Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges

Abstract

Although first-line antidepressants offer therapeutic benefit, about 35% of depressed patients are not adequately treated, creating a large unmet medical need. These medicines mostly enhance the synaptic levels of serotonin and/or norepinephrine. Evidence from preclinical and clinical studies implicate dopamine hypofunction in the pathophysiology of depression. Triple reuptake inhibitors (TRIs), which elevate dopamine in addition to serotonin and norepinephrine, may demonstrate greater efficacy, with the reversal of anhedonia and improved tolerability. Medicinal chemistry efforts have resulted in more than 10 clinical candidates, although clinical candidates have failed to demonstrate superior efficacy compared to placebo or existing antidepressants. Hence, the successful development of future TRIs for depression will demand strong translational evidence, an optimal dosing regimen, and better tolerability. TRIs also hold therapeutic potential for other indications, with four candidates under clinical development for attention deficit hyperactivity disorder, binge eating disorder, cocaine addiction, obesity, and type 2 diabetes. Clinical studies have indicated a lower abuse potential for TRIs than psychostimulants.

Developmental role of adenosine kinase for the expression of sex-dependent neuropsychiatric behavior

“…Amphetamine challenge provides details into the brain’s dopaminergic functioning: hyperfunction is indicative of schizophrenia-like phenotypes (Pezze et al, 2014), while hypofunction is related to attention deficit/hyperactivity disorder (ADHD) (Del Campo et al, 2011; Fone and Nutt, 2005; Trinh et al, 2003) or depression (Subbaiah, 2017). We observed that gestational loss of ADK produces schizophrenia-like amphetamine hyper-responsiveness in both male and female mice.…”

Pharmacological Characterization of Toludesvenlafaxine as a Triple Reuptake Inhibitor

“…In recent years, the triple monoamine reuptake inhibition hypothesis has been increasingly recognized as a potentially beneficial strategy to treat depression ( Subbaiah, 2018 ). Dopamine (DA) plays an essential role in the etiology of depression ( Dunlop BW and Nemeroff, 2007 ; Belujon and Grace, 2017 ).…”

Synthesis, Docking, 3-D-Qsar, and Biological Assays of Novel Indole Derivatives Targeting Serotonin Transporter, Dopamine D2 Receptor, and Mao-A Enzyme: In the Pursuit for Potential Multitarget Directed Ligands

“…Many adverse effects associated with first-generation antidepressants (mainly tricyclic and monoamine oxidase inhibitors, –MAOi–) were partially overcome by the arrival of second-generation antidepressants, including selective serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NRIs), and dual antidepressants (SNRIs), with the latter being advantageous as they can treat a wide range of symptoms [ 16 , 17 , 18 , 19 ]. However, much less approved antidepressants do target the dopamine system, notwithstanding dopamine has also been implicated in the pathophysiology of depression [ 20 ].…”

“…Due to the aforementioned causes, MDD is nowadays recognized as a complex dynamic system [ 29 ] endowed with a complex pathophysiology. For this reason, depression symptoms and its underlying causes are more likely to be treated by a multitarget approach, by using promiscuous drugs also defined as multi-target directed ligands (MTDLs): A single drug molecule that selectively targets multiple receptors, so that different pathways conducting to the disease can be modified by using a single molecule [ 20 , 30 , 31 , 32 ].…”