J. Uekermann

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).

Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature.

Objective:We present 3 new cases of psychotic symptoms in patients with adult attention-deficit/hyperactivity disorder while regularly treated with a stimulant therapy with methylphenidate. Methods:Existing literature about this theme is reviewed, and potential mechanisms are discussed. Results and Conclusions:Medication with methylphenidate should be avoided in patients with vulnerability to schizophrenia and in drug addiction, but reported cases without these risk factors demonstrate that a careful and regular psychiatric monitoring is essential in all patients treated with methylphenidate.

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.

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

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.

P01-415 - Association between albumin and social cognition in attention-deficit-hyperactivity-disorder (ADHD)

Introduction Albumin is a protein which serves as a transporter for a variety of metabolites and as a storage for a lot of substances. Although albumin cannot pass the blood-brain-barrier and thus influence the CNS directly, a negative relation between cognitive impairment and serum albumin level has been observed in studies of normal and pathological aging. The aim of the present study was to investigate the association between albumin and social cognition in ADHD. Method 20 adult patients with ADHD and 20 healthy controls participated in a double-blind within subjects crossover study. Participants completed the Moral-Judgment-Test, Tuebingen Affect Battery, the Movie for the Assessment of Social Cognition (MASC) and Cambridge Behaviour Scale (EQ). In addition, ADHD symptoms were assessed by the Wender Utah Rating Scale (WURS-K) and ADHD Self Rating Scale. Serum albumin levels were determined after blood withdrawal. Results In the patient group serum albumin levels were negatively associated with ADHD pathology measured by WURS-K. In addition, a low level of albumin was related with poorer performance in theory of mind, moral judgment competence and affective prosody tasks. Conclusions The results suggest that albumin is related to social cognition in younger patients with ADHD. This is, to the knowledge of the authors, the first investigation, in which the association between albumin and cognition has been investigated in ADHD. Thus the findings of the present study need replication and the neural mechanisms have to be explored in future studies. Further studies are needed to exclude a possible medication effect.

P03-141 - Attachment in adult patients with attention-deficit hyperactivity disorder (ADHD)

Introduction Adult patients with ADHD suffer from marriage problems and increased divorce rates significantly more often. There are, however, only a few studies which analyse romantic attachment to a partner or romantic relationships among patients with ADHD in view of attachment theory. Aims The aim of the present study is to research if ADHD patients show a diminished quality of romantic relationships in comparison to a matched sample of healthy controls. Furthermore, correlations between ADHD specific characteristics and particular variables of partnership perception and psychosomatic discomfort were analysed within the ADHD subgroup. Methods We recruited 39 patients with ADHD and compared them with a matched sample of healthy controls. Self-estimation measures were used to examine the quality of attachment, dimensions of attachment, love styles, psychosomatic discomfort and ADHD specific symptoms. Results In comparison to the control sample, adult ADHD patients show a significantly reduced quality of relationships. ADHD patients rank themselves as more scared of attachment and showing more avoidance of interpersonal relationships in general as well as romantic relationships. They also feel less romantic love. ADHD specific characteristics correlate moderately with the attachment dimensions “Fear” and “Avoidance”, the love style “Mania” and psychosomatic discomfort. Conclusions This study lends further support to the assumption that adult patients with ADHD show an impaired quality of attachment, increased fear and avoidance of relationships as well as less romantic love. The results strongly underline the necessity to account for individual attachment styles in psychotherapy of ADHD.