Triple Reuptake Inhibitors: A Premise and Promise

Abstract

On the horizon there is a new class of psychoactive medications which work by inhibiting the neuronal reuptake of serotonin, norepinephrine, and dopamine. There are multiple potential indications for these drugs. Research suggests that they may have a role in treating depressive disorders, and it is plausible they may have potential efficacy in obesity, addiction, and pain syndromes. The current review describes some of the molecules in development presently and explores the research relevant to possible clinical uses for this class of medications.

Vortioxetine: a meta-analysis of 12 short-term, randomized, placebo-controlled clinical trials for the treatment of major depressive disorder

“…10 Therefore, new pharmacological agents with novel mechanisms of action are needed for patients who do not respond to conventional antidepressant treatments. 6,[11][12][13][14] The development of vortioxetine, an antidepressant with a novel mechanism of action, which was approved by the U.S. Food and Drug Administration (FDA) in September 2013 for the treatment of MDD, is timely. 15 Vortioxetine is a selective serotonin reuptake inhibitor (SSRI) that binds to the presynaptic serotonin reuptake site, increasing the level of serotonin (5-HT) in the neuronal synapse and selectively binding to a variety of other serotonin receptors.…”

Criticisms of drugs in early development for the treatment of depression: what can be improved?

“…However, clinical research findings are mixed regarding whether broader-spectrum agents or highly 5-HT-selective agents confer the best efficacy, likely resulting from the involvement of each neurotransmitter in multiple biological functions [20,22]. For instance, the superiority of liafensine (BMS-820836) over duloxetine and escitalopram in patients with TRD has not been shown, leading the manufacturer to cease development.…”

“…Furthermore, given the association of complex alterations in signaling by the neurotransmitters 5-HT, NE and DA with MDD, triple reuptake inhibitors (TRIs) were designed to be more effective and safer antidepressants [20,21]. Likewise, stimulants that induce release and block reuptake of NE and DA have been found to augment and hasten the antidepressant response when combined with various classes of antidepressants [20].…”

“…Likewise, stimulants that induce release and block reuptake of NE and DA have been found to augment and hasten the antidepressant response when combined with various classes of antidepressants [20].…”

“…If this is replicated in subsequent studies, future TRIs should be designed to minimize blockade at histaminergic, 5-HT, cholinergic and a-adrenergic receptors, as AEs such as sexual dysfunction, sedation and weight gain are common in SSRIs and SNRIs [20].…”