Depression, Depressionen

Mood Effects in Epilepsy Patients:

Initial uncontrolled clinical observations and, more recently, a prospective study (Harden et al 1999) and a retrospective data analysis (Elger et al unpublished data, 1998) suggest that VNS reduces depressive symptoms in patients with epitepsy - reductions that are not entirely accounted for by reduced seizure activity. During the clinical trials of VNS for epilepsy (Ben-Menachem et at 1994; Handforth et al 1998) several investigators noted mood improvements in their patients. Although decreased seizure frequency likely accounted for some of these improvements, the clinical impression was that they went beyond those attributable to improved seizure control alone. For example, some patients with minimal or no improvement in seizure frequency also reported substantial improvements in mood. lmproved quatity of life was also seen, and without seizure frequency changes in some patients. Thus, while no specific measures of depressive symptoms were obtained during the epilepsy trials, these repeated reports frorn independent investigators suggested that VNS might be associated with significant mood improvement. This is reminiscent of the “psychotropic“ effects reported in epilepsy patients treated with carbamazepine, which led to the clinical trials in mood-disordered patients (Ballenger and Post 1980). In a recent prospective study of patients with epilepsy (N = 34), a trend toward mood improvements was seen in the 14 who received VNS, based on the Cornell Dysthymia Rating Scale (p < .1; Harden et al 1999). The significant improvement in seizure frequency found in the VNS group was not retated to mood changes on an individual basis. The authors suggested that VNS might improve mood independent of seizure frequency reduction.

PET Studies of Limbic Activation

In 10 patients with epilepsy who received VNS, PET measurements were taken three times before and then during VNS (Henry et al 1998). The results demonstrated increased brain blood flow from rest to during VNS in the rostral medulla, thalamus, hypothalamus, insula, and postcentral gyrus, with greater activation on the right side (contralateral to the device). In contrast, blood flow was significantly decreased during stimulation bilaterally in the hippocampus, amygdala, and cingulate gyrus. The cingulate gyrus has been repeatedly implicated in imaging studies of depression pathogenesis, and a decline in cingulate activity with antidepressant response has been seen in numerous studies (sleep deprivation [Ebert et al 1994: Wu et al 1992], selective serotonin reuptake inhibitor treatment [Mayberg et al 1997], symptom provocation with drugs [Bremner et al 1997]. Thus, VNS changes in activity of the brainstem, limbic system, and other CNS areas are compatible with antidepressant activity.

Anticonvulsants as Mood Stabilizers

A third reason for considering the role of VNS in the treatment of rnood disorders is the substantial evidence that anticonvutsant medications have mood-stabilizing effects (Goodwin and Jamison 1990; Post et al 1992). Within the last 20 years, several anticonvulsants have found a role in mood stabilization (carbamazepine [ lenger and Post 1980; Okuma et al 1973], vatproic acid [ and Delucchi 1989; Swann et al 1997]) or as antidepressants in (depressed phase) bipolar disorder (lam otrogine; Faterni et al 1997). Further, it is weil established that our most effective antidepressant treatment, ECT, has powerful anticonvulsant effects (Sackeim 1999; Sackeim et al 1983). Thus. it is reasonable to hypothesize that an effective antiepileptic device might also have antidepres sant or mood-stabilizing effects.

Neurochemical Changes

The basic mechanisms of action of VNS are unknown. However, both clinical and animal studies indicate that VNS likely results in changes in serotonin (Ben-Menachem et al 1995), norepinephrine (Krahl et al 1998), GABA, and glutamate (Walker et al 1999) -neurotransmitters implicated in the pathogenesis of major depression. Vagus nerve stimulation in animals activates the LC, the main source of CNS norepinephrine-containing neuronal cellbodies (Naritoku et al 1995). In patients with epilepsy, VNS appears to increase cerebrospinal fluid 5-hydroxyindoleacetic acid - a metabolite of serotonin (Ben-Menachem et al 1995). Since many of the currently available therapies are believed to work using the same neurotransmitters (serotonin or norepineprine), it was hypothesized that VNS might also have antidepressant activity.

Further, there is a long history of autonomic nervous system dysfunction in depressed patients, which is medicated by the vagus nerve. These abnormalities include differences in heart rate variability (for review, see Glassman 1998). Thus, if depressed patients have abnormalities in brain regions that control the vagus nerve (top-down regulation), then stimulating the vagus nerve might theoretically engage this dysfunctional circuit (a bottom-up approach).

Summary

Several lines of evidence pointed toward the possible benefit of VNS as an antidepressant or mood-stabilizing treatment. These included clinical observations in epilepsy patients. anatomic afferent connections of the left vagus nerve to the CNS and to structures relevant to mood regulation, the anticonvulsant activity of VNS taken in the context of the role of anticonvulsant medications or ECT in treating mood disorders, neurochemical studies indicat ing VNS effects on key neurotransmitters involved in mood regulation. and evidence that VNS changes the metabolic activity of key limbic System structures. This evidence led to the initial open trial described in the companion article in this journal (Rush et al 2000).