Depression, Depressionen

Editorial
Given the excitement among clinicians, sufferers, and scientists about a potential therapeutic advance for a treatment-resistant disorder, and despite the considerable “circumstantial“ evidence for efficacy, colleagues must abide for now with some circumspection until efficacy is established. lt is true that many signs are positive: the unexpected rnood irnprovement in epileptics treated with VNS (unassociated with change in seizure frequency); positron emission tomography studies revealing activation of limbic structures; neurochemical findings suggesting influences on serotonin, norepinephrine, -y-aminobutyric acid, and glutamate (our “usual suspects“); neuronal path ways that link vagal afferents eventually to the amygdala and infralimbic cortex: and evidence that locus ceruleus (LC) function is involved with VNS effects (Krahl et al 1998). The current report extends the optimism for psy chotropic potential from these earlier observations by reporting improvement in 40% of a sample of 30 MDD patients with chronicity and recurrence, combined with multiple adequate treatment failures. The reason to be at least tem skeptical is of course the track record of many promising psychiatric treatments when matched against the daunting challenges of placebo and subject/rater blinding. The potency of a placebo that combines novelty, surgery, and electrical stimulation is likely to be quite high, but no doubt mitigated to some extent by a chronic and refractory condition. Still (and we are speaking from experience with this clinical population), placebo and blinding can be a recipe for disappointment. The good news is that a multicenter, controlled trial is planned.

The NCP System for delivering VNS (Shachter and Saper 1998) is a nifty device that has the advantage of several thousand patient years of experience. lt does require surgery, a procedure similar to implanting a pacemaker in a pouch in the left chest wall and approaching the left vagus nerve in the neck, as with an endarterectomy, to attach the lead. A connection is made between device and lead by tunneling subcutaneously. Stimulus parameters can be refined and the device operated remotely. Although the intensity of stimulation determines the degree of comfort. most patients find a dose they can tolerate without having to drop out of treatment, and an external magnet allows the patient to transiently suspend the stimulus when it is uncomfortable or interferes with function. Hoarseness of voice is the most common complaint. but throat or other pain, cough, and dyspnea also can occur. Surgical complications are a risk, of course, but are typically transient. No dropouts due to adverse events are reported in the Rush et al (2000) trial. The long-term consequences of vagus stimulation remain to be observed, but benefits may accrue, such as the possibility of other psychotherapeutic targets, possible synergistic effects with other treatments, and evidence of irnprovement in word recognition memory with the treatment (Clark et al 1999).

Left vagus stimulation is thought to have minimal impact on cardiac function, less than that of right vagus stimulation, but as noted in the review by George and colleagues, transient asystoles lasting 10-‐20 sec have been observed during implantation. Further, since the device has been widely used in severe, treatment-refractory epilepsy, sudden deaths have occurred, but no more, and possibly less, than the number predicted as a consequence of sudden unexpected, unexplained death in epilepsy (Annegers et al 1998).

Only five of 30 subjects were considered complete responders. At a cost per device of over $9000, and when additional costs of surgery and management are considered, the price of this outcome could be estimated at between $300.000 and $600,000 to generate the five full responders. At these prices benefits surely need to be sustained, and the evidence presented suggests this to be the case for both the full and partial responders. The NCP System is generally covered by third parties for epilepsy, a hopeful predictor of coverage if the device establishes efficacy in TRD. Needless to say, predictors of response would greatly improve the cost-benefit analysis; furthermore, early identification of good candidates for VNS could avoid repeated failed trials of other interventions, leading to cost savings. On the other hand, for the patient with TRD, living the one life he or she has been issued, calculations of therapeutic possibility replace those of cost.