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

Zepf, Florian Daniel; Holtmann, Martin; Stadler, Christina; Demisch, L.; Schmitt, Marcus; Wöckel, Lars; Poustka, Fritz

doi:10.1055/s-2007-1004593

Cited by 51 publications

(56 citation statements)

References 31 publications

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“…By omitting these influences, we are not suggesting they are unimportant. Each appears to play a significant role in the development of one pathway or another to antisocial behavior (e.g., De Sanctis, Nomura, Newcorn, & Halperin, 2012; Frick & Marsee, 2006; Frick & White, 2008; Lansford, Malone, Dodge, Pettit, & Bates, 2010; Zepf et al, 2008). However, in presenting our model we focus on processes that link specifically to the developmental pathway we describe and/or reduce complexity by limiting the number of levels of analyses and predictors presented.…”

Section: Heterotypic Continuitymentioning

confidence: 99%

Comorbidities and continuities as ontogenic processes: Toward a developmental spectrum model of externalizing psychopathology

2013

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Research on child and adolescent mental health problems has burgeoned since the inaugural issue of Development and Psychopathology was published in 1989. In the quarter century since, static models of psychopathology have been abandoned in favor of transactional models, following the agenda set by editor Dante Cicchetti and other proponents of the discipline. The transactional approach, which has been applied to autism, depression, self-injury, and delinquency, (a) specifies vulnerabilities and risk factors across multiple levels of analysis spanning genes to cultures, (b) identifies multifinal and equifinal pathways to psychopathology, and (c) transcends traditional disciplinary boundaries. However, as noted by Rutter and Sroufe (2000), specific mechanisms of continuity, discontinuity, and comorbidity of psychopathology must be identified if we wish to understand etiology fully. In this article, we present a model of early-onset externalizing behavior in which comorbidities and continuities are viewed as ontogenic processes: products of complex longitudinal transactions between interdependent individual-level vulnerabilities (e.g., genetic, epigenetic, allostatic) and equally interdependent contextual risk factors (e.g., coercive parenting, deviant peer group affiliations, neighborhood criminality). Through interactions across levels of analysis, some individuals traverse along the externalizing spectrum, beginning with heritable trait impulsivity in preschool and ending in antisociality in adulthood. In describing our model, we note that (a) the approach outlined in the DSM to subtyping externalizing disorders continues to obscure developmental pathways to antisociality, (b) molecular genetics studies will likely not identify meaningful subtypes of externalizing disorder, and (c) ontogenic trait approaches to psychopathology are much more likely to advance the discipline in upcoming years.

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Section: Heterotypic Continuitymentioning

confidence: 99%

Comorbidities and continuities as ontogenic processes: Toward a developmental spectrum model of externalizing psychopathology

2013

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“…For example, premature response control ('waiting') on the rat 5-CSRT task and human CPT is influenced by 5-HT receptor manipulations and central 5-HT depletion (Carli et al, 2006;Carli and Samanin, 2000;Dougherty et al, 2007;Harrison et al, 1997;Robinson et al, 2007;Walderhaug et al, 2002Walderhaug et al, , 2008. Furthermore, 5-HT depletion also impaired go/no-go inhibition in rats and hostile aggressive children with ADHD (Harrison et al, 1999;Masaki et al, 2006;Zepf et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Serotonin Depletion Impairs Waiting but not Stop-Signal Reaction Time in Rats: Implications for Theories of the Role of 5-HT in Behavioral Inhibition

Eagle

Lehmann

Theobald

et al. 2008

Neuropsychopharmacol

121

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Central serotonin (5-HT) function is thought to be a critical component of behavioral inhibition and impulse control. However, in recent clinical studies, 5-HT manipulations failed to affect stop-signal reaction time (SSRT), which is a fundamental process in behavioral inhibition. We investigated the effect of central 5-HT depletion (intracerebroventricular 5,7-dihydroxytryptamine) in rats on two aspects of behavioral inhibition, SSRT and 'waiting', using the stop-signal task. 5-HT depletion had no effects on SSRT or any other primary measure on the stop-signal task. However, within the same task, there was a deficit in 'waiting' in 5-HT-depleted rats when they were required to withhold from responding in the terminal element of the stop-signal task for an extended period. D-Amphetamine had dosedependent, but not 5-HT-dependent effects on SSRT. Conversely, the dose that tended to improve, or decrease, SSRT (0.3 mg/kg) impaired the ability to wait, again independently of 5-HT manipulation. These findings suggest that SSRT and 'waiting' are distinct measures of behavioral inhibition, and show that 5-HT is critical for some forms of behavioral inhibition but not others. This has significant implications for the treatment of conditions such as attention deficit and hyperactivity disorder, substance abuse, and affective disorders, in which inhibitory and impulse-control deficits are common.

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“…The neurodietary challenge procedure ATD Moja-De was previously used successfully with children and adolescents and had few side effects due to the administration regimen that adapted dosage to body weight (26, 36–38, 41–44). The dosage per 10 kg of body weight contained L-PHE (1.32 g), L-LEU (1.32 g), L-ILE (0.84 g), L-MET (0.5 g), L-VAL (0.96 g), L-THR (0.6 g), and L-LYS (0.96 g).…”

Section: Methodsmentioning

confidence: 99%

Dietary tryptophan depletion in humans using a simplified two amino acid formula – a pilot study

Linden

Helmbold

Kempf

et al. 2016

Food & Nutrition Research

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BackgroundAcute 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.ObjectiveThis 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.DesignSeventy-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.ResultsBoth 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.ConclusionsThis 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.

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

Cited by 51 publications

References 31 publications

Comorbidities and continuities as ontogenic processes: Toward a developmental spectrum model of externalizing psychopathology

Comorbidities and continuities as ontogenic processes: Toward a developmental spectrum model of externalizing psychopathology

Serotonin Depletion Impairs Waiting but not Stop-Signal Reaction Time in Rats: Implications for Theories of the Role of 5-HT in Behavioral Inhibition

Dietary tryptophan depletion in humans using a simplified two amino acid formula – a pilot study

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