Marco Grabemann

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).

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.

No clear effects of acute tryptophan depletion on processing affective prosody in male adults with ADHD

Adults with attention deficit hyperactivity disorder (ADHD) have difficulties processing affective prosody, and research evidence demonstrates the importance of brain serotonin (5‐HT) in the neurobiology of ADHD. This study aimed to investigate whether diminished brain 5‐HT synthesis, as achieved by acute tryptophan depletion (ATD), can impair the processing of affective prosody in adults with ADHD.

Evaluation of the CAARS Infrequency Index for the Detection of Noncredible ADHD Symptom Report in Adulthood

The reliance on self-reports in detecting noncredible symptom report of attention-deficit/hyperactivity disorder in adulthood (aADHD) has been questioned due to findings showing that symptoms can easily be feigned on self-report scales. In response, Suhr and colleagues developed an infrequency index for the Conners’ Adult ADHD Rating Scale (CII) and provided initial validation for its utility in detecting noncredible symptom report. The aim of this study was to evaluate the utility of the CII in detecting noncredible aADHD symptom report by using a simulation design. Data did not support the validity of the CII for the detection of noncredible aADHD symptoms, as it failed to differentiate instructed malingerers from genuine patients with sufficient accuracy. It is concluded that there is a need for infrequency scales composed of items that were specifically developed to be endorsed infrequently and embedded within valid self-report scales.

Acute tryptophan depletion – converging evidence for decreasing central nervous serotonin synthesis in rodents and humans

We read the comment provided by Simon N. Young (1) on the articles (2–5) in the special issue of Acta Psychiatrica Scandinavica (6) dealing with the acute tryptophan depletion (ATD) methodology with great interest. ATD is a pharmacological method designed to lower central nervous system (CNS) synthesis of the neurotransmitter serotonin (5-HT) for a brief period that can also be used in both adults and young people (7). As 5-HT plays an important role in behavioral inhibition (8– 10) and other important processes in the brain (11–14), ATD is a translational method to study the effects of changes in CNS 5-HT function that has particular value, as discussed at a recent symposium dedicated to the role of 5-HT in psychopathology (7–11, 15). The author of this particular comment expressed concerns that ATD might not always decrease CNS 5-HT synthesis and that the lack of the amino acid histidine (HIS) in the depletion mixtures used might influence the results due to the potential role of 5-HT–histamine interactions in any observed outcome. We appreciate the comments made and would like to address the issues raised, point by point. Young argues that ‘there is no evidence that ATD does always decrease serotonin release (in humans)’. This is contradictory by decades of work in rodents and in humans demonstrating that ATD can decrease 5-HT synthesis and release in rodents and lower 5-HIAA in human CSF (16–19). In one of our laboratories, the acute tryptophan depletion (ATD) protocol termed ‘Moja-De’ has been shown to decrease 5-HT release in rodents (20, 21) and to lower tryptophan (TRP) comparably in humans (22), suggesting that this mixture successfully decreases 5-HT synthesis as postulated. While some experiments (23) fail to detect changes in central 5-HT function after ATD, this is the exception rather than the rule in published studies. The author of this comment was also concerned that there would be regional variations in the inhibition of serotonin function. This is logical and consistent with published data on the effects of Moja-De ATD in mice. Mouse studies indicated that depletion of TRP was comparable across different brain areas but that the extent of decrease in 5-HIAA varied by region (20, 21). Regional release of 5-HT is controlled by a combination of cell firing including regionally selective input, the concentration of 5-HT1b receptors on terminals, the amount of tryptophan hydroxylase, and many other factors (24). However, there is no evidence that 5-HT release happens only in selective regions, but we agree the magnitude of ATD effects on release is likely to vary between regions despite comparable depletion of TRP. As regards potential interactions between 5-HT and histamine, we agree that measurement of histidine after depletion of TRP or any other formula lacking HIS is of interest. Young has questioned the results of ATD experiments in which HIS was not included, stating that ‘histidine is an essential amino acid’. However, the essentiality of this amino acid is not clearly established (25). It has been reported that HIS was not necessary for the maintenance of nitrogen balances in short-term (26, 27). Kriengsunyos et al. (28) observed after a long-term histidine depletion administered to healthy adults that there were no effects on the protein metabolism (urinary nitrogen excretion and nitrogen balance). They suggested that the essentiality of this amino acid in healthy adults is still unclear as there are some components that may serve as sources of HIS, although the data they reported indicate that this amount may not be enough for maintain the HIS pool. The other concern expressed by Young was that effects of ATD could reflect disruption of a histamine–serotonin interaction, as ATD would cause a dramatic decrease in histamine synthesis. This is possible, as it is well established that the neurotransmitter histamine is formed from HIS (29), and histamine turnover seems to occur faster than other biogenic amines, such as norepinephrine or 5-HT (30). Therefore, in the absence of HIS, competition from the amino acid mixtures could indeed lower histamine production. However, neither the control nor the ATD mixture in most studies contains histidine, and so histamine would not be differentially affected by the ATD mixture, but should be comparably depleted in both control and ATD mixtures. Nevertheless, it is possible that some interaction between histamine depletion and 5-HT depletion could have behavioral effects. Unfortunately, no behavioral effects of histamine depletion have been clearly established in the literature. A study by Young and his collaborators of HIS depletion effects on sensory and motor behavior in healthy adults (31) showed that HIS in plasma decreased 20% and the ratio HIS/ΣLNAA decreased 59%, but there were no behavioral effects of this depletion. Finally, we disagree with the statement that ‘the relevance of such animal studies to the far more complex human brain is uncertain’. It is well known that validation of translational methods has allowed modeling many aspects of the neuropsychopathology with the use of appropriate animal models, the majority of them throughout the use of rodents (32, 33). Translation of behavioral findings is challenging, due to limits in extrapolating simple behavioral tasks in rodents to sophisticated behaviors in humans. However, biochemical studies of ATD effects in humans and rodents have shown considerable concordance. For example, our studies in humans (5, 22) have been validated in mice (20, 21), consistent with the field as described above (16–19). As Dr. Young points out, detailed anatomic studies of 5-HT synthesis in the human brain are technologically demanding and rarely conducted. However, the concordance between the dependent measures that can be collected in humans (CSF 5-HIAA for example) and comparable measures in rodents (tissue 5-HIAA content, 5-HT and 5-HIAA content in microdialysate) supports the concordance of findings after ATD in humans. In summary, there is convincing and converging evidence that ATD decreases 5-HT synthesis in the brain in both rodents and humans. Interactions between 5-HT and

No Clear Association between Impaired Short-Term or Working Memory Storage and Time Reproduction Capacity in Adult ADHD Patients

Objective Altered time reproduction is exhibited by patients with adult attention deficit hyperactivity disorder (ADHD). It remains unclear whether memory capacity influences the ability of adults with ADHD to reproduce time intervals. Method We conducted a behavioral study on 30 ADHD patients who were medicated with methylphenidate, 29 unmedicated adult ADHD patients and 32 healthy controls (HCs). We assessed time reproduction using six time intervals (1 s, 4 s, 6 s, 10 s, 24 s and 60 s) and assessed memory performance using the Wechsler memory scale. Results The patients with ADHD exhibited lower memory performance scores than the HCs. No significant differences in the raw scores for any of the time intervals (p > .05), with the exception of the variability at the short time intervals (1 s, 4 s and 6 s) (p < .01), were found between the groups. The overall analyses failed to reveal any significant correlations between time reproduction at any of the time intervals examined in the time reproduction task and working memory performance (p > .05). Conclusion We detected no findings indicating that working memory might influence time reproduction in adult patients with ADHD. Therefore, further studies concerning time reproduction and memory capacity among adult patients with ADHD must be performed to verify and replicate the present findings.

Serum albumin correlates with affective prosody in adult males with attention-deficit hyperactivity disorder

The aim of this study was to determine the relationship between serum albumin, affective prosody, and symptoms of attention-deficit hyperactivity disorder (ADHD) found coincidentally in a recently published study. Here, serum albumin levels were assessed as a covariate. Twenty healthy male adults (controls) and 20 adult male patients with ADHD participated in the study on two study days. Serum albumin levels and performance in an affective prosody task were assessed, and correlations were determined. Serum albumin had a significant correlation with performance on an affective prosody task on both of the 2 study days. The same correlations were not significant in the healthy control group. There was no difference in the serum albumin level between patients with ADHD and healthy controls. The association between serum albumin and affective prosody in adults with ADHD is a novel finding. However, to date, there is no clear theory that explains this association. Future research should analyze whether serum albumin influences causes changes in performance in affective prosody using experimental designs.

Neue Wege in der Diagnostik der ADHS bei Erwachsenen

Objective Diagnosing Attention-Deficit-Hyperactivity Disorder (ADHD) in adults requires that ADHD has already been present in childhood. However, recall of ADHD-symptoms in childhood is fallible, for example influenced by mood. Furthermore, diagnostics need a procedure to handle oblivion and judgment biases. The Essen-Interview-for-school-days-related-biography (EIS-B) addresses these problems and offers a tool for retrospectively diagnosing childhood ADHD in adults. Method 36 patients with ADHD, 27 patients with depression or adjustment disorders and 39 healthy controls were included in the pilot study. All participants were comparable regarding age and gender. Results Internal consistency varied between α = 0.58 and α = 0.97, split-half-reliability was r = 0.98, inter-rater-reliability yielded κ = 0.66. Retest-reliability varied between r = 0.40 and r = 0.88. Sensitivity was 82 %. Specificity yielded 100 %. Discussion The results indicate that EIS-B is a reliable and valid interview to retrospectively elucidate symptoms of childhood ADHD in adult patients. Further studies should aim for replication of our results using a larger sample size.

P03-130 - Effects of a diminished serotonin synthesis on memory and impulsive aggression in adult ADHD

Introduction Numerous results from investigations including children with ADHD show associations between a diminished serotonin synthesis and memory impairments as well as higher aggression scores. The aim of the present study was the investigation of the association between a diminished serotonin synthesis, logical memory and impulsive aggression in male adult patients with ADHD. Method Twenty male adult patients with ADHD and twenty healthy controls were recruited for this double-blind within subjects crossover study. Subjects completed the Rapid Tryptophan Depletion (RTD) Test or a placebo condition (balanced amino acid load) on either one of two examination days. Clinical variables and general intellectual functioning were assessed. The neuropsychological test battery included the subtest logical memory from the Wechsler Memory Scale (WMS-R), self-assessment of aggression as well as the Point Subtraction Aggression Game (PSAG). Results Statistical analysis revealed significant memory impairments of ADHD patients, which were associated with severity of symptoms in early childhood as well as subjective aggression scores. Effects of the tryptophan depletion were not found, neither for the logical memory subtest nor performance in the PSAG. Conclusions In contrast to previous studies, these findings suggest that the serotonergic system as reflected by the RTD Test has no effect on memory performance or impulsive aggression. However, these results may be due to possible interactions of other catecholamine systems with the serotonergic system that were not controlled in this study. Therefore an additional study is needed to further explore the catecholamine systems and their effects on memory and impulsive aggression.

P01-426 - A diminished serotonin level influences the performance in a modified AX-continuous performance task in adult ADHD

Introduction Attention deficit disorder (ADHD) is a psychiatric disorder, which is characterized by deficits of executive functions (EF) and impulsivity. Whereas a variety of studies on the involvement of the dopaminergic system in ADHD exists, the impact of the serotonergic system to EF in ADHD in adults is underinvestigated. Aims To ascertain the effects of rapid tryptophan depletion (RTD) and the resultant reduction of the central nervous levels of serotonin on the EF of male adult patients with ADHD. Methods 20 ADHD patients and 20 healthy controls completed the RTD test on one day and a placebo on another day in a double-blind within subject crossover design.- In addition, the subtest alertness of the TAP and a modified Version of the Continuous performance test (AX-CPT) with three stimulus conditions (AX, AY, BX) were administered. Results Statistical analysis revealed significant shorter reaction times, more errors and more omission errors in the ADHD group in the AX-CPT. The omissions error rate increased in both groups in the RTD condition but not in the placebo condition. Statistical analyses did not yield any significant differences between groups in the subtest alertness and no significant interaction of group and effect of the RTD condition could be observed. Conclusions In addition to higher impulsivity of patients with ADHD as reflected by shorter reaction times and higher error rates, the results of the present study imply an involvement of the serotonergic system as reflected by RTD in sustained and selective attention.