Role of serotonin and norepinephrine transporters in antidepressant-induced arterial hypertension: a pharmacoepidemiological-pharmacodynamic study

Abstract

Purpose Some reports have described arterial hypertension (AH) in patients treated by serotonin reuptake inhibitor (SRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants. The mechanism remains discussed, some authors suggesting a role of SERT (SERotonin Transporter) inhibition whereas others discussing NET (NorEpinephrine Transporter) involvement. The present study used the pharmacoepidemiological-pharmacodynamic (PE-PD) method to investigate the role of these transporters in SRI-and SNRI-induced AH. Methods The study involved two successive approaches: first, a PE study (disproportionality analysis) investigating in VigiBase®, the World Health Organization Individual Case safety Report (ICSR) database, the relationships between exposure to SRI AND SNRI, and reports of AH. The primary analysis compared patients receiving one SRI (or one SNRI) with non-users. Secondary analyses were performed according to the pharmacological classes. Results are expressed as reporting odds ratios (ROR) with 95% CI and information component (IC), an indicator for disproportionate Bayesian reporting. Second, we performed a PD study using linear regression analyses to explore the association between the AH signal and binding affinities for NET and SERT (expressed as their pKi ratio) of SRIs and SNRIs. Results A significant ROR value was found for each individual SRI (except fluvoxamine) and each individual SNRI. ROR values were also significant for SRIs and SNRIs in general with higher values for SNRIs than for SRIs. Similar trends were found using IC. A significant correlation was found between the signal of AH and the NET/SERT pKi ratio (y = 6.57x -2.55, R 2 = 0.68, Pearson coefficient correlation = 0.82). Conclusion The present study found a positive association between the NET/SERT pKi ratio and the occurrence of arterial hypertension with SRI and SNRI antidepressants. These results are important for the selection of antidepressants in hypertensive and/or at risk depressive patients as well as for future development of antidepressants devoid of hypertensive effect.

Identification of different side effects between PARP inhibitors and their polypharmacological multi‐target rationale

“…Niraparib was the only PARPi to have reported cases of hypertension (102.25 per 100 000 R x )—an established side effect to niraparib 56 —whereas the other PARPi had cases of hypotension. It has been hypothesised that hypertension might be produced due to an off‐target disruption of dopamine 57 and noradrenaline metabolism via the inhibition of DAT (dopamine transporter), NET (norepinephrine transporter) and SERT (serotonin transporter) by niraparib (Figure 1). 15 Despite the complexity associated with blocking several transporters and its potential opposing effects on blood pressure, it remains a plausible hypothesis 58 .…”

“…Niraparib was the only PARPi to have reported cases of hypertension (102.25 per 100 000 R x )-an established side effect to niraparib 56 whereas the other PARPi had cases of hypotension. It has been hypothesised that hypertension might be produced due to an off-target disruption of dopamine 57 and noradrenaline metabolism via the inhibition of DAT (dopamine transporter), NET (norepinephrine transporter)…”

Hypertension in Association With Anxiety and Depression – A Narrative Review

“…However, Humbert et al analysed the WHO pharmacovigilance database and showed that the use of SSRIs significantly increases the risk of hypertension (30). Humbert et al suggested that hypertension can be a possible adverse effect explained by SERT inhibition and its vasoconstrictor effects and/or inhibited nitric oxidase vasodilatation effect, while the pharmacoepidemiologicalpharmacodynamic study found a positive correlation of the NET/SERT pKi ratio with the occurrence of hypertension in patients treated with SSRIs, as well as SNRIs (31). One cohort study in primary care in London was conducted to assess the risk of incident hypertension over 10 years and it showed the correlation of antidepressant use with developing hypertension (and other cardiovascular risks such as DM and hyperlipidaemia), possibly regarding the use of SSRIs in anxiety treatment (14).…”

“…That finding is important because nocturnal BP is reported to be a value predictor of cardiovascular mortality regardless of sex and age (34). Among SNRIs, venlafaxine shows a significantly higher risk of hypertension in a dose of 150 mg per day, but the risk is reduced by its extended release (ER) form (31). It is recommended that venlafaxine users be screened and monitored for hypertension, while duloxetine users are advised to monitor their BP if they have a prior diagnosis of hypertension or CVD (35).…”

Assessment of psychiatric comorbidities and serotonergic or noradrenergic medication use on blood pressure using 24‐hour ambulatory blood pressure monitoring

“…Furthermore, there is a positive association between the binding affinities of SSRIs and SNRIs for norepinephrine and serotonin transporters and arterial HTN. 27 , 28 Based on this concept, we designed this retrospective study to assess both nighttime and daytime BP variability using 24‐hour ABPM in patients with and without psychiatric conditions and with or without SSRIs/SNRIs treatment. We hypothesized that patients on SSRIs/SNRIs would experience elevated BP, as measured by ABPM.…”