How antidepressant drugs act: A primer on neuroplasticity as the eventual mediator of antidepressant efficacy

Abstract

Depression is conventionally viewed as a state of chemical imbalance, and antidepressants are suggested to act through increasing monoaminergic neurotransmission. These views are currently considered simplistic. This article examines the animal and human literature on the neurohistological mechanisms underlying stress, depression and antidepressant treatment. Pathological stress and depression are associated with changes such as loss of dendritic spines, shrinkage of the dendritic tree and loss of synapses in the hippocampus and prefrontal cortex. There is also a decrease in glia. Apoptosis may occur under extreme circumstances. In contrast, there is increased dendritic arborization and synaptogenesis in the amygdala. Antidepressant treatment protects against and even reverses some but not all of these stress-induced neurohistological changes. Pathological stress results in an aberrant neuroplasticity response characterized by abnormally increased activity in the amygdala and by impaired functioning of the hippocampus, prefrontal cortex and downstream structures. This aberrant neuroplasticity response directly explains most of the clinical symptoms of depression. Antidepressant treatment protects against stress-induced pathoplastic neurohistological and neurocognitive changes. Antidepressant treatment also restores functional neuroplasticity in stressed organisms and, thereby, presumably, facilitates re-adaptation through learning and memory mechanisms. Thus, the stress–depression syndrome and the therapeutic and prophylactic efficacy of antidepressant treatments can be explained through a hardwiring analogy. In this context, glutamate is an important neurotransmitter.

Curcumin for the treatment of major depression: A randomised, double-blind, placebo controlled study

“…Examples include anti-inflammatory treatments influencing immuno-inflammation such as cyclooxygensase-2 (COX-2) inhibitors, aspirin, minocycline and polyunsaturated fatty acids (Berk et al, 2013a, Fond et al, 2014, Muller, 2013 and antioxidant therapies to increase antioxidant defences and lower free radical damage such as n-acetyl cysteine, Ebselen, vitamin E and coenzyme-Q 10 (Berk et al, 2013b, Scapagnini et al, 2012. Interestingly, despite pharmaceutical antidepressants originally being heralded as targeting monoaminergic actions, there is also evidence that they can modulate immuno-inflammation, reduce oxidative stress, enhance neurotrophic factors and influence HPA activity (Abdel-Wahab and Salama, 2011, Andrade and Rao, 2010, Hannestad et al, 2011, Kocki et al, 2012, Schule, 2007.…”

Electroconvulsive shocks decrease α2-adrenoceptor binding in the Flinders rat model of depression

“…This suggests that the perirhinal cortex may play a key role both in the phenotypic expression of depressive symptoms as well as in the antidepressant response after ECS. Both stress and depression are associated with decreased neuroplasticity in hippocampus (Videbech and Ravnkilde, 2004), increased aberrant neuroplasticity in the amygdala and decreased neuroplasticity in the perirhinal cortex (Andrade and Rao, 2010). As a more potent stimulator of neuroplasticity than antidepressants, ECT has been shown to normalize these aberrant changes (Chen et al, 2009;Hellsten et al, 2002).…”

“…The up-regulation of α 2 -adrenoceptors as a result of decreased noradrenaline release in depressed patients is reversed by antidepressants with either reuptake inhibition and/or antagonism properties (Andrade and Rao, 2010). ECS also potentiates the release of noradrenaline; rats chronically treated with ECS have significantly increased release of noradrenaline from the frontal cortex as compared to chronic sham controls, which probably mediates a compensatory down-regulation of the presynaptic α 2 -adrenoceptors (Thomas et al, 1992).…”

A Primer for the Conceptualization of the Mechanism of Action of Electroconvulsive Therapy, 1: Defining the Question

“…Merely filling a tank with gasoline does not make a car run. 16 It is therefore necessary to identify downstream effects of a treatment, whether the treatment is fluoxetine or ECT. These downstream effects include actions on receptors, intracellular messengers, gene expression, protein synthesis, neuroplasticity changes, and changes in the functioning in different neuronal circuits in the brain.…”