Psychological and Psychiatric Events Following Immunization with Five Different Vaccines against SARS-CoV-2.

BACKGROUND: Despite the high number of vaccines administered against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide, the information on the psychological/psychiatric adverse events following immunization (AEFI) with these newly developed vaccines remains scarce. OBJECTIVE: To describe the frequency of psychological/psychiatric symptoms among recipients of five different anti-SARS-CoV-2 vaccines and to explore the factors associated with their development reported in the nationwide Mexican registry of AEFI against SARS-CoV-2. METHODS: Descriptive study of all the psychological/psychiatric symptoms, including anxiety, panic attacks, insomnia, and agitation reported to the Mexican Epidemiological Surveillance System from 21 December 2020 to 27 April 2021, among adult (≥18 years old) recipients of 7,812,845 doses of BNT162b2, ChAdOx1 nCov-19, rAd26-rAd5, Ad5-nCoV, or CoronaVac. The factors associated with their development are determined by multivariate regression analysis. RESULTS: There were 19,163 AEFI reports during the study period; amongst them, 191 (1%) patients had psychological/psychiatric symptoms (median age of 41 years, interquartile range of 32-54; 149 [78%] women) for an observed incidence of 2.44 cases per 100,000 administered doses (95% confidence interval [CI] 2.12-2.82), 72.8% of psychiatric AEFIs were reported among recipients of BNT162b2. The median time from vaccination to symptom onset was 35 min (interquartile range: 10-720). Overall, the most common psychological/psychiatric symptoms were anxiety in 129 (67.5%) patients, panic attacks in 30 (15.7%), insomnia in 25 (13%), and agitation in 11 (5.7%). After adjusting for the confounding factors, the odds for developing psychological/psychiatric symptoms were higher for those concurrently reporting syncope (odds ratio [OR]: 4.73, 95% CI: 1.68-13.33); palpitations (OR: 2.47, 95% CI: 1.65-3.70), and dizziness (OR: 1.59, 95% CI: 1.10-2.28). CONCLUSION: In our population, psychological/psychiatric symptoms were extremely infrequent AEFIs. No severe psychiatric AEFIs were reported. Immunization stress-related responses might explain most of the detected cases.

Can regular physical exercise be a treatment for panic disorder? A systematic review.

INTRODUCTION: In the last few decades, exercise has been explored as a potential tool to reduce symptoms experienced by patients with panic disorder (PD). This systematic review aims to assess the effects of regular exercise interventions on panic severity, global anxiety, and depression symptoms of these patients. AREAS COVERED: A search was conducted on PubMed, ISI Web of Science, and Cochrane Central Register of Controlled Trials using search terms related to PD and exercise. Eight trials were included, Furthermore, regular exercise programs presented different methodological characteristics. There is o clear evidence indicating that regular exercise programs (at least two 20-minute sessions per week for at least 6 weeks) reduce panic-related symptoms. Regular exercise is effective in improving global anxiety measures and depression. EXPERT OPINION: Continuous aerobic exercise is the main type of intervention in the literature, generally providing a limited prescription. Currently, it is recommended the interval training, with intense and shorter stimuli, and long-term duration trials. However, despite the use of self-selected intensities and control based on the internal load be interesting as recommendation to increase adherence, careful is needed regarding training prescription due to scarce evidence.

Cannabidiol-induced panicolytic-like effects and fear-induced antinociception impairment: the role of the CB1 receptor in the ventromedial hypothalamus.

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 CB1 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 CB1 receptor selective antagonist AM251, followed by NMDA microinjections in the VMH. RESULTS: The morphological procedures demonstrated distribution of labelled CB1 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 CB1 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 CB1 receptor-endocannabinoid signalling mechanism in VMH.

The Blockade of µ1- and κ-Opioid Receptors in the Inferior Colliculus Decreases the Expression of Panic Attack-Like Behaviours Induced by Chemical Stimulation of the Dorsal Midbrain.

BACKGROUND: Gamma-aminobutyric acid (GABA)ergic and opioid systems play a crucial role in the neural modulation of innate fear organised by the inferior colliculus (IC). In addition, the IC is rich in GABAergic fibres and opioid neurons, which are also connected to other mesencephalic structures, such as the superior colliculus and the substantia nigra. However, the contribution of distinct opioid receptors (ORs) in the IC during the elaboration and expression of innate fear and panic-like responses is unclear. The purpose of the present work was to investigate a possible integrated action exerted by ORs and the GABAA receptor-mediated system in the IC on panic-like responses. METHODS: The effect of the blockade of either µ1- or κ-ORs in the IC was evaluated in the unconditioned fear-induced responses elicited by GABAA antagonism with bicuculline. Microinjections of naloxonazine, a µ1-OR antagonist, or nor-binaltorphimine (nor-BNI), a κ-OR antagonist, were made into the IC, followed by intramesencephalic administration of the GABAA-receptor antagonist bicuculline. The defensive behaviours elicited by the treatments in the IC were quantitatively analysed, recording the number of escapes expressed as running (crossing), jumps, and rotations, over a 30-min period in a circular arena. The exploratory behaviour of rearing was also recorded. RESULTS: GABAA-receptor blockade with bicuculline in the IC increased defensive behaviours. However, pretreatment of the IC with higher doses (5 µg) of naloxonazine or nor-BNI followed by bicuculline resulted in a significant decrease in unconditioned fear-induced responses. CONCLUSIONS: These findings suggest a role played by µ1- and κ-OR-containing connexions and GABAA receptor-mediated neurotransmission on the organisation of panic attack-related responses elaborated by the IC neurons.

Auricular Chromotherapy in the Treatment of Psychologic Trauma, Phobias, and Panic Disorder.

Auricular chromotherapy has shown promising results in the treatment of psychologic trauma and anxiety disorders, such as phobias and panic attacks. With its relatively easy and quick technical application, this procedure could be an indispensable tool for physicians. However, its mechanism of action is not yet understood completely. Objective: To treat patients suffering from trauma, phobia, and panic attack with auricular chromotherapy. Materials and Methods: The protocol was applied in 160 patients (135 who experienced traumas; 15 patients with specific phobias and 10 patients with panic disorder). They are 134 women, 26 men, ages 20-60. Results: The treatment showed 93% of positive response. Conclusion: This procedure shows the possibility of drawing a path from the external ear to traumatic memories, anxiety disorders and phobias.

Treatment-resistant panic disorder: a systematic review.

INTRODUCTION: The prevalence of panic disorder (PD) in the population is high and these patients have work impairment, high unemployment rates, seek medical treatment more frequently and have more hospitalizations than people without panic symptoms. Despite the availability of pharmacological, psychological and combined treatments, approximately one-third of all PD patients have persistent panic attacks and other PD symptoms after treatment. AREAS COVERED: MEDLINE/Pubmed, CENTRAL, PsycINFO and Web of Science databases were searched for clinical trials in treatment-resistant PD. Only studies published between 1980 and 2015, in English, with human subjects, considered "journal articles" and clinical trial were included. We included trials recruiting only adult subjects with treatment-resistant PD, consistent with criteria from DSM-III to DSM5. We included all prospective experimental studies. Case, case series, retrospective studies or studies with <10 PD subjects were not included. EXPERT OPINION: Only 11 articles were included in this review. There were few quality studies, only two were randomized, controlled and double blind. Augmentation of the pharmacological treatment with cognitive-behavioral therapy demonstrated some short-term efficacy in treatment-resistant PD. There were also preliminary evidences of efficacy for monotherapy with reboxetine and olanzapine, and augmentation with pindolol, divalproex sodium, aripiprazole and olanzapine in short-term treatment.

In a rat model of panic, corticotropin responses to dorsal periaqueductal gray stimulation depend on physical exertion.

Panic disorder patients are exquisitely and specifically sensitive to hypercapnia. The demonstration that carbon dioxide provokes panic in fear-unresponsive amygdala-calcified Urbach-Wiethe patients emphasizes that panic is not fear nor does it require the activation of the amygdala. This is consonant with increasing evidence suggesting that panic is mediated caudally at midbrain's dorsal periaqueductal gray matter (DPAG). Another startling feature of the apparently spontaneous clinical panic is the counterintuitive lack of increments in corticotropin, cortisol and prolactin, generally considered 'stress hormones'. Here we show that the stress hormones are not changed during DPAG-evoked panic when escape is prevented by stimulating the rat in a small compartment. Neither did the corticotropin increase when physical exertion was statistically adjusted to the same degree as non-stimulated controls, as measured by lactate plasma levels. Conversely, neuroendocrine responses to foot-shocks were independent from muscular effort. Data are consonant with DPAG mediation of panic attacks.

Evidence of a suffocation alarm system sensitive to clinically-effective treatments with the panicolytics clonazepam and fluoxetine.

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.

Panic disorder and exercise avoidance

Objectives: 1) To identify whether patients with panic disorder in general and those with the respiratory subtype in particular actively avoid exercise; 2) to investigate physiological differences in cardiopulmonary function parameters in patients with panic disorder in general, patients with the respiratory subtype of panic disorder, and healthy controls upon exercise challenge. Methods: Patients with panic disorder were classified as having either the respiratory or the non-respiratory subtype. Both groups were compared to controls in terms of exercise avoidance patterns and performance on cardiopulmonary exercise testing. Results: Patients with panic disorder exhibited higher exercise avoidance scores and worse performance on cardiopulmonary exercise testing as compared with controls. No differences were found between patients with the respiratory and non-respiratory subtypes. Conclusions: Exercise avoidance is present in panic disorder and is associated with poorer performance on cardiopulmonary exercise testing. These findings are not limited to patients with the respiratory subtype of the disorder. .

The panic disorder respiratory ratio: a dimensional approach to the respiratory subtype

OBJECTIVE: The respiratory ratio is a dimensional construct of the respiratory subtype of panic disorder (PD). The respiratory subtype has been correlated with an increased sensitivity to CO2 inhalation, positive family history of PD and low comorbidity with depression. The objective of our study was to determine whether the respiratory ratio is correlated with CO2-induced panic attacks and other clinical and demographic features. METHODS: We examined 91 patients with PD and submitted them to a double-breath 35% CO2 challenge test. The respiratory ratio was calculated based on the Diagnostic Symptom Questionnaire (DSQ) scores recorded in a diary in the days preceding the CO2 challenge. The scores of the respiratory symptoms were summed and divided by the total DSQ score. RESULTS: The respiratory ratio was correlated with CO2 sensitivity, and there was a non-statistically significant trend towards a correlation with a family history of PD. CONCLUSIONS: The positive correlation between the respiratory ratio and the anxiety elicited by the CO2 inhalation indicates that the intensity of respiratory symptoms may be proportional to the sensitivity to carbon dioxide.

Panic disorder and the respiratory system: clinical subtype and challenge tests / Transtorno do pânico e sistema respiratório: subtipo clínico e testes de provocação

INTRODUCTION: Respiratory changes are associated with anxiety disorders, particularly panic disorder (PD). The stimulation of respiration in PD patients during panic attacks is well documented in the literature, and a number of abnormalities in respiration, such as enhanced CO2 sensitivity, have been detected in PD patients. Investigators hypothesized that there is a fundamental abnormality in the physiological mechanisms that control breathing in PD. METHODS: The authors searched for articles regarding the connection between the respiratory system and PD, more specifically papers on respiratory challenges, respiratory subtype, and current mechanistic concepts. CONCLUSIONS: Recent evidences support the presence of subclinical changes in respiration and other functions related to body homeostasis in PD patients. The fear network, comprising the hippocampus, medial prefrontal cortex, amygdala and its brainstem projections, may be abnormally sensitive in PD patients, and respiratory stimulants like CO2 may trigger panic attacks. Studies indicate that PD patients with dominant respiratory symptoms are particularly sensitive to respiratory tests compared to those who do not manifest dominant respiratory symptoms, representing a distinct subtype. The evidence of changes in several neurochemical systems might be the expression of the complex interaction among brain circuits.

INTRODUÇÃO: As anormalidades respiratórias estão associadas a transtornos de ansiedade, especialmente ao transtorno do pânico (TP). A estimulação respiratória em pacientes com TP durante os ataques de pânico está bem documentada na literatura, e vários problemas respiratórios como uma elevada sensibilidade ao CO2 foram detectados em pacientes com TP. Os pesquisadores levantam a hipótese de que existe um distúrbio fundamental nos mecanismos fisiológicos que controlam a respiração no TP. MÉTODOS: Os autores pesquisaram artigos sobre a conexão entre o sistema respiratório e TP, mais especificamente artigos sobre testes respiratórios, subtipo respiratório e conceitos mecanicistas atuais. CONCLUSÕES: Evidências recentes apoiam a existência de alterações subclínicas na respiração e em outras funções relacionadas à homeostase corporal em pacientes com TP. O circuito do medo, composto pelo hipocampo, córtex pré-frontal medial, amígdala e suas projeções para o tronco encefálico, pode estar anormalmente sensível em pacientes com TP, e os estimulantes respiratórios, como o CO2, podem desencadear ataques de pânico. Estudos indicam que os pacientes com TP que apresentam sintomas respiratórios dominantes são particularmente sensíveis a testes respiratórios, comparados àqueles que não manifestam sintomas respiratórios dominantes, representando um subtipo distinto. A constatação de anormalidades em vários sistemas neuroquímicos pode ser a expressão da interação complexa entre os circuitos cerebrais.

Panic-like behaviors in Carioca High-and Low-conditioned Freezing rats

Panic disorder involves both recurrent unexpected panic attacks and persistent concern about having additional attacks. Electrical stimulation of the dorsal periaqueductal gray (dPAG) is an animal model of both panic attack and panic disorder, whereas contextual fear conditioning represents a model of anticipatory anxiety. Previous research indicated that anxiety has an inhibitory effect on panic attack-like behavior. However, still unclear is the role that anticipatory anxiety plays in panic disorder-like behaviors. This issue was investigated with two lines of animals selectively bred for high (Carioca High-Freezing) and low (Carioca Low-Freezing) freezing in response to contextual cues associated with footshock. The results suggest that although anticipatory anxiety might exert an inhibitory effect on the expression of panic attack, it might also facilitate the pathogenesis of panic disorder.

Panic-like behaviors in Carioca High-and Low-conditioned Freezing rats

Panic disorder involves both recurrent unexpected panic attacks and persistent concern about having additional attacks. Electrical stimulation of the dorsal periaqueductal gray (dPAG) is an animal model of both panic attack and panic disorder, whereas contextual fear conditioning represents a model of anticipatory anxiety. Previous research indicated that anxiety has an inhibitory effect on panic attack-like behavior. However, still unclear is the role that anticipatory anxiety plays in panic disorder-like behaviors. This issue was investigated with two lines of animals selectively bred for high (Carioca High-Freezing) and low (Carioca Low-Freezing) freezing in response to contextual cues associated with footshock. The results suggest that although anticipatory anxiety might exert an inhibitory effect on the expression of panic attack, it might also facilitate the pathogenesis of panic disorder.(AU)

Factores ambientales y psicosociales vinculados a síntomas de ataque de pánico después del terremoto y tsunami del 27 de febrero de 2010 en la zona central de Chile / Environmental and psychosocial factors associated with panic attack symptoms after the February 27 2010 earthquake and tsunami in the Central Zone of Chile

La presente investigación proporciona una primera evaluación de síntomas de ataque de pánico y su relación con algunas variables asociadas con la magnitud del daño sufrido por las personas expuestas al terremoto del 27 de Febrero de 2010 en la zona central de Chile. Un total de 150 habitantes de diversas localidades fueron evaluados para determinar la presencia de síntomas de ataque de pánico dentro de las dos semanas posteriores a la catástrofe. Los resultados indican más síntomas de crisis de pánico en aquellas personas que sufrieron pérdidas de bienes y en aquellos que estuvieron expuestos al tsunami o riesgo de tsunami. Se discute la necesidad de evaluar otros trastornos (p.e., estrés post-traumático) y poblaciones (p.e., niños), así como también la importancia de crear indicadores cuantitativos del impacto de estas catástrofes, basados en la combinación de variables tales como la intensidad del sismo y la magnitud del daño personal.

The present research provides a first screening of the presence of panic attack symptoms and their relation to some variables associated with the magnitude of the damage suffered by individuals exposed to the earthquake occurred on February 27 2010 in the central zone of Chile. A total of 150 adults that lived in several cities and villages of the central zone of Chile were as-sessed to determine the presence of panic attack symptoms within the first two weeks after the catastrophe. The results indicate more physical and psychical panic attack symptoms on those individuals that lose some of their belongings and on those that were exposed to the tsunami or risk of tsunami. The discussion emphasizes the need for evaluating further disorders (e.g., post-traumatic stress) and to examine at-risk populations (e.g., children). It is suggested the importance of creating quantitative indexes based on variables such as extent of the loss, physical damage and quake intensity, to asses the individual impact of this sort of catastrophes.

Effects of contextual fear conditioning and pentylenetetrazol on panic-like reactions induced by dorsal periaqueductal gray stimulation with N-methyl-D-aspartate

Electrical or chemical stimulation of the dorsal periaqueductal gray (DPAG) has been accepted as an animal model of panic attacks. This study investigates the influence of anticipatory anxiety in the occurrence of panic-like behavior induced by N-methyl-D-aspartate (NMDA) microinjection into the DPAG of rats. Behavioral (i.e., contextual fear conditioning) and pharmacological (i.e., pentylenetetrazol) manipulations were employed as animal models of anticipatory anxiety. In the first experiment, animals exposed to contextual cues that had been previously associated with electric footshocks through contextual fear conditioning were less likely than non-conditioned control animals to display defensive reactions such as running and jumping in response to microinjection of NMDA (0.3 µl of 15.0 µg/µl) into the DPAG. In the second experiment, rats were injected intraperitoneally with the anxiogenic drug pentylenetetrazol (PTZ, 15 mg/kg) 5 minutes before receiving intra-DPAG microinfusion with the same dose of NMDA as in Experiment 1. Panic-related behaviors were registered in an experimental arena immediately after NMDA microinfusion. As compared with saline pre-treated animals, PTZ significantly attenuated NMDA-induced panic-like reactions. These results further demonstrate the usefulness of DPAG chemical stimulation as an animal model of panic attacks and suggest that behavioral and pharmacological activation of the brain mechanisms underlying anticipatory anxiety might exert an antipanic-like effect.

Effects of contextual fear conditioning and pentylenetetrazol on panic-like reactions induced by dorsal periaqueductal gray stimulation with N-methyl-D-aspartate

Electrical or chemical stimulation of the dorsal periaqueductal gray (DPAG) has been accepted as an animal model of panic attacks. This study investigates the influence of anticipatory anxiety in the occurrence of panic-like behavior induced by N-methyl-D-aspartate (NMDA) microinjection into the DPAG of rats. Behavioral (i.e., contextual fear conditioning) and pharmacological (i.e., pentylenetetrazol) manipulations were employed as animal models of anticipatory anxiety. In the first experiment, animals exposed to contextual cues that had been previously associated with electric footshocks through contextual fear conditioning were less likely than non-conditioned control animals to display defensive reactions such as running and jumping in response to microinjection of NMDA (0.3 µl of 15.0 µg/µl) into the DPAG. In the second experiment, rats were injected intraperitoneally with the anxiogenic drug pentylenetetrazol (PTZ, 15 mg/kg) 5 minutes before receiving intra-DPAG microinfusion with the same dose of NMDA as in Experiment 1. Panic-related behaviors were registered in an experimental arena immediately after NMDA microinfusion. As compared with saline pre-treated animals, PTZ significantly attenuated NMDA-induced panic-like reactions. These results further demonstrate the usefulness of DPAG chemical stimulation as an animal model of panic attacks and suggest that behavioral and pharmacological activation of the brain mechanisms underlying anticipatory anxiety might exert an antipanic-like effect.(AU)