Florian Daniel Zepf

Diminished Serotonergic Functioning in Hostile Children with ADHD: Tryptophan Depletion Increases Behavioural Inhibition

INTRODUCTION Serotonergic (5-HT) functioning has been shown to account for a variety of behavioural characteristics, in particular aggressive and impulsive behaviour. This study explored the effects of rapid tryptophan depletion (RTD) and the ensuing reduction of brain 5-HT synthesis on behavioural inhibition in passive avoidance learning assessed in a computerized go/no-go task. METHODS 22 male patients with an ICD-10 diagnosis of ADHD were administered RTD within an amino acid drink lacking tryptophan, the natural precursor of 5-HT, thus lowering the central nervous 5-HT synthesis rate in a placebo-controlled double-blind within-subject crossover-design. 4 hours after RTD/placebo intake the patients were subjected to a go/no-go task for assessment of behavioural inhibition. RESULTS Highly hostile aggressive patients showed increased inhibition errors under RTD compared to placebo. Low hostile aggressive patients showed lower rates of inhibition errors and thus better performance under RTD compared to placebo. DISCUSSION The data suggest that in ADHD levels of trait-aggressive characteristics influence the susceptibility to changed behavioural inhibition after an acute 5-HT dysfunction. The detected influence of 5-HT could also be relevant as regards behavioural inhibition being subject to a developmental change in 5-HT functioning.

Bipolar disorder in children and adolescents in Germany: national trends in the rates of inpatients, 2000-2007

OBJECTIVES Increasing admission and prevalence rates of bipolar disorder (BD) are a matter of controversy in international child and adolescent psychiatry. We seek to contribute to this discussion by presenting data obtained in a population of German children and adolescents. METHODS Nationwide, whole population changes in inpatient admissions of BD and other psychiatric disorders between 2000 and 2007 were analyzed in individuals aged up to 19 years using registry data from the German Federal Health Monitoring System. RESULTS Inpatient admissions for BD in individuals aged up to 19 years increased from 1.13 to 1.91 per 100,000 or 68.5% between 2000 and 2007 (odds ratio: 1.69; 95% confidence interval: 1.41-2.02), with a nonsignificant decline in children less than 15 years and the largest relative increase in adolescents aged 15-19 years. Inpatient rates for depressive disorders increased by 219.6% and for hyperkinetic disorder by 111.3%. Conduct disorders increased by 18.1%, considerably less than the 38.1% general rise for all mental disorders in children and adolescents. The only significant decline in a diagnostic category occurred for psychotic disorders (-11.8%). BD inpatient admission represented only 0.22% of all mental disorder admissions in 2000 and 0.27% in 2007. CONCLUSIONS An elevation of inpatient admissions of BD in Germany in adolescents was detected, exceeding the general trend for increased mental disorder admissions. The results may indicate a higher clinical awareness and appreciation of mood symptoms at earlier ages and, in part, a reconceptualization of previously diagnosed psychotic disorders in youth. However, a diagnosis of BD in youngsters is still extremely rare in Germany. Diagnoses were based on the judgment of the treating physician. A correction for multiple admissions in the data set is not possible.

Effects of acute tryptophan depletion on brain serotonin function and concentrations of dopamine and norepinephrine in C57BL/6J and BALB/cJ mice.

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.

Diminished 5-HT functioning in CBCL pediatric bipolar disorder-profiled ADHD patients versus normal ADHD: susceptibility to rapid tryptophan depletion influences reaction time performance†‡

There is a current debate on characterizing children with pediatric bipolar disorder (PBD) through a profile within the child behaviour checklist (CBCL), and on the involvement of the 5‐HT system in the underlying neurobiological processes of PBD. The aim of the present paper was to investigate reaction time performance in patients with CBCL‐PBD and to discriminate ADHD from ADHD with CBCL‐PBD with respect to diminished 5‐HT functioning and reaction time.

Influence of rapid tryptophan depletion on laboratory-provoked aggression in children with ADHD.

Background: The present study investigated the effects of rapid tryptophan depletion (RTD), and the ensuing reduction of central nervous system levels of serotonin (5-HT), upon reactive aggression in patients with attention deficit/hyperactivity disorder (ADHD). Furthermore, it was asked whether the relation between 5-HT function and behavioural aggression in patients is influenced by their age, the intensity of their attention problems or their comorbid symptoms. Methods: The study employed a double-blind, within-subject crossover design. On day 1, 22 male adolescent patients with ADHD were subjected to RTD and the subsequent reduction of central 5-HT levels. On day 2, they received a tryptophan-balanced amino acid mixture (BAL), which acted as a placebo. On both days, 4.5 h after the intake of the RTD/BAL amino acids, reactive aggressive behaviour was provoked using a competitive reaction time game, which consisted of both high and low provocation conditions. Results: The number of aggressive responses was significantly higher after low provocation during acute tryptophan depletion, in comparison to the placebo. Furthermore, this study provides evidence that neither age nor the intensity of attention symptoms in ADHD patients had an impact on the relation between 5-HT and reactive aggression. Conclusion: This study indicates that in children with ADHD, there is an inverse relationship between 5-HT and aggression.

Effects of tryptophan depletion on reactive aggression and aggressive decision‐making in young people with ADHD

Kötting WF, Bubenzer S, Helmbold K, Eisert A, Gaber TJ, Zepf FD. Effects of tryptophan depletion on reactive aggression and aggressive decision‐making in young people with ADHD.

The impact of acute tryptophan depletion on attentional performance in adult patients with ADHD.

To date, the impact of the neurotransmitter serotonin (5‐HT) on different neuropsychological functions in adults with attention deficit hyperactivity disorder (ADHD) is underinvestigated. We aimed to examine the effects of acute tryptophan depletion (ATD) and the resulting reduction in central nervous 5‐HT synthesis on target/non‐target discrimination ability and sustained attention in adults with ADHD using an AX‐Continuous Performance Test (AX‐CPT).

Social reinforcement can regulate localized brain activity

Social learning is essential for adaptive behavior in humans. Neurofeedback based on functional magnetic resonance imaging (fMRI) trains control over localized brain activity. It can disentangle learning processes at the neural level and thus investigate the mechanisms of operant conditioning with explicit social reinforcers. In a pilot study, a computer-generated face provided a positive feedback (smiling) when activity in the anterior cingulate cortex (ACC) increased and gradually returned to a neutral expression when the activity dropped. One female volunteer without previous experience in fMRI underwent training based on a social reinforcer. Directly before and after the neurofeedback runs, neural responses to a cognitive interference task (Simon task) were recorded. We observed a significant increase in activity within ACC during the neurofeedback blocks, correspondent with the a-priori defined anatomical region of interest. In the course of the neurofeedback training, the subject learned to regulate ACC activity and could maintain the control even without direct feedback. Moreover, ACC was activated significantly stronger during Simon task after the neurofeedback training when compared to before. Localized brain activity can be controlled by social reward. The increased ACC activity transferred to a cognitive task with the potential to reduce cognitive interference. Systematic studies are required to explore long-term effects on social behavior and clinical applications.

The Effects of Acute Tryptophan Depletion on Reactive Aggression in Adults with Attention-Deficit/Hyperactivity Disorder (ADHD) and Healthy Controls

Background The 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 Findings Twenty 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/Significance Together 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.

Reduced serotonergic functioning changes heart rate in ADHD.

Reduced mean heart rate (HR) was shown to be a biophysiological marker for aggression, which in turn was proven to be related to changed serotonergic neurotransmission. A total of 16 ADHD-diagnosed boys were subjected to rapid tryptophan depletion (RTD) and a placebo in a double-blind within-subject crossover-design. Mean HR was assessed under RTD/placebo. Low impulsive patients behaving aggressively under RTD showed a lowered HR under RTD versus placebo. Diminished 5-HT functioning was associated with lowered HR and aggressive behaviour.