Depression, Depressionen

Objectives
Depression is now being recognized as a chronic or recurrent, disabling lifelong illness, rather than an isolated single episode from which lasting recovery can be expected. A well-tolerated treatment that provides both acute symptom relief and longer term benefits for this lifelong illness is needed (Glass 1999).

Vagus Nerve Stimulation (VNS), delivered by the NCP System (Cyberonics, Houston) for treatment-resistant partial-onset seizures in epilepsy, has been commercially available in Europe since 1994 and in the United States since 1997. The idea of using VNS as a treatment for clinical depression was initially based on 1) clinical observations of improved cognition and mood during studies of patients with epilepsy (Handforth et al 1998; Vagus Nerve Stimulation Study Group 1995) and 2) the fact that several anticonvulsant medications, including carbamazepine (Ballenger and Post 1978; Okuma et al 1973), gabapentin (Harden et al 1999a; Letterman and Markowitz 1999), lamotrigine (Calabrese et al 1999; Fatemi et al 1997), and valproate (Swann et al 1997), are used to treat mood disorders. Whereas decreased seizure frequency may have accounted for some mood improvement in patients with epilepsy who were treated with VNS, even some of those with little or no seizure improvement also reported substantial mood improvements (Harden et al 1999b; G. Elger et al, unpublished data, 1999). A detailed rationale for the use of VNS in the treatment of depression is provided in another article in this issue (George et al 2000).

Objectives

Our four-site study assessed the safety and efficacy of VNS in treating patients with treatment-resistant, chronic or recurrent, nonpsychotic, major depressive, bipolar I or bipolar II (both in the depressed phase) disorders. Vagus Nerve Stimulation was used with or without antidepressant medications. We aimed to 1) determine the degree and timing of antidepressant effects, if any, utilizing reliable, clinical assessments; 2) determine the safety and tolerability of VNS in this patient group; and 3) determine whether a randomized safety and efficacy study was warranted.

This open-label, nonrandomized, single-arm study of VNS was designed to enroll up to 45 patients to obtain a total of 30 treated patients who had implants under Investigational Device Exemptions (1980) approval from the United States Food and Drug Administration and appropriate institutional review board approvals.

Recruitment/Consent

All aspects of the protocol were managed in compliance with current United States regulations and international guidelines pertaining to good clinical practices.² The protocol and all amendments were reviewed and approved by each study site's institutional review board. Each patient signed a written informed consent.

We selected subjects who had prominent and definitive histories of treatment resistance, which in turn led to a sample with a very chronic prior history characterized by multiple treatment attempts in both the current and previous episodes, to ensure that the risk of an entirely untested intervention requiring surgery would be a logical and ethical consideration for every patient or participant.

Methods and Materials

Study Population

Patients had to have a DSM-IV diagnosis of major depressive disorder (MDD) or bipolar I or II disorder (American Psychiatric Association 1994). They had to be in a major depressive episode (MDE). The current MDE had to be >2 years in duration, or the patient (whether with unipolar or bipolar disorder) had to have >4 MDEs in his or her lifetime.

Patients also met the following inclusion/exclusion criteria. Men and women 18 to 70 years old were eligible, except for pregnant women and women not using acceptable birth control methods, which included abstinence. Patients had to

1) score >3 on the Antidepressant Treatment History Form (ATHF; Oquendo et al 1999; Prudic et al 1990, 1996; Sackeim et al 1990), indicating that they had failed on >2 antidepressant medication treatments from different medication classes during the current MDE³

2) have had no substantial clinical improvement with psychotherapy (at least 6 weeks);

3) score >20 on the 28-item Hamilton Depression Rating Scale⁴ (HDRS₂₈ Hamilton 1960, 1967; Williams 1988);

4) score < 50 on the Global Assessment of Function (GAF; American Psychiatric Association 1994); and

5) have an >lQ 70 (investigator judgment). Those with bipolar disorder had to have either resistance, intolerance, or a medical contraindication to lithium.

² protocol was conducted in compliance with the Investigational Device Exemptions Manual (1996: IDE Number G980099) and was monitored hy Cyberonics, Inc.

³ ciasses included selective serotonin reuptake inhibitors, heterocyclic antidepressants, monoamine oxidase inhibitors, other antidepressant medications, Iithium, electroconvulsive therapy, und anticonvulsants.

⁴ The 28-item Hamilton Depression Rating Scale includes atypical symptom features (anergia, hypersomnia, increased appetite, and rejection sensitivity).