SCZ Group Research Articles

T143. NOT A NUISANCE ANY MORE: GLOBAL FMRI SIGNAL AT REST, PROCESSING SPEED AND SYMPTOM SEVERITY IN SCHIZOPHRENIA

BackgroundBefore data from resting-state functional magnetic resonance imaging (rs-fMRI) is analyzed, the global signal (GS) - average blood-oxygen level dependent (BOLD) signal across all voxels in the brain - is normally removed through global signal regression (GSR). This convention arose in order to control for changes in brain activity that are usually of no interest but may be caused by non-neuronal factors, including changes in respiratory rate, arterial CO2 levels or cardiac pulsation. However, recent studies have indicated that GS may systematically vary between patients with schizophrenia and healthy controls. In addition to testing this notion, we also studied if the dynamic variance of global signal across time carried any meaningful information that relates to overall symptom severity and information processing speed in patients with schizophrenia.MethodsData was collected from 39 in a clinically stable, medicated early stage of schizophrenia (median duration of illness= 6.5 years), and 34 sex, age and parental socioeconomic-status matched healthy controls over a 10-minute period of eyes-open rest at TR=2.5s (3T Philips Achieva, 240 time points, dual-echo, gradient-echo EPI). Scores were obtained from the Signs and Symptoms of Psychotic Illness (SSPI) scale and the Digit Symbol Substitution Test (DSST). Rs-fMRI time-series data were motion-corrected (using 6 parameters), slice-time corrected, reoriented with structural images, band-pass filtered (0.01–0.1 Hz), scrubbed using ArtRepair for framewise displacement and transformed to MNI space. SPM8 and the advanced version of the Data Processing Assistant for resting-state fMRI (DPARSFA) were used for this purpose. GS mean was computed from all grey matter voxels using a template mask in MNI space, using grand mean scaling to a base of 1000, averaged across all time-points. The variance of GS across time (dynamic GS variance) was computed from the entire 10-minutes of acquisition (240 time points).ResultsIndependent-sample t-tests used to compare GS mean between controls (mean[sd] = 3135.1[1244.4]) and the SCZ group (mean[sd] = 3207.8[1191.7]) yielded no significant results [t(71) = -0.14, p = .89]. The temporal variance of GS did not differ between controls (mean[sd] = 113.05[59.41]) and the SCZ group (mean[sd] = 118.02[57.93]) [t(71) = -0.36, p = .72]. In the SCZ group there was a significant correlation between the total SSPI score reflecting overall illness severity (□ = -.322, p < 0.05) and the mean GS. This relationship was especially pronounced for the syndrome of Reality Distortion (rho = -.344, p < 0.05) and Disorganization (rho = -.303, p = 0.065), where higher symptom severity was seen in patients with lower mean GS.Dynamic variance in GS was higher in healthy controls with lower mean DSST (r = -.364, p = 0.04), but no such relationship was seen in the SCZ group (r = .066, p = .694). Notably, when compared to controls (mean[sd] = 57.4[9.40]), patients (mean[sd]=42.4[9.97]) had significantly lower DSST scores [t(69) = 6.47, p < 0.001]. Neither GS nor GS variance related to root mean square of framewise displacement in the 2 groups.DiscussionWe did not find an overall increase or reduction in the global signal in patients with schizophrenia. Nevertheless, the strength of global signal obtained from resting fMRI is related to severity of persisting symptoms of schizophrenia, whereas the dynamic variance of this signal relates to the speed of processing ability assessed outside the scanner in healthy subjects. With emerging evidence relating global signal to cognitive vigilance and overall brain connectivity, our results indicate that global signal is a parameter of interest that should not be automatically discarded in resting fMRI studies of schizophrenia

S165. ALTERED ASSOCIATION BETWEEN PARIETAL GRAY-MATTER VOLUME AND DISSOCIATIVE SYMPTOMS IN SCHIZOPHRENIA: A VOXEL-BASED MORPHOMETRY STUDY

BackgroundThe presence of dissociative symptoms has been constantly reported in patients with schizophrenia. Dissociative-like experience is also part of the prodromal symptoms in those who have higher risk for psychosis. While the underlying neurobiological causes of dissociative symptoms in patients with schizophrenia remains unclear, a history of trauma seems to be related to their dissociative symptoms, as is seen in dissociative disorders. The traumatic experience has been linked to volumetric alterations in patients with schizophrenia. The current study aimed to explore the associations between past traumatic experience, brain volume alteration and the presence of dissociative symptoms in patient with schizophrenia.MethodsWe employed voxel-based morphometry (VBM) to compare the distributions of gray matter volumes (GMV) in 20 patients with schizophrenia (SCZ, 10 Male) and 26 age- and sex-matched healthy volunteers (HV, 11 male). All participants underwent high resolution T1-weighted anatomical images on a 3T MRI system. Past traumatic experience was examined by Brief Betrayal Trauma Survey (BBTS), and the dissociative symptoms were measured by Traumatic Dissociation Scale (TDS).ResultsWe found a significant GMV reduction in right thalamus area in SCZ relative to HV group (p=0.01, whole-brain FWE corrected). The GMV in thalamus was negatively associated with high-betrayal traumatic experience in SCZ group (r=-0.48, p=0.033), but not in HV (r=-0.08, p=0.71). While examining the association between GMV and dissociative experience, a significant group by dissociation interaction was observed in the left superior parietal lobule/angular gyrus (SPL/AG) was observed (p=0.024, whole-brain cluster corrected), where negative correlations was observed in HV (r=-0.62, p=0.001) but positive correlations were observed in SCZ group (r=0.67, p=0.001). In SCZ group, both traumatic experience and the left SPL/AG GMV significantly predicted the dissociative experience (p=0.001 and p=0.011, respectively; R2 increased from 0.56 to 0.70 by adding the left SPL/AG GMV into the prediction model).DiscussionIn line with previous literature, we observed a decreased thalamic GMV in SCZ group, which is uniquely associated with their high-betrayal traumatic experience. Superior parietal lobe and angular gyrus has been reported to involved in dissociative experiences in psychiatric illnesses, and modulates sensory, cognitive and self processing in schizophrenia. The positive association we observed between SPL/AG GMV and dissociation experience in SCZ suggests its crucial role in dissociative psychopathology observed in schizophrenia spectrum disorder. Future studies focusing on functional and connectivity alterations of superior parietal/angular area in SCZ and its contribution to dissociative symptoms is warranted.

S10. ASTROGLIAL PATHOLOGY IN SCHIZOPHRENIA: A META-ANALYSIS OF MRS STUDIES OF ANTERIOR CINGULATE MYOINOSITOL

BackgroundSeveral lines of evidence support a role for astroglial pathology in schizophrenia. 1H-MRS does not specifically differentiate between brain cell types; nevertheless, given that myo-inositol (mIns) is particularly abundant in astroglia rather than neuron and microglial cells, it can be considered an astroglial marker. mIns levels in the brain can decrease after brain injury with an efflux of mIns from astrocytes occurring as an osmoregulatory response. Many small sized studies have reported on mIns concentration in schizophrenia, but to date these have not been pooled to estimate a collective effect size. Examining the state of mIns deficit is a critical step to delineate the role of astroglial cells in schizophrenia. We conducted a meta-analysis to investigate the aberrations in myo-inositol levels in the ACC of patients with schizophrenia and measured using magnetic resonance spectroscopy (MRS).MethodsMedline, Google Scholar, Ovid Online and EMBASE databases were searched for studies published until September 2017. Search terms included full forms and variations of magnetic resonance spectroscopy, MRS, schizophrenia, psychosis, myo-inositol, inositol, Ins, mI, mIns. We included all 1H-MRS studies reporting mIns values for patients satisfying DSM or ICD based criteria for a primary psychotic disorder (SCZ) in comparison to a healthy controls (HC) group. We screened all identified abstracts, filtered studies that did not satisfy inclusion criteria, hand-searched references and contacted experts to locate further studies. 9 studies were identified that included 223 patients in SCZ group and 231 HCs. We excluded studies that reported only on comorbid illnesses, did not compare patients and HCs, or failed to report data required to construct effect size metrics. A random-effects and fixed-effects, inverse-weighted variance model was used to calculate the pooled effect size. Mean values were extracted and verified independently and effect sizes were computed based on Excel Macro produced by Major Depressive Disorder Neuroimaging Database (MaND) investigators.ResultsContrary to our expectations, in SCZ, there were no significant differences in ACC mIns in patients compared to HC (RFX=0.359, p= 0.057; 95% CI, -0.728 to 0.011; heterogeneity p = 0.0004). In the SCZ group, the mean effect size (Cohen’s d) was d= 0.39, indicating a medium sized difference. There were several methodological issues in the reported studies. Notably, most studies reported on mIns spectrum only when seeking differences in other metabolites; voxel placements were not standardized across the published studies; majority of patients were medicated, in various stages of illness. There was no statistical evidence for a publication bias (p=0.8).DiscussionThere is a medium effect-size, albeit statistically insignificant, reduction in the concentration of mIns in the anterior cingulate cortex in patients with schizophrenia. Given that mIns is the most readily accessible cortical marker in vivo for astroglial activity, it may be feasible to use MRS to stratify patients with astroglial abnormality from those without such an abnormality in schizophrenia.

F8. SEARCHING FOR A STRATIFICATION MARKER FOR ANTIOXIDANT USE IN SCHIZOPHRENIA AND BIPOLAR DISORDER: A META-ANALYSIS OF MRS STUDIES OF ANTERIOR CINGULATE GLUTATHIONE

BackgroundGlutathione [GSH] is a major intracellular antioxidant that disposes peroxides and protects neurons and glial cells from oxidative stress. In both schizophrenia and bipolar disorder, atypical levels of GSH has been demonstrated, particularly in the anterior cingulate cortex (ACC), though no consistent results have emerged due to limitations in sample size. Examining the state of GSH deficit in schizophrenia is a critical step when attempting to correct putative redox imbalance in this illness using agents such as N-Acetyl Cysteine (NAC). We conducted a meta-analysis to investigate the aberrations in GSH levels in the ACC of patients with schizophrenia and bipolar disorder measured using magnetic resonance spectroscopy (MRS).MethodsMedline, Google Scholar, Ovid Online and EMBASE databases were searched for studies published until September 2017. Search terms included magnetic resonance spectroscopy, MRS, schizophrenia, psychosis, psychotic, bipolar disorder, glutathione, GSH. We included all 1H-MRS studies reporting GSH values for patients satisfying DSM or ICD based criteria for a primary psychotic disorder (SCZ) or bipolar disorder (BPAD) in comparison to a healthy controls (HC) group. We screened all identified abstracts, filtered studies that did not satisfy inclusion criteria, hand-searched references and contacted experts to locate further studies. We excluded studies that reported only on comorbid illnesses, did not compare patients and HCs, or failed to report data required to construct effect size metrics. After initial screening, a total of 261 patients and 185 controls were considered for the meta-analysis from the SCZ group; 464 patients and 245 controls were considered for the meta-analysis from the BPAD group. A random-effects, inverse-weighted variance model was used to calculate the pooled effect size. Mean values were extracted and verified independently. Effect sizes were computed based on excel macro, produced by Major Depressive Disorder Neuroimaging Database investigators.ResultsContrary to our expectations, in SCZ, there were no significant differences in ACC GSH in patients compared to HC (RFX p= 0.74; 95% CI, -0.24 to 0.17; FFX p= 0.71; heterogeneity p = 0.58). In BPAD, there were highly significant differences in the ACC GSH, with patients having higher GSH concentrations than HC (RFX: p= 0.0003; 95% CI, 0.14 to 0.5; heterogeneity p=0.70). In the BPAD group, the mean effect size (SMD) was d= 0.32, indicating a small to medium sized difference. A network meta-analysis revealed significantly higher GSH levels in BPAD compared to SCZ (RFX p= 0.01; 95% CI, 0.08 to 0.63; SMD=0.36; heterogeneity p = 0.71). There were several methodological issues in the reported studies. Notably, most acquisitions were not optimized to collect GSH spectra; polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC) were not quantified in most studies; voxel placements were not standardized across the published studies; majority of patients were medicated, in various stages of illness.DiscussionThere are no major differences in concentration of ACC glutathione in the anterior cingulate cortex in patients with schizophrenia, though in bipolar disorder, GSH levels appear elevated. Given that GSH is the most readily accessible cortical redox marker in vivo, current status of MRS literature is insufficient to prepare for stratified therapeutics with antioxidants among patients with schizophrenia. Nevertheless, abnormalities in the redox system may be more pronounced in bipolar disorder compared to schizophrenia, and could serve to guide stratification in samples lacking diagnostic clarity (e.g. in First Episode Psychosis clinics).

Hippocampal Subregions Across the Psychosis Spectrum.

Converging evidence suggests that hippocampal subregions subserve different functions, and are differentially affected by psychosis illness progression. Despite this fact, studies have not often studied subregions cross-sectionally across the psychosis spectrum. Furthermore, little is known about associations between subregion volumes and hippocampus-mediated cognition. A total of 222 participants (61 ultra high risk [UHR], 91 schizophrenia [SCZ], and 70 healthy volunteers) underwent a 3T MRI scan, as well as structured clinical interviews and a cognitive battery. Hippocampal subfield analysis was conducted with Freesurfer. We compared subregion volumes across groups, controlling for age, gender, and intracranial volume. We also examined associations in the UHR and SCZ groups between hippocampal subregion volumes and verbal learning, visual learning, and working memory. We found a dose-dependent relationship such that the SCZ group showed significantly greater subfield volume reductions than the UHR group, which in turn showed significantly greater subfield volume reductions than the healthy volunteer group. We also found associations between subregion volume and cognitive performance in the visual memory, verbal memory, and working memory domains. Our study examined hippocampal subregion volumes cross-sectionally in a large sample across the psychosis spectrum, as well as links with hippocampus-mediated cognitive function. Our findings suggest that hippocampal abnormalities emerge before first psychosis episode onset, and may be etiologically informative.

Neural correlates of preserved facial affect perception in high functioning schizophrenia

Individuals with ‘high functioning’ schizophrenia (HF-SCZ) may have preserved facial affect perception (FAP) compared to individuals with ‘low functioning’ schizophrenia (LF-SCZ). The neural mechanisms supporting preserved FAP in HF-SCZ have yet to be evaluated. This study compared brain activation during FAP performance in HF-SCZ, LF-SCZ, and controls. Results demonstrated greater activation in the precuneus in CON compared to both SCZ groups, while HF-SCZ activated this region intermediate to controls and LF-SCZ. These preliminary findings suggest greater precuneus activation may be related to preserved FAP in HF-SCZ compared to LF-SCZ, though future research is needed to further evaluate differences between groups.

Impact of Familial Loading on Prefrontal Activation in Major Psychiatric Disorders: A Near-Infrared Spectroscopy (NIRS) Study

Family history (FH) is predictive of the development of major psychiatric disorders (PSY). Familial psychiatric disorders are largely a consequence of genetic factors and typically exhibit more severe impairments. Decreased prefrontal activity during verbal fluency testing (VFT) may constitute an intermediate phenotype for PSY. We investigated whether familial PSY were associated with a greater severity of prefrontal dysfunction in accordance with genetic loading. We measured prefrontal activity during VFT using near-infrared spectroscopy (NIRS) in patients with schizophrenia (SCZ, n = 45), major depressive disorder (MDD, n = 26) or bipolar disorder (BIP, n = 22) and healthy controls (HC, n = 51). We compared prefrontal activity among patients with or without FH and HC. Patients in the SCZ, MDD and BIP patient groups had lower prefrontal activity than HC subjects. Patients with and without FH in all diagnostic groups had lower prefrontal activity than HC subjects. Moreover, SCZ patients with FH had lower prefrontal activity than SCZ patients without FH. When we included patients with SCZ, MDD or BIP in the group of patients with PSY, the effects of psychiatric FH on prefrontal activity were enhanced. These findings demonstrate the association of substantially more severe prefrontal dysfunction with higher genetic loading in major psychiatric disorders.

Metabolomics and lipidomics analyses by 1H nuclear magnetic resonance of schizophrenia patient serum reveal potential peripheral biomarkers for diagnosis

Using 1H NMR-based metabolomics in association to chemometrics analysis, we analyzed here the metabolic differences between schizophrenia patients (SCZ) compared to healthy controls (HCs). HCs and SCZ patients underwent clinical interview using the Structured Clinical Interview for DSM Disorders (SCID). SCZ patients were further assessed by Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Global Assessment of Functioning Scale (GAF), and Clinical Global Impressions Scale (CGI). Using the principal component analysis (PCA) and supervised partial least-squares discriminate analysis (PLS-DA) in obtained NMR data, a clear group separation between HCs and SCZ patients was achieved. Interestingly, all metabolite compounds identified as exclusively present in the SCZ group, except for the gamma-aminobutyric acid (GABA), were never previously associated with mental disorders. Although the initial perception of an absence of obvious biological link among the different key molecules exclusively observed in each group, and no identification of any specific pathway yet, the present work represents an important contribution for the identification of potential biomarkers to inform diagnosis, as it was possible to completely separate the affected SCZ patients from HCs, with no outliers or exceptions. In addition, the data presented here reinforced the role of the modulation of glycolysis pathway and the loss of GABA interneuron/hyperglutamate hypothesis in SCZ.

The serotonin transporter gene 5-HTTLPR polymorphism is associated with affective psychoses but not with schizophrenia: A large-scale study in the Russian population

BackgroundAffective syndrome is thought to be a key feature that differentiates schizophrenia from schizoaffective disorder (SA) and bipolar disorder with psychotic features (BDP). However genetic underpinnings of these differences remain unresolved. ObjectivesWe compared clinical variables of affective psychoses (SA, BDP and schizophrenia with affective symptoms (AFF SCZ)) and schizophrenia without affective symptoms (non-AFF SCZ) and searched for a genetic variant that may differentiate affective psychosis from non-AFF SCZ. MethodsA total of 2677 subjects, including 831 patients with affective psychosis, 785 patients with non-AFF SCZ and 1061 healthy controls, were used. Clinical symptoms were assessed with the PANSS. The sample was genotyped for 5-HTTLPR polymorphism of the serotonin transporter gene. ResultsThe diagnostic groups differed significantly on demographic and clinical variables. The percentage of men was higher, the current age and age at illness onset were lower in non-AFF SCZ and SA compared to AFF SCZ and BDP. The severity of positive and negative symptoms decreased significantly from group to group in the following manner: non-AFF SCZ>AFF SCZ>SA>BDP. There was the association between 5-HTTLPR polymorphism and affective psychosis (p=0.01). The frequency of the SS genotype was higher in the affective psychosis group compared to non-AFF SCZ and controls. No differences in the genotype distribution were identified between the non-AFF SCZ group and controls. LimitationsDifficulties in the differentiation between non-AFF SCZ and AFF SCZ or SA and between AFF SCZ and SA due to uncertain diagnostic boundaries between these conditions. ConclusionsSA is intermediate between non-AFF SCZ and BDP in the severity of positive and negative symptoms. The first episode patients, carriers of the SS genotype have a higher risk of developing affective psychosis than non-AFF SCZ. This finding carries implications for the prognosis of psychosis outcomes in the first-episode patients.

Inflammatory evidence for the psychosis continuum model

BackgroundInflammation and immune activation have been implicated in the pathophysiology of severe mental disorders. Previous studies of inflammatory markers, however, have been limited with somewhat inconsistent results. AimsWe aimed to determine the effect sizes of inflammatory marker alterations across diagnostic groups of the psychosis continuum and investigate association to antipsychotic medications. MethodsPlasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), and von Willebrand factor (vWf) were measured in patients (n=992) with schizophrenia spectrum (SCZ, n=584), schizoaffective disorder (SA, n=93), affective spectrum disorders (AFF, n=315), and healthy controls (HC, n=638). ResultsLevels of sTNF-R1 (p=1.8×10−8, d=0.23) and IL-1Ra (p=0.002, d=0.16) were increased in patients compared to HC. The SCZ group had higher levels of sTNF-R1 (p=8.5×10−8, d=0.27) and IL-1Ra (p=5.9×10−5, d=0.25) compared to HC, and for sTNF-R1 this was also seen in the SA group (p=0.01, d=0.3) and in the AFF group (p=0.002, d=0.12). Further, IL-1Ra (p=0.004, d=0.25) and vWf (p=0.02, d=0.21) were increased in the SCZ compared to the AFF group. There was no significant association between inflammatory markers and use of antipsychotic medication. ConclusionWe demonstrate a small increase in sTNF-R1 and IL-1Ra in patients with severe mental disorders supporting a role of inflammatory mechanisms in disease pathophysiology. The increase was more pronounced in SCZ compared to AFF supporting a continuum psychosis model related to immune factors.

Cluster analysis differentiates high and low community functioning in schizophrenia: Subgroups differ on working memory but not other neurocognitive domains

BackgroundSchizophrenia is characterized by impairment in multiple aspects of community functioning. Available literature suggests that community functioning may be enhanced through cognitive remediation, however, evidence is limited regarding whether specific neurocognitive domains may be treatment targets. We characterized schizophrenia subjects based on their level of community functioning through cluster analysis in an effort to identify whether specific neurocognitive domains were associated with variation in functioning. MethodsSchizophrenia (SCZ, n=60) and control (CON, n=45) subjects completed a functional capacity task, social competence role-play, functional attainment interview, and a neuropsychological battery. Multiple cluster analytic techniques were used on the measures of functioning in the schizophrenia subjects to generate functionally-defined subgroups. MANOVA evaluated between-group differences in neurocognition. ResultsThe cluster analysis revealed two distinct groups, consisting of 36 SCZ characterized by high levels of community functioning (HF-SCZ) and 24 SCZ with low levels of community functioning (LF-SCZ). There was a main group effect for neurocognitive performance (p<0.001) with CON outperforming both SCZ groups in all neurocognitive domains. Post-hoc tests revealed that HF-SCZ had higher verbal working memory compared to LF-SCZ (p≤0.05, Cohen's d=0.78) but the two groups did not differ in remaining domains. ConclusionThe cluster analysis classified schizophrenia subjects in HF-SCZ and LF-SCZ using a multidimensional assessment of community functioning. Moreover, HF-SCZ demonstrated rather preserved verbal working memory relative to LF-SCZ. The results suggest that verbal working memory may play a critical role in community functioning, and is a potential cognitive treatment target for schizophrenia subjects.

Comparison of visual perceptual organization in schizophrenia and body dysmorphic disorder

People with schizophrenia are impaired at organizing potentially ambiguous visual information into well-formed shape and object representations. This perceptual organization (PO) impairment has not been found in other psychiatric disorders. However, recent data on body dysmorphic disorder (BDD), suggest that BDD may also be characterized by reduced PO. Similarities between these groups could have implications for understanding the RDoC dimension of visual perception in psychopathology, and for modeling symptom formation across these two conditions. We compared patients with SCZ (n=24) to those with BDD (n=20), as well as control groups of obsessive–compulsive disorder (OCD) patients (n=20) and healthy controls (n=20), on two measures of PO that have been reliably associated with schizophrenia-related performance impairment. On both the contour integration and Ebbinghaus illusion tests, only the SCZ group demonstrated abnormal performance relative to controls; the BDD group performed similarly to the OCD and CON groups. In addition, on both tasks, the SCZ group performed more abnormally than the BDD group. Overall, these data suggest that PO reductions observed in SCZ are not present in BDD. Visual processing impairments in BDD may arise instead from other perceptual disturbances or attentional biases related to emotional factors.

Cannabis abuse is associated with better emotional memory in schizophrenia: A functional magnetic resonance imaging study

In schizophrenia cannabis abuse/dependence is associated with poor compliance and psychotic relapse. Despite this, the reasons for cannabis abuse remain elusive, but emotions may play a critical role in this comorbidity. Accordingly, we performed a functional magnetic resonance imaging study of emotional memory in schizophrenia patients with cannabis abuse (dual-diagnosis, DD). Participants comprised 14 DD patients, 14 non-abusing schizophrenia patients (SCZ), and 21 healthy controls (HC) who had to recognize positive and negative pictures while being scanned. Recognition of positive and negative emotions was prominently impaired in SCZ patients, relative to HC, while differences between DD and HC were smaller. For positive and negative stimuli, we observed significant activations in frontal, limbic, temporal and occipital regions in HC; in frontal, limbic and temporal regions in DD; and in temporal, parietal, limbic and occipital regions in the SCZ group. Our results suggest that emotional memory and prefrontal lobe functioning are preserved in DD relative to SCZ patients. These results are consistent with previous findings showing that cannabis abuse is associated with fewer negative symptoms and better cognitive functioning in schizophrenia. Longitudinal studies will need to determine whether the relative preservation of emotional memory is primary or secondary to cannabis abuse in schizophrenia.

Sensation-seeking, social anhedonia, and impulsivity in substance use disorder patients with and without schizophrenia and in non-abusing schizophrenia patients

Substance use disorders (SUDs) are common in patients with schizophrenia and this comorbidity is associated with a poorer prognosis, relative to non-abusing patients. One hypothesis that has been advanced in the literature is that dual diagnosis (DD) patients may have a different personality profile than non-abusing schizophrenia patients. The present case-control study aimed to characterize levels of personality traits (sensation-seeking, social anhedonia, and impulsivity) in substance abuse/dependence patients with (DD group; n=31) and without schizophrenia (SUD group; n=39), relative to non-abusing schizophrenia patients (SCZ group; n=23), and healthy controls (n=25). Impulsivity was assessed using the Barratt Impulsivity Scale. Sensation-seeking was assessed using the Zuckerman Sensation Seeking Scale. Social anhedonia was assessed with the Chapman Social Anhedonia Scale. We found that sensation-seeking was significantly higher in DD and SUD, relative to SCZ patients. We found that social anhedonia was significantly elevated in DD and SCZ, relative to healthy controls. We found that impulsivity was significantly higher in DD, SCZ and SUD patients, compared to healthy controls. The results suggest that sensation-seeking is prominent in substance abuse/dependence (irrespective of schizophrenia), social anhedonia is prominent in schizophrenia (irrespective of substance abuse/dependence), and impulsivity is prominent in all three populations.

A Comparison of Facial Emotion Processing in Neurological and Psychiatric Conditions

Patients suffering from various neurological and psychiatric disorders show different levels of facial emotion recognition (FER) impairment, sometimes from the early phases of the disease. Investigating the relative severity of deficits in FER across different clinical and high-risk populations has potential implications for the diagnosis and treatment of these diseases, and could also allow us to understand the neurobiological mechanisms of emotion perception itself. To investigate the role of the dopaminergic system and of the frontotemporal network in FER, we reanalyzed and compared data from four of our previous studies investigating FER performance in patients with frontotemporal dysfunctions and/or dopaminergic system abnormalities at different stages. The performance of patients was compared to the performance obtained by a specific group of matched healthy controls using Cohen’s d effect size. We thus compared emotion and gender recognition in patients with frontotemporal dementia (FTD), amnestic mild cognitive impairment (aMCI), Alzheimer’s disease (AD) at the mild dementia stage, major depressive disorder, Parkinson’s disease treated by l-DOPA (PD-ON) or not (PD-OFF), remitted schizophrenia (SCZ-rem), first-episode schizophrenia treated by antipsychotic medication (SCZ-ON), and drug-naïve first-episode schizophrenia (SCZ-OFF), as well as in unaffected siblings of patients with schizophrenia (SIB). The analyses revealed a pattern of differential impairment of emotion (but not gender) recognition across pathological conditions. On the one hand, dopaminergic medication seems not to modify the moderate deficits observed in SCZ and PD groups (ON vs. OFF), suggesting that the deficit is independent from the dopaminergic system. On the other hand, the observed increase in effect size of the deficit among the aMCI, AD, and FTD groups (and also among the SIB and SCZ-rem groups) suggests that the deficit is dependent on neurodegeneration of the frontotemporal neural networks. Our transnosographic approach combining clinical and high-risk populations with the impact of medication provides new information on the trajectory of impaired emotion perception in neuropsychiatric conditions, and on the role of the dopaminergic system and the frontotemporal network in emotion perception.

Inferential-Reasoning Impairment in Schizophrenia-Spectrum Disorders

The performance of 15 participants with schizophrenia-spectrum disorders (SCZ) on an inferential-reasoning task was compared with that of 15 healthy-control participants (HC). The SCZ group showed poorer inferential reasoning than HCs, independent of their negative or positive symptoms. These findings are consistent with previous research showing deficits of reasoning in schizophrenia, and indicate that this deficit is independent of severity of delusions.

Evolution of Substance use, Neurological and Psychiatric Symptoms in Schizophrenia and Substance use Disorder Patients: A 12-Week, Pilot, Case–Control Trial with Quetiapine

Neurological and psychiatric symptoms are consequences of substance abuse in schizophrenia and non-schizophrenia patients. The present case–control study examined changes in substance abuse/dependence, and neurological and psychiatric symptoms in substance abusers with [dual diagnosis (DD) group, n = 26] and without schizophrenia [substance use disorder (SUD) group, n = 24] and in non-abusing schizophrenia patients (SCZ group, n = 23) undergoing 12-week treatment with the atypical antipsychotic, quetiapine. Neurological and psychiatric symptoms were evaluated with the Positive and Negative Syndrome Scale, the Calgary Depression Scale for Schizophrenia, the Extrapyramidal Symptoms Rating Scale, and the Barnes Akathisia Rating Scale. At endpoint, DD and SCZ patients were receiving significantly higher doses of quetiapine (mean = 554 and 478 mg/day, respectively), relative to SUD patients (mean = 150 mg/day). We found that SUD patients showed greater improvement in weekly dollars spent on alcohol and drugs and SUD severity, compared to DD patients. At endpoint, there was no significant difference in dollars spent, but DD patients still had a higher mean SUD severity. Interestingly, DD patients had significantly higher parkinsonism and depression than SCZ patients at baseline and endpoint. On the other hand, we found that SUD patients had significantly more akathisia at baseline, improved more than SCZ patients, and this was related to cannabis abuse/dependence. Finally, SUD patients improved more in Positive and Negative Syndrome Scale positive scores than DD and SCZ patients. Taken together, our results provide evidence for increased vulnerability to the adverse effects of alcohol and drugs in schizophrenia patients. They also suggest that substance abuse/withdrawal may mimic some symptoms of schizophrenia. Future studies will need to determine the role quetiapine played in these improvements.

Inferential-Reasoning Impairment in Schizophrenia-Spectrum Disorders

The performance of 15 participants with schizophrenia-spectrum disorders (SCZ) on an inferential-reasoning task was compared with that of 15 healthy-control participants (HC). The SCZ group showed poorer inferential reasoning than HCs, independent of their negative or positive symptoms. These findings are consistent with previous research showing deficits of reasoning in schizophrenia, and indicate that this deficit is independent of severity of delusions.

Decreased Neuregulin 1 C-terminal fragment in Brodmann's area 6 of patients with schizophrenia

Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. A decrease in NRG1-ErbB4 signalling has also been associated with the disease. β-amyloid precursor protein-cleaving enzyme (BACE1) processes type III NRG1 precursor, a major neuregulin variant expressed in the brain, to release NRG1 fragments that trigger signalling events and activation of neurotransmitter receptors. Experimental evidence suggests that muscarinic acetylcholine receptors (CHRM) regulate BACE1 expression. Having recently shown that CHRM1 levels are decreased selectively in frontal cortex regions of a subpopulation of schizophrenic patients (muscarinic receptor deficit schizophrenia, MRDS) we aimed to compare the protein expression of BACE1 and NRG1 in the agranular frontal cortex Brodmann's area 6 of SCZ subjects with normal levels of CHRM1 (N = 19), MRDS ( N = 20), and age/gender-matched non-psychiatric (healthy) controls (HC; N = 20). Western blot analysis of post-mortem samples showed that the levels of BACE1 and full-length NRG1 precursor (130 kDa) did not differ significantly between the three groups. In contrast, the levels of the NRG1 C-terminal fragment (NRG1-CTF) were decreased by approximately 50% in both schizophrenic groups compared to the HC group ( p < 0.0027). The ratio of NRG1-CTF versus NRG1 precursor was significantly reduced in the SCZ groups compared to the HC group ( p = 0.051). There was no correlation between the levels of either full-length NRG1, NRG1-CTF, or BACE1 and the final recorded doses of antipsychotic drugs for the subjects with schizophrenia. A positive correlation was found between BACE1 and full-length NRG1 precursor in the HC group ( r 2 = 0.671, p < 0.001) but not in the schizophrenic groups. These data suggest that the proteolytic processing of NRG1 is impaired in schizophrenia.

SRD5A2 is associated with increased cortisol metabolism in schizophrenia spectrum disorders

Objective Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is documented in bipolar disorder and schizophrenia, but the mechanism is unclear; recently, increased activity of cortisol metabolizing enzymes was indicated in these disorders. We investigated whether five genes involved in cortisol metabolism were associated with altered activity of cortisol metabolizing enzymes in bipolar disorder (BD) and schizophrenia spectrum disorders (SCZ). Methods A case–control sample of subjects with BD (N = 213), SCZ (N = 274) and healthy controls (N = 370) from Oslo, Norway, were included and genotyped from 2003 to 2008. A sub-sample (healthy controls: N = 151; SCZ: N = 40; BD: N = 39) had estimated enzyme activities based on measurements of urinary free cortisol, urinary free cortisone and metabolites. A total of 102 single nucleotide polymorphisms (SNPs) in the SRD5A1, SRD5A2, AKR1D1, HSD11B1 and HSD11B2 genes were genotyped, and significant SNPs analyzed in the sub-sample. Results There was a significant association of rs6732223 in SRD5A2 (5α-reductase) with SCZ (p = 0.0043, Bonferroni corrected p = 0.030, T risk allele). There was a significantly increased 5α-reductase activity associated with rs6732223 (T allele) within the SCZ group (p = 0.011). Conclusions The present data suggest an interaction between SCZ and SRD5A2 variants coding for the enzyme 5α-reductase, giving rise to increased 5α-reductase activity in SCZ. The findings may have implications for cortisol metabolizing enzymes as possible drug targets.