Novel Techniques Offer Hope for Treatment-Resistant Depression

Liam Davenport

September 07, 2017

PARIS ― For patients with long-standing, treatment-resistant depression (TRD), two novel techniques, one targeting brainwaves and the other utilizing noninvasive stimulation of the vagus nerve, may offer hope for achieving remission, results of two pilot studies suggest.

It is currently estimated that up to one third of patients with depression have TRD. For these patients, there are few proven treatment options.

In one study, investigators assessed neurofeedback, in which patients were taught to vary their brainwaves in response to audio and visual signals. Results showed that eight of the 20 participants with TRD responded to the treatment, and five achieved remission. Moreover, no adverse events were observed.

In the second study, researchers examined transcutaneous vagal nerve stimulation (taVNS) as an alternative to surgically implanted stimulators in five patients with TRD. Although use of the device was hampered by technical problems, there was a sign of improvement, indicating further study is warranted.

Both studies were presented here at the 30th European College of Neuropsychopharmacology (ECNP) Congress.

Neurofeedback: Response and Remission

In the first investigation, Eunjin Cheon, MD, PhD, Department of Psychiatry, Yeungnam University College of Medicine, Daegu, South Korea, and colleagues built on previous findings in which neurofeedback was shown to improve depressive symptoms and executive function.

They assessed 21 adult patients with TRD, defined as a patient's having persistent total scores of ≥14 on the Hamilton Rating Scale for Depression (HAM-D) and ongoing functional impairment, despite adequate trials of antidepressants.

The patients were assigned to receive either neurofeedback plus medication (n = 12) or medication only (n = 9). The patients who received medication only served as a control group. Neurofeedback was delivered in 12 to 24 sessions over 12 weeks. It consisted of 30 min of beta/sensorimotor rhythm training and 30 min of alpha/theta training.

Serum brain-derived neurotrophic factor (BDNF) levels were assessed in both groups before and after treatment. A battery of measures was administered at baseline and at weeks 1, 4, and 12; these consisted of the HAM-D, the Beck Depression Inventory, the Clinical Global Impression-Severity scale, the Euro Quality of Life Questionnaire 5-Dimensional Classification (EQ-5D), and the Sheehan Disability Scale (SDS).

At week 12, the cumulative response and remission rates in the neurofeedback group were 66.7% (n = 8) and 42.7% (n = 5), respectively. Significant reductions on all five assessment scores were shown between baseline and week 12 (P < .01).

Moreover, the changes in scores on the HAM-D, the EQ-5D, and the SDS over the 12-week study period were significantly higher in the neurofeedback group than in the control group (P < .05).

The investigators note that no significant improvements in assessment scores were observed in the control group. Also, neither group showed significant changes in serum BDNF levels between pretreatment and posttreatment assessments.

An "Otherwise Untreatable" Group

In a statement, Dr Cheon said this was a small study, "so we are a long way from this finding its way into the clinic."

However, she noted that this is the first time neurofeedback has been shown to achieve remission and functional recovery in patients with TRD. "This is particularly important because this is an otherwise untreatable group of patients."

Dr Cheon told Medscape Medical News that the technique "could be used widely" if it is proven to be effective in further studies.

"This neurofeedback machine is very compact, and it's easy to deal with. It's not that difficult to do. And the most amazing thing about this kind of treatment is it doesn't cause even mild side effects."

Dr Cheon said she believes that clinically, neurofeedback would be used in combination with medication. That would increase the likelihood of achieving remission in patients who often receive regimens of two medications as well as other neuromodulation therapies.

The investigators have received approval from the study's ethical board to further investigate the technique's potential, and they are in the process of recruiting more patients.

Henricus G. Ruhe, MD, PhD, Department of Psychiatry Radboudumc, Nijmegen, the Netherlands, who is a member of the ECNP Scientific Advisory Panel, called the study "very interesting" in a press release.

"Although the number of included patients is small, we should consider this pilot study as promising and suggesting that alternative approaches (relative to antidepressants) might be beneficial in nonresponding depressed patients," he said.

More work is now needed to replicate the results and to compare this strategy with alternative treatment options, such as psychotherapy or additional pharmacotherapeutic steps, added Dr Ruhe.

"This will enable the community to determine where neurofeedback must be positioned and/or when it should be recommended in future guidelines."

Vagus Nerve Stimulation

In the second study, Anna Zofia Antosik-Wójcinska, PhD, Institute of Psychiatry and Neurology, Warsaw, Poland, and colleagues conducted a pilot study in which five patients with major TRD were assigned taVNS for 4 hours per day in conjunction with standard medication.

The average age of the patients was 53.6 years (range, 32 - 83 years); the mean time since the diagnosis of mental disorders was 17 years. The average number of episodes of depression was 4.7.

The patients self-administered taVNS to the auricular branch of the vagus nerve, which supplies the skin of the concha. Two of the participants were treated in the hospital, and three performed the technique at home. The mean duration of taVNS was 2.7 months.

Overall, the researchers found that the treatment was well tolerated. The majority of complaints were related to the nature of the equipment rather than adverse events experienced during or after treatment.

Two patients experienced clinical improvements with taVNS, although another reported reductions in involuntary movements of the neck and torso. The other three patients did not experience significant improvements in depressive symptoms.

The researchers note that, owing to the small number of patients and the technical problems that arose with the equipment, it is not possible to determine the effectiveness of taVNS in TRD. They are therefore calling for multicenter, randomized trials.

Dr Antosik-Wójcinska told Medscape Medical News that the investigators themselves are planning a larger study, "but at this moment we are trying to find funds for it, which is very difficult in Poland.

"We hope that maybe next year we will start the new study on a bigger group, because we think that this an opportunity that is different from the surgical method, but offering the same possibilities and good tolerance," she added.

Dr Antosik-Wójcinska pointed out that, owing to the technical problems that patients encountered when using the device, what is needed is a device that is easy to use, particularly by patients who are not technically minded.

In their study, "there were people who had a lot of problems with using it, with the electrode in the auricle. And we think that maybe new technical solutions could offer possibilities for those kinds of people," she said.

"Intriguing Observations"

Asked for comment, Andreas Meyer-Lindenberg, MD, PhD, director at the Central Institute of Mental Health, Mannheim, Germany, who was not involved in either study, told Medscape Medical News that the observations are intriguing and may "add to our range of biological therapies" for depression.

"If you take vagal nerve stimulation, it's been shown to work in the case of implanted stimulators, and if we have something that doesn't require surgical implantation, that will of course increase the uptake," said Dr Meyer-Lindenberg.

"The limitation is it's first observations and it wasn't a controlled study, and the response rates are probably going to be different in a controlled study," he added.

"The other thing is that stimulation at the ear seems to be something that some people don't tolerate well, which is expected, given that that's what the vagus nerve does."

The research was supported by the 2015 Yeungnam University Research Grant. The investigators have disclosed no relevant financial relationships.

30th European College of Neuropsychopharmacology (ECNP) Congress. Posters P.1.i.001 and P.2.f.009, presented September 3, 2017.

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