One of the most common anxiety disorders is panic disorder (PD), with a 12 month prevalence in the US and in Europe estimated at 1.8 and 2.7% of the population, respectively [1, 2]; the main clinical feature of which is an unexpected panic attack (PA) that arises in the absence of any situational or emotional triggers, reaching its peak intensity within minutes, that is manifested by intense physical and cognitive symptoms, such as fear of recurrence, general health concerns, and behavioral changes [3, 4]. In addition to spontaneous PA, its other forms include situationally predisposed PA, "symptomatically mild" ("minor") PA [5], in which less than 4 out of 13 symptoms listed in the DSM-IV are present, and "nocturnal" panic attacks that occur during phase 2 of the sleep cycle [6].
Panic disorder in its "pure" form is found only in 24.6% of cases, in 36.7% of cases it is accompanied by a comorbid disorder, in 13.3% -by 2, and in 23.5%-by 3 or more mental disorders, mainly anxiety and diseases of depressive spectrum [7]. Lecrubier et al. had shown that individuals with isolated panic attacks are more prone to the development of depression (45.6%) than to development of a panic disorder [8].
To date, the greatest clinical evidence of efficacy in the treatment of PD has been demonstrated with the use of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) (drugs of first choice) and benzodiazepine tranquilizers (drugs of second choice) [9]. Disadvantages of SSRIs/SNRIs therapy include delayed onset of therapeutic effect (2-6 weeks), and side effects at the start of therapy, which can limit its use in the treatment of PD, especially given the importance of achievement of rapid anxiolytic effect [10, 11]. While benzodiazepines have immediate onset of action, their side effect profile is significant and includes excessive sedation, slow reaction time, dizziness, and possible paradoxical reactions such as anxiety [12]. In addition, knowledge of benzodiazepines' high risk of dependence [13, 14], often forces patients with PD leading an active lifestyle, to seek other, alternative methods of treatment. These side effects in themselves can exacerbate PD and become the triggers of panic attacks. Historically, 18% of patients receiving SSRIs and 15% of patients receiving benzodiazepines drop-out from clinical studies [8]. To our knowledge, the contemporary scientific literature contains practically no data on the treatment of refractory PD, where both first- and second-line treatment options are ineffective. Additionally, there are frequent clinical scenarios where PD exists concomitantly with other psychiatric comorbidities or where panic attacks don't reach the diagnostic threshold of a panic disorder, but nevertheless have a significant impact on the course of the underlying disease and impair social functioning. Thus, the search for an alternative treatment modality with non-habit forming anxiolytic effect and minimal side effects aimed at rapid relief of panic attacks represents an urgent unmet need in the treatment of PD.
Anxiety symptoms can occur in a variety of mental and substance abuse disorders. In particular, "neurovegetative" (poor sleep, sweating, loss of appetite, tremors, high blood pressure), anxiety and depressive symptoms are well established components of opioid and alcohol dependence and withdrawal, which are currently being treated with psychotropic drugs, including benzodiazepines, valproate and antiadrenergic agents [8, 15].
Xenon is a monatomic inert gas with very low chemical reactivity. It is colorless, odorless and heavy. Xenon has a very low blood-gas partition coefficient, rapidly penetrates the blood-brain barrier, which makes it an ideal general anesthetic. Xenon is a competitive N-methyl-d-aspartate (NMDA) receptor antagonist, which it exhibits through binding to glycine site of glutamatergic NMDA receptor [16]. In addition, xenon reduces excitatory neurotransmission through downregulation of 5-HT3 [17], nicotinic acetylcholine [18], potassium channel [19], HCN channel [20], and AMPA [21]. It also increases inhibitory neurotransmission by upregulating TREK1 [22]. Of relevance to fear associated conditions such as PD, the role of NMDA receptors in modulation of fear memories has previously been suggested [23]. Accordingly, Meloni et al. demonstrated that administration of xenon gas in a rat model of fear memory reconsolidation-a state in which recalled memories become susceptible to modification, reduced conditioned fear induced freezing [24].
Other psychiatric uses of xenon have been explored, for example, promising results on the use of inhaled xenon in opioid and alcohol withdrawal states, based on its pharmacokinetic effects have been reported [25-28]; in particular, its anti-stress properties, decreased sensitivity to pain and improved adaptation [29, 30]. However, there is paucity of research on the use of xenon outside of anesthesiology and addiction. According to some authors, its therapeutic properties are likely based on its effect on the glutamatergic system neuromodulation [31] via inhibition of NMDA receptors and reduction in binding of glutamate [31-33]. It was also shown that xenon at a dose of 30-50-70% in the gas mixture does not alter plasma concentrations of dopamine and norepinephrine, but causes a significant reduction of the level of adrenaline and cortisol [34].
It should also be noted that due to the biochemical inertness xenon, it exhibits no acute or chronic toxicity [35], embryotoxic or teratogenic effects, it is non-allergenic [18, 33], and does not alter the integrity of brain structures [36].
In recent studies it was demonstrated that the glutamatergic system plays a significant role in the regulation of anxiety. In particular, blockade of glutamatergic transmission in the periaqueductal gray matter lead to restoration of normal behavior in animals, and glutamate antagonists exhibited anxiolytic properties in experimental conditions [37].
In addition, preclinical studies have shown that blocking the glycine site NMDA-glutamate receptors results in anxiolytic effects [38]. Some supporting evidence that implicates glutamate in the pathogenesis of anxiety disorders stems from the efficacy of pregabalin, in which the mechanism of action is associated with inhibition of glutamate release [39]. Thus, on the basis of clinical data previously obtained from the use of xenon in anesthesiology and addiction medicine, as well as based on its receptor activity profile (reduction of glutamatergic neurotransmission) it can be expected that xenon possesses an independent anti-anxiety effect. The preliminary experience of using xenon in the outpatient treatment of various psychiatric and addictive diseases has been marked by its clear anxiolytic effect, which triggered our desire to study xenon's effect on specific anxiety disorders. PD was selected because of its paroxysmal, easily quantifiable nature and a high degree of recurrence, and also because the "panic attack" phenomenon occurs widely in other anxiety states.
The clinical study presented aimed to: (a) study efficacy and adverse effect profile of xenon in acute treatment as a monotherapy for "pure" PD; (b) assess efficacy and adverse effect profile of xenon in treatment of PD in the presence of other mental illness comorbidities; and (c) quantify the duration of xenon's therapeutic effect.
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Methods
Patients
This investigator-initiated study was performed under a prospective clinical trial protocol approved by the Institute of Mental Health and Addictology, which is accredited by the Ministry of Health of the Russian Federation to conduct clinical trials (#57689). Study conduct was in compliance with all ethical standards and good clinical practice. All study participants provided written informed consent prior to undergoing any protocol-related procedures. The study was registered at https://www.isrctn.com (number in process, application #32439). Ninety outpatients with a diagnosis of "panic disorder" (F41.0) according to ICD-10 were enrolled through the Institute of Mental Health and Addictology. Five patients dropped out of the study due to minor side effects, predominantly lightheadedness and headaches, and 4 patients dropped out of the study for unspecified reasons. As the intention to treat analysis was not utilized due to the open label design of the study, 81 patients with PD (49 women and 32 men), mean age was 35.2 years (range 18-69) were studied. Patients were randomized into 2 groups: with "pure" PD (group 1) and "comorbid" PD, when it was co-diagnosed with other mental illnesses (group 2). All patients with isolated PD (group 1, n = 42) received monotherapy with xenon at the aforementioned schedule, while the majority of patients (94.9%) with PD and comorbid conditions, which were predominantly depression (group 2, n = 39), in addition to xenon administration continued treatment for comorbid psychiatric disorders, which mainly consisted of antidepressants (SSRIs and SNRIs). In these patients, the reason for xenon treatment was the increase in the frequency and severity of panic attacks despite ongoing treatment with stable pharmacotherapy of at least 3-6 months' duration.
Xenon administration
Administration of xenon was performed through inhalation of xenon-oxygen mixtures that were escalated from 15%/85% to 30%/70% with titration increments of 5% per session. Each patient in the study underwent between 6 and 7 treatments with xenon-oxygen mixture. The first three sessions were carried out daily and from session 4 onward-every other day. The selected dosing regime and the composition of the gas mixtures were based on the historical evidence of safety of subanesthetic use of xenon in imaging [40-42].
Medical grade xenon ("medksenon"®, 99.9999%, manufacturer: Atommedcenter, Moscow, Russia) and medical grade oxygen in separate containers were admixed. Mixing and administration of gases in preset concentration and volume was accomplished with the use of the medical device MAGi-AMTS1, which enables the operator to adjust the concentration of xenon in the gas mixture, and which contains the electronic flow meter with a software module that allows for such adjustments. Administration of xenon-oxygen mixture to the patient was carried out via a face mask. Patients were asked to slowly inhale, holding breath for 5-10 s; exhale into the loop and after 35-40 s exhale outside the contour and breath in the new portion of gas mixture. Xenon inhalation lasted from 2.5 to 4 min, and the xenon consumption was capped at 3.0 L per procedure. The patients were assessed subjectively by the provider, while the vital signs (pulse, blood pressure, oxygen saturation) were continuously monitored.
Patient assessment
Patients were evaluated after each xenon inhalation and at 30 and 180 days after completion of treatment. To this end, we employed clinical psychopathological and clinical catamnestic methods, and psychometric scales that are widely used internationally to assess the treatment of mental disorders. Scale Assessment, Zung Self-Rating Anxiety Scale (SAS) was performed prior to starting therapy (V1), and at 1 and 6 months after treatment. According to this scale, SAS index of less than 45 points corresponds to the normal value, 45-59-to mild-to-moderate degree of anxiety, 60-74-to high degree of anxiety, more than 75-to an extremely high-level of anxiety. Hospital Anxiety and Depression Scale (Hospital Anxiety and Depression Scale, HADS_T-anxiety subscale, HADS_D-Depression subscale) was used prior to the (V1), after the third (V3) and sixth (V6) xenon administrations. Categories for the assessment for each of the following subscales are as follows: 0-7 points-normal (absence of reliable pronounced symptoms of anxiety/depression); 8-10 points-subclinical anxiety/depression; 11 points and above-symptomatic anxiety/depression. Clinical Global Impression Scale (CGI-I-improvement subscale, CGI-S-severity of the disease subscale) was used before treatment and after each of the following 6 xenon treatments (V1, V2, V3, V4, V5, V6).
Statistical analysis of the results was carried out via statistical and analytical methods using Microsoft Excell 2000 program and with Statistica statistical tools (https://www.statsoft.com/, https://www.statsoft.ru/).
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Results
The two groups of patients, with "pure" PD (group 1, n = 42) and with "comorbid" PD (group 2, n = 39) were well matched (Table 1). For patients in group 2 the following comorbid disorders were most commonly observed: mixed anxiety-depressive disorder (43.6%), bipolar affective disorder (10.3%), recurrent depressive disorder (10.3%), obsessive-compulsive disorder (5.1%), and other nonpsychotic mental disorders (12.8%, heading F48).
