Preview: Schizophrenia Bulletin - current issue
Schizophrenia Bulletin Current Issue
Published: Sat, 15 Apr 2017 00:00:00 GMT
Last Build Date: Thu, 13 Apr 2017 12:45:17 GMT
Adolescent Stress as a Driving Factor for Schizophrenia Development—A Basic Science Perspective
AbstractSchizophrenia has been associated with heightened stress responsivity in adolescence that precedes onset of psychosis. We now report that multiple stressors during adolescence in normal rats leads to deficits in adults analogous to that seen in schizophrenia patients. Moreover, impairment of stress control by lesion of the prelimbic prefontal cortex in adolescence caused previously subthreshold levels of stress to induce these deficit states when tested as adults. Thus, predisposition to stress hyper-responsivity, or exposure to substantial stressors, during adolescence can trigger a cascade of events that result in a schizophrenia-like profile in adults. This data can provide crucial information with respect to identifying markers for schizophrenia vulnerability early in life and, by mitigating the impact of stressors, prevent the transition to psychosis.
Can RDoC Help Find Order in Thought Disorder?
AbstractThought disorder is a pernicious and nonspecific aspect of numerous serious mental illnesses (SMIs) and related conditions. Despite decades of empirical research on thought disorder, our present understanding of it is poor, our clinical assessments focus on a limited set of extreme behaviors, and treatments are palliative at best. Applying a Research Domain Criteria (RDoC) framework to thought disorder research offers advantages to explicate its phenotype; isolate its mechanisms; and develop more effective assessments, treatments, and potential cures. In this commentary, we discuss ways in which thought disorder can be understood within the RDoC framework. We propose operationalizing thought disorder within the RDoC construct of language using psycholinguistic sciences, to help objectify and quantify language within individuals; technologically sophisticated paradigms, to allow naturalistic behavioral sampling techniques with unprecedented ecological validity; and computational modeling, to account for a network of interconnected and dynamic linguistic, cognitive, affective, and social functions. We also highlight challenges for understanding thought disorder within an RDoC framework. Thought disorder likely does not occur as an isomorphic dysfunction in a single RDoC construct, but rather, as multiple potential dysfunctions in a network of RDoC constructs. Moreover, thought disorder is dynamic over time and context within individuals. In sum, RDoC is a useful framework to integrate multidisciplinary research efforts aimed at operationalizing, understanding, and ameliorating thought disorder.
Computational Psychiatry and the Challenge of Schizophrenia
AbstractSchizophrenia research is plagued by enormous challenges in integrating and analyzing large datasets and difficulties developing formal theories related to the etiology, pathophysiology, and treatment of this disorder. Computational psychiatry provides a path to enhance analyses of these large and complex datasets and to promote the development and refinement of formal models for features of this disorder. This presentation introduces the reader to the notion of computational psychiatry and describes discovery-oriented and theory-driven applications to schizophrenia involving machine learning, reinforcement learning theory, and biophysically-informed neural circuit models.
Thought Disorder in Schizophrenia and Bipolar Disorder Probands, Their Relatives, and Nonpsychiatric Controls
AbstractThought disorder (TD) has long been associated with schizophrenia (SZ) and is now widely recognized as a symptom of mania and other psychotic disorders as well. Previous studies have suggested that the TD found in the clinically unaffected relatives of SZ, schizoaffective and bipolar probands is qualitatively similar to that found in the probands themselves. Here, we examine which quantitative measures of TD optimize the distinction between patients with diagnoses of SZ and bipolar disorder with psychotic features (BP) from nonpsychiatric controls (NC) and from each other. In addition, we investigate whether these same TD measures also distinguish their respective clinically unaffected relatives (RelSZ, RelBP) from controls as well as from each other. We find that deviant verbalizations are significantly associated with SZ and are co-familial in clinically unaffected RelSZ, but are dissociated from, and are not co-familial for, BP disorder. In contrast, combinatory thinking was nonspecifically associated with psychosis, but did not aggregate in either group of relatives. These results provide further support for the usefulness of TD for identifying potential non-penetrant carriers of SZ-risk genes, in turn enhancing the power of genetic analyses. These findings also suggest that further refinement of the TD phenotype may be needed in order to be suitable for use in genetic studies of bipolar disorder.
Rethinking Thought Disorder
AbstractIt has been 30 years since Holzman introduced a special issue of the Schizophrenia Bulletin entitled “Thought Disorder in Schizophrenia.” He pointed out in his Editor’s Introduction that in contrast to the explosion of interest at that time in the biological aspects of schizophrenia, there were important areas of study that represented “... relatively neglected aspects of the psychopathology of schizophrenia, namely the varieties of thinking disorders (emphasis added) characteristic of schizophrenic patients and their possible underlying mechanisms.” Perhaps presciently, he ended his introduction by expressing hope that the articles included in that issue would lead to further intensive study of the cognitive (emphasis added) dysfunctions in schizophrenia. There has, indeed, been extensive research conducted in further understanding cognitive dysfunctions in schizophrenia, but considerably less so in understanding thought disorder.
Prefrontal Cortex Dysfunction Increases Susceptibility to Schizophrenia-Like Changes Induced by Adolescent Stress Exposure
AbstractStress during adolescence is a risk factor for schizophrenia, and medial prefrontal cortex (mPFC) dysfunction is proposed to interfere with stress control, increasing the susceptibility to stress. We evaluated the impact of different stressful events during adolescence (restraint stress [RS], footshock [FS], or the combination of FS and RS) on behaviors correlated with schizophrenia in rats as adults. At adulthood, animals were tested for anxiety responses (elevated plus-maze), cognitive function (novel-object recognition test) and dopamine (DA) system responsivity (locomotor response to amphetamine and DA neuron activity in the ventral tegmental area (VTA) using in vivo electrophysiology). All adolescent stressors impaired weight gain and induced anxiety-like responses in adults. FS and FS + RS also disrupted cognitive function. Interestingly, only the combination of FS and RS induced a DA hyper-responsivity as indicated by augmented locomotor response to amphetamine and increased number of spontaneously active DA neurons which was confined to the lateral VTA. Additionally, prelimbic (pl) mPFC lesions triggered a DA hyper-responsivity in animals exposed to FS alone during adolescence. Our results are consistent with previous studies showing long-lasting changes induced by stressful events during adolescence. The impact on DA system activity, however, seems to depend on intense multiple stressors. Our data also suggest that plPFC dysfunction increases the vulnerability to stress in terms of changes in the DA system. Hence, stress during adolescence could be a precipitating factor for the transition to schizophrenia, and stress control at this vulnerable period may circumvent these changes to prevent the emergence of psychosis.
Physical Activity Levels and Psychosis: A Mediation Analysis of Factors Influencing Physical Activity Target Achievement Among 204 186 People Across 46 Low- and Middle-Income Countries
AbstractPhysical activity (PA) can help reduce cardiovascular disease and premature mortality in people with psychosis. However, there is a paucity of representative data on PA in people with psychosis, especially from low- and middle-income countries (LMICs). Moreover, data on subclinical psychosis and PA is absent. This study explored whether complying with PA recommendations of 150 minutes of moderate-vigorous PA per week is related to: (1) psychotic symptoms without a psychosis diagnosis (subclinical psychosis); and (2) clinical psychosis (psychosis diagnosis). A total of 204 186 participants aged 18–64 years from 46 LMICs recruited via the World Health Survey were subdivided into those with (1) no psychosis diagnosis and no psychotic symptoms in the past 12 months (controls); (2) subclinical psychosis; and (3) psychosis diagnosis. People with a psychosis diagnosis had significantly higher odds for low PA in the overall sample (OR = 1.36; 95% CI = 1.04–1.78; P = .024) and among males (OR = 2.29; 95% CI = 1.57–3.34; P < .0001) but not females (OR = 0.93; 95% CI = 0.67–1.30; P = .6712). No difference was found among those with subclinical psychosis vs controls. Mediation analyses demonstrated that mobility difficulties explained the largest amount of low PA among males (18.5%) followed by self-care difficulties (16.3%), depression (16.1%), cognition (11.8%), pain and discomfort (11.4%), interpersonal activities (8.6%), sleep and energy (7.2%), and vision (3.0%). The results from the largest dataset on PA and psychosis and first in LMICs, found that psychosis diagnosis (especially among males) but not subclinical psychosis, is associated with physical inactivity. Population level interventions seeking to increase PA among people with psychosis may help improve health outcomes.
Relationship Between Objectively Measured Sedentary Behavior and Cognitive Performance in Patients With Schizophrenia Vs Controls
Objective:Sedentary behavior (SB) is associated with poor cognitive performance in the general population. Although people with schizophrenia are highly sedentary and experience marked cognitive impairments, no study has investigated the relationship between SB and cognition in people with schizophrenia.
Methods:A total of 199 inpatients with schizophrenia (mean [SD] age 44.0 [9.9] years, 61.3% male, mean [SD] illness duration 23.8 [6.5]) and 60 age and sex matched controls were recruited. Sedentary behavior and physical activity (PA) were captured for 7 consecutive days with an accelerometer. Cognitive performance was assessed using the Vienna Test System, and the Grooved Pegboard Test. Multivariate regression analyses adjusting for important confounders including positive and negative symptoms, illness duration, medication, and PA were conducted.
Results:The 199 patients with schizophrenia engaged in significantly more SB vs controls (581.1 (SD 127.6) vs 336.4 (SD 107.9) min per day, P < .001) and performed worse in all cognitive performance measures (all P < .001). Compared to patients with high levels of SB (n = 89), patients with lower levels of SB (n = 110) had significantly (P < .05) better motor reaction time and cognitive processing. In the fully adjusted multivariate analysis, SB was independently associated with slower motor reaction time (β = .162, P < .05) but not other cognitive outcomes. Lower levels of PA were independently associated with worse attention and processing speed (P < .05).
Conclusion:Our data suggest that higher levels of sedentary behavior and physical inactivity are independently associated with worse performance across several cognitive domains. Interventions targeting reductions in SB and increased PA should be explored.
Temporal Lobe Volume Decrements in Psychosis Spectrum Youths
AbstractStructural brain abnormalities have been amply demonstrated in schizophrenia. These include volume decrements in the perirhinal/entorhinal regions of the ventromedial temporal lobe, which comprise the primary olfactory cortex. Olfactory impairments, which are a hallmark of schizophrenia, precede the onset of illness, distinguish adolescents experiencing prodromal symptoms from healthy youths, and may predict the transition from the prodrome to frank psychosis. We therefore examined temporal lobe regional volumes in a large adolescent sample to determine if structural deficits in ventromedial temporal lobe areas were associated, not only with schizophrenia, but also with a heightened risk for psychosis. Seven temporal lobe regional volumes (amygdala [AM], hippocampus, inferior temporal gyrus, parahippocampal gyrus, superior temporal gyrus, temporal pole, and entorhinal cortex [EC]) were measured in 386 psychosis spectrum adolescents, 521 adolescents with other types of psychopathology, and 359 healthy adolescents from the Philadelphia Neurodevelopment Cohort. Total intracranial and left EC volumes, which were both smallest among the psychosis spectrum, were the only measures that distinguished all 3 groups. Left AM was also smaller in psychosis spectrum compared with healthy subjects. EC volume decrement was strongly correlated with impaired cognition and less robustly associated with heightened negative/disorganized symptoms. AM volume decrement correlated with positive symptoms (persecution/special abilities). Temporal lobe volumes classified psychosis spectrum youths with very high specificity but relatively low sensitivity. These MRI measures may therefore serve as important confirmatory biomarkers denoting a worrisome preclinical trajectory among at-risk youths, and the specific pattern of deficits may predict specific symptom profiles.
Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample
AbstractGlutamine plus glutamate (Glx), as well as N-acetylaspartate compounds (NAAc, N-acetylaspartate plus N-acetyl-aspartyl-glutamate), a marker of neuronal viability, can be quantified with proton magnetic resonance spectroscopy (1H-MRS). We used 1H-MRS imaging to assess Glx and NAAc, as well as total-choline (glycerophospho-choline plus phospho-choline), myo-inositol and total-creatine (creatine plus phosphocreatine) from an axial supraventricular slab of gray matter (GM, medial-frontal and medial-parietal) and white matter (WM, bilateral-frontal and bilateral-parietal) voxels. Schizophrenia subjects (N = 104) and healthy controls (N = 97) with a broad age range (16 to 65) were studied. In schizophrenia, Glx was increased in GM (P < .001) and WM (P = .01), regardless of age. However, with greater age, NAAc increased in GM (P < .001) but decreased in WM (P < .001) in schizophrenia. In patients, total creatine decreased with age in WM (P < .001). Finally, overall cognitive score correlated positively with WM neurometabolites in controls but negatively in the schizophrenia group (NAAc, P < .001; and creatine [only younger], P < .001). We speculate the results support an ongoing process of increased glutamate metabolism in schizophrenia. Later in the illness, disease progression is suggested by increased cortical compaction without neuronal loss (elevated NAAc) and reduced axonal integrity (lower NAAc). Furthermore, this process is associated with fundamentally altered relationships between neurometabolite concentrations and cognitive function in schizophrenia.
Abnormal Grey Matter Arteriolar Cerebral Blood Volume in Schizophrenia Measured With 3D Inflow-Based Vascular-Space-Occupancy MRI at 7T
AbstractMetabolic dysfunction and microvascular abnormality may contribute to the pathogenesis of schizophrenia. Most previous studies of cerebral perfusion in schizophrenia measured total cerebral blood volume (CBV) and cerebral blood flow (CBF) in the brain, which reflect the ensemble signal from the arteriolar, capillary, and venular compartments of the microvasculature. As the arterioles are the most actively regulated blood vessels among these compartments, they may be the most sensitive component of the microvasculature to metabolic disturbances. In this study, we adopted the inflow-based vascular-space-occupancy (iVASO) MRI approach to investigate alterations in the volume of small arterial (pial) and arteriolar vessels (arteriolar cerebral blood volume [CBVa]) in the brain of schizophrenia patients. The iVASO approach was extended to 3-dimensional (3D) whole brain coverage, and CBVa was measured in the brains of 12 schizophrenia patients and 12 matched controls at ultra-high magnetic field (7T). Significant reduction in grey matter (GM) CBVa was found in multiple areas across the whole brain in patients (relative changes of 14%–51% and effect sizes of 0.7–2.3). GM CBVa values in several regions in the temporal cortex showed significant negative correlations with disease duration in patients. GM CBVa increase was also found in a few brain regions. Our results imply that microvascular abnormality may play a role in schizophrenia, and suggest GM CBVa as a potential marker for the disease. Further investigation is needed to elucidate whether such effects are due to primary vascular impairment or secondary to other causes, such as metabolic dysfunction.
Aerobic Exercise Improves Cognitive Functioning in People With Schizophrenia: A Systematic Review and Meta-Analysis
AbstractCognitive deficits are pervasive among people with schizophrenia and treatment options are limited. There has been an increased interest in the neurocognitive benefits of exercise, but a comprehensive evaluation of studies to date is lacking. We therefore conducted a meta-analysis of all controlled trials investigating the cognitive outcomes of exercise interventions in schizophrenia. Studies were identified from a systematic search across major electronic databases from inception to April 2016. Meta-analyses were used to calculate pooled effect sizes (Hedges g) and 95% CIs. We identified 10 eligible trials with cognitive outcome data for 385 patients with schizophrenia. Exercise significantly improved global cognition (g = 0.33, 95% CI = 0.13–0.53, P = .001) with no statistical heterogeneity (I2 = 0%). The effect size in the 7 studies which were randomized controlled trials was g = 0.43 (P < .001). Meta-regression analyses indicated that greater amounts of exercise are associated with larger improvements in global cognition (β = .005, P = .065). Interventions which were supervised by physical activity professionals were also more effective (g = 0.47, P < .001). Exercise significantly improved the cognitive domains of working memory (g = 0.39, P = .024, N = 7, n = 282), social cognition (g = 0.71, P = .002, N = 3, n = 81), and attention/vigilance (g = 0.66, P = .005, N = 3, n = 104). Effects on processing speed, verbal memory, visual memory and reasoning and problem solving were not significant. This meta-analysis provides evidence that exercise can improve cognitive functioning among people with schizophrenia, particularly from interventions using higher dosages of exercise. Given the challenges in improving cognition, and the wider health benefits of exercise, a greater focus on providing supervised exercise to people with schizophrenia is needed.
Structural Network Disorganization in Subjects at Clinical High Risk for Psychosis
AbstractPrevious network studies in chronic schizophrenia patients revealed impaired structural organization of the brain’s rich-club members, a set of highly interconnected hub regions that play an important integrative role for global brain communication. Moreover, impaired rich-club connectivity has also been found in unaffected siblings of schizophrenia patients, suggesting that abnormal rich-club connectivity is related to familiar, possibly reflecting genetic, vulnerability for schizophrenia. However, no study has yet investigated whether structural rich-club organization is also impaired in individuals with a clinical risk syndrome for psychosis. Diffusion tensor imaging and probabilistic tractography was used to construct structural whole-brain networks in 24 healthy controls and 24 subjects with an at-risk mental state (ARMS). Graph theory was applied to quantify the structural rich-club organization and global network properties. ARMS subjects revealed a significantly altered structural rich-club organization compared with the control group. The disruption of rich-club organization was associated with the severity of negative psychotic symptoms and led to an elevated level of modularity in ARMS subjects. This study shows that abnormal structural rich-club organization is already evident in clinical high-risk subjects for psychosis and further demonstrates the impact of rich-club disorganization on global network communication. Together with previous evidence in chronic schizophrenia patients and unaffected siblings, our findings suggest that abnormal structural rich-club organization may reflect an endophenotypic marker of psychosis.
Testing the Validity of Taxonic Schizotypy Using Genetic and Environmental Risk Variables
Background:Meehl regarded schizotypy as a categorial liability for schizophrenia that is the product of genes, environment, and gene-environment interactions. We sought to test whether schizophrenia-related genotypes and environmental risk factors predict membership in classes defined by taxometric analyses of positive (cognitive-perceptual), negative (interpersonal), and disorganized schizotypy.
Methods:Participants (n = 500) completed the Schizotypal Personality Questionnaire (SPQ) and provided information on the following risk factors: cannabis use, pregnancy and obstetric complications, social adjustment, and family history of psychosis. Saliva samples were obtained so that the frequency of single-nucleotide polymorphism (SNP) alleles associated with risk for developing schizophrenia could be determined. Genotyped SNPs were rs1625579 (MIR137), rs7004633 (MMP16), rs7914558 (CNNM2), and rs12966547 (CCDC68). Sets of SPQ items were subject to multiple coherent cut kinetic (CCK) analyses, including mean-above-minus-below-a-cut, maximum covariance, maximum eigenvalue, and latent modes analyses.
Results:CCK analyses indicated latent taxonicity of schizotypy across the 3 item sets. The cognitive-perceptual class had a base rate of 25%, and membership was predicted by the rs7004633 SNP (odds ratio = 2.33, 95% confidence interval = 1.15–4.72 in adjusted analyses). Poor social adjustment predicted memberships in the interpersonal (16%) and disorganized (21%) classes. Classes were found not to be mutually exclusive.
Conclusions:Schizotypy is taxonic and schizotypy class membership is predicted by genetic and environmental factors that predict schizophrenia. The findings hold the promise that a more complete understanding of schizotypy as a schizophrenia liability state will come from investigation of other genes and environmental factors associated with schizophrenia.
Social Adversity and Psychosis: The Mediating Role of Cognitive Vulnerability
Background:Social adversity is a risk factor for psychosis, but the translating mechanisms are not well understood. This study tests whether the relationship between social adversity and psychosis is mediated by cognitive vulnerability in the form of low perceived social rank, negative schemas related to self and other, and loneliness and whether the putative mediations are specific to psychosis or are largely explained by depression.
Methods:The study was a survey in a community sample (N = 2350) from Germany (n = 786), Indonesia (n = 844), and the United States (n = 720). Mediation path analysis with structural equation modeling was used to test for the specificity of the hypothesized paths to psychosis controlling for depression.
Results:Social adversity had a significant medium to large effect on positive (R2 = .20) and negative symptoms (R2 = .38). Social rank, negative schemas, and loneliness significantly mediated the relationship between social adversity and negative symptoms and the models explained a large amount of the variance (R2 = .43–.44). For positive symptoms, only negative schemas were a significant mediator (R2 = .27).
Discussion:The results emphasize the role of social adversity in psychosis and support the assumption that cognitive vulnerability is a relevant translating mechanism as postulated by the social defeat hypothesis and cognitive models of psychosis. This underlines the relevance of the clinical practice of targeting beliefs in cognitive interventions for psychosis. It also indicates that targeting cognitive vulnerability in people experiencing social adversity could be a promising approach to prevention.
Depression in Schizophrenia: Associations With Cognition, Functional Capacity, Everyday Functioning, and Self-Assessment
AbstractDepressed mood has a complex relationship with self-evaluation of personal competence in multiple populations. The absence of depression may be associated with overestimation of abilities, while mild depression seems to lead to accurate self-assessment. Significant depression may lead to underestimation of functioning. In this study, we expand on our previous work by directly comparing the association between different levels of depression, everyday functioning, cognitive and functional capacity performance, and self-assessment of everyday functioning in a large (n = 406) sample of outpatients with schizophrenia. Participants with very low self-reported depression overestimated their everyday functioning compared with informant reports. Higher levels of depression were associated with more accurate self-assessment, but no subgroup of patients underestimated their functioning. Depressive symptom severity was associated with poorer informant-rated social functioning, but there were no differences in vocational functioning, everyday activities, cognitive performance, and functional capacity associated with the severity of self-reported depression. There was minimal evidence of impact of depression on most aspects of everyday functioning and objective test performance and a substantial relationship between depression and accuracy of self-assessment.
Genetic and Environmental Contributions to the Association Between Cannabis Use and Psychotic-Like Experiences in Young Adult Twins
AbstractTo investigate contributions of genetic and environmental risk factors and possible direction of causation for the relationship between symptoms of cannabis use disorders (CUD) and psychotic-like experiences (PLEs), a population-based sample of 2793 young adult twins (63.5% female, mean [range] age 28.2 [19–36] y) were assessed for symptoms of CUD and PLEs using the Composite International Diagnostic Interview. Latent risk of having symptoms of CUD or PLEs was modeled using Item Response Theory. Co-twin control analysis was performed to investigate effect of familiar confounding for the association between symptoms of CUD and PLEs. Biometric twin models were fitted to estimate the heritability, genetic and environmental correlations, and direction for the association. Lifetime use of cannabis was reported by 10.4 % of the twins, and prevalence of PLEs ranged from 0.1% to 2.2%. The incidence rate ratio of PLEs due to symptoms of CUD was 6.3 (95% CI, 3.9, 10.2) in the total sample and 3.5 (95% CI, 1.5, 8.2) within twin pairs. Heritability estimates for symptoms of CUD were 88% in men and women, and for PLEs 77% in men and 43% in women. The genetic and environmental correlations between symptoms of CUD and PLEs were 0.55 and 0.52, respectively. The model allowing symptoms of CUD to cause PLEs had a better fit than models specifying opposite or reciprocal directions of causation. The association between symptoms of CUD and PLEs is explained by shared genetic and environmental factors and direct effects from CUD to risk for PLEs.
Microglia Activation and Schizophrenia: Lessons From the Effects of Minocycline on Postnatal Neurogenesis, Neuronal Survival and Synaptic Pruning
AbstractThe implication of neuroinflammation in schizophrenia, sustained by recent genetic evidence, represents one of the most exciting topics in schizophrenia research. Drugs which inhibit microglia activation, especially the classical tetracycline antibiotic minocycline are currently under investigation as alternative antipsychotics. However, recent studies demonstrated that microglia activation is not only a hallmark of neuroinflammation, but plays important roles during brain development. Inhibition of microglia activation by minocycline was shown to induce extensive neuronal cell death and to impair subventricular zone (SVZ) neurogenesis and synaptic pruning in the early postnatal and adolescent rodent brain, respectively. These deleterious effects contrast with the neuroprotective actions of minocycline at adult stages. They are of potential importance for schizophrenia, since minocycline triggers similar pro-apoptotic effects in the developing brain as NMDA receptor (NMDAR) antagonists, known to induce long-term schizophrenia-like abnormalities. Moreover, altered postnatal neurogenesis, recently described in the human striatum, was proposed to induce striatal dopamine dysregulation associated with schizophrenia. Finally, the effect of minocycline on synapse remodeling is of interest considering the recently reported strong genetic association of the pruning-regulating complement factor gene C4A with schizophrenia. This raises the exciting possibility that in conditions of hyperactive synaptic pruning, as supposed in schizophrenia, the inhibitory action of minocycline turns into a beneficial effect, with relevance for early therapeutic interventions. Altogether, these data support a differential view on microglia activation and its inhibition. Further studies are needed to clarify the relevance of these results for the pathogenesis of schizophrenia and the use of minocycline as antipsychotic drug.
Identification of Gene Loci That Overlap Between Schizophrenia and Educational Attainment
AbstractThere is evidence for genetic overlap between cognitive abilities and schizophrenia (SCZ), and genome-wide association studies (GWAS) demonstrate that both SCZ and general cognitive abilities have a strong polygenic component with many single-nucleotide polymorphisms (SNPs) each with a small effect. Here we investigated the shared genetic architecture between SCZ and educational attainment, which is regarded as a “proxy phenotype” for cognitive abilities, but may also reflect other traits. We applied a conditional false discovery rate (condFDR) method to GWAS of SCZ (n = 82 315), college completion (“College,” n = 95 427), and years of education (“EduYears,” n = 101 069). Variants associated with College or EduYears showed enrichment of association with SCZ, demonstrating polygenic overlap. This was confirmed by an increased replication rate in SCZ. By applying a condFDR threshold <0.01, we identified 18 genomic loci associated with SCZ after conditioning on College and 15 loci associated with SCZ after conditioning on EduYears. Ten of these loci overlapped. Using conjunctional FDR, we identified 10 loci shared between SCZ and College, and 29 loci shared between SCZ and EduYears. The majority of these loci had effects in opposite directions. Our results provide evidence for polygenic overlap between SCZ and educational attainment, and identify novel pleiotropic loci. Other studies have reported genetic overlap between SCZ and cognition, or SCZ and educational attainment, with negative correlation. Importantly, our methods enable identification of bi-directional effects, which highlight the complex relationship between SCZ and educational attainment, and support polygenic mechanisms underlying both cognitive dysfunction and creativity in SCZ.
BDNF Val66Met Genotype Interacts With a History of Simulated Stress Exposure to Regulate Sensorimotor Gating and Startle Reactivity
AbstractReduced expression of Brain-Derived Neurotrophic Factor (BDNF) has been implicated in the pathophysiology of schizophrenia. The BDNF Val66Met polymorphism, which results in deficient activity-dependent secretion of BDNF, is associated with clinical features of schizophrenia. We investigated the effect of this polymorphism on Prepulse Inhibition (PPI), a translational model of sensorimotor gating which is disrupted in schizophrenia. We utilized humanized BDNFVal66Met (hBDNFVal66Met) mice which have been modified to carry the Val66Met polymorphism, as well as express humanized BDNF in vivo. We also studied the long-term effect of chronic corticosterone (CORT) exposure in these animals as a model of history of stress. PPI was assessed at 30ms and 100ms interstimulus intervals (ISI). Analysis of PPI at the commonly used 100ms ISI identified that, irrespective of CORT treatment, the hBDNFVal/Met genotype was associated with significantly reduced PPI. In contrast, PPI was not different between hBDNFMet/Met and hBDNFVal/Val genotype mice. At the 30ms ISI, CORT treatment selectively disrupted sensorimotor gating of hBDNFVal/Met heterozygote mice but not hBDNFVal/Val or hBDNFMet/Met mice. Analysis of startle reactivity revealed that chronic CORT reduced startle reactivity of hBDNFVal/Val male mice by 51%. However, this was independent of the effect of CORT on PPI. In summary, we provide evidence of a distinct BDNFVal66Met heterozygote-specific phenotype using the sensorimotor gating endophenotype of schizophrenia. These data have important implications for clinical studies where, if possible, the BDNFVal/Met heterozygote genotype should be distinguished from the BDNFMet/Met genotype.
Polygenic Risk for Schizophrenia Influences Cortical Gyrification in 2 Independent General Populations
AbstractSchizophrenia is highly heritable, whereas the effect of each genetic variant is very weak. Since clinical heterogeneity and complexity of schizophrenia is high, considerable effort has been made to relate genetic variants to underlying neurobiological aspects of schizophrenia (endophenotypes). Given the polygenic nature of schizophrenia, our goal was to form a measure of additive genetic risk and explore its relationship to cortical morphology. Utilizing the data from a recent genome-wide association study that included nearly 37 000 cases of schizophrenia, we computed a polygenic risk score (PGRS) for each subject in 2 independent and healthy general populations. We then investigated the effect of polygenic risk for schizophrenia on cortical gyrification calculated from 3.0T structural imaging data in the discovery dataset (N = 315) and replication dataset (N = 357). We found a consistent effect of the polygenic risk for schizophrenia on cortical gyrification in the inferior parietal lobules in 2 independent general-population samples. A higher PGRS was significantly associated with a lower local gyrification index in the bilateral inferior parietal lobles, where case-control differences have been reported in previous studies on schizophrenia. Our findings strongly support the effectiveness of both PGRSs and endophenotypes in establishing the genetic architecture of psychiatry. Our findings may provide some implications regarding individual differences in the genetic risk for schizophrenia to cortical morphology and brain development.
My Experience With Psychiatric Services
My experience with psychiatric services has been bad and good—a poison and a cure. However, without those services I would not be where I am today. Psychiatric services were unable to aid someone close to me for 3 years before their death. They appeared different under the influence of psychiatric drugs. I had similar symptoms of anxiety and depression and breakdowns in early adulthood and services did not help me. Of the 3 psychiatrists I utilized, 2 of them were domineering. I feared winding up drugged or dead. I dropped out of treatment and into poverty for 15 years.