Depression, Depressionen

Editorial
The important clinical findings will now stimulate research into the mechanism of the antidepressive effects of VNS. lt will be important to determine which of the complex array of VNS effects are shared by the anticonvulsant and antidepressant actions. The laboratory animal models available to study anticonvulsant mechanisms have more validity and more reliable end points than animal models of depression. With these models and selective lesions in specific pathways in combination with systemic or local pharmacologic interventions, it should be possible to clarify the central anticonvulsant mechanisms involved.

The vagus nerve has a large percentage of afferent sensory fibers (over 80%) that terminate in the nucleus of the solitary tract. This in turn projects to many brain areas, including the main norepinephrine-containing nucleus, the LC, and the parabrachial nucleus, which have extensive projections to all levels of the forebrain.

lt is interesting that LC lesions or inactivation of the LC by lidocaine reverse the seizure-attenuating effects of VNS, suggesting that the noradrenergic system is an important part of the anticonvulsant effects (Krahl et al 1998). This is supported by the finding that VNS enhances retention of memory in humans (Clark et al 1999) and that, at least in rats, vagal efferents are not involved in the effect (Clark et al 1998). Activation of the LC via vagal mechanisms (i.e., colon distention) involves both corticotrophin-releasing factor and excitatory amino acids (Lechner et al 1997). Whether or not the LC is a major factor in the antidepressant effects will be an important discovery. lt is interesting that the vagus nerve may be involved in the short-term improvement of depressed patients‘ moods following endotoxin administration, which increases plasma cytokines (Bauer et al 1995), since many brain responses to intravenous cytokines are dependent in part on the vagus nerve (Fleshner et al 1998).

With the use of VNS for the treatment of epilepsy, it has been possible to study VNS-induced changes in regional cerebral blood flow and a variety of neurochemical mea sures in cerebrospinal fluid. Some idea of the essential factors can be obtained through comparison of responders with nonresponders. A similar process can be used with VNS as a treatment for depression. lt will be very interesting to observe whether or not VNS produces the same physiologic and behavioral changes in both the epileptic and depressed patients. Just as the discovery of the monoamine oxidase inhibitors led to the monamine theories of depression, the effectiveness of VNS will now stimulate progress in developing the anatomic and neurophysiologic aspects of antidepressant action.

The reports by Rush et al and George et al are received with enthusiasm for the promise they hold for psychiatry, tempered by scientific skepticism. That controlled trials and animal studies are in the offing is of considerable importance for establishing efficacy and understanding mechanism of action. For now, compassionate use in selected TRD patients - those with the greatest chronicity and severity and multiple aggressive antidepressant trial failures - appears justified.

WAC 812
Boston, MA 02114-3117

Department of Psychiatry
Yale University School of Medicine
34 Park Street
New Haven, CT 06510