Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder

Background

Brain imaging studies suggest that volume reductions and compromised white matter integrity occur in schizophrenia and bipolar disorder (BD). However, the cellular correlates have not yet been identified. To address this issue we assessed oligodendrocyte, astrocyte and microglial populations in postmortem white matter from schizophrenia, BD and nonpsychiatric control samples.

Methods

The density, areal fraction and spatial distribution of glial fibrillary acidic protein (GFAP)-expressing astrocytes and ionized calcium-binding adaptor molecule-1 (IBA-1)-expressing microglia as well as the density, nuclear size and spatial distribution of Nissl-stained oligodendrocytes were quantified in postmortem white matter adjacent to the dorsolateral prefrontal cortex (Brodmann area 9) in schizophrenia, BD and control samples (n = 20). In addition, the oligodendrocyte-associated proteins myelin basic protein and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) were quantified in the same samples by enzyme-linked immunosorbent assay and immunoblotting.

Results

Oligodendrocyte density (p = 0.012) and CNPase protein levels (p = 0.038) differed between groups, being increased in BD compared with control samples. The GFAP area fraction (p = 0.05) and astrocyte spatial distribution (p = 0.040) also differed between groups, reflecting decreased area fraction and increased cell clustering in both schizophrenia and BD samples.

Limitations

Oligodendrocytes were identified using morphological criteria.

Conclusion

This study provides evidence for glial pathology in prefrontal white matter in schizophrenia and BD. Changes in oligodendrocyte and astrocyte populations in white matter in the major psychiatric disorders may reflect disruptions in structural or metabolic support of axons.     

Static and Dynamic Characteristics of Cerebral Blood Flow During the Resting State in Schizophrenia

Background:

The cerebral network that is active during rest and is deactivated during goal-oriented activity is called the default mode network (DMN). It appears to be involved in self-referential mental activity. Atypical functional connectivity in the DMN has been observed in schizophrenia. One hypothesis suggests that pathologically increased DMN connectivity in schizophrenia is linked with a main symptom of psychosis, namely, misattribution of thoughts.

Methods:

A resting-state pseudocontinuous arterial spin labeling (ASL) study was conducted to measure absolute cerebral blood flow (CBF) in 34 schizophrenia patients and 27 healthy controls. Using independent component analysis (ICA), the DMN was extracted from ASL data. Mean CBF and DMN connectivity were compared between groups using a 2-sample t test.

Results:

Schizophrenia patients showed decreased mean CBF in the frontal and temporal regions (P < .001). ICA demonstrated significantly increased DMN connectivity in the precuneus (x/y/z = −16/−64/38) in patients than in controls (P < .001). CBF was not elevated in the respective regions. DMN connectivity in the precuneus was significantly correlated with the Positive and Negative Syndrome Scale scores (P < .01).

Conclusions:

In schizophrenia patients, the posterior hub—which is considered the strongest part of the DMN—showed increased DMN connectivity. We hypothesize that this increase hinders the deactivation of the DMN and, thus, the translation of cognitive processes from an internal to an external focus. This might explain symptoms related to defective self-monitoring, such as auditory verbal hallucinations or ego disturbances.Key words: psychosis, default mode network, arterial spin labeling, functional connectivity, precuneus     

Oxidation and nitration in dopaminergic areas of the prefrontal cortex from patients with bipolar disorder and schizophrenia

Background

Increased oxidative stress is strongly implicated in bipolar disorder (BD), where protein oxidation, lipid peroxidation and oxidative damage to DNA have been consistently reported. High levels of dopamine (DA) in mania are also well-recognized in patients with BD, and DA produces reactive oxygen species and electron-deficient quinones that can oxidize proteins when it is metabolized.

Methods

Using immunohistochemistry and acceptor photobleaching Förster resonance energy transfer (FRET), we examined oxidation and nitration of areas immunoreactive for the DA transporter (DAT) and tyrosine hydroxylase (TH) in the postmortem prefrontal cortex from patients with BD, schizophrenia and major depression as well as nonpsychiatric controls.

Results

We found increased oxidation of DAT-immunoreactive regions in patients with BD (F_3,48 = 6.76, p = 0.001; Dunnett post hoc test p = 0.001) and decreased nitration of TH-immunoreactive regions in both patients with BD (F_3,45 = 3.10, p = 0.036; Dunnett post hoc test p = 0.011) and schizophrenia (p = 0.027). On the other hand, we found increased global levels of oxidation in patients with BD (F_3,44 = 6.74, p = 0.001; Dunnett post hoc test p = 0.001) and schizophrenia (p = 0.020), although nitration levels did not differ between the groups (F_3,46 = 1.75; p = 0.17).

Limitations

Limitations of this study include the use of postmortem brain sections, which may have been affected by factors such as postmortem interval and antemortem agonal states, although demographic factors and postmortem interval were accounted for in our statistical analysis.

Conclusion

These findings suggest alterations in levels of protein oxidation and nitration in DA-rich regions of the prefrontal cortex in patients with BD and schizophrenia, but more markedly in those with BD.     

NAAG peptidase inhibitors block cognitive deficit induced by MK-801 and motor activation induced by d-amphetamine in animal models of schizophrenia

The most widely validated animal models of the positive, negative and cognitive symptoms of schizophrenia involve administration of d-amphetamine or the open channel NMDA receptor blockers, dizocilpine (MK-801), phencyclidine (PCP) and ketamine. The drug ZJ43 potently inhibits glutamate carboxypeptidase II (GCPII), an enzyme that inactivates the peptide transmitter N-acetylaspartylglutamate (NAAG) and reduces positive and negative behaviors induced by PCP in several of these models. NAAG is an agonist at the metabotropic glutamate receptor 3 (mGluR3). Polymorphisms in this receptor have been associated with expression of schizophrenia. This study aimed to determine whether two different NAAG peptidase inhibitors are effective in dopamine models, whether their efficacy was eliminated in GCPII knockout mice and whether the efficacy of these inhibitors extended to MK-801-induced cognitive deficits as assessed using the novel object recognition test. ZJ43 blocked motor activation when given before or after d-amphetamine treatment. (R,S)-2-phosphono-methylpentanedioic acid (2-PMPA), another potent NAAG peptidase inhibitor, also reduced motor activation induced by PCP or d-amphetamine. 2-PMPA was not effective in GCPII knockout mice. ZJ43 and 2-PMPA also blocked MK-801-induced deficits in novel object recognition when given before, but not after, the acquisition trial. The group II mGluR antagonist {"type":"entrez-nucleotide","attrs":{"text":"LY341495","term_id":"1257705759","term_text":"LY341495"}}LY341495 blocked the effects of NAAG peptidase inhibition in these studies. 2-PMPA was more potent than ZJ43 in a test of NAAG peptidase inhibition in vivo. By bridging the dopamine and glutamate theories of schizophrenia with two structurally different NAAG peptidase inhibitors and demonstrating their efficacy in blocking MK-801-induced memory deficits, these data advance the concept that NAAG peptidase inhibition represents a potentially novel antipsychotic therapy.     

Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia

Background:

The kynurenic acid (KYNA) hypothesis for schizophrenia is partly based on studies showing increased brain levels of KYNA in patients. KYNA is an endogenous metabolite of tryptophan (TRP) produced in astrocytes and antagonizes N-methyl-D-aspartate and α7* nicotinic receptors.

Methods:

The formation of KYNA is determined by the availability of substrate, and hence, we analyzed KYNA and its precursors, kynurenine (KYN) and TRP, in the cerebrospinal fluid (CSF) of patients with schizophrenia. CSF from male patients with schizophrenia on olanzapine treatment (n = 16) was compared with healthy male volunteers (n = 29).

Results:

KYN and KYNA concentrations were higher in patients with schizophrenia (60.7 ± 4.37nM and 2.03 ± 0.23nM, respectively) compared with healthy volunteers (28.6 ± 1.44nM and 1.36 ± 0.08nM, respectively), whereas TRP did not differ between the groups. In all subjects, KYN positively correlated to KYNA.

Conclusion:

Our results demonstrate increased levels of CSF KYN and KYNA in patients with schizophrenia and further support the hypothesis that KYNA is involved in the pathophysiology of schizophrenia.     

Basic Self-Disturbance Predicts Psychosis Onset in the Ultra High Risk for Psychosis “Prodromal” Population

Introduction

Phenomenological research indicates that disturbance of the basic sense of self may be a core phenotypic marker of schizophrenia spectrum disorders. Basic self-disturbance refers to a disruption of the sense of ownership of experience and agency of action and is associated with a variety of anomalous subjective experiences. In this study, we investigated the presence of basic self-disturbance in an “ultra high risk” (UHR) for psychosis sample compared with a healthy control sample and whether it predicted transition to psychotic disorder.

Methods

Forty-nine UHR patients and 52 matched healthy control participants were recruited to the study. Participants were assessed for basic self-disturbance using the Examination of Anomalous Self-Experience (EASE) instrument. UHR participants were followed for a mean of 569 days.

Results

Levels of self-disturbance were significantly higher in the UHR sample compared with the healthy control sample (P < .001). Cox regression indicated that total EASE score significantly predicted time to transition (P < .05) when other significant predictors were controlled for. Exploratory analyses indicated that basic self-disturbance scores were higher in schizophrenia spectrum cases, irrespective of transition to psychosis, than nonschizophrenia spectrum cases.

Discussion

The results indicate that identifying basic self-disturbance in the UHR population may provide a means of further “closing in” on individuals truly at high risk of psychotic disorder, particularly of schizophrenia spectrum disorders. This may be of practical value by reducing inclusion of “false positive” cases in UHR samples and of theoretical value by shedding light on core phenotypic features of schizophrenia spectrum pathology.     

Outcomes of Secondary Laminoplasty for Patients with Unsatisfactory Results after Anterior Multilevel Cervical Surgery

Objective

To investigate the causes for failed anterior cervical surgery and the outcomes of secondary laminoplasty.

Methods

Seventeen patients failed anterior multilevel cervical surgery and the following conservative treatments between Feb 2003 and May 2011 underwent secondary laminoplasty. Outcomes were evaluated by the Japanese Orthopaedic Association (JOA) Scale and visual analogue scale (VAS) before the secondary surgery, at 1 week, 2 months, 6 months, and the final visit. Cervical alignment, causes for revision and complications were also assessed.

Results

With a mean follow-up of 29.7±12.1 months, JOA score, recovery rate and excellent to good rate improved significantly at 2 months (p<0.05) and maintained thereafter (p>0.05). Mean VAS score decreased postoperatively (p<0.05). Lordotic angle maintained during the entire follow up (p>0.05). The causes for secondary surgery were inappropriate approach in 3 patients, insufficient decompression in 4 patients, adjacent degeneration in 2 patients, and disease progression in 8 patients. Complications included one case of C5 palsy, axial pain and cerebrospinal fluid leakage, respectively.

Conclusion

Laminoplasty has satisfactory results in failed multilevel anterior surgery, with a low incidence of complications.     

Glycine site N-methyl-d-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats

Background

Glutamate N-methyl-d-aspartate (NMDA) receptor antagonists exert fast-acting antidepressant effects, providing a promising way to develop a new classification of antidepressant that targets the glutamatergic system. In the present study, we examined the potential antidepressant action of 7-chlorokynurenic acid (7-CTKA), a glycine recognition site NMDA receptor antagonist, in a series of behavioural models of depression and determined the molecular mechanisms that underlie the behavioural actions of 7-CTKA.

Methods

We administered the forced swim test, novelty-suppressed feeding test, learned helplessness paradigm and chronic mild stress (CMS) paradigm in male rats to evaluate the possible rapid antidepressant-like actions of 7-CTKA. In addition, we assessed phospho-glycogen synthase kinase-3β (p-GSK3β) level, mammalian target of rapamycin (mTOR) function, and postsynaptic protein expression in the medial prefrontal cortex (mPFC) and hippocampus.

Results

Acute 7-CTKA administration produced rapid antidepressant-like actions in several behavioural tests. It increased p-GSK3β, enhanced mTOR function and increased postsynaptic protein levels in the mPFC. Activation of GSK3β by {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 completely blocked the antidepressant-like effects of 7-CTKA. Moreover, 7-CTKA did not produce rewarding properties or abuse potential.

Limitations

It is possible that 7-CTKA modulates glutamatergic transmission, thereby causing enduring alterations of GSK3β and mTOR signalling, although we did not provide direct evidence to support this possibility. Thus, the therapeutic involvement of synaptic adaptions engaged by 7-CTKA requires further study.

Conclusion

Our findings demonstrate that acute 7-CTKA administration produced rapid antidepressant-like effects, indicating that the behavioural response to 7-CTKA is mediated by GSK3β and mTOR signalling function in the mPFC.     

Dimethylated lysine 9 of histone 3 is elevated in schizophrenia and exhibits a divergent response to histone deacetylase inhibitors in lymphocyte cultures

Background

A restrictive chromatin state has been thought to be operant in the pathophysiology of schizophrenia. Our objective was to ascertain whether differences exist between baseline levels of a repressive chromatin mark such as dimethylated lysine 9 of histone 3 (H3K9me2) in patients with schizophrenia and healthy controls and whether a histone deacetylase (HDAC) inhibitor in an in vitro assay would differentially affect chromatin structure based on diagnosis.

Methods

We obtained blood samples from 19 healthy controls and 25 patients with schizophrenia and isolated their lymphocytes. We measured baseline H3K9me2 levels (normalized to total histone 1) in the lymphocytes from all participants via Western blot analysis. To examine the effects of an HDAC inhibitor on H3K9me2, we cultured the lymphocytes from participants with trichostatin A (TSA) for 24 hours and then measured changes in H3K9me2 relative to the control condition (dimethyl sulfoxide).

Results

Patients with schizophrenia had significantly higher mean baseline levels of H3K9me2 than healthy controls (6.52 v. 2.78, p = 0.028). Moreover, there was a significant negative correlation between age at onset of illness and levels of H3K9me2 (Spearman’s rho = −0.588, p = 0.008). In the lymphocyte cultures, TSA induced divergent responses in terms of H3K9me2 levels from patients with schizophrenia compared with healthy controls (F_1,14 = 5.082, p = 0.041).

Limitations

The use of lymphocytes to study schizophrenia has its limitations because they may not be appropriate models of synaptic activity or other brain-specific activities.

Conclusion

Our results provide further evidence that schizophrenia is associated with a restrictive chromatin state that is also less modifiable using HDAC inhibitors.     

Impact of cognitive performance on the reproducibility of fMRI activation in schizophrenia

Background

Longitudinal functional magnetic resonance imaging (fMRI) studies in patients with schizophrenia allow exploration of the course of the illness and brain activity after therapy. A crucial question, however, is whether fMRI findings are reliable, because they can be affected by performance deficits in patients with schizophrenia. Our aim was to evaluate the reproducibility of fMRI activations in highly integrated language areas in patients with schizophrenia, taking into account task performance.

Methods

Ten patients with schizophrenia and 10 matched healthy controls were scanned twice, 21 months apart, while performing a story comprehension task. The reproducibility of the activations in each participant was evaluated globally by the percentage of spatial overlap between the 2 sessions and locally by a voxel-wise computation of the between-session relative standard deviation. We performed between-group comparisons both with and without the inclusion of comprehension scores (measuring task performance) as a covariate.

Results

On average, patients with schizophrenia had significantly lower comprehension scores than controls (4.5/12 v. 7.8/12, p = 0.002). The mean spatial overlap between fMRI sessions was 30.6% in the patient group and 47.0% in the control group (p = 0.017). Locally, the lower reproducibility in patients was most prominent in the left posterior middle temporal gyrus, inferior frontal gyrus and medial prefrontal cortex (p < 0.001 uncorrected for multiple comparisons). Comprehension scores were positively correlated with both reproducibility measures in patients (overlap: r = 0.82, p = 0.004; relative standard deviation: several significant clusters at p < 0.001). When we included the comprehension scores as a covariate, most of the local between-group differences in reproducibility were removed, and the difference in overlap was not significant.

Limitations

Owing to the small sample size, we could not investigate the impact of clinical subtypes and different types of medications on reproducibility.

Conclusion

Our findings suggest that the greater variability in activation in patients with schizophrenia compared with controls concerns high-level areas and is mainly attributable to deficient task performance. Consequently, cognitive performance must be carefully controlled when longitudinal fMRI studies are undertaken.     

Hippocampal and caudate volume reductions in antipsychotic-naive first-episode schizophrenia

Background

Enlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode schizophrenia. Studies investigating brain structure in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether ventricular enlargement and hippocampal and caudate volume reductions are morphological traits of antipsychotic-naive first-episode schizophrenia.

Methods

We obtained high-resolution 3-dimensional T₁-weighted magnetic resonance imaging scans for 38 antipsychotic-naive first-episode schizophrenia patients and 43 matched healthy controls by use of a 3-T scanner. We warped the brain images to each other by use of a high-dimensional intersubject registration algorithm. We performed voxel-wise group comparisons with permutation tests. We performed small volume correction for the hippocampus, caudate and ventricles by use of a false discovery rate correction (p < 0.05) to control for multiple comparisons. We derived and analyzed estimates of brain structure volumes. We grouped patients as those with (n = 9) or without (n = 29) any lifetime substance abuse to examine the possible effects of substance abuse.

Results

We found that hippocampal and caudate volumes were decreased in patients with first-episode schizophrenia. We found no ventricular enlargement, differences in global volume or significant associations between tissue volume and duration of untreated illness or psycho-pathology. The hippocampal volume reductions appeared to be influenced by a history of substance abuse. Exploratory analyses indicated reduced volume of the nucleus accumbens in patients with first-episode schizophrenia.

Limitations

This study was not a priori designed to test for differences between schizophrenia patients with or without lifetime substance abuse, and this subgroup was small.

Conclusion

Reductions in hippocampal and caudate volume may constitute morphological traits in antipsychotic-naive first-episode schizophrenia patients. However, the clinical implications of these findings are unclear. Moreover, past substance abuse may accentuate hippocampal volume reduction. Magnetic resonance imaging studies addressing the potential effects of substance abuse in antipsychotic-naive first-episode schizophrenia patients are warranted.     

Phase 2 Trial of an Alpha-7 Nicotinic Receptor Agonist (TC-5619) in Negative and Cognitive Symptoms of Schizophrenia

Objectives:

This trial was conducted to test the effects of an alpha7 nicotinic receptor full agonist, TC-5619, on negative and cognitive symptoms in subjects with schizophrenia.

Methods:

In 64 sites in the United States, Russia, Ukraine, Hungary, Romania, and Serbia, 477 outpatients (18–65 years; male 62%; 55% tobacco users) with schizophrenia, treated with a new-generation antipsychotic, were randomized to 24 weeks of placebo (n = 235), TC-5619, 5mg (n = 121), or TC-5619, 50mg (n = 121), administered orally once daily. The primary efficacy measure was the Scale for the Assessment of Negative Symptoms (SANS) composite score. Key secondary measures were the Cogstate Schizophrenia Battery (CSB) composite score and the University of California San Diego Performance-Based Skills Assessment-Brief Version (UPSA-B) total score. Secondary measures included: Positive and Negative Syndrome Scale in Schizophrenia (PANSS) total and subscale scores, SANS domain scores, CSB item scores, Clinical Global Impression-Global Improvement (CGI-I) score, CGI-Severity (CGI-S) score, and Subject Global Impression-Cognition (SGI-Cog) total score.

Results:

SANS score showed no statistical benefit for TC-5619 vs placebo at week 24 (5mg, 2-tailed P = .159; 50mg, P = .689). Likewise, no scores of CSB, UPSA-B, PANSS, CGI-I, CGI-S, or SGI-Cog favored TC-5619 (P > .05). Sporadic statistical benefit favoring TC-5619 in some of these outcome measures were observed in tobacco users, but these benefits did not show concordance by dose, country, gender, or other relevant measures. TC-5619 was generally well tolerated.

Conclusion:

These results do not support a benefit of TC-5619 for negative or cognitive symptoms in schizophrenia.Key words: schizophrenia, negative symptoms, cognition     

The Relationship between Impulsivity and Quality of Life in Euthymic Patients with Bipolar Disorder

Objective

Bipolar disorder (BD) is characterized by elevated impulsivity, even during periods of remission. Many recovered BD patients have functional impairments, which can lead to poor quality of life (QoL). The aim of this study was to investigate the association between impulsivity and QoL in euthymic BD patients.

Methods

A total of 56 remitted or recovered patients with type I or II BD, diagnosed based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, were recruited. Psychiatrists administered the Clinical Global Impression (CGI) for BD and the Global Assessment of Functioning (GAF) scales and then interviewed the subjects to assess clinical variables. Patients completed the Barratt Impulsiveness Scale (BIS-11) and the World Health Organization Quality of Life Assessment Instrument-Brief Form (WHOQoL-BREF). Pearson correlations, univariate regression analyses, and multiple linear regression analyses were performed.

Results

The BIS-11 total score was significantly correlated with the WHOQoL-BREF total score (r=-0.55, p<0.01) and with the WHOQoL-BREF subscales. After controlling for GAF score and other clinical variables, the BIS-11 total score (β=-0.43, p=0.001) was independently associated with overall QoL. Additionally, the BIS-11 total score was particularly strongly associated with the physical, psychological, and social domains of the multi-dimensional QoL scale.

Conclusion

Our results suggest that high impulsivity is related to low QoL in euthymic BD patients. Further studies are needed to examine whether interventions for high impulsivity effectively improve QoL in patients with BD.     

Epigenetic Regulation in the Brain after Spinal Cord Injury : A Comparative Study

Objective

After spinal cord injury (SCI), functional and structural reorganization occurs at multiple levels of brain including motor cortex. However, the underlying mechanism still remains unclear. The current study was performed to investigate the alterations in the expression of the main regulators of neuronal development, survival and death, in the brain following thoracic contusive SCI in a mouse model.

Methods

Eight-week-old female imprinting control region mice (n=60; 30-35 g) were used in this study. We analyzed the expression levels of regulators such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and histone deacetylase (HDAC) 1 in the brain following thoracic contusive SCI.

Results

The expression of BDNF levels were elevated significantly compared with control group at 2 weeks after injury (p<0.05). The expression of NGF levels were elevated at 2, 4 weeks compared with control group, but these difference were not significant (p>0.05). The GDNF levels were elevated at 2 week compared with control group, but these differences were not significant (p>0.05). The difference of HDAC1 levels were not significant at 2, 4 and 8 weeks compared with control group (p>0.05).

Conclusion

These results demonstrate that the upregulation of BDNF may play on important role in brain reorganization after SCI.     

Risk Factors Associated with Germinal Matrix-Intraventricular Hemorrhage in Preterm Neonates

Objective

The purpose of this study is to identify the risk factors associated with the development of germinal matrix-intraventricular hemorrhage (GM-IVH) and the relationship of the severity of disease and prematurity.

Methods

A total of 168 premature neonates whose birth weight ≤1500 g or gestational age ≤34 weeks were examined by cranial ultrasound (CUS) for detection of GM-IVH among the babies admitted between January 2011 and December 2012 in our medical center neonatal intensive care unit. The babies were divided into two groups : GM-IVH and non-IVH. Clinical presentations, precipitating factors of the patients and maternal factors were analyzed.

Results

In univariate analysis, gestational age, birth weight, delivery method, presence of premature rupture of membrane (PROM) and level of sodium and glucose were statistically meaningful factors (p<0.05). But only two factors, gestational age and presence of patent ductus arteriosus (PDA) were statistically meaningful in multivariate logistic regression (p<0.05). Delivery method [normal vaginal delivery (NVD) to Caeserean section] was borderline significant (p<0.10).

Conclusion

Presence of PDA and gestational age were the important risk factors associated with development of GM-IVH.     

Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls

Background

Patients with schizophrenia show increased brain and cerebrospinal fluid (CSF) concentrations of the endogenous N-methyl-d-aspartate receptor antagonist kynurenic acid (KYNA). This compound is an end-metabolite of the kynurenine pathway, and its formation indirectly depends on the activity of kynurenine 3-monooxygenase (KMO), the enzyme converting kynurenine to 3-hydroxykynurenine.

Methods

We analyzed the association between KMO gene polymorphisms and CSF concentrations of KYNA in patients with schizophrenia and healthy controls. Fifteen single nucleotide polymorphisms (SNPs) were selected covering KMO and were analyzed in UNPHASED.

Results

We included 17 patients with schizophrenia and 33 controls in our study. We found an association between a KMO SNP (rs1053230), encoding an amino acid change of potential importance for substrate interaction, and CSF concentrations of KYNA.

Limitations

Given the limited sample size, the results are tentative until replication.

Conclusion

Our results suggest that the nonsynonymous KMO SNP rs1053230 influences CSF concentrations of KYNA.     

Differential effects of serotonergic and noradrenergic antidepressants on brain activity during a cognitive control task and neurofunctional prediction of treatment outcome in patients with depression

Background

We investigated the differential effects of serotonergic and noradrenergic antidepressants on brain activation in patients with major depressive disorder during a Stroop task. We predicted that pretreatment hyperactivity in the rostral anterior cingulate cortex would predict better treatment outcomes.

Methods

In total, 20 patients underwent naturalistic open-label clinical treatment with citalopram (n = 12) or reboxetine (n = 8). We performed functional magnetic resonance imaging at baseline and after 6 weeks of treatment.

Results

There were no significant group differences in clinical characteristics, treatment outcomes or baseline fMRI activations. The group by time interaction revealed significant voxels in the right amygdala–hippocampus complex (p < 0.05, family-wise error corrected by use of the bilateral amygdala and hippocampus mask image as a small volume), indicating a posttreatment blood oxygen level–dependent signal decrease in the citalopram group. Pretreatment hyperactivity in the rostral anterior cingulate cortex was not related to symptom improvement.

Limitations

Our study was a nonrandomized clinical trial.

Conclusion

These results indicate that serotonergic and noradrenergic antidepressants have a differential effect on brain activity, especially in the amygdala and hippocampus.     

BDNF protein levels are decreased in transformed lymphoblasts from lithium-responsive patients with bipolar disorder

Objective

Brain-derived neurotrophic factor (BDNF) is a key factor in neuroplasticity and has been implicated in the affective disorders; studies have demonstrated elevated BDNF in patients taking lithium and other mood stabilizers. The objective of our study was to analyze BDNF in lithium-responsive patients with bipolar disorder (BD) to further understand the role of BDNF in the pathophysiology of BD.

Methods

Using enzyme-linked immunosorbent assay, we measured transformed B lymphocytes for BDNF protein.

Results

BDNF levels were 36% lower in lymphoblasts from patients with BD (n = 12), compared with matched control participants (n = 13), and 55% lower when compared with their unaffected relatives (n = 14). Lithium significantly decreased BDNF levels in patients with BD and healthy control participants, although BDNF levels remained lower (33%) in the BD group posttreatment.

Conclusion

Decreased BDNF may constitute part of the pathophysiologic process of BD in a lithium-responsive subgroup of individuals with this disease. A compensatory mechanism protecting the genetically predisposed unaffected relatives from phenotypic expression of BD is suggested.Medical subject headings: bipolar disorder, brain-derived neurotrophic factor, enzyme-linked immunosorbent assay, lithium