate cortex?

ObjectivesQuite a number of patients diagnosed with major depression are resistant to several well carried-out psychopharmacological interventions. It remains unclear as to how the serotonergic system is implicated in the phenomenon of treatment-resistance.MethodsWe examined the involvement of post-synaptic 5-HT_2A receptors in the pathophysiology of treatment-resistance in unipolar melancholic major depression with ¹²³I-5-I-R91150 SPECT. 15 antidepressant-naïve (ADN) first-episode depressed patients, 15 antidepressant-free treatment-resistant depressed (TRD) patients and 15 never-depressed individuals, matched for age and gender were studied.ResultsCompared to ADN patients and healthy controls, TRD patients displayed significantly lower 5-HT_2A receptor binding index (BI) in the dorsal regions of the prefrontal and the anterior cingulate cortex. No significant 5-HT_2A receptor BI differences between ADN patients and controls were observed.ConclusionsAt the cortical level, 5-HT_2A receptor BI does not significantly differ in first-episode melancholic depressed patients compared to healthy controls. This observation might imply a limited short-term impact on the serotonergic system in first episode depression. Our results also suggest that when encountered with treatment-resistance, the 5-HT_2A receptors in the DPFC-ACC axis are significantly down-regulated. However, whether this assumed underlying pathophysiological mechanism is due solely to abnormalities in the serotonergic system remains to be answered.This article is part of a Special Issue entitled ‘Anxiety and Depression’.     

DHEA and DHEA-S levels in hospitalized adolescents with first-episode schizophrenia and conduct disorder: A comparison study

IntroductionIncreasing evidence exists indicating an association of DHEA and DHEA-S blood levels with psychosis, however many of the findings remain contradictory based on different phases of the illness, different treatments and at a range of ages. To date no studies exist investigating the levels of these neurosteroids in adolescents with psychosis. Such an investigation would be important in order to exclude effects of chronic illness, long-term treatment and repeated hospitalizations.MethodPeripheral venous blood samples for DHEA, DHEA-S and cortisol determination were collected from first-time hospitalized adolescents with diagnoses of schizophrenia as well as from patients with conduct disorder. Patients were rated with the Positive and Negative Syndrome Scale (PANSS), the Hamilton Scale for depression (HAM-D), the Overt Aggression Scale (OAS) and the impulsivity scale (IS).ResultsDHEA levels in adolescents with schizophrenia were significantly higher than in patients with conduct disorder (p = 0.002). Blood levels of DHEA and DHEA-S in schizophrenia correlated with the total PANSS scores (both p < 0.05). No correlations were detected between any of the neurosteroid blood levels and clinical rating scales in the control group.ConclusionsIt may be proposed that individuals in their early stages of schizophrenia psychosis may develop a protective or compensatory neurosteroid response to the first onset of psychosis. Such a putative upregulatory DHEA mechanism may become desensitized with progression to chronic illness. The temporal relationship of investigation of neurosteroid levels in adolescents compared to such investigation in adults may provide important and relevant information.     

Lower Vitamin C Levels Are Associated With Less Improvement in Negative Symptoms in Initially Antipsychotic-Naïve Patients With First-Episode Psychosis

Low levels of vitamin C have been observed in patients with schizophrenia and psychosis, and vitamin C may affect the dopaminergic system. Likewise, antipsychotic medication modulates striatal dopamine D2 receptors. We measured vitamin C levels in 52 patients with first-episode psychoses (24 females, age 23.1 ± 5.2 years) and 57 matched HCs (20 females, age 22.7 ± 4.3 years) before and after 6 weeks where patients received aripiprazole monotherapy (mean dose 10.4 mg ± 4.8 mg). At baseline, patients displayed lower levels of vitamin C (57.4 ± 25.9 µM) than controls (72.7 ± 21.4 µM) (t = 3.4, P = .001). Baseline symptoms and vitamin C levels were not correlated. Higher baseline vitamin C levels were associated with more improvement in negative symptoms (n = 39, R²= 0.20, F = 8.2, P = .007), but not with age, sex, or p-aripiprazole. Because negative symptoms are generally considered challenging to alleviate, a potential adjunctive effect of vitamin C on treatment response should be tested in future randomized clinical trials.     

首发精神分裂症患者使用阿立哌唑后血清IL-2、IL-4水平变化的探讨

目的：探讨首发精神分裂症患者血清细胞因子IL-2、IL-4与正常人的差异,比较分析首发精神分裂症患者经过阿立哌唑治疗前后症状改变及细胞因子IL-2、IL-4的变化。方法选择35例首发精神分裂症患者作为研究组,35例健康志愿者作为对照组,通过流式细胞学技术测定血清标本中IL-2、IL-4的水平,用PANSS量表评定精神症状。结果（1）首发精神分裂症患者IL-2、IL-4水平与正常对照组相比,差异无统计学意义（P＞0．05）。（2）首发精神分裂症患者阿立哌唑治疗后较治疗前IL-4水平降低,差异有统计学意义（P＜0．01）。（3）首发精神分裂症阳性症状患者血清IL-2、IL-4水平在治疗前均高于对照组（P＜0．05）。（4）首发精神分裂症阳性症状患者经阿立哌唑治疗前后血清IL-2、IL-4水平差异有统计学意义（ P＜0．05）。结论首发精神分裂症患者免疫功能存在异常,非典型抗精神病药物阿立哌唑具有下调IL-2、IL-4水平的作用,阳性症状亦得到改善。