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

Figures & data

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.

Table 1 Various antidepressants showing the improvement of depression or the risk of switching to mania based on their affinities for NET

Antidepressants	KD, nM*	Dose	Dose/KD	Dose risk
	NET	Min–Max	Min–Max	Min–Max
Tertiary amine tricyclics
Amitriptyline	35.0	50–300	1.43–8.57	(++)–(++)
Clomipramine	38.0	25–200	0.66–5.26	(−)–(++)
Dosulepin	46.0	25–125	0.54–2.72	(−)–(+)
Imipramine	29.5	75–300	2.54–10.17	(+)–(+++)
Doxepin	37.0	150–300	4.05–8.11	(++)–(++)
Lofepramine	5.4	25–300	4.63–55.56	(++)–(+++)
Trimipramine	2,450.0	50–150	0.02–0.06	(−)–(−)
Secondary amine tricyclics
Amoxapine	16.1	100–400	6.21–24.84	(++)–(+++)
Desipramine	0.8	75–300	93.75–375.00	(+++)–(+++)
Desmethylclomipramine	2.5	10–25	4.00–10.00	(++)–(+++)
Nortriptyline	4.4	50–150	11.36–34.09	(+++)–(+++)
Protriptyline	1.4	15–40	10.71–28.57	(+++)–(+++)
Tetracyclics
Maprotiline	11.1	50–150	4.50–13.51	(+++)–(+++)
Mianserin	71.0	30–90	0.42–1.27	(−)–(+)
SARI
Trazodone	8,500.0	25–400	0.00–0.05	(−)–(−)
SSRIs
Citalopram	4,070.0	20–80	0.00–0.02	(−)–(−)
Fluoxetine	240.0	10–60	0.04–0.25	(−)–(−)
Fluvoxamine	1,300.0	100–300	0.08–0.23	(−)–(−)
Paroxetine	40.0	20–50	0.50–1.25	(−)–(+)
Sertraline	420.0	25–200	0.06–0.48	(−)–(−)
SNRIs
Nefazodone	360.0	100–600	0.28–1.67	(−)–(+)
Venlafaxine	1,060.0	150–225	0.14–0.21	(−)–(−)

Notes: K_D is the equilibrium dissociation constant. −, no possibility; +, possibility (>1); ++, strong possibility (>3); +++, very strong possibility (>10).

* Reprinted from Eur J Pharmacol, Tatsumi M, Groshan K, Blakely RD, Richelson E, Pharmacological profile of antidepressants and related compounds at human monoamine transporters, 249–258,⁵² Copyright (1997), with permission from Elsevier. http://www.sciencedirect.com/science/journal/00142999.

Abbreviations: max, maximum; min, minimum; NET, noradrenaline transporter; SARI, serotonin-2 antagonist/reuptake inhibitor; SNRI, serotonin and noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

TatsumiMGroshanKBlakelyRDRichelsonEPharmacological profile of antidepressants and related compounds at human monoamine transportersEur J Pharmacol19973402–32492589537821

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