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Abstract 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.

Background: Acute tryptophan depletion (ATD) is a well-established dietary method in translational brain research used to briefly lower central nervous serotonin (5-hydroxytryptamine (5-HT)) synthesis. A simplified two amino acid ATD formula (ATDPHE/LEU) was developed while reducing the overall amount of amino acids (AAs), with the objective of administration especially in children and adolescents in future studies. Objective: This study investigated tryptophan (TRP) influx rates across the blood-brain barrier (BBB) after dietary ATDPHE/LEU administration relative to the ATD Moja-De protocol that has been established for use in children and adolescents. Design: Seventy-two healthy adults (50% females) were randomized into four groups and administered ATD Moja-De, its TRP-balanced control condition (BAL), ATDPHE/LEU, or its respective control mixture (BALPHE/LEU) in a counterbalanced, double-blind, between-subjects design. Blood samples were collected at baseline and at hourly intervals for 6 h after AA intake. Questionnaires about mood, taste, and challenge tolerance were completed at fixed time points. Results: Both challenge mixtures significantly reduced central nervous TRP influx as calculated by Michaelis–Menten kinetics relative to baseline and the respective control conditions with only mild and comparable side effects. A greater decline in TRP influx over the BBB after ATDPHE/LEU administration when compared with ATD Moja-De was detected without group effects for taste, challenge tolerance, and mood. There was unintended initial short increase in plasma TRP concentrations observed after ATDPHE/LEU intake, and a possible redistribution between free and protein-bound TRP triggered by protein synthesis stimulated by the ingested AAs may account for this finding. Moreover, a decline in TRP influx after BALPHE/LEU administration over a 6-h period was observed, and the large amount of PHE in the BALPHE/LEU mixture may be a possible explanation for this particular phenomenon, which could have led to an unexpected increase in displacement of TRP at the BBB in this control condition. Conclusions: This pilot study provides preliminary evidence for the possibility of lowering TRP influx as calculated by Michaelis–Menten kinetics into the brain by using a simplified ATD protocol in humans. The simplified composition of only two AAs, the lower overall AA amount, and the appropriate tolerance are characteristics of the newly developed ATDPHE/LEU protocol. Future studies focusing on the effects of the ATDPHE/LEU protocol and its respective control condition on CSF 5-HIAA concentrations, as well as neurochemical studies in rodents, are needed to further validate this newly developed AA mixture before definite conclusions about its usability in ATD-related research in humans, its specificity, and additional effects can be made.

Background: The synthesis of the neurotransmitters serotonin (5-HT) and dopamine (DA) in the brain can be directly altered by dietary manipulation of their relevant precursor amino acids (AA). There is evidence that altered serotonergic and dopaminergic neurotransmission are both associated with impaired attentional control. Specifically, phasic alertness is one specific aspect of attention that has been linked to changes in 5-HT and DA availability in different neurocircuitries related to attentional processes. The present study investigated the impact of short-term reductions in central nervous system 5-HT and DA synthesis, which was achieved by dietary depletion of the relevant precursor AA, on phasic alertness in healthy adult volunteers; body weight–adapted dietary tryptophan and phenylalanine–tyrosine depletion (PTD) techniques were used. Methods: The study employed a double-blind between-subject design. Fifty healthy male and female subjects were allocated to three groups in a randomized and counterbalanced manner and received three different dietary challenge conditions: acute tryptophan depletion (ATD, for the depletion of 5-HT; N=16), PTD (for the depletion of DA; N=17), and a balanced AA load (BAL; N=17), which served as a control condition. Three hours after challenge intake (ATD/PTD/BAL), phasic alertness was assessed using a standardized test battery for attentional performance (TAP). Blood samples for AA level analyses were obtained at baseline and 360 min after the challenge intake. Results: Overall, there were no significant differences in phasic alertness for the different challenge conditions. Regarding PTD administration, a positive correlation between the reaction times and the DA-related depletion magnitude was detected via the lower plasma tyrosine levels and the slow reaction times of the first run of the task. In contrast, higher tryptophan concentrations were associated with slower reaction times in the fourth run of the task in the same challenge group. Conclusion: The present study is the first to demonstrate preliminary data that support an association between decreased central nervous system DA synthesis, which was achieved by dietary depletion strategies, and slower reaction times in specific runs of a task designed to assess phasic alertness in healthy adult volunteers; these findings are consistent with previous evidence that links phasic alertness with dopaminergic neurotransmission. A lack of significant differences between the three groups could be due to compensatory mechanisms and the limited sample size, as well as the dietary challenge procedures administered to healthy participants and the strict exclusion criteria used. The potential underlying neurochemical processes related to phasic alertness should be the subject of further investigations.

Introduction: This article presents diagnostic rates for specific mental disorders in a German pediatric inpatient population over a period of 20 years with respect to migration background and socioeconomic status (SES). Methods: Diagnostic data were obtained over a period of 20 years from 8,904 patients who visited a child and adolescent psychiatry mental health service in Germany. Data from 5,985 diagnosed patients (ICD-9 and ICD-10 criteria) were included with respect to gender, migration background, and SES. Results:Migration- and gender-specific effects were found for both periods of assessment. The group of boys with a migration background showed significantly higher rates of reactions to severe stress, adjustment disorders, and posttraumatic stress disorder compared to their male, non-migrant counterparts. Conversely, boys without a migration background showed a significantly higher percentage rate of hyperkinetic disorders than male migrants. Similar results were found for female migrants in the latter assessment period (ICD-10). In addition, female migrants showed lower rates of emotional disorders whose onset occurs in childhood compared to their non-migrant counterparts. Conclusions: Data from this investigation provide preliminary evidence that the prevalence of various psychiatric disorders in children and adolescents is influenced by migration background and SES.

Although the prevalence rates of sleep disorders at different stages of childhood and adolescence have been well established, little is known about the developmental course of general sleep problems. This also holds true for the bidirectional relationship between sleep problems and emotional as well as behavioral difficulties. This longitudinal study investigated the general pattern and the latent trajectory classes of general sleep problems from a large community sample aged 5 to 14 years. In addition, this study examined the predictive value of emotional/behavioral difficulties (i.e., anxiety/depression, attention problems, and aggressive behavior) on sleep problems latent trajectory classes, and vice-versa. Participants (N = 1993) were drawn from a birth cohort of Western Australian children born between 1989 and 1991 who were followed until 14 years of age. Sleep problems were assessed at ages 5, 8, 10, and 14, respectively, whereas anxiety/depression, attention problems, and aggressive behavior were assessed at ages 5 and 17 years. Latent growth curve modeling revealed a decline in an overall pattern of sleep problems during the observed 10-year period. Anxiety/depression was the only baseline factor that predicted the longitudinal course of sleep problems from ages 5 to 14 years, with anxious and depressed participants showing faster decreasing patterns of sleep problems over time than those without anxiety or depression. Growth mixture modeling identified two classes of sleep problem trajectories: Normal Sleepers (89.4%) and Troubled Sleepers (10.6%). Gender was randomly distributed between these groups. Childhood attention problems, aggressive behavior, and the interaction between gender and anxiety/depression were significantly predictive of membership in the group of Troubled Sleepers. Group membership in Troubled Sleepers was associated with higher probability of having attention problems and aggressive behavior in mid-adolescence. Boys and girls with behavioral difficulties, and girls with emotional difficulties were at increased risk of having sleep problems during later childhood and adolescence. Developmental trajectories of sleep problems were also predictive of behavioral difficulties in later life. Findings from this study provide empirical evidence for the heterogeneity of sleep problems and their development, and emphasize the importance of understanding sleep problems and their relationship to children and adolescents’ mental health.

BackgroundThe neurotransmitter serotonin (5-HT) has been linked to the underlying neurobiology of aggressive behavior, particularly with evidence from studies in animals and humans. However, the underlying neurobiology of aggression remains unclear in the context of attention-deficit/hyperactivity disorder (ADHD), a disorder known to be associated with aggression and impulsivity. We investigated the effects of acute tryptophan depletion (ATD), and the resulting diminished central nervous serotonergic neurotransmission, on reactive aggression in healthy controls and adults with ADHD.Methodology/principal findingsTwenty male patients with ADHD and twenty healthy male controls were subjected to ATD with an amino acid (AA) beverage that lacked tryptophan (TRP, the physiological precursor of 5-HT) and a TRP-balanced AA beverage (BAL) in a double-blind, within-subject crossover-study over two study days. We assessed reactive aggression 3.25 hours after ATD/BAL intake using a point-subtraction aggression game (PSAG) in which participants played for points against a fictitious opponent. Point subtraction was taken as a measure for reactive aggression. Lowered rates of reactive aggression were found in the ADHD group under ATD after low provocation (LP), with controls showing the opposite effect. In patients with ADHD, trait-impulsivity was negatively correlated with the ATD effect on reactive aggression after LP. Statistical power was limited due to large standard deviations observed in the data on point subtraction, which may limit the use of this particular paradigm in adults with ADHD.Conclusions/significanceTogether with previous findings, the data provide preliminary evidence of an inverse association between trait-impulsivity and the ATD effect on reactive aggression after LP (as assessed by the PSAG) in patients with ADHD and that this relationship can be found in both adolescents and adults. Because of limited statistical power larger sample sizes are needed to find main effects of ATD/BAL administration on reactive aggression in adults with ADHD.

BACKGROUND: Attentional processes in children play a critical role in daily school demands and accomplishments. Studies on the association of attentional processes with school achievement and age in healthy school children are scarce. The aim of the present study was to identify correlations between dimensions of attentional performance, scholastic achievement and age. METHODOLOGY/PRINCIPAL FINDINGS: An extensive testing battery was used to assess a wide range of attentional dimensions. A principal component analysis revealed three factors that are related to attentional performance (distractibility, lapses of attention, cognitive speed). Age was negatively associated with distractibility, lapses of attention and cognitive speed, indicating that distractibility and lapses of attention decreased with age in healthy children and resulted in lower cognitive speed. CONCLUSIONS/SIGNIFICANCE: Attentional processes in healthy children should be measured in relation to distractibility, lapses of attention and cognitive speed.

Acute tryptophan depletion (ATD) is a method of lowering brain serotonin (5-HT). Administration of large neutral amino acids (LNAA) limits the transport of endogenous tryptophan (TRP) across the blood brain barrier by competition with other LNAAs and subsequently decreases serotonergic neurotransmission. A recent discussion on the specificity and efficacy of the ATD paradigm for inhibition of central nervous 5-HT has arisen. Moreover, side effects such as vomiting and nausea after intake of amino acids (AA) still limit its use. ATD Moja-De is a revised mixture of AAs which is less nauseating than conventional protocols. It has been used in preliminary clinical studies but its effects on central 5-HT mechanisms and other neurotransmitter systems have not been validated in an animal model. We tested ATD Moja-De (TRP-) in two strains of mice: C57BL/6J, and BALB/cJ, which are reported to have impaired 5-HT synthesis and a more anxious phenotype relative to other strains of mice. ATD Moja-De lowered brain TRP, significantly decreased 5-HT synthesis as indexed by 5-HTP levels after decarboxlyase inhibition, and lowered 5-HT and 5-HIAA in both strains of mice, however more so in C57BL/6J than in BALB/cJ. Dopamine and its metabolites as well as norepinephrine were not affected. A balanced (TRP+) control mixture did not raise 5-HT or 5-HIAA. The present findings suggest that ATD Moja-De effectively and specifically suppresses central serotonergic function. These results also demonstrate a strain-specific effect of ATD Moja-De on anxiety-like behavior.