We have medications that can affect serotonin, norepinephrine, and-to a lesser extent-dopamine. Many other neurotransmitters are involved with mood disorders, but we have no medications yet to target them. Neurostimulation offers a non-systemic somatic approach to depression, often with an improved side effect profile. More in this Q&A.
We have asked Dr Scott Aaronson to answer questions on neurostimulation as it relates to the treatment of mood disorders. He is speaking at this year’s PsychCongress in a presentation titled “Neurostimulation in the Treatment of Mood Disorders.” Dr Aaronson is Clinical Associate Professor in Psychiatry at the University of Maryland School of Medicine and Director of Clinical Research Programs and TMS Services at the Sheppard Pratt Health System in Baltimore, Maryland.
Q: What is neurostimulation and why do we need it?
A. Neurostimulation is a modulation of the central or peripheral nervous system by electrical or magnetic impulses. This is commonly used in neurosurgery and neurology for a variety of applications, including pain management, hearing and visual prostheses, and control of Parkinsonism. There is a long history of psychiatric use related to electroconvulsive therapy (ECT), but more recently, devices providing vagus nerve stimulation (VNS) and transcranial magnetic stimulation (TMS) have both been cleared by the Federal Drug Administration (FDA) for use in depression. Several other devices are currently in the process of review by the FDA or undergoing clinical trials.
There is a tendency to look at somatic therapies for depression being exclusively through neurochemicals, but the brain is as much electrical as it is chemical. After 4 decades of antidepressant drug development, we have not moved much beyond the monoamine hypothesis. We have drugs that can effect serotonin, norepinephrine, and-to a lesser extent-dopamine. Many other neurotransmitters are involved with mood disorders, but we have no medications yet to target them. We can alter neurochemicals by neurostimulation as well as alter aberrant neuronal activity. Neurostimulation offers a non-systemic somatic approach to depression, often with an improved side effect profile.
Q: What methods of neurostimulation are currently available and how do they work?
A. Electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), and transcranial magnetic stimulation (TMS).
The oldest neurostimulation intervention, ECT has been used since 1938. It has the highest rate of response for treatment resistant depression (TRD) of any somatic intervention, up to 60%.1
Treatment involves inducing a generalized seizure, either through unilateral or bilateral electrical stimulation done while the patient is under general anesthesia along with a paralytic agent. The adverse effect burden is quite high and includes the effects of anesthesia, post-ictal confusion, and short term memory loss. There is a high frequency of relapse with 65% of successfully treated patients ill again within 6 months.2 Newer techniques under investigation may reduce adverse effects-ultra brief pulse induction, magnetic seizure therapy, or more focally induced seizures. It is more acceptable as an acute treatment than a chronic one. Most insurance will support the use of ECT.
Treatment involves the implantation of a small battery driven device in the upper chest with electrical leads that are tunneled under the skin and wrapped around the left vagus nerve in the neck. Stimulation is delivered continuously throughout the day for 30 seconds every 5 minutes. This stimulation is carried through the vagus nerve into the brain and has an effect on neurotransmitter synthesis and release. Response to this intervention takes up to 6 months to build and continued improvement has been shown over 5 years.
While having FDA approval since 2005, the use of VNS has been severely limited because of the reluctance of insurance carriers, including Medicare, to provide support, claiming that the evidence for its use has not justified the expense. A recent study looked at dosing of VNS and even low doses show efficacy over time.3 It is hoped that the coming release of new data looking at the efficacy of VNS over 5 years of treatment might encourage a re-evaluation of its use in patients with chronic severe unipolar and bipolar depression.
The use of TMS has experienced significant growth in its use since its FDA clearance in 2009. TMS involves the use of a rapidly moving magnetic field to induce a small electric current in the left dorsolateral prefrontal cortex of the brain, an area that has decreased activity when patients are depressed. There are now 2 devices cleared by the FDA-the Neuronetics device (since 2009) and a device from Brainsway (since 2013). The latter uses a different magnetic configuration and purports to offer deeper stimulation.
Outcomes studies on the Neuronetics device demonstrate a 58% response rate in normal clinical practice in a population with moderately treatment resistant depression (patients failed an average of 2.5 antidepressants prior to treatment).4 The Brainsway study has yet to be published, so comparisons are difficult, but the treatment paradigm uses 5 treatments a week for 5 weeks, rather than 6 with TMS and 20 minutes rather than 37.5 minutes of treatment during every session.
Insurers are slowly increasing their support of this intervention, and many companies now have coverage policies. Issues about treatment of bipolar depression and the use of maintenance treatment have yet to be clarified from research studies. Several other devices are in the process of either FDA review or in clinical trials.
Q. Who are the right patients for neurostimulation?
A. ECT candidates are patients who require quick responses due to severity, suicide risk, or psychosis and are usually fully disabled by their depressions. They have often failed several other interventions, including medications and psychotherapy.
Should VNS become a more reliably covered intervention, one of the best populations would be patients with severe illness that has been chronic. In my experience, ECT responders who require maintenance ECT are ideal candidates. Often they can be maintained with VNS and no longer require ECT. As well, VNS has demonstrated efficacy and has FDA approval for use with bipolar depression, often a population that has limited options for treatment.
TMS, in its current format, is likely not as reliable with severe depression as ECT. It probably will work best with moderate to marked depressions. My experience suggests a better response when used in addition to antidepressant medication but it may also be useful in patients who have been intolerant of multiple antidepressant medications given the lack of systemic side effects. TMS is very well tolerated with only a small incidence of mild to moderate headache during the time of stimulation which is usually for only 4 seconds during each 30 seconds of treatment. The main barriers to use are insurance coverage, time commitment (45 minutes, 5 days a week for up to 6 weeks), and availability of equipment which varies by location.
Q. What does the future hold for neurostimulation?
A.Neurostimulation will likely occupy a greater piece of the psychiatric treatment paradigm. It offers effective interventions for people with severe illness and a non-pharmacologic intervention for patients with moderate to marked presentations. New devices in development may permit shorter courses of treatment and even the possibility of home use.
Suggested reading: Cusin C, Doherty DD. Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS. Biol Mood Anxiety Disord. 2012;2:14.
Dr Aaronson reports that he is a consultant for Neuronetics; an investigator for Neuronetics, Cervel Neurotech, and Neosync; and received a research grant from Stanley Medical Research Institute for Transcranial Direct Current Stimulation.
1. Kellner CH, Knapp RG, Petrides G, et al. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry. 2006;63:1337-1344.
2. Sackheim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: A randomized controlled trial. JAMA. 2001;285:1299-1307.
3. Aaronson ST, Carpenter LL, Conway CR, et al. Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects. Brain Stimul. 2013;6:631-640.
4. Carpenter LL1, Janicak PG, Aaronson ST, et al. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety. 2012;29:587-596.