Depression, with serious medical, social and economic consequences, represents a significant burden to both patients and society. Unfortunately, reports suggest that despite the progress that has been made in pharmacologic and psychological treatments, many MDD patients only partially benefit or do not benefit at all [1
]. Additionally, pharmacologic treatments often have a high rate of relapse and intolerable side effects, which further the call for new treatment of MDD.
VNS is a relatively new FDA-approved somatic treatment for depressive disorders [1
] and may provide long-term sustained benefits [1
]. The limitations and adverse events related to VNS are quite obvious, including the involvement of surgery, perioperative risks, and potentially significant side effects such as hoarseness, throat pain, coughing, dyspnea, paresthesia, and muscle. Thus, VNS treatment is limited only to those patients who have exhausted the standard somatic treatments for MDD due to intolerance or lack of response [8
The underlying mechanism of antidepressant action using VNS is not fully understood. Hypotheses are based on the anatomy and function of the vagus nerve, which is implicated in mood control [19
]. It is known that the vagus nerve is a mixed nerve composed of about 80% afferent fibers. It is speculated that antidepressant effects of VNS are attributed partially to the projection of afferent fibers to the nucleus tractus solitaries, which is further connected directly and indirectly with brain structures including reticular formation in the medulla, parabrachial nucleus, the locus coeruleus, the amygdala, hypothalamus, insula, thalamus, orbitofrontal cortex, and other limbic regions responsible for mood and anxiety regulation [5
This clinical trial aims to overcome these limitations by introducing a novel method of stimulating superficial branches of the vagus nerve to treat MDD. The evidence supporting the feasibility of this trial includes: 1) two proofs of concept, non-controlled, clinical trials demonstrated that tVNS can be used as an effective treatment for treatment-resistant MDD in both senior patients [18
] and in epilepsy patients [20
], another important indication of the VNS; 2) An fMRI study [21
] showed that tVNS at specific ear regions can produce significant fMRI signal decreases, which is similar to the brain activity changes produced by VNS [22
]. It is important to note that the same stimulation at ear regions without vagal supply could not evoke similar fMRI signal changes. In addition, only after tVNS, psychometric assessment of research subjects revealed significant improvement in well-being; and 3) two animal studies [25
] demonstrated that stimulation of the certain areas of the ear with vagus nerve supplies can evoke firing of the vagus nerve and produce relatively specific physiological changes (e.g. decreased arterial pressure, heart rate, and intragastric pressure). Thus, results from both human and animal studies have endorsed the rational of the treatments.
In a previous study in senior patients with resistant MDD, Xu and colleagues [18
] found that compared with the drug only group, drug plus electroacupuncture stimulation at a point in the ear where the vagus nerve is distributed can produce greater HAM-D score reduction and more good responders. However, the lack of an accepted control group significantly limited the interpretation of the study. In this protocol, we have included an active control group (sham tVNS), and used a double-blinded design, which could significantly enhance the quality of the clinical trial.
Compared with traditional VNS, tVNS has the advantage of being low cost, safe and non-invasive. Thus, it can be used on patients with mild to moderate MDD. If this study is successful, the results will significantly extend the application of VNS treatment to MDD and other disorders (including epilepsy, bipolar disorder, and morbid obesity) and will result in direct benefit to the patients suffering from these highly prevalent disorders.
Additionally, we believe that this study will also enhance our understanding of acupuncture mechanisms. As an important branch of acupuncture treatment and with extensive application in past decades, auricular acupuncture, with specific indication of different ear acupoints, remains a mystery. The tVNS treatment for MDD provides a unique angle as well as a model to investigate the biological basis underlying acupoint specificity.
Finally, to blind both the investigator and patient, we applied two pairs of carbon-impregnated silicone electrodes, only one of which was wired to give electrical output; thus, neither patients nor physicians know whether they received real or sham tVNS. This double-blinded design can significantly improve the quality of the trial and will shed new light on the development of methodologies in clinical trials of acupuncture treatment.
In summary, in this clinical trial, we are evaluating the efficacy of tVNS in mild and moderate MDD patients using a randomized and double-blinded design. The success of the trial will significantly improve the application of this promising new method.
The first participants were included on May 18, 2011. There are 49 participants recruited until the point when this paper was submitted on September, 2012.