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1.  Quantifying the effect of body mass index, age, and depression severity on 24-h activity patterns in persons with a lifetime history of affective disorders 
BMC Psychiatry  2016;16(1):317.
Background
Patients with affective disorders of different ages have been found to present weight changes and different circadian activity patterns. This study assessed the effects of age, Body Mass Index (BMI) and depression severity on the activity-rest cycle in persons with affective disorders using a novel multifactorial 24-h analysis method.
Methods
Two hundred and thirty-six participants aged between 14 and 85 years underwent 5 to 22 days of actigraphy monitoring (mean duration = 14 days). BMI was also recorded and symptom severity was assessed with the Hamilton Depression Rating Scale (HDRS). Participants were divided into two groups: healthy controls (n = 68) and participants with a lifetime diagnosis of affective disorders (n = 168). First, the multiple regression method was employed to formulate the circadian activity pattern in term of the factors age, BMI and HDRS. For each group, the functional linear analysis method was applied to assess the relative effects of the factors. Finally, Wald-tests were used to assess the contribution of each factor on the circadian activity pattern.
Results
In the affective disorders group, higher BMI was associated with higher activity levels from 3 am until 5.30 am and with lower activity levels from 10 am until 10.30 pm. Older age was associated with less activity across the day, evening, and night - from 11 am until 5.30 am. Higher HDRS scores were associated with higher activity around 1:30 am. In healthy controls, the effects of BMI and age on activity patterns were less pronounced and affected a narrower portion of the 24-h period.
Conclusion
These findings suggest that older age and higher BMI are linked to lower daytime activity levels. Higher BMI and worse symptom severity were also associated with nocturnal activity patterns suggestive of sleep disturbances. The influence of age and BMI on 24-h activity profiles appear to be especially pronounced in people with affective disorders.
doi:10.1186/s12888-016-1023-2
PMCID: PMC5017039  PMID: 27612556
Functional linear model; Multiple regression method; Body mass index; Actigraphy; Circadian activity pattern; Depression; Affective disorders
2.  Impaired causal awareness and associated cortical–basal ganglia structural changes in youth psychiatric disorders 
NeuroImage : Clinical  2016;12:285-292.
Background
Cognitive impairments contribute significantly to disease burden in young individuals presenting with major psychiatric disorders. The capacity to encode the consequences of one's actions may be of particular importance for real-world functioning due to its fundamental role in goal-directed behavior.
Methods
Here, we investigated a dimensional measure of causal awareness during a probabilistic learning task in 92 young individuals with an admixture of major mood and psychotic illnesses, at early and more established stages. Using automated gray matter segmentation of T1-weighted images, we estimated the volume and shapes of major subcortical structures and investigated their association with causal awareness.
Results
The low causal awareness (LCA) group (n = 35) reported increased social disability (p = .004) and reduced right pallidal size, specifically within the dorsolateral surfaces (p = .02), relative to the unimpaired high causal awareness (HCA) patients (n = 57). In early-stage illness, LCA had a smaller right thalamus (p = .002) relative to HCA. Exploratory investigations suggested that in developed psychotic syndromes, causal awareness was correlated with left hippocampal size (p = .006) whereas, in more persistent affective disorders, causal awareness was correlated with left amygdala size (p = .013), specifically within the anterior aspect.
Discussion
Low causal awareness occurs across diagnoses and stages of illness and is associated with poor functional outcomes. Our results suggest that there may be shared neural underpinnings of its dysfunction in the early course of mood and psychotic disorders, however in more established illness, there is greater neurobiological divergence in causal awareness correlates between diagnoses.
Highlights
•Impaired awareness of causal relationships occurs trans-diagnostically.•Participants with low causal awareness have poorer functional outcomes.•Low causal awareness was associated with reduced right pallidal size•Low causal awareness was associated with a lateralized limbic-pallidal circuit.•Results suggest common neural dysfunction in early mood and psychotic disorders.
doi:10.1016/j.nicl.2016.06.017
PMCID: PMC4983644  PMID: 27551665
Instrumental learning; Causal awareness; Volumetrics; Shape analysis; Pallidum; Youth
3.  The underlying neurobiology of key functional domains in young people with mood and anxiety disorders: a systematic review 
BMC Psychiatry  2016;16:156.
Background
Mood and anxiety disorders are leading causes of disability and mortality, due largely to their onset during adolescence and young adulthood and broader impact on functioning. Key factors that are associated with disability and these disorders in young people are social and economic participation (e.g. education, employment), physical health, suicide and self-harm behaviours, and alcohol and substance use. A better understanding of the objective markers (i.e. neurobiological parameters) associated with these factors is important for the development of effective early interventions that reduce the impact of disability and illness persistence.
Methods
We systematically reviewed the literature for neurobiological parameters (i.e. neuropsychology, neuroimaging, sleep-wake and circadian biology, neurophysiology and metabolic measures) associated with functional domains in young people (12 to 30 years) with mood and/or anxiety disorders.
Results
Of the one hundred and thirty-four studies selected, 7.6 % investigated social and economic participation, 2.1 % physical health, 15.3 % suicide and self-harm behaviours, 6.9 % alcohol and substance use, whereas the majority (68.1 %) focussed on clinical syndrome.
Conclusions
Despite the predominance of studies that solely examine the clinical syndrome of young people the literature also provides evidence of distinct associations among objective measures (indexing various aspects of brain circuitry) and other functional domains. We suggest that a shift in focus towards characterising the mechanisms that underlie and/or mediate multiple functional domains will optimise personalised interventions and improve illness trajectories.
doi:10.1186/s12888-016-0852-3
PMCID: PMC4878058  PMID: 27215830
Depression; Anxiety; Bipolar; Functional outcomes; Biomarkers; Neurobiology; Neuropsychology; Personalised psychiatry
4.  Retinal Microvessels Reflect Familial Vulnerability to Psychotic Symptoms: A Comparison of Twins Discordant for Psychotic Symptoms and Controls 
Schizophrenia research  2015;164(0):47-52.
Mounting evidence suggests that individuals with schizophrenia have an underlying vulnerability to cardiovascular disease, and a recent study suggested that this vulnerability might be reflected in the retinal microvasculature. The purpose of this study was to test the hypothesis that the retinal microvessels reflect familial vulnerability to psychotic symptoms. Participants were 531 adolescent and young adult twins who took part in the Brisbane Longitudinal Twin Study and the Twins Eye Study in Tasmania. The twins had photographs taken of their retina when they were adolescents or young adults (M age=20.6 years), and retinal vessel diameter was assessed using computer software. The twins completed an assessment of psychosis symptoms approximately six years later. We compared retinal venular diameters of individuals with one or more symptoms of psychosis (n=45), their unaffected co-twins (n=24), and controls (n=462). Individuals with one or more symptoms of psychosis had wider venules (standardized mean=0.29) than controls (standardized mean=-0.04; p=.03), and unaffected co-twins had venular diameters that were intermediate (standardized mean=0.13) between the two groups, suggesting that wide venules may represent a proxy marker of familial vulnerability to psychosis symptoms. Consistent with previous work, there were no differences in arteriolar diameter between individuals with and without symptoms of psychosis. Findings suggest that wide retinal venules may serve as a proxy marker of familial liability to psychosis symptoms. The pathophysiological mechanisms linking psychosis and cardiovascular disease may be operative from early in life, possibly at the level of the microvasculature.
doi:10.1016/j.schres.2015.01.045
PMCID: PMC4409503  PMID: 25694186
Psychosis; retinal vessel diameter; twin
5.  A Double-Blind Randomized Controlled Trial of Oxytocin Nasal Spray and Social Cognition Training for Young People With Early Psychosis 
Schizophrenia Bulletin  2014;41(2):483-493.
Social-cognitive deficits contribute to poor functional outcomes in early psychosis; however, no effective pharmacological treatments exist for these problems. This study was the first to investigate the efficacy of an extended treatment of oxytocin nasal spray combined with social cognition training (SCT) to improve social cognition, clinical symptoms, and social functioning in early psychosis. In a double-blind, randomized, placebo-controlled, between-subjects trial, 52 individuals (aged 16–35 years) diagnosed with an early psychosis schizophrenia-spectrum illness were recruited. Participants received oxytocin (24 International Units) or placebo nasal spray twice-daily for 6 weeks, combined with group SCT (2 × 1 hour weekly sessions for 6 weeks). An additional dose of oxytocin was administered before each weekly session. Assessments were conducted at baseline, post-treatment, and at 3-month follow-up. Primary outcomes included the Reading the Mind in the Eyes Test, the Scale for the Assessment of Positive and Negative Symptoms, and the Social Functioning Scale. Secondary outcomes included self-report and behavioral assessments of social cognition, symptom severity, and social functioning. Results showed that on all primary and secondary outcomes, there was no benefit of oxytocin nasal spray treatment in comparison to placebo. Exploratory post hoc analysis suggested that increased use of nasal spray was, however, associated with reductions in negative symptoms in the oxytocin condition only. This study represents the first evaluation of oxytocin treatment for early psychosis. Although results suggest no benefit of oxytocin treatment, results also highlight an urgent need to consider nasal spray delivery and dose-related variables for future clinical trials.
doi:10.1093/schbul/sbu094
PMCID: PMC4332939  PMID: 24962607
neuropeptides; emotion recognition; social behavior; schizophrenia
6.  Autonomic nervous system dysfunction in psychiatric disorders and the impact of psychotropic medications: a systematic review and meta-analysis 
Background
Autonomic nervous system (ANS) dysfunction is a putative underlying mechanism for increased cardiovascular disease risk in individuals with psychiatric disorders. Previous studies suggest that this risk may be related to psychotropic medication use. In the present study we systematically reviewed and analyzed published studies of heart rate variability (HRV), measuring ANS output, to determine the effect of psychiatric illness and medication use.
Methods
We searched for studies comparing HRV in physically healthy adults with a diagnosed psychiatric disorder to controls and comparing HRV pre- and post-treatment with a psychotropic medication.
Results
In total, 140 case–control (mood, anxiety, psychosis, dependent disorders, k = 151) and 30 treatment (antidepressants, antipsychotics; k = 43) studies were included. We found that HRV was reduced in all patient groups compared to controls (Hedges g = −0.583) with a large effect for psychotic disorders (Hedges g = −0.948). Effect sizes remained highly significant for medication-free patients compared to controls across all disorders. Smaller and significant reductions in HRV were observed for specific antidepressants and antipsychotics.
Limitations
Study quality significantly moderated effect sizes in case–control analyses, underscoring the importance of assessing methodological quality when interpreting HRV findings.
Conclusion
Combined findings confirm substantial reductions in HRV across psychiatric disorders, and these effects remained significant even in medication-free individuals. Reductions in HRV may therefore represent a significant mechanism contributing to elevated cardiovascular risk in individuals with psychiatric disorders. The negative impact of specific medications on HRV suggest increased risk for cardiovascular disease in these groups, highlighting a need for treatment providers to consider modifiable cardiovascular risk factors to attenuate this risk.
doi:10.1503/jpn.140217
PMCID: PMC4764485  PMID: 26447819
7.  Genetic and Environmental Contributions to Functional Connectivity Architecture of the Human Brain 
Cerebral Cortex (New York, NY)  2016;26(5):2341-2352.
One of the grand challenges faced by neuroscience is to delineate the determinants of interindividual variation in the comprehensive structural and functional connection matrices that comprise the human connectome. At present, this endeavor appears most tractable at the macroanatomic scale, where intrinsic brain activity exhibits robust patterns of synchrony that recapitulate core functional circuits at the individual level. Here, we use a classical twin study design to examine the heritability of intrinsic functional network properties in 101 twin pairs, including network activity (i.e., variance of a network's specific temporal fluctuations) and internetwork coherence (i.e., correlation between networks' specific temporal fluctuations). Five of 7 networks exhibited significantly heritable (23.3–65.2%) network activity, 6 of the 21 internetwork coherences were significantly heritable (25.6–42.0%), and 11 of the 21 internetwork coherences were significantly influenced by common environmental factors (18.0–47.1%). These results suggest that the source of interindividual variation in functional connectome has a modular architecture: individual modules represented by intrinsic connectivity networks are genetic controlled, while environmental factors influence the interplays between the modules. This work further provides network-specific hypotheses for discovery of the specific genetic and environmental factors influencing functional specialization and integration of the human brain.
doi:10.1093/cercor/bhw027
PMCID: PMC4830303  PMID: 26891986
connectome; environmental contribution; heritability; intrinsic connectivity network; twins
8.  The Genetic and Environmental Contributions to Internet Use and Associations With Psychopathology: A Twin Study 
Excessive internet use has been linked to psychopathology. Therefore, understanding the genetic and environmental risks underpinning internet use and their relation to psychopathology is important. This study aims to explore the genetic and environmental etiology of internet use measures and their associations with internalizing disorders and substance use disorders. The sample included 2,059 monozygotic (MZ) and dizygotic (DZ) young adult twins from the Brisbane Longitudinal Twin Study (BLTS). Younger participants reported more frequent internet use, while women were more likely to use the internet for interpersonal communication. Familial aggregation in ‘frequency of internet use’ was entirely explained by additive genetic factors accounting for 41% of the variance. Familial aggregation in ‘frequency of use after 11 pm’, ‘using the internet to contact peers’, and ‘using the internet primarily to access social networking sites’ was attributable to varying combinations of additive genetic and shared environmental factors. In terms of psychopathology, there were no significant associations between internet use measures and major depression (MD), but there were positive significant associations between ‘frequency of internet use’ and ‘frequency of use after 11 pm’ with social phobia (SP). ‘Using the internet to contact peers’ was positively associated with alcohol abuse, whereas ‘using the internet to contact peers’ and ‘using the internet primarily to access social networking sites’ were negatively associated with cannabis use disorders and nicotine symptoms. Individual differences in internet use can be attributable to varying degrees of genetic and environmental risks. Despite some significant associations of small effect, variation in internet use appears mostly unrelated to psychopathology.
doi:10.1017/thg.2015.91
PMCID: PMC4756632  PMID: 26693596
twins; internet use; substance use disorders; internalizing disorders
9.  Circadian rhythmicity in emerging mood disorders: state or trait marker? 
Background
Circadian rhythm disturbances overlap with the symptoms of mood episodes and may trigger or prolong mood symptoms. There is limited research on the role of circadian disturbances in mood disorders in young people and/or first episode cases of unipolar and bipolar disorders.
Methods
Actigraphy was undertaken for about 14 days in 63 post-pubertal individuals aged 13–25 years with a recent onset of a mood disorder meeting recognised diagnostic criteria. We examined associations between three easily interpretable markers of circadian rhythm activity (amplitude, acrophase and rhythmicity index) and demography and clinical characteristics. Then, circadian markers were compared between diagnostic groups, controlling for potential confounders.
Results
Longer duration of illness was correlated with reduced circadian rhythmicity and lower levels of activity over 24 h. A delay in the timing of maximum activity was associated with the level of manic but not depressive symptoms. The circadian rhythmicity index differentiated unipolar from bipolar cases, and in bipolar but not unipolar disorder, the rhythmicity was less robust in those with more severe manic or depressive symptoms.
Conclusions
Less robust circadian rhythmicity, especially associated with increasing symptom severity, may represent a more specific or a trait marker of young people with mood disorders who are at higher risk of a bipolar course of illness.
doi:10.1186/s40345-015-0043-z
PMCID: PMC4712181  PMID: 26763505
Circadian rhythm; Bipolar; Unipolar; Adolescence; Young adult; Trait
10.  Head Motion and Inattention/Hyperactivity Share Common Genetic Influences: Implications for fMRI Studies of ADHD 
PLoS ONE  2016;11(1):e0146271.
Head motion (HM) is a well known confound in analyses of functional MRI (fMRI) data. Neuroimaging researchers therefore typically treat HM as a nuisance covariate in their analyses. Even so, it is possible that HM shares a common genetic influence with the trait of interest. Here we investigate the extent to which this relationship is due to shared genetic factors, using HM extracted from resting-state fMRI and maternal and self report measures of Inattention and Hyperactivity-Impulsivity from the Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour (SWAN) scales. Our sample consisted of healthy young adult twins (N = 627 (63% females) including 95 MZ and 144 DZ twin pairs, mean age 22, who had mother-reported SWAN; N = 725 (58% females) including 101 MZ and 156 DZ pairs, mean age 25, with self reported SWAN). This design enabled us to distinguish genetic from environmental factors in the association between head movement and ADHD scales. HM was moderately correlated with maternal reports of Inattention (r = 0.17, p-value = 7.4E-5) and Hyperactivity-Impulsivity (r = 0.16, p-value = 2.9E-4), and these associations were mainly due to pleiotropic genetic factors with genetic correlations [95% CIs] of rg = 0.24 [0.02, 0.43] and rg = 0.23 [0.07, 0.39]. Correlations between self-reports and HM were not significant, due largely to increased measurement error. These results indicate that treating HM as a nuisance covariate in neuroimaging studies of ADHD will likely reduce power to detect between-group effects, as the implicit assumption of independence between HM and Inattention or Hyperactivity-Impulsivity is not warranted. The implications of this finding are problematic for fMRI studies of ADHD, as failing to apply HM correction is known to increase the likelihood of false positives. We discuss two ways to circumvent this problem: censoring the motion contaminated frames of the RS-fMRI scan or explicitly modeling the relationship between HM and Inattention or Hyperactivity-Impulsivity.
doi:10.1371/journal.pone.0146271
PMCID: PMC4712830  PMID: 26745144
11.  Heritability of head motion during resting state functional MRI in 462 healthy twins 
NeuroImage  2014;102(0 2):424-434.
Head motion (HM) is a critical confounding factor in functional MRI. Here we investigate whether HM during resting state functional MRI (RS-fMRI) is influenced by genetic factors in a sample of 462 twins (65% female; 101 MZ (monozygotic) and 130 DZ (dizygotic) twin pairs; mean age: 21 (SD=3.16), range 16–29). Heritability estimates for three HM components—mean translation (MT), maximum translation (MAXT) and mean rotation (MR)—ranged from 37 to 51%. We detected a significant common genetic influence on HM variability, with about two-thirds (genetic correlations range 0.76–1.00) of the variance shared between MR, MT and MAXT. A composite metric (HM-PC1), which aggregated these three, was also moderately heritable (h2=42%). Using a sub-sample (N=35) of the twins we confirmed that mean and maximum translational and rotational motions were consistent “traits” over repeated scans (r=0.53–0.59); reliability was even higher for the composite metric (r=0.66). In addition, phenotypic and cross-trait cross-twin correlations between HM and resting state functional connectivities (RS-FCs) with Brodmann areas (BA) 44 and 45, in which RS-FCs were found to be moderately heritable (BA44: h2¯=0.23 (sd=0.041), BA45: h2¯=0.26 (sd=0.061)), indicated that HM might not represent a major bias in genetic studies using FCs. Even so, the HM effect on FC was not completely eliminated after regression. HM may be a valuable endophenotype whose relationship with brain disorders remains to be elucidated.
doi:10.1016/j.neuroimage.2014.08.010
PMCID: PMC4252775  PMID: 25132021
Head Motion; resting state fMRI; twin study; heritability; Broca’s area
12.  Genetic Architecture of Subcortical Brain Regions: Common and Region-Specific Genetic Contributions 
Genes, brain, and behavior  2014;13(8):821-830.
Understanding the etiology of patterns of variation within and covariation across brain regions is key to advancing our understanding of the functional, anatomical and developmental networks of the brain. Here we applied multivariate twin modeling and principal component analysis (PCA) to investigate the genetic architecture of the size of seven subcortical regions (caudate nucleus, thalamus, putamen, pallidum, hippocampus, amygdala and nucleus accumbens) in a genetically informative sample of adolescents and young adults (N=1,038; mean age=21.6 ± 3.2 years; including 148 monozygotic and 202 dizygotic twin pairs) from the Queensland Twin IMaging (QTIM) Study. Our multivariate twin modeling identified a common genetic factor that accounts for all the heritability of intracranial volume (0.88) and a substantial proportion of the heritability of all subcortical structures, particularly those of the thalamus (0.71 out of 0.88), pallidum (0.52 out of 0.75) and putamen (0.43 out of 0.89). In addition, we also found substantial region-specific genetic contributions to the heritability of the hippocampus (0.39 out of 0.79), caudate nucleus (0.46 out of 0.78), amygdala (0.25 out of 0.45) and nucleus accumbens (0.28 out of 0.52). This provides further insight into the extent and organization of multiple genetic factors, which include developmental and general growth pathways, as well as functional specialization and maturation trajectories that influence each subcortical region.
doi:10.1111/gbb.12177
PMCID: PMC4241157  PMID: 25199620
Subcortical Volumes; Twin Study; Covariation; Structural MRI; Heritability; Multivariate
13.  Associations between Depression and Anxiety Symptoms with Retinal Vessel Caliber in Adolescents and Young Adults 
Psychosomatic medicine  2014;76(9):732-738.
Objective
Previous longitudinal studies suggest that depression and anxiety are associated with risk for cardiovascular disease. The aim of the present study was to test whether an association between depression and anxiety symptoms and retinal vessel caliber, an indicator of subclinical cardiovascular risk, is apparent as early as adolescence and young adulthood.
Methods
Participants were 865 adolescents and young adults who participated in the Brisbane Longitudinal Twin Study and the Twin Eye Study in Tasmania. Participants completed the Somatic and Psychological Health Report (SPHERE), including assessments of depression/anxiety and somatic symptom subscales, when they were M=16.5 years, and they underwent retinal imaging M=2.5 years later (range=2 years before to 7 years after the depression/anxiety assessment). Retinal vessel caliber was assessed using computer software.
Results: Depression and anxiety symptoms were associated with wider retinal arteriolar caliber in this sample of adolescents and young adults (β=0.09, p=.016), even after adjusting for other cardiovascular risk factors (β=0.08, p=.025). Multiple regression analyses revealed that affective symptoms of depression/anxiety were associated with retinal vessel caliber independently of somatic symptoms.
Conclusions
Depression and anxiety symptoms are associated with measurable signs in the retinal microvasculature in early life, suggesting that pathological microvascular mechanisms may be operative in the association between depression and anxiety with cardiovascular disease starting as early as adolescence.
doi:10.1097/PSY.0000000000000117
PMCID: PMC4290848  PMID: 25373892
depression; anxiety; retinal vessel caliber; cardiovascular; adolescence; young adults
14.  Youth Early-intervention Study (YES) – group interventions targeting social participation and physical well-being as an adjunct to treatment as usual: study protocol for a randomized controlled trial 
Trials  2015;16:333.
Background
It is increasingly acknowledged that clinical interventions for young persons with mental disorders need to optimize social, vocational and physical functioning, and take into account developmental needs, rather than focusing only on the traditional target of psychiatric symptom change. However, few interventions for youth presenting to mental health services offer a coherent rationale for multi-faceted approaches that efficiently address all these targets.
This trial uses two facilitated group therapy modules (social and physical activity) as a vehicle for promoting clinical, cognitive, social and vocational change. The modules are an adjunct to usual treatments offered to youth attending mental health services in Sydney, Australia.
Methods/Design
The design is a 2-arm, parallel group cross-over, randomized clinical trial (RCT) that examines the efficacy of this adjunctive youth early intervention program (called “YES”) for improving social, vocational, mental and physical health functioning in a trans-diagnostic sample of 120 young persons aged 14–25 years who are currently receiving a range of “usual treatments” for clinically diagnosed anxiety, affective and/or psychotic disorders.
Individuals who provide written informed consent are offered 2 group therapy modules (each comprising 4 hours per week for 8 weeks) with a 3-week “pause” between modules. Randomization determines whether individuals commence with module A or module B. The sample will be assessed pre-randomization, and at week 1 and week 8 (after completion of the first module), and at week 11 (commencement of second module) and week 19 (completion of second module). Final follow–up is 1-year post trial entry.
Discussion
If the findings of this exploratory trial demonstrate benefits in the target domains, then it will be important to extend the research by undertaking: (a) a comparison of the YES program to a control intervention in a randomized controlled trial, (b) an explanatory study of putative mediators of change, and (c) a multi-center trial with a number of trained therapists offering the group modules combined with a longer follow-up period.
Trial registration
Australian New Zealand Controlled Trial Registration: ACTRN1262400175673, Date: 16 July 2015
doi:10.1186/s13063-015-0834-7
PMCID: PMC4525721  PMID: 26243349
Youth; Adolescents; Mental disorders; Physical health; Psychological intervention; Exercise; Functioning; Randomized; Cross-over
15.  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 
Trials  2015;16:247.
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)
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0762-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-015-0762-6
PMCID: PMC4469257  PMID: 26037484
Depression; Prevention; OMEGA-3 fatty acid; Antidepressants; Randomised controlled trial; Older adults
16.  The Relationship between Sleep-Wake Cycle and Cognitive Functioning in Young People with Affective Disorders 
PLoS ONE  2015;10(4):e0124710.
Although early-stage affective disorders are associated with both cognitive dysfunction and sleep-wake disruptions, relationships between these factors have not been specifically examined in young adults. Sleep and circadian rhythm disturbances in those with affective disorders are considerably heterogeneous, and may not relate to cognitive dysfunction in a simple linear fashion. This study aimed to characterise profiles of sleep and circadian disturbance in young people with affective disorders and examine associations between these profiles and cognitive performance. Actigraphy monitoring was completed in 152 young people (16–30 years; 66% female) with primary diagnoses of affective disorders, and 69 healthy controls (18–30 years; 57% female). Patients also underwent detailed neuropsychological assessment. Actigraphy data were processed to estimate both sleep and circadian parameters. Overall neuropsychological performance in patients was poor on tasks relating to mental flexibility and visual memory. Two hierarchical cluster analyses identified three distinct patient groups based on sleep variables and three based on circadian variables. Sleep clusters included a ‘long sleep’ cluster, a ‘disrupted sleep’ cluster, and a ‘delayed and disrupted sleep’ cluster. Circadian clusters included a ‘strong circadian’ cluster, a ‘weak circadian’ cluster, and a ‘delayed circadian’ cluster. Medication use differed between clusters. The ‘long sleep’ cluster displayed significantly worse visual memory performance compared to the ‘disrupted sleep’ cluster. No other cognitive functions differed between clusters. These results highlight the heterogeneity of sleep and circadian profiles in young people with affective disorders, and provide preliminary evidence in support of a relationship between sleep and visual memory, which may be mediated by use of antipsychotic medication. These findings have implications for the personalisation of treatments and improvement of functioning in young adults early in the course of affective illness.
doi:10.1371/journal.pone.0124710
PMCID: PMC4405360  PMID: 25898321
17.  Testing the role of circadian genes in conferring risk for psychiatric disorders 
Disturbed sleep and disrupted circadian rhythms are a common feature of psychiatric disorders, and many groups have postulated an association between genetic variants in circadian clock genes and psychiatric disorders.
Using summary data from the association analyses of the Psychiatric Genomics Consortia (PGC) for schizophrenia, bipolar disorder and Major Depressive Disorder, we evaluated the evidence that common SNPs in genes encoding components of the molecular clock influence risk to psychiatric disorders. Initially, gene-based and SNP p-values were analysed for 21 core circadian genes. Subsequently, an expanded list of genes linked to control of circadian rhythms was analysed.
After correcting for multiple comparisons, none of the circadian genes were significantly associated with any of the three disorders. Several genes previously implicated in the etiology of psychiatric disorders harboured no SNPs significant at the nominal level of p < 0.05, and none of the the variants identified in candidate studies of clock genes that were included in the PGC datasets were significant after correction for multiple testing. There was no evidence of an enrichment of associations in genes linked to control of circadian rhythms in human cells.
Our results suggest that genes encoding components of the molecular clock are not good candidates for harbouring common variants that increase risk to bipolar disorder, schizophrenia or Major Depressive Disorder.
doi:10.1002/ajmg.b.32230
PMCID: PMC4397914  PMID: 24687905
18.  Childhood- versus Adolescent-Onset Antisocial Youth with Conduct Disorder: Psychiatric Illness, Neuropsychological and Psychosocial Function 
PLoS ONE  2015;10(4):e0121627.
Objective
The present study investigates whether youths with childhood-onset antisocial behavior have higher rates of psychiatric illness, neuropsychological and psychosocial dysfunction than youths who engage in antisocial behavior for the first time in adolescence. Prior studies have generally focused on single domains of function in heterogeneous samples. The present study also examined the extent to which adolescent-onset antisocial behavior can be considered normative, an assumption of Moffitt’s dual taxonomy model.
Method
Forty-three subjects (34 males, 9 females, mean age = 15.31, age range 12–21) with a diagnosis of conduct disorder (CD) were recruited through Headspace Services and the Juvenile Justice Community Centre. We compared childhood-onset antisocial youths (n = 23) with adolescent-onset antisocial youths (n = 20) with a conduct disorder, across a battery of psychiatric, neuropsychological and psychosocial measures. Neuropsychological function of both groups was also compared with normative scores from control samples.
Results
The childhood-onset group displayed deficits in verbal learning and memory, higher rates of psychosis, childhood maltreatment and more serious violent behavior, all effects associated with a large effect size. Both groups had impaired executive function, falling within the extremely low range (severely impaired).
Conclusions
Childhood-onset CD displayed greater cognitive impairment, more psychiatric symptoms and committed more serious violent offences. The finding of severe executive impairment in both childhood- and adolescent-onset groupings challenges the assumption that adolescent-onset antisocial behavior is a normative process.
doi:10.1371/journal.pone.0121627
PMCID: PMC4383334  PMID: 25835393
19.  Body mass, cardiovascular risk and metabolic characteristics of young persons presenting for mental healthcare in Sydney, Australia 
BMJ Open  2015;5(3):e007066.
Objectives
To determine the body mass, cardiovascular and metabolic characteristics of young people presenting for mental healthcare.
Design
Cross-sectional assessments of body mass, cardiovascular and metabolic risk factors.
Setting
Two primary-care based sites in Sydney, Australia for young people in the early stages of mental disorders.
Participants
A clinical sample of young people (12–30 years) with mental health problems.
Outcome measures
Daily smoking rates, body mass index (BMI), blood glucose and lipids, blood pressure (BP) and pulse rate.
Results
Of 1005 young people who had their BMI determined (62% female; 19.0±3.5 years), three quarters (739/1005) also had BP recordings and one-third (298/1005) had blood sampling. Clinically, 775 were assigned to one of three diagnostic categories (anxious-depression: n=541; mania-fatigue, n=104; developmental-psychotic n=130). The profile of BMI categories approximated that of the comparable segments of the Australian population. Older age, lower levels of social functioning and higher systolic BP were all associated with high BMI. In a subset (n=129), current use of any psychotropic medication was associated (p<0.05) with increased BMI. Almost one-third of cases were current daily smokers (compared to population rate of 11%). Males had a higher proportion of raised glucose and high-density lipoprotein (HDL) compared to females (9.3% and 34.1% vs 2.1% and 5.9%, respectively). Overall, there was no relationship between BMI and fasting glucose but significant relationships with triglycerides and HDL were noted. Furthermore, there were no significant relationships between diagnostic subgroup and metabolic profiles.
Conclusions
Daily smoking rates are increased among young people presenting for mental healthcare. However, these young people do not demonstrate adverse cardiometabolic profiles. The high levels of smoking, and association of BMI with adverse social circumstances, suggest that risk factors for chronic disease are already present and likely to be compounded by medication and social disadvantage.
doi:10.1136/bmjopen-2014-007066
PMCID: PMC4386215  PMID: 25818274
MENTAL HEALTH; body mass index; blood chemistry; metabolic; young people
20.  The N-Methyl-D-Aspartate Receptor as a Neurobiological Intersection Between Bipolar Disorder and Alcohol Use: A Longitudinal Mismatch Negativity Study 
Background:
Comorbid risky alcohol use in bipolar disorder (BD) is recognized for its high prevalence and clinical relevance, though understanding of its neurobiological underpinning is limited. The N-methyl-D-aspartate (NMDA) receptor has recognized alterations in BD and is a major site of ethanol’s effects in the brain. The present study aimed to examine the NMDA receptor system in adolescents and young adults with BD by evaluating the longitudinal changes in a robust marker of NMDA function, mismatch negativity (MMN), in relation to changes in alcohol use patterns.
Methods:
Forty-six BD patients (aged 16–30) were recruited at baseline and 59% (n = 27) returned for follow-up 17.9 +/- 7.3 months later. At both time-points a two-tone, passive, duration-deviant MMN paradigm was conducted and alcohol measures were collected. Pearson’s correlations were performed between changes in MMN amplitudes and changes in alcohol use. Multiple regression was used to assess whether MMN amplitudes at baseline could predict alcohol use at follow-up.
Results:
Reduction in risky drinking patterns was associated with increased temporal MMN and decreased fronto-central MMN. Larger temporal MMN at baseline was a significant predictor of greater alcohol use at follow-up.
Conclusions:
Results suggest risky alcohol use in BD may further compound pre-existing NMDA receptor abnormalities and, importantly, reducing alcohol use early in stages of illness is associated with changes in MMN. This highlights the importance of monitoring alcohol use from first presentation. In addition, preliminary results present an exciting potential for utility of MMN as a neurobiological marker used to determine risk for alcohol misuse in BD.
doi:10.1093/ijnp/pyu113
PMCID: PMC4438551  PMID: 25603860
alcohol; bipolar disorder; longitudinal; mismatch negativity; NMDA receptor
21.  The Sleep Or Mood Novel Adjunctive therapy (SOMNA) trial: a study protocol for a randomised controlled trial evaluating an internet-delivered cognitive behavioural therapy program for insomnia on outcomes of standard treatment for depression in men 
BMC Psychiatry  2015;15:16.
Background
Insomnia is a significant risk factor for depression onset, can result in more disabling depressive illness, and is a common residual symptom following treatment cessation that can increase the risk of relapse. Internet-based cognitive behavioural therapy for insomnia has demonstrated efficacy and acceptability to men who are less likely than women to seek help in standard care. We aim to evaluate whether internet delivered cognitive behavioural therapy for insomnia as an adjunct to a standard depression therapeutic plan can lead to improved mood outcomes.
Methods/Design
Male participants aged 50 years or more, meeting Diagnostic and Statistical Manual of Mental Disorders criteria for current Major Depressive Episode and/or Dysthymia and self-reported insomnia symptoms, will be screened to participate in a single-centre double-blind randomised controlled trial with two parallel groups involving adjunctive internet-delivered cognitive behavioural therapy for insomnia and an internet-based control program. The trial will consist of a nine-week insomnia intervention period with a six-month follow-up period. During the insomnia intervention period participants will have their depression management coordinated by a psychiatrist using standard guideline-based depression treatments. The study will be conducted in urban New South Wales, Australia, where 80 participants from primary and secondary care and direct from the local community will be recruited. The primary outcome is change in the severity of depressive symptoms from baseline to week 12.
Discussion
This study will provide evidence on whether a widely accessible, evidence-based, internet-delivered cognitive behavioural therapy for insomnia intervention can lead to greater improvements than standard treatment for depression alone, in a group who traditionally do not readily access psychotherapy. The study is designed to establish effect size, feasibility and processes associated with implementing e-health solutions alongside standard clinical care, to warrant undertaking a larger more definitive clinical trial.
Trial registration
Australian and New Zealand Clinical Trials Registry ACTRN12612000985886.
doi:10.1186/s12888-015-0397-x
PMCID: PMC4321324  PMID: 25652579
Depression; Insomnia; Adjunctive; e-health; Cognitive behavioural therapy; Randomised controlled trial; Men
22.  Elderly care recipients’ perceptions of treatment helpfulness for depression and the relationship with help-seeking 
Objective
This study aims to examine perceptions of the helpfulness of treatments/interventions for depression held by elderly care recipients, to examine whether these beliefs are related to help-seeking and whether the experience of depression affects beliefs about treatment seeking, and to identify the characteristics of help-seekers.
Method
One hundred eighteen aged care recipients were surveyed on their beliefs about the helpfulness of a variety of treatments/interventions for depression, on their actual help-seeking behaviors, and on their experience of depression (current and past).
Results
From the sample, 32.4% of the participants screened positive for depression on the Geriatric Depression Scale, and of these, 24.2% reported receiving treatment. Respondents believed the most helpful treatments for depression were increasing physical activity, counseling, and antidepressant medication. Help-seeking from both professional and informal sources appeared to be related to belief in the helpfulness of counseling and antidepressants; in addition, help-seeking from informal sources was also related to belief in the helpfulness of sleeping tablets and reading self-help books. In univariate analyses, lower levels of cognitive impairment and being in the two lower age tertiles predicted a greater likelihood of help-seeking from professional sources, and female sex and being in the lower two age tertiles predicted greater likelihood of help-seeking from informal sources. In multivariate analyses, only lower levels of cognitive impairment remained a significant predictor of help-seeking from professional sources, whereas both lower age and female sex continued to predict a greater likelihood of help-seeking from informal sources.
Conclusion
Beliefs in the helpfulness of certain treatments were related to the use of both professional and informal sources of help, indicating the possibility that campaigns or educational programs aimed at changing beliefs about treatments may be useful in older adults.
doi:10.2147/CIA.S70086
PMCID: PMC4309791  PMID: 25653512
older adults; help-seeking; depression; prevalence; perceptions of treatments
23.  Ambulatory sleep-wake patterns and variability in young people with emerging mental disorders 
Background
The nature of sleep-wake abnormalities in individuals with mental disorders remains unclear. The present study aimed to examine the differences in objective ambulatory measures of the sleep-wake and activity cycles across young people with anxiety, mood or psychotic disorders.
Methods
Participants underwent several days of actigraphy monitoring. We divided participants into 5 groups (control, anxiety disorder, unipolar depression, bipolar disorder, psychotic disorder) according to primary diagnosis.
Results
We enrolled 342 participants aged 12–35 years in our study: 41 healthy controls, 56 with anxiety disorder, 135 with unipolar depression, 80 with bipolar disorder and 30 with psychotic disorders. Compared with the control group, sleep onset tended to occur later in the anxiety, depression and bipolar groups; sleep offset occurred later in all primary diagnosis groups; the sleep period was longer in the anxiety, bipolar and psychosis groups; total sleep time was longer in the psychosis group; and sleep efficiency was lower in the depression group, with a similar tendency for the anxiety and bipolar groups. Sleep parameters were significantly more variable in patient subgroups than in controls. Cosinor analysis revealed delayed circadian activity profiles in the anxiety and bipolar groups and abnormal circadian curve in the psychosis group.
Limitations
Although statistical analyses controlled for age, the sample included individuals from preadolescence to adulthood. Most participants from the primary diagnosis subgroups were taking psychotropic medications, and a large proportion had other comorbid mental disorders.
Conclusion
Our findings suggest that delayed and disorganized sleep offset times are common in young patients with various mental disorders. However, other sleep-wake cycle disturbances appear to be more prominent in broad diagnostic categories.
doi:10.1503/jpn.130247
PMCID: PMC4275328  PMID: 25203899
24.  A cross-sectional exploration of the clinical characteristics of disengaged (NEET) young people in primary mental healthcare 
BMJ Open  2014;4(12):e006378.
Objective
Youth with mental health problems often have difficulties engaging in education and employment. In Australia, youth mental health services have been widely established with a key aim of improving role functioning; however, there is little knowledge of those who are not engaged in employment, education or training (NEET) and the factors which may influence this. This study aimed to examine NEET status and its correlates in a sample of such youth.
Design
Cross-sectional data from a longitudinal cohort study.
Setting
Between January 2011 and August 2012, young people presenting to one of the four primary mental health centres in Sydney or Melbourne were invited to participate.
Participants
Young adults (N=696) aged between 15 and 25 years (M=19.0, SD=2.8), 68% female, 58% (n=404) attended headspace in Sydney.
Measures
Individuals ‘Not in any type of Education, Employment or Training’ in the past month were categorised as NEET. Demographic, psychological and clinical factors alongside disability and functioning were assessed using clinical interview and self-report.
Results
A total of 19% (n=130/696) were NEET. NEETs were more likely to be male, older, have a history of criminal charges, risky cannabis use, higher level of depression, poorer social functioning, greater disability and economic hardship, and a more advanced stage of mental illness than those engaged in education, training or work. Demographics such as postsecondary education, immigrant background and indigenous background, were not significantly associated with NEET status in this sample.
Conclusions
One in five young people seeking help for mental health problems were not in any form of education, employment and training. The commonly observed risk factors did not appear to influence this association, instead, behavioural factors such as criminal offending and cannabis use appeared to require targeted intervention.
doi:10.1136/bmjopen-2014-006378
PMCID: PMC4275674  PMID: 25537785
NEET; youth; unemployment; role functioning; clinical stage
25.  Delayed circadian phase is linked to glutamatergic functions in young people with affective disorders: a proton magnetic resonance spectroscopy study 
BMC Psychiatry  2014;14:345.
Background
While the association between affective disorders and sleep and circadian disturbance is well established, little is known about the neurobiology underpinning these relationships. In this study, we sought to determine the relationship between a marker of circadian rhythm and neuronal integrity (N-Acetyl Aspartate, NAA), oxidative stress (glutathione, GSH) and neuronal-glial dysfunction (Glutamate + Glutamine, Glx).
Methods
Fifty-three young adults (age range 15–33 years, mean = 21.8, sd = 4.3) with emerging affective disorders were recruited from a specialized tertiary referral service. Participants underwent clinical assessment and actigraphy monitoring, from which sleep midpoint was calculated as a marker of circadian rhythm. Proton magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC). The metabolites NAA, GSH and Glx were obtained, and expressed as a ratio to Creatine.
Results
Neither NAA or GSH were associated with sleep midpoint. However, higher levels of ACC Glx were associated with later sleep midpoints (rho = 0.35, p = 0.013). This relationship appeared to be independent of age and depression severity.
Conclusions
This study is the first to demonstrate that delayed circadian phase is related to altered glutamatergic processes. It is aligned with animal research linking circadian rhythms with glutamatergic neurotransmission as well as clinical studies showing changes in glutamate with sleep interventions. Further studies may seek to examine the role of glutamate modulators for circadian misalignment.
doi:10.1186/s12888-014-0345-1
PMCID: PMC4276104  PMID: 25496061
Depression; Youth; Circadian; Sleep; Bipolar; Affective; Glutamate; Glx; Spectroscopy; Actigraphy

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