Preliminary results from the Australian Genetics of Bipolar Disorder Study: A nation-wide cohort.

OBJECTIVE: The Australian Genetics of Bipolar Disorder Study is a nation-wide cohort of adults living with bipolar disorder. The study aims to detect the relationships between genetic risk, symptom severity, and the lifetime prevalence of bipolar disorder, treatment response and medication side effects, and patterns and costs of health care usage. METHODS: A total of 6682 participants (68.3% female; aged 44.8 ± 13.6 years [range = 18-90]) were recruited in three waves: a nation-wide media campaign, a mail-out based on prescriptions for lithium carbonate and through the Australian Genetics of Depression Study. Participants completed a self-report questionnaire. A total of 4706 (70%) participants provided a saliva sample and were genotyped and 5506 (82%) consented to record linkage of their Pharmaceutical and Medicare Benefits Schedule data. RESULTS: Most participants were living with bipolar I disorder (n = 4068) while 1622 participants were living with bipolar II disorder and 992 with sub-threshold bipolar disorder. The mean age of bipolar disorder diagnosis was 32.7 ± 11.6 years but was younger in bipolar I (p = 2.0E-26) and females (p = 5.7E-23). Excluding depression with onset prior to bipolar disorder diagnosis, 64.5% of participants reported one or more co-occurring psychiatric disorders: most commonly generalised anxiety disorder (43.5%) and posttraumatic stress disorder (20.7%). Adverse drug reactions were common and resulted in discontinuation rates ranging from 33.4% for lithium to 63.0% for carbamazepine. CONCLUSION: Our findings highlight the high rate of comorbidities and adverse drug reactions among adults living with bipolar disorder in the general Australian population. Future genomic analyses focus on identifying genetic variants influencing pharmacotherapy treatment response and side effects.

Towards a youth mental health paradigm: a perspective and roadmap.

Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.

Improving access to mental health care: a system dynamics model of direct access to specialist care and accelerated specialist service capacity growth.

OBJECTIVE: To simulate the impact on population mental health indicators of allowing people to book some Medicare-subsidised sessions with psychologists and other mental health care professionals without a referral (direct access), and of increasing the annual growth rate in specialist mental health care capacity (consultations). DESIGN: System dynamics model, calibrated using historical time series data from the Australian Bureau of Statistics, HealthStats NSW, the Australian Institute of Health and Welfare, and the Australian Early Development Census. Parameter values that could not be derived from these sources were estimated by constrained optimisation. SETTING: New South Wales, 1 September 2021 - 1 September 2028. MAIN OUTCOME MEASURES: Projected mental health-related emergency department presentations, hospitalisations following self-harm, and deaths by suicide, both overall and for people aged 15-24 years. RESULTS: Direct access (for 10-50% of people requiring specialist mental health care) would lead to increases in the numbers of mental health-related emergency department presentations (0.33-1.68% of baseline), hospitalisations with self-harm (0.16-0.77%), and deaths by suicide (0.19-0.90%), as waiting times for consultations would increase, leading to disengagement and consequently to increases in adverse outcomes. Increasing the annual rate of growth of mental health service capacity (two- to fivefold) would reduce the frequency of all three outcomes; combining direct access to a proportion of services with increased growth in capacity achieved substantially greater gains than an increase in service capacity alone. A fivefold increase in the annual service growth rate would increase capacity by 71.6% by the end of 2028, compared with current projections; combined with direct access to 50% of mental health consultations, 26 616 emergency department presentations (3.6%), 1199 hospitalisations following self-harm (1.9%), and 158 deaths by suicide (2.1%) could be averted. CONCLUSION: The optimal combination of increased service capacity growth (fivefold) and direct access (50% of consultations) would have double the impact over seven years of accelerated capacity growth alone. Our model highlights the risks of implementing individual reforms without knowledge of their overall system effect.

Does circadian dysrhythmia drive the switch into high- or low-activation states in bipolar I disorder?

OBJECTIVES: Emerging evidence suggests a role of circadian dysrhythmia in the switch between "activation" states (i.e., objective motor activity and subjective energy) in bipolar I disorder. METHODS: We examined the evidence with respect to four relevant questions: (1) Are natural or environmental exposures that can disrupt circadian rhythms also related to the switch into high-/low-activation states? (2) Are circadian dysrhythmias (e.g., altered rest/activity rhythms) associated with the switch into activation states in bipolar disorder? (3) Do interventions that affect the circadian system also affect activation states? (4) Are associations between circadian dysrhythmias and activation states influenced by other "third" factors? RESULTS: Factors that naturally or experimentally alter circadian rhythms (e.g., light exposure) have been shown to relate to activation states; however future studies need to measure circadian rhythms contemporaneously with these natural/experimental factors. Actigraphic measures of circadian dysrhythmias are associated prospectively with the switch into high- or low-activation states, and more studies are needed to establish the most relevant prognostic actigraphy metrics in bipolar disorder. Interventions that can affect the circadian system (e.g., light therapy, lithium) can also reduce the switch into high-/low-activation states. Whether circadian rhythms mediate these clinical effects is an unknown but valuable question. The influence of age, sex, and other confounders on these associations needs to be better characterised. CONCLUSION: Based on the reviewed evidence, our view is that circadian dysrhythmia is a plausible driver of transitions into high- and low-activation states and deserves prioritisation in research in bipolar disorders.

A Mental Wealth perspective: crossing disciplines to understand the value of collective mental and social assets in the post-COVID-19 era.

BACKGROUND: A reconceptualised global strategy is key as nations begin to shift from crisis management to medium- and long-term planning to rebuild and strengthen their economic, social and public health systems. Efforts towards measuring, modelling, and forecasting Mental Wealth could serve as the catalyst for this reconceptualization. The Mental Wealth approach builds systemic resilience through investments which promote collective cognitive and emotional wellbeing. This paper presents the theoretical foundations for Mental Wealth. It presents, for the first time, literature across the disciplines of health and social sciences, economics, business, and humanities to underpin the development of an operational metric of Mental Wealth. DISCUSSION: An approach which embeds social and psychological dimensions of prosperity, alongside the economic, is needed to inform the effective allocation of investments in the post-pandemic world. The authors advocate for a transdisciplinary framework of Mental Wealth to be applied in innovating population-level policy interventions to address the growing challenges brought on by COVID-19. Mental Wealth highlights the value generated by the deployment of collective mental assets and supporting social infrastructure. In order to inform this position, a review of the literature on the concepts underpinning Mental Wealth is presented, limitations of current measurement tools of mental and social resources are evaluated, and a framework for development of a Mental Wealth metric is proposed. CONCLUSION: There are challenges in developing an operational Mental Wealth metric. The breadth of conceptual foundations to be considered is extensive, and there may be a lack of agreement on the appropriate tools for its measurement. While variability across current measurement approaches in social resources, wellbeing and mental assets contributes to the difficulty creating a holistic and generic metric, these variations are now clearer. The operationalisation of the Mental Wealth metric will require comprehensive mapping of the elements to be included against the data available.

Effects of omega-3 polyunsaturated fatty acid supplementation on cognitive functioning in youth at ultra-high risk for psychosis: secondary analysis of the NEURAPRO randomised controlled trial.

BACKGROUND: Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. AIMS: To investigate whether omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. METHOD: Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n-3 PUFA levels predicted change in cognitive performance. RESULTS: The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (ηp2 = 0.09) and BACS composite score (ηp2 = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (ηp2 = 0.02), but the composite score remained significant (ηp2 = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. CONCLUSIONS: We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n-3 PUFAs.

Implementing a digital health model of care in Australian youth mental health services: protocol for impact evaluation.

BACKGROUND: The World Economic Forum has recently highlighted substantial problems in mental health service provision and called for the rapid deployment of smarter, digitally-enhanced health services as a means to facilitate effective care coordination and address issues of demand. In mental health, the biggest enabler of digital solutions is the implementation of an effective model of care that is facilitated by integrated health information technologies (HITs); the latter ensuring the solution is easily accessible, scalable and sustainable. The University of Sydney's Brain and Mind Centre (BMC) has developed an innovative digital health solution - delivered through the Youth Mental Health and Technology Program - which incorporates two components: 1) a highly personalised and measurement-based (data-driven) model of youth mental health care; and 2) an industrial grade HIT registered on the Australian Register of Therapeutic Goods. This paper describes a research protocol to evaluate the impact of implementing the BMC's digital health solution into youth mental health services (i.e. headspace - a highly accessible, youth-friendly integrated service that responds to the mental health, physical health, alcohol or other substance use, and vocational concerns of young people aged 12 to 25 years) within urban and regional areas of Australia. METHODS: The digital health solution will be implemented into participating headspace centres using a naturalistic research design. Quantitative and qualitative data will be collected from headspace health professionals, service managers and administrators, as well as from lead agency and local Primary Health Network (PHN) staff, via service audits, Implementation Officer logs, online surveys, and semi-structured interviews, at baseline and then three-monthly intervals over the course of 12 months. DISCUSSION: At the time of publication, six headspace centres had been recruited to this study and had commenced implementation and impact evaluation. The first results are expected to be submitted for publication in 2021. This study will focus on the impact of implementing a digital health solution at both a service and staff level, and will evaluate digital readiness of service and staff adoption; quality, usability and acceptability of the solution by staff; staff self-reported clinical competency; overall impact on headspace centres as well as their lead agencies and local PHNs; and social return on investment.

The NEURAPRO Biomarker Analysis: Long-Chain Omega-3 Fatty Acids Improve 6-Month and 12-Month Outcomes in Youths at Ultra-High Risk for Psychosis.

BACKGROUND: NEURAPRO was a multicenter, placebo-controlled trial of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) in 304 individuals at ultra-high risk for psychotic disorders. The study failed to show benefits of n-3 PUFAs over placebo. Although the randomized controlled trial design is placed at the top of the evidence hierarchy, this methodology has limitations in fish oil randomized controlled trials, as not only is the test agent present in the intervention group, but also n-3 fats are present in the diet and the body tissue of all participants. METHODS: Analysis of biomarker data (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA], n-3 index, EPA+DHA) collected as part of NEURAPRO was conducted on 218 participants with longitudinal biomarker data to determine if n-3 PUFAs measured in erythrocytes at baseline and month 6 predicted clinical outcomes. RESULTS: Increases of the n-3 index, EPA, and DHA predicted less severe psychopathology and better functioning at both follow-up time points. Higher baseline levels and increases of n-3 index also predicted overall clinical improvement at month 6 (n-3 index baseline: adjusted odds ratio [95% confidence interval (CI)] = 1.79 [1.30-2.48]; n-3 PUFA increase: adjusted odds ratio [95% CI] = 1.43 [1.16-1.76]) and at month 12 (n-3 index baseline: adjusted odds ratio [95% CI] = 2.60 [1.71-3.97]; n-3 PUFA increase: adjusted odds ratio [95% CI] = 1.36 [1.06-1.74]). CONCLUSIONS: These data suggest that n-3 PUFAs can exert therapeutic effects in ultra-high-risk individuals. This finding has implications for early intervention and treatment guidelines, as n-3 PUFA supplementation can easily and safely be used in a wide variety of settings, from primary care to specialist services.

Supplementation with the omega-3 long chain polyunsaturated fatty acids: Changes in the concentrations of omega-3 index, fatty acids and molecular phospholipids of people at ultra high risk of developing psychosis.

Omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) are necessary for optimum mental health, with recent studies showing low n-3 LCPUFA in people at ultra-high risk (UHR) of developing psychosis. Furthermore, people at UHR of psychosis had increased erythrocyte sphingomyelin (SM) and reduced phosphatidylethanolamine (PE) concentrations as well as 27 erythrocyte phospholipid species that differed when compared to erythrocytes from age matched people not at UHR of psychosis. The aim of this analysis was to evaluate the effect of n-3 supplementation on the different erythrocyte lipid species (including SM and PE concentrations) in people at UHR of psychosis. Participants were randomly assigned to fish oil (containing 840 mg EPA and 560 mg DHA per day) or placebo (paraffin oil) for 6 months. Fasted blood samples were taken at baseline and post intervention. Mass spectrometry was used to analyse the molecular phospholipids and fatty acid composition of erythrocytes for both groups. The n-3 index was significantly increased from 3.0% to 4.12% after 6 months of receiving n-3 capsules. Fish oil capsules increased the phospholipid molecular species containing n-3 LCPUFA, and concomitant decreases in n-6 LCPUFA species. SM species did not show any significant changes in n-3 LCPUFA group however, three SM species (SM 16:0, SM 18:0, SM 18:1) significantly increased after 6 months of supplementation with placebo. N-3 supplementation for 6 months led to higher n-3 incorporation into erythrocytes, at the expense of n-6 PUFA across all phospholipid classes analyzed and may have prevented the increase in SM seen in the placebo group.

Neurocognition as a predictor of transition to psychotic disorder and functional outcomes in ultra-high risk participants: Findings from the NEURAPRO randomized clinical trial.

BACKGROUND: Neurocognitive impairments experienced by individuals at ultra-high risk (UHR) for psychosis are potential predictors of outcome within this population, however there is inconsistency regarding the specific neurocognitive domains implicated. This study aimed to examine whether baseline neurocognition predicted transition to psychosis, or functional outcomes, at medium-term (mean = 3.4 years) follow-up, while controlling for other clinical/treatment variables associated with transition to psychosis. METHOD: Analysis of data collected as part of a multi-centre RCT of omega-3 fatty acids and cognitive-behavioural case management (NEURAPRO) for UHR individuals was conducted on the 294 participants (134 males, 160 females) who completed neurocognitive assessment (Brief Assessment of Cognition for Schizophrenia) at baseline. Transition to psychosis was determined using the Comprehensive Assessment of At-Risk Mental States (CAARMS), and functioning was measured with the Global Functioning: Social and Role Scales. RESULTS: Mean baseline z-scores indicated that UHR participants performed a quarter to half a standard deviation below normative means in all domains (range mean z = -0.24 to -0.47), except for executive functioning (mean z = 0.16). After adjusting for covariates, poorer Executive (p = .010) and Motor (p = .030) functions were predictive of transition to psychosis. Processing Speed and Verbal Fluency were significant predictors of role functioning at 12 months (p = .004), and social functioning at medium-term follow-up (p = .015), respectively. CONCLUSIONS: Neurocognitive abilities are independent predictors of both transition to psychosis and functional outcomes within the UHR population. Further research is needed to determine the best combination of risk variables in UHR individuals for prediction of psychosis transition, functioning and other psychopathology outcomes.

Effect of ω-3 Polyunsaturated Fatty Acids in Young People at Ultrahigh Risk for Psychotic Disorders: The NEURAPRO Randomized Clinical Trial.

IMPORTANCE: A promising treatment to prevent onset and improve outcomes in patients at ultrahigh risk for psychosis is dietary supplementation with long-chain ω-3 polyunsaturated fatty acids (PUFAs). OBJECTIVE: To determine whether treatment with ω-3 PUFAs in combination with a high-quality psychosocial intervention (cognitive behavioral case management [CBCM]) is more effective than placebo plus CBCM. DESIGN, SETTING, AND PARTICIPANTS: NEURAPRO, a double-blind, placebo-controlled, randomized clinical trial, was conducted from March 1, 2010, to September 30, 2014, in 10 specialized early psychosis treatment services in Australia, Asia, and Europe. The primary analysis used the intention-to-treat approach. INTERVENTIONS: A daily dose of 1.4 g of ω-3 PUFAs or placebo (paraffin oil), plus 20 or fewer sessions of CBCM over the 6-month study period. MAIN OUTCOMES AND MEASURES: The primary outcome was transition to psychosis status at 6 months. The secondary outcomes were general levels of psychopathology and functioning, as assessed by the Brief Psychiatric Rating Scale (BPRS) (range, 24-168), Scale for the Assessment of Negative Symptoms (SANS) (range, 0-125), Montgomery-Åsberg Depression Rating Scale (MADRS) (range, 0-60), Young Mania Rating Scale (YMRS) (range, 0-44), Social and Occupational Functioning Assessment Scale (SOFAS) (range, 0-100), and the Global Functioning: Social and Role scale (range, 0-10). For SOFAS and Global Functioning: Social and Role scale, higher scores were better; for other measures, lower scores were better. RESULTS: In this study of 304 adults at ultrahigh risk for psychotic disorders, 153 (50.3%) received ω-3 PUFAs and 151 (49.7%) received placebo. In all, 139 (45.7%) were male; mean (SD) age was 19.1 (4.6) years. The Kaplan-Meier-estimated 6-month transition rates were 5.1% (95% CI, 1.3%-8.7%) in the control group and 6.7% (95% CI, 2.3%-10.8%) in the ω-3 PUFA group. At 12 months, the rates were 11.2% (95% CI, 5.5%-16.7%) in the control group and 11.5% (95% CI, 5.8%-16.9%) in the ω-3 PUFA group. No significant difference was observed between the transition rates of both groups (hazard ratio, 1.1; 95% CI, 0.55-2.23; P = .76, stratified log-rank test). CONCLUSIONS AND RELEVANCE: This trial clearly failed to replicate the findings of the original single-center trial. The most likely explanation is that ω-3 PUFAs lack efficacy under these conditions. However, the lower-than-expected transition rate may have prevented a test of the main hypothesis. Given the substantial symptomatic and functional improvement in both groups, the other treatments received (ie, CBCM and antidepressants) likely produced a ceiling effect beyond which ω-3 PUFAs, even if effective, could not be shown to confer additional benefits. Nevertheless, the main conclusion is that ω-3 PUFAs are not effective under conditions where good quality, evidence-based psychosocial treatment is available. TRIAL REGISTRATION: anzctr.org.au Identifier: 12608000475347.

Youth depression alleviation: the Fish Oil Youth Depression Study (YoDA-F): A randomized, double-blind, placebo-controlled treatment trial.

AIM: US authorities have recommended 'black-box' warnings for antidepressants because of the increased risk of suicidality for individuals up to age 25. There is thus a clinical and ethical imperative to provide effective treatment for youth depression with an acceptable risk-benefit balance. Long-chain omega-3 polyunsaturated fatty acids (PUFAs) play an important role in a range of physiological processes in living organisms. Supplementation with omega-3 PUFAs has been shown to have a range of beneficial effects on both physical and mental health, and results of previous trials suggest that omega-3 PUFAs may be a safe and effective treatment for depression. However, conclusions from these trials have been limited by their relatively small sample sizes. METHODS: This trial will test the effectiveness of a 12-week parallel group, double-blind, randomized, placebo-controlled trial of 1.4 g day(-1) omega-3 PUFAs in help seeking 15- to 25-year-olds (N = 400) presenting with major depressive disorder. The primary hypothesis is that young people will show greater improvement of depressive symptoms after 12 weeks of treatment with omega-3 PUFAs plus cognitive behavioural case management compared with treatment with placebo plus cognitive behavioural case management. CONCLUSION: Because of using a large sample, results from this study will provide the strongest evidence to date to inform the use of omega-3 PUFAs as first-line therapy in young people presenting with major depressive disorder. The study also heralds an important step towards indicated prevention of persistent depression, which may reduce the burden, stigmatization, disability and economic consequences of this disorder.

The effect of 12-wk ω-3 fatty acid supplementation on in vivo thalamus glutathione concentration in patients "at risk" for major depression.

OBJECTIVES: As life expectancy increases, the need to prevent major health disorders is clear. Depressive symptoms are common in older adults and are associated with cognitive decline and greater risk for transitioning to major depression. Oxidative stress may be implicated in the pathophysiology of major depression and can be measured in vivo using proton magnetic resonance spectroscopy via the neurometabolite glutathione (GSH). Evidence suggests ω-3 fatty acid (FA) supplementation may prevent depression and directly affect GSH concentration. The aim of this study was to examine the effect of ω-3 FA supplementation on in vivo GSH concentration in older adults at risk for depression. METHODS: Fifty-one older adults at risk for depression were randomized to receive either four 1000-mg ω-3 FA supplements daily (containing eicosapentaenoic acid 1200 mg plus docosahexaenoic acid 800 mg) or placebo (four 1000-mg paraffin oil placebo capsules daily) for 12 wk. Participants underwent magnetic resonance spectroscopy, as well as medical, neuropsychological, and self-report assessments at baseline and after 12 wk of supplementation. GSH was measured in the thalamus and calculated as a ratio to creatine. Depressive symptoms were measured using the Patient Health Questionnaire. RESULTS: Compared with the group given the ω-3 FA supplements, the placebo group had greater change in the GSH-to-creatine ratio in the thalamus (t = 2.00; P = 0.049) after the 12 wk intervention. This increase was in turn associated with a worsening of depressive symptoms (r = 0.43; P = 0.043). CONCLUSIONS: Depressive symptom severity in older adults appears to be associated with increased brain levels of GSH, a key marker of oxidative stress. Importantly, ω-3 FA supplementation may attenuate oxidative stress mechanisms, thereby offering benefits for depression prevention.

The Beyond Ageing Project Phase 2--a double-blind, selective prevention, randomised, placebo-controlled trial of omega-3 fatty acids and sertraline in an older age cohort at risk for depression: study protocol for a randomized controlled trial.

BACKGROUND: Late-life depression is associated with high rates of morbidity, premature mortality, disability, functional decline, caregiver burden and increased health care costs. While clinical and public health approaches are focused on prevention or early intervention strategies, the ideal method of intervention remains unclear. No study has set out to evaluate the role of neurobiological agents in preventing depressive symptoms in older populations at risk of depression. METHODS/DESIGN: Subjects with previously reported sub-threshold depressive symptoms, aged 60 to 74 years, will be screened to participate in a single-centre, double-blind, randomised controlled trial with three parallel groups involving omega-3 fatty acid supplementation or sertraline hydrochloride, compared with matching placebo. Subjects will be excluded if they have current depression or suicide ideation; are taking antidepressants or any supplement containing omega-3 fatty acid; or have a prior history of stroke or other serious cerebrovascular or cardiovascular disease, neurological disease, significant psychiatric disease (other than depression) or neurodegenerative disease. The trial will consist of a 12 month treatment phase with follow-up at three months and 12 months to assess outcome events. At three months, subjects will undergo structural neuroimaging to assess whether treatment effects on depressive symptoms correlate with brain changes. Additionally, proton spectroscopy techniques will be used to capture brain-imaging markers of the biological effects of the interventions. The trial will be conducted in urban New South Wales, Australia, and will recruit a community-based sample of 450 adults. Using intention-to-treat methods, the primary endpoint is an absence of clinically relevant depression scores at 12 months between the omega-3 fatty acid and sertraline interventions and the placebo condition. DISCUSSION: The current health, social and economic costs of late-life depression make prevention imperative from a public health perspective. This innovative trial aims to address the long-neglected area of prevention of depression in older adults. The interventions are targeted to the pathophysiology of disease, and regardless of the effect size of treatment, the outcomes will offer major scientific advances regarding the neurobiological action of these agents. The main results are expected to be available in 2017. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12610000032055 (12 January 2010).

Sleep quality in healthy older people: relationship with ¹H magnetic resonance spectroscopy markers of glial and neuronal integrity.

The hippocampus and thalamus assume a significant role in the overnight consolidation of memories, a process that is negatively impacted by sleep disruption. Emerging evidence suggests that disturbances of sleep in older people may co-occur with underlying neurobiological changes. This study sought to assess glial and neuronal integrity in these regions in relation to subjective sleep disturbance in a healthy older sample. Forty-three healthy older people (mean age = 70, SD = 5.0) were assessed clinically and medically and screened for cognitive and depressive symptoms, as well as sleep disturbance. Single voxel hippocampal and thalamus metabolite ratios of N-acetyl aspartate (NAA) and myo-inositol (mI) with total creatine (Cr + PCr) were measured using magnetic resonance spectroscopy at 3-Tesla. Higher hippocampal mI/Cr + PCr ratios were significantly correlated with poorer self-reported sleep quality (r = .42, p < .01) and less sleep efficiency (r = -0.42, p < .01) as recorded by the Pittsburgh Sleep Quality Index (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989). No other significant correlations were observed within the hippocampus or within the thalamus. These results indicate that in healthy older people, subjective sleep disturbance may be associated with glial alterations in the hippocampus. Future research is now needed to examine these associations with respect to objective sleep measures and overnight memory consolidation.

A systematic review and meta-analysis of proton magnetic resonance spectroscopy and mismatch negativity in bipolar disorder.

Aberrant glutamate neurotransmission has been implicated in the pathophysiology of bipolar disorder with accumulating evidence from imaging, post-mortem and pathology studies. Studies investigating in vivo changes to the glutamatergic system have not been as consistent and warrant clarification. Studies utilizing proton-magnetic resonance spectroscopy ((1)H-MRS) have reported increased levels of combined glutamate and glutamine ("Glx"), which have been linked to impairments in N-methyl-d-aspartate (NMDA) receptor function. Similarly, neurophysiological studies utilising mismatch negativity (MMN) as an index of NMDA receptor function, have reported impairments in bipolar disorder. Here, we provide a systematic review of the literature in regards to the concentration of Glx and the magnitude of MMN in bipolar disorder. Separate meta-analyses revealed that bipolar disorder was associated with increased Glx concentration and decreased MMN-both measured frontally. The current findings corroborate previous evidence indicating that bipolar disorder is characterized by a perturbed frontal glutamate system. These observed changes in bipolar disorder might manifest as impairments in neuronal-glial interactions that lead to disrupted neuronal output and ultimately result in the characteristic neurocognitive sequelae associated with this disorder.

Neurophysiological biomarkers support bipolar-spectrum disorders within psychosis cluster.

BACKGROUND: Mismatch negativity (MMN) and P3a are event-related potentials that index deviance detection and the orienting response, respectively. We have previously shown that the MMN/P3a complex is impaired in patients with schizophrenia and affective spectrum psychoses, which suggests that it may index a common pathophysiology and argues against the purported specificity in schizophrenia. Further research is warranted to determine whether patients with bipolar-spectrum disorders show similar impairments in these biomarkers. METHODS: We assessed patients aged 15-30 years with early schizophrenia-spectrum disorders (schizophrenia, schizoaffective disorder, schizophreniform disorder), early bipolar-spectrum disorders (bipolar I or II, with and without psychotic features) and healthy, matched controls. We acquired MMN/P3a amplitudes during a 2-tone, auditory paradigm with 8% duration deviants. Clinical, psychosocial and neuro psychological assessments were also undertaken. RESULTS: We included 20 patients with schizophrenia-spectrum disorders, 20 with bipolar-spectrum disorders and 20 controls in our study. Both patient groups showed significantly reduced frontocentral MMN and central P3a amplitudes. The schizophrenia-spectrum group had additional impairments in left temporal MMN and frontal P3a. Both patient groups performed worse than controls across psychosocial and clinical measures; however, only the schizophrenia-spectrum group performed significantly worse than controls for cognitive measures. Correlational analyses between patient groups revealed associations between frontocentral or left temporal MMN and psychiatric symptomatology or quality of life measures. LIMITATIONS: Limitations to our study include the modest sample size and the lack of control with regards to the effects of other (i.e., nonantipsychotic) psychotropic medications. CONCLUSION: Compared with patients in early stages of schizophrenia-spectrum disorders, those in the early stages of bipolar-spectrum disorders are similarly impaired in established biomarkers for schizophrenia. These findings support a shared diathesis model for psychotic and bipolar disorders. Furthermore, MMN/P3a may be a biomarker for a broader pathophysiology that overlaps traditional diagnostic clusters.

No clear potentiation of antidepressant medication effects by folic acid+vitamin B12 in a large community sample.

BACKGROUND: Observational studies link low folate levels to depressive symptoms and to poor antidepressant medication response. Evidence supports a role for folate in potentiating the effect of antidepressant medications. AIM: This prospective study examines the effects of folic acid+vitamin B12 supplementation and antidepressant medication in a community-based study of older adults with depressive symptoms. METHOD: A randomised controlled trial investigated the effectiveness of a medicinal and two behavioural preventive interventions over a two year period. The medicinal intervention compared dietary supplementation of 400 mcg/d folic acid+100 mcg/d vitamin B12 to placebo. Self reported use of antidepressant medication over two years was recorded. Participants were screened for psychological distress using the Kessler Distress 10-Scale (K-10; >15 eligible) and the main outcome measure was change in depressive symptoms on the Patient Health Questionnaire-9 (PHQ-9) at six weeks, six, 12 and 24 months. Nine hundred adults aged 60-74 years were included in the analysis, of whom 209 (23.2%) reported antidepressant use during the follow-up period. RESULTS: A mixed model repeated measures analysis of variance for reduction in depressive symptoms found no significant three-way interaction between supplement group and antidepressant use over time on the PHQ-9 [F4, 825.1=0.32, p=0.87]. A small interaction between supplement group and antidepressant use over time was found for K-10 scores (F4, 799.5=2.50, p=0.0414). CONCLUSIONS: There was little evidence for the potentiation of antidepressant medication by folic acid+B12 supplementation on depressive symptomatology. Further research should examine whether effects might be found at higher folic acid dosages or among clinical populations.

Early intervention for cognitive decline: is there a role for multiple medical or behavioural interventions?

AIM: Early medical or behavioural intervention to slow cognitive decline might be a viable strategy for reducing disability and rates of institutional care in older persons. This paper details the published work supporting cross-sectional and longitudinal associations between vascular risk factors, depressive symptoms and progressive cognitive decline. Evidence for the beneficial effects of providing relevant interventions is assessed. METHODS: Relevant published work from the areas of dementia research, 'vascular depression' and the cognitive benefits that might result from treating vascular risk factors, managing depression or promoting nutrition, cognitive or physical exercise was ascertained from electronic database searches and recent reviews of key areas. RESULTS: The existing published work does not provide many examples of early intervention strategies that target vascular strategies or active treatment of depression to reduce the rate of cognitive decline. Most studies have major limitations including the evaluation of only single-risk-factor interventions, the observational designs and the inadequate measurement of cognition. An optimal early intervention strategy might be to target multiple risk factors within relevant experimental or health service frameworks. CONCLUSIONS: Early identification and multifaceted reduction of vascular risk factors, active management of depression, engagement in cognitive activity and physical exercise and promotion of better nutrition might together help to slow some forms of cognitive decline or progression to dementia. This health services approach now requires systematic evaluation.

headspace: Australia's National Youth Mental Health Foundation--where young minds come first.

headspace, Australia's national youth mental health initiative, was created in 2006 in response to the recognition that the existing health system needed to be much more accessible and effective for young people with mental and substance use disorders. With funding of more than $54 million from the Australian Government, a carefully constructed and selected system of 30 "communities of youth services", or integrated service hubs and networks, across the nation is being established, supported by programs for community awareness, workforce training and evidence-based resource material. headspace aims to improve access, and service cohesion and quality, and ultimately health and social outcomes, for young people aged 12-25 years experiencing mental illness and related substance use problems. Within the Council of Australian Governments framework, this will require synergistic planning with, and co-investment on behalf of, state and territory governments, as well as the support and involvement of local communities and the wider Australian society.