Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Estimating multimodal brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study.

Objective: Schizophrenia is a multifaceted disorder associated with structural brain heterogeneity. Despite its relevance for identifying illness subtypes and informative biomarkers, structural brain heterogeneity in schizophrenia remains incompletely understood. Therefore, the objective of this study was to provide a comprehensive insight into the structural brain heterogeneity associated with schizophrenia. Methods: This meta- and mega-analysis investigated the variability of multimodal structural brain measures of white and gray matter in individuals with schizophrenia versus healthy controls. Using the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6139 individuals for a given brain measure, we examined variability in cortical thickness, surface area, folding index, subcortical volume and fractional anisotropy. Results: We found that individuals with schizophrenia are distinguished by higher heterogeneity in the frontotemporal network with regard to multimodal structural measures. Moreover, individuals with schizophrenia showed higher homogeneity of the folding index, especially in the left parahippocampal region. Conclusions: Higher multimodal heterogeneity in frontotemporal regions potentially implies different subtypes of schizophrenia that converge on impaired frontotemporal interaction as a core feature of the disorder. Conversely, more homogeneous folding patterns in the left parahippocampal region might signify a consistent characteristic of schizophrenia shared across subtypes. These findings underscore the importance of structural brain variability in advancing our neurobiological understanding of schizophrenia, and aid in identifying illness subtypes as well as informative biomarkers.

Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Virtual Ontogeny of Cortical Growth Preceding Mental Illness.

BACKGROUND: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.

Family emotional climate in childhood and risk of PTSD in adult children of Australian Vietnam veterans.

The mechanisms of intergenerational transmission of posttraumatic stress disorder (PTSD) from parent to child are not yet known. We hypothesised that the mechanisms involved in trauma transmission may be dependent upon sex specific caregiver-child dyads and these dyads may have a differential impact on post-traumatic stress disorder (PTSD). A non-clinical sample of adult offspring (N = 306) of Australian Vietnam veterans was interviewed in-person to assess the relationship between family emotional climate and caregiver attachment with the offspring's adult experience of post-traumatic stress disorder (PTSD). Attachment to the veteran father was not associated with sons' PTSD, but was for daughters. Attachment to mother was associated with PTSD and depression for both sons and daughters, with positive and warm attachment related to reduced PTSD diagnosis and its symptom clusters. A less positive family emotional environment was related to increased PTSD symptoms in daughters, while for sons a negative relationship style with their mother was related to increased frequency and severity of numbing/avoidance behaviours and hyperarousal symptoms. The findings suggest that sex-related differences in caregiver-child dyads do have a differential impact on PTSD symptom domains and may be one environmental mechanism by which trauma is transmitted across generations.

Military Combat, Posttraumatic Stress Disorder, and the Course of Alcohol Use Disorders in a Cohort of Australian Vietnam War Veterans.

The present study examined the course of diagnosed alcohol use disorders (AUDs) in a cohort of Australian veterans of the Vietnam War (N = 388) who were assessed 22 and 36 years after returning home. Standardized interviews provided data on AUDs, posttraumatic stress disorder (PTSD), other psychiatric diagnoses, and combat exposure. Overall, 148 veterans (38.1%) had no history of alcohol-related diagnoses, 151 veterans (38.9%) had a past AUD diagnosis that was not current at the second assessment point, and 89 veterans (22.9%) had a current AUD diagnosis at the second assessment. Less education, lower intelligence test scores, and misconduct were individual risk factors for AUDs, as were first-interview diagnoses of PTSD, antisocial personality disorder, generalized anxiety, and dysthymia, but not depression; these variables were all nonsignificant after controlling for combat exposure and PTSD. Multinomial regression was used to assess the relative contributions of combat exposure and PTSD to the course of AUDs. Combat exposure and PTSD had different patterns of association with AUDs whereby combat exposure, but not PTSD, was associated with a history of AUDs, odds ratio (OR) = 1.02, but not with current AUDs, whereas PTSD, but not combat exposure, was associated with current AUDs, OR = 3.37. Current numbing and avoidance symptoms were associated with current AUDs, OR = 4.48. The results do not support a mutual maintenance model of PTSD and AUDs but are consistent with a self-medication model, which suggests treatment for PTSD may have beneficial effects on AUDs.

Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium.

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

Growing up with a father with PTSD: The family emotional climate of the children of Australian Vietnam veterans.

A non-clinical sample of male Australian Vietnam veterans, their wives, and adult offspring were interviewed in-person in a national epidemiological study to assess the relationship between the mental ill-health of veterans and the emotional climate of the family while the children were growing up. Veterans were assessed 17 years before their children using standardised psychiatric diagnostic interviews. Family emotional climate was assessed using offspring ratings of parental attachment, and codings of positive and negative family relationship styles based on five minute speech samples provided by the offspring. Sons and daughters had different views of their mothers and fathers, and were less positive towards their fathers particularly if he had posttraumatic stress disorder (PTSD). Veteran PTSD and depression significantly negatively impacted the family emotional climate, while mothers' mental health was not related. Veteran PTSD symptoms were lowest in secure attachment to the veteran and highest in inconsistent attachment for both sons and daughters, but were not related to attachment to the mother. Veteran PTSD was related to daughters' but not sons' perceptions of family emotional climate. The impact of veterans' PTSD on their families' emotional climate is more marked for daughters than sons.

The mental health of sons and daughters of Australian Vietnam veterans.

Background: War service increases the risk of post-traumatic stress disorder (PTSD) to combatants, and has been shown to increase the risk of PTSD in their offspring. The extent to which there is an excess compared with the general population is not yet established, nor whether PTSD increases the risk of other psychiatric problems. Methods: A national sample of 133 sons and 182 daughters of a cohort of 179 Australian Vietnam veterans' families were assessed in person, using structured psychiatric interviews. The prevalence of trauma exposures, DSM-IV (Diagnostic and Statistical Manual of Mental Disorders Fourth Edition) diagnoses and suicidality were compared with the Australian Bureau of Statistics' 2007 National Survey of Mental Health and Wellbeing data matched for age and sex. The risk of mental health problems potentially attributable to PTSD was also assessed. Results: Sons and daughters were more likely than population expectations to report exposures to natural disasters, fire or explosions and transport accidents, and sons more likely to report exposure to toxic chemicals whereas daughters were more likely to report sexual assault. Sons and daughters had higher prevalences of alcohol and other substance dependence, depression and anxiety, and PTSD, and children's PTSD was associated with substance dependence, depression and suicidal ideation. There were strong associations between children's PTSD and comorbid conditions of substance use disorders, depression and anxiety. Conclusions: Higher rates of mental health problems in veterans' families, together with comorbidity with PTSD and the link between veterans' and children's PTSD, suggest that the effects of trauma may continue into subsequent generations.

Combat, Posttraumatic Stress Disorder, and Smoking Trajectory in a Cohort of Male Australian Army Vietnam Veterans.

Background: Whether trauma exposure itself or consequent posttraumatic stress disorder (PTSD) is primarily responsible for smoking and failure to quit remains unclear. Methods: A cohort of male Australian Vietnam veterans (N = 388) was interviewed twice, 22 and 36 years after their return to Australia using standardized psychiatric diagnostic and health interviews and assessment of combat exposure. The smoking trajectory over time revealed a spectrum of outcomes (never smoked, early quitters, late quitters, and continuing smokers). Analysis used multivariate statistics to assess the relative contributions of combat trauma exposure and PTSD while controlling for potential confounders. Results: The trajectory of smoking over time revealed that 21.9% of veterans had never smoked, 45.1% had quit smoking by the time of wave 1, 16.2% were current smokers at wave 1 who had quit by the time of wave 2, 2.8% were late adopters who were current smokers, and 13.9% were continuing smokers. Smoking was associated in single-predictor models with demographics, intelligence, combat exposure, PTSD symptom clusters and diagnosis, and alcohol disorders. Multivariate analysis revealed that PTSD, combat, and intelligence were related to the smoking spectrum but, after adding demographics and other Axis I psychiatric diagnoses, only combat remained significant. No PTSD symptom cluster uniquely predicted smoking status. Conclusions: The results suggest that trauma exposure in the form of military combat may be a more robust predictor of smoking status over time than PTSD. It may be stress itself, rather than poststress disorder, that is more germane to smoking and failure to quit. Implications: Exposure to traumatic stress and development of PTSD have been implicated separately in the maintenance of smoking. This longitudinal cohort study of smoking in war veterans up to three decades postwar enabled evaluation of traumatic stress exposure in combat and the course of PTSD in smoking and quitting while controlling for intelligence, background disadvantage, and other psychiatric conditions. Combat rather than PTSD emerged as more significant to smoking status, suggesting that it may be the traumatic stress itself rather than the development of a poststress disorder that is more germane to smoking in war veterans.

Raising the standard of care in the treatment of schizophrenia: Yes we can!

OBJECTIVE: In response to evidence of deteriorating outcomes of people with schizophrenia we recently published a critical review in the journal concerning why outcomes for schizophrenia are not improving. A published commentary on our review raised criticisms that we aim to address herein. METHOD: Published data related to four issues raised in the commentary were reviewed. RESULTS: There is a body of evidence that supports the possibility of dramatic improvements in treatment effectiveness, presented in our critical review, and these can be achieved within existing financial resources and present day understanding of the pathophysiology of schizophrenia. However, the commentary leads us to highlight four current obstacles to improving treatment effectiveness: (1) the belief of many psychiatrists that long-term antipsychotic medication raises the cardiovascular mortality rate in schizophrenia when the opposite is almost certainly the case; (2) the need to improve psychiatrist training in diagnostic and communication skills, especially with first episode presentations; (3) the requirement for comprehensive and structured assessment of the highly prevalent deficits in insight and decision making capacity associated with schizophrenia; and (4) the need for improved intervention design to minimise the impact of these deficits on treatment choice and refusal. CONCLUSION: With a sense of professional urgency, a genuinely respectful and caring partnership between clinicians, affected individuals and their families, and researchers, with relative little innovation, we conclude that the standard of care can definitely be raised now in the treatment of schizophrenia.

The Course and Correlates of Combat-Related PTSD in Australian Vietnam Veterans in the Three Decades After the War.

Australian male Vietnam veterans (N = 388) were assessed 22 and 36 years after their return to Australia using standardized diagnostic interviews, with added data from Army records and self-report questionnaires. Among veterans who ever had posttraumatic stress disorder (PTSD), 50.3% had a current diagnosis at the second assessment; of those who had a current diagnosis at Wave 1, 46.9% were also current at Wave 2. Late onset occurred for 19.0% of veterans, of whom 60.8% were current at Wave 2. Multivariate analysis compared veterans with no history of PTSD (n = 231) with veterans who had ever had PTSD (n = 157) to assess risk factors for PTSD incidence; and veterans with a history, but not current PTSD (n = 78) with veterans who had current PTSD at the second assessment (n = 79) to assess risk factors for failure to remit. Incidence was associated with lower education, shorter Army training predeployment, higher combat, excess drinking, and help-seeking after return to Australia. Prevalence was associated with having a father who saw combat in World War II, being injured in battle, having a lower intelligence test score, experiencing higher combat, and having a diagnosis of phobia at the first assessment. Only combat was common to incidence and prevalence.

White Matter Disruptions in Schizophrenia Are Spatially Widespread and Topologically Converge on Brain Network Hubs.

White matter abnormalities associated with schizophrenia have been widely reported, although the consistency of findings across studies is moderate. In this study, neuroimaging was used to investigate white matter pathology and its impact on whole-brain white matter connectivity in one of the largest samples of patients with schizophrenia. Fractional anisotropy (FA) and mean diffusivity (MD) were compared between patients with schizophrenia or schizoaffective disorder (n = 326) and age-matched healthy controls (n = 197). Between-group differences in FA and MD were assessed using voxel-based analysis and permutation testing. Automated whole-brain white matter fiber tracking and the network-based statistic were used to characterize the impact of white matter pathology on the connectome and its rich club. Significant reductions in FA associated with schizophrenia were widespread, encompassing more than 40% (234ml) of cerebral white matter by volume and involving all cerebral lobes. Significant increases in MD were also widespread and distributed similarly. The corpus callosum, cingulum, and thalamic radiations exhibited the most extensive pathology according to effect size. More than 50% of cortico-cortical and cortico-subcortical white matter fiber bundles comprising the connectome were disrupted in schizophrenia. Connections between hub regions comprising the rich club were disproportionately affected. Pathology did not differ between patients with schizophrenia and schizoaffective disorder and was not mediated by medication. In conclusion, although connectivity between cerebral hubs is most extensively disturbed in schizophrenia, white matter pathology is widespread, affecting all cerebral lobes and the cerebellum, leading to disruptions in the majority of the brain's fiber bundles.

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

The treatment of schizophrenia: Can we raise the standard of care?

OBJECTIVE: There is evidence that over time health outcomes of people with schizophrenia are deteriorating rather than improving both in terms of mortality rate and levels of morbidity, even in Australia where service resourcing is substantial. Our objective was to examine the evidence of whether poor outcomes reflect decreases in treatment effectiveness and, if so, what are the barriers to improving standards of care. This review will argue that the confidence of clinicians to diagnose schizophrenia early, and provide assertive and long-term care, may be being undermined by a series of controversies in the published literature and discrepancies in clinical practice guidelines. METHOD: A critical review was conducted of the evidence regarding six issues of high clinical relevance to the treatment of schizophrenia formulated as questions: (1) Is schizophrenia a progressive disease? (2) Does relapse contribute to disease progression and treatment resistance? (3) When should the diagnosis of schizophrenia be made? (4) Should maintenance antipsychotic medication be discontinued in fully remitted first-episode patients? (5) Do antipsychotic medications cause deleterious reductions in cortical grey matter volumes? and (6) Are long-acting injectable antipsychotics more effective in reducing relapse rate compared to oral formulations? RESULTS: There is reliable evidence for schizophrenia being a progressive disease with emergent treatment resistance in most cases, that relapse contributes to this treatment resistance, that maintenance antipsychotic medication should not be discontinued in remitted first-episode patients, that antipsychotic medication does not appear to cause deleterious grey matter volume changes, that maintenance antipsychotic medication reduces the mortality rate in schizophrenia and that long-acting injectable antipsychotics are more effective in preventing relapse than oral formulations. CONCLUSION: There is an urgent need to re-engineer the early management of schizophrenia and to routinely evaluate this type of innovation within practice-based research networks. A proposal for an assertive treatment algorithm is included.

Cognitive Subtypes of Schizophrenia Characterized by Differential Brain Volumetric Reductions and Cognitive Decline.

IMPORTANCE: Cognitively distinct subgroups of schizophrenia have been defined based on premorbid and current IQ, but little is known about the neuroanatomical differences among these cognitive subgroups. OBJECTIVES: To confirm previous findings related to IQ-based subgroups of patients with schizophrenia in an independent sample and extend those findings to determine the extent to which brain volumetric differences correspond to the IQ-based subgroups. DESIGN, SETTING, AND PARTICIPANTS: A total of 183 participants were assessed at the outpatient settings of Neuroscience Research Australia and Lyell McEwin Hospital from September 22, 2009, to August 1, 2012. Patients were classified using cluster analysis on the basis of current and premorbid IQ differences. Regional magnetic resonance imaging (MRI) brain volumes were compared among the IQ-based subgroups using analysis of covariance with intracranial volume and age as covariates. MAIN OUTCOMES AND MEASURES: Wechsler Adult Intelligence Scale, third edition, scores; Wechsler Test of Adult Reading scores; Positive and Negative Syndrome Scale scores; and MRI brain volumes. RESULTS: Ninety-six outpatients (mean [SD] age, 35.7 [8.4] years; age range, 18-51 years; 59 men) with schizophrenia or schizoaffective disorder and 87 healthy controls (mean [SD] age, 31.9 [8.4] years; age range, 20-50 years; 46 men) were studied. Sixty-two patients and 67 healthy controls underwent structural MRI of the brain. Cluster analyses revealed 25 putatively preserved patients (26%), 33 moderately deteriorated patients (34%), 27 severely deteriorated patients (28%), and 11 compromised patients (12%). Negative symptom scores were significantly worse in the severely deteriorated group relative to the putatively preserved group (F2,82 = 13.8, P < .001, effect size [ES] = 1.40). Patient subgroups analyzed revealed significantly reduced inferior parietal volume relative to controls (F3,113 = 9.7, P < .001, ES = 0.85-1.24). The severely deteriorated group had significantly reduced total hippocampal (mean [SEM], 8309.6 [175.0] vs 9024.0 [145.5]; P = .01), lingual gyrus (mean [SEM], 11 996.0 [531.5] vs 13 838.1 [441.9]; P = .05), and superior temporal sulcus (mean [SEM], 4697.8 [192.0] vs 5446.0 [159.6]; P = .05) gray matter volumes relative to the putatively preserved group (ES = 0.91-1.10). CONCLUSIONS AND RELEVANCE: Using an independent sample, we obtained proportions in each IQ-based subgroup that were similar to our previous work. Inferior parietal volume reduction was characteristic of schizophrenia relative to controls, and the severely deteriorated IQ group had widespread volumetric reductions. Classifying cognitive heterogeneity in schizophrenia provides a platform to better characterize the neurobiological underpinnings of the illness and its treatment.