Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT04661475 |
| Other study ID # |
13/2020 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2021 |
| Est. completion date |
March 2, 2023 |
Study information
| Verified date |
December 2020 |
| Source |
Sultan Qaboos University |
| Contact |
Mohammed Salim A Alawi, MD |
| Phone |
+14379725277 |
| Email |
alalawim[@]squ.edu.om |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Major depressive disorder (MDD) is a highly prevalent and disabling condition for which the
currently available treatments are not fully effective. Existing unmet needs include rapid
onset of action and optimal management of concurrent agitation. Preliminary data support
Dexmedetomidine as an antidepressant with fast onset of action, which would be especially
helpful for patients experiencing treatment resistant depression, and agitation This trial
will recruit 76 participants from the ECT waiting list at department of psychiatry and
randomize them to either Dexmedetomidine infusion (0.5µg/kg/hr for 15 mins ) adjunct to ECT
or Placebo adjunct to ECT( Saline) treatment arm added to standard anesthetic induction in
depressed patients who have been prescribed ECT utilizing fixed randomization schedule that
allocate subjects in to a 1:1 ratio between two arms.. Participants will receive ECT as
described in the study schedule and as decided by their treating physician. Throughout the
study, clinical, neuroimaging, molecular, and cognitive assessments will be conducted.
The trial aims to show that compared with Placebo adjunct to ECT( Saline) treatment,
Dexmedetomidine infusion adjunctive treatment will lead to higher and faster response rate in
depression, lesser number of ECT sessions required to achieve antidepressant response, less
incidence of confusion post ECT and comparable incidence of side effects . This could lead to
faster, more effective treatment for patient with depression
Description:
Dexmedetomidine adjuvant treatment for depressed patients undergoing ECT. A double blind,
placebo controlled, randomized Feasibility Study Protocol.
Introduction Major depressive disorder (MDD) is one of the most common mental illnesses, with
lifetime prevalence around 7.2% (Lim et al., 2018). MDD has a detrimental impact on the
quality of life and the ability to function of those affected by it and is considered one of
the leading causes of disability worldwide (Vos et al., 2015). Moreover, MDD is associated
with a significant disease burden for the affected individuals, their families and society at
large (GBD 2015 DALYs and HALE Collaborators et al., 2016). By 2030, MDD is predicted to have
the highest impact (i.e. most debilitating) among all conditions worldwide (Mathers et al.,
2006). Although full remission is seen as the ultimate target for individuals suffering from
MDD, existing evidence suggests that approximately two-thirds of MDD patients fail to attain
or maintain full remission with the currently available antidepressant treatments (Trivedi et
al., 2006). Individuals who do not have a satisfactory response to at least two different
antidepressants at their adequate dose/duration of treatment are considered to be
treatment-resistant depression (TRD) patients (Fava et al., 2003). TRD or difficult to treat
depression (DTD) represents a clinical challenge, with a significant burden that is hard to
estimate, as this condition is multi-episodic, often pervasive, with chronic and severe
symptoms (Fekadu et al., 2018; Zhou et al., 2015).
Depression is a heterogenous disorder, both phenotypically and neurobiologically, with
psychomotor agitation being a significant clinical challenge when treating individuals with
this disabling condition (Fried et al., 2015). Another pragmatic challenge is the
optimization of treatments for patients who exhibit concurrent subthreshold symptomatology of
hypomania or mania. Although there are several guidelines available for the treatment of
unipolar depression, bipolar depression and bipolar mania, specific treatments for depression
with psychomotor agitation, depression with anxious- distress and depression with mixed
features are scarce. Hence, there is a need for new therapeutic agents that could target this
subset of depressed individuals.
Dexmedetomidine (DEX). DEX, (S)-4-[1-(2,3 dimethylphenyl)ethyl]-3H-imidazole], is a selective
and potent α2-adrenergic receptor (α2-AR) agonist which was approved for the sedation of
patients admitted to intensive care units (ICUs) by the FDA in 1999 (McCutcheon et al.,
2006).
Mechanistic evidence of DEX antidepressant activity DEX Pharmacological characteristics
{INSERT FIGURE 1} DEX is the S-enantiomer of the veterinary sedative: medetomidine. DEX is a
highly selective α2-adrenoceptor agonist with an α2:α1 selectivity ratio of 1620:1
(Scott-Warren et al., 2015). DEX exerts its agonistic action on (A) subtype of α2
adrenoceptor; an activation of A subtype of α2 seems to lead to a protective effect against
depression (Rivero et al., 2016; Schramm et al., 2001). Additionally, this activation appears
to have analgesic and anxiolytic properties (Weerink et al., 2017). A recent comprehensive
review noted that DEX has organ-protective effects, including neuroprotection,
cardio-protection and renoprotection, through modulating gene expression, channel activation,
transmitter release, and apoptotic and necrotic cell death. DEX shows protective effects in a
variety of animal models of ischemia/reperfusion injury, including in the intestine,
myocardial, renal, lung, cerebral and liver (Biccard et al., 2008; Wijeysundera et al.,
2003).
DEX has been found to have anti-inflammatory properties and play a role in preventing the
brain from stress response due to ischemic/reperfusion injury (Dahmani et al., 2005; Gu et
al., 2011). Studies have demonstrated that sedation with DEX significantly decreases cytokine
production, including IL-1p, TNF-[alpha], and IL-6, in critically ill patients and that DEX
decreases the levels of TNF-[alpha], IL-1 and IL-6 to an even greater extent than propofol
(Venn et al., 2001).
Following intravenous administration, DEX exhibits the following pharmacokinetic properties:
a rapid distribution phase with a distribution half-life of approximately 6 minutes; a
terminal elimination half-life of approximately 2 hours; and steady-state volume of
distribution of approximately 118 liters. Clearance is estimated to be approximately 39
liters per hour. The mean body weight associated with this clearance estimate was 72 kg. DEX
exhibits linear kinetics in the dosage range of 0.2 to 0.7 mg/kg/hr when administered by IV
infusion for up to 24 hours (Weerink et al., 2017).
Preclinical Data on DEX antidepressant potential Moon et al. (2018) conducted the first
animal study exploring the antidepressant effects of DEX on the depressive behaviors of
sleep-deprived mice (Moon et al., 2018). The mice in this study were studied in 5 groups,
with 10 mice in each group, as follows: control, sleep deprivation, sleep deprivation and 0.5
μg/ kg of DEX, sleep deprivation and 1 μg/kg, and sleep deprivation and 2 μg/kg DEX.
Depressive behaviors were determined using the forced swimming and tail suspension tests
(Holmes et al., 2005). In order to assess the effect of DEX on the expression of tyrosine
hydroxylase (TH), 5-hydroxytryptamine (5-HT; serotonin), tryptophan hydroxylase (TPH) and D1
dopamine receptor, Western Blots and immunohistochemistry tests were run on mouse brain
tissue. The sleep deprivation took 7 days in total, from day one, after the induction, DEX
was injected into the mice once daily for 6 days, with dosing specific to the group
allocation. After 6 days of DEX injections, depressive behaviors were assessed among the five
groups and then brain tissues were examined. The results showed that sleep deprivation
induced depressive behaviors in the form of increased latency to immobility in the forced
swimming test and tail suspension test. Additionally, sleep deprived mice had decreased
expressions of TPH, 5-HT, and D1 dopamine receptor, and increased TH expression. After 6
injections, DEX-alleviated depressive behaviors were evident through decreased latency to
immobility, increased expressions of TPH, 5-HT, and D1 dopamine receptor, and decreased HT
expression. The effects were statistically significant and incremental in a dose-dependent
manner.
In another animal study conducted by Gao et al., DEX improved learning and memory impairment
caused by ECT in depressed mice. DEX cognitive neuroprotection was achieved by suppressing
excessive up-regulation of NR2B, a subunit of the NMDA receptor (Gao et al., 2016).
Noteworthy, ketamine (another agent with rapid antidepressant effects) likely exerts its
antidepressant properties through its antagonism of the NR2B-subunit-containing NMDA
receptors (Gass et al., 2018). Therefore, one could suggest that DEX may exert its
antidepressant action, at least in part, through modulation of NMDA receptors. Table 2
summarizes four preclinical animal studies postulating DEX antidepressant potential.
Clinical data on DEX A number of studies have shown showed positive outcomes following the
use of DEX for the management of agitation among ICU patients, including a reduction in the
number of cases of delirium, and shorter stays in ICU, which is likely due to an increased
ease in moving off of mechanical ventilation, as well as an improvement in overall survival
(Bougarel et al., 2011; Constantin et al., 2016; Dahmani et al., 2005; Ebert et al., 2000;
Gao et al., 2016; Gass et al., 2018; Holmes et al., 2005; Ji et al., 2017; Jun et al., 2017;
MacMillan et al., 1996; Moon et al., 2018; Venn et al., 2001; Weerink et al., 2017; Yuen et
al., 2008).
DEX has been utilized by different specialties like anesthesiology, surgery, neurosurgery,
and dentistry, for its sedative and anti-inflammatory potentials (Chandanwale et al., 2017).
DEX has various clinical advantages, including induction of moderate sedation, a wide
therapeutic index, the absence of infusion rates adaptation outside hepatic insufficiency and
pronounced analgesic action (Reade et al., 2009). DEX is commonly used in an off-label manner
in pediatric intensive care units (Baarslag et al., 2017). Additionally, DEX has proven to be
an effective drug for MRI sedation, as well as the ambulatory sedation of pediatric
population (Mason et al., 2008; Siddappa et al., 2011).
More recently, Yu et al. (2019) published the first study examining the efficacy of
post-delivery DEX infusion in preventing postpartum blues or postpartum depressive symptoms
(measured by Edinburgh Postnatal Depression Scale -EPDS), postpartum self-harm ideation (at
postpartum days 7 and 42), pain symptoms and sleep problems. This study was a double-blind
randomized placebo-controlled clinical trial, conducted at tertiary care university hospital
in China. The subjects (n = 600) were women who underwent elective cesarean section under
spinal anesthesia and accepted patient-controlled intravenous analgesia (PCIA). Participants
were at least 18 years of age and class II according American Society of Anesthesiologists.
Exclusion criteria included history of bipolar or psychotic disorder; suicidal state;
allergies to a2-AR agonists; drug and/or alcohol abuse within the past 6 months; and use of
another a2-AR agonist or a2-AR antagonist during the observation. Individuals assigned to the
DEX group received 0.5 µg/kg intravenous DEX after delivery, at an infusion speed of 0.375
ml/kg per hour and infusion time of 20 minutes. The control group received 0.125 ml/kg
intravenous 0.9% normal saline immediately after delivery at an infusion speed of 0.375 ml/kg
per hour and infusion time of 20 minutes. The PCIA protocol for the control group consisted
of 150 µg sufentanil diluted to 150 ml and administered at a continuous dose of 0.04 µg/kg
per hour and a bolus dose of 2.0 µg, with a lockout of 8 minutes. DEX arm PCIA protocol was
150 µg sufentanil plus 150 µg DEX diluted to 150 ml, with the continuous dose of sufentanil
0.04 µg/kg per hour and DEX 0.04 µg/kg per hour, and a bolus dose of 2 µg, with a lockout of
8 minutes. The PCIA pump was stopped 48 hours postoperatively. All participants were
monitored for pulse oxygen saturation, electrocardiogram, and noninvasive blood pressure for
48 hours after surgery. Participants were followed at 6, 24, and 48 hours for side effects
and the status of sedation analgesia and slumber.
Antenatal and postnatal depressive symptoms were assessed with the Edinburgh Postnatal
Depression Scale (EPDS), with an EPDS of 10 or higher indicating threshold for antenatal
depressive symptoms. Sleep quality was assessed with the Insomnia Severity Index (ISI). After
delivery, depressive symptoms EPDS and ISI were noted by blinded investigators by telephone
at 7 and 42 days after delivery. If participant could not be contacted on 7 and 42 days, the
investigator would try to reach them again by phone within 2 days. If participant was not
contactable, they were deemed lost to follow-up. Sedation was assessed using the Ramsay
sedation scores, recorded at 6, 24, and 48 hours after surgery. Postoperative analgesia was
assessed using the numerical rating scale (NRS), recorded at 6, 24, and 48 hours after
surgery. The quality of sleep was assessed with the ISI before surgery and on postpartum days
2, 7, and 42. The results showed good compliance, with 276 of 300 (92%) participants in the
control group and 281 of 300 (93.67%) in the DEX group completing all follow up visits. There
were no significant differences regarding demographic or clinical characteristics between the
two groups, including significant antenatal depressive scores among DEX and control
individuals (27.8% vs 30.1%, P = 0.55).
The incidence of PDS (EDPS score of ≥ 10) in the control group and DEX group were 16.3% and
5.7%, respectively, significantly lower among the individuals who were administered DEX (P
<0.001). The EPDS score (mean and SD) at postpartum day 7 (1.93 ± 3.36 vs 4.23± 4.37,
p<0.001) and at postpartum day 42 (1.99± 3.18 vs 4.68 ± 4.78, p<0.001) in the DEX group were
also significantly lower than that observed in the control group. Logistic regression
analysis showed that stress during pregnancy, antenatal depressive symptoms, life stress
events, and domestic violence were risk factors for PDS. Notably, logistic analysis showed
that the prophylactic use of DEX was a protective factor against PDS adjusted odds ratios
(0.230; 95% CI: 0.104-0.510). Postpartum analgesia scores at 24 and 48 hours postpartum
within the DEX group were significantly lower than that in the control group (P <0.001). The
sleep score (ISI) at postpartum 48 hours in the DEX group was significantly better than that
in the control group (P <0.001). Compared with the control group, the incidence of self-harm
ideation in the DEX group significantly decreased at postpartum day 7 (4.0% vs 1.1%, P =
0.03) and day 42 (2.9% vs 0.4%, P = 0.04). No significant difference was observed in the
incidence of nausea, vomiting, or dizziness between the control and the DEX group (1.07% vs
1.45%, P = 0.98; 2.85% vs 4.23%, P = 0.34; 10.68 vs 11.27, P = 0.83). Hypotension,
bradycardia, hypoxemia, and respiratory depression were not observed in either of the two
groups at 48 hours postpartum.
The impact of DEX on EPDS scores at day 42, showed an effect size of Cohen's D = 0.6 (Yu et
al., 2019). This study seems to suggest promising results for the prophylactic effects of DEX
against the emergence of postpartum depression. Ge Huang et al., 2020 reported a case of
patient with resistant cancer pain and comorbid depressive illness who improved from mood and
pain perspectives after treated with co-administration of DEX and morphine intrathecal.
Depression was assessed by HAMD-6 before and after 1 week, one and three month of DEX
addition to the regimen. The results showed positive changes in depressive symptoms and
quality of life over the next 3 months.
No trials to date, however, have explored the efficacy of DEX for the treatment of
individuals with a current episode of MDD.Taking together all existing pre-clinical and
clinical data (despite their limitations) and the known pharmacological properties of DEX, we
believe that there could be a potential use for DEX beyond its current use to manage
agitation and to induce sedation in ICU settings, i.e., there seems to be a rationale for
further exploration of the putative rapid antidepressant effects of DEX. The anti-agitation
properties of DEX could be especially useful for individuals with depression accompanied by
agitation or with mixed features. There is also potential for DEX to be used as a monotherapy
when fast onset of action is required, as well as an alternative and/or as adjunctive therapy
for other fast action interventions for MDD (ECT, rTMS).
Aims and Hypotheses The primary aim of the DEX-ECT study is to explore the effect of
adjunctive DEX on response rate among a sample of depressed patients undergoing ECT using an
RCT design with the hypothesis that adjunct DEX, compared with adjunct placebo (saline
treatment), given prior to standard anesthesia will lead to a higher response rate. Secondary
aims are to investigate the remission rate, tolerability and acceptability of adjunctive DEX.
We hypothesize that DEX arm will show higher remission rate in depressive symptoms with no
statistically significant difference in the rate of side effects during and post ECT between
the two arms).
Design and study site A double blind, parallel group, placebo controlled, randomized
feasibility trial will be conducted at, Department of Psychiatry, Queens University, Canada,
over 6 week period. Enrolled patients will be randomized to DEX infusion (0.5µg/kg/hr for 15
mins ) adjunct to ECT or Placebo adjunct( Saline) treatment arm added to standard anesthetic
induction in depressed patients who have been prescribed ECT utilizing fixed randomization
schedule that allocate subjects in to a 1:1 ratio between two arms. Both subjects and outcome
assessors will be blinded to the treatment arm to which participants are allocated. Given
non- maleficence principle, the anesthetic team will be aware of treatment allocation, and
should safety concern arise research investigators will be informed as well.
Allocation concealment, randomization All participants will be randomly allocated to the
dexmedetomidine group (Dex group) or the control group (Normal Saline) using a
computer-generated random number with a 1:1 allocation. An independent investigator, not
involved in the clinical management or data collection, keep allocation data. The allocation
details will be delivered in a sealed, opaque envelope in order to enable patients and
assessors to remain blinded to group allocation. Prior to ECT, anesthesiologists who will not
participate in data analysis will be informed about allocation, and the related data will be
gathered during ECT by an independent staff blinded to treatment allocation. On the day of
each treatment the anaesthetist. will open the package and prepare the injection away from
the ECT team and patient to maintain their blinding. Patients will receive the same allocated
study medication throughout their course of ECT. The allocation will not be revealed until
final statistical analysis is completed. The final decision to end ECT will rest with the
treating clinical team in consultation with the patient and the local ECT treatment team.
Sample Size Power estimates for continuous MADRS scores assumed a two-tailed alpha level of
0.05. Effect size estimate, Cohen's d=0.66 for DEX on post-partum depression symptoms scores
was derived from previous study (Yu et al, 2019). A group of 76 patients randomly assigned in
a 1:1 ratio (38 DEX versus 38 Placebo) will provide 80% power to detect a significant
difference in the mean changes in MADRS scores between the two study arms. Since this is a
feasibility study, 30 participants per each arm could be acceptable (Billingham, S. A.,
Whitehead, A. L., & Julious, S. A. (2013).
