Pradeep Rao

Human breast milk and adipokines - A potential role for the soluble leptin receptor (sOb-R) in the regulation of infant energy intake and development

Concentrations of different adipokines in human breast milk are thought to be able to affect energy intake of the infant. Leptin is a hormone synthesized by adipose tissue and the human placenta and favors satiety. The availability of leptin in breast milk is influenced by epithelial cells of the mammary gland that are known to be able to produce leptin, as well as leptin from maternal circulation that is transported to the breast milk, and which can thus in turn reach neonatal blood after absorption. Research so far as mainly focused on leptin concentrations in breast milk. However, evidence suggests that in addition to leptin concentrations levels of the so-called soluble leptin receptor (sOb-R), the main high-affinity binding protein for leptin in humans, are necessary in order to calculate the free leptin index (FLI) and to assess function of the leptin axis. FLI is calculated from the ratio of leptin to the sOb-R, and serves as the main parameter for assessing function of the leptin axis throughout maturation and development. Here we propose that assessing sOb-R levels in addition to leptin concentrations in breast milk could serve as a valuable tool to investigate effects of the leptin axis in breast milk because sOb-R concentrations can impact available leptin levels, and which in turn can have significant implications for infant energy intake and related development.

Disruptive mood dysregulation disorder in ICD-11: a new disorder or ODD with a specifier for chronic irritability?

important aspect in the light of the ongoing discussion on DMDD and ODD. ODD as a diagnostic category has been around for many years, but DMDD as a diagnosis is new. However, this does not mean that ODD is either correct or ideal as a diagnostic category, and that it does not need any further revision. Indeed, there may yet be unintentional benefits of the controversy over DMDD. There is reason to believe the current conceptualisation of ODD conflates two commonly co-occurring but distinct phenotypes, irritability and noncompliance/oppositional behaviours. Studied as distinct phenomena, these constructs, respectively, show prospective associations with depressive/anxiety problems, and with conduct disorder and ADHD [3–5]. We believe that these findings suggest that both the disorders, DMDD and ODD, require an equal amount of scrutiny as diagnostic categories as regards their validity. Another relevant related area is the issue of hierarchy in diagnosis. As the authors have pointed out, DSM-5 mandates a preferential diagnosis of DMDD over ODD, when features of both are deemed to be present. This could, potentially, be construed as meaning that DMDD is a more severe form of ODD. But there are no empirical data, to date, to suggest that this is the case. Further research is therefore needed to clarify constructs that constitute valid individual diagnostic categories as well as potential overlap between categories. At this stage it is not possible to determine in advance which of the different views on this important clinical topic is correct. As reflected in the US National Institute of Mental Health Research Domain Criteria Initiative, a close examination of particular constructs in mental illness may fruitfully inform better taxonomies and diagnoses [6]. We believe the controversy over DMDD, and in particular its phenotypic overlap with ODD, may be an impetus for a To the Editor,

No detectable effects of Acute Tryptophan Depletion on Short-Term Immune System Cytokine Levels in Healthy Adults

Abstract 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-1β (IL-1β) 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-1β 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.

Differences in serum zinc levels in acutely ill and remitted adolescents and young adults with bulimia nervosa in comparison with healthy controls – a cross-sectional pilot study

Background Research has implicated that changes in zinc (Zn) metabolism may be associated with the biological underpinnings of eating disorders, in particular anorexia nervosa. However, to date research on the role of Zn in patients with bulimia nervosa (BN) is scarce. Objective We aimed to explore serum Zn concentrations in young patients with BN, with a focus on the stage of the disorder, comparing acutely ill and recovered patients with BN with healthy controls. Methods Serum Zn concentrations were obtained from healthy controls and from acutely ill and remitted young patients with BN. Mean duration of remission was 4.0±3.5 years. Results Remitted patients showed elevated serum Zn concentrations when compared to controls (Cohen’s d=2.022), but concentrations were still in the normal range. Acutely ill patients also had higher serum Zn levels when compared to controls (all values still being within the reference range, Cohen’s d=0.882). There was no difference between acutely ill and remitted patients with BN in serum Zn concentrations. Of note, remitted patients had a significantly higher body weight when compared to the other two groups. Overall, there were no significant differences in dietary preferences with regard to Zn containing foods between the groups. Conclusion The present study provides preliminary evidence that the underlying factors for changes in Zn serum concentrations in young patients with BN do not vary with regard to the stage of illness (acute versus remitted BN). Further prospective research is needed in order to disentangle the possible interplay between serum Zn status and bulimic eating behaviors.

Atypical antipsychotic prescribing patterns amongst Child and Adolescent Mental Health Services clinicians in a defined National Health Service Trust

Background In the last decade, the prescription of atypical antipsychotics in minors, by all specialists, has increased. The use has been both licensed and ‘off-label’, with the aim of targeting different symptoms and clinical conditions. However, most research around safety and efficacy of these pharmacological agents has been conducted in adults and with repeated calls for such research in minors in vain. Objectives This survey aims to describe current prescribing practices in a ‘real-world’ scenario and to compare the results with existing research to evaluate lessons learnt. Methods The survey consisted of a semi-structured questionnaire that aimed to evaluate the current practices of Child and Adolescent Mental Health Services (CAMHS) prescribers. A total of 31 questionnaires sent out yielded 24 completed returns (77.41%). A literature search yielded articles that described prescribing trends over the last decade. The results from the survey were compared with the existing literature. Results The commonest indication for using atypical antipsychotics in minors was psychosis (75%). Other indications included reduced behavioural control (50%), tic disorders (37.5%), ADHD and anxiety disorders. Atypical antipsychotics were the commonest first-line medications for managing behavioural control with Risperidone (54%) being the most preferred agent. Second-line medications included Quetiapine (7%) and Olanzapine (15%). Doses were lower for managing behavioural control, and atypical antipsychotics were trialled for up to 8 weeks, and with duration of treatment extending up to 9 months. When such medications were used for non-psychotic presentations, most common target symptoms were aggression (85%), agitation (54%) and anxiety (54%). Most prescribers reported peer/expert opinion and their own clinical experience as evidence base for their use and clinical practice. Conclusions In the investigated sample, atypical antipsychotics continue to be used as first-line medications for psychotic and non-psychotic psychiatric presentations in minors, despite an absence of clear evidence comparable to the adult literature, and also despite repeated calls for in-depth research in this particular population. Although the present survey was conducted amongst psychiatrists, this has implications for all prescribers in children and adolescents, regardless of their specialty.

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.

Intensive community treatment and support “Youth Wraparound” service in Western Australia: A case and feasibility study

Multiple services are often needed to address the needs of young people with complex emotional or behavioural needs. The Youth Wraparound model of service aims to provide all health and supportive services from one coordinating agency. While this has been researched overseas, there are currently few examples of this described in the Australian psychiatric context.

Nitrous oxide (N 2 O) and subsequent open-label SSRI treatment of adolescents with depression (NOTAD): study protocol for a randomised controlled trial

BackgroundThe 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/designIn 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.DiscussionWe 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 registrationAustralian and New Zealand Clinical Trials Registry, ACTRN12616001568404. Registered on 14 November 2016.

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

&NA; 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.

Attention-deficit/hyperactivity disorder and the encoding of emotional information

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by difficulties with sustaining attention, motor control, and impulsivity. Although rarely considered central to the disorder, deficits in the encoding of social information have been observed amongst boys with ADHD (and distinct from comorbid problems with aggression) as long ago as the late 1990s (1,2). In their seminal reformulation, Crick and Dodge (3) describe social information processing (SIP) as a cycle of six distinct processes: (i) encoding of cues, (ii) interpretation of cues, (iii) clarification of goals, (iv) response access or construction, (v) response decision, and (vi) behavioural enactment. SIP research has focused predominantly on aggressive children and has shed light on hostile attributions of intent (process ii) and aggressogenic response evaluation and decision-making (RED) processes (4,5). Little attention has been paid to encoding per se and the role of affective information in determining the encoding of social information either with ADHD or neurotypical populations. In the target paper, Kis and his colleagues have shown that—even as adults—people with ADHD can struggle with emotional SIP, in particular, the encoding of affective information derived from prosodic aspects of verbal communication. Moreover, patients with ADHD struggle with anger-signaling information in voices. Affective prosody reflects the emotional aspects of language and includes aspects such as pitch and timbre and is known to be deficient in people with ADHD (4). Affective or emotional aspects of language prevail over semantics where there is dissonance between the two. In other words, how something is said (tone, rhythm, loudness, etc.) has greater impact than the content. If this is then processed poorly either due to inattention or deficient encoding (as possibly is the case in patients with ADHD), there is potential for misinterpretation; this includes misinterpretations well documented under the banner of hostile intent attributions. Despite the wellrecognized social dysfunction in patients with ADHD, there is surprisingly little research to address the important clinical issue of emotional perception or affective prosody in patients with ADHD. The study by Kis et al. published in the current edition of the journal extends previous work indicating that adults with ADHD have trouble identifying prosodic affect cues for semantically incongruent statements (5), and helps to clarify that this deficit in not an artefact of problems with executive functioning. In conjunction with the recent paper by Bisch et al. (6), it also helps to clarify the nature of integrated multimodal processing of affective-laden social information. Unlike Bisch et al., who found no interaction between modality (auditory vs. visual) and group status (ADHD vs. neurotypical [NT] participants), the findings by Kis et al. point to a specific auditory processing deficit for adults with ADHD. As Kis et al. also used the German adaptation of the Florida Affective Battery, in contrast to the study by Bisch et al. (6), we await further studies to determine whether methodological differences account for the SIP findings. These studies represent a reinvigoration of the study of SIP and its role in patients with disruptive behaviour disorders and how this line of inquiry points toward important future directions. Several aspects of research on SIP may have impeded the development of the area. Following the lead of Kenneth Dodge and other pioneers, SIP-related research has been marked by an over-reliance on hypothetical vignettes and explicit self-report; development of more ecologically valid approaches including assessments of real-time and modalityspecific processing of social information has been slow. SIP research has been dominated by examination of interpretation (e.g., ‘why did that happen?’) as reflected by hostile attribution of intent, and response planning (e.g., ‘what would you do next?’), and comparatively little attention has been paid to other steps and to encoding in particular. Further limitations to the development are reflected in the limited conceptual toolbox that focused on hypothetical scenarios without analyses of specific modalities and a failure to interrogate