Jürgen Gallinat

The serotonin syndrome scale: first results on validity.

Abstract As a modification of the diagnostic criteria of the serotonin syndrome proposed by Sternbach, we developed the Serotonin syndrome scale for the operationalized assessment of both the presence and the severity of the core symptoms of the serotonin syndrome. In a first study on the validity of this scale, the relationships between the serotonin syndrome score (SSS) and both the paroxetine plasma levels (n = 42) and the loudness dependence of the auditory evoked potentials (LDAEP; n = 24) were investigated in depressed patients treated with paroxetine. A strong LDAEP is supposed to indicate low central serotonergic neurotransmission, and vice versa. The SSS was positively related to paroxetine plasma levels and negatively to the LDAEP. Both results support the validity of the serotonin syndrome scale. Using a SSS > 6 as diagnostic criterion, mild serotonin syndromes were diagnosed in 5 of our 42 patients. The Serotonin syndrome scale may become a useful tool for clinicians and scientists dealing with the serotonin syndrome.

Serotonergic dysfunction in schizophrenia assessed by the loudness dependence measure of primary auditory cortex evoked activity

Increased serotonergic activity is discussed as an important pathogenetic factor in schizophrenia. Further support for this hypothesis is difficult to obtain due to the lack of valid indicators of the brains serotonin system. A great deal of evidence discovered through human and animal studies suggests that a weak loudness dependence of auditory evoked potentials (LDAEP) indicates high serotonergic activity and vice versa. The LDAEP is a measure of auditory cortex activity, reflecting increase or decrease of auditory evoked potential amplitudes with increasing tone loudness, which is probably modulated by the serotonergic innervation there. This is true only for the LDAEP of the primary auditory cortex, since this region is more highly innervated by serotonergic fibers than the secondary auditory cortex. The LDAEP (N1/P2 component) of 25 inpatients with schizophrenia free of medication and 25 healthy controls matched by age and gender, were recorded. Using dipole source analysis, the LDAEP of primary (tangential dipole) and this of secondary auditory cortex (radial dipole) was separately analyzed. Following a 4-week treatment with the 5-HT(2) antagonists clozapine or olanzapine, patients were once again studied. The LDAEP of the primary, but not of the secondary auditory cortex, was significantly weaker in the patients with schizophrenia than in healthy volunteers, indicating enhanced serotonergic neurotransmission. After treatment with the 5-HT(2) antagonists, the LDAEP (of the right hemisphere) tended to be increased, indicating normalization of serotonergic function in the patients with schizophrenia. These results suggest that the loudness dependence of primary auditory cortex evoked activity is well suitable to assess serotonergic dysfunction in schizophrenia.

P300 subcomponents reflect different aspects of psychopathology in schizophrenia

BACKGROUND The aim of the study was to investigate abnormalities of P300 subcomponents in schizophrenic patients as well as relationships between these subcomponents and positive versus negative schizophrenic symptoms. METHODS Nineteen schizophrenic patients and 19 healthy controls were tested with an auditory event-related potential oddball paradigm designed to elicit the P300. The P300 data were analyzed by separating P300 subcomponents with a recently developed dipole source model. RESULTS Compared to healthy controls, schizophrenic patients showed reduced P300 amplitudes of the temporo-basal dipoles, corresponding mainly to P3b. Positive symptoms of the Positive and Negative Syndrome Scale correlated positively with the temporo-basal but not with temporo-superior dipole P300 activities, whereas negative symptoms correlated positively with the temporo-superior but not with temporo-basal dipole activities. CONCLUSIONS The P300 subcomponents separated with the dipole model are affected in a different manner by positive versus negative symptoms. Furthermore, the positive correlation between the severity of psychopathology and the P300 amplitudes of the different dipole activities appears to be a state-dependent effect, which has to be separated from the P300 amplitude reduction as a trait marker in schizophrenic patients.

Digitized analysis of abnormal hand–motor performance in schizophrenic patients

Many studies have shown a high prevalence of discrete neuromotor disturbances in schizophrenic patients. It was hypothesized that these disturbances are lateralized and reflect a neurodevelopmental disorder underlying schizophrenia. A new method for assessing subtle motor dysfunction and hemispheric asymmetries is the registration of hand movements with a digitizing tablet. Using this method, we studied hand-motor dysfunction and its lateralization in schizophrenics, as compared with healthy controls. All subjects (27 schizophrenic patients, 13 of them without neuroleptic medication, the others under neuroleptics; 31 healthy controls) drew super-imposed concentric circles. We computed kinematic parameters reflecting velocity and automatization to quantify neurological soft signs (NSS). The patients had significant impairments of regularity of repetitive hand movements, as compared with the healthy controls (F> or =5.35; p< or =0.024(*)). Comparing differences of left- and right-hand performance between patients and controls, we found longer stroke duration (F=(15,98); p=0.000***) and decreased automatization (F=18,14; p=0.000***), especially on the left side in schizophrenic patients. Measuring hand movements with a digitizing tablet is a sensitive method for assessing subtle motor dysfunction in schizophrenic patients, not reflected in the scores of clinical scales. Our findings show NSS in schizophrenic patients, independently of neuroleptics. Further, the hypothesis of lateralization of cerebral structures generating NSS towards the right hemisphere in schizophrenia is supported.

P300 subcomponents in obsessive-compulsive disorder.

Hyperactivity in the frontal cortex, leading to acceleration of attentional and cognitive processes, is discussed as pathogenetic factor in obsessive-compulsive disorder (OCD), as supported by findings of neuroimaging studies. This dysfunction in patients with OCD could be reflected by the auditory event-related P300 component, since one subcomponent of the P300, the so-called P3a, is mainly generated in frontal regions. The P300 of 21 patients with OCD free of medication and 21 age- and sex-matched healthy controls was studied, and dipole source analysis was used, allowing the separation of the subcomponents P3a and P3b with high reliability. No difference concerning the P3a between OCD and healthy subjects was found. OCD patients, however, showed a larger P3b amplitude and a shorter P3b latency (only right hemisphere) as well as a shorter reaction time to target tones as the healthy controls. Since the P3b, generated mainly in the temporo-parietal junction, is related to attentional and higher cognitive functions, whereas the P3a is more related to unspecific orienting reactions, the P3b abnormalities found in these patients could be an electrophysiological correlate of overfocussed attention and faster cognitive processes in OCD, possibly due to higher arousal and noradrenergic function. Regarding the findings with small P300 amplitudes and long latencies in most of the other psychiatric patients, it is remarkable that OCD is one of the few psychiatric diseases being characterized by larger P3b amplitudes and shorter latencies.

MARKERS FROM EVENT-RELATED POTENTIAL SUBCOMPONENTS AND REACTION TIME FOR INFORMATION PROCESSING DYSFUNCTION IN SCHIZOPHRENIA

Abstract Event-related potentials (ERPs) can serve as markers for cognitive processing stages. Identification of those ERPs altered in schizophrenia offer information about cognitive dysfunction. Auditory evoked potentials (AEPs) were elicited within an oddball paradigm in 35 schizophrenic patients and compared with 35 healthy controls. N100 and P200, as well as N200, frontal P300 and parietal P300 subcomponents, were separated using dipole source analysis. The amplitudes of the N100 and the parietal P300 measured in schizophrenics were diminished. The input-related processing stages (N100 and P200) were not altered, whereas later, the deviant and task-related processes (N200, frontal P300, parietal P300 and reaction time) were significantly prolonged in schizophrenia.

Loudness dependence of auditory evoked potentials in obsessive-compulsive disorder: a pilot study

In recent years it has been suggested that a serotonergic dysfunction is involved in the pathogenesis of obsessive-compulsive disorder (OCD). The loudness dependence of auditory evoked potentials (AEPs) is one of the best validated indicators of the activity of the serotonin system in humans. To explore the validity of the hypothesis of a serotonergic dysfunction in OCD, the loudness dependence of AEPs of 22 medication-free OCD patients were compared with those of 22 age- and gender-matched healthy subjects. Auditory evoked N1/P2 activity to tones of increasing intensity was studied using dipole source analysis. Contrary to the hypothesis, OCD patients and healthy controls did not differ in their LDAEPs of the tangential dipole in particular, located in the primary auditory cortex and closely related to central serotonergic activity. Furthermore, no significant correlation was found between the severity of obsessive-compulsive or depressive symptoms and the loudness dependence of AEPs. These findings do not support the hypothesis of a serotonergic dysfunction in OCD patients.

Loudness dependence of auditory evoked potentials is not associated with polymorphisms or haplotypes in the serotonin transporter gene in a community-based sample of German healthy volunteers

Three previous studies found an association between the loudness dependence (LD) of the auditory evoked potential N1/P2 component, an indicator of central serotonergic neurotransmission, and a functional variation in the promoter region of the 5-hydroxytryptamine transporter (5-HTT) gene (rs4795541 Ins/Del). The results of these three studies were contradictory and possibly biased by the recruitment methods used. We therefore aimed to re-investigate this association (rs4795541) using a community-based sample randomly selected from the general population and to extend the analysis to four further putative variations in this gene (rs3783594, rs3794808, rs140701, rs6354). In this carefully recruited sample, genotypes or haplotypes under investigation were not associated with LD. We speculate that the LD endophenotype depends more on genetic variations in components of the serotonergic system controlling release than on those controlling the uptake mechanism.

The serotonin syndrome scale: First results on validity

As a modification of the diagnostic criteria of the serotonin syndrome proposed by Sternbach, we developed the Serotonin syndrome scale for the operationalized assessment of both the presence and the severity of the core symptoms of the serotonin syndrome. In a first study on the validity of this scale, the relationships between the serotonin syndrome score (SSS) and both the paroxetine plasma levels (n = 42) and the loudness dependence of the auditory evoked potentials (LDAEP; n = 24) were investigated in depressed patients treated with paroxetine. A strong LDAEP is supposed to indicate low central serotonergic neurotransmission, and vice versa. The SSS was positively related to paroxetine plasma levels and negatively to the LDAEP. Both results support the validity of the serotonin syndrome scale. Using a SSS > 6 as diagnostic criterion, mild serotonin syndromes were diagnosed in 5 of our 42 patients. The Serotonin syndrome scale may become a useful tool for clinicians and scientists dealing with the serotonin syndrome.

Event-Related Potentials and EEG as Indicators of Central Neurophysiological Effects of Acamprosate

The homotaurine derivate acamprosate has been proven to be efficient in reducing alcohol intake both in animal models and in human trials. However, the pharmacokinetic and pharmacodynamic properties of this drug in humans and its underlying mechanism of action are not well known. Earlier studies suggested that acamprosate is effective mainly by increasing GABAnergic neurotransmission. More recently the involvement of excitatory amino acid receptors has been discussed. Zeise et al. (1993) found in intracellular in vitro recordings from rat neocortical neurons that the discharge activity evoked by pulses of l-glutamate is reduced by acamprosate. Extracellular in vivo recordings from rat neocortical neurons revealed that excitatory and inhibitory postsynaptic potentials (EPSP, IPSP) as well as responses to locally administered excitatory amino acids [l-glutamate, l-aspartate, l-homocysteate, and N-methyl-d-aspartate (NMDA)] are reduced by acamprosate. Serotonergic effects of acamprosate may also be of importance. Acamprosate has been found to increase tryptamine-induced convulsions, to increase serotonin concentrations in both blood and cerebral tissue of rats, and to increase the binding capacity of serotonin 1d and 2 receptors (Nalpas et al. 1990; Daoust et al. 1989).