Identifying pathways to early-onset metabolic dysfunction, insulin resistance and inflammation in young adult inpatients with emerging affective and major mood disorders.

AIM: Young people with common mood disorders face the prospect of shortened life expectancy largely due to premature cardiovascular disease. Metabolic dysfunction is a risk factor for premature cardiovascular disease. There is an ongoing debate whether metabolic dysfunction can be simply explained by weight gain secondary to psychotropic medications or whether shared genetic vulnerability, intrinsic immune-metabolic disturbances or other system perturbations (e.g. dysregulated sympathetic nervous system, circadian dysfunction) are more relevant determinants of premature cardiovascular disease. Thus, we aimed to investigate underlying drivers of metabolic dysfunction and premature cardiovascular disease in young people in the early phases of common mood disorders. METHODS: We evaluated the relationships between insulin resistance (assessed by HOMA2-IR) and body mass index (BMI), sex, diagnosis, medication, inflammatory markers and hormonal factors in 327 inpatients with emerging affective and major mood disorders admitted to the Young Adult Mental Health Unit, St Vincent's Private Hospital, Sydney. RESULTS: While HOMA2-IR scores were positively associated with BMI (rs  = 0.465, p < .001), they were also higher in those prescribed mood stabilizers (p = .044) but were not associated with specific diagnoses, other medication types or the number of prescribed medications. Further, high-sensitivity C-reactive protein levels (but not thyroid-stimulating hormone and ferritin levels) were positively associated with HOMA2-IR (rs  = 0. 272, p < .001) and BMI (rs  = . 409, p < .001). CONCLUSIONS: In addition to BMI, other non-specific markers of inflammation are associated with early metabolic dysfunction in young people with emerging affective and major mood disorders.

Online interventions for people hospitalized for deliberate self-harm and problematic alcohol use: Lessons learned from the iiAIM trial.

Deliberate self-harm and suicide affect all age groups, sexes, and regions, and their prevention is a global health priority. Acute alcohol misuse and chronic alcohol misuse are strong, modifiable risk factors, and Internet interventions aiming to reduce alcohol misuse and comorbid mental health problems (e.g., depression) are a promising and effective treatment modality. The research team aimed to evaluate the feasibility and effectiveness of an Internet-based comorbidity intervention primarily aiming to reduce alcohol consumption, and secondarily to reduce readmission for deliberate self-harm and improve psychological outcomes among people hospitalized for deliberate self-harm who also engage in problematic alcohol use. However, due to several barriers to recruitment, the trial could not be completed and was discontinued. The authors present a "Lessons Learned" discussion and describe the Internet Intervention for Alcohol Improvement (iiAIM) trial, discuss the key barriers experienced by the research team, and recommend potential solutions that may help future trials in this area.

Protocol for a young adult mental health (Uspace) cohort: personalising multidimensional care in young people admitted to hospital.

INTRODUCTION: Currently, the literature on personalised and measurement-based mental healthcare is inadequate with major gaps in the development and evaluation of 21st century service models. Clinical presentations of mental ill health in young people are heterogeneous, and clinical and functional outcomes are often suboptimal. Thus, treatments provided in a person-centred and responsive fashion are critical to meet the unique needs of young people and improve individual outcomes. Personalised care also requires concurrent assessment of factors relating to outcomes and underlying neurobiology. This study builds on a completed feasibility study and will be the first to incorporate clinical, cognitive, circadian, metabolic and hormonal profiling with personalised and measurement-based care in a cohort of young people admitted to hospital. METHODS AND ANALYSIS: This prospective, transdiagnostic, observational study will be offered to all young people between the ages of 16 and 30 years admitted to the inpatient unit of the participating centre. In total, 400 participants will be recruited. On admission to hospital, young people will undergo clinical and diagnostic assessment, cognitive testing, self-report questionnaires, metabolic and hormonal data collection, and anthropomorphic measurements. Participants will wear an actigraphy watch for at least 1 week during admission to measure circadian patterns and sleep-wake cycles. A feedback session between clinician and participant will occur after clinical and other laboratory assessments to tailor individual treatment plans, explain the ongoing process of measurement-based care, and provide participant and family education. Associations between cognitive impairments, disturbed sleep-wake behaviours, circadian rhythms, clinical symptoms and functional impairments will be evaluated to improve the understanding of parameters affecting clinical outcomes. ETHICS AND DISSEMINATION: This study protocol was approved by the Human Research Ethics Committees of the University of Sydney (HREC USYD 2015/867) and St Vincent's Hospital (HREC SVH 17/045). This study will be published on completion in a peer-reviewed journal.

Neurocognitive functioning predicts suicidal behaviour in young people with affective disorders.

BACKGROUND: Neurocognitive impairment is recognised as a risk factor for suicidal behaviour in adults. The current study aims to determine whether neurocognitive deficits also predict ongoing or emergent suicidal behaviour in young people with affective disorders. METHODS: Participants were aged 12-30 years and presented to early intervention youth mental health clinics between 2008 and 2018. In addition to clinical assessment a standardised neurocognitive assessment was conducted at baseline. Clinical data was extracted from subsequent visits using a standardised proforma. RESULTS: Of the 635 participants who met inclusion criteria (mean age 19.6 years, 59% female, average follow up 476 days) 104 (16%) reported suicidal behaviour during care. In 5 of the 10 neurocognitive domains tested (cognitive flexibility, processing speed, working memory, verbal memory and visuospatial memory) those with suicidal behaviour during care were superior to clinical controls. Better general neurocognitive function remained a significant predictor (OR=1.94, 95% CI 1.29- 2.94) of suicidal behaviour in care after controlling for other risk factors. LIMITATIONS: The neurocognitive battery used was designed for use with affective and psychotic disorders and may not have detected some deficits more specific to suicidal behaviour. CONCLUSION: Contrary to expectations, better neurocognitive functioning predicts suicidal behaviour during care in young people with affective disorders. While other populations with suicidal behaviour, such as adults with affective disorders or young people with psychotic disorders, tend to experience neurocognitive deficits which may limit their capacity to engage in some interventions, this does not appear to be the case for young people with affective disorders.

Youth Mental Health Tracker: protocol to establish a longitudinal cohort and research database for young people attending Australian mental health services.

INTRODUCTION: Mental disorders are a leading cause of long-term disability worldwide. Much of the burden of mental ill-health is mediated by early onset, comorbidities with physical health conditions and chronicity of the illnesses. This study aims to track the early period of mental disorders among young people presenting to Australian mental health services to facilitate more streamlined transdiagnostic processes, highly personalised and measurement-based care, secondary prevention and enhanced long-term outcomes. METHODS AND ANALYSIS: Recruitment to this large-scale, multisite, prospective, transdiagnostic, longitudinal clinical cohort study ('Youth Mental Health Tracker') will be offered to all young people between the ages of 12 and 30 years presenting to participating services with proficiency in English and no history of intellectual disability. Young people will be tracked over 3 years with standardised assessments at baseline and 3, 6, 12, 24 and 36 months. Assessments will include self-report and clinician-administered measures, covering five key domains including: (1) social and occupational function; (2) self-harm, suicidal thoughts and behaviour; (3) alcohol or other substance misuse; (4) physical health; and (5) illness type, clinical stage and trajectory. Data collection will be facilitated by the use of health information technology. The data will be used to: (1) determine prospectively the course of multidimensional functional outcomes, based on the differential impact of demographics, medication, psychological interventions and other key potentially modifiable moderator variables and (2) map pathophysiological mechanisms and clinical illness trajectories to determine transition rates of young people to more severe illness forms. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the Human Research Ethics Committee of the Sydney Local Health District (2019/ETH00469). All data will be non-identifiable, and research findings will be disseminated through peer-reviewed journals and scientific conference presentations.

Transdiagnostic neurocognitive subgroups and functional course in young people with emerging mental disorders: a cohort study.

BACKGROUND: Neurocognitive impairments robustly predict functional outcome. However, heterogeneity in neurocognition is common within diagnostic groups, and data-driven analyses reveal homogeneous neurocognitive subgroups cutting across diagnostic boundaries. AIMS: To determine whether data-driven neurocognitive subgroups of young people with emerging mental disorders are associated with 3-year functional course. METHOD: Model-based cluster analysis was applied to neurocognitive test scores across nine domains from 629 young people accessing mental health clinics. Cluster groups were compared on demographic, clinical and substance-use measures. Mixed-effects models explored associations between cluster-group membership and socio-occupational functioning (using the Social and Occupational Functioning Assessment Scale) over 3 years, adjusted for gender, premorbid IQ, level of education, depressive, positive, negative and manic symptoms, and diagnosis of a primary psychotic disorder. RESULTS: Cluster analysis of neurocognitive test scores derived three subgroups described as 'normal range' (n = 243, 38.6%), 'intermediate impairment' (n = 252, 40.1%), and 'global impairment' (n = 134, 21.3%). The major mental disorder categories (depressive, anxiety, bipolar, psychotic and other) were represented in each neurocognitive subgroup. The global impairment subgroup had lower functioning for 3 years of follow-up; however, neither the global impairment (B = 0.26, 95% CI -0.67 to 1.20; P = 0.581) or intermediate impairment (B = 0.46, 95% CI -0.26 to 1.19; P = 0.211) subgroups differed from the normal range subgroup in their rate of change in functioning over time. CONCLUSIONS: Neurocognitive impairment may follow a continuum of severity across the major syndrome-based mental disorders, with data-driven neurocognitive subgroups predictive of functional course. Of note, the global impairment subgroup had longstanding functional impairment despite continuing engagement with clinical services.

Right care, first time: a highly personalised and measurement-based care model to manage youth mental health.

Mood and psychotic syndromes most often emerge during adolescence and young adulthood, a period characterised by major physical and social change. Consequently, the effects of adolescent-onset mood and psychotic syndromes can have long term consequences. A key clinical challenge for youth mental health is to develop and test new systems that align with current evidence for comorbid presentations and underlying neurobiology, and are useful for predicting outcomes and guiding decisions regarding the provision of appropriate and effective care. Our highly personalised and measurement-based care model includes three core concepts: ▶ A multidimensional assessment and outcomes framework that includes: social and occupational function; self-harm, suicidal thoughts and behaviour; alcohol or other substance misuse; physical health; and illness trajectory. ▶ Clinical stage. ▶ Three common illness subtypes (psychosis, anxious depression, bipolar spectrum) based on proposed pathophysiological mechanisms (neurodevelopmental, hyperarousal, circadian). The model explicitly aims to prevent progression to more complex and severe forms of illness and is better aligned to contemporary models of the patterns of emergence of psychopathology. Inherent within this highly personalised approach is the incorporation of other evidence-based processes, including real-time measurement-based care as well as utilisation of multidisciplinary teams of health professionals. Data-driven local system modelling and personalised health information technologies provide crucial infrastructure support to these processes for better access to, and higher quality, mental health care for young people. CHAPTER 1: MULTIDIMENSIONAL OUTCOMES IN YOUTH MENTAL HEALTH CARE: WHAT MATTERS AND WHY?: Mood and psychotic syndromes present one of the most serious public health challenges that we face in the 21st century. Factors including prevalence, age of onset, and chronicity contribute to substantial burden and secondary risks such as alcohol or other substance misuse. Mood and psychotic syndromes most often emerge during adolescence and young adulthood, a period characterised by major physical and social change; thus, effects can have long term consequences. We propose five key domains which make up a multidimensional outcomes framework that aims to address the specific needs of young people presenting to health services with emerging mental illness. These include social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness type, stage and trajectory. Impairment and concurrent morbidity are well established in young people by the time they present for mental health care. Despite this, services and health professionals tend to focus on only one aspect of the presentation - illness type, stage and trajectory - and are often at odds with the preferences of young people and their families. There is a need to address the disconnect between mental health, physical health and social services and interventions, to ensure that youth mental health care focuses on the outcomes that matter to young people. CHAPTER 2: COMBINING CLINICAL STAGE AND PATHOPHYSIOLOGICAL MECHANISMS TO UNDERSTAND ILLNESS TRAJECTORIES IN YOUNG PEOPLE WITH EMERGING MOOD AND PSYCHOTIC SYNDROMES: Traditional diagnostic classification systems for mental disorders map poorly onto the early stages of illness experienced by young people, and purport categorical distinctions that are not readily supported by research into genetic, environmental and neurobiological risk factors. Consequently, a key clinical challenge in youth mental health is to develop and test new classification systems that align with current evidence on comorbid presentations, are consistent with current understanding of underlying neurobiology, and provide utility for predicting outcomes and guiding decisions regarding the provision of appropriate and effective care. This chapter outlines a transdiagnostic framework for classifying common adolescent-onset mood and psychotic syndromes, combining two independent but complementary dimensions: clinical staging, and three proposed pathophysiological mechanisms. Clinical staging reflects the progression of mental disorders and is in line with the concept used in general medicine, where more advanced stages are associated with a poorer prognosis and a need for more intensive interventions with a higher risk-to-benefit ratio. The three proposed pathophysiological mechanisms are neurodevelopmental abnormalities, hyperarousal and circadian dysfunction, which, over time, have illness trajectories (or pathways) to psychosis, anxious depression and bipolar spectrum disorders, respectively. The transdiagnostic framework has been evaluated in young people presenting to youth mental health clinics of the University of Sydney's Brain and Mind Centre, alongside a range of clinical and objective measures. Our research to date provides support for this framework, and we are now exploring its application to the development of more personalised models of care. CHAPTER 3: A COMPREHENSIVE ASSESSMENT FRAMEWORK FOR YOUTH MENTAL HEALTH: GUIDING HIGHLY PERSONALISED AND MEASUREMENT-BASED CARE USING MULTIDIMENSIONAL AND OBJECTIVE MEASURES: There is an urgent need for improved care for young people with mental health problems, in particular those with subthreshold mental disorders that are not sufficiently severe to meet traditional diagnostic criteria. New comprehensive assessment frameworks are needed to capture the biopsychosocial profile of a young person to drive highly personalised and measurement-based mental health care. We present a range of multidimensional measures involving five key domains: social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness type, stage and trajectory. Objective measures include: neuropsychological function; sleep-wake behaviours and circadian rhythms; metabolic and immune markers; and brain structure and function. The recommended multidimensional measures facilitate the development of a comprehensive clinical picture. The objective measures help to further develop informative and novel insights into underlying pathophysiological mechanisms and illness trajectories to guide personalised care plans. A panel of specific multidimensional and objective measures are recommended as standard clinical practice, while others are recommended secondarily to provide deeper insights with the aim of revealing alternative clinical paths for targeted interventions and treatments matched to the clinical stage and proposed pathophysiological mechanisms of the young person. CHAPTER 4: PERSONALISING CARE OPTIONS IN YOUTH MENTAL HEALTH: USING MULTIDIMENSIONAL ASSESSMENT, CLINICAL STAGE, PATHOPHYSIOLOGICAL MECHANISMS, AND INDIVIDUAL ILLNESS TRAJECTORIES TO GUIDE TREATMENT SELECTION: New models of mental health care for young people require that interventions be matched to illness type, clinical stage, underlying pathophysiological mechanisms and individual illness trajectories. Narrow syndrome-focused classifications often direct clinical attention away from other key factors such as functional impairment, self-harm and suicidality, alcohol or other substance misuse, and poor physical health. By contrast, we outline a treatment selection guide for early intervention for adolescent-onset mood and psychotic syndromes (ie, active treatments and indicated and more specific secondary prevention strategies). This guide is based on experiences with the Brain and Mind Centre's highly personalised and measurement-based care model to manage youth mental health. The model incorporates three complementary core concepts: ▶A multidimensional assessment and outcomes framework including: social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness trajectory. ▶Clinical stage. ▶Three common illness subtypes (psychosis, anxious depression, bipolar spectrum) based on three underlying pathophysiological mechanisms (neurodevelopmental, hyperarousal, circadian). These core concepts are not mutually exclusive and together may facilitate improved outcomes through a clinical stage-appropriate and transdiagnostic framework that helps guide decisions regarding the provision of appropriate and effective care options. Given its emphasis on adolescent-onset mood and psychotic syndromes, the Brain and Mind Centre's model of care also respects a fundamental developmental perspective - categorising childhood problems (eg, anxiety and neurodevelopmental difficulties) as risk factors and respecting the fact that young people are in a period of major biological and social transition. Based on these factors, a range of social, psychological and pharmacological interventions are recommended, with an emphasis on balancing the personal benefit-to-cost ratio. CHAPTER 5: A SERVICE DELIVERY MODEL TO SUPPORT HIGHLY PERSONALISED AND MEASUREMENT-BASED CARE IN YOUTH MENTAL HEALTH: Over the past decade, we have seen a growing focus on creating mental health service delivery models that better meet the unique needs of young Australians. Recent policy directives from the Australian Government recommend the adoption of stepped-care services to improve the appropriateness of care, determined by severity of need. Here, we propose that a highly personalised approach enhances stepped-care models by incorporating clinical staging and a young person's current and multidimensional needs. It explicitly aims to prevent progression to more complex and severe forms of illness and is better aligned to contemporary models of the patterns of emergence of psychopathology. Inherent within a highly personalised approach is the incorporation of other evidence-based processes, includingreal-time measurement-based care and use of multidisciplinary teams of health professionals. Data-driven local system modelling and personalised health information technologies provide crucial infrastructure support to these processes for better access to, and higher quality of, mental health care for young people.

Developing neurocognitive standard clinical care: A study of young adult inpatients.

Neuropsychological assessments have provided the field of psychiatry with important information about patients. As an assessment tool, a neuropsychological battery can be useful in a clinical setting; however, implementation as standard clinical care in an inpatient unit has not been extensively evaluated. A computerized cognitive battery was administered to 103 current young adult inpatients (19.2 ±â€¯3.1 years; 72% female) with affective disorder. Neurocognitive tasks included Verbal Recognition Memory (VRM), Attention Switching (AST), Paired Association Learning (PAL), and Rapid Visual Processing (RVP). Patients also completed a computerized self-report questionnaire evaluating subjective impressions of their cognition. Hierarchical cluster analysis determined three neurocognitive subgroups: cluster 1 (n = 17) showed a more impaired neurocognitive profile on three of the four variables compared to their peers in cluster 2 (n = 59), and cluster 3 (n = 27), who had the most impaired attentional shifting. Two of the four neurocognitive variables were significantly different between all three cluster groups (verbal learning and sustained attention). Overall group results showed an association between poorer sustained attention and increased suicidal ideation. These findings strengthen the idea that neurocognitive profiles may play an important role in better understanding the severity of illness in young inpatients with major psychiatric disorders.

A case study of feedback and cognitive assessment of a young adult inpatient with major depressive disorder.

OBJECTIVES: Neurocognitive assessment and feedback to a young adult inpatient. METHODS: Computerised neurocognitive assessment and feedback. RESULTS: A collaborative process of personalised intervention. CONCLUSIONS: Personalised feedback in this setting can be employed as a management tool to identify and prioritise care.

The course of neuropsychological functioning in young people with attenuated vs discrete mental disorders.

AIM: Clinical staging of mental disorders is designed to facilitate the selection of stage-appropriate interventions, early in the course of illness. Neuropsychological performance, particularly at early stages of mental disorder, is a strong predictor of medium-term functional outcomes. Despite this, the longitudinal examination of neuropsychological profiles in early stages of illness is poorly researched. Thus, we examined baseline and longitudinal neuropsychological profiles of young patients with attenuated syndromes vs those with discrete disorders. METHODS: Neuropsychological testing of 497 help-seeking young people (21.2 ± 3 years; 56% female). Clinical staging, assigned separately from testing, rated 262 individuals as "attenuated syndrome" (stage 1b) and 235 as "discrete" or "persistent" disorder (stage 2+). Follow-up testing was undertaken in 170 individuals (54% at stage 1b) after 19.8 ± 9 months (range: 3 to 51 months). RESULTS: At baseline, attenuated and discrete/persistent disorders significantly differed in 4 of the 9 neuropsychological measures (verbal learning, verbal memory, visual memory and set shifting). Despite this, both groups showed similar improvement in neuropsychological functioning at follow-up, particularly in processing speed, sustained attention and visual memory. Longitudinal improvement in cognition corresponded with increases in socio-occupational functioning. DISCUSSION: The degree of baseline neuropsychological dysfunction discriminates those with attenuated syndromes from those with a discrete/persistent disorder. Furthermore, improvement in neuropsychological functioning corresponded with improvement in clinical and functional status, despite stage of illness. This suggests that neuropsychological functioning remains relatively stable in young people with a mental illness and may be a critical window for intervention.

Neurocognitive clusters: A pilot study of young people with affective disorders in an inpatient facility.

BACKGROUND: There is growing evidence to support the need for personalised intervention in the early stages of a major psychiatric illness, as well as the clear delineation of subgroups in psychiatric disorders based on cognitive impairment. Affective disorders are often accompanied by neurocognitive deficits; however a lack of research among young adult inpatients highlights the need to assess the utility of cognitive testing in this population. METHODS: A computerised cognitive battery was administered to 50 current inpatient young adults (16-30 years; 75% female) with an affective disorder. Patients also completed a computerised self-report questionnaire (to measure demographics and clinical features) that included items evaluating subjective impressions of their cognition. RESULTS: Hierarchical cluster analysis determined two neurocognitive subgroups: cluster 1 (n = 16) showed more severe impairments in sustained attention and memory as well as higher anxiety levels, compared to their peers in cluster 2 (n = 30) who showed the most impaired attentional switching. Across the sample, poor sustained attention was significantly correlated with higher levels of current anxiety and depressive symptoms, whereas poor verbal memory was significantly associated with increased psychological distress. LIMITATIONS: This study has a relatively small sample size (due to it being a pilot/feasibility study). Furthermore, future studies should aim to assess inpatient samples compared to community care samples, as well as healthy controls, on a larger scale. CONCLUSIONS: The findings suggest neurocognitive profiles are important in understanding phenotypes within young people with severe affective disorders. With clear subgroups based on cognitive impairment being demonstrated, the clinical utility and use of new and emerging technologies is warranted in such inpatients facilities. This pilot/feasibility study has strengthened the utility of cognitive screening as standard clinical care in an inpatient unit.

Using New and Innovative Technologies to Assess Clinical Stage in Early Intervention Youth Mental Health Services: Evaluation Study.

BACKGROUND: Globally there is increasing recognition that new strategies are required to reduce disability due to common mental health problems. As 75% of mental health and substance use disorders emerge during the teenage or early adulthood years, these strategies need to be readily accessible to young people. When considering how to provide such services at scale, new and innovative technologies show promise in augmenting traditional clinic-based services. OBJECTIVE: The aim of this study was to test new and innovative technologies to assess clinical stage in early intervention youth mental health services using a prototypic online system known as the Mental Health eClinic (MHeC). METHODS: The online assessment within the MHeC was compared directly against traditional clinician assessment within 2 Sydney-based youth-specific mental health services (headspace Camperdown and headspace Campbelltown). A total of 204 young people were recruited to the study. Eligible participants completed both face-to-face and online assessments, which were randomly allocated and counterbalanced at a 1-to-3 ratio. These assessments were (1) a traditional 45- to 60-minute headspace face-to-face assessment performed by a Youth Access Clinician and (2) an approximate 60-minute online assessment (including a self-report Web-based survey, immediate dashboard of results, and a video visit with a clinician). All assessments were completed within a 2-week timeframe from initial presentation. RESULTS: Of the 72 participants who completed the study, 71% (51/72) were female and the mean age was 20.4 years (aged 16 to 25 years); 68% (49/72) of participants were recruited from headspace Camperdown and the remaining 32% (23/72) from headspace Campbelltown. Interrater agreement of participants' stage, as determined after face-to-face assessment or online assessment, demonstrated fair agreement (kappa=.39, P<.001) with concordance in 68% of cases (49/72). Among the discordant cases, those who were allocated to a higher stage by online raters were more likely to report a past history of mental health disorders (P=.001), previous suicide planning (P=.002), and current cannabis misuse (P=.03) compared to those allocated to a lower stage. CONCLUSIONS: The MHeC presents a new and innovative method for determining key clinical service parameters. It has the potential to be adapted to varied settings in which young people are connected with traditional clinical services and assist in providing the right care at the right time.

White matter integrity alterations in post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a debilitating condition which can develop after exposure to traumatic stressors. Seventy-five adults were recruited from the community, 25 diagnosed with PTSD along with 25 healthy and 25 trauma-exposed age- and gender-matched controls. Participants underwent clinical assessment and magnetic resonance imaging. A previous voxel based morphometry (VBM) study using the same subject cohort identified decreased grey matter (GM) volumes within frontal/subcortical brain regions including the hippocampus, amygdala, and anterior cingulate cortex (ACC). This study examines the microstructural integrity of white matter (WM) tracts connecting the aforementioned regions/structures. Using diffusion tensor imaging, we investigated the integrity of frontal/subcortical WM tracts between all three subject groups. Trauma exposed subjects with and without PTSD diagnosis were identified to have significant disruption in WM integrity as indexed by decreased fractional anisotropy (FA) in the uncinate fasciculus (UF), cingulum cingulate gyrus (CCG), and corpus callosum (CC), when compared with healthy non-trauma-exposed controls. Significant negative correlations were found between total Clinician Administered PTSD scale (CAPS) lifetime clinical subscores and FA values of PTSD subjects in the right UF, CCG, CC body, and right superior longitudinal fasciculus (SLF). An analysis between UF and SLF FA values and VBM determined rostral ACC GM values found a negative correlation in PTSD subjects. Findings suggest that compromised WM integrity in important tracts connecting limbic structures such as the amygdala to frontal regions including the ACC (i.e., the UF and CCG) may contribute to impairments in threat/fear processing associated with PTSD.

Frontal and subcortical grey matter reductions in PTSD.

Post-traumatic stress disorder (PTSD) is characterised by a range of debilitating psychological, physical and cognitive symptoms. PTSD has been associated with grey matter atrophy in limbic and frontal cortical brain regions. However, previous studies have reported heterogeneous findings, with grey matter changes observed beyond limbic/frontal areas. Seventy-five adults were recruited from the community, 25 diagnosed with PTSD along with 25 healthy and 25 trauma exposed age and gender matched controls. Participants underwent clinical assessment and magnetic resonance imaging. The data-analyses method Voxel Based Morphometry (VBM) was used to estimate cortical grey matter volumes. When compared to both healthy and trauma exposed controls, PTSD subjects demonstrated decreased grey matter volumes within subcortical brain regions-including the hippocampus and amygdala-along with reductions in the anterior cingulate cortex, frontal medial cortex, middle frontal gyrus, superior frontal gyrus, paracingulate gyrus, and precuneus cortex. Significant negative correlations were found between total CAPS lifetime clinical scores/sub-scores and GM volume of both the PTSD and TC groups. GM volumes of the left rACC and right amygdala showed a significant negative correlation within PTSD diagnosed subjects.

Hippocampal glutamate is increased and associated with risky drinking in young adults with major depression.

BACKGROUND: Risky drinking in young people is harmful, highly prevalent and often complicated by comorbid mental health problems that compound alcohol-induced impairment. The hippocampus and the glutamate system have been implicated in the pathophysiology of alcoholism and depression. This study aimed to determine whether risky drinking is associated with glutamate levels recorded within the hippocampus of young adults with major depression. METHODS: Sixty-three young persons with major depression (22.1±3.1 years; 65% female) and 38 healthy controls were recruited. Participants completed the alcohol use disorder identification test and underwent proton magnetic resonance spectroscopy to measure in vivo glutamate levels within the hippocampus following a period of at least 48h of abstinence. RESULTS: Young adults with depression had significantly increased hippocampal glutamate levels and a positive association between the level of alcohol use and glutamate. Regression analysis revealed that higher levels of hippocampal glutamate were predicted by having increased levels of risky drinking and depression. LIMITATIONS: Small sample sizes for testing diagnosis by risky drinking interaction and use of creatine ratios rather than the absolute concentrations of glutamate. DISCUSSION: The hippocampus is a critical region; given its role in learning and memory as well as mood regulation, and the neurochemical changes observed in this study may precede structural changes, which are commonly observed in both depression and alcohol misuse. These findings suggest that young adults with major depression who engage in risky drinking may be at increased risk of glutamate excitotoxicity.

Cluster analysis reveals abnormal hippocampal neurometabolic profiles in young people with mood disorders.

While numerous studies have employed magnetic resonance spectroscopy (MRS) to determine in vivo neurometabolite levels associated with mood disorders the findings in both unipolar depression and bipolar disorder have been mixed. Data-driven studies may shed new light on this literature by identifying distinct subgroups of patients who may benefit from different treatment strategies. The objective of the present study was to utilize hierarchical cluster analysis in order to generate new hypotheses with respect to neurometabolic profiling of mood disorder. Participants were 165 young persons (18-30 yrs) with a mood disorder and 40 healthy controls. Neurometabolite levels were recorded via proton-MRS ((1)H MRS). The ratios (relative to creatine) of glutamate (GLU), N-acetyl aspartate (NAA) and myo-inositol (MI) measured within the hippocampus. Self-reported and clinician rated symptoms as well as cognition were also measured. The unipolar depression (N=90) and bipolar disorder (N=75) groups did not significantly differ (from each other or controls) in their levels of GLU, NAA or MI. Cluster analyses derived four subgroups of patients who were distinguished by all three metabolites. There was a pattern of positive association between NAA and GLU, whereby clusters were abnormally increased (clusters 1, 2) or normal (cluster 4) or abnormally decreased (cluster 3) in these neurometabolites. These findings suggest that there are neurometabolic abnormalities in subgroups of young people with mood disorder, which may occur despite diagnostic similarities. Such evidence highlights that the underlying neurobiology of mood disorder is complex and MRS may have unique utility in delineating underlying neurobiology and targeting treatment strategies.

Cognitive dysfunction and functional disability in alcohol-dependent adults with or without a comorbid affective disorder.

INTRODUCTION: Little is known about the relationship between cognitive dysfunction and functional disability in alcohol dependence with comorbid affective disorders. We investigated the neuropsychology of alcohol dependence in detoxified adults with and without affective comorbidity and examined the factors associated with prolonged functional disability. METHODS: From a total of 42 participants (age range = 18-44 years), 12 out of 21 alcohol-dependent participants had a comorbid affective disorder, 12 had an affective disorder only, and 9 were healthy controls. Participants completed a semi-structured clinical interview, questionnaires and comprehensive neuropsychological assessment. RESULTS: Following detoxification (median = 35 days; M = 41.2 days, SD = 17.9), visual learning and memory functioning was worse in alcohol-dependent individuals. Comorbid affective disorders did not appear to exacerbate cognitive dysfunction. Psychiatric comorbidity and current depressive symptoms were predictive of poorer functional disability. Furthermore, learning and memory, and response inhibition, contributed significantly and independently to predicting functional disability over and above clinical and demographic factors. CONCLUSIONS: Psychiatric comorbidity does not appear to be associated with more pronounced neuropsychological dysfunction in alcohol dependence. Conversely, both comorbid affective disorders and cognitive factors were critical in determining the functional outcomes of alcohol-dependent adults recently undergoing medically supervised inpatient detoxification.