Introduction
In patients with severe depression who do not respond to conventional pharmacological or psychotherapeutic treatments, deep brain stimulation (DBS) has emerged as a treatment option (1,2). DBS is believed to modulate pathological network brain activity through electrical stimulation (3). However, the efficacy of DBS for depression remains inconclusive (4) and one possible reason for these unsatisfactory results is that previous studies did not consider psychiatric comorbidities, such as anxiety disorders.
Generalized anxiety disorder (GAD) is characterized by persistent and excessive worry that interferes with daily life functioning. It is commonly co-occurring with depression (5), leading to reduced quality of life and increased suicide risk (6). To date, only case reports have described the treatment outcomes of DBS for severe anxiety or GAD. One case report from our research group describes improvements in a patient with anorexia nervosa, severe anxiety, and depression symptoms from DBS in the bed nucleus of stria terminalis (BNST) (7). Initially, the patient received DBS in the medial forebrain bundle (MFB) area which effectively reduced depressive and anxiety symptoms but was discontinued due to side-effects (blurred vision). Two years later, the DBS target was switched to BNST resulting in improvements in depression and anxiety symptoms. A similar recovery was described by McLaughlin et al. who reported a positive outcome after DBS in the ventral capsule/ventral striatum (VC/VS) in a patient with anorexia nervosa, depression, and GAD (8).
The above reports describe DBS delivered into BNST or VC/VS which are brain targets in close anatomical proximity to one another, believed to be part of the anxiety network (9,10). Other DBS anxiety network targets include the ventral anterior limb of the internal capsule (vALIC), and nucleus accumbens (NAc). DBS targeting this network has shown promise in treating obsessive-compulsive disorder (OCD), see Meyer et al. for review (11), with some studies showing reduced symptoms of depression and anxiety which indicate that the anxiety network may also influence mood regulation (12,13).
However, DBS studies on patients with treatment-resistant depression, targeting the anxiety network, have yielded mixed results. For example, Dougherty et al. found no significant differences in depressive symptoms between patients randomized to active or sham stimulation in VC/VS after twelve weeks (14) and after two years, only seven of the 30 patients showed a treatment response. In contrast, Van der Wal et al. found that active vs. sham DBS in vALIC significantly reduced depressive symptoms, although differences in study design complicate direct comparisons to other studies (15). Open-label studies targeting BNST (16), NAc (17), or BNST and NAc simultaneously (18) showed treatment response of depression in a majority of the patients after one year or longer.
Given the limited research on DBS for patients with treatment-resistant depression and comorbid anxiety or GAD, we here present two cases that were initially planned for DBS in the MFB area. Based on our previous results in reducing anxiety symptoms in OCD through DBS in BNST, we included BNST as an additional target (13). Both patients received bilateral dual electrodes in the MFB and BNST, randomized to either target, followed by cross-over stimulation for six months. The patients were then followed for up to five years, with monitoring of depressive and anxiety symptoms and overall functioning.