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.

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.

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

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.

Dose response and concentration response relationship of apomorphine in patients with Parkinson's disease and end-of-dose akinesia.

The motor response and the PK-PD relationship of the dopamine agonist, apomorphine, after ascending single doses (0.5, 1, 2, 4 mg s.c.), was investigated in 10 patients with advanced Parkinson's disease presenting end-of-dose motor fluctuations. Aim of the study was to investigate the exact pharmacodynamic effects of different apomorphine doses on the magnitude and duration of motor responses in parkinsonian fluctuators. The average improvement in the magnitude of the motor response (% change of baseline score in the Columbia University Rating Scale) elicited by apomorphine was negligible with 0.5 mg, 10% after the 1 mg dose, 22% after 2 mg, and 25% after 4 mg. If a 20% improvement is considered clinically relevant, a response was seen in 0/10 patients (0.5 mg), 2/10 patients (1 mg), 6/10 patients (2 mg), and 6/8 patients (4 mg). The duration of response was about 0.25 h (1 mg), 0.58 h (2 mg), and 0.72 h (4 mg). An explorative analysis of individual plasma concentration vs. effect curve, yielded a steep, sigmoidal concentration effect relationship with fast equilibrium at the effect site. The EC50 of the individual curves averaged 20 pMol/ml. However, several curves exhibited proteresis, making the application of a PK-PD model impossible. The reason for proteresis is not clear, it might indicate acute tolerance as well as a redistribution of apomorphine from the effect site.

Glutamine synthetase activity in patients with Parkinson's disease.

According to current concepts, the excitatory amino acid glutamate is involved in the pathogenesis of Parkinson's disease (PD). Overactivity of glutamatergic projection neurons and beneficial effect of antiglutamatergic substances in animal experiments suggest that excess supply of glutamate might contribute to the pathophysiology of PD. Reduced activity of the glutamate metabolizing enzyme glutamine synthetase (GS) leads to decreased uptake of glutamate and thus abundant glutamate. Here we report that PD patients and age-matched controls are comparable with respect to GS activity in peripheral blood mononuclear cells (PBMC). These results imply no systemic dysregulation of the enzyme GS in patients with PD.

Pharmacodynamics of levodopa coadministered with apomorphine in parkinsonian patients with end-of-dose motor fluctuations.

The modification of the pharmacodynamic response to a single oral dose of levodopa/benserazide by the coadministration of the dopamine agonist apomorphine was investigated in parkinsonian patients with end-of-dose motor fluctuations. The relation between levodopa plasma concentrations and motor response was examined in a double-blind, randomized, crossover design in 10 patients with idiopathic Parkinson's disease with end-of-dose motor fluctuations. Oral single-dose challenges with 100 mg of levodopa/25 mg of benserazide were carried out twice in each patient, under coadministration with apomorphine (1 mg/h) or 0.9% saline (placebo) subcutaneously. The sum scores (sigma score) of the Columbia University Rating Scale (CURS) were used as effect parameters for pharmacodynamic assessment. A sigmoidal Emax model was fitted to the data using a semiparametric pharmacokinetic-pharmacodynamic approach. Levodopa pharmacokinetics were not significantly modified by the coadministration of apomorphine. The area under the curve was 1599 +/- 615 ng.ml-1 h. (levodopa + saline) and 1821 +/- 625 ng.ml-1.h (levodopa + apomorphine). Cmax was 1094 +/- 476 ng.ml-1 (levodopa + saline) and 1129 +/- 435 ng.ml-1 (levodopa + apomorphine). Under both experimental regimens, the maximum clinical response to levodopa (Emax) yielded a decrease in the CURS sigma rating of about 20 score points. Estimates of the EC50 of levodopa decreased significantly from 430 +/- 163 ng.ml-1 (levodopa + saline) to 315 +/- 123 ng+ml-1 (levodopa + apomorphine) (95% confidence interval [CI] 0.51 -0.98, point estimator 0.75). The mean duration of the motor response rose from 1.9 +/- 0.5 h (levodopa + saline) to 3.0 +/- 0.9 h (levodopa + apomorphine (95% CI 1.23 to 2.06, point estimator 1.60). Thus, a reduction of the threshold levels for levodopa (EC50) was accompanied by approximately 50% gain in on-phase duration, but not in an increased magnitude of the motor response (Emax).

Circadian profiles of melatonin in melancholic depressed patients and healthy subjects in relation to cortisol secretion and sleep.

Circadian secretion of melatonin was measured in melancholic depressed patients (n = 9) and age- and sex-matched healthy control patients (n = 9). The mean age of the depressed patients was 29 years, i.e. younger than in most earlier studies, and a drug-free interval of 3 weeks preceded the investigations. Melatonin secretion was similar in depressed patients and healthy subjects with no significant differences at any of the time points, thus not confirming earlier studies in which depressed patients were found to have lower melatonin levels than control patients. The discrepancy between our result and earlier studies may be explained by different patient characteristics such as age, duration of illness, previous treatment, and alcohol intake. It is conceivable that a diminution of nocturnal melatonin secretion in depressed patients might only occur during the long-term course of the depressive illness and/or its pharmacological treatment.

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.

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 nonresponders to lorazepam can be distinguished with regard to plasma HVA, anxiety and dyskinetic/parkinsonic movements.

Concentration-effect relationship of levodopa in patients with Parkinson's disease after oral administration of an immediate release and a controlled release formulation.

1. The relationship between plasma concentration of levodopa and motor-response was investigated in 12 patients with Parkinson's disease who showed marked response fluctuations, after a single oral dose of an immediate release (IR) formulation (100 mg levodopa/25 mg genserazide) and a controlled release (CR) formulation (300 mg levodopa/75 mg benserazide), using a double-blind, randomized, cross-over design. 2. The sum score of the Columbia University Rating Scale (CURS sigma) was used for pharmacodynamic assessment. A sigmoidal Emax-model was fitted to the data using a semiparametric pharmacokinetic/dynamic approach. 3. The dose-corrected AUC of levodopa after the IR-formulation was 27.5 (+/- 9.1 s.d.) ng ml-1 h per mg and 23.2 (+/- 4.6 s.d.) ng ml-1 h per mg after the CR-formulation. Cmax was 1714 (+/- 1027 s.d.) ng ml-1 after the IR-formulation and 1494 (+/- 383 s.d.) ng ml-1 after the CR-formulation. 4. With both preparations, the maximal response to levodopa (Emax) was a decrease in the CURS sigma rating of about 27 scores. Estimates of the EC50 of levodopa were 495 (+/- 144 s.d.) ng ml-1 (IR) and 1024 (+/- 502 s.d.) ng ml-1 (CR), respectively (95%-CI: 1.51-2.66, point estimator 1.95). The mean duration of the motor response was 1.9 (+/- 0.5 s.d.) h (IR) and 2.8 (+/- 0.7 s.d.) h (CR), respectively (95%-CI: 1.12-2.04, point estimator 1.53).(ABSTRACT TRUNCATED AT 250 WORDS)

[Case report: treatment of a patient with sleep phase advance disorder with phototherapy]. / Kasuistik: Behandlung einer Patientin mit vorverlagerter Schlafphase mit Lichttherapie.

We report on a patient with a moderate form of a sleep-phase advance syndrome. As a biological correlate we found an early temperature and cortisol minimum before midnight, respectively. Light therapy during the evening hours (2500 Lux) given over 17 months induced a complete remission of the symptoms. The good treatment outcome could be maintained after the end of daily light therapy by only sporadic application.

Fluctuations in Parkinson's disease. Pathogenetic significance of levodopa's cerebral pharmacokinetics and pharmacodynamics.

The pathogenetic mechanisms which are responsible for the clinical manifestation of motor-fluctuations are poorly understood. Peripheral pharmacokinetics do obviously not play a significant role. For a better understanding of fluctuations exact knowledge and precise characterization of the levodopa induced motor-response (MR) might be useful. In a number of studies it has been demonstrated that this MR follows the "all or none" rule after a levodopa threshold concentration has been exceeded. Such a threshold is considered to exist in the plasma-compartiment as well as in the cerebral effect-compartiment. The specific character of the MR can be modified by the coadministration of dopamine-agonists. Dopamine-agonists lower the levodopa threshold and they reduce the time-lag between levodopa plasmaconcentration and MR. The duration of the MR can be prolonged but the intensity (amplitude) of the MR cannot be augmented. Most of these data to levodopa pharmacodynamics can be explained by a model which is presented in this paper and which is mainly based on cerebral pharmacokinetic mechanisms.

Influence of chronic beta-adrenoreceptor blocker treatment on melatonin secretion and sleep quality in patients with essential hypertension.

The nocturnal production of melatonin synthesis has been associated with circadian mechanisms of the organization of sleep. It is well known that the synthesis of melatonin is under the control of pineal beta 1-adrenoreceptors. In this study the effect of ten weeks treatment with the beta-adrenoreceptor (beta-AR) blockers propranolol and ridazolol on melatonin synthesis and on sleep quality was examined in 42 patients suffering from essential hypertension. Before and after 6 and 10 weeks of beta-AR-blocker administration urinary sulfatoxymelatonin excretion rates were measured and sleep factors were evaluated by using a standardized sleep inventory consisting of self-rating sleepiness scales. After 6 and 10 weeks of treatment, a significant about 50 percent reduction of sulfatoxymelatonin was measured. No relationship between these reductions and changes in sleep factors was found. The results indicate that a reduced nightly amplitude of melatonin has minor significance for the organization of physiological sleep. Furthermore, it is suggested that pineal mechanisms beside the beta 1-adrenergic receptor transduction system serve to maintain the melatonin signal to a considerable extent during a chronic beta 1-AR blockade.

Interleukin-2, soluble interleukin-2-receptor, neopterin, L-tryptophan and beta 2-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 beta 2-microglobulin (beta 2-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 CSF L-TRP and beta 2-M of patients and controls. In CSF of RRMS patients neopterin and L-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.

Increased concentrations of phosphatidylinositol (PI) and decreased esterification of arachidonic acid into phospholipids in platelets from patients with schizoaffective disorders or atypic phasic psychoses.

The concentration of various phospholipids (PLs) and sphingomyelin in platelets and the amount of [14C] arachidonic acid ([14C]-AA) esterified in phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylcholine (PC) were measured. The platelet-rich plasmas from unmedicated patients with psychiatric disorders and healthy controls were incubated for 30 min with 1 microM [14C]-AA. Platelets from patients with a schizoaffective disorder according to RDC criteria, a schizophreniform disorder (DSM III criteria) or an atypical phasic psychosis according to FC criteria contained twice as much PI and had significantly increased concentrations of PC as compared to controls (p less than 0.05, t-test). A highly significant (40-70%) reduced rate of esterification of [14C]-AA into PI/PS, PC and PE was found in platelets from patients with schizophreniform, schizoaffective and major depressive disorders but not in platelets from patients with chronic schizophrenia. The largest reduced esterification of [14C]-AA (about 70%) was found in PI/PS of platelets from patients with schizoaffective disorders (1.9 +/- 0.7 vs 6.3 +/- 1.7 mumol [14C]-AA/mol PI/PS; p less than 10(-4), t-test). The results indicate that changes in the metabolism of arachidonic acid and phosphatidylinositol and, to a lesser degree, of phosphatidylcholine in platelets are characteristic of patients with a likely favorable outcome of a psychotic episode.

Light exposure patterns in schizophrenia.

Spontaneous light exposure patterns were studied in 10 chronic schizophrenic patients. Half of our schizophrenic patients exposed themselves to bright light exceeding ordinary indoor illumination. There was a significant positive correlation between the percentage of exposure to bright light and the Brief Psychiatric Rating Scale subscore anergia and a significant negative correlation with depression.

Abnormal electroretinography in schizophrenic patients with a history of sun gazing.

Electroretinographic (ERG) measurements were performed in 9 schizophrenic patients and in 13 control subjects. The measurements of schizophrenic patients as a group did not differ from those of normals. However, 6 schizophrenic patients who had a past history of sun gazing showed a decrease in retinal responsiveness under conditions of light adaptation. These results suggest that a subgroup of schizophrenic patients, who show deviant light-related behavior, have abnormal ERG. We postulate that an abnormality in retinal dopaminergic neurons, which are known to reduce light responsiveness of horizontal and ganglion cells, is the underlying pathophysiology of this clinical finding.