[Show abstract][Hide abstract] ABSTRACT: 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 Scandi-navica (6) dealing with the acute tryptophan depletion (ATD) methodology with great interest. ATD is a pharmacological method designed to lower central nervous system (CNS) syn-thesis of the neurotransmitter serotonin (5-HT) for a brief per-iod 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 psychopa-thology (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 seroto-nin 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 experi-ments (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 hista-mine, 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 inter-action, 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 his-tamine 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 mix-tures could indeed lower histamine production. However, nei-ther the control nor the ATD mixture in most studies contains histidine, and so histamine would not be differen-tially affected by the ATD mixture, but should be compara-bly depleted in both control and ATD mixtures. Nevertheless, it is possible that some interaction between his-tamine 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 trans-lational 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, bio-chemical 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
[Show abstract][Hide abstract] ABSTRACT: Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.
[Show abstract][Hide abstract] ABSTRACT: A 20 item observational measure of social functioning, the Impression of Interviewee rating scale, is one of three measures devised to assess the broader autism phenotype. The sample studied included families containing at least two individuals with autism spectrum disorder; observations were undertaken by the researcher who interviewed the subject. An exploratory factor analysis suggested a single factor was most appropriate (Cronbach's α of 0.78). There was a modest but significant retest correlation of 0.42. Correlations between live ratings and blind consensus ratings of vignettes were high (0.93). Correlations with the interview measures were moderate but statistically significant. In conclusion, the observational scale provides a promising start but further work is required before general use can be recommended.
Journal of Autism and Developmental Disorders 04/2013; · 3.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Animal experiments and studies in adults have shown that the neurotransmitter serotonin (5-HT) plays an important role in learning and memory processes. However, data on this relationship in young persons are scarce, and neurodietary research in this age group is limited compared with the extensive literature on adults. Here, we aimed to explore the effects of a diminished central nervous 5-HT synthesis, which is achieved by acute tryptophan depletion (ATD) Moja-De , on memory function in young males with attention deficit hyperactivity disorder (ADHD). METHOD: Twenty-two male patients with ADHD (ages 9-15 years, mean 10.95 ± 1.17 years) received ATD, thus diminishing central nervous 5-HT synthesis, and a tryptophan-balanced amino acid load (BAL) in a randomized, double-blind, within-subject, crossover design study. Approximately 1.7 h after administration of ATD/BAL, verbal declarative memory was assessed using the 'Auditory Verbal-Learning-Test' (AVLT). RESULTS: There were no significant effects of ATD administration on verbal declarative memory function. CONCLUSION: In this study, changes in 5-HT neurotransmission were not associated with specific aspects of verbal declarative memory in young persons with ADHD. Future studies with healthy control groups that address effects of covarying attentional processes are warranted.
[Show abstract][Hide abstract] ABSTRACT: Evidence from animal studies suggests that leptin metabolism is associated with zinc (Zn) status. However, research investigating this relationship in adolescents and young adults with anorexia nervosa (AN) is scarce; the present study aims to fill that gap.
Serum concentrations of leptin, the soluble leptin receptor (sOB-R) and the free leptin index (FLI) were obtained in healthy control subjects (n=19), acutely ill individuals (n=14) and recovered patients with AN (n=15). Serum Zn concentrations noted in previous research data were also incorporated for all groups.
Leptin, FLI and Zn concentrations were higher in recovered subjects with AN when compared with acutely ill AN patients. Remitted patients showed higher sOB-R concentrations but no difference in FLI compared with the control group. Leptin and FLI were lower in the acutely ill patients compared with the control subjects, who showed no differences in Zn concentrations. Zn concentrations were not correlated with leptin, sOB-R or FLI concentrations in any of the three investigated subgroups.
The present investigation does not entirely support an association between Zn, Leptin and FLI concentrations in subjects with AN, possibly due to limited statistical power. Further research and replication of the present findings related to the interaction between leptin and Zn is warranted. However, with respect to serum leptin levels the data of the present investigation indicate that acutely ill and remitted patients with AN differ as regards serum leptin concentrations and FLI, which is in line with previous research.
[Show abstract][Hide abstract] ABSTRACT: The Music Therapy Rating Scale (MAKS), originally developed in 1996, was evaluated again in 2009 using a sample of 62 children from a psychiatric unit and from different primary schools, with measures at three different time points during therapy process. The scale is intended as an objective rating of a client’s musical behavior. The evaluation of the scale was to determine any possible ambiguity or weakness in the discriminatory power of the scale items. After excluding such items, the results show high reliability (α > .75) and good objectivity with trained raters (r > .70) for the two main scales and a significant sensitivity to change.
[Show abstract][Hide abstract] ABSTRACT: Cognitive abilities develop during the first 2 decades and start to decrease in the 6th decade of life. There is strong heritability of general cognitive ability as well as of specific cognitive functions which might increase with age till about age 80. Cognitive disorders derive from this physiological cognitive development; they are also under genetic control. This paper discusses age-specific genetic influences on cognitive functions in interplay with environmental factors and compares these determinants across the life span.
Der Nervenarzt 11/2009; 80(11):1312-21. · 0.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Was bedeutet das Wort Autismus? Bekanntlich wurde dieser Begriff, der Selbstbezogenheit (vom griechischen „autos“ = selbst)
meint, von Eugen Bleuler in Zürich für eine Symptomatik bei schizophrenen Psychosen in die Psychiatrie eingeführt. Bleuler
beschrieb damit eine Loslösung von der Wirklichkeit zusammen mit dem relativen oder absoluten Überwiegen des Innenlebens.
Damit ist dieser Begriff aber weit entfernt von jener Beschreibung einer psychiatrischen Störung, die bei Kindern schon sehr
früh auftritt und die unabhängig voneinander 1943 von Leo Kanner (USA) und 1944 von Hans Asperger (Österreich) publiziert
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Neural Transmission 12/2008; 116(1):105-8. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Calendar calculation is the ability to quickly name the day that a given date falls on. Previous research has suggested that savant calendar calculation is based on rote memory and the use of rule-based arithmetic skills. The objective of this study was to identify the cognitive processes that distinguish calendar calculation in savant individuals from healthy calendar calculators.
Savant calendar calculators with autism (ACC, n=3), healthy calendar calculators (HCC, n=3), non-savant subjects with autism (n=6) and healthy calendar calculator laymen (n=18) were included in the study. All participants calculated dates of the present (current month). In addition, ACC and HCC also calculated dates of the past and future 50 years.
ACC showed shorter reaction times and fewer errors than HCC and non-savant subjects with autism, and significantly fewer errors than healthy calendar calculator laymen when calculating dates of the present. Moreover, ACC performed faster and more accurate than HCC regarding past dates. However, no differences between ACC and HCC were detected for future date calculation.
The findings may imply distinct calendar calculation strategies in ACC and HCC, with HCC relying on calendar regularities for all types of dates and an involvement of (rote) memory in ACC when processing dates of the past and the present.
Psychological Medicine 11/2008; 39(8):1355-63. · 5.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Twenty-two patients with ADHD received the rapid tryptophan depletion test (RTD) thus lowering the central-nervous 5-HT synthesis rate within a placebo-controlled double-blind within-subject crossover design. Reaction time was assessed using a competitive reaction time game with low and high provocation after both depletion and placebo intake. The study sample was divided into high and low scorers according to their CBCL-PBD scores.
Comparing those six patients with the highest and clinically significant CBCL-PBD scores versus those six patients with the lowest, patients with a high CBCL-PBD score showed a slower reaction time under RTD compared to patients with low CBCL-PBD scores after high provocation. CBCL-'aggression' discriminated between the two groups.
The results suggest alterations in 5-HT functioning in CBCL-PBD-spectrum patients, and 'aggression' as a potential moderator variable to ADHD.
Human Psychopharmacology Clinical and Experimental 07/2008; 23(4):291-9. · 2.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: In children with pediatric bipolar disorder (PBD), a consistent pattern of elevations in hyperactivity, depression/anxiety, and aggression has been identified on the child behavior checklist (CBCL-PBD profile). The aim of the present study was to estimate the prevalence of the CBCL-PBD profile in a child psychiatric sample, and to determine ICD-10 diagnoses in CBCL-PBD patients.
We studied a sample of 939 consecutively referred children and adolescents, aged 4-18 years. ICD-10 discharge diagnoses were established in consensus conferences. The CBCL 4-18 was completed by parents as part of the diagnostic routine.
A total of 62 subjects (6.6%; 95% CI=5.2-8.4) met criteria for the CBCL-PBD phenotype. More than 75% of CBCL-PBD subjects were clinically diagnosed with disruptive behavior disorders (ADHD, ODD, and CD). Two patients (0.2% of the total sample) received a formal diagnosis of bipolar disorder, but did not show the CBCL-PBD phenotype.
A considerable number of children in Germany are referred to psychiatric care with a mixed phenotype of aggression, anxiety, depression and attention problems. Our study demonstrated a comparable prevalence and similar clinical characteristics as reported from other countries using different diagnostic approaches. However, the CBCL-PBD phenotype does not correspond with clinical consensus diagnoses of bipolar disorder, but with severe disruptive behavior disorders.
Journal of Neural Transmission 02/2008; 115(2):155-61. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autism has been associated with enhanced local processing on visual tasks. Originally, this was based on findings that individuals with autism exhibited peak performance on the block design test (BDT) from the Wechsler Intelligence Scales. In autism, the neurofunctional correlates of local bias on this test have not yet been established, although there is evidence of alterations in the early visual cortex. Functional MRI was used to analyze hemodynamic responses in the striate and extrastriate visual cortex during BDT performance and a color counting control task in subjects with autism compared to healthy controls. In autism, BDT processing was accompanied by low blood oxygenation level-dependent signal changes in the right ventral quadrant of V2. Findings indicate that, in autism, locally oriented processing of the BDT is associated with altered responses of angle and grating-selective neurons, that contribute to shape representation, figure-ground, and gestalt organization. The findings favor a low-level explanation of BDT performance in autism.
Journal of Neural Transmission 02/2008; 115(3):545-52. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate long-term effects of methylphenidate (MPH) treatment in ADHD children on the development of nicotine use disorders (SUD-N).
Multisite retrospective non-randomised longitudinal study with 215 ADHD children (diagnosis at 9.2 years of age; reassessment for SUD-N at 21.9 years of age) strictly parallel allocated to MPH treated (n = 106) and drug naive (n = 109) children.
There was no difference between the groups with respect to frequency (84% MPH; 89% non-MPH; chi(2) = 1.6; p = 0.21) and age of onset for first cigarette smoking (log rank 1.68; p = 0.19). Continuous smoking was reached by 51% (MPH) and 61% (non-MPH) of the patients. Survival analyses revealed a small and nominally significant delay in age of onset for continuous smoking in the MPH-group (log rank = 3.85; p = 0.049). Nicotine dependency was reached by 20% (MPH) and 27% (non-MPH). Age of onset does not differ between groups (log rank = 2.24; p = 0.13).
Limited evidence due to the non-randomised nature of the study is given that MPH does not induce SUD-N. The data suggests there may be a beneficial effect of MPH on delay of onset for continuous nicotine consumption in ADHD patients.
Journal of Neural Transmission 02/2008; 115(2):335-9. · 3.05 Impact Factor