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

View Article: PubMed Central - PubMed

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 (KD) 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.

No MeSH data available.


Related in: MedlinePlus

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.
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f2-ndt-12-2373: 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.

Mentions: From these hypotheses, it is supported that noradrenaline is involved in the pathophysiology of BD, as well as being associated with the switch to mania. In this context, it is suggested that both the antidepressant effect of and the switching to mania caused by noradrenaline are issues of particular importance in the context of BD. Augmentation of noradrenaline can be the result of the following three actions (Figures 1 and 2): (A) increasing noradrenaline in the synaptic cleft by noradrenaline reuptake inhibitory action; (B) inhibition of noradrenaline deactivation by MAOIs; and (C) release of noradrenaline by α2-autoreceptor blockage. The following three sources underlie this evidence. For (A), antidepressants are involved with noradrenaline reuptake transporter (NRT), and noradrenaline reuptake inhibitors (NRIs) were more effective than placebo for bipolar depression.15 In addition, avoiding antidepressant use has generally been proposed in clinical guidelines, considering the potential risk for switching to mania or rapid cycling during the treatment.16,44 Thus, NRT may participate in the pathophysiology of BD. For (B), the development of an 11C-harmine brain-imaging technique led to the interesting observation that brain monoamine oxidase (MAO) levels were elevated in a number of cortical, striatal, and midbrain areas in subjects suffering from major depressive disorder.45 However, even after the complete characterization of MAO-A and MAO-B subtypes, many aspects of the physiological actions of these enzymes are unclear.46 MAO is localized intracellularly.47 Thus, in the cell, pathway (B) works through pathway (A). From the pharmacological point of view, pathway (A) takes precedence over pathway (B) in the mechanism of switching to mania (Figure 2). For (C), mirtazapine is an antidepressant that blocks the α2-autoreceptor. It was shown in a case report that mirtazapine induced switching to a manic state.48 In contrast, another report showed that this medicine did not induce switching to a manic state.49 Large-scale follow-up studies are needed to understand the effects of mirtazapine.


Noradrenaline plays a critical role in the switch to a manic episode and treatment of a depressive episode
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.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5036557&req=5

f2-ndt-12-2373: 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.
Mentions: From these hypotheses, it is supported that noradrenaline is involved in the pathophysiology of BD, as well as being associated with the switch to mania. In this context, it is suggested that both the antidepressant effect of and the switching to mania caused by noradrenaline are issues of particular importance in the context of BD. Augmentation of noradrenaline can be the result of the following three actions (Figures 1 and 2): (A) increasing noradrenaline in the synaptic cleft by noradrenaline reuptake inhibitory action; (B) inhibition of noradrenaline deactivation by MAOIs; and (C) release of noradrenaline by α2-autoreceptor blockage. The following three sources underlie this evidence. For (A), antidepressants are involved with noradrenaline reuptake transporter (NRT), and noradrenaline reuptake inhibitors (NRIs) were more effective than placebo for bipolar depression.15 In addition, avoiding antidepressant use has generally been proposed in clinical guidelines, considering the potential risk for switching to mania or rapid cycling during the treatment.16,44 Thus, NRT may participate in the pathophysiology of BD. For (B), the development of an 11C-harmine brain-imaging technique led to the interesting observation that brain monoamine oxidase (MAO) levels were elevated in a number of cortical, striatal, and midbrain areas in subjects suffering from major depressive disorder.45 However, even after the complete characterization of MAO-A and MAO-B subtypes, many aspects of the physiological actions of these enzymes are unclear.46 MAO is localized intracellularly.47 Thus, in the cell, pathway (B) works through pathway (A). From the pharmacological point of view, pathway (A) takes precedence over pathway (B) in the mechanism of switching to mania (Figure 2). For (C), mirtazapine is an antidepressant that blocks the α2-autoreceptor. It was shown in a case report that mirtazapine induced switching to a manic state.48 In contrast, another report showed that this medicine did not induce switching to a manic state.49 Large-scale follow-up studies are needed to understand the effects of mirtazapine.

View Article: PubMed Central - PubMed

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 (KD) 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.

No MeSH data available.


Related in: MedlinePlus