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Introduction: Neurofilament light chain (NfL), a blood biomarker of neuronal injury, shows promise in distinguishing neurodegenerative disorders from psychiatric conditions. This is especially relevant in psychosis, given neurological conditions such as autoimmune encephalitis and Niemann Pick Type C disease (NPC) may initially present with psychotic symptoms. Whilst NfL levels have been studied in established schizophrenia cases, their levels in first-episode psychosis (FEP) and ultra-high risk (UHR) for psychosis individuals remain largely unexplored. This study aimed to compare plasma NfL in people with FEP or UHR with healthy controls, as well as explore its associations with clinical data., Method: We retrospectively analysed plasma NfL in 63 participants, consisting of 29 individuals with FEP, 10 individuals with UHR, and 24 healthy controls. We used general linear models (GLM), which were bootstrapped, to compute bias-corrected and accelerated (BCa) 95 % confidence intervals (CIs)., Results: Mean NfL levels were 5.2 pg/mL in FEP, 4.9 pg/mL in UHR, and 5.9 pg/mL in healthy controls. Compared to healthy controls, there were no significant differences in NfL levels in the FEP group (β = -0.22, 95 % CI [-0.86, 0.39], p = 0.516) nor UHR group (β = -0.37, 95 % CI [-0.90, 0.19], p = 0.182). There were no significant associations between NfL levels and clinical variables in the FEP group., Discussion: Our study is the first to demonstrate that plasma NfL levels are not significantly elevated in individuals at UHR for psychosis compared to healthy controls, a finding also observed in the FEP cohort. These findings bolster the potential diagnostic utility of NfL in differentiating between psychiatric and neurodegenerative disorders., Competing Interests: Declaration of competing interest We are grateful for the funding that supported this work: the Trisno Family Research Grant in Old Age Psychiatry, three NorthWestern Mental Health Research Seed Grants, MACH MRFF, and NHMRC (1185180). MK is supported by the Research Training Program Scholarship from the Department of Psychiatry, University of Melbourne with contributions from the Australian Commonwealth Government, and the Ramsay Hospital Research Foundation. AFS is supported by the Swedish federal government under the ALF agreement. VLC is supported by a National Health and Medical Research Council Investigator Fellowship (1177370) and the University of Melbourne Dame Kate Campbell Fellowship. CP was supported by a National Health and Medical Research Council (NHMRC) L3 Investigator Grant (1196508) and NHMRC Program Grant (ID: 1150083)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models., Methods: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD ( n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models)., Results: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS., Conclusions: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: O.H. has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Fujirebio, Genentech, Novartis, Novo Nordisk, Roche, and Siemens. M.W. has received research support from Eli Lilly, Bristol-Myers Squib, Pfizer, Roche, Vtesse, and Actelion. He has also received consultancy/speaking fees from Biomarin, Actelion, Mallinckrodt and Orphan Pharmaceuticals. A.J.W. has received grant/fellowship support from the Trisno Family Gift and Deakin University. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Programme (outside submitted work). K.B. has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Julius Clinical, Lilly, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programmes for Biogen, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Programme, outside the work presented in this paper.

Objective: The appropriateness and clinical utility of neuroimaging in psychiatric populations has been long debated, and the ambiguity of guideline recommendations is well established. Most of the literature is focused on first-episode psychosis. The investigators aimed to review ordering practices and identify risk factors associated with neuroradiological MRI abnormalities and their clinical utility in a general psychiatric population., Methods: A retrospective file review was undertaken for 100 consecutive brain MRI scans for adult psychiatric inpatients who received scanning as part of their clinical care in an Australian hospital., Results: Brain MRI was abnormal in 79.0% of scans; in these cases, 72.2% of patients required further investigation or follow-up, with 17.7% requiring urgent referral within days to weeks, despite only 3.7% of admitted patients undergoing MRI during the study period. Psychiatrically relevant abnormalities were found in 32.0% of scans. Abnormalities were more likely to be found in the presence of cognitive impairment, older age, and longer duration of psychiatric disorder. Psychiatrically relevant abnormalities had further associations with older age at onset of the psychiatric disorder and a weak association with abnormal neurological examination. Multiple indications for imaging were present in 57.0% of patients; the most common indications were physical, neurological, and cognitive abnormalities., Conclusions: Brain MRI is a useful part of psychiatric management in the presence of certain neuropsychiatric risk factors. The present findings suggest that treating teams can judiciously tailor radiological investigations while limiting excessive imaging. Future research in larger cohorts across multiple centers may contribute to shaping more consistent neuroimaging guidelines in psychiatry.

Objective: To explore the cortical morphological associations of the psychoses of epilepsy., Methods: Psychosis of epilepsy (POE) has two main subtypes - postictal psychosis and interictal psychosis. We used automated surface-based analysis of magnetic resonance images to compare cortical thickness, area, and volume across the whole brain between: (i) all patients with POE (n = 23) relative to epilepsy-without psychosis controls (EC; n = 23), (ii) patients with interictal psychosis (n = 10) or postictal psychosis (n = 13) relative to EC, and (iii) patients with postictal psychosis (n = 13) relative to patients with interictal psychosis (n = 10)., Results: POE is characterised by cortical thickening relative to EC, occurring primarily in nodes of the cognitive control network; (rostral anterior cingulate, caudal anterior cingulate, middle frontal gyrus), and the default mode network (posterior cingulate, medial paracentral gyrus, and precuneus). Patients with interictal psychosis displayed cortical thickening in the left hemisphere in occipital and temporal regions relative to EC (lateral occipital cortex, lingual, fusiform, and inferior temporal gyri), which was evident to a lesser extent in postictal psychosis patients. There were no significant differences in cortical thickness, area, or volume between the postictal psychosis and EC groups, or between the postictal psychosis and interictal psychosis groups. However, prior to correction for multiple comparisons, both the interictal psychosis and postictal psychosis groups displayed cortical thickening relative to EC in highly similar regions to those identified in the POE group overall., Significance: The results show cortical thickening in POE overall, primarily in nodes of the cognitive control and default mode networks, compared to patients with epilepsy without psychosis. Additional thickening in temporal and occipital neocortex implicated in the dorsal and ventral visual pathways may differentiate interictal psychosis from postictal psychosis. A novel mechanism for cortical thickening in POE is proposed whereby normal synaptic pruning processes are interrupted by seizure onset., Competing Interests: Conflicts of interest None of the authors have any conflict of interest to disclose., (Copyright © 2022 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far., Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD)., Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022., Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery., Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2 = 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2 = 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery., Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.

Background: Pineal volume reductions have been reported in schizophrenia and clinical high-risk states for the development of psychosis, supporting the role of melatonin dysregulation in the pathophysiology of psychosis. However, it remains unclear whether pineal volume is associated with the later onset of psychosis in individuals at clinical high-risk (CHR) of psychosis or if pineal atrophy is specific to schizophrenia among different psychotic disorders., Methods: This magnetic resonance imaging study examined the volume of and cyst prevalence in the pineal gland in 135 individuals at CHR of psychosis [52 (38.5%) subsequently developed psychosis], 162 with first-episode psychosis (FEP), 89 with chronic schizophrenia, and 87 healthy controls. The potential contribution of the pineal morphology to clinical characteristics was also examined in the CHR and FEP groups., Results: Pineal volumes did not differ significantly between the CHR, FEP, and chronic schizophrenia groups, but were significantly smaller than that in healthy controls. However, pineal volumes were not associated with the later onset of psychosis in the CHR group or FEP sub-diagnosis (i.e., schizophrenia, schizophreniform disorder, affective psychosis, and other psychoses). No significant differences were observed in the prevalence of pineal cysts between the groups, and it also did not correlate with clinical characteristics in the CHR and FEP groups., Conclusion: These results suggest that pineal atrophy is a general vulnerability marker of psychosis, while pineal cysts do not appear to contribute to the pathophysiology of psychosis., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Increased severity of neurological soft signs (NSS) in schizophrenia have been associated with abnormal brain morphology in cerebello-thalamo-cortical structures, but it is unclear whether similar structures underlie NSS prior to the onset of psychosis. The present study investigated the relationship between severity of NSS and grey matter volume (GMV) in individuals at ultra-high risk for psychosis (UHR) stratified for later conversion to psychosis. Structural T1-weighted MRI scans were obtained from 56 antipsychotic-naïve UHR individuals and 35 healthy controls (HC). The UHR individuals had follow-up data (mean follow-up: 5.2 years) to ascertain clinical outcome. Using whole-brain voxel-based morphometry, the relationship between NSS and GMV at baseline was assessed in UHR, HC, as well as individuals who later transitioned (UHR-P, n = 25) and did not transition (UHR-NP, n = 31) to psychosis. NSS total and subscale scores except motor coordination were significantly higher in UHR compared to HC. Higher signs were also found in UHR-P, but not UHR-NP. Total NSS was not associated with GMV in the whole sample or in each group. However, in UHR-P individuals, greater deficits in sensory integration was associated with lower GMV in the left cerebellum, right insula, and right middle frontal gyrus. In conclusion, NSS are present in UHR individuals, particularly those who later transitioned to a psychotic disorder. While these signs show little overall variation with GMV, the association of sensory integration deficits with lower GMV in UHR-P suggests that certain brain areas may be implicated in the development of specific neurological abnormalities in the psychosis prodrome., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk., Objective: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-)., Design, Setting, and Participants: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020., Main Outcomes and Measures: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group)., Results: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001)., Conclusions and Relevance: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.

Background/objectives: The aim was to identify whether performance on olfactory identification can distinguish neurological/neurodegenerative disorders (NNDs) from primary psychiatric disorders (PPDs)., Methods: This is a cross-sectional retrospective study of inpatients assessed in Neuropsychiatry, Royal Melbourne Hospital. Data extracted from the admission records included: demographics, tobacco use, medical comorbidities, cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), and odor identification using the Sniffin' Sticks Screening 12 test. The final diagnosis for patients was informed by established diagnostic criteria., Results: A total 121 patients were included. Eighty-eight patients (73%) were diagnosed with neurological or neurodegenerative disease, including Alzheimers dementia, frontotemporal dementia, Lewy body parkinsonian-related dementias (Parkinson disease, multiple system atrophy, dementia with Lewy bodies) and other neurological causes of dementia; 33 patients (27%) were diagnosed with PPDs (including mood and psychotic disorders). Patients who scored ≤8 on the Sniffin' Sticks Screening 12 test were more likely to have NND than PPD, even after adjustment for age, sex and tobacco use (P=0.009, adjusted odds ratios=3.85, 95% confidence interval=1.40-10.62). Receiver operating characteristic curve analyses demonstrated that a score of ≤8 differentiated NND from PPD with sensitivity of 57% and specificity of 73% (receiver operating characteristic area under the curve of 0.67, P=0.004)., Conclusions: Patients with neuropsychiatric difficulties who score 8 or less on Sniffin' Sticks are more likely to have a neurodegenerative illness. A cut-off score of 8 is potentially a "red flag" for clinicians faced with the diagnostic question of PPD versus NND., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Psychosis of epilepsy (POE) can be a devastating condition, and its neurobiological basis remains unclear. In a previous study, we identified reduced posterior hippocampal volumes in patients with POE. The hippocampus can be further subdivided into anatomically and functionally distinct subfields that, along with the hippocampal fissure, have been shown to be selectively affected in other psychotic disorders and are not captured by gross measures of hippocampal volume. Therefore, in this study, we compared the volume of selected hippocampal subfields and the hippocampal fissure in 31 patients with POE with 31 patients with epilepsy without psychosis. Cortical reconstruction, volumetric segmentation, and calculation of hippocampal subfields and the hippocampal fissure were performed using FreeSurfer. The group with POE had larger hippocampal fissures bilaterally compared with controls with epilepsy, which was significant on the right. There were no significant differences in the volumes of the hippocampal subfields between the two groups. Our findings suggest abnormal development of the hippocampus in POE. They support and expand the neurodevelopmental model of psychosis, which holds that early life stressors lead to abnormal neurodevelopmental processes, which underpin the onset of psychosis in later life. In line with this model, the findings of the present study suggest that enlarged hippocampal fissures may be a biomarker of abnormal neurodevelopment and risk for psychosis in patients with epilepsy., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Impaired olfactory identification has been reported as a first sign of schizophrenia during the earliest stages of illness, including before illness onset. The aim of this study was to examine the relationship between volumes of these regions (amygdala, hippocampus, gyrus rectus and orbitofrontal cortex) and olfactory ability in three groups of participants: healthy control participants (Ctls), patients with first-episode schizophrenia (FE-Scz) and chronic schizophrenia patients (Scz). Exploratory analyses were performed in a sample of individuals at ultra-high risk (UHR) for psychosis in a co-submission paper (Masaoka et al., 2020). The relationship to brain structural measures was not apparent prior to psychosis onset, but was only evident following illness onset, with a different pattern of relationships apparent across illness stages (FE-Scz vs Scz). Path analysis found that lower olfactory ability was related to larger volumes of the left hippocampus and gyrus rectus in the FE-Scz group. We speculate that larger hippocampus and rectus in early schizophrenia are indicative of swelling, potentially caused by an active neurochemical or immunological process, such as inflammation or neurotoxicity, which is associated with impaired olfactory ability. The volumetric decreases in the chronic stage of Scz may be due to degeneration resulting from an active immune process and its resolution., Competing Interests: Declaration of Competing Interest Christos Pantelis has participated on Advisory Boards for Janssen-Cilag, Astra-Zeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organized by Astra-Zeneca, Janssen-Cilag, Eli-Lilly, Pfizer, Lundbeck and Shire., (Copyright © 2020. Published by Elsevier B.V.)

Background: Australian and US guidelines recommend routine brain imaging, either computed tomography or magnetic resonance imaging, to exclude structural lesions in presentations for first-episode psychosis. The aim of this review was to examine the evidence for the appropriateness and clinical utility of this recommendation by assessing the frequency of abnormal radiological findings in computed tomography and magnetic resonance imaging scans among patients with first-episode psychosis., Methods: PubMed and Embase database were searched from inception to April 2018 using appropriate MeSH or Emtree terms. Studies were included in the review if they reported data on computed tomography or magnetic resonance imaging scan findings of individuals with first-episode psychosis. No restriction on the geographical location of the study or the age of participants was applied. We calculated the percentage of abnormal radiological findings in each study, separately by the two diagnostic methods., Results: There were 16 suitable studies published between 1988 and 2017, reporting data on an overall 2312 patients with first-episode psychosis. Most were observational studies with a retrospective design and the majority examined patients with computed tomography. While structural abnormalities were a relatively common finding, these rarely required clinical intervention (range across studies: 0-60.7%; median: 3.5%) and were very rarely the cause of the psychotic symptoms (range: 0-3.3%; median: 0%). Only 2 of the 16 studies concluded that brain imaging should be routinely ordered in first-episode psychosis., Conclusion: There is insufficient evidence to suggest that brain imaging should be routinely ordered for patients presenting with first-episode psychosis without associated neurological or cognitive impairment. The appropriate screening procedure for structural brain lesions is conventional history-taking, mental status and neurological examination. If intracranial pathology is suspected clinically, a magnetic resonance imaging or computed tomography scan should be performed depending on the clinical signs, the acuity and the suspected pathology. National guidelines should reflect evidence-based data.

Objective: Psychosis of epilepsy (POE) occurs more frequently in temporal lobe epilepsy, raising the question as to whether abnormalities of the hippocampus are aetiologically important. Despite decades of investigation, it is unclear whether hippocampal volume is reduced in POE, perhaps due to small sample sizes and methodological limitations of past research., Methods: In this study, we examined the volume of the total hippocampus, and the hippocampal head, body and tail, in a large cohort of patients with POE and patients with epilepsy without psychosis (EC). One hundred adults participated: 50 with POE and 50 EC. Total and subregional hippocampal volumes were manually traced and compared between (1) POE and EC; (2) POE with temporal lobe epilepsy, extratemporal lobe epilepsy and generalised epilepsy; and (3) patients with POE with postictal psychosis (PIP) and interictal psychosis (IP)., Results: Compared with EC the POE group had smaller total left hippocampus volume (13.5% decrease, p<0.001), and smaller left hippocampal body (13.3% decrease, p=0.002), and left (41.5% decrease, p<0.001) and right (36.4% decrease, p<0.001) hippocampal tail volumes. Hippocampal head volumes did not differ between groups., Conclusion: Posterior hippocampal volumes are bilaterally reduced in POE. Volume loss was observed on a posteroanterior gradient, with severe decreases in the tail and moderate volume decreases in the body, with no difference in the hippocampal head. Posterior hippocampal atrophy is evident to a similar degree in PIP and IP. Our findings converge with those reported for the paradigmatic psychotic disorder, schizophrenia, and suggest that posterior hippocampal atrophy may serve as a biomarker of the risk for psychosis, including in patients with epilepsy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that presents with a spectrum of clinical manifestations from infancy and childhood or in early or mid-adulthood. Progressive neurological symptoms including ataxia, dystonia and vertical gaze palsy are a hallmark of the disease, and psychiatric symptoms such as psychosis and mood disorders are common. These latter symptoms often present early in the course of NPC and thus these patients are often diagnosed with a major psychotic or affective disorder before neurological and cognitive signs present and the diagnosis is revised. The commonalities and characteristics of psychotic symptoms in both NPC and schizophrenia may share neuronal pathways and mechanisms and provide potential targets for research in both disorders. The neurobiology of NPC and its relationship to the pattern of neuropsychiatric and cognitive symptoms is described in this review. A number of neurobiological models are proposed as mechanisms by which NPC causes psychiatric and cognitive symptoms, informed from models proposed in schizophrenia and other metabolic disorders. There are a number of symptomatic and illness-modifying treatments for NPC currently available. The current evidence is discussed; focussing on two medications which have shown promise, miglustat and hydroxypropyl-β-cyclodextrin.

Objectives: This clinical update review focuses on the management of the neuropsychiatric manifestations of Huntington's disease (HD). The review highlights current issues regarding pharmacological and non-pharmacological treatment, putative therapeutics and recent relevant research findings in this area., Conclusions: Neuropsychiatric symptoms may precede the classic motor clinical symptoms of HD (prodromal HD) by decades and cause significant functional impairment. Early recognition and comprehensive non-pharmacological, usually in combination with pharmacological, treatment is essential.

Objective: Ventricular enlargement is common in established schizophrenia; however, data from ultra high-risk for psychosis and first-episode psychosis studies are inconclusive. This study aims to investigate ventricular volumes at different stages of psychosis., Methods: Ventricular volumes were measured using a semi-automated and highly reliable method, for 89 established schizophrenia, 162 first-episode psychosis, 135 ultra high-risk for psychosis and 87 healthy controls using 1.5T magnetic resonance images. Clinical outcome diagnoses for ultra high-risk for psychosis were evaluated at long-term follow-up (mean: 7.5 years)., Results: Compared to controls, we identified significant ventricular enlargement of 36.2% in established schizophrenia ( p < 0.001). Ventricular enlargement was not significant in first-episode psychosis (6%) or ultra high-risk for psychosis (-3%). Examination across stages of schizophrenia-spectrum diagnoses subgroups revealed a significant linear trend ( p = 0.006; established schizophrenia = 36.2%, first-episode psychosis schizophrenia = 18.5%, first-episode psychosis schizophreniform = -4.2% and ultra high-risk for psychosis-schizophrenia converters = -18.5%)., Conclusion: Ventricular enlargement is apparent in patients with established schizophrenia but is not a feature at the earliest stages of illness (ultra high-risk for psychosis and first-episode psychosis). Further research is needed to fully characterize the nature and timing of ventricular volume changes early in the course of illness and how these changes impact outcomes.

Most individuals at ultra-high risk (UHR) for psychosis do not transition to frank illness. Nevertheless, many have poor clinical outcomes and impaired psychosocial functioning. This study used voxel-based morphometry to investigate if baseline grey and white matter brain densities at identification as UHR were associated with functional outcome at medium- to long-term follow-up. Participants were help-seeking UHR individuals (n = 109, 54M:55F) who underwent magnetic resonance imaging at baseline; functional outcome was assessed an average of 9.2 years later. Primary analysis showed that lower baseline grey matter density, but not white matter density, in bilateral frontal and limbic areas, and left cerebellar declive were associated with poorer functional outcome (Social and Occupational Functioning Assessment Scale [SOFAS]). These findings were independent of transition to psychosis or persistence of the at-risk mental state. Similar regions were significantly associated with lower self-reported levels of social functioning and increased negative symptoms at follow-up. Exploratory analyses showed that lower baseline grey matter densities in middle and inferior frontal gyri were significantly associated with decline in Global Assessment of Functioning (GAF) score over follow-up. There was no association between baseline grey matter density and IQ or positive symptoms at follow-up. The current findings provide novel evidence that those with the poorest functional outcomes have the lowest grey matter densities at identification as UHR, regardless of transition status or persistence of the at-risk mental state. Replication and validation of these findings may allow for early identification of poor functional outcome and targeted interventions., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Structural Magnetic Resonance Imaging (MRI) studies have attempted to use brain measures obtained at the first-episode of psychosis to predict subsequent outcome, with inconsistent results. Thus, there is a real need to validate the utility of brain measures in the prediction of outcome using large datasets, from independent samples, obtained with different protocols and from different MRI scanners. This study had three main aims: 1) to investigate whether structural MRI data from multiple centers can be combined to create a machine-learning model able to predict a strong biological variable like sex; 2) to replicate our previous finding that an MRI scan obtained at first episode significantly predicts subsequent illness course in other independent datasets; and finally, 3) to test whether these datasets can be combined to generate multicenter models with better accuracy in the prediction of illness course. The multi-center sample included brain structural MRI scans from 256 males and 133 females patients with first episode psychosis, acquired in five centers: University Medical Center Utrecht (The Netherlands) (n=67); Institute of Psychiatry, Psychology and Neuroscience, London (United Kingdom) (n=97); University of São Paulo (Brazil) (n=64); University of Cantabria, Santander (Spain) (n=107); and University of Melbourne (Australia) (n=54). All images were acquired on 1.5-Tesla scanners and all centers provided information on illness course during a follow-up period ranging 3 to 7years. We only included in the analyses of outcome prediction patients for whom illness course was categorized as either "continuous" (n=94) or "remitting" (n=118). Using structural brain scans from all centers, sex was predicted with significant accuracy (89%; p<0.001). In the single- or multi-center models, illness course could not be predicted with significant accuracy. However, when reducing heterogeneity by restricting the analyses to male patients only, classification accuracy improved in some samples. This study provides proof of concept that combining multi-center MRI data to create a well performing classification model is possible. However, to create complex multi-center models that perform accurately, each center should contribute a sample either large or homogeneous enough to first allow accurate classification within the single-center., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Two thirds of individuals identified as ultra-high risk (UHR) for psychosis do not transition to psychosis over the medium to long-term (non-transition; UHR-NT). Nevertheless, many of these individuals have persistent attenuated psychotic symptoms (APS). The current study examined whether there were differences in baseline grey matter volume (i.e. at initial identification as UHR) in UHR-NT individuals whom had APS compared to those without APS (No-APS) at medium to long-term follow-up., Methods: Participants were help-seeking individuals who were identified as being at UHR for psychosis between 2 and 12years previously (mean=7.5). The sample consisted of 109 participants who underwent a Magnetic Resonance Imaging scan at baseline and who had not been observed to develop a psychotic disorder over the follow-up period (UHR-NT). Using voxel-based morphometry, baseline grey matter volume (GMV) was compared between participants with (N=30) and without (N=79) APS at follow-up., Results: At baseline, the APS and No-APS groups were clinically indistinguishable. At follow-up, the APS group had significantly worse symptoms and impaired functioning. Individuals with APS had reduced baseline GMV in frontal, temporal, posterior and cingulate regions compared to those without APS at follow-up. Reduced GMV was associated with more severe positive, negative and depressive symptoms and lower global functioning in the combined UHR-NT cohort. These associations were independent of later APS outcome., Discussion: This study found that differences in regional GMV are discernible at an early stage of UHR and may be specific to individuals who have APS and psychopathology at follow-up. Our findings suggest that lower GMV at baseline may confer neurobiological risk for later APS and/or increased psychopathology while the absence of these structural abnormalities might be protective., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Investigation of aberrant large-scale brain networks offers novel insight into the role these networks play in diverse psychiatric disorders such as schizophrenia. Although studies report altered functional brain connectivity in participants at ultra-high risk (UHR) for psychosis, it is unclear whether these alterations extend to structural brain networks., Methods: Whole-brain structural covariance patterns of 133 participants at UHR for psychosis (51 of whom subsequently developed psychosis) and 65 healthy control (HC) subjects were studied. Following data preprocessing (using VBM8 toolbox), the mean signal in seed regions relating to specific networks (visual, auditory, motor, speech, semantic, executive control, salience, and default-mode) were extracted, and voxel-wise analyses of covariance were conducted to compare the association between whole-brain signal and each seed region for UHR and HC individuals. The UHR participants who transitioned to psychosis were compared with the UHR participants who did not., Results: Significantly reduced structural covariance was observed in the UHR sample compared with the HC sample for the default-mode network, and increased covariance was observed for the motor and executive control networks. When the UHR participants who transitioned to psychosis were compared with the UHR participants who did not, aberrant structural covariance was observed in the salience, executive control, auditory, and motor networks., Conclusions: Whole-brain structural covariance analyses revealed subtle changes of connectivity of the default-mode, executive control, salience, motor, and auditory networks in UHR individuals for psychosis. Although we found significant differences, these are small changes and tend to reflect largely intact structural networks., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

We present a case of tuberous sclerosis complex (TSC) diagnosed in adulthood in a man initially referred for specialist neuropsychiatric assessment with psychosis and obsessive-compulsive symptoms (OCS) on a background of epilepsy and intellectual disability. To our knowledge, this is the first reported patient with TSC featuring both psychosis and OCS. This patient highlights the importance of comprehensive re-evaluation of atypical presentations of intellectual disability, epilepsy and associated neuropsychiatric symptoms, even in adulthood. This is particularly relevant in the context of significant advances in genetics, neuroscience, imaging and treatments for heritable neurogenetic disorders., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Three types of orbitofrontal cortex (OFC) sulcogyral patterns have been identified in the general population. The distribution of these three types has been found to be altered in individuals at genetic risk of psychosis, and in patients with first episode psychosis (FEP) and chronic schizophrenia. This study aims at establishing whether altered OFC sulcogyral patterns were present in a large cohort of individuals at ultra high risk (UHR) for psychosis. OFC pattern type was classified and the number of posterior and intermediate sulci present on the surface of the OFC was counted. OFC sulcogyral type and the number of sulci were compared between controls (n=58) and UHR participants who transitioned (n=49) versus those who did not transition (n=77) to psychosis. Finally, the relationship between sulcogyral type and number of sulci with intellectual quotient (IQ), symptom severity and social functioning of UHR individuals was explored. In line with other studies conducted in chronic schizophrenia and FEP, UHR individuals who later transitioned to psychosis showed a reduced incidence of the Type I OFC on the right hemisphere compared to controls (χ(2)=19.847, p<0.001). These highly consistent results point towards the protective effect of possessing a Type I OFC in the right hemisphere. Furthermore, OFC sulcus counts revealed that controls presented with a higher number of posterior (right hemisphere; χ(2)=11.658, p=0.003) and intermediate sulci (left: χ(2)=6.643, p=0.036; right: χ(2)=11.726, p=0.020) when compared to UHR individuals. However, no associations between OFC types or sulcus count and IQ, symptoms and functioning were observed., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A shallow olfactory sulcus has been reported in schizophrenia, possibly reflecting abnormal forebrain development during early gestation. However, it remains unclear whether this anomaly exists prior to the onset of psychosis and/or differs according to illness stage. In the current study, magnetic resonance imaging was used to investigate the length and depth of the olfactory sulcus in 135 ultra high-risk (UHR) individuals [of whom 52 later developed psychosis (UHR-P) and 83 did not (UHR-NP)], 162 patients with first-episode psychosis (FEP), 89 patients with chronic schizophrenia, and 87 healthy controls. While there was no group difference in the length of the sulcus, UHR-P subjects had significantly shallower olfactory sulcus at baseline as compared with UHR-NP and control subjects. The depth of this sulcus became increasingly more superficial as one moved from UHR-P subjects to FEP patients to chronic schizophrenia patients. Finally, the depth of the olfactory sulcus in the UHR-P subjects was negatively correlated with the severity of negative symptoms. These findings suggest that the altered depth of the olfactory sulcus, which exists before psychosis onset, could be predictive of transition to psychosis, but also suggest ongoing changes of the sulcus morphology during the course of the illness., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Three types of OFC sulcogyral patterns have been identified in the general population. The distribution of these three types has been found altered in individuals at genetic risk of psychosis, first episode psychosis (FEP) and chronic schizophrenia. The aim of this study was to replicate and extend previous research by additionally investigating: intermediate and posterior orbital sulci, cortical thickness, and degree of gyrification/folding of the OFC, in a large sample of FEP patients and healthy controls. OFC pattern type was classified based on a method previously devised, using T1-weighted magnetic resonance images. Cortical thickness and local gyrification indices were calculated using FreeSurfer. Occurrence of Type I pattern was decreased and Type II pattern was increased in FEP patients for the right hemisphere. Interestingly, controls displayed an OFC pattern type distribution that was disparate to that previously reported. Significantly fewer intermediate orbital sulci were observed in the left hemisphere of patients. Grey matter thickness of orbitofrontal sulci was reduced bilaterally, and left hemisphere reductions were related to OFC pattern type in patients. There was no relationship between pattern type and degree of OFC gyrification. An interaction was found between the number of intermediate orbital sulci and OFC gyrification; however this group difference was specific to only the small subsample of people with three intermediate orbital sulci. Given that cortical folding is largely determined by birth, our findings suggest that Type II pattern may be a neurodevelopmental risk marker while Type I pattern may be somewhat protective. This finding, along with compromised orbitofrontal sulci thickness, may reflect early abnormalities in cortical development and point toward a possible endophenotypic risk marker of schizophrenia-spectrum disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

It remains unclear whether brain structural abnormalities observed before the onset of psychosis are specific to schizophrenia or are common to all psychotic disorders. This study aimed to measure regional gray matter volume prior to the onset of schizophreniform and of affective psychoses. We investigated 102 subjects at ultrahigh risk (UHR) of developing psychosis recruited from the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia. Twenty-eight of these subjects developed psychosis subsequent to scanning: 19 schizophrenia, 7 affective psychoses, and 2 other psychoses. We examined regional gray matter volume using 1.5 mm thick, coronal, 1.5 Tesla magnetic resonance imaging and voxel-based morphometry methods of image analysis. Subjects were scanned at presentation and were followed up clinically for a minimum of 12 months, to detect later transition to psychosis. We found that both groups of subjects who subsequently developed psychosis (schizophrenia and affective psychosis) showed reductions in the frontal cortex relative to UHR subjects who did not develop psychosis. The subgroup that subsequently developed schizophrenia also showed smaller volumes in the parietal cortex and, at trend level, in the temporal cortex, whereas those who developed an affective psychosis had significantly smaller subgenual cingulate volumes. These preliminary findings suggest that volumetric abnormalities in UHR individuals developing schizophrenia vs affective psychoses comprise a combination of features that predate both disorders and others that may be specific to the nature of the subsequent disorder.

Objectives: To investigate if low-dose lithium may counteract the microstructural and metabolic brain changes proposed to occur in individuals at ultra-high risk (UHR) for psychosis., Methods: Hippocampal T2 relaxation time (HT2RT) and proton magnetic resonance spectroscopy ((1)H-MRS) measurements were performed prior to initiation and following three months of treatment in 11 UHR patients receiving low-dose lithium and 10 UHR patients receiving treatment as usual (TAU). HT2RT and (1)H-MRS percentage change scores between scans were compared using repeated measures ANOVA and correlated with behavioural change scores., Results: Low-dose lithium significantly reduced HT2RT compared to TAU (p=0.018). No significant group by time effects was seen for any brain metabolites as measured with (1)H-MRS, although myo-inositol, creatine, choline-containing compounds and NAA increased in the group receiving low-dose lithium and decreased or remained unchanged in subjects receiving TAU., Conclusions: This pilot study suggests that low-dose lithium may protect the microstructure of the hippocampus in UHR states as reflected by significantly decreasing HT2RT. Larger scale replication studies in UHR states using T2 relaxation time as a proxy for emerging brain pathology seem a feasible mean to test neuroprotective strategies such as low-dose lithium as potential treatments to delay or even prevent the progression to full-blown disorder.

Context: People experiencing possible prodromal symptoms of psychosis have a very high risk of developing the disorder, but it is not possible to predict, on the basis of their presenting clinical features, which individuals will subsequently become psychotic. Recent neuroimaging studies suggest that there are volumetric differences between individuals at ultra-high risk (UHR) for psychosis who later develop psychotic disorder and those who do not. However, the samples examined to date have been small, and the findings have been inconsistent., Objective: To assess brain structure in individuals at UHR for psychosis in a larger and more representative sample than in previous studies by combining magnetic resonance imaging data from 5 different scanning sites., Design: Case-control study., Setting: Multisite., Participants: A total of 182 individuals at UHR and 167 healthy controls. Participants were observed clinically for a mean of 2 years. Forty-eight individuals (26.4%) in the UHR group developed psychosis and 134 did not., Main Outcome Measures: Magnetic resonance images were acquired from each participant. Group differences in gray matter volume were examined using optimized voxel-based morphometry., Results: The UHR group as a whole had less gray matter volume than did controls in the frontal regions bilaterally. The UHR subgroup who later developed psychosis had less gray matter volume in the left parahippocampal cortex than did the UHR subgroup who did not., Conclusions: Individuals at high risk for psychosis show alterations in regional gray matter volume regardless of whether they subsequently develop the disorder. In the UHR population, reduced left parahippocampal volume was specifically associated with the later onset of psychosis. Alterations in this region may, thus, be crucial to the expression of illness. Identifying abnormalities that specifically predate the onset of psychosis informs the development of clinical investigations designed to predict which individuals at high risk will subsequently develop the disorder.

We describe the presentation of an adolescent with juvenile-onset Niemann-Pick disease type C (NPC) who presented with post-ictal psychosis in the context of a developing seizure disorder. After demonstrating mild gait disturbance beginning at the age of 4 years, he was diagnosed with NPC at age 12 on the basis of 95% of cultured fibroblasts staining positive for filipin and a reduced fibroblast cholesterol esterification rate. He then developed a seizure disorder at age 15, where clusters of seizures produced typical psychotic symptoms, including hallucinations and delusions. His seizure disorder responded to valproate, which resulted in a settling of his psychotic symptoms. Whilst post-ictal psychosis is rarely reported prior to the age of 16, NPC in adolescents and adults is particularly psychotogenic and may increase the risk for post-ictal psychosis in the pediatric population.

Although the hippocampus is a key brain region in the pathophysiology of schizophrenia, it is unclear whether structural or biochemical abnormalities predate illness onset. In this study, we used magnetic resonance imaging and spectroscopy data acquired prior to both the onset of psychosis and treatment with antipsychotics to determine this. Sixty-six young people clinically at ultra high-risk of development of psychosis were recruited, 59 of whom did not later develop a psychotic disorder and 7 who had done so after at least 24 months follow-up. These participants were compared with 29 healthy comparison subjects on multiple independent magnetic resonance measures: hippocampal volume, hippocampal T2 relaxation time, and medial temporal lobe metabolite concentrations (including N-acetylaspartate). We found similar reductions in left hippocampal volume in the at-risk group compared to comparison subjects regardless of later transition status; on the right this only reached significance for the at-risk group who did not transition to psychosis. T2 relaxation time in the left hippocampal head was significantly elevated in the later-psychotic group, and this elevation positively correlated with total positive symptoms in the UHR group as a whole. Medial temporal lobe metabolite concentrations did not differ. These findings suggest that there are subtle pathological changes in the hippocampus prior to the development of psychosis, but that they are limited to the left hippocampal head. However, standard measures of neuroanatomical disturbance do not appear to be predictive of later transition, and instead are likely to be non-specific and common in cases that later develop a non-psychotic disorder., (Copyright 2010 Elsevier Inc. All rights reserved.)

The aim of the present study was to investigate whether volumetric abnormalities of the caudate nuclei predate the onset of psychotic illness. Caudate nuclei volume (CNVs), excluding the tail, were measured using region-of-interest (ROI) tracing of magnetic resonance imaging (MRI) scans acquired on a 1.5T scanner. Subjects included 39 individuals deemed at ultra-high risk of psychosis who converted to psychosis (UHR-P) after initial MRI scanning; 39 matched individuals at ultra-high risk who did not convert to psychosis (UHR-NP); and 39 matched healthy controls. All subjects were neuroleptic-naïve. After adjusting CNVs for intracranial volume (ICV), univariate analyses of variance and repeated measures analyses of variance were undertaken to examine the relationship of CNVs to psychosis transition and to family history of psychosis. Pearson's correlations were used to investigate the relationship of psychopathological scores to CNVs. CNVs did not differ significantly between UHR individuals and healthy controls, and there was no significant difference between converters and non-converters to psychosis. In the UHR group, presence of family history of psychosis was not related to CNVs. There was no correlation between CNVs and either positive or negative symptoms of schizophrenia. Significant associations were found between larger CNV and increased errors on a spatial working memory task but better verbal fluency performance. These data suggest that the caudate is macroscopically normal prior to illness onset, while the relationship to tasks of executive function may implicate the caudate together with its connections to prefrontal regions. Future research should examine changes longitudinally together with analysis of shape to assess subregions of the caudate that connect with prefrontal cortex.

Background: Pituitary volume is currently measured as a marker of hypothalamic-pituitary-adrenal hyperactivity in patients with psychosis despite suggestions of susceptibility to antipsychotics. Qualifying and quantifying the effect of atypical antipsychotics on the volume of the pituitary gland will determine whether this measure is valid as a future estimate of HPA-axis activation in psychotic populations., Aims: To determine the qualitative and quantitative effect of atypical antipsychotic medications on pituitary gland volume in a first-episode psychosis population., Method: Pituitary volume was measured from T1-weighted magnetic resonance images in a group of 43 first-episode psychosis patients, the majority of whom were neuroleptic-naïve, at baseline and after 3months of treatment, to determine whether change in pituitary volume was correlated with cumulative dose of atypical antipsychotic medication., Results: There was no significant baseline difference in pituitary volume between subjects and controls, or between neuroleptic-naïve and neuroleptic-treated subjects. Over the follow-up period there was a negative correlation between percentage change in pituitary volume and cumulative 3-month dose of atypical antipsychotic (r=-0.37), i.e. volume increases were associated with lower doses and volume decreases with higher doses., Conclusions: Atypical antipsychotic medications may reduce pituitary gland volume in a dose-dependent manner suggesting that atypical antipsychotic medication may support affected individuals to cope with stress associated with emerging psychotic disorders.

In this review, we describe neuropsychological and brain imaging findings in the early stages of psychosis and schizophrenia. We focus on recent clinical high-risk studies and consider whether the evidence supports these as 'endophenotypes' of a vulnerability to the illness or as 'biomarkers' of illness onset and transition. The findings suggest that there are a number of processes at psychosis onset that may represent biomarkers of incipient illness. These neurobiological indices particularly implicate the integrity of frontal and temporal cortices, which may or may not be related to the genetics of psychosis (i.e. potential 'endophenotypes'). However, these brain regions are dynamically changing during normal maturation, meaning that any putative neurobiological markers identified at the earliest stages of illness may be relatively unstable.We suggest that, while such measures maybe readily identified as potential neurobiological markers of established illness, they are inconsistent at (or around) the time of illness onset when assessed cross-sectionally. Instead,identification of more valid risk markers may require longitudinal assessment to ascertain normal or abnormal trajectories of neurodevelopment. Accordingly, we assert that the current conceptualisations of potential biomarkers and/or 'endophenotypes' for schizophrenia may need to be reconsidered in the context of normal and abnormal brain maturational processes at the time of onset of psychotic disorders.

Morphologic abnormalities of the superior temporal gyrus (STG) have been reported in schizophrenia, but have not been extensively studied in other psychotic disorders such as affective psychosis. In the present study, magnetic resonance imaging was used to examine the volumes of the STG and its subregions [planum polare (PP), Heschl gyrus (HG), planum temporale (PT), rostral STG, and caudal STG] in 162 first-episode patients with various psychotic disorders [46 schizophrenia (31 schizophrenia and 15 schizoaffective disorder), 57 schizophreniform disorder, 34 affective psychosis, and 25 other psychoses] and 62 age- and sex-matched healthy controls. The first-episode schizophrenia patients had significantly less gray matter in HG, PT, and caudal STG bilaterally compared with all other groups, but there was no difference between the controls and affective psychosis, schizophreniform disorder, or other psychoses for any STG subregion. The STG white matter volume did not differ between groups. Our findings indicate that morphologic abnormalities of the STG gray matter are specific to schizophrenia among various psychotic disorders, implicating its role in the underlying pathophysiology of schizophrenia.

Reductions in the size of the anterior callosum have been described for both first-episode and established schizophrenia and bipolar affective disorder, but never in individuals with psychotic bipolar disorder. We recruited 110 first-episode psychosis subjects (74 schizophrenia spectrum and 36 affective psychosis) and 36 age- and gender-matched controls. The callosum was extracted from a mid-sagittal slice from T1-weighted magnetic resonance images, and total area, length and curvature of the callosum were compared. The schizophrenia-spectrum group showed reductions in thickness of the genu across schizophreniform and schizoaffective disorder and schizophrenia, and the schizoaffective disorder group also showed an increase in thickness in the splenium and isthmus. None of these changes were seen in the affective disorder group, although a non-significant increase in the region of the isthmus and splenium was seen, particularly in the depressed group. Psychotic affective disorders do not show the anterior callosal reductions that are seen in the schizophrenia-spectrum group at first episode. The schizoaffective patients show additional posterior callosal expansions that may be a marker of an affective diathesis. This suggests that schizoaffective disorder may represent two interacting illness processes or be mid-way along a continuum of these two broad categories of illness at first psychosis.

Volume reductions of the insular cortex have been described in schizophrenia, but it remains unclear whether other psychotic disorders such as affective psychosis also exhibit insular cortex abnormalities. In this study, we used magnetic resonance imaging to investigate the gray matter volume of the anterior (short) and posterior (long) insular cortices in 162 first-episode patients with various psychotic disorders (46 schizophrenia, 57 schizophreniform disorder, 34 affective psychosis, and 25 other psychoses) and 62 age- and gender-matched healthy comparison subjects. Patients with schizophrenia showed bilateral volume reduction of the anterior and posterior insular cortices compared with controls, but the remaining first-episode psychosis subgroups had normal insular volumes. The volumes of these insular subregions were significantly smaller in schizophrenia patients than in patients with schizophreniform disorder or affective psychoses. There was no association between the insular cortex volume and daily dosage or type of antipsychotic medication in any patient group. These findings suggest that the widespread volume reduction of the insular cortex is specific to established schizophrenia, implicating its role in the neurobiology of clinical characteristics associated with schizophrenia.

Morphologic abnormalities of the insular cortex have been described in psychotic disorders such as schizophrenia, but it remains unclear whether these changes predate the onset of psychosis or develop progressively over the course of illness. In this study, we used magnetic resonance imaging to investigate the gray matter volume of the long and short insular cortices in 97 neuroleptic-naïve individuals at ultra-high-risk (UHR) for developing psychosis [of whom 31 (32%) later developed psychosis (UHR-P) and 66 (68%) did not (UHR-NP)] and 55 age- and gender-matched healthy comparisons. We also conducted a longitudinal comparison of the insular cortex gray matter changes in 31 UHR individuals (20 UHR-NP and 11 UHR-P) and 20 controls for whom follow-up MRI data between 1 and 4 years later were available. In the cross-sectional comparison, the UHR-P subjects had a significantly smaller insular cortex compared with the UHR-NP subjects bilaterally and with the controls on the right hemisphere, especially for the short insular region. More severe negative symptoms in UHR-P subjects at baseline were associated with smaller volumes of the right long insular cortex. In the longitudinal comparison, the UHR-P subjects showed greater gray matter reduction of insular cortex bilaterally (-5.0%/year) compared with controls (-0.4%/year) or UHR-NP subjects (-0.6%/year). Our findings suggest that insular cortex gray matter abnormalities in psychotic disorders may reflect pre-existing vulnerability, but that there are also active progressive changes of the insular cortex during the transition period into psychosis. Whether these longitudinal changes are features of the disorder or related to treatment with antipsychotic medication remains to be determined.

Context: Longitudinal magnetic resonance imaging studies have shown progressive gray matter reduction in the superior temporal gyrus during the earliest phases of schizophrenia. It is unknown whether these progressive processes predate the onset of psychosis., Objective: To examine gray matter reduction of the superior temporal gyrus over time in individuals at risk for psychosis and in patients with first-episode psychosis., Design: Cross-sectional and longitudinal comparisons., Setting: Personal Assessment and Crisis Evaluation Clinic and Early Psychosis Preventions and Intervention Centre., Participants: Thirty-five ultrahigh-risk individuals (of whom 12 later developed psychosis [UHRP] and 23 did not [UHRNP]), 23 patients with first-episode psychosis (FEP), and 22 control subjects recruited from the community., Main Outcome Measures: Volumes of superior temporal subregions (planum polare, Heschl gyrus, planum temporale, and rostral and caudal regions) were measured at baseline and follow-up (mean, 1.8 years) and were compared across groups., Results: In cross-sectional comparisons, only the FEP group had significantly smaller planum temporale and caudal superior temporal gyrus than other groups at baseline, whereas male UHRP subjects also had a smaller planum temporale than controls at follow-up. In longitudinal comparison, UHRP and FEP patients showed significant gray matter reduction (approximately 2%-6% per year) in the planum polare, planum temporale, and caudal region compared with controls and/or UHRNP subjects. The FEP patients also exhibited progressive gray matter loss in the left Heschl gyrus (3.0% per year) and rostral region (3.8% per year), which were correlated with the severity of delusions at follow-up., Conclusions: A progressive process in the superior temporal gyrus precedes the first expression of florid psychosis. These findings have important implications for underlying neurobiologic features of emerging psychotic disorders and emphasize the importance of early intervention during or before the first episode of psychosis.

Morphologic abnormalities of the insular cortex have been described in psychotic disorders such as schizophrenia, but it remains unknown whether these abnormalities develop progressively over the course of the illness. In the current study, longitudinal magnetic resonance imaging data were obtained from 23 patients with first-episode psychosis (FEP), 11 patients with chronic schizophrenia, and 26 healthy controls. The volumes of the short (anterior) and long (posterior) insular cortices were measured on baseline and follow-up (between 1 and 4 years later) scans and were compared across groups. In cross-sectional comparison at baseline, the FEP and chronic schizophrenia patients had significantly smaller short insular cortex than did controls. In longitudinal comparison, the FEP patients showed significant gray matter reduction of the insular cortex over time (-4.3%/2.0 years) compared with controls (0.3%/2.2 years) without significant subregional effects, but there was no difference between chronic schizophrenia patients (-1.7%/2.4 years) and controls. The gray matter loss of the left insular cortex over time in FEP patients was correlated with the severity of positive and negative symptoms at follow-up. These findings indicate that patients with psychotic disorders have smaller gray matter volume of the insular cortex especially for its anterior portion (short insula) at first expression of overt psychosis, but also exhibit a regional progressive pathological process of the insular cortex during the early phase after the onset, which seems to reflect the subsequent symptomatology.

Background: Schizophrenia and related psychoses are associated with brain structural abnormalities. Recent findings in 'at risk' populations have identified progressive changes in various brain regions preceding illness onset, while changes especially in prefrontal and superior temporal regions have been demonstrated in first-episode schizophrenia patients. However, the timing of the cortical changes and their regional extent, relative to the emergence of psychosis, has not been clarified. We followed individuals at high-risk for psychosis to determine whether structural changes in the cerebral cortex occur with the onset of psychosis. We hypothesized that progressive volume loss occurs in prefrontal regions during the transition to psychosis., Methods: 35 individuals at ultra-high risk (UHR) for developing psychosis, of whom 12 experienced psychotic onset by 1-year follow-up ('converters'), participated in a longitudinal structural MRI study. Baseline and follow-up T1-weighted MR images were acquired and longitudinal brain surface contractions were assessed using Cortical Pattern Matching., Results: Significantly greater brain contraction was found in the right prefrontal region in the 'converters' compared with UHR cases who did not develop psychosis ('non-converters')., Conclusions: These findings show cortical volume loss is associated with the onset of psychosis, indicating ongoing pathological processes during the transition stage to illness. The prefrontal volume loss is in line with structural and functional abnormalities in schizophrenia, suggesting a critical role for this change in the development of psychosis.

Background: Abnormalities of the anterior cingulate cortex (ACC) are frequently implicated in the pathophysiology of psychotic disorders, but whether such changes are apparent before psychosis onset remains unclear. In this study, we characterized prepsychotic ACC abnormalities in a sample of individuals at ultra-high-risk (UHR) for psychosis., Methods: Participants underwent baseline magnetic resonance imaging and were followed-up over 12-24 months to ascertain diagnostic outcomes. Baseline ACC morphometry was then compared between UHR individuals who developed psychosis (UHR-P; n = 35), those who did not (UHR-NP; n = 35), and healthy control subjects (n = 33)., Results: Relative to control subjects, UHR-P individuals displayed bilateral thinning of a rostral paralimbic ACC region that was negatively correlated with negative symptoms, whereas UHR-NP individuals displayed a relative thickening of dorsal and rostral limbic areas that was correlated with anxiety ratings. Baseline ACC differences between the two UHR groups predicted time to psychosis onset, independently of symptomatology. Subdiagnostic comparisons revealed that changes in the UHR-P group were driven by individuals subsequently diagnosed with a schizophrenia spectrum psychosis., Conclusions: These findings indicate that anatomic abnormalities of the ACC precede psychosis onset and that baseline ACC differences distinguish between UHR individuals who do and do not subsequently develop frank psychosis. They also indicate that prepsychotic changes are relatively specific to individuals who develop a schizophrenia spectrum disorder, suggesting they may represent a diagnostically specific risk marker.

Abnormal neurodevelopment in midline structures such as the adhesio interthalamica (AI) has been reported in psychotic disorders, but it is unknown whether individuals at risk for the disorder share the AI findings observed in patients with florid psychosis. Magnetic resonance imaging of 162 patients with first-episode psychosis (FEP), 89 patients with chronic schizophrenia, 135 individuals at ultra high-risk (UHR) of psychosis (of whom 39 later developed psychosis), and 87 healthy controls were used to investigate the length and prevalence of the AI. The relation of the AI length to lateral ventricular enlargement was also explored. The patients with FEP and chronic schizophrenia as well as UHR individuals had a shorter AI than the controls, but there was no difference in the AI findings between the UHR individuals who did and did not subsequently develop psychosis. There was a negative correlation between the AI length and lateral ventricular volume in all the diagnostic groups. The absence of the AI was more common in the chronic schizophrenia patients when compared with all other groups. These results support the notion that the AI absence or shorter length could be a neurodevelopmental marker related to vulnerability to psychopathology, but also suggest that schizophrenia patients may manifest progressive brain changes related to ongoing atrophy of the AI after the onset.

Ethyl-eicosapentaenoic acid (E-EPA) is an omega-3 fatty acid that has been used in a range of neuropsychiatric conditions with some benefits. However, its mechanism of action is unknown. Here, we investigate its effects on in vivo brain metabolism in first-episode psychosis (FEP). Proton magnetic resonance spectroscopy at 3 T was performed in the temporal lobes of 24 FEP patients before and after 12 weeks of treatment in the context of a larger double-blind, placebo-controlled E-EPA augmentation study. Treatment group effects for glutathione (F1,12=6.1, p=0.03), and a hemisphere-by-group interaction for glutamine/glutamate (F1,20=4.4, p=0.049) were found. Glutathione increased bilaterally and glutamate/glutamine increased in the left hemisphere following E-EPA administration. Improvement in negative symptoms correlated with metabolic brain changes, particularly glutathione (r=-0.57). These results suggest that E-EPA augmentation alters glutathione availability and modulates the glutamine/glutamate cycle in early psychosis, with some of the metabolic brain changes being correlated with negative symptom improvement. Larger confirmatory studies of these postulated metabolic brain effects of E-EPA are warranted.

Background: Grey matter changes have been described in individuals who are pre- and peri-psychotic, but it is unclear if these changes are accompanied by changes in white matter structures., Aims: To determine whether changes in white matter occur prior to and with the transition to psychosis in individuals who are pre-psychotic who had previously demonstrated grey matter reductions in frontotemporal regions., Method: We used magnetic resonance imaging (MRI) to examine regional white matter volume in 75 people with prodromal symptoms. A subset of the original group (n=21) were rescanned at 12-18 months to determine white matter volume changes. Participants were retrospectively categorised according to whether they had or had not developed psychosis at follow-up., Results: Comparison of the baseline MRI data from these two subgroups revealed that individuals who later developed psychosis had larger volumes of white matter in the frontal lobe, particularly in the left hemisphere. Longitudinal comparison of data in individuals who developed psychosis revealed a reduction in white matter volume in the region of the left fronto-occipital fasciculus. Participants who had not developed psychosis showed no reductions in white matter volume but increases in a region subjacent to the right inferior parietal lobule., Discussion: The reduction in volume of white matter near the left fronto-occipital fasciculus may reflect a change in this tract in association with the onset of frank psychosis.

Schizophrenia is associated with significant brain abnormalities, including changes in brain metabolites as measured by proton magnetic resonance spectroscopy (MRS). What remains unclear is the extent to which these changes are a consequence of the emergence of psychotic disorders or the result of treatment with antipsychotic medication. We assessed 34 patients with first episode psychosis (15 antipsychotic naïve) and 19 age- and gender-matched controls using short-echo MRS in the medial temporal lobe bilaterally. Overall, there were no differences in any metabolite, regardless of treatment status. However, when the analysis was limited to patients with a diagnosis of schizophrenia, schizophreniform or schizoaffective disorder, significant elevations of creatine/phosphocreatine (Cr/PCr) and myo-inositol (mI) were found in the treated group. These data indicate a relative absence of temporal lobe metabolic abnormalities in first episode psychosis, but suggest that some treatment-related changes in mI might be apparent in patients with schizophrenia-spectrum diagnoses. Seemingly illness-related Cr/PCr elevations were also specific to the diagnosis of schizophrenia-spectrum disorder and seem worthy of future study.

Background: The shape of the corpus callosum may differ in schizophrenia, although no study has compared first-episode with established illness., Aims: To investigate the size and shape of the corpus callosum in a large sample of people with first-episode and established schizophrenia., Method: Callosal size and shape were determined using high-resolution magnetic resonance imaging on 76 patients with first-episode schizophrenia-spectrum disorders, 86 patients with established schizophrenia and 55 healthy participants., Results: There were no significant differences in total area across groups. Reductions in callosal width were seen in the region of the anterior genu in first-episode disorder (P<0.005). Similar reductions were seen in the chronic schizophrenia group in the anterior genu, but also in the posterior genu and isthmus (P=0.0005)., Conclusions: Reductions in anterior callosal regions connecting frontal cortex are present at the onset of schizophrenia, and in established illness are accompanied by changes in other regions of the callosum connecting cingulate, temporal and parietal cortices.

Objectives: The characterization, aetiology, and course of verbal memory deficits in schizophrenia remain ill defined. The impact of antipsychotic medications is also unclear. The purpose of the present paper was to investigate verbal memory performance in established schizophrenia (SZ) and first-episode schizophreniform psychosis (FE)., Method: Performances of 32 SZ and 33 FE patients were compared to those of 47 healthy volunteers on measures of verbal working memory, verbal associative learning and story recall., Results: Story recall deficits, but not deficits in working memory or paired associate learning, were demonstrated by both patient groups. Patients treated with typical neuroleptics had more impairment in associative learning with arbitrary word pairings than those treated with atypicals, regardless of patient group., Conclusions: The results are consistent with the notion that some neuropsychological impairment is present at the time of psychosis onset and that this impairment is non-progressive. However, deficits may be specific to subclasses of memory function.

A case of presumed Hashimoto's encephalopathy (HE) is presented. The presentation included memory loss, delusions, functional decline and culminated in a generalized seizure. Anti-thyroid antibodies were detected and symptoms resolved with prednisolone. Patients with HE may present with prominent neuropsychiatric symptoms, attract psychiatric diagnoses and present to psychiatric services. Primarily a diagnosis of exclusion, HE should be considered in cases of encephalopathy in which standard investigations are negative.

Reports of abnormal activation of the dorsolateral prefrontal cortex (dlPFC) are common in functional neuroimaging studies of schizophrenia, although very few have examined brain activity in patients close to the onset of illness. In this H(2)(15)O PET study, eight young male patients with first-episode schizophreniform psychosis and age-matched control subjects performed a version of the Stroop task that we have previously shown to engage the middle-frontal gyrus. At the time of testing, patients were antipsychotic-naïve and were scanned within 1 week of initial contact with our clinical program. All patients received a later diagnosis of schizophrenia 6 months after participating in the study. Whole-brain (within-group) and region-of-interest (between-group) analyses were carried out and data underwent spatial reproducibility testing. Compared with healthy subjects, patients showed significantly greater reaction-time (RT) interference but normal RT accuracy on the Stroop task. This pattern correlated with significant under-activation of the posterior left middle-frontal gyri in the patient versus control group. These findings support an emerging model of impaired cognitive control in schizophrenia and suggest that there is significant dysfunction of the dlPFC close to the onset of illness that may coincide with, or be modulated by, the transition-to-illness phase.