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BackgroundBetween 30 and 60% of adults with unipolar or bipolar disorders exhibit impairments across multiple domains. However, little is known about impaired functioning in youth with mood disorders.AimsTo examine the prevalence of objective, subjective and observer-rated disability in a large, representative sample of young people with a primary mood disorder.MethodIndividuals aged 16–25 years presenting to youth mental health services for the first time with a primary mood disorder participated in a systematic diagnostic and clinical assessment. Impairment was assessed using objective (unemployment or disability payments), observer- (Social and Occupational Functioning Assessment Scale; SOFAS) and self-rated measures (role functioning according to the Brief Disability Questionnaire).ResultsOf 1241 participants (83% unipolar; 56% female), at least 30% were functionally impaired on the objective, self-rated and/or observer-rated measures, with 16% impaired according to all three criteria. Even when current distress levels were taken into account, daily use of cannabis and/or nicotine were significantly associated with impairment, with odds ratios (OR) ranging from about 1.5 to 3.0. Comorbid anxiety disorders were related to lower SOFAS scores (OR = 2–5).ConclusionsLevels of disability were significant, even in those presenting for mental healthcare for the first time. Functional impairment did not differ between unipolar and bipolar cases, but some evidence suggested that females with bipolar disorder were particularly disabled. The prevalence of comorbid disorders (50%) and polysubstance use (28%) and their association with disability indicate that more meaningful indicators of mood episode outcomes should focus on functional rather than symptom-specific measures. The association between functioning and nicotine use requires further exploration.

Objective We aim to provide a targeted integration to investigate neuronal mechanisms underlying mismatch negativity (MMN) in bipolar disorder (BD), by looking at the association between temporal MMN and in vivo hippocampal glutathione (GSH) measured via proton magnetic resonance spectroscopy ( 1 H-MRS). Methods Twenty-eight people with BD and 22 matched controls underwent a two-tone passive, duration deviant MMN paradigm as well as 1 H-MRS. GSH concentration in the left hippocampus was determined and Pearson's correlations were used to identify associations between MMN amplitude and in vivo GSH concentration. Results In controls MMN amplitude was negatively associated with GSH at the left temporal site ( r =−0.542, 95% C.I.: −0.810, −0.060), and a similar trend at the right ( r =−0.374, 95% C.I.: −0.678, 0.007). There were no significant associations in BD. Conclusions The results provide insight into the relationship between MMN and in vivo GSH, and demonstrate that the metabolite system regulating MMN is abnormal in BD, compared to controls. This may indicate a lack of tightly regulated hippocampal NMDA functioning, or that NMDA receptor regulation in BD is mediated by other factors. Significance These results provide insight into the underlying basis of hippocampal NMDA disturbances implicated in BD.

Aims: To examine the rates and clinical characteristics of mild cognitive impairment (MCI) in older people with depressive symptoms and to determine the relative contribution of hippocampal volume and MCI to memory change. Method: One hundred and fifty-two participants with lifetime Major Depression and remitted or mild symptoms and 28 healthy controls underwent psychiatric and neuropsychological assessments. Magnetic resonance imaging was also conducted in a subset of the patients (n = 81) and healthy controls (n = 18). Results: MCI was diagnosed in 75.7% of the patients and was associated with increasing age, medical burden, vascular risk factors, later age of depression onset and smaller hippocampi. Multiple regression showed that both hippocampal volume and MCI diagnosis mediate memory performance in depression. Conclusions: MCI occurs in older adults with a history of depression and is not simply due to symptom severity. Memory change is linked to underlying hippocampal atrophy in this patient group.

Aberrant eye gaze mechanisms have been implicated in autism spectrum disorders (ASD). Studies of eye movements in children with ASD reveal diminished eye gaze duration and lack of specific eye gaze fixation to the eyes and/or mouth compared with controls. However, findings to date have been contradictory. We examined eye-tracking studies on face processing in children with ASD and conducted meta-analyses to examine whether these children demonstrate atypical fixation on primary facial regions. Twenty eye-tracking studies in children with ASD were reviewed, of which the results from 14 studies were incorporated in the meta-analyses that evaluated fixation duration on (i) eyes (eight studies) and (ii) mouth (six studies). The results reveal that children with ASD have significantly reduced gaze fixation to the eye region of faces. The results of the meta-analyses indicate that ASD patients have significant impairments in gaze fixation to the eyes. On the other hand, no significant difference was uncovered in terms of fixation to the mouth region; however, this finding needs to be interpreted with caution because of the significant heterogeneity in the mouth fixation studies. The findings of this meta-analysis add further clarity to an expanding literature and suggest that specific eye gaze fixation to the eye region may represent a robust biomarker for the condition. The heterogeneity associated with the mouth fixation data precludes any definitive statement as to the robustness of these findings.

Background: With predicted increases in dementia incidence, interventions targeting neuroplasticity and neuroprotection are required. Cognitive Training (CT) is an intervention which has been shown to improve aspects of cognition, but the pathophysiological mechanisms contributing to its efficacy are unknown. Objective: We aimed to explore the neurobiological correlates of CT using Mismatch Negativity (MMN), a neurophysiological marker of pre-attentive information processing, which in turn, is postulated to underpin higher-order cognitive processes. Methods: As part of a larger randomized controlled trial, forty 'at risk' (i.e., mild cognitive impairment or late-life depression) participants aged 51-79 years underwent neurophysiological, neuropsychological, and psychiatric assessments before and after a multi-faceted seven-week CT program or a 'treatment-as-usual' seven-week waitlist period. Results: The treatment group demonstrated significantly increased fronto-central MMN responses (p < 0.05), as well as improved phonemic verbal fluency (p < 0.05) and decreased self-rated memory difficulties (p < 0.05) following CT, in comparison to the waitlist control group. However, there were no significant correlations between enhanced MMN and cognitive/psychosocial outcomes. Conclusions: Results from this preliminary investigation indicate that CT is associated with enhanced neurophysiological mechanisms suggestive of improved pre-attentive processing, which may reflect alterations in underlying neurobiology. Further research is warranted to confirm these findings, to explicate whether CT is associated with restorative or compensatory neuroplastic processes and to determine whether MMN is a useful biomarker for treatment response. © 2014 - IOS Press and the authors. All rights reserved.

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.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.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.

Evidence shows that there are reductions in gray matter volume (GMV) and changes in long association white matter fibres within the left insula-temporoparietal junction (TPJ) during the early stages of psychotic disorders but less is known about short association fibres (sAFs). In this study we sought to characterise the changes in sAFs and associated volumetric changes of the left insula-TPJ during the early stages of psychosis. Magnetic resonance imaging was obtained from a sample of young people with psychosis (n = 42) and healthy controls (n = 45), and cortical parcellations of the left insula-TPJ were used as seeding masks to reconstruct 13 sAFs. Compared to healthy counterparts, the psychosis group showed significant reductions in fractional anisotropy (FA) in the sAFs connecting the superior (STG) and middle temporal gyri (MTG) and as well as reduced GMV within the inferior temporal gyrus and increased white matter volume (WMV) within Heschl's gyrus (HG). Furthermore, adolescent-onset psychosis subjects (onset 18 year or earlier) showed FA reductions in the STG-HG sAF when compared to adult-onset subjects, but this was not associated with changes in GMV nor WMV of the STG or HG. These findings suggest that during the early stages of psychosis, changes in sAFs and associated cortical GMV and WMV appear to occur independently, however age of onset of a psychotic syndrome/disorder influences the pattern of neuroanatomical abnormalities.

Risky alcohol consumption and tobacco smoking is highly prevalent in bipolar disorder (BD) and is associated with increased formation of neural reactive oxygen species. Proton magnetic resonance spectroscopy ((1)H-MRS) is an in vivo imaging modality that allows quantification of glutathione (GSH) concentration, the brains primary antioxidant. Sixty-four patients with BD and 49 controls (18-30 years) completed self-report questionnaires regarding alcohol and tobacco use and underwent (1)H-MRS. Levels of GSH in the hippocampus and anterior cingulate cortex (ACC) were determined. Within-group Pearson's correlations were used to explore the relationship between alcohol use and GSH concentration for BD and controls, covarying for age, gender, family history of alcohol dependence and smoking status. Relationships between GSH and presence/severity of alcohol-induced blackouts were determined using Spearman's correlations. In BD, reduced hippocampal-GSH associated with higher alcohol use (R = -0.489, p

The Transitions Study was designed to establish a cohort of young people (12-25 years) seeking help for mental health problems, in order to longitudinally explore and refine a clinical staging model of the development and progression of mental disorders. This paper presents the baseline demographic and clinical characteristics of the cohort, particularly the nature and severity of psychopathology.All eligible young people attending one of four headspace clinical services were invited to participate, and completed a battery of self-report and interviewer-administered measures of psychopathology and functional impairment at baseline, which will be repeated at the annual follow up.Of 1615 eligible clients, 802 young people (66% women; mean age = 18.3 years) consented to participate and completed baseline assessments (participation rate = 50%). The severity of mental health problems varied, with 51% meeting the criteria for probable caseness related to generalized anxiety, 45% presenting with moderate to severe depressive symptoms and over a third experiencing subthreshold psychotic symptomatology. Disordered eating (32%) and problematic tobacco (56%), cannabis (30%) and alcohol (38%) use also affected a significant proportion. Overall, 39% of the cohort were classed as being functionally impaired at baseline.The Transitions Study recruited a heterogeneous cohort at baseline in relation to the nature and severity of mental health problems and levels of functional impairment. The variation in clinical presentations within the cohort, from mild, through moderate to severe levels of psychopathology and impairment, increases the likelihood of the Transitions Study ultimately being able to achieve its aims of empirically testing a clinical staging model for mental disorders.

Background The circadian abnormality of delayed sleep phase has been suggested to characterise a subgroup of depressed young adults with different risk factors and course of illness. We aim to assess the prevalence and factors, particularly substance use, associated with such delay in a large help-seeking cohort of young people with mental health problems. Methods From a consecutively recruited sample of 802 help-seeking young people, 305 (38%) had at least moderate depressive symptoms (QIDS-C16 >10), sleep data and did not have a chronic severe mental illness. Demographic and clinical characteristics were evaluated through self report and clinical interview. Delayed sleep phase was defined as a sleep onset between the hours of 02:00 a.m. – 06:00 a.m. and the characteristics of this group were compared to normal phase sleepers. Results Delayed sleep onset was reported amongst 18% (n = 56/305) of the depressed group compared to 11% of the non-depressed young people. Amongst the depressed group, delayed sleep onset was associated with tobacco, alcohol and cannabis misuse and short sleep duration (x̅: 5.8 hrs vs. x̅: 7.8 hrs). There were no differences in demographic factors, personality traits or symptoms. Tobacco smoking was very common: In logistic regression analyses only tobacco use (OR 2.28, 95% CI: 1.04 - 5.01) was associated with delayed sleep onset. There was no interaction with age. Conclusions Delayed sleep onset was twice as common in depressed young people as the general population and young people with other mental health problems, and is a potential marker for a subgroup of mood disorders. Those with delayed sleep onset were not more severely depressed but had short sleep duration, a risk for chronic psychological ill health, and higher levels of tobacco use. Nicotine use was common in this group, has biological evidence as a sleep disrupter, and requires specifically addressing in this population.

Emotional processing has been reported to effect sensory gating as measured by the event-related potential known as P50. Because both P50 and emotional processing are dysfunctional in bipolar disorder (BD), we sought to investigate the impact that concurrent emotional processing has on sensory gating in this psychiatric population. P50 was recorded using a paired-click paradigm. Peak-to-peak amplitudes for stimulus 1 (S1) and stimulus 2 (S2) were acquired during the presentation of disgust and neutral faces to young adults with BD (n = 19) and controls (n = 20). Social functioning and quality-of-life self-reported measures were also obtained. The BD group had significantly larger P50 amplitudes elicited by the S2-disgust response compared with controls, but no significant difference in overall P50 sensory gating was found between the groups. There were also no differences between groups in S1-disgust or in either of the neutral P50 amplitudes. The BD group showed significant associations between sensory gating to disgust and measures of social functioning. Importantly, BD showed impaired filtering of auditory information when paired with an emotionally salient image. Thus, it appears that patients with the greatest impairment in sensory gating also have the most difficulty engaging in social situations.

Background Distress and/or dysfunction are well established as key reasons for help-seeking. We explore the characteristics of groups defined by high or low distress or disability in young people with unipolar depression (UP) or bipolar disorder (BD). Methods Individuals aged 12 to 25 years presenting to youth mental health services for the first time with a primary diagnosis of UP or BD were assessed using the Kessler Psychological Distress Scale (Kessler-10) and the Work and Social Adjustment Scale (WSAS). Four groups with high or low distress or impairment were defined (according to scores above or below the group medians for the Kessler-10 and WSAS). Multinomial logistic regression (MNLR) was used to examine how cases with high levels of distress and disability (reference group) differed from the other three groups. Results and discussion The sample comprised 1,746 cases (90% UP, 56% female) with a median age of 17.5 years. Median scores on the Kessler-10 and WSAS were both high (30 and 20, respectively) and were significantly inter-correlated (r = 0.62); the high impairment/distress group was the largest sub-group (39% of cases). The MNLR analysis demonstrated that younger age was associated with lower impairment groups (irrespective of distress level), whilst male gender was associated with lower distress (irrespective of impairment). Compared to the low impairment/distress cases, the high impairment/distress group was significantly more likely to use cannabis and/or alcohol. Age, substance use and possibly gender are probably better predictors of distress/impairment sub-group than mood disorder sub-type in youth.

Background Clinical staging of mental disorders proposes that individuals can be assessed at various sub-syndromal and later developed phases of illness. As an adjunctive rating, it may complement traditional diagnostic silo-based approaches. In this study, we sought to determine the relationships between clinical stage and neuropsychological profile in young persons presenting to youth-focused mental health services. Methods Neuropsychological testing of 194 help-seeking young people (mean age 22.6 years, 52% female) and 50 healthy controls. Clinical staging rated 94 persons as having an ‘attenuated syndrome’ (stage 1b) and 100 with a discrete or persistent disorder (stage 2/3). Results The discrete disorder group (stage 2/3) showed the most impaired neuropsychological profile, with the earlier stage (1b) group showing an intermediate profile, compared to controls. Greatest impairments were seen in verbal memory and executive functioning. To address potential confounds created by ‘diagnosis’, profiles for those with a mood syndrome or disorder but not psychosis were also examined and the neuropsychological impairments for the stage 2/3 group remained. Conclusions The degree of neuropsychological impairment in young persons with mental disorders appears to discriminate those with attenuated syndromes from those with a discrete disorder, independent of diagnostic status and current symptoms. Our findings suggest that neuropsychological assessment is a critical aspect of clinical evaluation of young patients at the early stages of a major psychiatric illness.

Background People in midlife with established psychosis or bipolar disorder exhibit patterns of cortical thinning across several brain regions. It is unclear whether these patterns are indicative of a continuously active pathological process, residual effects of an earlier illness phase or pre-illness onset developmental risk factors. Here, we investigated whether cortical thinning is evident in younger patients in the early phase of psychosis or bipolar disorder and the relationship between cortical thinning and neurocognitive performance in young people. Methods Magnetic resonance imaging was obtained from a sample of young patients with psychosis (n = 40; mean age 23.5 years), bipolar disorder (n = 73; mean age 21.9 years) or controls (n = 49; mean age 24.2 years). Group differences in cortical thickness were assessed using statistical difference maps, and regions of cortical thinning were correlated with medication dosage and performance on neurocognitive tasks. As initial comparisons using multiple corrections found no differences between the groups, follow-up analysis with a significance threshold of p < 0.001 was performed. Results and discussion As distinct from reported findings in older subjects, young patients with psychosis have less extensive thinning in parietal-temporal areas and do not demonstrate significant thinning in the insula or dorsal lateral prefrontal cortex. Young patients with bipolar disorder exhibit cortical thinning in regions more consistent with those previously reported in paediatric bipolar patients. Although there were some differences in the regions of cortical thinning between the two groups, the shared regions of cortical thinning were correlated with neurocognitive deficits in visual sustained attention, semantic verbal fluency and verbal learning and memory that are commonly reported in young people with either psychosis or bipolar disorder. Electronic supplementary material The online version of this article (doi:10.1186/2194-7511-1-3) contains supplementary material, which is available to authorized users.

Background Alcohol misuse is highly prevalent in bipolar disorder (BD) and has been associated with increased formation of reactive oxygen species in the CNS. Proton magnetic resonance spectroscopy ( 1 H-MRS) is an in vivo tissue-based imaging modality that allows the investigation of changes in the brains primary antioxidant, glutathione (GSH), as a result of alcohol use in this population. Methods Thirty-three patients with BD and 17 controls aged 18–30 years were recruited. Participants completed the Alcohol Use Disorders Identification Test (AUDIT) and underwent 1 H-MRS. Levels of GSH in the anterior cingulate cortex (ACC) were determined. ANOVA was conducted to determine differences between high and low risk drinking bipolar participants and controls. Results ANOVA with all groups revealed a significant difference in GSH between bipolar high and low risk drinkers, with those in the high-risk group displaying reduced GSH levels. A significant negative correlation was found between total AUDIT score and GSH in bipolar ( R =−0.478, p =0.005) which remained significant when controlling for age and medication status. Limitations Our participant sample consisted of a heterogeneous group of patients, most of whom were medicated at time of testing. Conclusions Young people with emerging BD who drink at risky levels display reduced levels of ACC-GSH. Increased oxidative stress and its resulting neurotoxic effects may be especially detrimental in an emerging bipolar sample where the illness trajectory is unclear and the brain is still undergoing significant development.

Objectives To determine the prevalence of recent alcohol, nicotine or cannabis use in young persons presenting for mental healthcare. Design A cross-sectional study of young people seeking mental healthcare completed self-report questionnaires regarding their use of alcohol, nicotine or cannabis. Setting Data were collected from two sites as part of the national headspace services programme. Participants 2122 young people aged 12–30 years provided information as part of a patient register; a subset of N=522 participants also provided more detailed information about their patterns of alcohol use. Outcome measures Prevalence levels of recent alcohol, nicotine or cannabis use within relevant age bands (12–17, 18–19 and 20–30) or primary diagnostic categories. Results The rates for use at least weekly of alcohol for the three age bands were 12%, 39% and 45%, and for cannabis 7%, 14% and 18%, respectively. The rates of daily nicotine use for the three age bands were 23%, 36% and 41%. The pattern of alcohol use was characterised by few abstainers as well as many risky drinkers. Age of onset across all three substances was approximately 15 years. Individuals who used any of the three substances more frequently were likely to be older, male or have psychotic or bipolar disorders. Conclusions Frequent use of alcohol, nicotine or cannabis in young people seeking mental healthcare is common. Given the restricted legal access, the patterns of use in those aged 12–17 years are particularly notable. Reductions in substance use needs to be prioritised within services for at-risk young people.

To determine if disturbed sleep-wake cycle patterns in young people with evolving mental disorder are associated with stages of illness.The sleep-wake cycle was monitored using actigraphy across 4 to 22 days. Participants (21 healthy controls and 154 persons seeking help for mental health problems) were aged between 12 and 30 years. Those persons seeking mental health care were categorized as having mild symptoms (stage 1a), an 'attenuated syndrome' (stage 1b) or an 'established mental disorder' (stage 2+).The proportions of individuals with a delayed weekdays sleep schedule increased progressively across illness stages: 9.5% of controls, 11.1% of stage 1a, 25.6% of stage 1b, and 50.0% of stage 2+ (χ(2) (3 d.f.) = 18.4, P 0.001). A similar pattern was found for weekends (χ(2) (3 d.f.) = 7.6, P = 0.048). Compared with controls, stage 1b participants had later sleep onset on weekends (P = 0.015), and participants at stages 1b and 2+ had later sleep offset on both weekdays and weekends (P 0.020). Compared with controls, all participants with mental disorders had more wake after sleep onset (P 0.029) and those at stages 1a and 2+ had lower sleep efficiency (P 0.040). Older age, medicated status and later weekdays sleep offset were found to be the three strongest correlates of later versus earlier clinical stages.In relation to clinical staging of common mental disorders in young people, the extent of delayed sleep phase is associated with more severe or persistent phases of illness.

International audience; BACKGROUND: After 30 years of consensus-derived diagnostic categories in mental health, it is time to head in new directions. Those categories placed great emphasis on enhanced reliability and the capacity to identify them via standardized checklists. Although this enhanced epidemiology and health services planning, it failed to link broad diagnostic groupings to underlying pathophysiology or specific treatment response. DISCUSSION: It is time to adopt new goals that prioritize the validation of clinical entities and foster alternative strategies to support those goals. The value of new dimensions (notably clinical staging), that are both clinically relevant and directly related to emerging developmental and neurobiological research, is proposed. A strong emphasis on 'reverse translation' (that is, working back from the clinic to the laboratory) underpins these novel approaches. However, it relies on using diagnostic groupings that already have strong evidence of links to specific risk factors or patterns of treatment response. SUMMARY: The strategies described abandon the historical divides between clinical neurology, psychiatry and psychology and adopt the promotion of pathways to illness models.

Antisocial behaviours and psychopathic traits place an individual at risk for criminality, mental illness, substance dependence, and psychosocial dysfunction. Social cognition deficits appear to be associated with psychopathic traits and are believed to contribute to interpersonal dysfunction. Most research investigating the relationship of these traits with social cognition has been conducted either in children or adult forensic settings. We investigated whether psychopathic traits were associated with social cognition in 91 young people presenting for mental healthcare (aged between 15 and 25 years). Participants completed symptom severity measures, neuropsychological tests, the Reading the Mind in the Eyes Test of social cognition (RMET), and the Antisocial Process Screening Device (APSD) to assess psychopathic personality traits. Correlation analyses showed poorer social cognition was associated with greater psychopathic traits (r = −.36, p = .01). Interestingly, social cognition performance predicted unique variance in concurrent psychopathic personality traits above gender, IQ sustained attention, and working memory performance. These findings suggest that social cognitive impairments are associated with psychopathic tendencies in young people presenting for community mental healthcare. Research is needed to establish the directionality of this relationship and to determine whether social cognition training is an effective treatment amongst young people with psychopathic tendencies.

Background Reducing suicidal behaviour is a major public health goal. Expanding access to care has been identified as a key strategy. In Australia, a national network of primary-care based services (headspace) has been established for young people with mental ill-health. This study determines the socio-demographic, psychopathological and illness-stage correlates of suicidal ideation in young persons attending headspace services. Methods Suicidal ideation was recorded using the specific suicide item of the Hamilton Depression Rating Scale (HDRS) in a cohort of subjects aged 12-30 years (N = 494) attending headspace services. Results Of the 494 young persons assessed, 32% (158/494) had a positive response to any level of the HDRS suicide item, consisting of 16% (77/494) reporting that life was not worth living and a further 16% (81/494) reported thoughts of death or suicidal ideation. Young women (19%; 94/494) were more likely to report any positive response as compared with young men (13%; 64/494) [χ2(2,494) = 13.6, p 2(1,347) = 0.0, p = 0.87). However, more serious levels of suicidal ideation were more common in those with depressive disorders or later stages of illness. In multivariate analyses, the major predictors of the degree of suicidal ideation were increasing levels of clinician-rated depressive symptoms (beta = 0.595, p Conclusions Feelings that life is not worth living, thoughts of death or suicidal ideation are common in young people seeking mental health care. These at-risk cognitions are evident before many of these individuals develop severe or persistent mental disorders. Thoughts of death or suicidal ideation may well need to be a primary intervention target in these young people.

To date, most studies of white matter changes in Bipolar Disorder (BD) have been conducted in older subjects and with well-established disorders. Studies of young people who are closer to their illness onset may help to identify core neurobiological characteristics and separate these from consequences of repeated illness episodes or prolonged treatment. Diffusion tensor imaging (DTI) was used to examine white matter microstructural changes in 58 young patients with BD (mean age 23 years; range 16–30 years) and 40 controls. Whole brain voxelwise measures of fractional anisotropy (FA), parallel diffusivity (λ//) and radial diffusivity (λ⊥) were calculated for all subjects. White matter microstructure differences (decreased FA corrected p

This study evaluated the potential of circadian measures as early markers of mood disorders subtypes. Patients with bipolar disorders had significantly lower levels and later onset of melatonin secretion than those with unipolar depression. Furthermore, abnormal phase angles between sleep, melatonin and temperature were found in several patients.

Background Clinical symptoms and neuropsychological deficits are longitudinally associated with functional outcome in chronic psychiatric cohorts. The current study extended these findings to young and early-course psychiatric outpatients, with the aim of identifying cognitive markers that predict later socio-occupational functioning. Methods At baseline, 183 young psychiatric outpatients were assessed. Ninety-three returned for follow-up (M = 21.6 years old; SD = 4.5) with an average re-assessment interval of 21.6 months (SD = 7.0), and primary diagnoses of major depressive disorder (n = 34), bipolar disorder (n = 29), or psychosis (n = 30). The primary outcome measure was cross-validated with various other functional measures and structural equation modelling was used to map out the interrelationships between predictors and later functional outcome. Results Good socio-occupational functioning at follow-up was associated with better quality of life, less disability, current employment and being in a romantic relationship. The final structural equation model explained 47.5% of the variability in functional outcome at follow-up, with baseline neuropsychological functioning (a composite of memory, working memory and attentional switching) the best independent predictor of later functional outcome. Notably, depressive and negative symptoms were only associated with functioning cross-sectionally. Diagnosis at follow-up was not associated with functional outcome. Conclusions Neuropsychological functioning was the single best predictor of later socio-occupational outcome among young psychiatric outpatients. Therefore, framing psychiatric disorders along a neuropsychological continuum is likely to be more useful in predicting functional trajectory than traditional symptom-based classification systems. The current findings also have implications for early intervention utilising cognitive remediation approaches.

Oxidative stress has recently been reported to assume a significant role in the pathophysiology of bipolar disorder. Several studies have demonstrated the replenishment of glutathione (GSH) diminishes oxidative cellular damage and ameliorates depressive symptoms in this disorder. Whilst the mechanism by which GSH exerts any clinical effect is unknown it has been proposed that it involves the bolstering of antioxidant defences by increasing the bioavailability of GSH, which in turn reverses clinical symptoms of depression. Such a proposal is predicated on the implicit assumption that GSH is diminished in these patients prior to GSH supplementation. However hitherto no study has reported in vivo measures of GSH in patients with bipolar disorder. Using magnetic resonance spectroscopy we obtained in vivo measures of GSH in young people with bipolar disorder and contrasted these with matched healthy controls. Young people with bipolar disorder were found to have no diminution in baseline GSH concentration and, furthermore, no significant correlations were found between GSH and clinical scores of depression or mania. The results do not support the hypothesis that oxidative stress is involved in the primary pathophysiology of bipolar disorder.

article i nfo Emotion Recognition Depression Anxiety Previous research has suggested that psychotic symptoms are associated with impairments in social cogni- tion. However, there is limited research evaluating this association in the context of younger patients with a broad range of mental health problems. In the present study, we evaluated social cognitive performance in 115 treatment-seeking participants who presented to a youth mental health service with affective or psy- chotic disturbances. Participants completed symptom severity measures, a social cognition task (the Reading the Mind in the Eyes Test (RMET)), and a standardised battery of neuropsychological tests. Analyses based on diagnostic groups showed that patients with psychotic illnesses (n = 23) showed impaired performance on the RMET compared to patients with primarily bipolar (n = 40) and depressive illnesses (n = 52). Perfor- mance on the RMET was negatively correlated with positive and negative psychotic symptoms, but not affec- tive and anxiety symptoms. Performance on the RMET also was the strongest concurrent predictor of positive psychotic symptoms in a regression model that also included predicted intelligence, demographic variables, and neurocognition. RMET performance did not, however, predict negative symptoms above tests of sustained attention and verbal learning, nor was performance associated with any other symptoms of mental illness. Social cognitive impairments may provide a valuable marker for the presence of positive psychotic symptoms in young people with mental illness. Additionally, these impairments may have a role in the aetiology and maintenance of psychotic symptoms. Research is now needed to establish the nature of the re- lationship between social cognition and psychotic symptoms across different facets of social cognition. Re- search is also needed to investigate whether targeted social cognition treatments reduce risk for the development of positive psychotic symptoms.

For many young people, binge drinking is the most common form of alcohol misuse, particularly in those with a depressive disorder. Nonetheless, relatively little is known about the effects that the combination of depression and binge drinking has on neuropsychological outcomes. This study aimed to determine whether binge drinkers with depression show more pronounced neuropsychological dysfunction compared to their peers with depression alone or binge drinking alone. Neuropsychological testing was conducted on help-seeking young people (18-30 years) recently diagnosed with a depressive disorder and classified as either 'binge drinkers' (n=43) or 'non-bingers' (n=48). Two healthy control groups (i.e. binge drinkers, n=24 and non-bingers, n=21) were additionally recruited and also underwent the same testing. Qualitatively, binge-drinking patients with depression performed consistently below controls, depression alone, or binge drinking alone. In keeping with our hypotheses, visual learning and memory was significantly reduced in depressed binge drinkers, whereas mental flexibility was reduced at a trend level. There were no significant differences in neuropsychological performance in depressed alone or binge drinking alone individuals compared to controls. The findings suggest that when treating young people with a depressive disorder, strategies targeting binge drinking may contribute to preventing potential neurobiological changes underlying poorer long-term clinical outcomes.

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.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.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 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.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.

Little is known about how sex influences functional brain maturation. The current study investigated sex differences in the maturation of event-related potential (ERP) amplitudes during an auditory oddball task (N = 170; age = 6-17 years). Performance improved with age. N200 amplitude declined with age: parietal sites showed earlier development than temporal and frontal locations. Girls showed greater bilateral frontal P300 amplitude development, approaching the higher values observed in boys during childhood. After controlling for age, right frontal P300 amplitude was associated with reaction time in girls. The findings demonstrate sex differences in ERP maturation in line with behavioral and neuroimaging studies.

The study aims to apply clinical staging to young people who present for mental health care; to describe the demographic features, patterns of psychological symptoms, disability correlates and clinical stages of those young people; and to report longitudinal estimates of progression from less to more severe stages.The study uses cross-sectional and longitudinal assessments of young people managed in specialized youth clinics. On the basis of clinical records, subjects were assigned to a specific clinical 'stage' (i.e. 'help-seeking', 'attenuated syndrome', 'discrete disorder' or 'persistent or recurrent illness').Young people (n = 209, mean age = 19.9 years (range = 12-30 years), 48% female) were selected from a broader cohort of n = 1483 subjects. Ten percent were assigned to the earliest 'help-seeking' stage, 54% to the 'attenuated syndrome' stage, 25% to the 'discrete disorder' stage and 11% to the later 'persistent or recurrent illness' stage. The interrater reliability of independent ratings at baseline was acceptable (κ = 0.71). Subjects assigned to the 'attenuated syndrome' stage reported symptom and disability scores that were similar to those assigned to later stages. Longitudinally (median = 48 weeks), transition to later clinical stages were 11% of the 'help-seeking', 19% of the 'attenuated syndrome' and 33% of the 'discrete disorder' groups.Among young people presenting for mental health care, most are clinically staged as having 'attenuated syndromes'. Despite access to specialized treatment, a significant number progress to more severe or persistent disorders.

Circadian disturbances may play a key role in the pathogenesis of some forms of mood disorders. Despite marked changes in circadian rhythms during the normal course of adolescence and young adulthood, less is known about changes in the 24-h sleep-wake cycle in young persons with mood disorders.Seventy-five young participants with mood disorders (unipolar: n=46, 20.1 ± 4.7 years old; bipolar I or II: n=29, 23.2 ± 4.3) and 20 healthy participants (24.8 ± 2.5 years old) underwent actigraphy monitoring during a depressive phase over seven consecutive days and nights. Sleep phase delay was defined as mean sleep onset ≥ 1:30 am and/or sleep offset ≥ 1 0:00 am.A delayed sleep phase was found in 62% of participants with bipolar disorders when depressed, compared with 30% of those with unipolar depression (χ(2)=6.0, p=0.014) and 10% of control participants (χ(2)=11.2, p0.001). Sleep offset times were significantly later in subjects with mood disorders compared to the control group, and later in those with bipolar as compared with unipolar disorders (all p ≤ 0.043).This study was cross-sectional and the depressed groups were somewhat younger compared to the healthy controls. Longitudinal studies are required to determine the predictive significance of these findings.Young patients with mood disorders, especially those with bipolar disorders, are particularly likely to have a delayed sleep phase. Therapies focused on advancing sleep phase may be of specific benefit to these young persons.

Historically, brain tumour resection has relied upon standardised anatomical atlases and classical mapping techniques for successful resection. While these have provided adequate results in the past, the emergence of new technologies has heralded a wave of less invasive, patient-specific techniques for the mapping of brain function. Functional magnetic resonance imaging (fMRI) and, more recently, diffusion tensor imaging (DTI) are two such techniques. While fMRI is able to highlight localisation of function within the cortex, DTI represents the only technique able to elucidate white matter structures in vivo. Used in conjunction, both of these techniques provide important presurgical information for thorough preoperative planning, as well as intraoperatively via integration into frameless stereotactic neuronavigational systems. Together, these techniques show great promise for improved neurosurgical outcomes. While further research is required for more widespread clinical validity and acceptance, results from the literature provide a clear road map for future research and development to cement these techniques into the clinical setup of neurosurgical departments globally.

To facilitate early intervention, there is a need to distinguish unipolar versus bipolar illness trajectories in adolescents and young adults with adult-type mood disorders.Detailed clinical and neuropsychological evaluation of 308 young persons (aged 12 to 30 years) with moderately severe unipolar and bipolar affective disorders.Almost 30% (90/308) of young people (mean age=19.4±4.4yr) presenting for care with affective disorders met criteria for a bipolar-type syndrome (26% with bipolar I). Subjects with bipolar- and unipolar-type syndromes were of similar age (19.8 vs. 19.2yr) and reported comparable ages of onset (14.5 vs. 14.3yr). Clinically, those subjects with unipolar and bipolar-type disorders reported similar levels of psychological distress, depressive symptoms, current role impairment, neuropsychological dysfunction and alcohol or other substance misuse. Subjects with unipolar disorders reported more social anxiety (p0.01). Subjects with bipolar disorders were more likely to report a family history of bipolar (21% vs. 11%; [χ(2)=4.0, p.05]) or psychotic (19% vs. 9%; [χ(2)=5.5, p.05]), or substance misuse (35% vs. 23%; [χ(2)=3.9, p.05]), but not depressive (48% vs. 53%; χ(2)=0.3, p=.582]) disorders.Young subjects with bipolar disorders were best discriminated by a family history of bipolar, psychotic or substance use disorders. Early in the course of illness, clinical features of depression, or neuropsychological function, do not readily differentiate the two illness trajectories.

Mild cognitive impairment (MCI) refers to a transitory state between healthy aging and dementia. Biomarkers are needed to facilitate early identification of MCI and predict progression to dementia. One potential neurophysiological biomarker, mismatch negativity (MMN), is an event-related potential reflecting fundamental, pre-attentive cognitive processes. MMN is reduced in normal aging and dementia and in neuropsychiatric samples and is associated with verbal memory deficits and poor executive functioning. This study aimed to investigate auditory MMN and its relationship to neuropsychological performance in MCI. Twenty-eight MCI participants and fourteen controls, aged ≥50 years, underwent neurophysiological and neuropsychological assessment, and completed questionnaires pertaining to disability. Relative to controls, the MCI group demonstrated reduced temporal MMN amplitude (p < 0.01). Reduced right temporal MMN was significantly associated with poorer verbal learning (r = 0.496; p < 0.01) and reduced left temporal MMN was significantly associated with increased self-reported disability (r = -0.419; p < 0.05). These results indicate that patients with MCI exhibit altered pre-attentive information processing, which in turn is associated with memory and psychosocial deficits. These findings overall suggest that MMN may be a viable neurophysiological biomarker of underlying disease in this 'at risk' group.

While the profiling of subtypes of Attention Deficit Hyperactivity Disorder (AD/HD) have been the subject of considerable scrutiny, both psychometrically and psychophysiologically, little attention has been paid to the effect of diagnoses comorbid with AD/HD on such profiles. This is despite the greater than 80% prevalence of comorbidity under the DSM-IV-TR diagnostic definitions. Here we investigate the event related potential (ERP) and psychometric profiles of Controls, AD/HD, and comorbid AD/HD (particularly AD/HD+ODD/CD) groups on six neurocognitive tasks thought to probe the constructs of selective and sustained attention, response inhibition and executive function. Data from 29 parameters extracted from a child group (age range 6 to 12; 52 Controls and 64 AD/HD) and from an adolescent group (age range 13 to 17; 79 Controls and 88 AD/HD) were reduced via a Principal Components Analysis, the 6 significant eigenvectors then used as determinants of cluster membership via a Two-Step Cluster Analysis. Two clusters were found in the analysis of the adolescent age group - a cluster dominated by Control and AD/HD participants without comorbidity, while the second cluster was dominated by AD/HD participants with externalising comorbidity (largely oppositional defiant/conduct disorder ODD/CD). A similar segregation within the child age group was not found. Further analysis of these objectively determined clusters in terms of their clinical diagnoses indicates a significant effect of ODD/CD comorbidity on a concurrent AD/HD diagnosis. We conclude that comorbid externalising behaviour in AD/HD constitutes a distinct pathological entity in adolescence. Refereed/Peer-reviewed

Cannabis use is prevalent among the early psychosis (EP) population. The event-related potentials, mismatch negativity (MMN) and P3a are reduced in EP. Cannabinoids have been shown to modulate N-methyl-D-aspartate receptors which are involved in MMN generation.This study is the first to investigate the effects of cannabis use on MMN/P3a in EP.EP was defined as a history of psychosis or psychotic symptoms with no progression to date to chronic schizophrenia. Twenty-two EP patients with cannabis use (EP + CANN), 22 non-cannabis-using EP patients (EP-CANN) and 21 healthy controls participated in this study. MMN/P3a was elicited using a two-tone, auditory paradigm with 8% duration deviants.As expected, EP-CANN showed marked reductions in MMN/P3a amplitudes compared to controls. However, EP + CANN showed evidence of a different pattern of neurophysiological expression of MMN/P3a compared to non-using patients, most notably in terms of delayed frontal MMN/P3a latencies.This study provides further evidence that MMN/P3a deficits are present during early psychosis and suggests that this biomarker may have utility in differentiating substance- from non-substance-related psychoses.

Classically, disorders associated with ‘alcohol-related brain damage’ (ARBD) occur as a result of chronic excessive alcohol misuse and confer significant physical and psychological disability to the individual as well as to the community. These phenotypes are often difficult to detect at early stages and therefore early intervention and treatment is limited. It remains unresolved as to whether there are neurobiological markers of the early stages of such brain damage in young ‘at-risk’ drinkers, who probably experience ‘alcohol-induced brain impairment’ prior to the onset of ARBD, per se. This review focuses on neurobiological (in particular, neuropsychological and neuroimaging) markers that are associated with alcohol misuse in young people (13–24 years of age). The findings from this review suggest that a clearer understanding of alcohol misuse (particularly with regards to binge drinking) is needed. Despite this, neurocognitive profile along with supporting neuroimaging evidence appears to be particularly important in the early detection of brain changes that result from excessive alcohol use. In young alcohol misusers, these preventable and potentially reversible deficits may be progressive but if left unresolved such deficits eventually become major contributors to poor outcome (long term) and hamper adherence to treatment. We address five key themes in this review: (i) there are specific drinking patterns in young people; (ii) youth represents a critical period in brain development that is particularly vulnerable to alcohol misuse; (iii) the extent to which there are pre-existing versus alcohol-induced neurobiological changes remains unclear; (iv) vulnerability markers may be mediated by mental health and substance use comorbidities; and (v) cognitive remediation would be a likely candidate for early prevention and treatment as it could help to develop efficient meta-cognitive skills to prevent relapse in young drinkers.

Mismatch negativity (MMN) is a neurophysiological indicator of the brain's ability to extract relevant information from an irrelevant background. MMN has been described as a reliable biomarker of schizophrenia and more recently it has found to be impaired in the early stages of psychosis. In addition, drugs (including alcohol) that block glutamate's N-methyl-D-aspartate receptor have been shown to reduce MMN. This study aims to determine whether risky alcohol consumption in young patients with psychotic disorder further impacts or changes their MMN response. Patients with high-alcohol use were found to show reduced temporal MMN amplitudes compared with patients with low-alcohol use and controls. In contrast, early psychosis patients with low-alcohol use showed reduced fronto-central MMN amplitudes compared with controls; whereas patients with high-alcohol use showed an intermediate response at these sites. Correlational analysis revealed distinct patterns of association between MMN and alcohol use in patients with early psychosis compared with controls. This study shows that early psychosis outpatients who engaged in risky drinking have decreased temporal MMN amplitudes, compared with their peers. This may reflect an additive effect of N-methyl-D-aspartate receptor hypofunction and high-alcohol consumption. Language: en

Depression in older people has been consistently linked with a variety of neurobiological brain changes. One measure of preattentive auditory processing, the mismatch negativity (MMN), has not been previously examined in late-life depression. This study examined MMN elicited by duration deviant stimuli in older people with lifetime depression, and explored its relationship with neuropsychological functioning and disability.Twenty-two older health-seeking patients (mean age=65.2 years) with lifetime major depressive disorder and twelve age and sex-matched control participants (mean age=64.6 years) completed detailed clinical and neuropsychological assessments and the WHO-DAS as a measure of disability. MMN amplitudes were elicited using a two-tone passive auditory oddball paradigm and measured at frontal (Fz), central (Cz) and temporal (left and right mastoid: M1 and M2, respectively) sites.Patients with depression demonstrated reduced mean MMN amplitude at temporal (M1, t=3.1, p0.01; M2, t=3.8, p0.01), but not fronto-central sites. Reduced temporal MMN amplitudes did not relate to depressive symptom severity, but were associated with reduced semantic fluency and greater self-rated functional disability.The contribution of depressive symptom 'state' and medications on MMN need to be considered.Reduced mean amplitudes of mastoid MMN in older patients with lifetime depression may reflect underlying brain changes. This preattentive marker relates to neuropsychological probes of frontotemporal circuits, and importantly, is associated with disability. Longitudinal analysis of MMN in this group will determine its predictive utility as a biomarker for ongoing cognitive decline and illness chronicity.

The study aims to compare social functioning in young people considered to be at risk of psychosis with those meeting criteria for first episode psychosis (FEP) and controls, and to determine the association between social functioning and positive and negative symptoms, depressive symptoms, and social anxiety.This study examined social functioning in 20 individuals at risk of psychosis, 20 FEP patients and 20 healthy controls. Social functioning was measured using the Social Functioning Scale and World Health Organization Disability Assessment Scale. Psychiatric variables were also measured using the Comprehensive Assessment of At-Risk Mental States, the Brief Psychiatric Rating Scale, the Brief Social Phobia Scale, and the Depression Anxiety and Stress Scale.At-risk individuals had comparable social deficits to the FEP group, and both patient groups had significantly poorer social functioning than controls. Importantly, social functioning was most strongly associated with depressive and social anxiety symptoms and to a lesser extent with positive symptoms. However, negative symptoms did not appear to relate to social functioning.Social functioning impairments precede the onset of full-threshold psychosis and may therefore be a significant marker for the illness. Additionally, associated psychiatric symptoms such as depression and social anxiety may provide an avenue for early interventions of social functioning deficits in psychosis.

Early stages of affective or psychotic disorders may be accompanied by neuropsychological changes that help to predict risk of developing more severe disorders. A comprehensive set of neuropsychological measures was collected in 109 help-seeking young people (16 to 30 years; 54 females), recently diagnosed with an affective or psychotic disorder and presenting with current depression. Hierarchical cluster analysis determined three clusters: one deemed to have a “poor memory” profile (n = 40); another with a “poor mental flexibility” profile (n = 38) and a third with widespread difficulties plus “impaired attention and memory” (n = 31). In general, the three clusters were comparable in demographic, functional and clinical factors suggesting some unique role for neurocognitive impairments. A discriminant function analysis confirmed that the clusters were best characterized by performance in “attentional” versus “learning/memory” measures. Furthermore, profiles of independent neuropsychological variables validated the original solution for two of the clusters, distinguishing all cluster-groups on an attentional measure. The findings of this study suggest that despite presenting with very similar levels of current depressive symptomatology, young help-seeking individuals in the early stages of illness have underlying neuropsychological heterogeneity. Distinct neuropsychological profiling may help to predict later psychiatric outcomes and enhance individually-tailored early intervention strategies. (JINS, 2011, 17, 267–276)

Background Reduced mismatch negativity (MMN) and P3a amplitudes are neurophysiological biomarkers for schizophrenia that index deviance detection and the orienting response, respectively. First-episode psychosis (FEP) patients show reduced amplitudes of the ‘MMN/P3a complex’, but it is unclear whether this occurs across the FEP spectrum. Methods Fifty-three young people (17–36 years) were assessed: 17 FEP affective-spectrum (bipolar disorder with psychotic features and major depressive disorder with psychotic features), 18 FEP schizophrenia-spectrum (schizophrenia, schizoaffective disorder, and schizophreniform disorder), and 18 healthy controls. MMN/P3a was acquired during a two-tone, auditory paradigm with 8% duration deviants. Clinical, psychosocial and neuropsychological assessments were also undertaken. Results FEP schizophrenia- and FEP affective-spectrum showed significantly reduced fronto-central MMN and central P3a amplitudes compared to controls. FEP subgroups also showed significantly poorer cognitive and psychosocial functioning. The combined FEP sample showed significant correlations between fronto-central MMN amplitudes and cognitive measures. Discussion FEP schizophrenia-spectrum and FEP affective-spectrum were similarly impaired in two biomarkers for schizophrenia. FEP subgroups showed impairments in fronto-central MMN consistent with chronic patients. Similarly, both subgroups showed reductions in P3a; although the affective subgroup showed an ‘intermediate’ frontal response. These findings suggest that FEP patients with both affective and schizophrenia spectrum diagnoses share common neurobiological disturbances in deviance detection/orienting processes in the early phase of illness.

Background The ACTION study (Attention deficit hyperactivity disorder Controlled Trial Investigation Of a Non-stimulant) is a multi-center, double-blind, randomized cross-over trial of the non-stimulant medication, Atomoxetine, in children and adolescents with attention deficit hyperactivity disorder (ADHD). The primary aims are to examine the efficacy of atomoxetine for improving cognition and emotional function in ADHD and whether any improvements in these outcomes are more pronounced in participants with comorbid anxiety; and to determine if changes in these outcomes after atomoxetine are more reliable than changes in diagnostic symptoms of ADHD. This manuscript will describe the methodology and rationale for the ACTION study. Methods Children and adolescents aged 6 - 17 y with ADHD will be enrolled. Clinical interview and validated scales will be used to confirm diagnosis and screen for exclusion criteria, which include concurrent stimulant use, and comorbid psychiatric or neurological conditions other than anxiety. Three assessment sessions will be conducted over the 13-week study period: Session 1 (Baseline, pre-treatment), Session 2 (six weeks, atomoxetine or placebo), and Session 3 (13 weeks, cross-over after one-week washout period). The standardized touch-screen battery, "IntegNeuro™", will be used to assess cognitive and emotional function. The primary measure of response will be symptom ratings, while quality of life will be a secondary outcome. Logistic regression will be used to determine predictors of treatment response, while repeated measures of analysis will determine any differences in effect of atomoxetine and placebo. Results The methodology for the ACTION study has been detailed. Conclusions The ACTION study is the first controlled trial to investigate the efficacy of atomoxetine using objective cognitive and emotional function markers, and whether these objective measures predict outcomes with atomoxetine in ADHD with and without comorbid anxiety. First enrollment was in March 2008. The outcomes of this study will be a significant step towards a 'personalized medicine' (and therefore a more efficient) approach to ADHD treatment. Trial registration Australian and New Zealand Clinical Trials Registry ANZCTRN12607000535471.

Early stages of severe mood disorders may be accompanied by neurocognitive changes. Specifically, deficits in verbal memory have been linked to depression in young people. This study examined whether young adults with unipolar compared with bipolar depression showed similar neurocognitive deficits.A total of 57 young adults (16-32 years) were assessed in this study. Twenty with unipolar and 20 with bipolar depression, all currently depressed, were compared with 17 healthy controls. Neuropsychological assessment included psychomotor speed, attention for routine mental operations, attentional switching, executive control and verbal learning and memory.Both unipolar and bipolar subjects showed significant impairments in verbal memory and attentional switching compared with controls. Both mood disorder groups showed no impairments in psychomotor speed, attention for routine mental operations and executive control. Effects size calculations show that the unipolar and bipolar groups do not differ from each other across a range of neurocognitive measures.Neurocognitive deficits in young adults with current depressive syndromes appear to differ from those typically seen in older patients. In early adulthood, both unipolar and bipolar depression may be distinguished by poor verbal memory, despite intact speed of processing, attention and executive functions. This study suggests that there is utility in neuropsychological testing for young adults in the early stages of severe mood disorders. In order to prevent neurobiological changes inherent to the disease, pharmacological and non-pharmacological interventions that target verbal memory deficits may be optimally delivered early in the disease course.

Chronic cannabis use has been related to deficits in cognition (particularly memory) and the normal functioning of brain structures sensitive to cannabinoids. There is increasing evidence that conflict monitoring and resolution processes (i.e. the ability to detect and respond to change) may be affected.This study examined the ability to inhibit an automatic reading response in order to activate a more difficult naming response (i.e. conflict resolution) in a variant of the discrete trial Stroop colour-naming task.Event-related brain potentials to neutral, congruent and incongruent trials were compared between 21 cannabis users (mean 16.4 years of near daily use) in the unintoxicated state and 19 non-using controls.Cannabis users showed increased errors on colour-incongruent trials (e.g. "RED" printed in blue ink) but no performance differences from controls on colour congruent (e.g. "RED" printed in red ink) or neutral trials (e.g. "*****" printed in green ink). Poorer incongruent trial performance was predicted by an earlier age of onset of regular cannabis use. Users showed altered expression of a late sustained potential related to conflict resolution, evident by opposite patterns of activity between trial types at midline and central sites, and altered relationships between neurophysiological and behavioural outcome measures not evident in the control group.These findings indicate that chronic use of cannabis may impair the brain's ability to respond optimally in the presence of events that require conflict resolution and hold implications for the ability to refrain from substance misuse and/or maintain substance abstention behaviours.

The endogenous cannabinoid system is sensitive to the introduction of exogenous cannabinoids such as delta-9-tetrahydrocannabinol, which are known to impact upon memory functioning. We sought to examine the impact of chronic cannabis use upon memory-related brain function via examination of the subsequent memory effect (SME) of the event-related potential (ERP). The SME is predictive of recall outcome and originates in structures that are dense with cannabinoid receptors (hippocampus and parahippocampus). The SME and performance on a verbal memory task were compared between 24 cannabis users (mean 17 years of near daily use) in the unintoxicated state and 24 non-using controls. The task involved the presentation of word lists, each with a short delay before recall. ERPs were recorded during encoding and later averaged by outcome (correctly recalled/not recalled). Cannabis users showed poorer recall and altered patterns of SME activation: specifically, attenuation of the negative N4 and an increase in the late positive component. Duration of cannabis use and age of initial use correlated significantly with SME amplitudes. A longer history of use also correlated with greater recall that was related to N4 expression. The results indicate that relative to non-using controls, chronic users of cannabis have altered memory-related brain activation in the form of dysfunctional SME production and/or poorer neural efficiency, which is associated with deficits in memory recall. Greater alteration was associated with a longer history of cannabis use and an earlier onset of use. Neuroadaptation to the effects of chronic exposure may additionally play a role.

Objective Novelty and routinization-related information processing disturbances were examined in adolescent males with ADHD using an oddball paradigm and electrophysiological measurement of theta (4–7 Hz) activity. Methods Fifty-four unmedicated adolescent males (12–18 years) with Attention Deficit Hyperactivity Disorder (ADHD) and matched controls performed an auditory oddball task. Theta activity was sub-averaged, and Fourier Integrals with simultaneous measurement of electrodermal activity (EDA) was used to index response to stimulus novelty and routinization. Results ADHD participants showed an overall increase in theta activity to both novel and routine stimuli relative to controls. While controls showed increased theta activity in response to novel compared to routine targets across the brain, ADHD participants did not show this novelty-related increase in theta activity in the right anterior/frontal brain. Conclusions The findings of this study are consistent with disturbances in theta activity and the brain substrates of novelty relative to routinization-related processing in ADHD. Significance These findings show that there are distinct alterations in theta activity related to stimulus novelty and routinization during an auditory oddball task in ADHD, and they highlight the value of using an event-related approach to elucidate the neural substrates of stimulus processing in ADHD.

Measures of cognition support diagnostic and treatment decisions in attention deficit hyperactivity disorder. We used an integrative neuroscience framework to assess cognition and associated brain-function correlates in large attention deficit hyperactivity disorder and healthy groups. Matched groups of 175 attention deficit hyperactivity disorder children/adolescents and 175 healthy control subjects were assessed clinically, with the touch screen-based cognitive assessment battery "IntegNeuro" (Brain Resource Ltd., Sydney, Australia) and the "LabNeuro" (Brain Resource Ltd., Sydney, Australia) platform for psychophysiologic recordings of brain function and body arousal. IntegNeuro continuous performance task measures of sustained attention classified 68% of attention deficit hyperactivity disorder patients with 76% specificity, consistent with previous reports. Our additional cognitive measures of impulsivity, intrusive errors, inhibition, and response variability improved sensitivity to 88%, and specificity to 91%. Positive predictive power was 96%, and negative predictive power, 88%. These metrics were stable across attention deficit hyperactivity disorder subtypes and age. Consistent with their brain-based validity, cognitive measures were correlated with corresponding brain-function and body-arousal measures. We propose a combination of candidate cognitive "markers" that define a signature for attention deficit hyperactivity disorder: "sustained attention," "impulsivity," "inhibition," "intrusions," and "response variability." These markers offer a frame of reference to support diagnostic and treatment decisions, and an objective benchmark for monitoring outcomes of interventions.

Attentional impairment in depression is a cardinal feature of depression and has been proposed as a candidate endophenotype for major depressive disorder. Event‐related potentials (ERPs) elicited by oddball signal detection tasks provide objective markers of selective stimulus processing, and are pertinent endophenotypic markers for depression. While previous studies have sought to determine objective markers for attentional impairment in depression, evidence is inconsistent and may involve heterogeneity in relatively small samples. Here, we brought together oddball ERP recording with source localization of neural correlates of selective attention in outpatients with major depressive disorder (MDD; n = 78) and participants with depressed mood (PDM; n = 127) relative to healthy controls (CTL; n = 116). The key finding was a dimensional exaggeration of the P200 (140–270 ms) to both target (signal) and non‐target (noise) stimuli, most pronounced in MDD, followed by PDM, relative to CTL. This exaggeration was coupled with slower and more variable response times, suggesting that neural systems are attempting to compensate for a difficulty in discriminating signal from noise. P200 alterations were localised to limbic (hippocampal), temporal and ventral prefrontal regions, key components of the signal detection network. A subsequent reduction and delay in the P300 was also revealed for MDD indicating that the pronounced lack of discrimination in clinical depression may also lead to impaired stimulus evaluation. This P200 increase in depression could provide a potential mechanism for the attentional impairment frequently observed in depression and consequent alterations in the P300 may differentiate clinically significant depression. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.