- a major depressive episode lasting >2 years or >4 lifetime major depressive episodes
- nonresponse to ECT or ≥2 adequate antidepressant trials (ATHF scores >3) during their current major depressive episode (median duration: 4.7 years)
- DSM-IV diagnosis of major depressive disorder or bipolar type I or II disorder depressed phase.
- baseline scores ≥20 on the 28-item Hamilton Rating Scale for Depression (HRSD-28) and ≤50 on the Global Assessment of Functioning (GAF) scale.
Two weeks after implantation, the stimulator was turned on and adjusted for another 2 weeks to the maximum tolerable dose. Patients then received 8 weeks of fixed-dose stimulation. Participants who had been taking an antidepressant, mood stabilizer, second-generation antipsychotic, or other psychotropic at the same dosages for ≥4 weeks before the study could continue their medications during the VNS trial (median concurrent treatments: 4).
Three months after implantation, 18 of 59 subjects (30.5%) showed clinical response (≥50% improvement in HRSD-28 scores over baseline). Nine patients (15.3%) showed depression remission (HRSD-28 score ≤10). Median time to first response was 45.5 days.
Twenty participants (34%) showed a ≥50% reduction in baseline Montgomery-Asberg Depression Rating Scale (MADRS) scores, and 22 (37%) showed Clinical Global Impression-Improvement Scale (CGI-I) scores improving to 1 or 2.
Therapeutic effects did not differ among patients with unipolar and bipolar depression. Participants with mild to moderate depression (defined as 2 to 3 failed adequate trials) showed higher response rates (50% vs. 29.1%) than did those with more-severe depression (defined as ≥4 failed adequate trials).2
Among 28 patients followed for 1 year, 13 (46%) met HRSD-28 response criteria (≥ 50% score reduction) and 8 (29%) met remission criteria (score ≤ 10), showing gradual improvement.1 After 2 years, 44% of patients met HDRS-28 response criteria, and 22% met remission criteria, showing sustained benefit.7 How many subjects were taking one or more concomitant psychotropics is unknown.
In a double-blind controlled trial, 235 subjects ages 18 to 80 received VNS or a sham comparator.8 Treatment response and remission were defined as ≥50% reduction from baseline and ≤9, respectively, on the 24-item HRSD (HRSD-24). Patient selection criteria were similar to those of the open-label study.
All patients received VNS implants, which were inactive the first 2 weeks. Patients were then randomly assigned to active treatment (stimulator turned on) or sham control (stimulator left off). After 10 weeks of treatment, HRSD-24, CGI-I, and MADRS scores were similar between the VNS and sham groups, but Inventory of Depressive Symptomatology Self Report (IDS-SR) scores improved much more in the active treatment group (P<0.03). Patients in the sham group then had their stimulators turned on.
After 1 year of active treatment for both groups, response and remission rates more than doubled among 205 evaluable subjects (response: 14.4% to 29.8%; remission: 7.3% to 17.1%). MADRS and IDS-SR scores also improved. Three percent of subjects dropped out because of adverse events.
Another analysis of these data revealed significant improvement among the VNS treatment group vs. a comparator-matched control group of treatment-resistant patients across 2 years.8
Depression treatment among patients in the comparator group followed standard clinical practice.
Side Effects
Voice alteration or hoarseness was most commonly reported after 12 weeks in the open-label trial (55% of subjects). Headache (22%), cough (17%), shortness of breath (15%), neck pain (17%), dysphagia (20%), and pain (15%) were also reported.2 These effects emerge or increase with stimulation intensity and may be ameliorated by reducing the dose.
Small risks of infection (1%) and nerve damage (1%) were reported. Leaving the stimulator off for 14 days after implantation decreases nerve damage risk. Pain at the incision site (experienced by 30%) resolved after 1 to 2 weeks.2 Other adverse events included:
- hypomania in one bipolar patient; this was resolved by adjusting medication and reducing stimulation
- leg pain in 2 subjects
- worsened depression in 5 patients (2 of these may have been related to stimulation)
- emesis and diarrhea in 1 subject.
One patient with multiple cardiac risk factors developed a myocardial infarction but completed the trial after angioplasty and stent placement.2
After 1 year in the open-label trial, no subjects dropped out because of adverse events. Common side events included voice alteration (21%), shortness of breath (7%), and neck pain (7%). More-serious adverse events reported between the acute trial and 12-month follow-up included hypomania (2 episodes), one deep venous thrombophlebitits episode, and one episode each of back pain and appendicitis.1 No cognitive effects have been reported.
In the double-blind controlled trial, 31 of 235 subjects (13%) experienced worsening of depression, and 25 of the 31 depressed subjects attempted suicide.9 Whether these effects were related to the depression or VNS stimulation is unclear. Side effects reported more frequently in the active treatment group than in the sham control group included voice alteration (68% vs. 38%), cough (29% vs. 9%), shortness of breath (23% vs. 14%), dysphagia (21% vs. 10%), and neck pain (21% vs. 10%).