Correspondence

Discontinuation of Superolateral Medial Forebrain Bundle Deep Brain Stimulation for Treatment-Resistant Depression Leads to Critical Relapse

Major depression affects millions of people worldwide and has important social and economic consequences. Since up to 30% of patients do not respond to several lines of antidepressive drugs, deep brain stimulation (DBS) has been evaluated for the management of treatment-resistant depression (TRD). The superolateral branch of the medial forebrain bundle (slMFB) appears as a “hypothesis-driven target” because of its role in the reward-seeking system, which is dysfunctional in depression. Although initial results of slMFB-DBS from open-label studies were promising and characterized by a rapid clinical response, long-term outcomes of neurostimulation for TRD deserve particular attention. Therefore, we performed a systematic review focused on the long-term outcome of slMFB-DBS.

A literature search using Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria was conducted to identify all studies reporting changes in depression scores after one-year follow-up and beyond. Patient, disease, surgical, and outcome data were extracted for statistical analysis. The Montgomery-Åsberg Depression Rating Scale (ΔMADRS) was used as the clinical outcome, defined as percentage reduction from baseline to follow-up evaluation. Responders’ and remitters’ rates were also calculated.

From 56 studies screened for review, six studies comprising 34 patients met the inclusion criteria and were analyzed. After one year of active stimulation, ΔMADRS was 60.7% ± 4%; responders’ and remitters’ rates were 83.8% and 61.5%, respectively. At the last follow-up, four to five years after the implantation, ΔMADRS reached 74.7% ± 4.6%. The most common side effects were stimulation related and reversible with parameter adjustments.

slMFB-DBS appears to have a strong antidepressive effect that increases over the years. Nevertheless, to date, the overall number of patients receiving implantations is limited, and the slMFB-DBS surgical technique seems to have an important impact on the clinical outcome. Further multicentric studies in a larger population are needed to confirm slMFB-DBS clinical outcomes.

Treatment-resistant depression (TRD) is a major cause of disability, with large numbers of patients with depression who either fail to respond or stop responding to conventional treatment approaches. These patients are left with few options after failing psychopharmacological and psychotherapeutic approaches, other than neuromodulation (electroconvulsive therapy or repetitive transcranial magnetic stimulation) and newer treatments such as ketamine and esketamine. Patients with TRD undergo more medication trials and hospitalizations, have higher rates of disability, and have higher rates of suicide. Deep brain stimulation (DBS) in depression has the potential of providing a new treatment to address this serious condition after less invasive strategies have failed. A number of different targets involving modulation of mood neurocircuitry have been investigated in the last 15 years. This chapter will review the history and current evidence of DBS at various targets for the treatment of affective disorders and provide insights into the field.

Limited though promising evidence exists on the efficacy of Deep Brain Stimulation (DBS) of the Medial Forebrain Bundle (MFB) in otherwise intractable patients with Major Depression and Obsessive-Compulsive Disorder (OCD). Herein, we present acute and follow-up results (up to 5 years) of a 42 year old man with a diagnosis of treatment-resistant Bipolar Depression (BD) and comorbid OCD, successfully treated with DBS of the MFB. Regular follow-up visits with psychometric evaluations highlighted a considerable improvement of patient’s depressive and OC symptoms at 5 years from implant. According to the limited, reported experience, we support the efficacy and tolerability of DBS of the MFB as a promising intervention in patients with treatment-resistant BD and comorbid OCD, with specific emphasis on the long-term outcome.

Medial forebrain bundle (MFB) deep brain stimulation (DBS) has anti-depressant effects clinically and in depression models. Currently, therapeutic mechanisms of MFB DBS or how stimulation parameters acutely impact neurotransmitter release, particularly dopamine, are unknown. Experimentally, MFB DBS has been shown to evoke dopamine response in healthy controls, but not yet in a rodent model of depression.

The study investigated the impact of clinically used stimulation parameters on the dopamine induced response in a validated rodent depression model and in healthy controls.

The stimulation-induced dopamine response in Flinders Sensitive Line (FSL, n = 6) rat model of depression was compared with Sprague Dawley (SD, n = 6) rats following MFB DSB, using Fast Scan Cyclic Voltammetry to assess the induced response in the nucleus accumbens. Stimulation parameters were 130 Hz (“clinically” relevant) with pulse widths between 100 and 350 μs.

Linear mixed model analysis showed significant impact in both models following MFB DBS both at 130 and 60 Hz with 100 μs pulse width in inducing dopamine response. Furthermore, at 130 Hz the evoked dopamine responses were different across the groups at the different pulse widths.

The differential impact of MFB DBS on the induced dopamine response, including different response patterns at given pulse widths, is suggestive of physiological and anatomical divergence in the MFB in the pathological and healthy state. Studying how varying stimulation parameters affect the physiological outcome will promote a better understanding of the biological substrate of the disease and the possible anti-depressant mechanisms at play in clinical MFB DBS.

Approximately 50% of patients with major depressive disorder do not respond to their first antidepressant treatment. With more antidepressant treatment trials, an individual's likelihood of achieving remission decreases. Furthermore, treatment resistance has significant negative effects on global functioning. Therefore it is crucial that researchers and clinicians have a thorough understanding of treatment-resistant depression (TRD) and its potential treatments. TRD is broadly defined as a failure to achieve an adequate response to one or more adequate trials of antidepressant therapy. Treatment strategies include optimization, switching, combination, and augmentation. In more severe cases, neuromodulation may be employed. Ketamine and psychedelics are currently under investigation and show preliminary efficacy in rapidly improving depressive symptoms.