Neurostimulation for Mood Disorders
September 05, 2014 | US Psychiatric & Mental Health Congress 2014, Electroconvulsive Therapy, Mood Disorders, Transcranial Magnetic Stimulation
By Scott T. Aaronson, MD
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).
ECT
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.
VNS
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.
TMS
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.
Disclosures
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.
References
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. - See more at: http://www.psychiatrictimes.com/uspc2014/neurostimulation-mood-disorders#sthash.q22xAP3P.dpuf
http://www.psychiatrictimes.com/uspc2014/neurostimulation-mood-disorders
Tuesday, September 23 • 10:15am - 11:45am
Neurostimulation in the Treatment of Mood Disorders
Neurostimulation will continue to provide a novel, nonpharmacologic, somatic treatment for mood disorders and eventually other psychiatric illnesses, including obsessive-compulsive disorder, anxiety disorders, and addictive behaviors. This session will provide an up-to-date overview of developments in the use of transcranial magnetic stimulation, direct current stimulation, and electroconvulsive therapy. Relevant data pertaining to patient selection, treatment outcomes, and possible mechanisms of action will be discussed along with a look at the future of neurostimulation with regard to expanding patient populations and insurance support.
Faculty
Director, Clinical Research Programs, Sheppard Pratt Health System, Baltimore, Maryland; Director, TMS Services, Sheppard Pratt Health System, Baltimore, Maryland | | Scott T. Aaronson, MD, is Director of Clinical Research Programs at Sheppard Pratt Health System in Baltimore, Maryland, where he has been responsible for developing a research program dedicated to the development of medications, devices, and genetic tests for the treatment of illnesses across the spectrum of psychiatric...
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Tuesday September 23, 2014 10:15am - 11:45am
Room 2 - TBA (Rosen Shingle Creek Hotel)
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The cingulate cortex, fully transected in Ms. M’s case, is considered a pivotal region in depression neuroimaging studies. Visual inspection of the high resolution CT scans (Figure 1) demonstrates that the patient’s cingulate gyrus was transected at the junctional region of the dorsal anterior cingulate and the mid-cingulate. The transection occurred well forward of the posterior cingulate cortex. The cingulate (and underlying cingulum bundle) is a critical structure in mood disorders. Structural neuroimaging studies have demonstrated a reduction in gray matter volume in the left subgenual anterior cingulate in individuals with depression.18-20 Functional neuroimaging studies of the subgenual anterior cingulate cortex (Brodmann’s area [BA] 25) in depression have also shown this region to be hypometabolic compared with non-depressed controls.20 Other studies have demonstrated that when corrected for the volume loss occurring in this region with depression, BA 25 is actually hypermetabolic compared with nondepressed controls.21 Further, numerous treatment modalities, including medications,22 DBS,3 and sleep deprivation23 have demonstrated decreased metabolism of BA 25. More dorsal regions of the cingulate also have been identified as involved in depression. Studies have found that the dorsal anterior cingulate (dorsal to the corpus callosum and posterior to the genu of the corpus callosum) also undergoes change with depression: positron-emission tomography imaging studies assessing antidepressant and DBS antidepressant response demonstrate increased activation of this region.24,25 How might activation of the left vagus affect the fronto-limbic mood circuitry? Upstream vagal projections synapse with anterior components of these fronto-limbic circuits: most of the upstream afferent fibers of the vagus travel via the nucleus tractus solitaries (NTS).13 Fibers from the NTS project to the central nucleus of the amygdala as well as the nucleus accumbens. Additionally, animal models demonstrate the NTS, synapsing through the parabrachial nucleus, also send projections to the thalamus, the amygdala (particularly the central nucleus of the amygdala, but also the basolateral and other amygdalar nuclei), the anterior insula, and infralimbic cortex, lateral prefrontal cortex, and other cortical regions.13,26 Of note, the predominance of upstream vagal afferent pathways target regions in the anterior/temporal portions of these circuits (ie, amygdala, nucleus accumbens, insula, and prefrontal cortex). The connections between these regions would have been spared in the cingulotomy described in this case report (location of surgical lesion depicted in Figure 3). 
Neuroimaging studies of VNS in TRMD demonstrate that most of the acute effects of VNS in TRMD occur in anterior and temporal regions.27-30 These regions include the anterior cingulate, the insular region, lateral and medial prefrontal cortex, and orbitofrontal cortices. Given the known neuroanatomy and evidence from neuroimaging studies, two distinct (though by no means exclusive) methods by which VNS acts on the fronto-limbic mood circuitry emerge: amygdalar and lateral orbital-insular synaptic pathways. The amygdala is known to have extensive cortical projections, including the rostral insula and temporal pole; however, the strongest of these connections are with the medial prefrontal cortex rostral and ventral to the genu of the corpus callosum.17 Similarly, vagal projections to the lateral orbital cortex (and adjacent anterior insular regions), which likely interact with medial prefrontal regions, may be another mechanism by which VNS acts in TRMD. In both instances, these mechanisms of action seem to have minimal involvement with the posterior limbic/paralimbic circuitry and would not be affected by a bilateral cingulotomy. Understanding the anatomy of the cingulate gyrus and underlying white matter (cingulum bundle) and the mechanism by which this structure integrates with other components of the frontolimbic mood network may provide insights into the reasons for the success of VNS in an individual with a complete bilateral cingulotomy. The anatomy and interconnections of fibers making up the cingulate gyrus are very complex and beyond the scope of this case report. Mufson and Pandya31 used an autoradiographic tracer injection studies in Rhesus monkeys to analyze the constituent white matter components of the cingulum bundle. They found that most cingulum fibers arise from the thalamus, the cingulate cortex itself, and association areas (Figure 3). Fibers from all three origins project both rostrally and caudally. Interestingly, fibers arising from both the anterior and posterior portions of the cingulate cortex projected into prefrontal cortex; however, only fibers from the anterior portion (BA 24; Figure 3, panel A) project into the insula and amygdala. In contrast, fibers originating from the posterior cingulate cortex (BA 23; Figure 3, panel B) did not project to these structures.31 These tracer studies suggest that the principal direct communication between cingulate cortex and other central components (eg, amygdala) of the frontal-limbic circuitry implicated in mood disorders predominantly involves the more anterior cingulate regions. On the basis of this case report, it appears that direct communication between the posterior and anterior cingulate is not necessary for VNS to be efficacious in TRMD. Unlike DBS or VNS, a cingulotomy involves physically lesioning neuronal pathways: a complete bilateral transection of the cingulate cortex would likely cut at least much if not all of the synaptic communication between anterior and posterior components of the “default mode system” (medial and dorsal prefrontal cortex and posterior cingulate cortex).32 Recent studies33 suggest individuals with depression have problems “shifting out” of the default mode system when challenged. Because the default mode system has been associated with self-referential function, it can be suggested that persistent activity in the system may be associated with rumination on self-related, possibly negative thoughts.