NEUE ANSÄTZE IN DER NEUROPHYSIOLOGIE UND IHRE BEDEUTUNG FÜR DIE PSYCHOPHARMAKOLOGIE

Organisatoren: Georg Juckel (München), Ulrich Hegerl (München)

Referenten: E.Roy John (New York), Ulrich Hegerl (München), Irina Antonijevic (München),

Georg Juckel (München)

Diskutanten: Jürgen Gallinat (Berlin), Ulrich Hemmeter (Basel), Matthias Lemke (Kiel)

Ziel des Workshops ist es aufzuzeigen, daß moderne neurophysiologische Verfahren einen wichtigen Beitrag für psychopharmakologische Fragestellungen leisten können. Hierbei ist hervorzuheben, daß im Gegensatz zu allen anderen beim Menschen zur Anwendung kommenden Methoden neurophysiologische Verfahren aufgrund ihrer hohen zeitlichen Auflösung in der Lage sind, zentralnervöse Prozesse in deren zeitlichen Ablauf genau abzubilden. Dadurch können Psychopharmaka-Effekte auf das Nervensystem und die Motorik des Menschen valide erfaßt und klassifiziert werden. Dies erlaubt Rückschlüsse auf die Transmitter-, Hormon- und Rezeptorwirkungen von Psychopharmaka und hilft damit eine beim Menschen bestehende Lücke zu schließen, da beim Menschen diese Wirkungen z.B. mit biochemischen Methoden nicht direkt untersucht werden können. Möglicherweise gelingt durch das Heranziehen von neurophysiologischen Verfahren auch eine bessere und aussagekräftigere Therapieprädiktion, was insbesondere in der Depressionsbehandlung von großer Wichtigkeit wäre.

E. Roy John

Brain Research Laboratories, Department of Psychiatry, NYU School of Medicine, New York

Currently, we use quantitative analysis of spontaneous (EEG) and event-related potentials (ERPs), to develop 1) brain images of working memory (WM) and 2) biological classification of psychiatric patients. We measure WM via the presentation of information items, e.g., faces, letters, and numbers, in a priming set (S1) followed by a matching set (S2) of items that

must be compared with the previous sample. Items in sets S1 and S2 are flashed on a screen at a specific rate and probe stimuli consisting of blank flashes are flashed at the same rate during intervals before and after S1 and S2. We use very narrow band spectral analysis of the EEG and principal component analysis of ERPs to examine voltage fields or landscapes on the head during successive intervals of these delayed matches from sample tasks. Landscapes to probe stimuli after S1 differ from those before, reflecting the engagement of an extensive neuronal population in mediating WM of S1. Analysis of the difference landscape shows that it is a persisting image of the voltage fields elicited by both S1 and S2, varying as a function of the psychiatric patients have been subjected to cluster analysis based on EEG and ERP measurements evaluated relative to a normative data base. Preliminary results indicate that patients with different neurometric profiles respond to different pharmacotherapeutic treatments. Large-scale international collaborative studies are being organized to collect a

patient cohort of sufficient size for prospective confirmation of using predrug neurometric evaluations to predict selective treatment outcomes.

John ER, Prichep LS and Almas M. Subtyping of psychiatric patients by cluster analysis of QEEG. Brain Topogr 4(4) 321-326 (1992)

John ER, Prichep LS, Alper KR, Mas FG, Cancro R, Easton P and Sverdlov L. Quantitative electrophysiological characteristics and subtyping of schizophrenia. Biol Psychiatry 36 801-826 (1994)

John ER and Easton P. Quantitative electrophysiological studies of mental tasks. Biol Psychol 40(1-2) 101-113 (1995)

U. Hegerl , P. Mavrogiorgou, J. Gallinat, G. Juckel

Department of Psychiatry, Ludwig-Maximilians-Universität München

For a more specific application of psychoactive drugs in the individual patient, indicators of central neurochemical functions are urgently needed. Event related potentials reflect directly postsynaptic effects of cortical neurotransmitters (e.g. GABA, glutamate) and indirectly modulating effects of neuromodulators (e.g. serotonin, acetylcholine) on cortical neuronal functioning. They are therefore promising as noninvasive indicators of the function of neurochemical systems. Several recent studies suggest that a relatively specific relationship exists between the loudness dependence of the auditory evoked dipole activity (LDAEP) and central serotonergic function. Dipole source analysis represents an important methodological advance in this context, because auditory evoked N1/P2-subcomponents, generated by different cortical structures with different serotonergic innervations, can be separated. Converging evidence from clinical and preclinical studies suggest that a pronounced intensity dependence of the evoked activity of primary auditory cortices (tangential dipoles) indicates a low central serotonergic neurotransmission and vice versa. The hypothesis is tested that a strong LDAEP is related to a favorable clinical response to serotonin agonists in patients with affective disorders.

SSRI responders (50% decrease in Hamilton Depression Score after 4 weeks, n=12) were compared to corresponding nonresponders (n=17). Responders to preventive lithium treatment (no recurrence with hospitalisation during lithium medication in the last 4 years, n=14) were compared to the corresponding nonresponders (n=9). Auditory evoked potentials to stimuli with five different intensities were recorded (32 channels). Using dipole source analysis, the loudness dependence of the tangential N1/P2-dipole activity was calculated. Depressed patients responding to SSRI were characterized by a significantly stronger LDAEP (p=0.03). In addition, responders to preventive lithium treatment were also characterized by a significantly stronger LDAEP (p<0.01).

These results which are supported by earlier findings in the literature, suggest that patients with a strong LDAEP have a central serotonergic dysfunction and respond favorably to serotonin agonists. The LDAEP can give clinically relevant information concerning the response probability to serotonin agonists in individual patients.

Hegerl U, Juckel G (1993): Intensity dependence of auditory evoked potentials as indicator of central serotonergic neurotransmission - A new hypothesis. Biol Psychiatry 33: 173-187.

Juckel G, Molnar M, Hegerl U, Csepe V, Karmos G (1997): Auditory-evoked potentials as indicator of brain serotonergic activity - first evidence in behaving cats. Biol Psychiatry 41: 1181-1195.

Antonijevic IA, Murck H, Frieboes R-M, Steiger A

Max Planck Institute for Psychiatry, Kraepelinstr. 2-10, D-80804 Munich

An acute depressive disorder is characterised by sleep-EEG changes, including a decrease in REM latency, slow wave sleep (SWS), stage 2 sleep and sleep efficiency and an increase in time awake and REM density. Although not a single one of these changes is specific for depressive illness, the above described pattern of changes is commonly observed in patients with depression, but not in patients suffering from other disorders, such as dementia or anxiety disorders. Following remission of depression after longer-term antidepressive treatment, the sleep EEG is unchanged or improved, though not fully restored, pointing either to trait markers or scars of depressive illness. Unlike the long-term effects, acute effects of antidepressants are quite diverse. Thus, some newer antidepressants reduce REM sleep to a lesser extent than most tricyclic drugs (TCD), challenging the assumption that REM sleep suppression is critical for antidepressant efficacy. Interestingly, the TCD trimipramine does also not inhibit REM sleep.

We have examined sleep endocrine effects of a number of neuropeptides and steroids, in order to further clarify the pathomechanisms involved in depression and to eventually provide new treatment strategies. Thus, growth hormone-releasing hormone (GHRH) and neuropeptide Y (NPY) both promote sleep continuity and stage 2 sleep in patients with depression and matched healthy controls. CRH, which plays a key role for the pathophysiology of depression, has opposite effects, and NPY has been shown to act by inhibiting effects of CRH. Interestingly, we observed that effects of GHRH showed a pronounced sexual dimorphism: thus, sleep promotion was restricted to men (hatched bars), while in females, regardless of diagnosis, GHRH administration decreased sleep continuity and stage 2 sleep (filled bars).

female male female male female male female male

- controls - - patients - - controls - - patients -

Furthermore, we noted that the sleep pattern typically associated with an acute depressive episode differed between male and female patients, suggesting that gonadal steroids might modulate the sleep-EEG changes in patients with depression. Indeed, we and others have shown that oestrogen replacement in peri- and postmenopausal women can improve sleep continuity, can restore the normal SWS pattern and enhance sleep spindle activity.

In summary, we have observed gender differences in sleep-EEG alterations associated with depression as well as in the response to neuropeptide administration, suggesting that development of new treatment strategies which take these differences into account might provide antidepressants with a greater efficacy.

G. Juckel, A. Präßl, S. Froschmayr, P. Mavrogiorgou, U. Hegerl

Department of Psychiatry, Ludwig-Maximilians-Universität Munich

Under clinical conditions, atypical neuroleptics like clozapine or olanzapine seem to induce no extrapyramidal motor symptoms (EPMS). However, it is still an open question whether they produce EPMS at a subclinical level. Twenty-one schizophrenic patients (32.1±10.4 years, 13 males), unmedicated (n=8) and medicated with typical (n=6) and atypical neuroleptics (clozapine, olanzapine; n=7) and 30 healthy subjects (35.7±11.0 years, 12 males) were investigated, using an active measurement device allowing kinematic analysis of facial movements in detail, while watching a witty movie ("Mr. Bean"). The velocity of the facial expression "laughing" was highest in the unmedicated schizophrenic patients, but significantly lower in the patients under typical neuroleptics than in normals. Patients treated with atypical neuroleptics showed similar velocity values as the healthy subjects (Fig. 1). Since none of the patients had clinical signs of EPMS, it is concluded that kinematic analysis of facial expressions is able to reveal subclinical EPMS (Parkinsonism) induced by typical neuroleptics, but no such EPMS under atypical neuroleptics.

Fig. 1 Velocity of the facial expression "laughing" (left angle of mouth) to positive emotional stimuli ("Mr. Bean")