Chronic serotonin–norepinephrine reuptake transporter inhibition modifies basal respiratory output in adult mouse in vitro and in vivo

Abstract

Respiratory disturbances are a common feature of panic disorder and present as breathing irregularity, hyperventilation, and increased sensitivity to carbon dioxide. Common therapeutic interventions, such as tricyclic (TCA) and selective serotonin reuptake inhibitor (SSRI) antidepressants, have been shown to ameliorate not only the psychological components of panic disorder but also the respiratory disturbances. These drugs are also prescribed for generalized anxiety and depressive disorders, neither of which are characterized by respiratory disturbances, and previous studies have demonstrated that TCAs and SSRIs exert effects on basal respiratory activity in animal models without panic disorder symptoms. Whether serotonin-norepinephrine reuptake inhibitors (SNRIs) have similar effects on respiratory activity remains to be determined. Therefore, the current study was designed to investigate the effects of chronic administration of the SNRI antidepressant venlafaxine (VHCL) on basal respiratory output. For these experiments, we recorded phrenic nerve discharge in an in vitro arterially-perfused adult mouse preparation and diaphragm electromyogram (EMG) activity in an in vivo urethane-anesthetized adult mouse preparation. We found that following 28-d VHCL administration, basal respiratory burst frequency was markedly reduced due to an increase in expiratory duration (TE), and the inspiratory duty cycle (TI/Ttot) was significantly shortened. In addition, post-inspiratory and spurious expiratory discharges were seen in vitro. Based on our observations, we suggest that drugs capable of simultaneously blocking both 5-HT and NE reuptake transporters have the potential to influence the respiratory control network in patients using SNRI therapy.

Heart Rate Variability Changes in Patients With Major Depressive Disorder: Related to Confounding Factors, Not to Symptom Severity?

“…The observed lower respiratory rate in medicated patients in the relaxed state was consistent with some findings pointing out the specific influence of antidepressants on respiratory activity ( Warren and Solomon, 2012 ). Because of the small sample size, we abandoned further analyses.…”

Desmetramadol Has the Safety and Analgesic Profile of Tramadol Without Its Metabolic Liabilities: Consecutive Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Trials

“…48 It is unknown whether this respiratory depression by tramadol is mediated by its opioid or monoaminergic mechanism, because adrenergic agents also cause respiratory depression and naloxone failed to fully reverse it. 4,5,47,77,85 The effect of serotonin on ventilatory control is more uncertain and depends on the types of respiratory neuron and 5-hydroxytryptophan receptor. 2 In this study, mean respiration after tramadol and desmetramadol were minimally decreased compared with placebo, and this decrease was statistically significant in trial B, but not in trial A.…”

A case of behavioural hyperventilation associated with severe central sleep apnoea and follow-up management

“…Moreover, systemic administration of the noradrenergic tricyclic antidepressant desipramine has been shown to stabilise abnormal breathing patterns in NE deficient mice 6. A novel study using a non-anxiety/panic mouse model showed that basal respiratory burst frequency was markedly reduced after 28-day SNRI (venlafaxine) administration; this finding suggests drugs capable of simultaneously blocking the 5-HT and NE reuptake transporters have an ability to depress the central respiratory neural network 7. In sum this evidence suggests that regulation of the respiratory centre by stabilising respiratory control effects, which would be reflected by decreased in average AI and CL as seen in our patient, may be the underlying mechanism of duloxetine for treating hyperventilation-related CSA in this patient.…”