Noradrenaline plays a critical role in the switch to a manic episode and treatment of a depressive episode

Abstract

Although antidepressants may increase the risk of switching to mania in bipolar disorder (BD), clinicians have been using antidepressants to treat patients with bipolar depression. Appropriate treatments for bipolar depression remain controversial. In BD, antidepressants comprise a double-edged sword in terms of their efficacy in treating depression and the increased risk of switching. This review presents an important table outlining the benefit in terms of depression improvement and the risk of switching in the clinical setting. It also proposes strategies based on the characteristics of antidepressants such as their pharmacology, specifically the equilibrium dissociation constant (K_D) of the noradrenaline transporter. This table will be useful for clinicians while considering benefit and risk. Antidepressants augmenting noradrenaline may be effective in bipolar depression. However, it is easily presumed that such antidepressants may also have a risk of switching to mania. Therefore, antidepressants augmenting noradrenaline will be the recommended treatment in combination with an antimanic agent, or they may be used for short-term treatment and early discontinuation. The corresponding medical treatment guidelines probably need to be reevaluated and updated based on biological backgrounds. From previous studies, we understand that the stability of noradrenaline levels is important for BD amelioration, based on the pathophysiology of the disorder. It is hoped that researchers will reevaluate BD by conducting studies involving noradrenaline.

Keywords: 3-methoxy-4-hydroxyphenylglycol; antidepressants; biomarker; brain-derived neurotrophic factor; dopamine; homovanillic acid; mood disorder; selective serotonin reuptake inhibitor; serotonin and noradrenaline reuptake inhibitor; tricyclic antidepressant.

Figure 1

Schematic illustration showing the improvement or switching pathways induced by various antidepressants affecting the levels of noradrenaline. Notes: Augmentation of noradrenaline as various antidepressants can be the result of the three actions: (A) noradrenaline reuptake inhibitory action, (B) inhibitory action of noradrenaline deactivation, and (C) α2-autoreceptor inhibitory action.

Figure 2

Schematic illustration of the pathways leading to increasing noradrenaline levels as caused by the administration of various antidepressants. Notes: (A) Administration of a NRI increases the levels of noradrenaline at the synapse, resulting in activation of intracellular signal transduction cascades that are coupled with noradrenergic receptors. (B) Monoamine oxidase is deactivated by oxidative deamination of noradrenaline. Administration of a MAOI suppresses the levels of noradrenaline deactivation, resulting in increased levels of noradrenaline at the synapse. (C) Activated α2-autoreceptor inhibits the release of noradrenaline. Administration of an α2-autoreceptor inhibitor can promote noradrenaline release via suppression of this autoreceptor. Abbreviations: MAOI, monoamine oxidase inhibitor; NRI, noradrenaline reuptake inhibitor.