Functional connectivity of the vigilant-attention network in children and adolescents with attention-deficit/hyperactivity disorder.

The ability to maintain attention to simple tasks (i.e., vigilant attention, VA) is often impaired in attention-deficit/hyperactivity disorder (ADHD), but the underlying pathophysiological mechanisms at the brain network level are not clear yet. We therefore investigated ADHD-related differences in resting-state functional connectivity within a meta-analytically defined brain network of 14 distinct regions subserving VA (comprising 91 connections in total), as well as the association of connectivity with markers of behavioural dysfunction in 17 children (age range: 9-14 years) with a diagnosis of ADHD and 21 age-matched neurotypical controls. Our analyses revealed selective, rather than global, differences in the intrinsic coupling between nodes of the VA-related brain network in children with ADHD, relative to controls. In particular, ADHD patients showed substantially diminished intrinsic coupling for 7 connections and increased coupling for 4 connections, with many differences involving connectivity with the anterior insula. Moreover, connectivity strength of several aberrant connections was found to be associated with core aspects of ADHD symptomatology, such as poor attention, difficulties with social functioning, and impaired cognitive control, attesting to the behavioural relevance of specific connectivity differences observed in the resting state.

Atypical Antipsychotic Prescribing in Australian Children and Adolescents: A Survey of Medical Practitioners.

OBJECTIVE: Prescriptions for atypical antipsychotics in children and adolescents are increasing globally. However, a precise understanding of the clinical variables and evidence that prescribers consider before using these agents is lacking. While empirical literature on the long-term safety and efficacy of these medications is available, the literature concerning their use in these younger age groups is relatively sparse. In this study, we examined the current prescribing patterns of medical professionals employed by a public health service in Australia. METHODS: A survey examining their current practice when prescribing atypical antipsychotics to children and adolescents was completed by 103 physicians. Questions were asked about commonly prescribed atypical antipsychotics, indications, dose ranges, target symptoms, duration of treatment, and the evidence base(s) used when making treatment decisions. RESULTS: Physicians prescribed atypical antipsychotics for a wide range of indications in this age group, with the most common agents being risperidone, quetiapine, and olanzapine. Adverse effects were reported as the main reason for treatment discontinuation. More than half of the respondents indicated that the most common source of guidance/evidence they referred to when initiating prescriptions were peers or expert opinion. CONCLUSIONS: Children and adolescents were prescribed a number of atypical antipsychotics for a variety of indications, with variable perceived confidence and a relatively heavy reliance on "own or peer experience" as opposed to good quality evidence. Challenges exist for both prescribers and policymakers, and further "head-to-head" studies are needed in this age group to ensure that a balance is maintained between therapeutic benefit and safety.

Implication of saturated fats in the aetiology of childhood attention deficit/hyperactivity disorder - A narrative review.

Attention Deficit/Hyperactivity Disorder (ADHD) is the most common mental health disorder in the paediatric population. ADHD is highly comorbid with obesity, and has also been associated with poor dietary patterns such as increased consumption of refined carbohydrates and saturated fats. Although ADHD in children was associated with high consumption of saturated fats, so far there has been no evidence-based attempt to integrate dietary strategies controlling for intake of saturated fats into the etiological framework of the disorder. Evidence from human studies and animal models has shown that diets high in saturated fats are detrimental for the development of dopaminergic neurocircuitries, synthesis of neurofactors (e.g. brain derived neurotrophic factor) and may promote brain inflammatory processes. Notably, animal models provide evidence that early life consumption of a high saturated fats diet may impair the development of central dopamine pathways. In the present paper, we review the impact of high saturated fats diets on neurobiological processes in human studies and animal models, and how these associations may be relevant to the neuropathophysiology of ADHD in children. The validation of this relationship and its underlying mechanisms through future investigative studies could have implications for the prevention or exacerbation of ADHD symptoms, improve the understanding of the pathogenesis of the disorder, and help design future dietary studies in patients with ADHD.

Acute Tryptophan Depletion Moja-De: A Method to Study Central Nervous Serotonin Function in Children and Adolescents.

Serotonin (5-HT) is widely implicated as a key neurotransmitter relevant to a range of psychiatric disorders and psychological processes. The role of central nervous 5-HT function underlying these processes can be examined through serotonergic challenge methodologies. Acute tryptophan depletion (ATD) is a key challenge method whereby a diminished dietary intake of tryptophan-the amino acid precursor to brain 5-HT synthesis-results in temporary diminished central nervous 5-HT synthesis. While this particular methodology has been used in adult populations, it was only recently that modifications were made to enable the use of ATD in child and adolescent populations. Additionally, the Moja-De modification of the ATD challenge methodology has demonstrated benefits over other ATD techniques used previously. The aim of this protocol paper is to describe the ATD Moja-De methodology in detail, its benefits, as well as studies that have been conducted to validate the procedure in child and adolescent samples. The ATD Moja-De protocol provides a potential methodology for investigating the role of central nervous 5-HT via manipulation of brain tryptophan availability in human psychopathology from a developmental viewpoint.

No detectable effects of acute tryptophan depletion on short-term immune system cytokine levels in healthy adults.

Objectives: Recent research suggested an influence of diminished central nervous serotonin (5-HT) synthesis on the leptin axis via immunological mechanisms in healthy adult females. However, studies assessing immunological parameters in combination with dietary challenge techniques that impact brain 5-HT synthesis in humans are lacking. Methods: In the present trial, a pilot analysis was conducted on data obtained in healthy adult humans receiving either different dietary acute tryptophan depletion (ATD) challenge or tryptophan (TRP)-balanced control conditions (BAL) to study the effects of reduced central nervous 5-HT synthesis on serum tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 concentrations. The data of N = 35 healthy adults were analysed who were randomly subjected to one of the following two dietary conditions in a double-blind between-subject approach: (1) The Moja-De ATD challenge (ATD), or (2) TRP-balanced control condition for ATD Moja-De (BAL). Serum concentrations for the assessment of relevant parameters (TNF-α, IL-1ß and IL-6) and relevant TRP-related characteristics after the respective challenge procedures were assessed at baseline (T0) and in hourly intervals after administration over a period of 6 h (T1-T6). Results: The ATD condition did not result in significant changes to cytokine concentrations for the entire study sample, or in male and female subgroups. Depletion of CNS 5-HT via dietary TRP depletion appears to have no statistically significant short-term impact on cytokine concentrations in healthy adults. Conclusions: Future research on immunological stressors in combination with challenge techniques will be of value in order to further disentangle the complex interplay between brain 5-HT synthesis and immunological pathways.

Concurrent developmental course of sleep problems and emotional/behavioral problems in childhood and adolescence as reflected by the dysregulation profile.

OBJECTIVES: Longitudinal data on the course and relationship of concurrent psychopathology in youth are scarce but are of need for better practical patient care and prevention. This study explores the course of (and relationships over time) between sleep problems and concurrent dimensional difficulties relating to anxiety/depression, attention deficiency, and aggressive behaviors in childhood and adolescence. The latter three may jointly form a broad syndrome, the dysregulation profile. METHODS: Young people from the Raine Study, a large community cohort sample (N = 1625) were followed from age 5 to 17 years. Developmental courses of sleep problems and its concurrent regulatory difficulties were estimated separately and jointly. RESULTS: The majority of adolescents reported low levels of problems and which appeared to be stable over time, while a small group (rates between 7.8% and 10.1%) reported enduring problematic developmental courses. Sleep problems and regulatory difficulties shared a strong association in their development over time (individual's probabilities of having the same courses, i.e. low-low and high-high, were between 89.8% and 92.3%). Furthermore, having persistent sleep problems over time was associated with an increased risk of having regulatory difficulties by approximately 10 times, and vice versa. CONCLUSION: Findings from this study provide empirical evidence for a strong mutual association in the development of sleep problems and difficulties of dysregulation with emotion, cognition, and aggression. It may be suggested that a positive screening of one such psychopathological dimension should lead to a careful assessment, not only to reduce the problem in question but also to prevent the youth from further problems.

Using acute tryptophan depletion to investigate predictors of treatment response in adolescents with major depressive disorder: study protocol for a randomised controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are amongst the most prescribed antidepressants for adolescents with depressive symptoms and major depressive disorder. However, SSRIs have significant shortcomings as a first-line treatment considering that not all patients respond to these antidepressants. Amongst paediatric populations, meta-analyses indicate that up to approximately 40% of patients do not respond, and for those who do show benefit, there is substantial heterogeneity in response onset. The neurotransmitter serotonin (5-HT) plays a role in the clinical effectiveness and mechanisms of action of SSRIs. However, the exact and complete mechanism of action and reasons for the low response rate to SSRIs in some adolescent populations remains unknown. METHODS: To examine SSRI response and the role of 5-HT, this study will employ a randomised double-blind within subject, repeated measures design, recruiting adolescent patients with major depressive disorder. Participants will be subjected to acute tryptophan depletion (ATD) and the balanced control condition on two separate study days within a first study phase (Phase A), and the order in which these conditions (ATD/balanced control condition) occur will be random. This phase will be followed by Phase B, where participants will receive open label pharmacological treatment as usual with the SSRI fluoxetine and followed-up over a 12-week period. DISCUSSION: ATD is a neurodietary method typically used to investigate the impact of lowered brain 5-HT synthesis on mood and behaviour. The major hypothesis of this study is that ATD will be negatively associated with mood and cognitive functioning, therefore reflecting individual serotonergic sensitivity and related depressive symptoms. Additionally, we expect the aforementioned effects of ATD administration on mood to predict clinical improvement with regard to overall depressive symptomatology 12 weeks into SSRI treatment. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTR) ACTRN12616001561471 . Registered on 11 November 2016.

Effects of Dietary Acute Tryptophan Depletion (ATD) on NPY Serum Levels in Healthy Adult Humans Whilst Controlling for Methionine Supply-A Pilot Study.

Central nervous serotonin (5-HT) can influence behaviour and neuropsychiatric disorders. Evidence from animal models suggest that lowered levels of neuropeptide Y (NPY) may have similar effects, although it is currently unknown whether decreased central nervous 5-HT impact NPY concentrations. Given that the production of NPY is dependent on the essential amino acid methionine (MET), it is imperative to account for the presence of MET in such investigations. Hence, this study sought to examine the effects of acute tryptophan depletion (ATD; a dietary procedure that temporarily lowers central nervous 5-HT synthesis) on serum concentrations of NPY, whilst using the potential renal acid load indicator (PRAL) to control for levels of MET. In a double-blind repeated measures design, 24 adult humans randomly received an AA-load lacking in TRP (ATD) on one occasion, and a balanced control mixture with TRP (BAL) on a second occasion, both with a PRAL of nearly 47.3 mEq of MET. Blood samples were obtained at 90, 180, and 240 min after each of the AA challenges. ATD, and therefore, diminished substrate availability for brain 5-HT synthesis did not lead to significant changes in serum NPY concentrations over time, compared to BAL, under an acute acidotic stimulus.

Nitrous oxide (N2O) and subsequent open-label SSRI treatment of adolescents with depression (NOTAD): study protocol for a randomised controlled trial.

BACKGROUND: The first line of pharmacological treatment for severe depressive disorders in young people is selective serotonin reuptake inhibitors (SSRIs). However, beneficial clinical effects are rarely observed before several weeks into treatment. Nitrous oxide (N2O) has a long-standing safety record for pain relief and has been used in adults and young people. In adults with severe treatment-resistant depression, a single dose of N2O had significant antidepressant effects, with maximum antidepressant effects observed 24 h after administration. However, the antidepressant effects of N2O have never been investigated in adolescents with a confirmed diagnosis of depression in a prospective trial. The aims of this study are to (1) investigate whether a single inhaled N2O administration leads to antidepressant effects in adolescents with depression at 24 h, (2) determine whether combined N2O and SSRI administration (commenced after N2O intervention) provides a clinically significant improvement in mood over and above the benefits from SSRI administration alone, and, (3) investigate whether the effect seen following N2O administration can be used as a predictor of SSRI treatment response. METHODS/DESIGN: In this study, we will use a single-blind, randomised, placebo-controlled design. Patients aged between 12 and 17 years with major depressive disorder will be recruited. This study will consist of two phases: phase A and phase B. During phase A, participants will be randomised to receive either inhaled N2O or placebo (air) for 1 h. In phase B, participants will receive open-label pharmacological treatment with the SSRI fluoxetine and will be followed over a 12-week period. Participants will undertake mood assessments at 2 and 24 h after N2O or placebo administration (phase A) and weekly during the 12-week follow up in phase B. DISCUSSION: We expect an antidepressant effect from a single dose of inhaled N2O compared with placebo at 24 h after administration. Additionally, we expect that subjects treated with N2O will also show greater improvements than the placebo group after 6 and 12 weeks into fluoxetine treatment because of potential additive antidepressant effects. Such findings would be of clinical importance because currently children and adolescents often do not experience any symptom alleviation for several weeks following the initiation of SSRIs. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12616001568404 . Registered on 14 November 2016.

Bipolar disorder in children and adolescents: diagnostic inpatient rates from 2000 to 2013 in Germany.

BACKGROUND: Despite growing consensus on nosology and epidemiology of bipolar disorder (BD) in minors, differences remain. We contribute to this discussion by measuring long-term trends in the inpatient discharge rates of BD in minors. METHODS: Nationwide German inpatient discharge diagnoses of BD and other related psychiatric disorders were mapped between 2008 and 2013 using registry data from the German Federal Health Monitoring System. This was compared with previously published data, 2000-2007, to assess long-term trends in diagnosis of BD at discharge. Long-term trends (2000-2013) were also computed. RESULTS: Discharge diagnosis of BD increased by 18% (2.02-2.46 per 100,000) in minors. There was a significant increase of 24.1% in adolescents 15-19 years old (6.56-8.14 per 100,000). BD, at discharge, as a proportion of all psychiatric disorders, increased from 0.26% in 2008 to 0.27% in 2013. When analysing long-term trends (2000-2013), the rates for BD increased significantly as did trends for all mental disorders, except for psychotic disorders, which fell by almost 14%. Between 2000 and 2013, the rate for depression in minors increased by 730%. LIMITATIONS: The dataset consisted of cross-sectional administrative data points with diagnoses based on clinical criteria. CONCLUSIONS: The rate of BD as a discharge diagnosis in German minors has increased significantly, consistently exceeding the general trend for a rise in rates for mental disorders. Overall, the rate of discharge diagnosis of BD from inpatient units in Germany remains a small proportion of all psychiatric diagnoses.