Molecular basis and clinical perspectives of deep brain stimulation for major depressive disorder

Abstract

It is possible to consider the stimulation of the cingulate gyrus in its portion below the corpus callosum (SCC, or subcallosal cingulate cortex) as an effective, promising, and safe alternative intervention for treatment-resistant depression. In studies with deep brain stimulation - DBS, when follow-on with functional magnetic resonance imaging and/or PET-CT (Positron emission tomography–computed tomography) is performed, it is observed an increase in the blood supply and glucose metabolism in this region, which is the anterior part of the limbic system. This same location has good experimental results also for the treatment of anorexia nervosa. The hypotheses suggest a greater activation of the reward system, a greater sense of well-being, and a consequent reduction in depressive symptoms, the objective of the treatment. Over the last 20 years, multicenter studies have shown symptomatic improvement in 50–60% of patients, and about a third even reach criteria for remission of the depressive disorder.

Major depressive disorder (MDD) affects approximately 246 million people worldwide. ¹ Despite its high prevalence, MDD still presents significant drug resistance in up to one-third of the cases and, even with the advance of psychopharmacology, the adverse effects and tolerability are worrying factors for the drugs in development. ² In this context, deep brain stimulation (DBS) appears to be a promising alternative for refractory MDD, although individual response heterogeneity contributes to clinical trials with inconclusive outcomes.

In a first analysis, DBS is a surgical procedure in which the electrode is stereotactically implanted in specific neuroanatomical targets, providing continuous electrical stimulation similar to a pacemaker. ² This method represents the rebirth of neurosurgical techniques for the control of psychiatric conditions in a field of approximation between neurosurgery and psychiatry, called psychosurgery. Although it has existed for almost a century, since the first prefrontal leucotomies performed by neurosurgeon António Egas Moniz, ³ this area became widely known in the 1950s due to lobotomies performed by Walter Freeman. In the following decades, it returned to obscurantism after discussions about safety and controversial indications. ⁴ Currently, DBS is not yet an FDA-approved (Food and Drug Administration) technique for the treatment of depression, but it shows promise.

Regarding the fundamentals that support the biological plausibility of DBS for MDD and, therefore, increase the pre-test probability of its clinical efficacy, we start with the observational finding that there is pathological neural activity in depressed patients, whether due to hyperactivity or hypoactivity of certain neuroanatomical regions. Mayberg et al. hypothesized that DBS could reduce the abnormal hyperactivity of the subcallosal cingulate cortex (SCC) and lateral habenula (LHb) observed in depressed patients, as well as the ability to reverse the hypoactivity of the nucleus accumbens (NAc), also considered a depressing factor. Other areas that were stimulated are the ventral capsule, ventral striatum, internal capsule, medial forebrain, and inferior thalamic peduncle.^2,5

Initial reports on the efficacy of DBS in MDD were positive. However, large-scale randomized controlled trials (RCTs) did not demonstrate significant differences between control and treatment groups. The choice of stimulation target, the electrode placement technique, the patient selection, and the short-term follow-up were possible contributing factors for the negative results. Due to discrepancy between reports, Kisely et al., ⁶ performed a meta-analysis of 10 studies, mostly RCTs, which resulted in a significantly greater response (p < 0.0001) for the reduction of depressive symptoms in patients with active treatment compared to sham treatment. The most recent analyzes are only including blinded RCTs where the study design is to compare active pacing and sham pacing, thus controlling for placebo effects.^6,7

It is possible to consider the stimulation of the cingulate gyrus in its portion below the corpus callosum (SCC, or subcallosal cingulate cortex) as an effective, promising, and safe alternative intervention for treatment-resistant depression. ² In studies with DBS, when follow-on with functional magnetic resonance imaging and/or PET-CT (Positron emission tomography–computed tomography) is performed, it is observed an increase in the blood supply and glucose metabolism in this region, which is the anterior part of the limbic system. This same location has good experimental results also for the treatment of anorexia nervosa. ⁵ The hypotheses suggest a greater activation of the reward system, a greater sense of well-being, and a consequent reduction in depressive symptoms, the objective of the treatment. Over the last 20 years, multicenter studies have shown symptomatic improvement in 50–60% of patients, and about a third even reach criteria for remission of the depressive disorder. ⁸

The epidemiological and socioeconomic implications of MDD culminate in a serious public health issue with significant ethical considerations for individual and collective health. Health parameters indicate that depression is the second leading cause of years lived with disabilities worldwide. ¹ Analyzes also show that economic demands are growing. In the United States, for example, the incremental economic burden of adults with MDD was US$326 billion in 2018, 38% higher than in 2010. ⁹ From this complex socioeconomic scenario, ethics about ECP are not restricted to the invasive and risky nature of neurosurgical procedures but permeate the allocation of resources, distribution, and accessibility of neurotechnologies to vulnerable populations, and the role of the medical device industry in clinical trials. Issues related to these advances are addressed in parallel with the development of rigorously planned and hypothesis-based clinical trials. ¹⁰

Highlights

Deep brain stimulation (DBS) appears to be a promising alternative for refractory - MDD.

Deep brain stimulation - DBS is a surgical procedure in which the electrode is stereotactically implanted in specific neuroanatomical targets.

The stimulation of the cingulate gyrus in its portion below the corpus callosum (SCC, or subcallosal cingulate cortex) as an effective, promising, alternative intervention for treatment-resistant depression