Psychiatry - Research Publications
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ItemNo Preview AvailableAssociation of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis An ENIGMA Working Group Mega-analysis(AMER MEDICAL ASSOC, 2021-07)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.
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ItemNo Preview AvailableCognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings(SPRINGERNATURE, 2021-08)Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.
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ItemBroad clinical high-risk mental state (CHARMS): Methodology of a cohort study validating criteria for pluripotent risk(WILEY, 2019-06)AIM: The development of the ultra-high risk (UHR) criteria for psychosis created a new paradigm for the prevention research in psychiatry. Since (1) prevention research faces the challenge of achieving adequate statistical power when focusing on single low-incidence syndromes and (2) early clinical phenotypes are overlapping and non-specific, this study broadens the UHR state beyond psychosis as an outcome. The CHARMS (clinical high at-risk mental state) study aims to prospectively validate a set of trans-diagnostic criteria to identify help-seeking young people at risk of developing a range of serious mental illnesses. METHODS: This paper describes the methodology of the CHARMS study, which involves applying the CHARMS criteria to a cohort of help-seeking young people aged 12 to 25 attending youth mental health services in Melbourne. New referrals meeting the CHARMS criteria are allocated to the CHARMS+ group; referrals not meeting CHARMS threshold are allocated to CHARMS- group (control group); referrals meeting criteria for a full-threshold disorder are excluded. Transition status and clinical and functional outcomes are re-assessed at 6 and 12 months. CONCLUSIONS: This study will be the first to introduce and validate clinical criteria to identify a broader at-risk patient population, which may facilitate young people's access to clinical services and early treatment by reducing the reliance on "caseness" defined according to current diagnostic categories being required for service entry. These criteria may introduce a new, trans-diagnostic approach for understanding risk factors and pathogenic mechanisms that drive the onset of severe mental illness and the next generation of preventive intervention trials.
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ItemA systematic review and meta-analysis of prospective transition from major depression to bipolar disorder(WILEY, 2017-04)OBJECTIVE: Some people with major depressive disorder (MDD) may be at a pre-onset stage for bipolar disorder (BD), where early identification or prevention efforts may be feasible. We aimed to identify rates and characteristics predictive of transition to BD in prospective follow-up studies of people with MDD. METHODS: Using a systematic search strategy, we identified studies with a diagnostic ascertainment of MDD and BD of an adequate standard, and where the minimum length of follow-up was 6 months. We examined the incidence and point prevalence of BD and the pooled odds ratios (OR) for baseline predictors. RESULTS: From 5554 unique publications, 56 were included. Nearly a quarter of adults (22.5%) and adolescents with MDD followed up for a mean length of 12-18 years developed BD, with the greatest risk of transition being in the first 5 years. The meta-analysis identified that transition from MDD to BD was predicted by family history of BD (OR = 2.89, 95% CI: 2.01-4.14, N = 7), earlier age of onset of depression (g = -0.33, SE = 0.05, N = 6) and presence of psychotic symptoms (OR = 4.76, 95% CI: 1.79-12.66, N = 5). CONCLUSIONS: Participants with the identified risk factors merit closer observation and may benefit from prevention efforts, especially if outcomes broader than BD are considered.
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ItemModerated online social therapy for depression relapse prevention in young people: pilot study of a "next generation' online intervention(WILEY, 2018-08)AIM: Implementation of targeted e-mental health interventions offers a promising solution to reducing the burden of disease associated with youth depression. A single-group pilot study was conducted to evaluate the acceptability, feasibility, usability and safety of a novel, moderated online social therapy intervention (entitled Rebound) for depression relapse prevention in young people. METHODS: Participants were 42 young people (15-25 years) (50% men; mean age = 18.5 years) in partial or full remission. Participants had access to the Rebound platform for at least 12 weeks, including the social networking, peer and clinical moderator and therapy components. RESULTS: Follow-up data were available for 39 (92.9%) participants. There was high system usage, with 3034 user logins (mean = 72.2 per user) and 2146 posts (mean = 51.1). Almost 70% of users had ≥10 logins over the 12 weeks, with 78.5% logging in over at least 2 months of the pilot. A total of 32 (84%) participants rated the intervention as helpful. There was significant improvement between the number of participants in full remission at baseline (n = 5; none of whom relapsed) relative to n = 19 at 12-week follow-up (P < 0.001). Six (14.3%) participants relapsed to full threshold symptoms at 12 weeks. There was a significant improvement to interviewer-rated depression scores (Montgomery-Asberg Depression Rating Scale (MADRS); P = 0.014, d = 0.45) and a trend for improved strength use (P = 0.088, d = 0.29). The single-group design and 12-week treatment phase preclude a full understanding of the clinical benefits of the Rebound intervention. CONCLUSIONS: The Rebound intervention was shown to be acceptable, feasible, highly usable and safe in young people with major depression.
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ItemEthical considerations in preventive interventions for bipolar disorder(WILEY, 2017-04)AIM: Early intervention and prevention of serious mental disorders such as bipolar disorder has the promise of decreasing the burden associated with these disorders. With increasing early and preventive intervention efforts among cohorts such as those with a familial risk for bipolar disorder, there is a need to examine the associated ethical concerns. The aim of this review was to examine the ethical issues underpinning the clinical research on pre-onset identification and preventive interventions for bipolar disorder. METHODS: We undertook a PubMed search updated to November 2014 incorporating search terms such as bipolar, mania, hypomania, ethic*(truncated), early intervention, prevention, genetic and family. RESULTS: Fifty-six articles that were identified by this method as well as other relevant articles were examined within a framework of ethical principles including beneficence, non-maleficence, respect for autonomy and justice. The primary risks associated with research and clinical interventions include stigma and labelling, especially among familial high-risk youth. Side effects from interventions are another concern. The benefits of preventive or early interventions were in the amelioration of symptoms as well as the possibility of minimizing disability, cognitive impairment and progression of the illness. Supporting the autonomy of individuals and improving access to stigma-free care may help moderate the potential challenges associated with the risks of interventions. CONCLUSIONS: Concerns about the risks of early identification and pre-onset interventions should be balanced against the potential benefits, the individuals' right to choice and by improving availability of services that balance such dilemmas.
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ItemNo Preview AvailableImpaired olfactory ability associated with larger left hippocampus and rectus volumes at earliest stages of schizophrenia: A sign of neuroinflammation?(ELSEVIER IRELAND LTD, 2020-07)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.
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ItemSex differences in psychological distress, behavioural and emotional problems, and substance use in young people in out-of-home care(WILEY, 2020-05)Abstract The aim of the study was to examine sex differences in self‐reported psychological distress, behavioural and emotional problems, and substance use in young people living in out‐of‐home care (OoHC). One hundred seventy‐six young people aged 12–17 years (females 53.4%) in OoHC in metropolitan Melbourne, Australia, were interviewed. Participants completed self‐report measures: Kessler Psychological Distress Scale, Strengths and Difficulties Questionnaire, and the World Health Organization Alcohol, Smoking, and Substance Involvement Screening Test—Youth Version. Girls had more OoHC placement instability over the past year compared with boys (p = .019). Compared with boys, the girls had significantly higher levels of distress (p < .001) (p = .007), were more likely to have self‐reported emotional symptoms (p < .001) and peer relationship problems (p = .043) and were more likely to use sedatives (p = .004). Girls had more psychological distress, behavioural disturbance, and sedative abuse; placement instability might contribute to these problems. Greater integration across OoHC, mental health, and substance use sectors is required. Girls in OoHC may benefit from interventions targeting problems with peer relationship and substance use and supporting prosocial behaviour; such targets may reduce distress and emotional symptoms and possibly prevent longer term problems.
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ItemAripiprazole compared with placebo for auditory verbal hallucinations in youth with borderline personality disorder: Protocol for the VERBATIM randomized controlled trial(WILEY, 2019-12)AIM: Up to half of patients with borderline personality disorder report auditory verbal hallucinations that are phenomenologically indistinguishable from those in schizophrenia, occur early in the course of the disorder, and are enduring, distressing and disabling. In clinical practice, this symptom is widely assumed to be unresponsive to treatment with antipsychotic medication and early intervention is rarely offered. The Verbal Experiences Response in Borderline personality disorder to Aripiprazole TrIal Medication (VERBATIM) study aims to be the first controlled trial to investigate the effectiveness of conventional pharmacotherapy for this symptom in this patient group. METHOD: VERBATIM is a 12-week, triple-blind, single-centre, parallel groups randomised controlled trial, with a 27-week follow-up period. Participants between the ages of 15 and 25 years receive either aripiprazole or placebo daily, commencing at 2 mg and increasing to 10 mg by day 15. Further dose escalations (up to 30 mg) may occur, as clinically indicated. This trial was prospectively registered with the Australian and New Zealand Clinical Trials Registry ACTRN12616001192471 on 30/08/2016. RESULTS: The primary outcome is severity of auditory verbal hallucinations assessed using the Psychotic Symptom Rating Scale. Secondary outcomes include the severity of general psychopathology, borderline personality pathology, social and occupational functioning and change in brain resting state connectivity. The primary endpoint is week 12 and secondary endpoint is week 39. CONCLUSION: The results will inform treatment decisions for individuals with borderline personality disorder who present with auditory verbal hallucinations.
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ItemCan youth at high risk of illness progression be identified by measures of rumination and sleep-wake disturbance(WILEY, 2019-10)AIM: Clinical staging models offer a useful framework for understanding illness trajectories, where individuals are located on a continuum of illness progression from stage 0 (at-risk but asymptomatic) to stage 4 (end-stage disease). Importantly, clinical staging allows investigation of risk factors for illness progression with the potential to target trans-diagnostic mechanisms at an early stage, especially in help-seeking youth who often present with sub-threshold syndromes. While depressive symptoms, rumination and sleep-wake disturbances may worsen syndrome outcomes, the role of these related phenomena has yet to be examined as risk factors for trans-diagnostic illness progression in at-risk youth. METHODS: This study is a prospective follow-up of 248 individuals aged 12 to 25 years presenting to headspace services with sub-threshold syndromes (stage 1) classified under the clinical staging model to determine transition to threshold syndromes (stage 2). Factor analysis of depression, rumination and sleep-wake patterns was used to identify key dimensions and any associations between factors and transition to stage 2 at follow-up. RESULTS: At 1 year, 9% of cases met criteria for stage 2 (n = 22). One of three identified factors, namely the factor reflecting the commonalities shared between rumination and sleep-wake disturbance, significantly differentiated cases that transitioned to stage 2 vs those that did not demonstrate transition. Items loading onto this factor, labelled Anergia, included depression severity and aspects of rumination and sleep-wake disturbance that were characterized as introceptive. CONCLUSIONS: Common dimensions between rumination and sleep-wake disturbance present a detectable trans-diagnostic marker of illness progression in youth, and may represent a target for early intervention.