Stimulating the vagus nerve
VNS was introduced for treating refractory epilepsy in 1997. In 2005, it became the first FDA-approved implantable device for managing chronic or recurrent treatment-resistant depression.
The vagus nerve is the principal parasympathetic, efferent tract regulating heart rate, intestinal motility, and gastric acid secretion. Information about pain, hunger, and satiety is conveyed by these fibers to the median raphe nucleus and locus coeruleus, brain regions with significant serotonergic and noradrenergic innervation. These neurotransmitters also are believed to play a pivotal role in major depression.
With VNS, a pacemaker-like pulse generator is surgically implanted subcutaneously in the patient’s upper left chest. Wires extend from this device to the left vagus nerve (80% of whose fibers are afferent) located in the neck, to which the pulse generator sends electrical signals every few seconds (Table 3). The right vagus nerve is not used because it provides parasympathetic innervation to the heart. A clinician adjusts stimulation parameters using a computer and a noninvasive handheld device. Common adverse effects include voice alteration or hoarseness, cough, and shortness of breath, which occur during active stimulation because of the proximity of the electrodes to the laryngeal and pharyngeal branches of the vagus nerve. These effects may improve by adjusting stimulation intensity. The device permits a wide range of duty cycles, but preclinical animal studies indicate that >50% activation periods may damage the vagus nerve. If patients become too uncomfortable, they may deactivate the device with a magnet held over the implantation area.
Two open-label studies evaluated VNS to treat major depression. The first involved 10 weeks of stimulation in 59 subjects with chronic or recurrent, nonpsychotic, unipolar or bipolar depression who failed at least 2 adequate antidepressant trials in the current episode.8 Stable doses of concomitant antidepressants or mood stabilizers were allowed. After 3 months, 18 (31%) patients responded within an average of 45.5 days, and nearly 15% achieved remission. Response was defined as 50% reduction in baseline Hamilton Depression Rating Scale-28 (HDRS-28) score; remission was defined as HDRS-28 score ≤10. Further, clinical response did not differ between unipolar and bipolar depression patients.
In the second trial, 74 patients with treatment-resistant depression received fixed dose antidepressants and VNS for 3 months, followed by 9 months of flexibly dosed VNS and antidepressants.9 At 3 months, response (≥50% reduction in HDRS-28 score) and remission (HDRS-28 score <10) rates were 37% and 17%, respectively, and increased to 53% and 33% at 1 year.
A sham-controlled trial of VNS in 235 depressed patients used similar inclusion and exclusion criteria as in the open-label study by Sackeim et al.8,10 Two weeks after device implantation, patients were randomized to active treatment (stimulator turned on) or sham control (stimulator left off). At 3 months, the primary outcome measure—response rate based on HDRS-24 score—did not differ significantly between the active and control groups (15% vs 10%, respectively). There was, however, a significantly greater improvement in Inventory of Depressive Symptomatology-Self Report Scale scores with active VNS vs sham VNS.
Patients on sham treatment then were switched to active treatment and both groups were followed for 12 additional months, at which time response and remission rates nearly doubled for both groups.11 In a post-hoc analysis, the same investigators found significant improvement with VNS compared with a naturalistic, matched control group with similar treatment-resistant depression.12 The FDA considered this adequate to support efficacy and approved the device for chronic or recurrent treatment-resistant depression in an episode not responsive to at least 4 adequate treatment trials with pharmacotherapy or ECT. Perhaps because post-hoc analyses typically are not sufficient to gain FDA approval, most insurance companies do not reimburse for VNS treatment of depression, and VNS is not frequently used for refractory depression.
Table 3
Vagus nerve stimulation treatment parameters
| Parameter | Units | Range | Median value at 12 months in pivotal study |
|---|---|---|---|
| Output current | Milliamps (mA) | 0 to 3.5 | 1 |
| Signal frequency | Hertz (Hz) | 1.30 | 20 |
| Pulse width | Microseconds (µsec) | 130 to 1,000 | 500 |
| Duty cycle: ON time* | Seconds | 7 to 60 | 30 |
| Duty cycle: OFF time* | Minutes | 0.2 to 180 | 5 |
| *Stimulation cycle is 24 hours per day Source: Epilepsy patient’s manual for vagus nerve stimulation with the VNS Therapy™ system. Houston, TX: Cyberonics, Inc.; 2002, 2004. Depression physician’s manual. Houston, TX: Cyberonics, Inc.; 2005 | |||
A newer option: TMS
TMS is the most recently FDA-approved therapeutic neuromodulation technique for treating depression. In October 2008, a TMS device became available for patients failing to respond to 1 adequate antidepressant trial during the current episode.
TMS delivers intense, intermittent magnetic pulses produced by an electrical charge into a ferromagnetic coil. The pulse intensity is similar to that produced by MRI. The coil usually is placed on the scalp over the left dorsolateral prefrontal cortex (DLPFC) and pulses are delivered in a rapid, repetitive train, causing neuronal depolarization in a small area of the adjacent cerebral cortex, as well as distal effects in other relevant neural circuits (Table 4). TMS typically is administered on an outpatient basis. A standard treatment course for depression consists of 5 treatment sessions per week for 4 to 8 weeks, depending on symptom severity and how quickly patients respond.