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 (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.

ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines

“…Several lines of evidence implicate the noradrenergic (NE) system in the pathology of BPD. For instance, the concentrations of norepinephrine and its metabolites are significantly upregulated in the cerebrospinal fluid (CSF) of BPD patients during the manic state ( Kurita, 2016 ; Manji et al, 2003 ; Post et al, 1973 ; Post et al, 1978 ). In contrast, norepinephrine is downregulated in patients with depressive disorder ( Maas et al, 1971 ; Moret and Briley, 2011 ; Wiste et al, 2008 ) and associated with mood transition in BPD patients ( Kurita, 2016 ; Salvadore et al, 2010 ).…”

Quantification of Tyrosine Hydroxylase and ErbB4 in the Locus Coeruleus of Mood Disorder Patients Using a Multispectral Method to Prevent Interference with Immunocytochemical Signals by Neuromelanin

“…However, it has been reported that lithium does not affect TH-mRNA levels in the ventral tegmental area in rats [39]. Moreover, anti-psychotic medication has been reported to decrease CSF-NE levels in BD patients in the manic stage, who then change to the depressive stage [40,41]. In our study, the LC TH-ir in BD patients who used anti-psychotic drugs (n = 5, mean = 0.014, range 0.003-0.033) did not significantly differ from those who had not (n = 4, mean = 0.016, range 0.003-0.037, P = 0.850).…”

Dosage-related nature of escitalopram treatment-emergent mania/hypomania: a case series

“…Despite the importance of the phenomenon of mood switching, the precise mechanisms underlying the process have yet to be determined. However, researchers have hypothesized that antidepressant agents trigger manic/hypomanic symptoms by likely influencing the central serotonergic and catecholaminergic systems 6 – 8 for the following reasons. First, higher levels of urinary noradrenaline 9 , 10 and dopamine 10 , 11 have been associated with mania and switching to mania.…”

“… 12 Second, direct pharmacological treatment resulting in elevated catecholamine levels could mimic mania-like states. 8 Finally, several genetic polymorphisms linked with serotonergic and catecholaminergic systems have been proposed as putative risk factors for treatment-emergent mania/hypomania. 13 Although some studies have identified various risk factors for antidepressant-induced manic switch, 5 , 14 – 16 others have reported conflicting results.…”