Lothar Demisch

Intensity dependence of auditory evoked potentials (AEPs) as biological marker for cerebral serotonin levels: effects of tryptophan depletion in healthy subjects.

Abstract Rationale: The intensity dependence of the auditory evoked potentials (AEP) has been suggested to be a specific biological marker of central serotonergic activity. Objective: While previous studies used circumstantial evidence to support this hypothesis, we manipulated (decreased) cerebral levels of serotonin directly by using tryptophan depletion. Methods: Twelve healthy young subjects were investigated using placebo and two different amino acid mixtures in a double blind cross over design on three different occasions. AEPs recorded during tryptophan depletion were analyzed by dipole analysis and regional sources using methods published in the literature. Results: For none of the mixtures a significant effect of tryptophan depletion was found. There was a trend towards reduced intensity dependency after tryptophan depletion, especially in the right hemisphere. This reduction correlated with the amount of reduced tryptophan in plasma. Conclusions: The results indicate, in contrast to earlier indirect studies, that the intensity dependence of AEPs is not a specific marker of central serotonergic activity.

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

INTRODUCTION 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. METHODS 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. RESULTS 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. DISCUSSION 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.

Correlation of platelet MAO activity with introversion: A study on a German rural population

Platelet monoamine oxidase (MAO) activity and personality characteristics were correlated in a sample of 52 men (37 +/- SD 13 years) and 54 women (37 +/- SD 15 years) from a rural community. Personality characteristics were measured by using the Freiburger Persönlichkeitsinventar (FPI-A). In males, weak but significant linear correlations (Pearson product-moment and Spearman rank correlations) were found between platelet MAO activity (p-tyramine and benzylamine as substrates) and the extraversion/introversion dimension. In the females, however, there were no consistent significant correlations between MAO activity and FPI test scores. Comparing the top and bottom 25% of the platelet MAO distribution resulted in a significant difference for the second order factor extraversion in the group of men but not in the group of women. The significant correlation between MAO and introversion could not be attributed to cigarette smoking, food consumption, alcohol, or drugs. In accord with previous biochemical-behavior research, it is suggested that reduced platelet MAO activity may, to some extent, reflect an impulsive personality type.

Influence of rapid tryptophan depletion on laboratory-provoked aggression in children with ADHD.

Background: The present study investigated the effects of rapid tryptophan depletion (RTD), and the ensuing reduction of central nervous system levels of serotonin (5-HT), upon reactive aggression in patients with attention deficit/hyperactivity disorder (ADHD). Furthermore, it was asked whether the relation between 5-HT function and behavioural aggression in patients is influenced by their age, the intensity of their attention problems or their comorbid symptoms. Methods: The study employed a double-blind, within-subject crossover design. On day 1, 22 male adolescent patients with ADHD were subjected to RTD and the subsequent reduction of central 5-HT levels. On day 2, they received a tryptophan-balanced amino acid mixture (BAL), which acted as a placebo. On both days, 4.5 h after the intake of the RTD/BAL amino acids, reactive aggressive behaviour was provoked using a competitive reaction time game, which consisted of both high and low provocation conditions. Results: The number of aggressive responses was significantly higher after low provocation during acute tryptophan depletion, in comparison to the placebo. Furthermore, this study provides evidence that neither age nor the intensity of attention symptoms in ADHD patients had an impact on the relation between 5-HT and reactive aggression. Conclusion: This study indicates that in children with ADHD, there is an inverse relationship between 5-HT and aggression.

Catatonia : short-term response to lorazepam and dopaminergic metabolism

Therapeutic response to lorazepam and dopaminergic metabolism were investigated in 18 neuroleptically naive acute catatonic patients. They were diagnosed as catatonic according to criteria by Lohr and Rosebush and treated exclusively with lorazepam (2–4 mg) during the first 24 h. Dopaminergic metabolism (plasma HVA, plasma MHPG), anxiety (HAM-A) and parkinsonic/dyskinetic movements (SEPS, AIMS) were measured under standard conditions before initial treatment with lorazepam (day 0) and 24 h after initial treatment (day 1). On day 0 responders to lorazepam treatment (complete remission of catatonic syndrome after 24 h according to Rosebush and Lohr) showed significantly higher (P=0.004) plasma HVA (130.4±51.2 pmol/ml; means ± SD) than non-responders (no remission of catatonic syndrome after 24 h; 73.2±40.5 pmol/ml; means ± SD). On day 1 plasma HVA did not differ any more significantly between both groups Clinically, responders showed significantly higher HAM-A (P=0.025) and AIMS (P=0.022) scores as well as significantly lower SEPS (P=0.049) scores than non-responders on day 0. Hence catatonic short-term responders and non-responders to lorazepam can be distinguished with regard to plasma HVA, anxiety and dyskinetic/parkinsonic movements.

Interleukin-2, soluble interleukin-2-receptor, neopterin,l-tryptophan and β2-microglobulin levels in CSF and serum of patients with relapsing-remitting or chronic-progressive multiple sclerosis

Cerebrospinal fluid (CSF) and serum levels of interleukin-2 (IL-2), soluble IL-2 receptors (sIL-2R), neopterin,l-tryptophan (l-TRP) and β2-microglobulin ((β2-M) were measured in 31 untreated multiple sclerosis patients in acute exacerbation and 27 normal controls. Twenty-six patients showed the relapsing-remitting type of disease (RRMS); 5 had a chronic-progressive course (CPMS). No changes in serum IL-2 and sIL-2R were found between RRMS patients and controls, whereas serum and CSF levels as well as the CSF/serum ratio of neopterin were significantly elevated in the RRMS group. IL-2 was not detectable in CSF of patients or controls and sIL-2R levels were at the level of the lower detection (LD) sensitivity of the ELISA method. Four of 23 RRMS patients versus 1 of 25 controls showed CSF sIL-2R levels above the LD sensitivity, indicating a trend towards elevation in acute relapse. No difference was found in serum and CSFl-TRP and β2-M of patients and controls. In CSF of RRMS patients neopterin andl-TRP correlated negatively, reflecting the interferon-gamma mediated activation of macrophages in acute relapse. A significant positive correlation (Spearman rank 0.57,P = 0.001) between serum IL-2 levels and duration of acute relapse (mean 30 days) warrants further evaluation.

Influence of Dexamethasone on Nocturnal Melatonin Production in Healthy Adult Subjects

There is no conclusive evidence supporting an interaction between the pineal gland and the hypothalamic‐pituitary‐adrenal axis. In this study, 11 healthy adults (six women, five men; aged 18–47 years) received a placebo the first night and 1 mg dexamethasone the next night at either 1800 or 2300 h. Administration of 1 mg of dexamethasone was followed by an attenuation of the nocturnal production of melatonin in 9 of 11 subjects. A significant reduction was found between melatonin plasma levels before and after dexamethasone at 0400h (P < 0.01, t test for dependent groups). It is suggested that dexamethasone affects nocturnal production of melatonin by means of mechanisms within the pineal gland.

Substrate-typic changes of platelet monoamine oxidase activity in sub-types of schizophrenia

SummaryMonoamine oxidase (MAO) activity has been measured in the platelets of controls (n=42) and schizophrenic patients (n=49) of three subtypes, using β-phenylethylamine, p-tyramine, and tryptamine as substrates. Characteristic differences of MAO activity were observed between platelets of patients and controls; the differences were substrate-typic: decreased enzyme activity was found with all three substrates in platelets of the parnaoid subtype. With tryptamine, MAO activity was decreased in the platelets of all three sub-types of schizophrenia. With p-tyramine, MAO was low in patients with affective psychoses and paranoid schizophrenia.The value of MAO activity measurements as a means for distinguishing sub-types of schizophrenic disorders is improved by using two substrates; tryptamine and p-tyramine. Possible mechanisms of the substrate-typic changes of platelet MAO activity in schizophrenia are discussed.

Incorporation of 14C-arachidonic acid into platelet phospholipids of untreated patients with schizophreniform or schizophrenic disorders

The incorporation rate of 14C-labeled arachidonic acid (14C-AA) into membrane phospholipids was measured in a group of untreated (greater than 6 months) psychiatric patients (n = 33) and healthy controls (n = 31). Platelets from controls and from patients with schizophrenia (n = 10), schizophreniform disorder (n = 11), schizoaffective disorder (n = 6), major depression (n = 2), or an atypical psychosis (n = 4), diagnosed according to DSM-III, were incubated with 14C-AA. Platelets from patients with a schizophreniform and a schizoaffective disorder incorporated greater than 50% less 14C-AA than the platelets from controls. The incorporation rates of platelets from schizophrenic patients were slightly (18%), but not significantly, reduced compared to controls. Characterization of variables affecting arachidonic acid and phospholipid metabolism may be helpful in studies focused on the assessment of first-episode psychotic patients and in long-term outcome studies.

Plasma homovanillic acid concentrations in catatonia

We investigated the dopamine metabolite plasma homovanillic acid (plasma HVA) levels in 37 catatonic patients on the day of admission before initial medication as well as in 17 healthy controls. In a prospective study catatonic syndrome was diagnosed according to criteria of Lohr and Wiesniwski (1987) and Rosebush et al (1990) whereas comorbid diagnosis was made by Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, revised (DSM III/R) (APA 1987). On the day of admission blood samples were taken before initial medication. Compared to controls (80.1 +/- 40.1 pmol/mliter) catatonic patients showed significantly (P = 0.0286) increased plasma HVA (140.9 +/- 53.6 pmol/mliter). Catatonic patients free of neuroleptic medication (n = 21) differed significantly (p = 0.0416) from controls whereas neuroleptically treated catatonics (n = 16) did not. Our findings of increased plasma HVA in catatonia are explained by an alteration in either mesolimbic or mesocortical dopaminergic function, as is assumed in the case of schizophrenia. As an alternative, it may be due to increased nigrostriatal function, which can lead, as shown in animal experiments with the dopamine agonist amphetamine, to hypokinetic states resembling catatonia in humans.