Effects of once-daily ampreloxetine (TD-9855), a norepinephrine reuptake inhibitor, on blood pressure in subjects with symptomatic neurogenic orthostatic hypotension

2020 ◽  
Vol 79 ◽  
pp. e79
Author(s):  
H. Kaufmann ◽  
I. Biaggioni ◽  
W. Wang ◽  
B. Haumann ◽  
R. Vickery
2021 ◽  
Vol 8 ◽  
Author(s):  
Anna Calvi ◽  
Ilaria Fischetti ◽  
Ignazio Verzicco ◽  
Martino Belvederi Murri ◽  
Stamatula Zanetidou ◽  
...  

Individuals suffering from depressive disorders display a greater incidence of hypertension compared with the general population, despite reports of the association between depression and hypotension. This phenomenon may depend, at least in part, on the use of antidepressant drugs, which may influence blood pressure through different effects on adrenergic and serotoninergic pathways, as well as on histaminergic, dopaminergic, and cholinergic systems. This review summarizes extant literature on the effect of antidepressant drugs on blood pressure. Selective serotonin reuptake inhibitors are characterized by limited effects on autonomic system activity and a lower impact on blood pressure. Thus, they represent the safest class—particularly among elderly and cardiovascular patients. Serotonin–norepinephrine reuptake inhibitors, particularly venlafaxine, carry a greater risk of hypertension, possibly related to greater effects on the sympathetic nervous system. The norepinephrine reuptake inhibitor reboxetine is considered a safe option because of its neutral effects on blood pressure in long-term studies, even if both hypotensive and hypertensive effects are reported. The dopamine–norepinephrine reuptake inhibitor bupropion can lead to blood pressure increases, usually at high doses, but may also cause orthostatic hypotension, especially in patients with cardiovascular diseases. The norepinephrine–serotonin modulators, mirtazapine and mianserin, have minimal effects on blood pressure but may rarely lead to orthostatic hypotension and falls. These adverse effects are also observed with the serotonin-reuptake modulators, nefazodone and trazodone, but seldomly with vortioxetine and vilazodone. Agomelatine, the only melatonergic antidepressant drug, may also have limited effects on blood pressure. Tricyclic antidepressants have been associated with increases in blood pressure, as well as orthostatic hypotension, particularly imipramine. Oral monoamine–oxidase inhibitors, less frequently skin patch formulations, have been associated with orthostatic hypotension or, conversely, with hypertensive crisis due to ingestion of tyramine-containing food (i.e., cheese reaction). Lastly, a hypertensive crisis may complicate antidepressant treatment as a part of the serotonin syndrome, also including neuromuscular, cognitive, and autonomic dysfunctions. Clinicians treating depressive patients should carefully consider their blood pressure status and cardiovascular comorbidities because of the effects of antidepressant drugs on blood pressure profiles and potential interactions with antihypertensive treatments.


Author(s):  
Arthur Lo ◽  
Lucy Norcliffe-Kaufmann ◽  
Ross Vickery ◽  
David Bourdet ◽  
Jitendra Kanodia

Abstract Purpose Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic orthostatic hypotension (nOH) in patients with autonomic synucleinopathies. The purpose of this study was to characterize the pharmacokinetic and pharmacodynamic profiles of ampreloxetine in this target population. Methods Patients with nOH were enrolled in a multicenter, phase II clinical trial of ampreloxetine (NCT02705755). They received escalating doses over 5 days in the clinical research unit, followed by 20 weeks of open-label treatment and then a 4-week withdrawal. As neurochemical biomarkers of NET inhibition, we assayed plasma concentrations of norepinephrine (NE) and its main intraneuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) pre- and post-ampreloxetine. Results Thirty-four patients with nOH were enrolled. Plasma ampreloxetine concentrations increased with repeated escalating doses, with peak concentrations observed 6–9 h post-drug administration. The median ampreloxetine dose in the 20-week treatment phase was 10 mg once daily. Plasma ampreloxetine concentrations reached steady state by 2 weeks, with stable plasma levels over 24 h. No influence of age or renal function on ampreloxetine plasma concentrations was observed. On treatment, compared to baseline, plasma NE significantly increased by 71% (p < 0.005), plasma DHPG significantly declined by 22% (p < 0.05), and the NE:DHPG ratio significantly increased (p < 0.001). Conclusions Persistent elevation of plasma NE levels accompanied by reduced DHPG levels after ampreloxetine suggests reduced neuronal reuptake and metabolism of NE in postganglionic efferent sympathetic neurons. The findings are consistent with long-lasting NET inhibition, which may increase vasoconstrictor tone, supporting once-daily ampreloxetine dosing in patients with nOH.


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