The Noradrenergic Action in Antidepressant Treatments: Pharmacological and Clinical Aspects

Dec 16, 2010CNS neuroscience & therapeutics

How norepinephrine affects antidepressant treatments: drug actions and clinical effects

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Abstract

Noradrenergic action is an important element for increasing the efficacy of mixed action antidepressants.

Noradrenaline is a key neurotransmitter in major depression but has been less utilized clinically compared to serotonin-based treatments.
Selective noradrenergic reuptake inhibitors (NRIs) like Reboxetine have not significantly changed treatment outcomes.
Atomoxetine, used for ADHD, has shown mixed results when augmenting treatment in depressed patients.
Dual action antidepressants, such as serotonin noradrenaline reuptake inhibitors (SNRIs) and Bupropion, enhance noradrenergic transmission and demonstrate efficacy.
Tricyclic antidepressants, including Desipramine and Nortriptyline, exhibit a strong noradrenergic effect.
The antidepressant effects of Quetiapine may be linked to the noradrenergic action of its metabolite, Norquetiapine.

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Even though noradrenaline has been recognized as one of the key neurotransmitters in the pathophysiology of major depression (MD), noradrenergic compounds have been less extensively utilized in clinical practice, compared to selective serotonin reuptake inhibitors (SSRIs). The development of the first selective noradrenergic reuptake inhibitor (NRI), Reboxetine, has not substantially changed the state of the art. In addition, Atomoxetine, a relatively pure NRI used for the treatment of ADHD, has shown mixed results when administered in augmentation to depressed subjects. Through a Medline search from 2000 to 2010, the present article provides an updated overview of the main pharmacological and clinical aspects of antidepressant classes that, partially or selectively, act on the noradrenergic systems. The noradrenergic action plays an important clinical effect in different antidepressant classes, as confirmed by the efficacy of dual action antidepressants such as the serotonin noradrenaline reuptake inhibitors (SNRIs), the noradrenergic and dopaminergic reuptake inhibitor (NDRI) Bupropion, and other compounds (e.g., Mianserin, Mirtazapine), which enhance the noradrenergic transmission. In addition, many tricyclics, such as Desipramine and Nortriptyline, have prevalent noradrenergic effect. Monoamine oxidase inhibitors (MAOIs), moreover, block the breakdown of serotonin, noradrenaline, dopamine and increase the availability of these monoamines. A novel class of antidepressants--the triple reuptake inhibitors--is under development to selectively act on serotonin, noradrenaline, and dopamine. Finally, the antidepressant effect of the atypical antipsychotic Quetiapine, indicated for the treatment of bipolar depression, is likely to be related to the noradrenergic action of its metabolite Norquetiapine. Even though a pure noradrenergic action might not be sufficient to obtain a full antidepressant effect, a pronoradrenergic action represents an important element for increasing the efficacy of mixed action antidepressants. In particular, the noradrenergic action seemed to be related to the motor activity, attention, and arousal.

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The Noradrenergic Action in Antidepressant Treatments: Pharmacological and Clinical Aspects

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