Dexmedetomidine Adjuvant Treatment for Depressed Patients Undergoing ECT: A Double Blind, Placebo Controlled, Randomized Feasibility Study Protocol

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).