Subjective and physiological responses to the 35% carbon dioxide challenge in healthy and non-clinical control populations: a meta-analysis and systematic review

Liu, Jenny J. W.; Ein, Natalie; Gervasio, Julia; Vickers, Kristin S.

doi:10.1080/10615806.2019.1570803

Cited by 5 publications

(5 citation statements)

References 56 publications

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“…JNJ-61393215 at 90 mg showed a robust anxiolytic effect, driven by a decrease in most items on the PSL-IV, similar to the active comparator, alprazolam, supporting the potential anxiolytic effect properties of OX1R antagonists. The reduction in anxiety symptoms observed after administration of JNJ-61393215 90 mg and alprazolam was not paralleled by any changes in cardiovascular parameters: we observed marked interindividual variability in the changes in blood pressure and heart rate elicited by CO 2 inhalation, as well as in the effects of JNJ-61393215 and alprazolam on those measures, a finding consistent with a recent meta-analysis that highlighted the large variability and limited interpretability of the effects of the CO 2 challenge on cardiovascular parameters 25 .…”

Section: Discussionsupporting

confidence: 91%

“…JNJ-61393215 and alprazolam did not have any significant effects on cardiovascular parameters, such as blood pressure or heart rate (data not shown). Considerable variability of physiological parameters at baseline and after the CO 2 challenge was observed across the study population, which is consistent with the results of a recent meta-analysis 25 .…”

Section: Cardiovascular Parameterssupporting

confidence: 90%

“…In the SAD study, 72 male participants (aged 18 [19][20][21][22][23][24][25][26][27][28][29][30] were included. Females were excluded due to lack of preclinical reproductive and developmental toxicity results available at the time the study was conducted.…”

Section: Clinical Studies Pharmacokinetic Profiles and Safety Of Singmentioning

confidence: 99%

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Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans

et al. 2020

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Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO2 inhalation challenge to induce panic symptoms. In the rat CO2 model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO2-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90 mg demonstrated significant reduction (P < 0.02) in CO2-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO2 exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.

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Section: Discussionsupporting

confidence: 91%

Section: Cardiovascular Parameterssupporting

confidence: 90%

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Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans

et al. 2020

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“…Voluntary inhalation of CO 2 is widely used in human research to induce feelings of anxiety, fear and panic 13,14 . Humans vary in CO 2 sensitivity, with panic disorder patients being sensitive to even low concentrations 15–17 .…”

Section: Introductionmentioning

confidence: 99%

Variation in the onset of CO2-induced anxiety in female Sprague Dawley rats

Améndola

Ratuski

Weary

2019

Sci Rep

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Carbon dioxide (CO2) is commonly used to kill laboratory rats. Rats find CO2 aversive and aversion varies between individuals, indicating that rats vary in CO2 sensitivity. Healthy humans experience feelings of anxiety at concentrations similar to those avoided by rats, and these feelings are diminished by the administration of benzodiazepines. Our aim was to assess the effects of the benzodiazepine midazolam on individual thresholds of rat aversion to CO2. Six female Sprague Dawley rats were repeatedly exposed to CO2 gradual-fill in approach-avoidance testing. The first three exposures were to a control-treatment followed by three exposures to midazolam (0.375 mg/kg). Within each treatment aversion to CO2 was not affected by exposure number; however, tolerance increased from an average of 10.7% CO2 avoided during control sessions, to 15.5% CO2 avoided when treated with midazolam. These results indicate that rats experience anxiety when exposed to CO2, and that variation in rat CO2 sensitivity is driven by individual differences in the onset of these feelings of anxiety. No rat tolerated CO2 concentrations required to induce loss of consciousness.

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“…In a meta-analysis summarizing the effects of the CO 2 inhalation, an increase in self-reported subjective distress due to the CO 2 inhalation was consistently found. On the other hand, results regarding cardiovascular parameters were more heterogenous, with no significant overall effect (Liu et al 2019).…”

Section: Discussionmentioning

confidence: 90%

The role of the peripheral and central adrenergic system in the construction of the subjective emotional experience of panic

de Vos,

Schruers,

Debard

et al. 2024

Psychopharmacology

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Rationale Although the study of emotions can look back to over 100 years of research, it is unclear which information the brain uses to construct the subjective experience of an emotion. Objective In the current study, we assess the role of the peripheral and central adrenergic system in this respect. Methods Healthy volunteers underwent a double inhalation of 35% CO2, which is a well-validated procedure to induce an intense emotion, namely panic. In a randomized, cross-over design, 34 participants received either a β1-blocker acting selectively in the peripheral nervous system (atenolol), a β1-blocker acting in the peripheral and central nervous system (metoprolol), or a placebo before the CO2 inhalation. Results Heart rate and systolic blood pressure were reduced in both β-blocker conditions compared to placebo, showing effective inhibition of the adrenergic tone. Nevertheless, the subjective experience of the induced panic was the same in all conditions, as measured by self-reported fear, discomfort, and panic symptom ratings. Conclusions These results indicate that information from the peripheral and central adrenergic system does not play a major role in the construction of the subjective emotion.

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Subjective and physiological responses to the 35% carbon dioxide challenge in healthy and non-clinical control populations: a meta-analysis and systematic review

Cited by 5 publications

References 56 publications

Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans

Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans

Variation in the onset of CO2-induced anxiety in female Sprague Dawley rats

The role of the peripheral and central adrenergic system in the construction of the subjective emotional experience of panic

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