Handan Gunduz-Bruce

Brain-derived neurotrophic factor Val66met polymorphism and volume of the hippocampal formation

Magnetic resonance (MR) imaging studies have identified hippocampal structural alterations in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins that is widely expressed in the hippocampal formation and has been implicated in the neurobiology of schizophrenia. Polymorphisms in the BDNF gene may therefore confer risk for schizophrenia through hippocampal pathogenesis and/or making the hippocampus more susceptible to environmental insults. In this study, we investigated whether val66met, a functional and abundant missense polymorphism in the coding region of the BDNF gene, was associated with the volume of the hippocampal formation in 19 patients with first-episode schizophrenia and 25 healthy volunteers. A total of 124 contiguous T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF val66met locus. Mixed model analyses revealed a main effect of BDNF val66met genotype such that in the combined sample of patients and healthy volunteers, val/val homozygotes (N=27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N=17). In separate analyses by group, however, val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patients compared to healthy volunteers. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume and suggest that this effect may be greater among patients compared to healthy volunteers.

Clinical and Neuropsychological Correlates of White Matter Abnormalities in Recent Onset Schizophrenia

The objective of this study was to investigate the clinical and neuropsychological correlates of white matter abnormalities in patients with schizophrenia studied early in the course of illness. A total of 33 (21 male/12 female) patients with recent onset schizophrenia and 30 (18 male/12 female) healthy volunteers completed structural and diffusion tensor imaging exams. Patients also received clinical and neuropsychological assessments. Fractional anisotropy (FA) maps were compared between groups in the white matter using a voxelwise analysis following intersubject registration to Talairach space and correlated with functional indices. Compared to healthy volunteers, patients demonstrated significantly (p<0.001, cluster size ⩾100) lower FA within temporal lobe white matter regions corresponding approximately to the right and left uncinate fasciculus, left inferior fronto-occipital fasciculus, and left superior longitudinal fasciculus. There were no areas of significantly higher FA in patients compared to healthy volunteers. Lower FA in the bilateral uncinate fasciculus correlated significantly with greater severity of negative symptoms (alogia and affective flattening), and worse verbal learning/memory functioning. In addition, higher FA in the inferior fronto-occipital fasciculus correlated significantly with greater severity of delusions and hallucinations. White matter abnormalities are evident in patients with schizophrenia early in the course of illness, appearing most robust in left temporal regions. These abnormalities have clinical and neuropsychological correlates, which may be useful in further characterizing structure–function relations in schizophrenia and constraining neurobiological models of the disorder.

The acute effects of NMDA antagonism: From the rodent to the human brain

In the past decade, the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has received support from several lines of clinical evidence, including genetic, postmortem and human psychosis modeling. Recently, superiority of a mGluR2/3 receptor agonist over placebo was demonstrated in a randomized double-blind clinical trial in patients with schizophrenia. Considering the fact that currently available antipsychotics are all dopamine blockers to varying degrees without direct effects on glutamate transmission, this clinical trial highlights the potential utility of glutamatergic agents. In healthy volunteers, the NMDA channel antagonist ketamine induces transient cognitive dysfunction, perceptual aberrations and changes reminiscent of the negative symptoms of schizophrenia. However, how ketamine produces these effects is unclear. Preclinical data on NMDAR hypofunction offer further insights into the pathogenesis of the disorder as it relates to disorganized behavior, stereotypic movements and cognitive dysfunction in the rodent. This review evaluates the existing clinical and preclinical literature in an effort to shed light on the mechanism of action of ketamine as a probe to model NMDAR hypofunction in healthy volunteers. Included in this perspective are direct and indirect effects of ketamine at the neuronal level and in the intact brain. In addition to ketamines effects on presynaptic and postsynaptic function, effects on glia and other neurotransmitter systems are discussed. While increased extracellular glutamate levels following NMDA antagonist administration stand out as a well replicated finding, evidence suggests that ketamines effects are not restricted to pyramidal cells, but extend to GABAergic interneurons and the glia. In the glia, ketamine has significant downstream effects on the glutathione metabolism. Further studies are needed to identify the mechanistic connections between ketamines effects at the cellular and behavioral levels.

Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists

Drugs acting at metabotropic glutamate receptors (mGluRs) are among the most promising agents under development for the treatment of psychiatric disorders. The research in this area is at a relatively early stage, as there are no drugs acting at mGluRs that have been approved for the treatment of any psychiatric disorder. However, in the areas of schizophrenia, anxiety disorders and mood disorders, research conducted in animal models appears to translate well into efficacy in human laboratory-based models of psychopathology and in preliminary clinical trials. Further, the genes coding for mGluRs are implicated in the risk for a growing number of psychiatric disorders. This review highlights the best studied mGluR strategies for psychiatry, based on human molecular genetics, studies in animal models and preliminary clinical trials. It describes the potential value of mGluR2 and mGluR5 agonists and positive allosteric modulators for the treatment of schizophrenia. It also reviews evidence that group II mGluR agonists and positive allosteric modulators as well as group I mGluR antagonists might also treat anxiety disorders and some forms of depression, while mGluR2 and group I mGluR antagonists (particularly mGluR5 antagonists) might have antidepressant properties. This review also links growing insights into the role of glutamate in the pathophysiology of these disorders to hypothesized mGluR-related treatment mechanisms.

Are cannabis use disorders associated with an earlier age at onset of psychosis? A study in first episode schizophrenia

INTRODUCTION The purpose of this study is to determine if an earlier age at onset of positive symptoms in schizophrenia is associated with cannabis use disorders (CUD). METHODS 49 first-episode schizophrenia subjects with CUD were compared to 51 first-episode schizophrenia subjects with no substance use disorders for demographic and clinical variables. A multivariate logistic regression was performed to determine the joint relationship between variables significantly associated with CUD on univariate testing and ascertain if these variables independently predict CUD. Significance level was set at p<0.05. RESULTS 74% of CUD subjects had the onset of CUD before the onset of positive symptoms. Compared to non-substance abusing subjects, CUD subjects were predominantly male, younger at study entry, had an earlier age at onset of positive symptoms, less educational attainment, a lower self-socioeconomic status, better premorbid childhood social adjustment, a trend for poorer premorbid childhood academic adjustment, less motor abnormalities but more severe hallucinations and delusions. In the multivariate analysis, only male gender, worse socio-economic status, better premorbid childhood social adjustment, and more severe positive symptoms at study entry were associated with a lifetime history of CUD. DISCUSSION Although cannabis use precedes the onset of illness in most patients, there was no significant association between onset of illness and CUD that was not accounted for by demographic and clinical variables. Previous studies implicating CUD in the onset of schizophrenia may need to more comprehensively assess the relationship between CUD and schizophrenia, and take into account additional variables that we found associated with CUD.

Glutamatergic Modulation of Auditory Information Processing in the Human Brain

BACKGROUND Auditory mismatch negativity (MMN) and P300 event-related potentials (ERPs) are reduced in schizophrenia patients and healthy volunteers administered the N-methyl-D-aspartate glutamate receptor antagonist, ketamine. In rodents, N-acetylcysteine (NAC), a stimulator of the cystine-glutamate exchanger, attenuates the cognitive and behavioral effects of N-methyl-D-aspartate receptor antagonists. On the basis of these findings, we tested whether NAC would reduce ketamine effects on behavior, MMN, and P300 in healthy humans. METHODS This randomized, double-blind, placebo-controlled study consisted of 2 test days during which subjects (n = 16) were administered oral NAC (3000 mg in divided doses) or matching placebo 165 min before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Behavioral and ERP data including auditory MMN and P300 were collected during each test day. RESULTS Ketamine produced psychotic-like positive symptoms, reductions in working memory and sustained attention performance, and amplitude reductions for the frequency- and intensity-deviant MMNs and P300. NAC pretreatment did not reduce the behavioral or ERP effects of ketamine. In addition, NAC reduced frequency-deviant MMN amplitude and increased target and novelty P3 amplitudes. The decrements in frequency-deviant MMN amplitude produced by ketamine and NAC were not additive. CONCLUSIONS NAC did not attenuate the effects of ketamine in humans, in contrast to previous studies in animals. NAC merits further investigation as a cognitive enhancing agent due to its ability to increase the P300 amplitude.

Magnetic Resonance Imaging Predictors of Treatment Response in First-Episode Schizophrenia

Identifying neurobiological predictors of response to antipsychotics in patients with schizophrenia is a critical goal of translational psychiatry. Few studies, however, have investigated the relationship between indices of brain structure and treatment response in the context of a controlled clinical trial. In this study, we sought to identify magnetic resonance (MR) imaging measures of the brain that predict treatment response in patients experiencing a first-episode of schizophrenia. Structural MR imaging scans were acquired in 39 patients experiencing a first-episode of schizophrenia with minimal or no prior exposure to antipsychotics participating in a double-blind 16-week clinical trial comparing the efficacy of risperidone vs olanzapine. Twenty-five patients were classified as responders by meeting operationally defined treatment response criteria on 2 consecutive study visits. Fourteen patients never responded to antipsychotic medication at any point during the clinical trial. MR imaging scans were also acquired in 45 age- and sex-matched healthy volunteers. Cortical pattern matching methods were used to compare cortical thickness and asymmetry measures among groups. Statistical mapping results, confirmed by permutation testing, indicated that responders had greater cortical thickness in occipital regions and greater frontal cortical asymmetry compared with nonresponders. Moreover, among responders, greater thickness in temporal regions was associated with less time to respond. Our findings are consistent with the hypothesis that plasticity and cortical thickness may be more preserved in responders and that MR imaging may assist in the prediction of antipsychotic drug response in patients experiencing a first-episode of schizophrenia.

Volumetric and Shape Analysis of the Thalamus in First-Episode Schizophrenia

Thalamic abnormalities have been implicated in the pathogenesis of schizophrenia, although the majority of studies used chronic samples treated extensively with antipsychotics. Moreover, the clinical and neuropsychological correlates of these abnormalities remain largely unknown. Using high‐resolution MR imaging and novel methods for shape analysis, we investigated thalamic subregions in 35 (25 M/10 F) first‐episode schizophrenia patients compared with 33 (23 M/10 F) healthy volunteers. The right and left thalami were traced bilaterally on coronal brain slices and volumes were compared between groups. In addition, regional abnormalities were identified by comparing distances, measured from homologous thalamic surface points to the central core of each individuals surface model, between groups in 3D space. Patients had significantly less total thalamic volume compared with healthy volunteers. Statistical mapping demonstrated most pronounced shape abnormalities in the pulvinar; however, estimated false discovery rates in these regions were sizable. Smaller thalamus volume was significantly correlated with worse overall neuropsychological functioning and specific deficits were observed in the language, motor, and executive domains. There were no significant associations between thalamus volume and positive or negative symptoms. Our findings suggest that thalamic abnormalities are evident at the onset of a first episode of schizophrenia prior to extensive pharmacologic intervention and that these abnormalities have neuropsychological correlates. Hum Brain Mapp, 2009.

Patterns of stress in schizophrenia

Although it is widely recognized that stress plays a key role in the pathophysiology of schizophrenia, little is known regarding the particular types of stress patients experience. Less is known about the interplay among stressful events, personality mediators, and emotional responses. In this study, we investigated 10 stress dimensions in 29 patients with schizophrenia and 36 healthy volunteers using the Derogatis Stress Profile (DSP), and the relationship between these dimensions and symptoms in patients. Overall, patients had an approximate 0.75 standard deviation increase in stress compared with healthy volunteers. Significant increases in stress among patients compared with healthy volunteers were observed specifically in areas related to domestic environment, driven behavior, and depression, but not in health, attitude posture, time pressure, relaxation potential, role definition, hostility, or anxiety. More DSP-rated depression among patients correlated significantly with greater negative symptom severity. Patients with a shorter duration of antipsychotic drug exposure had significantly greater hostility than did patients with a longer duration of exposure, but did not differ in any other dimension. Continued investigation of domestic environmental stressors, driven behavior, and depression may be useful in identifying high-risk groups, and understanding symptom exacerbation and precipitants of relapse in patients already diagnosed with schizophrenia.

Cortisol levels in relation to hippocampal sub-regions in subjects with first episode schizophrenia

The etiology of hippocampal volumetric reductions in schizophrenia is largely unknown. In addition to genetic factors, environmental factors might also play a role. High levels of glucocorticoids are known to affect hippocampal volume in disorders such as Cushings syndrome, but the relationship between cortisol and hippocampal volumes has not been studied in schizophrenia. We obtained diurnal salivary cortisol levels and MRI images to explore the link between cortisol levels and regional hippocampal volumes in healthy controls (N=29) and subjects with first episode schizophrenia (N=16) at the time of first admission. T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Using ANOVA, cumulative daily cortisol exposure calculated as area under the curve for each subject revealed significantly higher cortisol levels in the patient group [F(1,43)=4.4 p=0.04]. However, there were no statistically significant associations between the cortisol measures and regional hippocampal volumes in the subjects, except a trend level link between anterior hippocampal volume and cortisol in the positive direction, in parallel to previous findings in healthy adolescents. Our findings do not suggest a robust association between cortisol levels and hippocampal volumes in a first episode schizophrenia sample. Larger scale studies are needed to conclude a link between the two measures, yet it is possible that the negative association that was previously shown in other disorders may not apply to schizophrenia.