Researchers led by 2019 BBRF Young Investigator Jean-Philippe Miron, M.D., Ph.D., have reported the first clinical test involving a new and more intensive way of delivering transcranial direct current stimulation (tDCS) in people with major depressive disorder. The new method is called spaced tDCS and involves multiple sessions per day delivered over a 2-week period.

tDCS is a form of non-invasive brain stimulation that is less powerful than transcranial magnetic stimulation (TMS), the most widely used non-invasive mode, or rapid-acting variants such as SAINT (Stanford Accelerated Intelligent Neuromodulatory Therapy). SAINT is based on intermittent theta-burst stimulation (iTBS), a specific form of TMS. Both TMS and iTBS-based approaches were pioneered by BBRF grantees and have been approved by the FDA for treatment of depression.

tDCS applies a comparatively weak direct current to the scalp (in the new study, 2 milliamperes) via two electrodes, held in place by a rubber headband worn by the patient. The delivery of electrical current is thought to alter the excitability of brain cells beneath the scalp, but it does not directly trigger nerve cell firing or inhibition as in TMS. tDCS is not rapid-acting—but, as Dr. Miron and colleagues point out, its minimal side-effect profile, simplicity of administration, and comparatively low cost make it an attractive potential alternative to TMS and iTBS.

Trials involving once-daily tDCS have been encouraging but inconsistent. Despite the record of mixed results, recent more intensive stimulation protocols involving two daily sessions of tDCS have been tested in small numbers of patients with schizophrenia. Meanwhile, animal studies have suggested that spaced tDCS stimulation—the delivery of more than one session per day, separated by “intersession” intervals—have suggested that the impact of tDCS stimulation on the excitability of cortical cells is significantly prolonged, compared to a single session.

The newly reported trial is the first clinical examination of spaced tDCS for major depression. The team tested the feasibility, safety and therapeutic effects of a spaced tDCS protocol consisting of five session per day over five consecutive weekdays, during a 2-week period. These 50 sessions were delivered in what is called an open-label trial, meaning those receiving the treatments knew they were getting the “real” treatment and not a placebo version. The team also included BBRF Scientific Council member and three-time grantee Zafris J. Daskalakis, M.D., Ph.D.; 2010 BBRF Young Investigator Daniel M. Blumberger, M.D.; and 2021 BBRF Young Investigator Cory R. Weissman, M.D., Ph.D.

Each of the five daily tDCS sessions lasted 20 minutes, with a 20-minute interval between sessions. The headgear containing the scalp electrodes was removed between sessions, during which time participants were allowed to read or use a computer or cellphone. The electrodes were placed over the right and left dorsolateral prefrontal cortex, with the latter (DLPFC) also being the target of TMS and iTBS protocols.

Thirty individuals were recruited for the trial, two-thirds of whom were female; 28 were included in the analysis. The participants were assessed for depression when initially screened, at “baseline” a week before treatments began, at the beginning of each treatment day, and at follow ups at 1 and 4 weeks following the final treatment session.

“The results demonstrate that the protocol is feasible, safe, and generally well-tolerated,” the team reported in the American Journal of Psychiatry. “The notable changes observed in depression scores at follow-up are promising and provide a basis for further investigations into this approach.”

Using a standard scale of depression symptom severity called HAM-D-17, the 28 participants analyzed had a mean score of 21.3 at baseline, and 15.3 and 13.2 one and four weeks after treatments were completed—significant improvements, even taking into account the placebo effect which tends to magnify the response rate in any clinical trial. The response rate—symptom reductions of 50% or greater—was 21.4% a week after treatments and a much higher 46.4% four weeks after. Rates of remission—in essence, the absence of symptoms—were 10.7% a week after treatments and 32.1% four weeks after. A graph showing changes in symptom scores over time shows both responders and non-responders registering modest declines over the first several days of spaced tDCS sessions, but with the subset of “responders” continuing to have symptom declines steadily and significantly from there, while the non-responders tended to level off and experienced no further symptom relief, on average.

In this therapy as in all other depression therapies, it is not yet understood why certain individuals respond and other don’t—although having a number of different therapeutic approaches is a great boon to patients, as those who don’t respond to one can then try another mode. But in their paper, the team did discuss why spaced tDCS sessions may have better effectiveness—comparable to that of TMS, for example—than once-daily tDCS sessions, which have had a mixed clinical record.

Experiments in animals, they said, indicate that spaced stimulation appears to increase the duration of the aftereffects of stimulation, and therefore, may be a more effective spur to neuroplasticity—the ability of neurons to change the strength of their connections, which has long been viewed as at the heart of antidepressant activity.

The team notes the two primary forms of neuroplasticity: one, triggered by short stimulation sessions, occurs soon after stimulation, and is transient, lasting a few hours. The other, induced by repeated sessions that are separated by an interval, may involve “more complex cellular and molecular mechanisms including those that can lead to new protein synthesis and can enhance synaptic function over periods of days.”

The latter longer-term effects of tDCS have been demonstrated, the team notes, in human experiments focusing on changes in the brain’s motor cortex. These also showed that spaced tDCS was more effective at increasing cortical excitability than single sessions, and that 20-minute intervals between sessions were more effective than having no interval between two sessions, or long intervals between them. In general, the question of how tDCS works, and what the optimal parameters are for spaced sessions, as well as targets in the brain and duration of each session, remain subjects for follow-up studies.

The pattern of gradual improvement over time in reduction of depression severity with spaced tDCS seen in this small trial “is consistent with other intensive or accelerated stimulation protocols [e.g., in TMS and iTBS], where effects appear progressively, sometimes beyond the treatment period.” Future trials might consider longer follow-ups, they said.

While safe, the spaced tDCS protocol involving 5 sessions daily over 2 weeks resulted in nearly two-thirds of the 28 participants developing mild but persistent contact dermatitis at the site of electrode placement—usually in the second half of the treatment course. In every case, these symptoms neither limited treatments nor required separate treatment and went away by the time of the follow-ups. But this side effect does indicate the need for close and daily monitoring of those who receive an intensive course of tDCS as was given in the trial, the team said.