Depression, Depressionen

Adverse Events

Adverse events were no different than those previously noted with VNS in patients with epilepsy. No patients discontinued VNS due to adverse events. Most typically occurred only while stimulation was on. No serious, unanticipated adverse events occurred during the study. One patient developed hypomania that resolved with a reduction in stimulation.

Given the small sample size, these findings are preliminary. Furthermore, ratings were not blinded. However, symptomatic responses were accompanied by very substantial improvements in overall function based on the MOS SF-36, which corroborates the symptomatic ratings.

In addition, there was no control group. Without a randomized, sham-control group. one cannot draw definite conclusions about effectiveness in this patient population. However, the severe, chronic, disabling, and treatment resistant nature of the depressive episodes in this patient sample suggests that only 5‐-10% of these patients would have been expected to improve spontaneously or to respond to any established treatment during the 3 months following implantation (Sackeim et al 1993; Thase and Rush 1995). The response rate that was found (i.e. 40%) substantially exceeds these expectations.

Although neither spontaneous improvement nor a placebo response can be absolutely excluded without a control group, several points argue against such effects in this study. First, no patient responded in the 2-week, postimplantation, single-blind recovery period. In fact, no change in HDRS₂₈ average scores between baseline (preimplantation) and recovery was found. This finding suggests that the responses obtained were due neither to the passage of time nor to the nonspecific effects of the treatment process. Second, the nature of the sample itself, with prolonged, index MDEs aggressively treated before study entry. argues against nonspecific effects causing these results.

Third, the follow-up data suggest that patients who initially improved retained that improvement after acute study exit. A pattern of sustained benefit is unlikely to be a “placebo response“ (Quitkin et al 1991; Shea et al 1992; Thase and Rush 1995). Underlying chronic depression and three or more previous affective episodes predict a statistically significant increase in the rate of relapse (Keller et al 1982), so significant relapse would be expected for this population. Since all responders to date have sustained the acute improvernents in the longer term, VNS appears to provide ongoing benefit for those who do respond. In fact, relapse rates of 20-30% have commonly been reported in patients with far less severe. nonresistant major depression while in continuation or maintenance medication treat ment studies (Doogan and Caillard 1992; Feiger et al 1999: Montgomery et al 1988, 1993; Montgomery and Dunbar 1993: Versiani et al 1999). Relapse rates were even higher (up to 50%) among patients who receive ECT (Sackeim 1994; Sackeim et al 1990; Shapira et al 1995). For patients who are medication resistant but who respond to ECT, relapse rates are even higher than for those who are less medication resistant (Devanand et al 1991; Prudic et al 1990; Sackeim et al 1990).

Other findings suggestive of antidepressant activity include:

1) the onset of hypomania in one patient,

2) the fact that two of the five (40%) patients taking no antidepressants responded (equivalent to the overall response rate), and

3) that the trend suggesting lower rather than higher current settings may be associated with a better response (nonblinded investigators would be biased to ward expecting higher settings to be more effective).

This study of VNS delivered by the NCP System in the treatment of patients with severe treatment-resistant depression encourages further investigation of the safety and efficacy of VNS in treatment-resistant depression, especially because the acute benefits of VNS seem to persist. Further studies are needed to determine if, as in epilepsy, benefits beyond those obtained acutely accrue over time.

Future studies should likely give consideration to the following questions:

1. Can nonresponders to VNS during the acute study become responders after long-term treatment with changes in stimulation parameters?

2. Does VNS continue to provide ongoing, sustained symptom relief over months or years following acute phase response?

3. Are there “predictors“ or “correlates“ of response or of time to response?

4. Can medication amounts or types be reduced or eliminated once a stable, sustained response to VNS is obtained?

5. Where does VNS fit into treatment algorithms for managing major depressive or bipolar disorder?

Preparation of this article was supported in part by contracts from Cyberonics Inc. (Houston) to the University of Texas Southwestern Medical Center, Columbia College of Physicians and Surgeons, Baylor College of Medicine, and the Medical University of South Carolina; by National Institute of Mental Health Grants Nos. MH 41115, DAOI 1434-OlAl, and MH 46673; by the Stanley Foundation; by the National Alliance for Research in Schizophrenia and Affective Disorders(NARSAD); and by the Sarah M. and Charles E. Seay Center for Basic and Applied Research in Psychiatry.

The authors especially appreciate the clinical assistance of Drs. Tal Burt, Sarah Lisanby, Kimberly Cress, and Christopher Johnson, as weIl as the assistance provided by Diane Stegman, Monica Molloy, Nicholas Oliver, and Holly Zboyan; the secretarial support of Fast Word, Inc. and David Savage (Dallas); the scientific, technical, and logistical support of Burke Barrett and Amber Hutchison (Cyberonics); and the administrative support of Cyberonics, Inc. (Houston).

Presented, in part, as a poster at the annual meeting of the American College of Neuropsychopharmacology, December 13, 1999, Acapulco, Mexico.