Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT03999736 |
| Other study ID # |
2019P000167 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
February 13, 2020 |
| Est. completion date |
February 9, 2021 |
Study information
| Verified date |
February 2021 |
| Source |
Mclean Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This is an add-on study to an existing multimodal neuroimaging study in MDD by investigating
the acute effects of DLPFC tDCS on threat vigilance in 24-44 patients with MDD, as part of an
open-label treatment intervention study. Behavioral and neural measures of threat vigilance
will be taken acutely and investigated as predictors of subsequent treatment response to a
four-week, fourteen-session DLPFC tDCS intervention, using a novel home-tDCS protocol. The
design takes advantage of an existing rich set of candidate baseline behavioral, neural and
molecular measures from the existing neuroimaging study, which could be used to predict
treatment response to tDCS and thereby, aid future patient selection for clinical trials.
Description:
BACKGROUND Importance: Over 50% of patients with major depressive disorder (MDD) do not
respond to initial treatment and relapse is common. Poor treatment response is likely due to
limited treatment options, the heterogeneous nature of MDD, its high comorbidity with other
psychiatric conditions (particularly anxiety disorders) and the lack of data to support a
targeted treatment approach. In addition, existing treatments can have negative side effects.
Thus, there is a great need for novel, more targeted treatments. Transcranial direct current
stimulation (tDCS) is a novel intervention that targets neural excitability and plasticity in
regions implicated in the cognitive features of MDD and anxiety disorders. This proposal
applies cognitive neuroscience approaches in a tDCS treatment study to establish biomarkers
of response to inform treatment selection and improve patient outcomes.
Cognitive neuropsychological features of mood and anxiety disorders: Depressed and anxious
patients typically show negative biases in emotional perception and memory, and such biases
are believed to play a fundamental role in the maintenance of emotional disorders. In terms
of neural correlates, functional magnetic resonance imaging (fMRI) studies have confirmed
hyperactive amygdala and/or hypoactive prefrontal activity in patients with MDD and anxiety
disorders, indicating an imbalance of activity within this cortico-limbic circuit. There is
evidence that treatment with antidepressant drugs (Paulus et al. 2005) can reduce amygdala
hyperactivity and cognitive behavioral therapy can increase frontal activation (Ritchey et
al. 2011). In addition, emerging fMRI findings indicate that pre-treatment neural markers can
be used to predict whether patients will respond to behavioral or drug treatments (McGrath et
al. 2014). Following the administration of a single dose of anxiolytic or antidepressant
treatment, early changes in emotional processing have been observed in healthy people and
clinical groups, in the absence of acute mood improvements. Critically, among patients, acute
cognitive effects - such as a reduction in vigilance to threat (e.g. fearful faces) - have
been shown to predict response to drug and behavioral treatments (Tranter et al. 2009;
Reinecke et al. 2013). Thus, baseline and acute behavioral and neural markers could be
leveraged to identify characteristics of likely responders to different treatments.
Specifically, treatments aiming to remediate prefrontal and amygdala dysfunction (underlying
negative biases) could be a critical target in patients with MDD and anxiety disorders
exhibiting these deficits.
Transcranial direct current stimulation: Mounting evidence from clinical trials indicates
that repeated administration (10-15 sessions over 2-4 weeks) of tDCS to the dorsolateral
prefrontal cortex (DLPFC) is a potentially effective treatment for MDD (Brunoni et al. 2015).
However, underlying mechanisms of action are unclear, although spectroscopy imaging suggests
that tDCS causes alterations in inhibitory neurotransmitter GABA (Stagg & Nitsche 2011), and
a recent review (Ironside & Perlo 2018) implicated protective effects on cognition as a
potential mechanism of action for DLPFC tDCS. An initial investigation in healthy volunteers
by the applicant revealed an anxiolytic-like effect (reduced threat vigilance) from a single
session of DLPFC tDCS vs sham tDCS on a behavioral test of proven clinical relevance
(Ironside et al. 2016). To investigate the neural correlates of this effect, the applicant
followed up with an fMRI study which found that, in a sample of trait anxious females, a
single session of DLPFC vs. sham tDCS reduced amygdala response to fearful faces (p < 0.05)
whilst simultaneously increasing frontal attentional control signals (p < 0.001) (Ironside et
al. 2019). This provides causal evidence that modulating activity directly in the DLPFC
inhibits amygdala response to threat in humans, highlighting a potential neural mechanism for
the prior behavioral reduction in vigilance. In addition, this offers initial mechanistic
insights into the efficacy tDCS in the treatment of MDD and anxiety disorders.
Candidate mechanisms of action for tDCS: These acute cognitive neuropsychological effects of
tDCS can mirror acute effects of antidepressant and anxiolytic treatment. This provides a
rationale for patient investigations of tDCS to characterize these as potential markers of
treatment response. The current proposal seeks to apply - the investigators believe for the
first time - these findings to patients receiving tDCS treatment for MDD, using behavioral,
neural and molecular measures to test the predictive validity of acute effects of tDCS on
behavioral threat vigilance (Aim 1), amygdala response to fear (Aim 2) and resting brain
activation (Aim 3) as markers of future treatment response. Additionally, evidence from
magnetic resonance spectroscopy (MRS) indicates that a change in the inhibitory
neurotransmitter GABA is implicated in the effects of tDCS (Stagg et al. 2009) and thus
exploratory analyses will probe the role of baseline GABA in treatment response.
SPECIFIC AIMS
AIM 1: Evaluate behavioral vigilance to threat as a biomarker of treatment response to tDCS
in MDD:
Hypothesis 1: The significant acute reduction in fear vigilance from a single session of tDCS
is similar to that seen with anxiolytic treatments in the same cognitive paradigm, which, for
anxiolytic treatment, was predictive of treatment response (Reinecke et al. 2013). This is
hypothesized as a potential mechanism of action for the clinical effects of tDCS in MDD.
Specifically, it is expected that, compared to non-responders, subsequent responders to tDCS
treatment will show reduced threat vigilance following acute tDCS administration.
AIM 2: Evaluate amygdala response to fear as a biomarker of treatment response to tDCS in
MDD:
Hypothesis 2: Previous findings show that frontal tDCS can reduce amygdalar threat reactivity
in high trait anxious females. The investigators hypothesize that this reduction in amygdala
threat reactivity is predictive of treatment response. Specifically, it is expected that,
compared to non-responders, subsequent responders to tDCS treatment will show decreased
amygdala response to fearful faces, following acute tDCS administration.
AIM 3: Evaluate functional connectivity changes as a biomarker of treatment response to tDCS
in MDD:
Hypothesis 3: The reduction in amygdala threat reactivity by tDCS is caused by increased
connectivity between frontal attentional control networks and the amygdala. Specifically, it
is expected that tDCS will increase resting state functional connectivity between frontal
attentional control networks and the amygdala in responders.
EXPLORATORY AIM: To evaluate baseline measures of DLPFC GABA as a predictor of treatment
response.
STUDY DESIGN Participants: Forty-four unmedicated adults with MDD will be offered an optional
add-on study to an existing large NIH-funded patient study. In current funding applications,
the investigators are requesting funding for 20 patients (existing fellowship funding is used
for 24 pilot participants).
Interventions: After the multimodal imaging protocol (MRS and fMRI, see Day 2; Table 1) from
the existing study is complete, participants will receive 14 sessions of bilateral prefrontal
bipolar tDCS (2mA for 20 mins/session) over four weeks (Day 3 - Day 33). TDCS is a
non-invasive neuromodulatory technique that uses weak electrical current to modify cortical
excitability and neural plasticity. Sessions 3-14 will be self-administered, in the
participants' homes, using a validated remote supervised protocol and specialized home use
device (Soterix Medical, New York, 2018).
Tasks: Participants will carry out computerized tasks, including the validated dot-probe
measurement of behavioral vigilance to threat (Reinecke et al. 2013; Ironside et al. 2016)
and validated fMRI scanner-based attentional control task with fearful distractor faces
(Bishop et al. 2007; Ironside et al. 2019). Crucially, these tasks will measure acute effects
of tDCS after only 1-2 sessions, before any treatment effects emerge.
Measurements: MRS and fMRI data will be acquired on a 3 Tesla (3T) Prisma scanner using a
64-channel head coil. Imaging measurements are taken at baseline (existing study) and after
the first tDCS session. The Montgomery-Asberg Depression Rating Scale (MADRS), Quick
Inventory of Depressive Symptomology (QIDS), State-Trait Anxiety Inventory-State (STAI-S),
and Smith-Hamilton Pleasure Scale (SHAPS) will be administered weekly to assess depression,
anxiety, and anhedonia.
Data analysis: Treatment response will be established as >50% reduction in MADRS scores
following all treatment and baseline/ acute measures will be tested for their power to
predict this response using regression analyses in R. FMRI data (task-based and resting) will
be pre-processed and analyzed using SPM12 and CONN.
RELEVANCE OF THE PROPOSED RESEARCH:
MDD is one of the leading causes of disease burden worldwide, characterized by treatment
resistance and high relapse. Clinical investigations of tDCS as a treatment for MDD show
promise but the mechanisms of action remain unclear. Therefore, an experimental medicine
model is needed to establish the behavioral, neural, and molecular characteristics of
responders to tDCS. Preliminary evidence suggests that tDCS reduces behavioral/neural
vigilance to threat but this has not yet been linked to treatment response in MDD. Through an
innovative approach taking advantage of an existing clinical sample and baseline behavioral,
neural and molecular measurements from an ongoing patient investigation, the proposed study
is expected to provide a better understanding of the mechanisms of action of tDCS in the
treatment of MDD. In addition, any potential biomarkers identified could be used for patient
selection and stratification in larger clinical trials and ultimately - after replications -
in treatment selection in the clinic. Finally, the employment of an innovative, home use tDCS
protocol including remote supervision and patient training/ assessment progresses feasibility
of this novel treatment, furthering the case for translation.
