Associations and Heritability of Auditory Encoding, Gray Matter, and Attention in Schizophrenia.

BACKGROUND: Auditory encoding abnormalities, gray-matter loss, and cognitive deficits are all candidate schizophrenia (SZ) endophenotypes. This study evaluated associations between and heritability of auditory network attributes (function and structure) and attention in healthy controls (HC), SZ patients, and unaffected relatives (UR). METHODS: Whole-brain maps of M100 auditory activity from magnetoencephalography recordings, cortical thickness (CT), and a measure of attention were obtained from 70 HC, 69 SZ patients, and 35 UR. Heritability estimates (h2r) were obtained for M100, CT at each group-difference region, and the attention measure. RESULTS: SZ patients had weaker bilateral superior temporal gyrus (STG) M100 responses than HC and a weaker right frontal M100 response than UR. Abnormally large M100 responses in left superior frontal gyrus were observed in UR and SZ patients. SZ patients showed smaller CT in bilateral STG and right frontal regions. Interrelatedness between 3 putative SZ endophenotypes was demonstrated, although in the left STG the M100 and CT function-structure associations observed in HC and UR were absent in SZ patients. Heritability analyses also showed that right frontal M100 and bilateral STG CT measures are significantly heritable. CONCLUSIONS: Present findings indicated that the 3 SZ endophenotypes examined are not isolated markers of pathology but instead are connected. The pattern of auditory encoding group differences and the pattern of brain function-structure associations differ as a function of brain region, indicating the need for regional specificity when studying these endophenotypes, and with the presence of left STG function-structure associations in HC and UR but not in SZ perhaps reflecting disease-associated damage to gray matter that disrupts function-structure relationships in SZ.

Characterizing the Effects of Quetiapine in Military Post-Traumatic Stress Disorder.

Objectives: A previous randomized placebo-controlled trial in military veterans posttraumatic stress disorder (PTSD) found that quetiapine improved global PTSD symptoms severity, depression and anxiety as well as the re-experiencing and hypearousal clusters. However, it is not known if individual symptoms had a preferential response to this medication. The goal of this study was to analyze the individual symptom response in this group of patients. Methods: Data from a previous trial was re-analyzed. Each of the of the scale items was analyzed individually using Repeated Measures Analysis of Variance. Results: Compared to placebo, there was a significant decline in the Clinician-Administered PTSD Scale intrusive memories and insomnia questions. In the Davidson Trauma Scale, greater improvements were observed on irritability, difficulty concentrating, hyperstartle and a trend was observed on avoiding thoughts or feelings about the event. Greater improvements compared with placebo were noted on the Hamilton Depression (HAM-D) middle and late insomnia items. On the Hamilton Anxiety scale (HAM-A), the insomnia item was significantly improved. Conclusions: Quetiapine demonstrated greater effect than placebo on several symptoms. The strongest response was seen on insomnia, which the highest significance level on the CAPS. The insomnia items of both the HAM-D and HAM-A also demonstrated improvement with quetiapine. These finding indicate quetiapine improved sleep measure. Insomnia can be a difficult problem to treat in PTSD patients, therefore quetiapine should be considered in difficult cases.

Identifying auditory cortex encoding abnormalities in schizophrenia: The utility of low-frequency versus 40 Hz steady-state measures.

Magnetoencephalography (MEG) and EEG have identified poststimulus low frequency and 40 Hz steady-state auditory encoding abnormalities in schizophrenia (SZ). Negative findings have also appeared. To identify factors contributing to these inconsistencies, healthy control (HC) and SZ group differences were examined in MEG and EEG source space and EEG sensor space, with better group differentiation hypothesized for source than sensor measures given greater predictive utility for source measures. Fifty-five HC and 41 chronic SZ were presented 500 Hz sinusoidal stimuli modulated at 40 Hz during simultaneous whole-head MEG and EEG. MEG and EEG source models using left and right superior temporal gyrus (STG) dipoles estimated trial-to-trial phase similarity and percent change from prestimulus baseline. Group differences in poststimulus low-frequency activity and 40 Hz steady-state response were evaluated. Several EEG sensor analysis strategies were also examined. Poststimulus low-frequency group differences were observed across all methods. Given an age-related decrease in left STG 40 Hz steady-state activity in HC (HC > SZ), 40 Hz steady-state group differences were evident only in younger participants' source measures. Findings thus indicated that optimal data collection and analysis methods depend on the auditory encoding measure of interest. In addition, whereas results indicated that HC and SZ auditory encoding low-frequency group differences are generally comparable across modality and analysis strategy (and thus not dependent on obtaining construct-valid measures of left and right auditory cortex activity), 40 Hz steady-state group-difference findings are much more dependent on analysis strategy, with 40 Hz steady-state source-space findings providing the best group differentiation.

Risk-Conferring Glutamatergic Genes and Brain Glutamate Plus Glutamine in Schizophrenia.

BACKGROUND: The proton magnetic resonance spectroscopy (1H-MRS) signals from glutamate (or the combined glutamate and glutamine signal-Glx) have been found to be greater in various brain regions in people with schizophrenia. Recently, the Psychiatric Genetics Consortium reported that several common single-nucleotide polymorphisms (SNPs) in glutamate-related genes confer increased risk of schizophrenia. Here, we examined the relationship between presence of these risk polymorphisms and brain Glx levels in schizophrenia. METHODS: 1H-MRS imaging data from an axial, supraventricular tissue slab were acquired in 56 schizophrenia patients and 67 healthy subjects. Glx was measured in gray matter (GM) and white matter (WM) regions. The genetic data included six polymorphisms genotyped across an Illumina 5M SNP array. Only three of six glutamate as well as calcium-related SNPs were available for examination. These included three glutamate-related polymorphisms (rs10520163 in CLCN3, rs12704290 in GRM3, and rs12325245 in SLC38A7), and three calcium signaling polymorphisms (rs1339227 in RIMS1, rs7893279 in CACNB2, and rs2007044 in CACNA1C). Summary risk scores for the three glutamate and the three calcium polymorphisms were calculated. RESULTS: Glx levels in GM positively correlated with glutamate-related genetic risk score but only in younger (≤36 years) schizophrenia patients (p = 0.01). Glx levels did not correlate with calcium risk scores. Glx was higher in the schizophrenia group compared to levels in controls in GM and WM regardless of age (p < 0.001). CONCLUSION: Elevations in brain Glx are in part, related to common allelic variants of glutamate-related genes known to increase the risk for schizophrenia. Since the glutamate risk scores did not differ between groups, some other genetic or environmental factors likely interact with the variability in glutamate-related risk SNPs to contribute to an increase in brain Glx early in the illness.

By our bootstraps: Comparing methods for measuring auditory 40 Hz steady-state neural activity.

Although the 40 Hz auditory steady-state response (ASSR) is of clinical interest, the construct validity of EEG and MEG measures of 40 Hz ASSR cortical microcircuits is unclear. This study evaluated several MEG and EEG metrics by leveraging findings of (a) an association between the 40 Hz ASSR and age in the left but not right hemisphere, and (b) right- > left-hemisphere differences in the strength of the 40 Hz ASSR. The contention is that, if an analysis method does not demonstrate a left 40 Hz ASSR and age relationship or hemisphere differences, then the obtained measures likely have low validity. Fifty-three adults were presented 500 Hz stimuli modulated at 40 Hz while MEG and EEG were collected. ASSR activity was examined as a function of phase similarity (intertrial coherence) and percent change from baseline (total power). A variety of head models (spherical and realistic) and a variety of dipole source modeling strategies (dipole source localization and dipoles fixed to Heschl's gyri) were compared. Several sensor analysis strategies were also tested. EEG sensor measures failed to detect left 40 Hz ASSR and age associations or hemisphere differences. A comparison of MEG and EEG head-source models showed similarity in the 40 Hz ASSR measures and in estimating age and left 40 Hz ASSR associations, indicating good construct validity across models. Given a goal of measuring the 40 Hz ASSR cortical microcircuits, a source-modeling approach was shown to be superior in measuring this construct versus methods that rely on EEG sensor measures.

Efficacy of Quetiapine Monotherapy in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: This was a 12-week randomized, placebo-controlled trial to assess the efficacy of quetiapine monotherapy in the treatment of posttraumatic stress disorder (PTSD). METHOD: Eighty patients were randomly assigned to treatment with either quetiapine or placebo. The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS). Secondary efficacy measures included the CAPS subscales, the Davidson Trauma Scale, the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scales for severity of Illness and improvement, the Hamilton Depression Rating Scale (HAM-D), and the Hamilton Anxiety Rating Scale (HAM-A). Safety measurements included adverse events, vital signs, the Abnormal Involuntary Movement Scale, the Barnes Akathisia Scale, the Simpson-Angus Scale, and the Arizona Sexual Experiences Scale. RESULTS: After a 1-week placebo run-in, quetiapine was started at a daily dosage of 25 mg and increased to a maximum of 800 mg; the average was 258 mg (range, 50-800 mg). Reductions in CAPS total, re-experiencing, and hyperarousal scores were significantly greater for the quetiapine group than for the placebo group. Greater improvements were also observed for quetiapine in scores on the Davidson Trauma Scale, CGI severity and improvement ratings, PANSS positive symptom and general psychopathology subscales, HAM-A, and HAM-D than for placebo. Adverse events were generally mild and expected based on prior studies of quetiapine in this and other patient population. There were no differences in safety measures between groups. CONCLUSION: Quetiapine monotherapy was efficacious in the treatment of PTSD. These findings suggest quetiapine as a single agent is effective in treating military PTSD.

Frontal slow-wave activity as a predictor of negative symptoms, cognition and functional capacity in schizophrenia.

BACKGROUND: Increased temporal and frontal slow-wave delta (1-4 Hz) and theta (4-7 Hz) activities are the most consistent resting-state neural abnormalities reported in schizophrenia. The frontal lobe is associated with negative symptoms and cognitive abilities such as attention, with negative symptoms and impaired attention associated with poor functional capacity. AIMS: To establish whether frontal dysfunction, as indexed by slowing, would be associated with functional impairments. METHOD: Eyes-closed magnetoencephalography data were collected in 41 participants with schizophrenia and 37 healthy controls, and frequency-domain source imaging localised delta and theta activity. RESULTS: Elevated delta and theta activity in right frontal and right temporoparietal regions was observed in the schizophrenia v. CONTROL GROUP: In schizophrenia, right-frontal delta activity was uniquely associated with negative but not positive symptoms. In the full sample, increased right-frontal delta activity predicted poorer attention and functional capacity. CONCLUSIONS: Our findings suggest that treatment-associated decreases in slow-wave activity could be accompanied by improved functional outcome and thus better prognosis.

Single-subject-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mild traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of sustained impairment in military and civilian populations. However, mild TBI (mTBI) can be difficult to detect using conventional MRI or CT. Injured brain tissues in mTBI patients generate abnormal slow-waves (1-4 Hz) that can be measured and localized by resting-state magnetoencephalography (MEG). In this study, we develop a voxel-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mTBI on a single-subject basis. A normative database of resting-state MEG source magnitude images (1-4 Hz) from 79 healthy control subjects was established for all brain voxels. The high-resolution MEG source magnitude images were obtained by our recent Fast-VESTAL method. In 84 mTBI patients with persistent post-concussive symptoms (36 from blasts, and 48 from non-blast causes), our method detected abnormalities at the positive detection rates of 84.5%, 86.1%, and 83.3% for the combined (blast-induced plus with non-blast causes), blast, and non-blast mTBI groups, respectively. We found that prefrontal, posterior parietal, inferior temporal, hippocampus, and cerebella areas were particularly vulnerable to head trauma. The result also showed that MEG slow-wave generation in prefrontal areas positively correlated with personality change, trouble concentrating, affective lability, and depression symptoms. Discussion is provided regarding the neuronal mechanisms of MEG slow-wave generation due to deafferentation caused by axonal injury and/or blockages/limitations of cholinergic transmission in TBI. This study provides an effective way for using MEG slow-wave source imaging to localize affected areas and supports MEG as a tool for assisting the diagnosis of mTBI.

Thalamus and posterior temporal lobe show greater inter-network connectivity at rest and across sensory paradigms in schizophrenia.

Although a number of recent studies have examined functional connectivity at rest, few have assessed differences between connectivity both during rest and across active task paradigms. Therefore, the question of whether cortical connectivity patterns remain stable or change with task engagement continues to be unaddressed. We collected multi-scan fMRI data on healthy controls (N=53) and schizophrenia patients (N=42) during rest and across paradigms arranged hierarchically by sensory load. We measured functional network connectivity among 45 non-artifactual distinct brain networks. Then, we applied a novel analysis to assess cross paradigm connectivity patterns applied to healthy controls and patients with schizophrenia. To detect these patterns, we fit a group by task full factorial ANOVA model to the group average functional network connectivity values. Our approach identified both stable (static effects) and state-based differences (dynamic effects) in brain connectivity providing a better understanding of how individuals' reactions to simple sensory stimuli are conditioned by the context within which they are presented. Our findings suggest that not all group differences observed during rest are detectable in other cognitive states. In addition, the stable differences of heightened connectivity between multiple brain areas with thalamus across tasks underscore the importance of the thalamus as a gateway to sensory input and provide new insight into schizophrenia.

MEG source imaging method using fast L1 minimum-norm and its applications to signals with brain noise and human resting-state source amplitude images.

The present study developed a fast MEG source imaging technique based on Fast Vector-based Spatio-Temporal Analysis using a L1-minimum-norm (Fast-VESTAL) and then used the method to obtain the source amplitude images of resting-state magnetoencephalography (MEG) signals for different frequency bands. The Fast-VESTAL technique consists of two steps. First, L1-minimum-norm MEG source images were obtained for the dominant spatial modes of sensor-waveform covariance matrix. Next, accurate source time-courses with millisecond temporal resolution were obtained using an inverse operator constructed from the spatial source images of Step 1. Using simulations, Fast-VESTAL's performance was assessed for its 1) ability to localize multiple correlated sources; 2) ability to faithfully recover source time-courses; 3) robustness to different SNR conditions including SNR with negative dB levels; 4) capability to handle correlated brain noise; and 5) statistical maps of MEG source images. An objective pre-whitening method was also developed and integrated with Fast-VESTAL to remove correlated brain noise. Fast-VESTAL's performance was then examined in the analysis of human median-nerve MEG responses. The results demonstrated that this method easily distinguished sources in the entire somatosensory network. Next, Fast-VESTAL was applied to obtain the first whole-head MEG source-amplitude images from resting-state signals in 41 healthy control subjects, for all standard frequency bands. Comparisons between resting-state MEG sources images and known neurophysiology were provided. Additionally, in simulations and cases with MEG human responses, the results obtained from using conventional beamformer technique were compared with those from Fast-VESTAL, which highlighted the beamformer's problems of signal leaking and distorted source time-courses.

Cortical thickness as a contributor to abnormal oscillations in schizophrenia?

INTRODUCTION: Although brain rhythms depend on brain structure (e.g., gray and white matter), to our knowledge associations between brain oscillations and structure have not been investigated in healthy controls (HC) or in individuals with schizophrenia (SZ). Observing function-structure relationships, for example establishing an association between brain oscillations (defined in terms of amplitude or phase) and cortical gray matter, might inform models on the origins of psychosis. Given evidence of functional and structural abnormalities in primary/secondary auditory regions in SZ, the present study examined how superior temporal gyrus (STG) structure relates to auditory STG low-frequency and 40 Hz steady-state activity. Given changes in brain activity as a function of age, age-related associations in STG oscillatory activity were also examined. METHODS: Thirty-nine individuals with SZ and 29 HC were recruited. 40 Hz amplitude-modulated tones of 1 s duration were presented. MEG and T1-weighted sMRI data were obtained. Using the sources localizing 40 Hz evoked steady-state activity (300 to 950 ms), left and right STG total power and inter-trial coherence were computed. Time-frequency group differences and associations with STG structure and age were also examined. RESULTS: Decreased total power and inter-trial coherence in SZ were observed in the left STG for initial post-stimulus low-frequency activity (~ 50 to 200 ms, ~ 4 to 16 Hz) as well as 40 Hz steady-state activity (~ 400 to 1000 ms). Left STG 40 Hz total power and inter-trial coherence were positively associated with left STG cortical thickness in HC, not in SZ. Left STG post-stimulus low-frequency and 40 Hz total power were positively associated with age, again only in controls. DISCUSSION: Left STG low-frequency and steady-state gamma abnormalities distinguish SZ and HC. Disease-associated damage to STG gray matter in schizophrenia may disrupt the age-related left STG gamma-band function-structure relationships observed in controls.

Frontal and superior temporal auditory processing abnormalities in schizophrenia.

BACKGROUND: Although magnetoencephalography (MEG) studies show superior temporal gyrus (STG) auditory processing abnormalities in schizophrenia at 50 and 100 ms, EEG and corticography studies suggest involvement of additional brain areas (e.g., frontal areas) during this interval. Study goals were to identify 30 to 130 ms auditory encoding processes in schizophrenia (SZ) and healthy controls (HC) and group differences throughout the cortex. METHODS: The standard paired-click task was administered to 19 SZ and 21 HC subjects during MEG recording. Vector-based Spatial-temporal Analysis using L1-minimum-norm (VESTAL) provided 4D maps of activity from 30 to 130 ms. Within-group t-tests compared post-stimulus 50 ms and 100 ms activity to baseline. Between-group t-tests examined 50 and 100 ms group differences. RESULTS: Bilateral 50 and 100 ms STG activity was observed in both groups. HC had stronger bilateral 50 and 100 ms STG activity than SZ. In addition to the STG group difference, non-STG activity was also observed in both groups. For example, whereas HC had stronger left and right inferior frontal gyrus activity than SZ, SZ had stronger right superior frontal gyrus and left supramarginal gyrus activity than HC. CONCLUSIONS: Less STG activity was observed in SZ than HC, indicating encoding problems in SZ. Yet auditory encoding abnormalities are not specific to STG, as group differences were observed in frontal and SMG areas. Thus, present findings indicate that individuals with SZ show abnormalities in multiple nodes of a concurrently activated auditory network.

Guided exploration of genomic risk for gray matter abnormalities in schizophrenia using parallel independent component analysis with reference.

One application of imaging genomics is to explore genetic variants associated with brain structure and function, presenting a new means of mapping genetic influences on mental disorders. While there is growing interest in performing genome-wide searches for determinants, it remains challenging to identify genetic factors of small effect size, especially in limited sample sizes. In an attempt to address this issue, we propose to take advantage of a priori knowledge, specifically to extend parallel independent component analysis (pICA) to incorporate a reference (pICA-R), aiming to better reveal relationships between hidden factors of a particular attribute. The new approach was first evaluated on simulated data for its performance under different configurations of effect size and dimensionality. Then pICA-R was applied to a 300-participant (140 schizophrenia (SZ) patients versus 160 healthy controls) dataset consisting of structural magnetic resonance imaging (sMRI) and single nucleotide polymorphism (SNP) data. Guided by a reference SNP set derived from ANK3, a gene implicated by the Psychiatric Genomic Consortium SZ study, pICA-R identified one pair of SNP and sMRI components with a significant loading correlation of 0.27 (p=1.64×10(-6)). The sMRI component showed a significant group difference in loading parameters between patients and controls (p=1.33×10(-15)), indicating SZ-related reduction in gray matter concentration in prefrontal and temporal regions. The linked SNP component also showed a group difference (p=0.04) and was predominantly contributed to by 1030 SNPs. The effect of these top contributing SNPs was verified using association test results of the Psychiatric Genomic Consortium SZ study, where the 1030 SNPs exhibited significant SZ enrichment compared to the whole genome. In addition, pathway analyses indicated the genetic component majorly relating to neurotransmitter and nervous system signaling pathways. Given the simulation and experiment results, pICA-R may prove a promising multivariate approach for use in imaging genomics to discover reliable genetic risk factors under a scenario of relatively high dimensionality and small effect size.

Comparison of outcomes for African Americans, Hispanics, and Non-Hispanic Whites in the CATIE study.

OBJECTIVE: Medication outcome literature in schizophrenia across racial-ethnic groups is sparse, with inconsistent findings. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study provided an opportunity for exploratory analyses of racial-ethnic outcomes. The study objective was to examine race-ethnicity outcomes for CATIE's main outcome (study discontinuation) and secondary outcomes. METHODS: CATIE participants included whites (non-Hispanic) (N=722), African Americans (N=506), and Hispanics (N=170). Survival analyses and mixed-effects regression modeling were conducted, with adjustment for baseline sociodemographic differences and baseline scores of the secondary outcomes. RESULTS: Racial-ethnic groups had unique patterns of outcomes. Hispanics were much more likely to discontinue for lack of efficacy from perphenazine (64% versus 42% non-Hispanic whites and 24% African Americans) and ziprasidone (71% versus 40% non-Hispanic whites and 24% African Americans); Hispanics' quality of life also declined on these medications. Non-Hispanic whites were more likely to discontinue for lack of efficacy in general (averaging olanzapine, quetiapine, and risperidone discontinuation rates). African Americans were less likely to continue after the first phase (32% continuing versus 40% for non-Hispanic whites and 41% Hispanics). Discontinuations were driven by research burden, personal issues, and unspecified loss to follow-up. Non-Hispanic whites had higher depression scores during the follow-up period. African Americans had fewer side effects. CONCLUSIONS: CATIE results did not show disparities favoring non-Hispanic whites. CATIE may have provided state-of-the-art treatment and thus reduced disparate treatments observed in community clinics. African Americans discontinued even after consideration of socioeconomic differences. Why perphenazine and ziprasidone may be less effective with Hispanics should be explored.

Temporal and frontal cortical thickness associations with M100 auditory activity and attention in healthy controls and individuals with schizophrenia.

BACKGROUND: Although gray matter (GM) abnormalities are frequently observed in individuals with schizophrenia (SCZ), the functional consequences of these structural abnormalities are not yet understood. The present study sought to better understand GM abnormalities in SCZ by examining associations between GM and two putative functional SCZ biomarkers: weak 100 ms (M100) auditory responses and impairment on tests of attention. METHODS: Data were available from 103 subjects (healthy controls=52, SCZ=51). GM cortical thickness measures were obtained for superior temporal gyrus (STG) and prefrontal cortex (PFC). Magnetoencephalography (MEG) provided measures of left and right STG M100 source strength. Subjects were administered the Trail Making Test A and the Connors' Continuous Performance Test to assess attention. RESULTS: A strong trend indicated less GM cortical thickness in SCZ than controls in both regions and in both hemispheres (p=0.06). Individuals with SCZ had weaker M100 responses than controls bilaterally, and individuals with SCZ performed more poorly than controls on tests of attention. Across groups, left STG GM was positively associated with left M00 source strength. In SCZ only, less left and right STG and PFC GM predicted poorer performance on tests of attention. After removing variance in attention associated with age, associations between GM and attention remained significant only in left and right STG. CONCLUSIONS: Reduced GM cortical thickness may serve as a common substrate for multiple functional abnormalities in SCZ, with structural-functional abnormalities in STG GM especially prominent. As suggested by others, functional abnormalities in SCZ may be a consequence of elimination of the neuropil (dendritic arbors and associated synaptic infrastructure) between neuron bodies.

Lateralized abnormalities in auditory M50 sensory gating and cortical thickness of the superior temporal gyrus in post-traumatic stress disorder: preliminary results.

Auditory sensory gating deficits have been reported in subjects with post-traumatic stress disorder (PTSD), but the hemispheric and neuronal origins of this deficit are not well understood. The objectives of this study were to: (1) investigate auditory sensory gating of the 50-ms response (M50) in patients diagnosed with PTSD by utilizing magnetoencephalography (MEG); (2) explore the relationship between M50 sensory gating and cortical thickness of the superior temporal gyrus (STG) measured with structural magnetic resonance imaging (MRI); and (3) examine the association between PTSD symptomatology and bilateral sensory gating. Seven participants with combat-related PTSD and eleven controls underwent the paired-click sensory gating paradigm. MEG localized M50 neuronal generators to the STG in both groups. The PTSD group displayed impaired M50 gating in the right hemisphere. Thinner right STG cortical thickness was associated with worse right sensory gating in the PTSD group. The right S1 M50 source strength and gating ratio were correlated with PTSD symptomatology. These findings suggest that the structural integrity of right hemisphere STG cortices play an important role in auditory sensory gating deficits in PTSD.

Duloxetine in military posttraumatic stress disorder.

The objective of this prospective study was to assess the efficacy and tolerability of duloxetine in the treatment of in military veterans with posttraumatic stress disorder (PTSD).Twenty subjects were enrolled in this 12-week, open-label trial. Diagnosis and symptom severity were assessed with the Clinician Administered PTSD Scale (CAPS). Depressive symptoms were assessed the Hamilton Depression Rating Scale. All subjects had a CAPS score of at least 60 at baseline. Subjects with lifetime history of psychotic disorders or bipolar illness were excluded. Fifteen participants completed 12 weeks of treatment, five dropped-out from the trial, 3 due to side effects. For patients who discontinued, missing values were estimated using "the last observation carried forward" method. Significant improvements were seen on: CAPS total and all subscales, depression and sleep measures. Most of the improvement was observed by week 2 of treatment. Nine participants (45%) were classified as responders, defined by 20% or greater improvement on CAPS total score. The mean daily dose of duloxetine was 81 mg. The most common side effects were constipation (20%) diarrhea (25%) and nausea (20%). Two subjects developed tachycardia, one withdrew from the trial due to this problem. Duloxetine had a fast onset of action and was effective in about half of the subjects, it was well tolerated in most subjects. These preliminary results in a difficult to treat population warrant the conduction of a double blind, placebo-controlled study of duloxetine in PTSD.

Cognitive abilities and 50- and 100-msec paired-click processes in schizophrenia.

OBJECTIVE: Abnormal 50- and 100-msec event-related brain activity derived from paired-click procedures are well established in schizophrenia. There is little agreement on whether group differences in the ratio score, i.e., the ratio of EEG amplitude after the second stimulus (S2) to the amplitude after the first stimulus (S1), reflect an encoding or gating abnormality. In addition, the functional implications remain unclear. In the present study, EEG and magnetoencephalography (MEG) were used to examine paired-click measures and cognitive correlates of paired-click activity. METHOD: EEG and whole-cortex MEG data were acquired during the standard paired-click paradigm in 73 comparison subjects and 79 schizophrenia patients. Paired-click ratio scores were obtained at 50 msec (P50 evoked potential at Cz, M50 at left and right superior temporal gyrus [STG]) and 100 msec (N100 at Cz, M100 at left and right STG). A cognitive battery assessing attention, working memory, and long-delay memory was administered. IQ was also estimated. RESULTS: Groups differed on ratio score and amplitude of S1 response. Ratio scores at 50 msec and 100 msec and S1 amplitude predicted variance in attention (primarily S1 amplitude), working memory, and long-delay memory. The attention findings remained after removal of variance associated with IQ. CONCLUSIONS: Associations between paired-click measures and cognitive performance in patients support 50-msec and 100-msec ratio and amplitude scores as clinically significant biomarkers of schizophrenia. In general, cognitive performance was better predicted by the ability to encode auditory information than the ability to filter redundant information.

Impact of antipsychotic medication on family burden in schizophrenia: longitudinal results of CATIE trial.

BACKGROUND: This study evaluated the effectiveness of first- and second-generation antipsychotics in reducing family burden associated with schizophrenia. METHODS: The family caregivers of 623 SCID-diagnosed patients enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) randomly assigned to a first-generation antipsychotic (perphenazine) or one of four second-generation drugs (olanzapine, quetiapine, risperidone or ziprasidone) were interviewed about resources provided and stresses experienced at baseline and followed for 18 months. Patient symptoms, side effects and service use were assessed as well. Hierarchical regression analyses evaluated the effect of treatment assignment on four burden factors: problem behavior, resource demands and disruption, impairment in activities of daily living and patient helpfulness. Intention-to-treat analyses with all available observations classified based on initial treatment assignment, including observations after medications changed were followed by secondary analyses excluding observations after the first medication change, i.e. only considering initial medication. RESULTS: Despite significant reductions on the problem behavior and resource demands/disruption factors, there were no significant differences between perphenazine and any of the second-generation medications. When only initial treatment period observations were included, patients were perceived as more helpful when medicated with perphenazine as compared to risperidone. In comparisons between second-generation drugs, patients on quetiapine were perceived as more helpful than those on risperidone (p=0.004). CONCLUSION: In this 18-month randomized trial, there was no evidence of superiority of second-generation antipsychotics in relieving family burden.

Somatosensory system deficits in schizophrenia revealed by MEG during a median-nerve oddball task.

Although impairments related to somatosensory perception are common in schizophrenia, they have rarely been examined in functional imaging studies. In the present study, magnetoencephalography (MEG) was used to identify neural networks that support attention to somatosensory stimuli in healthy adults and abnormalities in these networks in patient with schizophrenia. A median-nerve oddball task was used to probe attention to somatosensory stimuli, and an advanced, high-resolution MEG source-imaging method was applied to assess activity throughout the brain. In nineteen healthy subjects, attention-related activation was seen in a sensorimotor network involving primary somatosensory (S1), secondary somatosensory (S2), primary motor (M1), pre-motor (PMA), and paracentral lobule (PCL) areas. A frontal-parietal-temporal "attention network", containing dorsal- and ventral-lateral prefrontal cortex (DLPFC and VLPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), superior parietal lobule (SPL), inferior parietal lobule (IPL)/supramarginal gyrus (SMG), and temporal lobe areas, was also activated. Seventeen individuals with schizophrenia showed early attention-related hyperactivations in S1 and M1 but hypo-activation in S1, S2, M1, and PMA at later latency in the sensorimotor network. Within this attention network, hypoactivation was found in SPL, DLPFC, orbitofrontal cortex, and the dorsal aspect of ACC. Hyperactivation was seen in SMG/IPL, frontal pole, and the ventral aspect of ACC in patients. These findings link attention-related somatosensory deficits to dysfunction in both sensorimotor and frontal-parietal-temporal networks in schizophrenia.