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CO 2 exposure has been used to investigate the panicogenic response in patients with panic disorder. These patients are more sensitive to CO 2 , and more likely to experience the "false suffocation alarm" which triggers panic attacks. Imbalances in locus coeruleus noradrenergic (LC-NA) neurotransmission are responsible for psychiatric disorders, including panic disorder. These neurons are sensitive to changes in CO 2 /pH. Therefore, we investigated if LC-NA neurons are differentially activated after severe hypercapnia in mice. Further, we evaluated the participation of LC-NA neurons in ventilatory and panic-like escape responses induced by 20% CO 2 in male and female wild type mice and two mouse models of altered LC-NA synthesis. Hypercapnia activates the LC-NA neurons, with males presenting a heightened level of activation. Mutant males lacking or with reduced LC-NA synthesis showed hypoventilation, while animals lacking LC noradrenaline present an increased metabolic rate compared to wild type in normocapnia. When exposed to CO 2 , males lacking LC noradrenaline showed a lower respiratory frequency compared to control animals. On the other hand, females lacking LC noradrenaline presented a higher tidal volume. Nevertheless, no change in ventilation was observed in either sex. CO 2 evoked an active escape response. Mice lacking LC noradrenaline had a blunted jumping response and an increased freezing duration compared to the other groups. They also presented fewer racing episodes compared to wild type animals, but not different from mice with reduced LC noradrenaline. These findings suggest that LC-NA has an important role in ventilatory and panic-like escape responses elicited by CO 2 exposure in mice., Competing Interests: Declaration of competing interest The authors have no competing interests to declare and have no relevant financial or non- financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Antidepressant-induced paradoxical anxiety is a fairly common phenomenon seen in patients who are initiated on antidepressants. However, akathisia is a very uncommon manifestation of antidepressants. Much more rarely, antidepressants are also associated with the emergence of motor and vocal tics. This case adds to the growing literature of rare adverse events induced by antidepressants and aims to stimulate future research into the mechanism and risk factors of this phenomenon., Case Presentation: In this case report, we describe a patient with panic disorder and co-morbid Crohn's disease who developed worsening anxiety, akathisia and vocal tics upon initiation of fluvoxamine. This is the first case report to describe the emergence of both akathisia and vocal tics in the same patient following antidepressant initiation. After discontinuation of fluvoxamine, the patient's symptoms resolved., Conclusion: Antidepressant-induced akathisia and tics are often distressing both to the patient and their loved ones, and can be very puzzling to the clinician. It is important for clinicians to recognise that, although rare, antidepressants can adverse effects. When these symptoms arise, it should prompt immediate discontinuation of the offending antidepressant., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Cannabis sativa -derived substances such as cannabidiol (CBD) have attracted increasing clinical interest and consist in a new perspective for treating some neurological and psychiatric diseases., Aims: The aim of this work was to investigate the effect of acute treatment with CBD on panic-like defensive responses displayed by mice threatened by the venomous snake Bothrops jararaca ., Methods: Mice were habituated in the enriched polygonal arena for snake panic test. After recording the baseline responses of the tail-flick test, the prey were pretreated with intraperitoneal (i.p.) administrations of the endocannabinoid type 1 receptor (CB 1 ) antagonist AM251 (selective cannabinoid 1 receptor antagonist with an IC50 of 8 nM) at different doses, which were followed after 10 min by i.p. treatment with CBD (3 mg/kg). Thirty minutes after treatment with CBD, mice were subjected to confrontations by B. jararaca for 5 min, and the following defensive responses were recorded: risk assessment, oriented escape behaviour, inhibitory avoidance and prey-versus-snake interactions. Immediately after the escape behaviour was exhibited, the tail-flick latencies were recorded every 5 min for 30 min., Outcomes: Mice threatened by snakes displayed several anti-predatory defensive and innate fear-induced antinociception responses in comparison to the control. CBD significantly decreased the risk assessment and escape responses, with a consequent decrease in defensive antinociception. The CBD panicolytic effect was reversed by i.p. treatment with AM251., Conclusions: These findings suggest that the anti-aversive effect of CBD depends at least in part on the recruitment of CB 1 receptors.

Background: Sodium lactate (NaL) infusion and carbon dioxide (CO 2 ) inhalation are proven to provoke acute panic attacks (PAs) in patients with panic disorder (PD). A systematic literature search and meta-analysis were performed to compare the effect sizes of these methods., Methods: Odds ratios were calculated for each of the original studies and were pooled using the random-effects model., Results: Either NaL or CO 2 provocations significantly increased the rates of PAs in individuals with PD compared to those in healthy controls. However, the effect size of NaL infusion ( OR =25.13, 95% CI =15.48-40.80) was significantly greater than that of CO 2 inhalation ( OR =10.58, 95%CI =7.88-14.21)., Conclusion: The evidence for the efficacy of the two panic provocation tests is very strong. Yet, the results support the superiority of NaL infusion over CO 2 inhalation challenge as a panic provocation test. Thus, lactate seems a much stronger stimulus than CO 2 for the brain suffocation detector., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: 5-HT2A receptor (e.g. 25I-NBOMe) agonists not only pose risks of acute intoxication but also long-term effects and significant adverse reactions, e.g. hallucinogen persisting perception disorder (HPPD), derealization, and depersonalization., Aims: We evaluated the risk associated with single and repeated use of 25I-NBOMe. We aimed to identify factors that may increase the risk of HPPD, increase its severity and determine the time when the first symptoms appear. Herein, we report the first extensive evaluation of 25I-NBOMe-induced HPPD., Method: We assessed all reports (58) collected by The Pomeranian Pharmacovigilance Centre (PPC) from 2013 to 2020., Results: The study included a total of 58 reports of adverse reactions caused by 25I-NBOMe. In the case of 15 reports (in patients aged 19-26 years), symptoms persisted many months after the discontinuation of 25I-NBOMe. The most common were: pseudohallucinations, bizarre delusions, derealizations and in some cases development or worsening of depression has been diagnosed. HPPD-like symptoms were most common in patients who took the drug regularly (i.e., several times a month). The risk of HPPD-like symptoms is higher in patients who have severe visual pseudohallucinations, severe bizarre delusions, derealization and/or depersonalization onset immediately after taking the drug. Recurrence of HPPD symptoms may be provoked by many factors, however, there is some cases there is no apparent reason. HPPD after 25I-NBOMe use can last from 2 months up to 2 years. In some patients, pharmacological treatment was necessary due to 25I-NBOMe-induced HPPD and depression., Conclusions: The study showed long-lasting effects after 25I-NBOMe administration and allowed for the determination of HPPD risk factors., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: False suffocation alarm hypothesis has been widely used to explain carbon dioxide hypersensitivity in panic disorder (PD). However, hypersensitivity to carbon dioxide has been observed in other psychiatric disorders. We explored the specificity of carbon dioxide inhalation as a panic provocation test among psychiatric disorders via network meta-analysis., Methods: A systematic literature search on PubMed, EMBASE, and PsycNET was performed to acquire the studies using the carbon dioxide provocation test in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklists. Odds ratios (OR) for a panic attack (PA) induced by the carbon dioxide inhalation tests were extracted from each of the original studies and were pooled using the random-effects model., Results: Network meta-analysis on a pool of 2181 participants from 41 studies was used to compare the efficacy of carbon dioxide provocation tests among psychiatric disorders. The network meta-analysis showed that the odds for PA in response to carbon dioxide inhalation are higher in patients with PD, premenstrual dysphoric syndrome (PMDD), and social anxiety disorder (SAD) than healthy controls (HC). The odds for PA were not significantly different among patients with generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), and healthy controls (HC)., Conclusions: The vulnerability to the carbon dioxide provocation test is not limited to PD. The specificity of the test for PD is questionable, as individuals suffering from PMDD and SAD are also significantly more responsive to carbon dioxide inhalation compared to HC, OCD, MDD, and GAD. There may be shared underpinning biological mechanisms between PD, PMDD, and SAD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Mental health disorders are common in the United States and may cause significant disturbances in all aspects of a person's life. Individuals with mental health disorders often present to emergency departments for health care. Recognizing and managing common psychiatric emergencies may be challenging for non-mental health providers. The Diagnostic Statistical Manual-5 diagnostic criteria will be discussed and reviewed for panic attack and panic disorder. Both pharmacologic and nonpharmacologic treatment strategies will also be addressed. Adverse drug reactions associated with antipsychotics and selective serotonin reuptake inhibitors are another common psychiatric emergency that will be examined, offering potential management strategies. The objective of this clinical manuscript is to educate emergency health care providers about specific psychiatric emergencies, including panic attack, panic disorder, and adverse drug reactions associated with mental health treatment medications., (Copyright © 2021 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)

Background: Inhaling 35% carbon dioxide induces an emotional and symptomatic state in humans closely resembling naturally occurring panic attacks, the core symptom of panic disorder. Previous research has suggested a role of the serotonin system in the individual sensitivity to carbon dioxide. In line with this, we previously showed that a variant in the SLC6A4 gene, encoding the serotonin transporter, moderates the fear response to carbon dioxide in humans. To study the etiological basis of carbon dioxide-reactivity and panic attacks in more detail, we recently established a translational mouse model., Aim: The purpose of this study was to investigate whether decreased expression of the serotonin transporter affects the sensitivity to carbon dioxide., Methods: Based on our previous work, wildtype and serotonin transporter deficient (+/-, -/-) mice were monitored while being exposed to carbon dioxide-enriched air. In wildtype and serotonin transporter +/- mice, also cardio-respiration was assessed., Results: For most behavioral measures under air exposure, wildtype and serotonin transporter +/- mice did not differ, while serotonin transporter -/- mice showed more fear-related behavior. Carbon dioxide exposure evoked a marked increase in fear-related behaviors, independent of genotype, with the exception of time serotonin transporter -/- mice spent in the center zone of the modified open field test and freezing in the two-chamber test. On the physiological level, when inhaling carbon dioxide, the respiratory system was strongly activated and heart rate decreased independent of genotype., Conclusion: Carbon dioxide is a robust fear-inducing stimulus. It evokes inhibitory behavioral responses such as decreased exploration and is associated with a clear respiratory profile independent of serotonin transporter genotype.

Introduction: To improve therapeutic decision making, it is crucial that information regarding adverse drug reactions reaches patients. It is not enough to disseminate such findings through regulatory and scientific channels; targeted efforts to reach patients are necessary. One possible avenue is to collaborate with patient organizations., Objectives: The aim of this pilot study was to explore how adverse drug reactions can be communicated through patient organizations., Methods: A text describing a signal of levothyroxine and panic attacks was tailored to patients' needs, in terms of language, style and content, with emphasis placed on what to do when experiencing the symptoms described. The signal was communicated via the Dutch thyroid organization's digital newsletter, social media channels, website and print magazine., Results: The digital newsletter was distributed to around 5000 subscribers. On Facebook, 13,820 people viewed the message, with 2346 clicks in the message, indicating an intention to read the whole post. The interactions on social media were positive, and the tone was respectful., Conclusion: Patient organizations can help enable effective communication of adverse drug reactions to a relevant audience. The social media post generated more engagement than other communications from the patient organization, indicating a strong interest in this information. The additional patient experiences that were shared in the comments on social media further strengthened the original signal and its relevance to patients, creating an interesting feedback loop. The favourable experiences in this study support further consideration and exploration of this approach to communicate adverse drug reactions to patients.

Rationale: The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals., Objectives: This study was designed to explore the specific pattern of distribution of the CB 1 receptors in the VMH and to investigate the role played by this cannabinoid receptor in the effect of CBD on the control of defensive behaviours and unconditioned fear-induced antinociception., Methods: A panic attack-like state was triggered in Wistar rats by intra-VMH microinjections of N-methyl-D-aspartate (NMDA). One of three different doses of CBD was microinjected into the VMH prior to local administration of NMDA. In addition, the most effective dose of CBD was used after pre-treatment with the CB 1 receptor selective antagonist AM251, followed by NMDA microinjections in the VMH., Results: The morphological procedures demonstrated distribution of labelled CB 1 receptors on neuronal perikarya situated in dorsomedial, central and ventrolateral divisions of the VMH. The neuropharmacological approaches showed that both panic attack-like behaviours and unconditioned fear-induced antinociception decreased after intra-hypothalamic microinjections of CBD at the highest dose (100 nmol). These effects, however, were blocked by the administration of the CB 1 receptor antagonist AM251 (100 pmol) in the VMH., Conclusion: These findings suggest that CBD causes panicolytic-like effects and reduces unconditioned fear-induced antinociception when administered in the VMH, and these effects are mediated by the CB 1 receptor-endocannabinoid signalling mechanism in VMH.

Copeptin, the C-terminal part of the hypothalamic arginine vaspopressin (AVP) precursor, closely mirrors the production of AVP and was proposed as an easily measured novel marker of the individual stress level in man. First data in male volunteers proposed copeptin as a potential endocrine surrogate marker of cholecystokinin-tetrapeptide (CCK-4)-induced panic. We tried to replicate these pilot data and to extend them to the other sex. 46 healthy human subjects (29 men, 17 women) were given an intravenous bolus of 50 μg CCK-4. Basal and stimulated plasma copeptin was measured and panic symptoms were assessed using the Acute Panic Inventory (API). Basal copeptin was significantly lower in women vs. men, while men showed a significantly higher CCK-4-induced increase of copeptin. In contrast, female subjects displayed a signifcantly higher increase of API ratings by CCK-4. No significant correlations of panic symptoms and copeptin release induced by CCK-4 could be found, neither in man, nor in women, nor in the total sample. A sexual dimorphism in copeptin secretion and in panic response was demonstrated. Prior unexpected findings of copeptin release as an objective read-out of panic could not be replicated. The role of the vasopressinergic system in panic anxiety needs further study in panic patients and in healthy man, using also other panic provocation paradigms., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Recurrent panic attacks, comprising emotional and cardiovascular aversive responses, are common features in panic disorder, a subtype of anxiety disorder. The underlying brain circuitry includes nuclei of the hypothalamus, such as the dorsomedial hypothalamus (DMH). The endocannabinoid system has been proposed to modulate several biological processes in the hypothalamus. Thus, we tested the hypothesis that hypothalamic endocannabinoid signalling controls aversive responses in an animal model of panic attacks. Local infusion of NMDA into the DMH of rats induced panic-like behaviour. This effect was prevented by local, but not intraperitoneal, injection of a 2-arachidonoylglycerol (2-AG) hydrolysis inhibitor (MAGL inhibitor, URB602). The anandamide hydrolysis inhibitor (FAAH inhibitor), URB597, was ineffective. The anti-aversive action of URB602 was reversed by CB 1 and CB 2 antagonists (AM251 and AM630, respectively), and mimicked by CB 1 and CB 2 agonists (ACEA and JWH133, respectively). URB602 also prevented the cardiovascular effects of DMH-stimulation in anaesthetised animals. None of the treatments modified blood corticosterone levels. In conclusion, facilitation of 2-AG-signalling in the DMH modulates panic-like responses. The possible mechanisms comprise activation of both CB 1 and CB 2 receptors in this brain region., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background/aims: Little research effort has so far been dedicated to the analysis of the hypothalamic-pituitary-adrenal axis of aetiologically differing subgroups of patients with panic disorder (PD). The current study aimed at a deeper understanding of the cortisol stress response in cannabis-induced PD (CIPD) patients., Methods: Matched groups of 7 PD patients (mean age ± SD: 32.95 ± 9.04 years), 7 CIPD patients (31.94 ± 8.40 years), and 7 healthy controls (HC) (31.13 ± 8.57 years) were included in the study. The Trier Social Stress Test (TSST) was used for stress induction. Salivary cortisol samples were collected and panic- and depression-related questionnaires were applied., Results: A stress response to the TSST was found in 28.6% of PD patients, in 51.1% of CIPD patients, and in 100% of HC subjects. Statistical analyses revealed a cortisol hyporesponsiveness in PD and CIPD patients. While cortisol values of PD patients and HC participants differed significantly, CIPD patients' cortisol courses balanced between those of PD patients and HC subjects., Conclusions: Current findings show a distinctive pattern of the stress-induced cortisol reaction in CIPD patients, which is markedly different from the hormonal response in PD patients as well as HC subjects. Previous findings of cortisol hyporesponsiveness in PD patients compared to HC subjects were confirmed., (© 2019 S. Karger AG, Basel.)

Background: In this report, we describe a case of a patient with substance-induced anxiety disorder occurring after a single dose of 3,4-methylenedioxymethamphetamine. Furthermore, we describe the use and efficacy of the Primary Care Behavioral Health model, a collaborative approach to integrative primary mental health care, in evaluating and treating this rare mental health disorder., Case Presentation: Three days following ingestion of one dose of 3,4-methylenedioxymethamphetamine, a 35-year-old Hispanic man with no significant prior mental health history and no history of prior 3,4-methylenedioxymethamphetamine use presented to our hospital with severe, acute anxiety and panic symptoms. He was initially treated with a combination of behavioral therapy and the serotonin agonist buspirone. Buspirone ultimately proved ineffective, so it was discontinued in favor of the selective serotonin reuptake inhibitor sertraline. While awaiting the pharmacological onset of sertraline, the patient worked with a behavioral health consultant, who provided psychoeducation on the experience of panic, building relaxation skills, and modifying maladaptive thought patterns. Enhanced communication between the primary care provider and behavioral health consultant facilitated the planning and enactment of the patient's care plan. Approximately 2.5 months after his initial ingestion of 3,4-methylenedioxymethamphetamine, the patient's symptoms subsided. This improvement was attributed to the combination of the behavioral health intervention and sertraline at a dose of 50 mg daily. Six months after 3,4-methylenedioxymethamphetamine ingestion, the patient began to gradually taper sertraline and has had no resurgence of anxiety symptoms to date., Conclusions: Our patient's case not only demonstrates a rare presentation of 3,4-methylenedioxymethamphetamine-induced anxiety disorder but also provides support for the use of the Primary Care Behavioral Health model to deliver individualized, timely mental health care in a primary care setting.

Until recently, genetic research into panic disorder (PD) has had only limited success. Inspired by rodent research, demonstrating that the acid-sensing ion channel 1a (ASIC1a) is critically involved in the behavioral fear response to carbon dioxide (CO 2 ) exposure, variants in the human homologue gene amiloride-sensitive cation channel 2 (ACCN2) were shown to be associated with PD. However, the relationship between changes in brain pH and ACCN2, as done in rodents by CO 2 exposure, has not been investigated yet in humans. Here, we examined this link between the ACCN2 gene and the response to CO 2 exposure in two studies: in healthy volunteers as well as PD patients and using both behavioral and physiological outcome measures. More specifically, 107 healthy volunteers and 183 PD patients underwent a 35% CO 2 inhalation. Negative affect was assessed using visual analogue scales and the panic symptom list (PSL), and, in healthy volunteers, cardiovascular measurements. The single nucleotide polymorphism rs10875995 was significantly associated with a higher emotional response in PD patients and with an increase in systolic as well as diastolic blood pressure in healthy subjects. In all measurements, subjects homozygous for the T-allele showed a heightened reactivity to CO 2 . Furthermore, a trend towards an rs685012 genotype effect on the emotional response was found in PD patients. We provide the first evidence that genetic variants in the ACCN2 are associated with differential sensitivity to CO 2 in PD patients as well as healthy volunteers, further supporting ACCN2 as a promising candidate for future research to improve current treatment options.

Background: The potential role of drugs in the onset of panic attacks (PAs) is poorly understood., Aim: The objective of our study was to characterize drug-induced PAs., Method: We performed an analysis of PAs registered in the French pharmacovigilance database between 01/01/1985 and 05/11/2014., Results: Among the 163 recorded cases, 136 (83.4%) were directly related to drugs, mainly antidepressants (11.3%, mainly serotonin reuptake inhibitors), mefloquine (7.2%), isotretinoin (5.2%), rimonabant (3.6%) and corticosteroids (4.7%). PAs are labelled in the Summary of Product Characteristics (SmPC) for a minority (8.6%) of these drugs. In 31.4% of these cases, withdrawal of the suspected drug was performed more than a week after the onset of PAs. PAs could also be secondary to another adverse drug reaction (ADR; n = 14, 8.6%), mainly an allergy to antineoplastic or immunomodulating agents. In 13 cases (8.0%), PAs occurred during a drug-withdrawal syndrome, mainly after benzodiazepines or opioids. Most cases (73%) involved patients without any previous psychiatric disorder., Conclusion: This is the first pharmacoepidemiological study about iatrogenic PAs. Beside antidepressants, the most often encountered drugs are not indicated for psychiatric diseases. This study also reveals that iatrogenic PAs mostly occur in patients without any psychiatric medical history and that PAs can be triggered by another ADR. Lastly, the many cases with delayed management underline the need to raise awareness of this relatively unknown ADR among physicians, especially since PAs are generally not labelled in SmPCs of the suspected drugs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The effects of cannabinoids in brain areas expressing cannabinoid receptors, such as hypothalamic nuclei, are not yet well known. Several studies have demonstrated the role of hypothalamic nuclei in the organisation of behavioural responses induced through innate fear and panic attacks. Panic-prone states are experimentally induced in laboratory animals through a reduction in the GABAergic activity. The aim of the present study was to examine panic-like elaborated defensive behaviour evoked by GABA A receptor blockade with bicuculline (BIC) in the dorsomedial division of the ventromedial hypothalamus (VMHdm). We also aimed to characterise the involvement of endocannabinoids and the CB 1 cannabinoid receptor in the modulation of elaborated defence behavioural responses organised with the VMHdm. The guide-cannula was stereotaxicaly implanted in VMHdm and the animals were treated with anandamide (AEA) at different doses, and the effective dose was used after the pre-treatment with the CB 1 receptor antagonist AM251, followed by GABA A receptor blockade in VMHdm. The results showed that the intra-hypothalamic administration of AEA at an intermediate dose (5 pmol) attenuated defence responses induced through the intra-VMHdm microinjection of bicuculline (40 ng). This effect, however, was inhibited when applied central microinjection of the CB 1 receptor antagonist AM251 in the VMHdm. Moreover, AM251 potentiates de non-oriented escape induced by bicuculline, effect blocked by pre-treatment with the TRPV 1 channel antagonist 6-I-CPS. These results indicate that AEA modulates the pro-aversive effects of intra-VMHdm-bicuculline treatment, recruiting CB 1 cannabinoid receptors and the TRPV1 channel is involved in the AM251-related potentiation of bicuculline effects on non-oriented escape behaviour., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Selective stimulation of carotid chemoreceptors by intravenous infusion of low doses of potassium cyanide (KCN) produces short-lasting escape responses that have been proposed as a model of panic attack. In turn, preclinical studies suggest that facilitation of the endocannabinoid system attenuate panic-like responses. Here, we compared the effects of cannabinoid-related compounds to those of alprazolam, a clinically effective panicolytic, on the duration of the escape reaction induced by intravenous infusion of KCN (80μg) in rats. Alprazolam (1, 2, 4mg/kg) decreased escape duration at doses that did not alter basal locomotor activity. URB597 (0.1, 0.3, 1mg/kg; inhibitor of anandamide hydrolysis), WIN55,212-2 (0.1, 0.3, 1mg/kg; synthetic cannabinoid), arachidonoyl-serotonin (1, 2.5, 5mg/kg; dual TRPV1 and anandamide hydrolysis inhibitor), and cannabidiol (5, 10, 20, 40mg/kg; a phytocannabinoid) did not decrease escape duration. Alprazolam also prevented the increase in arterial pressure evoked by KCN, while bradycardia was unchanged. This study reinforces the validity of the KCN-evoked escape as a model of panic attack. However, it does not support a role for the endocannabinoid system in this behavioral response. These results might have implications for the screening of novel treatments for panic disorder., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We previously demonstrated that carbon dioxide inhalation could induce panic anxiety in a group of rare lesion patients with focal bilateral amygdala damage. To further elucidate the amygdala-independent mechanisms leading to aversive emotional experiences, we retested two of these patients (B.G. and A.M.) to examine whether triggering palpitations and dyspnea via stimulation of non-chemosensory interoceptive channels would be sufficient to elicit panic anxiety. Participants rated their affective and sensory experiences following bolus infusions of either isoproterenol, a rapidly acting peripheral β-adrenergic agonist akin to adrenaline, or saline. Infusions were administered during two separate conditions: a panic induction and an assessment of cardiorespiratory interoception. Isoproterenol infusions induced anxiety in both patients, and full-blown panic in one (patient B.G.). Although both patients demonstrated signs of diminished awareness for cardiac sensation, patient A.M., who did not panic, reported a complete lack of awareness for dyspnea, suggestive of impaired respiratory interoception. These findings indicate that the amygdala may play a role in dynamically detecting changes in cardiorespiratory sensation. The induction of panic anxiety provides further evidence that the amygdala is not required for the conscious experience of fear induced via interoceptive sensory channels., Significance Statement: We found that monozygotic twins with focal bilateral amygdala lesions report panic anxiety in response to intravenous infusions of isoproterenol, a β-adrenergic agonist similar to adrenaline. Heightened anxiety was evident in both twins, with one twin experiencing a panic attack. The twin who did not panic displayed signs of impaired cardiorespiratory interoception, including a complete absence of dyspnea sensation. These findings highlight that the amygdala is not strictly required for the experience of panic anxiety, and suggest that neural systems beyond the amygdala are also involved. Determining these additional systems could provide key neural modulation targets for future anxiolytic treatments., (Copyright © 2016 Khalsa, Feinstein et al.)

A subgroup of patients with Panic Disorder (PD) exhibits increased sensitivity to caffeine administration. However, the association between caffeine-induced panic attacks and post-caffeine hypothalamic-pituitary-adrenal (HPA)-axis activation in PD patients remains unclear. In a randomized, double-blind, cross-over experiment, 19 PD patients underwent a 400-mg caffeine-challenge and a placebo-challenge, both administered in the form of instant coffee. Plasma levels of adrenocorticotropic hormone (ACTH), cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed at both baseline and post-challenge. No patient panicked after placebo-challenge, while nine patients (47.3%) panicked after caffeine-challenge. Placebo administration did not result in any significant change in hormones' plasma levels. Overall, sample's patients demonstrated significant increases in ACTH, cortisol, and DHEAS plasma levels after caffeine administration. However, post-caffeine panickers and non-panickers did not differ with respect to the magnitude of the increases. Our results indicate that in PD patients, caffeine-induced panic attacks are not specifically associated with HPA-axis activation, as this is reflected in post-caffeine increases in ACTH, cortisol and DHEAS plasma levels, suggesting that caffeine-induced panic attacks in PD patients are not specifically mediated by the biological processes underlying fear or stress. More generally, our results add to the evidence that HPA-axis activation is not a specific characteristic of panic., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The neuropeptides orexin A and B play a role in reward and feeding and are critical for arousal. However, it was not initially appreciated that most prepro-orexin synthesizing neurons are almost exclusively concentrated in the perifornical hypothalamus, which when stimulated elicits panic-associated behavior and cardiovascular responses in rodents and self-reported "panic attacks" and "fear of dying" in humans. More recent studies support a role for the orexin system in coordinating an integrative stress response. For instance, orexin neurons are highly reactive to anxiogenic stimuli, are hyperactive in anxiety pathology, and have strong projections to anxiety and panic-associated circuitry. Although the two cognate orexin receptors are colocalized in many brain regions, the orexin 2 receptor (OX2R) most robustly maps to the histaminergic wake-promoting region, while the orexin 1 receptor (OX1R) distribution is more exclusive and dense in anxiety and panic circuitry regions, such as the locus ceruleus. Overall, this suggests that OX1Rs play a critical role in mobilizing anxiety and panic responses., Methods: Here, we used a CO2 -panic provocation model to screen a dual OX1/2R antagonist (DORA-12) to globally inhibit orexin activity, then a highly selective OX1R antagonist (SORA1, Compound 56) or OX2R antagonist (SORA2, JnJ10397049) to assess OX1R and OX2R involvement., Results: All compounds except the SORA2 attenuated CO2 -induced anxiety-like behaviors, and all but the SORA2 and DORA attenuated CO2 -induced cardiovascular responses., Conclusions: SORA1s may represent a novel method of treating anxiety disorders, with no apparent sedative effects that were present with a benzodiazepine., (© 2015 Wiley Periodicals, Inc.)

The inhalation of 35% carbon dioxide (CO₂) induces panic and anxiety in people with panic disorder (PD) and in people with various other psychiatric disorders. The anxiogenic effect of CO₂ in people with eating disorders has received sparse attention despite the fact that PD and bulimia nervosa (BN) have several common psychological and neurobiological features. This study compared CO₂-reactivity across three groups of participants: females with BN, females with PD, and female controls without known risk factors for enhanced CO₂-reactivity (e.g., social anxiety disorder, first degree relatives with PD). Reactivity was measured by self-reported ratings of panic symptomatology and subjective anxiety, analyzed as both continuous variables (change from room-air to CO₂) and dichotomous variables (positive versus negative responses to CO₂). Analyses of each outcome measure demonstrated that CO₂-reactivity was similar across the BN and PD groups, and reactivity within each of these two groups was significantly stronger than that in the control group. This is the first study to demonstrate CO₂-hyperreactivity in individuals with BN, supporting the hypothesis that reactivity to this biological paradigm is not specific to PD. Further research would benefit from examining transdiagnostic mechanisms in CO₂-hyperreactivity, such as anxiety sensitivity, which may account for this study's results., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Objectives: Carbon dioxide (CO2) hypersensitivity is hypothesized to be a robust endophenotypic marker of panic spectrum vulnerability. The goal of the current study was to explore the latent class trajectories of three primary response systems theoretically associated with CO2 hypersensitivity: subjective anxiety, panic symptoms, and respiratory rate (fR)., Methods: Participants (n = 376; 56% female) underwent a maintained 7.5% CO2 breathing task that included three phases: baseline, CO2 air breathing, and recovery. Growth mixture modeling was used to compare response classes (1…n) to identify the best-fit model for each marker. Panic correlates also were examined to determine class differences in panic vulnerability., Results: For subjective anxiety ratings, a three-class model was selected, with individuals in one class reporting an acute increase in anxiety during 7.5% CO2 breathing and a return to pre-CO2 levels during recovery. A second, smaller latent class was distinguished by elevated anxiety across all three phases. The third class reported low anxiety reported during room air, a mild increase in anxiety during 7.5% CO2 breathing, and a return to baseline during recovery. Latent class trajectories for fR yielded one class whereas panic symptom response yielded two classes., Limitations: This study examined CO2 hypersensitivity in one of the largest samples to date, but did not ascertain a general population sample thereby limiting generalizability. Moreover, a true resting baseline measure of fR was not measured., Conclusions: Two classes potentially representing different risk pathways were observed. Implications of results will be discussed in the context of panic risk research., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Rationale: Direct activation of the cannabinoid CB1 receptor in the dorsolateral periaqueductal gray (dlPAG) inhibits anxiety- and panic-related behaviours in experimental animals. It has remained unclear, however, whether the local endocannabinoid signalling is recruited as a protective mechanism against aversive stimuli., Objectives: The present study tested the hypothesis that the endocannabinoid system counteracts aversive responses in the dlPAG-stimulation model of panic attacks., Methods: All drugs were infused into the dlPAG of rats. Local chemical stimulation with N-methyl-D-aspartate (NMDA, 1 nmol) was employed to induce panic-like behavioural and cardiovascular responses in freely moving and anaesthetized animals, respectively. The neuronal activity in the dlPAG was investigated by c-Fos immunohistochemistry., Results: The selective CB1 receptor agonist, ACEA (0.005-0.5 pmol), prevented the NMDA-induced panic-like escape responses. More interestingly, increasing the local levels of endogenous anandamide with a fatty acid amide hydrolase (FAAH) inhibitor, URB597 (0.3-3 nmol), prevented both the behavioural response and the increase in blood pressure induced by NMDA. The effect of URB597 (3 nmol) was reversed by the CB1 receptor antagonist, AM251 (0.1 nmol). Moreover, an otherwise ineffective and sub-threshold dose of NMDA (0.5 nmol) was able to induce a panic-like response if local CB1 receptors were previously blocked by AM251 (0.1 nmol). Finally, URB597 prevented the NMDA-induced neuronal activation of the dlPAG., Conclusions: The endocannabinoid system in the dlPAG attenuates the behavioural, cellular and cardiovascular consequences of aversive stimuli. This process may be considered for the development of additional treatments against panic and other anxiety-related disorders.

The purpose of this study is to examine the association between oral contraceptive use (any current use, duration, and type) and major depressive disorder (MDD), generalized anxiety disorder (GAD), and panic disorder (PD) in a nationally representative sample of women in the USA. Data were drawn from 1,105 women aged 20-39 in the National Health and Nutrition Examination Surveys from 1999 to 2004. The associations between self-reported use of oral contraceptives in the past year and DSM-IV diagnosed and subthreshold MDD, GAD, and PD in the past year were assessed comparing oral contraceptive users to all non-users, former users, and former long-term users. Women using oral contraceptives had a lower past-year prevalence of all disorders assessed, other than subthreshold MDD. When adjusted for confounders, women using oral contraceptives in the past year had significantly lower odds of subthreshold PD, compared to former users (odds ratio (OR) = 0.34, 95 % CI 0.14-0.84). Effects estimates were strongest for monophasic (versus multiphasic) oral contraceptive users. Hormonal contraceptive use was associated with reduced risk of subthreshold PD. A potential mental health benefit of hormonal contraceptives has substantial public health implications; prospective longitudinal studies are needed to confirm whether hormonal contraceptive use improves mental health.

Dyspnea, 'hunger for air', and the urge to flee are the cardinal symptoms of respiratory-type panic attacks. Patients also show baseline respiratory abnormalities and a higher rate of comorbid and antecedent respiratory diseases. Panic attacks are also precipitated by both the infusion of 0.5 M sodium lactate and the inhalation of 5-7% carbon dioxide (CO2) in predisposed patients, but not in healthy volunteers nor patients without panic disorder. Further studies show that patients with panic are also hyper-responsive to hypoxia. These and other observations led Klein (1993) to suggest that clinical panic is the misfiring of a suffocation alarm system. In rats, cytotoxic hypoxia of chemoreceptor cells by intravenous injection of potassium cyanide (KCN) produces short-lasting flight behaviors reminiscent of panic attacks. KCN-induced flight behaviors are blocked both by denervation of chemoreceptor cells and lesion of dorsal periaqueductal gray matter, a likely substrate of panic. Herein, we show that KCN-evoked flight behaviors are also attenuated by both acute and chronic treatment with clonazepam (0.01-0.3 mg/kg, intraperitoneally (i.p.)) and fluoxetine (1-4 mg/kg/day, i.p. for 21 days), respectively. Attenuation of KCN-evoked panic-like behaviors by clinically-effective treatment with panicolytics adds fresh evidence to the false suffocation alarm theory of panic disorder., (© The Author(s) 2014.)

Objective: The dysbindin-1 (dystrobrevin-binding protein-1 [DTNBP-1]) gene has repeatedly been shown to be associated with psychotic disorder across diverse populations. In this study, we attempted to investigate the association of the rs3213207 (P1635) genetic polymorphism of the DTNBP1 gene with methamphetamine dependence and with methamphetamine-induced psychosis, manic episodes, and panic disorder in a male Malaysian population., Methods: This polymorphism was genotyped in 233 male methamphetamine-dependent subjects and in 301 male controls of the following 4 different ethnicities: Malay, Chinese, Kadazan-Dusun, and Bajau. Intergroup statistical analyses were performed by using the χ(2) test and the Fisher exact test where necessary. In cases of multiple comparisons, the Bonferroni correction was performed., Results: Our results indicated that the DTNBP1 rs3213207 polymorphism did not show any significant association with risk of methamphetamine dependence, either in the pooled subjects or after stratification into the 4 different ethnic groups (P > 0.05). Furthermore, we did not find any association of this polymorphism with methamphetamine-induced psychosis and episodes of methamphetamine-induced mania. However, there was a strong association between this polymorphism and the occurrence of methamphetamine-induced panic disorder in the pooled subjects (odds ratio [OR] = 6.739, P < 0.001) and in the Malay (OR = 11.93, P = 0.022) and Kadazan-Dusun (OR = 115.0, P < 0.001) groups., Conclusions: Our findings suggest that the DTNBP1 rs3213207 polymorphism may contribute to methamphetamine-induced panic disorder in the pooled Malaysian male population, especially in the Malay and Kadazan-Dusun ethnic groups. However, no association was found with methamphetamine dependence, methamphetamine-induced psychosis, or methamphetamine-induced mania.

The dorsomedial hypothalamus (DMH) has long been associated with the regulation of escape, a panic-related defensive response. Previous evidence has shown that the activation of serotonin (5-HT) 1A and 2A receptors impairs escape behavior induced by the electrical stimulation of the same region. In this study we further explore the relationship of the DMH with defense by investigating the effects of 5-HT1A activation on escape behavior generated in male Wistar rats by an ethologically based aversive stimuli, exposure to one of the open arms of the elevated T-maze (ETM). Aside from escape, the ETM also allows the measurement of inhibitory avoidance, a defensive response associated with generalized anxiety disorder. To evaluate locomotor activity, after ETM measurements animals were submitted to an open field. Results showed that intra-DMH administration of the 5-HT1A receptor agonist 8-OH-DPAT inhibited escape expression. Local administration of the 5-HT1A antagonist WAY-100635 by its own was ineffective, but blocked the panicolytic-like effect of 8-OH-DPAT. Chronic (21 days) systemic treatment with imipramine potentiated the anti-escape effect of 8-OH-DPAT. No significant effects of treatment with 8-OH-DPAT or imipramine on avoidance latencies or the number of lines crossed in the open field were found. These results indicate that 5-HT1A receptors within the DMH may play a phasic inhibitory role on ETM escape expression. As previously proposed, facilitation of 5-HT1A-mediated neurotransmission in the DMH may be involved in the mechanism of action of anti-panic compounds., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Many guidelines and regulations allow children and adolescents to be enrolled in research without the prospect of clinical benefit when it poses minimal risk. However, few systematic methods exist to determine when research risks are minimal. This situation has led to significant variation in minimal risk judgments, raising concern that some children are not being adequately protected. To address this concern, we describe a new method for implementing the widely endorsed "risks of daily life" standard for minimal risk. This standard defines research risks as minimal when they do not exceed the risks posed by daily life activities or routine examinations., Methods: This study employed a conceptual and normative analysis, and use of an illustrative example., Results: Different risks are composed of the same basic elements: Type, likelihood, and magnitude of harm. Hence, one can compare the risks of research and the risks of daily life by comparing the respective basic elements with each other. We use this insight to develop a systematic method, direct comparative analysis, for implementing the "risks of daily life" standard for minimal risk. The method offers a way of evaluating research procedures that pose the same types of risk as daily life activities, such as the risk of experiencing anxiety, stress, or other psychological harm. We thus illustrate how direct comparative analysis can be applied in practice by using it to evaluate whether the anxiety induced by a respiratory CO2 challenge poses minimal or greater than minimal risks in children and adolescents., Conclusions: Direct comparative analysis is a systematic method for applying the "risks of daily life" standard for minimal risk to research procedures that pose the same types of risk as daily life activities. It thereby offers a method to protect children and adolescents in research, while ensuring that important studies are not blocked because of unwarranted concerns about research risks.

Chest pain is often seen alongside with panic attacks. Moreover, panic disorder has been suggested as a risk factor for cardiovascular disease and even a trigger for acute coronary syndrome. Patients with coronary artery disease may have myocardial ischemia in response to mental stress, in which panic attack is a strong component, by an increase in coronary vasomotor tone or sympathetic hyperactivity setting off an increase in myocardial oxygen consumption. Indeed, coronary artery spasm was presumed to be present in cases of cardiac ischemia linked to panic disorder. These findings correlating panic disorder with coronary artery disease lead us to raise questions about the favorable prognosis of chest pain in panic attack. To investigate whether myocardial ischemia is the genesis of chest pain in panic attacks, we developed a myocardial perfusion study through research by myocardial scintigraphy in patients with panic attacks induced in the laboratory by inhalation of 35% carbon dioxide. In conclusion, from the data obtained, some hypotheses are discussed from the viewpoint of endothelial dysfunction and microvascular disease present in mental stress response., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Inhaling carbon dioxide (CO2)-enriched air induces fear and panic symptoms resembling real-life panic attacks, the hallmark of panic disorder. The present study aimed to describe the emotional and cardiovascular effects evoked by inhaling CO2, taking shortcomings of previous studies into account. Healthy volunteers underwent a double inhalation of 0, 9, 17.5, and 35% CO2, according to a randomized, cross-over design. In addition to fear, discomfort, and panic symptom ratings, blood pressure and heart rate were continuously monitored. Results showed a dose-dependent increase in all self-reports. Systolic and diastolic blood pressure rose with increasing CO2 concentration, whereas heart rate results were less consistent. Diastolic blood pressure and heart rate variation correlated with fear and discomfort. Based on this relationship and the observation that the diastolic blood pressure most accurately mimicked the degree of self-reported emotions, it might serve as a putative biomarker to assess the CO2-reactivity in the future., (Copyright © 2013 Elsevier B.V. All rights reserved.)

According to preclinical studies, glutamate has been implicated in the pathogenesis of anxiety. In order to elucidate the role of glutamate in anxiety and panic in humans, brain glutamate+glutamine (Glx) levels were measured during cholecystokinin-tetrapeptide (CCK-4)-induced panic using magnetic resonance spectroscopy (MRS). Eighteen healthy subjects underwent a CCK-4 challenge. MR spectra were obtained from the anterior cingulate cortex (ACC) using a single voxel point-resolved spectroscopy method and analyzed using LCModel. A combined fitting of Glx was performed. Panic was assessed using the Acute Panic Inventory (API) and Panic Symptom Scale (PSS) scores. Moreover, hypothalamic-pituitary-adrenal axis stimulation was monitored throughout the challenge. There was a significant panic response following CCK-4 as revealed by a marked increase in both the panic scores (API: F(1,17)=149.41; p<0.0001; PSS: F(1,17)=88.03; p<0.0001) and heart rate (HR: F(1,17)=72.79; p<0.0001). MRS measures showed a significant increase of brain Glx/creatine (Glx/Cr) levels peaking at 2-10 min after challenge (F(1,17)=15.94; p=0.001). There was also a significant increase in CCK-4-related cortisol release (F(6,11)=8.68; p=0.002). Finally, significant positive correlations were found between baseline Glx/Cr and both APImax (r=0.598; p=0.009) and maximum heart rate (HR(max)) during challenge (r=0.519; p=0.027). Our results suggest that CCK-4-induced panic is accompanied by a significant glutamate increase in the bilateral ACC. The results add to the hypothesis of a disturbance of the inhibitory-excitatory equilibrium and suggest that apart from static alterations rapid and dynamic neurochemical changes might also be relevant for the neural control of panic attacks.

Cholecystokinin-tetrapeptide (CCK-4)-induced panic attacks are reportedly attenuated by effective treatment with antipanic antidepressants in patients with panic disorder, but in healthy volunteers such effects are not well studied. The aim of this study was to assess the effect of 6-week treatment with an SSRI escitalopram on CCK-4-induced symptoms in healthy volunteers, who previously responded with a panic attack to CCK-4 challenge. A total of 18 healthy subjects (10 males and eight females, mean age 22.5 ± 5.8) received a 6-week treatment with escitalopram (10 mg/day) and placebo followed by CCK-4 challenge (50 μg) in a double-blind crossover design. The panic rate was 67% after treatment with escitalopram and 56% after treatment with placebo (p = 0.7). Thus, the results showed a significant reduction in CCK-4-induced panic rates without significant differences between escitalopram and placebo conditions. There were no significant effects of either treatment on any other variable of anxiety or cardiovascular indices. Secondary analysis showed no effect of gender or 5-HTTLPR polymorphism on response to CCK-4 challenge. This study demonstrated that in contrast to the findings in patients with panic disorder, in CCK-4-sensitive healthy volunteers the treatment with an antipanic SSRI did not cause a reduction of CCK-4-induced panic attacks beyond the effect of placebo. The mechanisms behind this discrepancy and the reasons of the decrease in sensitivity to CCK-4 challenge on repeated administration remain to be clarified in future studies., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

This systematic review assesses the current state of clinical and preclinical research on panic disorder (PD) in which the carbon dioxide (CO2) challenge was used as a trigger for panic attacks (PAs). A total of 95 articles published from 1984 to 2012 were selected for inclusion. Some hypotheses for PD evolved greatly due to the reproducibility of PAs in a controlled environment using the safe and noninvasive CO2 test. The 35% CO2 protocol was the method chosen by the majority of studies. Results of the test report specific sensitivity to hypercapnia in PD patients of the respiratory PD subtype. The CO2 challenge helped assess the antipanic effects of medication and non-pharmaceutical approaches such as physical exercise and cognitive behavioral therapy. The test was also used in studies about the genetic component of PD, in which twins and relatives of PD patients were analyzed.

The relevance of 5-HT1A and 5-HT2C receptors of the basolateral nucleus of the amygdala (BLA) in the mediation of anxiety-related defensive responses has long been acknowledged. Whereas strong evidence supports that activation of the latter receptors provokes anxiety, conflicting findings have been reported on the role played by the former binding site. In this study we further investigated the involvement of 5-HT1A receptors (5-HT1A-Rs) in the regulation of anxiety- and panic-related defensive behaviors. The results showed that intra-BLA injection of the 5-HT1A-R agonist 8-OH-DPAT (0.4-16nmol) in male Wistar rats impaired the acquisition of inhibitory avoidance in the elevated T-maze, increased the percentage of time spent in the lit compartment of the light-dark transition model and enhanced the number of punished drinking events in the Vogel conflict test, all changes compatible with an anxiolytic effect. This agonist also impaired escape expression in the elevated T-maze, suggestive of a panicolytic-like effect. 8-OH-DPAT-induced changes in the elevated T-maze and light-dark tests were blocked by previous local administration of the 5-HT1A-R antagonist WAY-100635 (0.37nmol) and were also observed after intra-BLA microinjection of the benzodiazepine receptor agonist midazolam (10-40nmol). Thus, stimulation of 5-HT1A-Rs in the BLA causes both anxiolytic- and panicolytic-like effects, what may have implications for the pathophysiology and treatment of generalized anxiety and panic disorders., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Aim: FAAH is a membrane enzyme that terminates the activity of a large class of endogenous signaling lipids. Recent studies suggest that the FAAH Pro129Thr polymorphism is a common mutation in the FAAH gene that is significantly associated with drug-addictive traits. This study investigated the association of the Pro129Thr polymorphism of the FAAH gene with methamphetamine dependence, methamphetamine-induced psychosis, manic episodes and panic disorder in a Malaysian population., Materials & Methods: This polymorphism was genotyped in 232 male methamphetamine-dependent subjects and in 241 male controls of four different ethnicities: Malay, Chinese, Kadazan-Dusun and Bajau. Intergroup statistical analyses were performed by using the χ(2)-square test and Fisher's exact test, where necessary. In cases of multiple comparisons, the Bonferroni correction was performed., Results: Our results indicated that the FAAH Pro129Thr polymorphism showed a significant association with risk of methamphetamine dependence in the pooled subjects (odds ratio [OR]: 2.017; p < 0.001) and in the Malay (OR: 2.829; p < 0.001) and Chinese (OR: 3.685; p < 0.001) groups. We also found an association of this polymorphism with episodes of methamphetamine-induced mania in the Malay group (OR: 2.836; p = 0.035). However, there was no association between this polymorphism and age of onset of drug use or the occurrence of methamphetamine-induced psychosis or of panic disorder., Conclusion: Our findings suggest that the FAAH Pro129Thr polymorphism may contribute to methamphetamine dependence in the Malay and Chinese ethnic groups.

Rats with chronic inhibition of GABA synthesis by infusion of l-allyglycine, a glutamic acid decarboxylase inhibitor, into their dorsomedial/perifornical hypothalamus are anxious and exhibit panic-like cardio-respiratory responses to treatment with intravenous (i.v.) sodium lactate (NaLac) infusions, in a manner similar to what occurs in patients with panic disorder. We previously showed that either NMDA receptor antagonists or metabotropic glutamate receptor type 2/3 receptor agonists can block such a NaLac response, suggesting that a glutamate mechanism is contributing to this panic-like state. Using this animal model of panic, we tested the efficacy of CBiPES and THIIC, which are selective group II metabotropic glutamate type 2 receptor allosteric potentiators (at 10-30 mg/kg i.p.), in preventing NaLac-induced panic-like behavioral and cardiovascular responses. The positive control was alprazolam (3mg/kg i.p.), a clinically effective anti-panic benzodiazepine. As predicted, panic-prone rats given a NaLac challenge displayed NaLac-induced panic-like cardiovascular (i.e. tachycardia and hypertensive) responses and "anxiety" (i.e. decreased social interaction time) and "flight" (i.e. increased locomotion) -associated behaviors; however, systemic injection of the panic-prone rats with CBiPES, THIIC or alprazolam prior to the NaLac dose blocked all NaLac-induced panic-like behaviors and cardiovascular responses. These data suggested that in a rat animal model, selective group II metabotropic glutamate type 2 receptor allosteric potentiators show an anti-panic efficacy similar to alprazolam.

Background: Adults with panic disorder (PD) and children with separation anxiety disorder (CSAD) show higher reactivity to CO(2). Our hypothesis was patients with adult separation anxiety disorder (ASAD) would show similar hypersensitivity to CO(2). In the present study, we determined whether sensitivity to CO(2) was enhanced in adult patients with separation anxiety disorder with no history of panic attacks., Methods: Patients with PD (n=38), adult separation anxiety disorder (ASAD) patients with no history of panic attacks (n=31), and healthy subjects (n=40) underwent a 35% CO(2) inhalation challenge procedure. Baseline and post-inhalation anxiety were assessed with the Acute Panic Inventory, Visual Analog Scale, and Anxiety Sensitivity Index-3 (ASI-3)., Results: As hypothesized the rate of CO(2)-induced panic attacks was significantly greater in PD and ASAD patient groups (55.3% and 51.6% respectively) than healthy comparison group (17.5%). Nine (69.2%) of 13 patients in PD group who have ASAD concurrent with PD had a CO(2)-induced panic attack. ASI-3 total scores were not different between PD and ASAD groups and both were significantly higher than controls. However, anxiety sensitivity did not predict the occurrence of panic attacks., Limitations: The researchers were not blind to the diagnosis and there was no placebo arm for comparison. Besides, parameters of respiratory physiology were not evaluated., Conclusion: ASAD was associated with CO(2) hypersensitivity quite similar to PD. This finding partly unfolds the complex relationship of 'CSAD, PD, and CO(2) hypersensitivity' and indicates that CO(2) hypersensitivity and separation anxiety extend together beyond childhood., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Neuropeptide S (NPS) regulates various biological functions by selectively activating the NPS receptor (NPSR). Recently, epidemiological studies revealed an association between NPSR single nucleotide polymorphisms and susceptibility to panic disorders. Here we investigated the effects of NPS in mice subjected to the elevated T maze (ETM), an assay which has been proposed to model anxiety and panic. Diazepam [1 mg/kg, intraperitoneally (i.p.)] elicited clear anxiolytic effects reducing the latency to emerge from the closed to the open (CO) arm without modifying the latencies from the open to the closed (OC) arm. By contrast, chronic fluoxetine (10 mg/kg i.p., once a day for 21 days) selectively increased OC latency, suggesting a panicolytic-like effect. NPS given intracerebroventricularly at 0.001-1 nmol elicited both anxiolytic- and panicolytic-like effects. However, although the NPS anxiolytic dose-response curve displayed the classical sigmoidal shape, the dose-response curve of the putative panicolytic-like effect was bell shaped with peak effect at 0.01 nmol. The behaviour of wild-type [NPSR(+/+)] and receptor knock out [NPSR(-/-)] mice in the ETM task was superimposable. NPS at 0.01 nmol elicited anxiolytic- and panicolytic-like effects in NPSR(+/+) but not in NPSR(-/-) mice. In conclusion, this study demonstrated that NPS, via selective activation of the NPSR, promotes both anxiolytic- and panicolytic-like actions in the mouse ETM., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Objectives: Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic-pituitary-adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared., Methods: Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed., Results: We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level., Conclusions: Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4.

Background: Previous studies examined caffeine use and caffeine dependence and risk for the symptoms, or diagnosis, of psychiatric disorders. The current study aimed to determine if generalized anxiety disorder (GAD), panic disorder, phobias, major depressive disorder (MDD), anorexia nervosa (AN), or bulimia nervosa (BN) shared common genetic or environmental factors with caffeine use, caffeine tolerance, or caffeine withdrawal., Method: Using 2,270 women from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, bivariate Cholesky decomposition models were used to determine if any of the psychiatric disorders shared genetic or environmental factors with caffeine use phenotypes., Results: GAD, phobias, and MDD shared genetic factors with caffeine use, with genetic correlations estimated to be 0.48, 0.25, and 0.38, respectively. Removal of the shared genetic and environmental parameter for phobias and caffeine use resulted in a significantly worse fitting model. MDD shared unique environmental factors (environmental correlation=0.23) with caffeine tolerance; the genetic correlation between AN and caffeine tolerance and BN and caffeine tolerance were 0.64 and 0.49, respectively. Removal of the genetic and environmental correlation parameters resulted in significantly worse fitting models for GAD, phobias, MDD, AN, and BN, which suggested that there was significant shared liability between each of these phenotypes and caffeine tolerance. GAD had modest genetic correlations with caffeine tolerance, 0.24, and caffeine withdrawal, 0.35., Conclusions: There was suggestive evidence of shared genetic and environmental liability between psychiatric disorders and caffeine phenotypes. This might inform us about the etiology of the comorbidity between these phenotypes.

Few studies have addressed whether the use of avoidance-oriented coping strategies is related to the development of panic in patients with panic disorder(PD). Self-report, clinician-rated, and physiological data were collected from 42 individuals who participated in a yohimbine biological challenge study, performed under double-blind, placebo-controlled conditions. Participants included 20 healthy controls and 22 currently symptomatic patients who met DSM-IV-TR diagnostic criteria for PD. Consistent with prediction, patients with PD who had higher perceived efficacy of avoidance-oriented strategies in reducing anxiety-related thoughts reported increased severity in panic symptoms during the yohimbine challenge condition as compared to the placebo. Further, patients with PD who had more fear of cognitive dyscontrol, cardiovascular symptoms, and publicly observable anxiety also reported increased severity in panic symptoms during the challenge. Healthy controls who had more fear of cardiovascular symptoms similarly reported increased severity in panic symptoms during the challenge. No effects were found for heart rate response to the challenge agent. These results provide support for the role of avoidance-oriented coping strategies and fear of anxiety-related symptoms as risk and maintenance factors in the development of panic symptoms, particularly within a biological challenge model.