Are Noradrenergic Transmission Reducing Drugs Antidepressants?

Abstract

Major depressive disorder (MDD) remains a significant public health problem worldwide, and revised treatment strategies are therefore urgently needed, including the creation of novel antidepressant compounds or using existing molecular entities in new ways. Etiologic theories of MDD from decades ago have suggested that synaptic deficiencies of monoaminergic neurotransmitters play a causative role in this neuropsychiatric disorder, and that boosting monoamines with drugs such as SSRIs, SNRIs, TCAs, and MAOIs has antidepressant effects and in some individuals can even induce hypomania or mania. While other factors, such as various intracellular molecular pathways and hippocampal neurogenesis, undoubtedly also play a role in MDD, monoaminergic boosting drugs nonetheless have clearly demonstrated antidepressant properties. There is also, however, a body of studies in the preclinical literature suggesting that monoaminergic transmission reducing drugs, including noradrenergic ones, also have antidepressant-like behavioral properties in rodents. Given that there is increasing evidence that the monoamines have u-shaped or Janus-faced dose-response properties, in which a mid-range value is “optimal” in a variety of behavioral and physiological processes, it is plausible that either too much or too little synaptic norepinephrine in key circuits may exacerbate MDD in some individuals. Here we briefly review rodent depression-related behavioral data, focusing on the forced swim test, from three major classes of noradrenergic transmission reducing drugs (alpha2 agonists, beta blockers, alpha1 antagonists), and find much support for the hypothesis that they have antidepressant-like properties. Whether these drugs are antidepressants in human subjects remains to be determined.

Frontal Alpha Asymmetry and Its Modulation by Monoaminergic Neurotransmitters in Depression

“…The hypothesis is also consistent with high left frontal activation and its associated increased FAA promoting suicidality [ 17 , 61 ]. It may also be consistent with bipolar disorder and its potentially elevated noradrenergic signaling increasing FAA [ 31 , 33 ], where one possibility is that elevated noradrenergic signaling may characterize both depression and hypomania/mania in bipolar disorder, which is differentially coupled with dopamine in these opposing mood states [ 93 , 94 ]. Since cortical control of the sympathetic nervous system, where norepinephrine is a major output molecule, is biased toward the right hemisphere [ 95 ], this lateralization could represent a compensatory mechanism for norepinephrine preferentially activating the left hemisphere and possibly inactivating the right.…”

Involvement of Anti-Inflammatory and Stress Oxidative Markers in the Antidepressant-like Activity of Aloysia citriodora and Verbascoside on Mice with Bacterial Lipopolysaccharide- (LPS-) Induced Depression

“…Despite clinical advances in the treatment of neuropsychiatric disorders, mood disorders such as major depressive disorder (MDD) are still considered an important public health problem. MDD is characterized by depressed mood and/or anhedonia, which may be related to other behavioral changes and vegetative symptoms that compromise physical and mental health [ 1 ]. Furthermore, depression is a leading cause of disability and affects approximately 300 million people worldwide [ 2 ].…”