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.