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Serotonin (5-HT) is a neurotransmitter that is thought to play a decisive role in many psychiatric disorders. The present special issue of the journal is composed of a selection of articles using the acute tryptophan depletion (ATD) technique, which is a safe physiological neurodietary method for lowering the synthesis rate of the neurotransmitter 5-HT in the brain. On one hand, studying the effects of a specific neurotransmitter on individuals may be realized by enhancing central nervous system neurotransmission of said neurotransmitter; in the case of 5-HT, administration of selective serotonin reuptake inhibitors (SSRIs) is one method for accomplishing this task. On the other hand, one may also try to draw conclusions about such effects by decreasing the availability of the neurotransmitter and comparing the resulting data with those gathered at a baseline assessment or from a control condition, an approach somewhat reversed from the first method. The aforementioned ATD method relies upon decreased administration of the essential amino acid tryptophan (TRP), the physiological precursor of 5-HT, to achieve a short-term reduction in brain 5-HT synthesis [1, 2]. By assessing changes in behavior [3, 4], physiological parameters [5], brain function [6], and neurochemical properties [2] following ATD administration and comparing the resulting findings to baseline or control conditions, researchers can draw conclusions about the effects of 5-HT on the brain and behavioral characteristics as well as biological variables. In other words, ATD exemplifies the concept of trying to draw conclusions about brain 5-HT function with respect to the effects observed, while subjects are under the influence of a short-term deficit in central nervous system 5-HT synthesis.

In this issue of Acta Psychiatrica Scandinavica, Kötting et al. [7] present data on the effects of a body weight–adapted ATD protocol in young people with attention deficit hyperactivity disorder (ADHD) with respect to aggressive behavior. This is the first published study investigating the effects of ATD on aggressive behavior that included female youths with ADHD. The results describe the differential effects of ATD on aggression in female and male youths with ADHD depending upon levels of provocation. Mette et al. [8] describe significant differences in attentional performance (omission errors) found in adult patients with ADHD and controls while subjected to ATD when compared with a control condition. Moreover, the patients’ reaction times decreased following ATD when compared with the control condition, whereas the opposite effects were observed in the control group. These observations implicate serotonergic neurotransmission in attentional processes in adults with ADHD – a finding of importance with respect to the still not fully understood pathophysiology of ADHD. Grabemann et al. [9] studied the effects of ATD on affective prosody in adult patients with ADHD, but did not find clear evidence supporting an association of 5-HT with impairments in affective prosody in these patients. Instead, difficulties in accurately processing affective prosody in male adults with ADHD may be associated with significant impairments in their ability to inhibit unwanted stimuli and impulses. Another study [10] examined the effects of ATD on verbal declarative memory in young people with ADHD; no clear effects were identified. Despite such non-significant findings, such information is of scientific value, especially considering that the pathophysiology of ADHD is not entirely understood.

Also in this special issue of the journal, van Donkelaar et al. [11] show that changes in central nervous system 5-HT function might not play as important a role as previously thought in acting as a mechanism behind the previously reported ability of phosphodiesterase inhibitors to improve short-term object memory in rats. However, the authors conclude that decreased cerebral blood flow may underlie ATD-induced object memory deficits in rats, most likely due to a decrease in NO synthesis. This hypothesis also has implications for human research and provides a future avenue for more mechanistic follow-up research on this important topic.

Together with previous research, the articles published in this issue show that ATD can be applied not only to different species [1, 2, 8-11] but also to young people [10]; this finding is of particular importance with respect to the developmental trajectory that is frequently observed in and associated with many neuropsychiatric disorders. Consequently, ATD may serve as one of a variety of methods for further disentangling the effects of 5-HT in psychiatric disorders that emerge in childhood or adolescence and follow a developmental trajectory. Moreover, ATD can be used in iterative translational research paradigms because of its effects on rodents and humans. This latter application closely adheres to this journal's newly established emphasis on research articles with clear translational foci, as outlined in Stephen Stahl's editorial [12], with ATD serving as an effective translational research approach for studying central nervous system 5-HT function in different species from a developmental viewpoint.

References

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  2. References
  • 1
    Biskup CS, Sanchez CL, Arrant A, Van Swearingen AE, Kuhn C, Zepf FD. Effects of acute tryptophan depletion on brain serotonin function and concentrations of dopamine and norepinephrine in C57BL/6J and BALB/cJ mice. PLoS ONE 2012;7:e35916.
  • 2
    Dingerkus VL, Gaber TJ, Helmbold K et al. Acute tryptophan depletion in accordance with body weight: influx of amino acids across the blood–brain barrier. J Neural Transm 2012;119:10371045.
  • 3
    Zimmermann M, Grabemann M, Mette C et al. The effects of acute tryptophan depletion on reactive aggression in adults with attention-deficit/hyperactivity disorder (ADHD) and healthy controls. PLoS ONE 2012;7:e32023.
  • 4
    Zepf FD, Stadler C, Demisch L, Schmitt M, Landgraf M, Poustka F. Serotonergic functioning and trait-impulsivity in attention-deficit/hyperactivity-disordered boys (ADHD): influence of rapid tryptophan depletion. Hum Psychopharmacol 2008;23:4351.
  • 5
    Zepf FD, Holtmann M, Stadler C, Wockel L, Poustka F. Reduced serotonergic functioning changes heart rate in ADHD. J Neural Transm 2009;116:105108.
  • 6
    Crockett MJ, Apergis-Schoute A, Herrmann B et al. Serotonin modulates striatal responses to fairness and retaliation in humans. J Neurosci 2013;33:35053513.
  • 7
    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. Acta Psychiatr Scand 2013;128:114123.
  • 8
    Mette C, Zimmermann M, Grabemann M et al. The impact of acute tryptophan depletion on attentional performance in adult patients with ADHD. Acta Psychiatr Scand 2013;128:124132.
  • 9
    Grabemann M, Mette C, Zimmermann M et al. No clear effects of acute tryptophan depletion on processing affective prosody in male adults with ADHD. Acta Psychiatr Scand 2013;128:142148.
  • 10
    Zepf FD, Landgraf M, Biskup CS et al. No effect of acute tryptophan depletion on verbal declarative memory in young persons with ADHD. Acta Psychiatr Scand 2013;128:133141.
  • 11
    Van Donkelaar EL, Prickaerts J, Akkerman S, Rutten K, Steinbusch HWM, Blokland A. No effect of acute tryptophan depletion phosphodiesterase inhibition-related improvements of short-term object memory in male Wistar rats. Acta Psychiatr Scand 2013;128:107113.
  • 12
    Stahl SM. Translating from Neuroscience to Psychiatry (and Back-Translating from Psychiatry to Neuroscience). Acta Psychiatr Scand 2013;128:103104.