Evidence-Based Pharmacotherapies for Panic Disorder

Abstract

This chapter presents a review of the primary psychopharmacological interventions for panic disorder and the empirically derived evidence supporting their continued use. Key factors such as dosing, contraindications, safety, tolerability, and polypharmacy are discussed. The chapter will include a currently supported tier structure for pharmacological treatment planning as well as means for how best to tailor regimens to specific patient needs. Comorbidities and practical applications are addressed as well. Lastly, the chapter closes with some emerging pharmacotherapies that show promise but for which empirical evidence supporting their use remains in its infancy.

1. Introduction

1.1 Panic disorder

In large part because this current text has an overall focus on panic disorder, a review of the signs and symptoms of the clinical presentation of panic disorder will not be provided here (please refer to relevant chapters in this book). Rather, the salient features of panic that represent potential pharmacological treatment targets will be highlighted as this chapter proceeds to review drug treatments for this disorder and its subtypes, common comorbidities, and disability. Panic disorder, per DSM-5 criteria, consists of recurrent panic attacks accompanied by at least a 1-month period in which one of the following occurs: (1) persistent concern about having additional attacks or their consequences, or (2) a significant maladaptive change in behavior due to the attacks [1]. Many panic patients display significant fear and avoidance of places and situations in which a panic attack has previously occurred or may occur in the future [termed agoraphobia]. As has been reviewed in several places throughout this text, panic disorder is common (approximately 3.8% prevalence per Western surveys) [2, 3, 4], often chronic, and can have a substantial effect on patient level of function and quality of life [5]. In fact, an estimated 15–20% of panic patients treated pharmacologically with leading effective drugs such as tricyclic antidepressants (TCAs), serotonin selective reuptake inhibitors (SSRIs), or benzodiazepines still meet for panic diagnostic criteria or have experienced symptom relapse as measured 6–12 months after treatment [6]. For these reasons, there continues to be compelling rationale for pursuing more effective treatments for this debilitating disorder.

At the time of clinical intake and initial symptom considerations, therapists should be mindful of other existing conditions that may include the presence of panic attacks or panic-like manifestations but are not true panic attacks in the DSM-5 diagnostic sense. Panic-like attacks, and more generalized anxiety, can accompany clinical presentations of depression, bipolar disorder, and substance use or substance withdrawal [1]. In addition, panic- and anxiety-like reactions can be initiated by exposure to stressors and cues related to tangible, “real-life” situations such as occupational, academic, interpersonal, or social difficulties and obstacles; these events would not be considered panic attacks in the diagnostic sense as: (1) they do not occur spontaneously, (2) may be better accounted for by situational aspects or presence of another disorder, or (3) can be considered reasonably predictable or provoked [1].

Panic attacks themselves, by nature, are foundationally physiological and largely driven by a surging activation of the autonomic nervous system (ANS) and, as such, proceed with about a 10-minute or less duration that coincides with arousing activation of the sympathetic division of the ANS followed by subsequent recruitment of the calming parasympathetic division of the ANS. It is this physiological aspect of panic attacks that is highly responsive to acute drug treatments such as a benzodiazepine. Of note, it is also this physiological aspect that leads many panic sufferers to seek primary care providers or urgent/emergent care for acute treatment [7]. The principally psychological elements of concern and worry about future attacks or their consequences, including avoidance of contexts or cues in which an attack may occur, are targeted by psychotherapeutic approaches such as cognitive behavioral therapy. That is not to say that pharmacological solutions cannot influence the clinical impact of psychological interventions [8]. This will be discussed in further detail later in this chapter.

2. Current pharmacological treatment practices for panic disorder

It has been well established that the most effective treatments for panic disorder include psychotherapies that capitalize on cognitive-behavioral methodologies [9]. That being said, it is also well known in psychiatry that pharmacological interventions, whether in tandem with psychotherapy or as a monotherapy, can provide these patients and clients with clinical benefits as well [10]. The heterogeneity of panic disorder, with possible variations in etiology, symptom profile, and underlying neural mechanisms, has resulted in a wide-ranging pharmacological treatment approach spanning multiple drug classes and several putative central nervous system targets and mechanisms of action [11, 12, 13]. In general, pharmacotherapies for panic disorder can be classified into first-, second-, and third-line agents with other drug classes often recruited for refractory cases (Figure 1). Not surprisingly, first-line treatments include the selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines [14]. The second-line drug interventions for panic include alternative classes of antidepressants including serotonin/norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, newer serotonin “multimodal” agents, mirtazapine, and to some extent, some antipsychotics and anticonvulsants [14]. Third-line agents are generally represented by beta blockers, buspirone, and hydroxyzine.

Figure 1.

Schematic illustration of the first-, second-, and third-line pharmacological treatments for panic disorder. Dashed lines indicate an approximation of the division between each drug tier based on the available literature discussed in this chapter. As the drug treatments progress from first- to third-line, there is a general increase in the potential side effects experienced by patients as well as a decrease in the overall empirical data available, either by number of studies performed and/or impact of reported studies. BZD: benzodiazepine; SSRI: serotonin selective reuptake inhibitor; CBT: cognitive behavioral therapy; TCA: tricyclic antidepressant; SNRI: serotonin-norepinephrine reuptake inhibitor; and MAOI: monoamine oxidase inhibitor. Created with BioRender.com.

2.1 First-line pharmacotherapies for panic disorder

2.1.1 Serotonin selective reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) are a safe and effective pharmacological choice for the treatment of a wide range of mood and anxiety disorders with a large body of empirical evidence supporting their administration [15]; this indication is present for treating panic disorder as well [16, 17, 18, 19]. A recent systematic review and meta-analysis by Chawla et al. [14] identified SSRIs as most closely associated with high remission and low risk of adverse events when the most common pharmacotherapies for panic were evaluated with sertraline (trade name Zoloft) and escitalopram (trade name Lexapro) showing clearest clinical benefit [14]. Relatedly, a network analysis by Du et al. [20] of 42 clinical trials encompassing almost 6000 panic disorder patients showed the SSRIs paroxetine, sertraline, fluoxetine, citalopram, and escitalopram to be more efficacious than placebo with the latter drug displaying the most robust efficacy [20].

2.1.2 Benzodiazepines

It is clear from the available empirical literature and clinical guidelines that benzodiazepines are effective in treating many signs and symptoms of panic disorders [16, 21, 22, 23] which as described above can include several physiological, stressor- and fear-related features (e.g., tachycardia, rapid breathing, increased perspiration, acute sense of dread, dizziness). In addition, there is effectiveness and safety data supporting the concurrent prescription of benzodiazepines and an antidepressant such as those already mentioned [23]. This may be particularly important during the initial stages of SSRI administration during which time there can be slow onset of SSRI-related benefits and acute increase in panic symptoms [6]. What is not so clear even after decades of research and clinical practice is: (1) the duration for which to prescribe benzodiazepines both short- and long-term, (2) the optimal dosages to use for the available short- and long-acting benzodiazepines, (3) whether or not chronic regimens or as-needed [PRN] indications are more beneficial as compared to the other, (4) the degree to which benzodiazepines may exceed antidepressants for treating panic disorder, or (5) the hierarchical structure for benzodiazepines as organized by clinical benefits [21] .

There is a degree of hesitancy in psychiatry to use benzodiazepines with some patients. This is primarily due to the potential for these drugs to be misused as a result of inherent factors a such as tolerance, dependence, and withdrawal (with its associated potential for rebound effects and symptom relapse). Additionally, there are significant adverse effects to be wary of as clinicians, including but not limited to, sedation, increased risk of falling, impaired memory, and cognitive slowing [17, 22, 24]. As a result, it is important for providers to consider panic disorder patients on a case-by-case basis when selecting antidepressants, benzodiazepines, or a combination of these.

As with many anxiety disorders, panic disorder is associated with incomplete remission and relapse even with first-line pharmacotherapies [14] [and possibly, concomitant psychotherapies]. As such, it is important for treating clinicians to generate a treatment algorithm that accounts for lack of remission, comorbidity, and combined treatment approaches. With regard to transitioning from first-line pharmacological options to a second-line agent, there are some suggestions for how to do so in the available literature. According to Ziffra [16], there are two potential strategies for changing the treatment of a panic patient who has been prescribed monotherapy with an SSRI for a reasonable amount of time with no significant change in symptoms. The first option is to add a second medication to the current SSRI such as a benzodiazepine or another antidepressant. The second alternative is to move to the second-line possibilities, most notably if the patient had little to no improvement with the SSRI alone or could not tolerate the side effects.

2.2 Second-line pharmacotherapies for panic disorder

2.2.1 Serotonin-norepinephrine reuptake inhibitors (SNRIs)

As of this writing, the only FDA-approved serotonin-norepinephrine reuptake inhibitor (SNRI) approved for panic disorder treatment is venlafaxine (trade name Effexor) [25, 26, 27]. A number of studies published in the mid-2000s identified superiority of venlafaxine over placebo in reducing panic symptoms in randomized, placebo-controlled, double-blind studies [25, 27, 28, 29, 30]. That being said, additional drugs in this class have FDA-approval for treatment of major depressive disorder (MDD) including desvenlafaxine (trade name Pristiq) and duloxetine (trade name Cymbalta) [16]. In addition, despite not having FDA approvals for use with panic disorder patients, there is some open-label evidence available that supports prescribing duloxetine for this clinical population [31] as well as FDA approval for this drug for treating generalized anxiety disorder (GAD) [16].

2.2.2 Tricyclic antidepressants (TCAs)

There is some debate in the field as to whether or not to consider the older tricyclic antidepressants (TCAs) as first- or second-line treatments for panic disorder. In short, the reported efficacy of these drugs, as compared to the SSRIs for example, suggests that they should be treated as first-line agents. However, the side effect profile (e.g., sedation, anticholinergic and cardiac adverse possibilities, weight gain) and potential drug interactions, including with benzodiazepines [14], associated with TCAs provide support for a secondary role within the pharmacological armamentarium available for panic disorder [32].

2.2.3 Monoamine oxidase inhibitors (MAOIs)

While widely considered to be an older antidepressant pharmacotherapy, monoamine oxidase inhibitors (MAOIs; e.g., phenelzine, trade name Nardil) can be considered second- [or possibly third-line] treatments for panic disorder treatment as they have similar side effect concerns and potential medical interactions as TCAs [18]. These potential adverse effects include the need for a low tyramine diet and hypertension monitoring as examples [33]. Yet, there remains strong provider support for keeping this class of drugs as a viable option despite the possible patient adjustments they may require.

2.2.4 “Multimodal” serotonin agents

There are also newer antidepressant drugs that, similar to SSRIs, are FDA-approved for the treatment of MDD and inhibit the reuptake of synaptic serotonin, namely, vilazodone (trade name Viibryd) and vortioxetine (trade names Trintellix/Brintellix). In addition to acting as serotonin reuptake inhibitors, these drugs act at several other classes of serotonin receptors [34] (vortioxetine) including as an agonist at 5-HT1a receptors (vilazodone) [35]. Empirical evidence suggests that these newer antidepressants may be effective for the treatment of panic disorder because of their shared similarity with SSRIs and their enhanced pharmacological profile [36, 37, 38, 39].

2.2.5 Mirtazepine

Mirtazapine is one drug for which there is some evidence for use with panic disorder [40] but the available literature is small and, similar to other drugs within this second-line, there are possible adverse effects such as sedation and weight gain to consider [41]. It should be noted here that most of the support for mirtazapine comes from work done over a decade ago and there has been little advancement in recent years.

2.2.6 Anticonvulsants

Clinical evidence supporting the use of anticonvulsants with panic disorder patients comes from the success of these drugs in treating bipolar disorder [42, 43, 44, 45] and, as such, the list of candidate agents includes topiramate, lamotrigine, carbamazepine, oxcarbazepine, valproic acid, gabapentin, and pregabalin. The most compelling empirical and clinical arguments, albeit somewhat limited, for using anticonvulsants with panic disorder are available for the latter three drugs. Valproic acid [trade name Depakote] acts at the primary inhibitory GABAergic transmitter systems in the brain and, as such, may help attenuate panic symptoms. Valproic acid is used for mood stabilization in bipolar disorder including in the presence of co-morbid panic [45]. However, as with most of its prescribing practices, valproic acid pharmacotherapy requires close monitoring due to its side effects profile and potential to alter some metabolic functions [46]. The evidence for prescribing gabapentin and pregabalin for panic disorder is scant and consists primarily of a few individual patient cases and open-label trials [47, 48, 49]. In addition, there is no FDA approval for the use of these two drugs in anxiety disorders nor is there enough evidence to formulate a treatment algorithm encompassing dosage level, frequency of dosage, or single versus in-tandem, multidrug administration [16]. As such, gabapentin and pregabalin are listed here by drug classification only and not in line with a treatment algorithm. There is simply insufficient evidence to describe them as even a third-line option.

2.3 Third-line pharmacotherapies for panic disorder

2.3.1 Antipsychotics

Selecting an antipsychotic pharmacotherapy for panic disorder likely represents an option when all others have been exhausted. In terms of first-generation (e.g., haloperidol, trade name Haldol) or second-generation antipsychotics (e.g., quetiapine, trade name Seroquel), there exists no available literature supporting their use or very little empirical evidence, respectively, with regard to with panic disorder [50]. In fact, a systematic review of the use of second-generation antipsychotics for anxiety disorders as a whole yielded no positive results [51]. As of this writing, there is a glimmer of support for prescribing quetiapine for GAD but nothing to suggest a use for panic disorder [16]. Lastly and understandably so, there exists no FDA approval for treating panic disorder with antipsychotics [16, 50].

2.3.2 Beta blockers

As mentioned in the Introduction, panic attacks by nature have a psychophysiological component to them as they mirror activation of the sympathetic nervous system complete with tachycardia and perception of impending threat. For this reason, there is compelling rationale to use beta blockers to stem many of these physiological effects; an approach consistent with the acute use of beta blockers to prevent hyper-arousals stemming from performance-based tasks like public speaking [52]. However, the potential clinical advantage of using beta blockers to prevent panic-related somatic manifestations and distress is surprisingly weak [11, 53] and thus relegates these drugs to the third-line tier at best.

2.3.3 Buspirone

The 5-HT1a partial agonist, buspirone, can be considered a third-line treatment option for panic disorder but that standing is somewhat tenuous given that: (1) there is only a small body of literature supporting its use here, (2) the best evidence appears to be its administration with a concomitant antidepressant, (3) the available literature reveals notable adverse effects and a high dropout rate [14], and (4) its FDA approval for treatment of anxiety disorders is limited to generalized anxiety disorder (GAD) [16, 54].

2.3.4 Hydroxyzine

An antihistamine with sedative properties, there is some small support of its use for anxiety, including panic disorder [55]. Despite having FDA approval for use with GAD, empirical evidence of hydroxyzine effectiveness for GAD is mixed [56, 57, 58]. Thus, one can consider administering hydroxyzine for panic disorder symptoms as a tertiary strategy [16].

3. Treatment planning

3.1 Assessment of comorbidities

A critical step in treatment planning for clients with possible panic disorder is the assessment of other psychological comorbidities, general medical conditions, or substance related elevations in arousal (e.g., caffeine, cannabis) that may mimic signs and symptoms of panic. With regard to the first factor, it is generally well established that anxiety disorders tend to cluster with one another from a symptomatologic and etiological standpoint [59]. As such, it is imperative for the treating clinician to address any barriers to treatment or exacerbation of symptoms presented by comorbidity. Common psychiatric comorbidities [and potential risk factors for developing panic disorder] include, but are not limited to, depression, substance use, disordered personality, and other anxiety disorders [16, 60, 61, 62, 63]. In consideration of the second factor, client and therapist should rule out any potential conditions that could be subjectively reported as panic attacks, including but not limited to, hyperthyroidism, epilepsy, hypoglycemia, cardiac issues, asthma or respiratory ailments, or dizziness/vertigo [16]. Regarding substance intake, clinicians should perform some type of timeline follow-back query to assess the client’s use of food, drink, consumables, or recreational drugs known to increase psychophysiological arousal. Relatedly, assessment of substance-induced anxiety disorder should occur as well.

3.2 Course of treatment: how much of which drug and for how long?

A critical question for which clinicians are still seeking answers is the type and duration of pharmacological interventions for panic disorder. There is still considerable debate regarding several key questions including, but not limited to: (1) for how long should patients take anti-panic medications to best ensure relapse is minimal and gains are maintained, (2) if medications are to be taken long-term, should maintenance doses be reduced or held at short-term therapeutic levels, (3) of the medications reviewed here, are there some that outperform others when length of treatment becomes the issue, (4) what are the persistent, or newly emerging, side effects of which to be wary, and (5) are there identifiable clinical or individual predictors of short- and long-term treatment outcome and relapse suppression? There have been a small number of clinical studies that have sought to answer these questions.

Two randomized trials conducted in the last decade investigated the long-term efficacy of two supported pharmacotherapies for panic disorder, SSRIs and clonazepam, administered in tandem with another type of treatment (CBT) or as compared to an alternative drug regimen [paroxetine], respectively. Nardi et al. [64] compared long-term (34 months) treatment with paroxetine or clonazepam in a study extended from an ongoing short-term investigation of the medications [64, 65]. In the earlier short-term study, both paroxetine and clonazepam displayed similar reductions in the patient-reported number of panic attacks and in overall level of anxiety as assessed with Hamilton Anxiety and Clinical Global Impression-Severity scores [65]. Patients reported a faster onset of drug effects and fewer adverse events with clonazepam as compared to paroxetine in the short-term. These effects on panic attack reduction and diminished anxiety held true for the long-term extension as did the fewer number of adverse events regarding clonazepam over paroxetine. Not surprisingly, the adverse events reported with clonazepam use were drowsiness and fatigue as well as impairments in memory and concentration while with long-term paroxetine, patients reported change in appetite and weight gain as well as diarrhea, constipation, and dry mouth.

A second long-term study of note directly compared the parallel combination of CBT and SSRIs with each treatment arm alone [66]. When assed over a 1-year treatment period, CBT + SSRI, CBT alone, and SSRI alone all resulted in a significant reduction in panic attack frequency. Of note, patients who received CBT alone reported a slower decline in panic attacks over time and more spontaneous panic attacks during the past year. The authors of this long-term study also highlight that patient symptoms improved at a faster rate with combined CBT and SSRIs particularly in those patients with co-occurring agoraphobia [66]. As will be discussed in the next section, there is certainly evidence for drug monotherapies for panic disorder but the most significant clinical gains may arise from the combination of pharmacotherapy with psychotherapy. In addition, most of the emerging data from this area suggest maintenance therapy of up to a year or more after an initial course of pharmacological treatment and symptom reduction [6].

3.3 Co-administration of pharmacotherapies with psychotherapy

The primary focus of this chapter is on the use of pharmacological agents to treat the signs and symptoms of panic disorder. However, this chapter would be incomplete if it did not highlight the importance of psychotherapy—namely cognitive behavioral therapy (CBT) for the effective treatment of panic disorder. The most effective interventions for anxiety disorders are CBT-based (for review see Otto and Deveney [67]) and, as such, therapists should seek out ways in which CBT and pharmacotherapy can mutually benefit one another [23, 67]. In addition, as alluded to earlier in this chapter, benzodiazepines are intended for short-term usage for management of panic symptoms and should be tapered when clinically indicated. This weaning can produce a withdrawal process that can acutely exacerbate panic and it is often recommended that a program such as Panic Control Treatment for Benzodiazepine (BZ) discontinuation be incorporated into treatment plans [68, 69, 70, 71, 72].

4. Future directions and exploratory pharmacotherapies

In order to address the shortcomings of the currently available pharmacotherapies for panic disorder, there has been a renewed interest in psychiatry in exploring additional alternative drug therapies. The search for new and innovative medications, for mood and anxiety disorders more broadly, has included psychedelics such as 3,4-methylenedioxymethamphetamine (MDMA), increasingly legal and available cannabinoids, orexinergic compounds, glutamatergic agents (e.g., D-Cycloserine, esketamine), and anesthetics (e.g., Xenon gas). As of this writing, scant empirical evidence exists to support the use of MDMA nor cannabinoids for panic disorder and there are, in fact, studies that suggest that the use of the latter class of drugs could be problematic [73, 74]. There are, as will be seen below, encouraging emerging findings supporting the use of compounds that act on orexin systems as well as the anesthetic, xenon.

4.1 Orexinergic pathways as a drug target for treating panic disorder

The orexin system is of particular interest as a pharmacological target for treating panic disorder due to the putative role of this neuropeptide in the underlying pathophysiology of panic including its regulatory functions related to chemo-, cardio-, and behavioral responses to fluctuations in CO2 and H+ [13, 75]. For example, activity within orexinergic hypothalamic neurons and along brainstem cardiorespiratory pathways is increased by CO2 or NaLac challenge [76, 77]. In addition, expression of orexin-1 receptors is rich in areas shown to mediate defensive, emotional, arousal and panic-like behaviors such as the noradrenergic locus coeruleus, serotonergic raphe nucleus, brainstem cardiorespiratory maintenance nuclei, the extended limbic system, and the periaqueductal gray [78, 79]. Consistent with this expression of orexin-1 receptors, selective antagonists can block panic behaviors and cardiovascular responses induced by CO2 challenge, at least when administered directly into the raphe [80].

A recent systematic review by Caldirola et al. [13] examined the empirical, translational evidence supporting the use of orexin receptor antagonists to treat panic disorder. The work reviewed by this group assessed compounds at iterative stages of drug development including preclinical animal studies and Phase I trials with psychiatrically healthy human participants. In the preclinical animal studies, investigators employed commonly used paradigms to produce panic-like behaviors in rodents including external (e.g., cage exchange between housed animal groups) and internal (e.g., sodium lactate, NaLac, injection or 20% CO2 inhalation) stressors. Systematic review by Caldirola’s team identified three orexin-1 receptor selective antagonists, compound 56, JNJ-54717793, and JNJ-61393215, that displayed an ability to block panic behaviors and cardiovascular responses induced by the aforementioned paradigms. Notably, there were some differences in effectiveness between tested compounds and as compared to benzodiazepine controls but each appeared to be effective without sedative effects or significant effects on sleep-wake cycles [13, 81, 82, 83]. Lastly, selective orexin-2 receptor antagonists did not show any significant capacity to block panic-related behaviors and responses.

The animal studies alluded to above were then subsequently followed by Phase I human trials with healthy participants. For example, Salvadore et al. [83] found that the selective orexin-1 receptor selective antagonist, JNJ-61393215, possessed a good tolerability and safety profile, showed no drowsiness or cardiovascular effects, and significantly reduced panic symptoms induced by a 35% CO2 inhalation challenge when assessed in healthy males. Complementary work by Kaufmann et al. [84] suggested that the selective orexin-1 receptor antagonist, ACT-539313, was generally safe and well tolerated with some reports of somnolence. Yet, the anxiolytic potential of this compound requires further exploration as early evidence suggests it may reduce anxiety associated with a 7.5% CO2 challenge but not necessarily test-elicited panic symptoms [84]. It is clear as of this writing that there remains much translational work to be done before the orexin-1 receptor antagonist class of drugs can be considered for panic disorder treatment.

4.2 Glutamatergic pathways as a drug target for treating panic disorder

In terms of glutamatergic agents acting as potential anti-panic medications, there is compelling data from the treatment of other anxiety and mood disorders that warrant further investigation. The antibiotic and partial NMDA receptor agonist, D-Cylcoserine (DCS), for example, has a recent history of potential use as a cognitive enhancer that may facilitate cognitive behavioral therapies (CBTs) for anxiety disorders such as specific phobias under specific therapeutic conditions [85]. The use of DCS as an adjunctive treatment for panic-related CBT was recently examined by Reinecke et al. [86] who showed that while DCS reduced bias for threatening faces and associated amygdala activity, it did not differ from placebo on clinical measures of panic-related signs and symptoms [86].

As of this writing, the anti-panic properties of esketamine have not been fully explored and the strongest data available support the use of ketamines as a rapid-onset pharmacotherapy for treatment resistant depression [87], but not yet for anxiety disorders.

The inhalation of the anesthetic, xenon, has been studied recently as a potential pharmacotherapy for panic disorder [88], in part because of the gas’ ability to decrease excitatory neurotransmission via interactions at glutamatergic NMDA and AMPA, serotonergic 5HT-3, and cholinergic nicotinic receptors [11, 89]. Dobrovolsky et al. [88] administered 6–7 inhalations of xenon at a sub-anesthetic dose for 2.4–4 minutes to a study sample consisting of panic disorder patients with and without psychiatric comorbidity. Symptom ratings, as measured by the Hospital Anxiety and Depression Scale and Zung Self-rating, global impression ratings, and frequency of panic attackers were all reduced following the xenon inhalations, with many patients reporting benefits after only 3 treatments. The authors reported xenon to be well tolerated, however, provided no putative mechanism of action. Continuing work with greater rigor and replicability than the existing studies should provide further insight into this unconventional, yet cautiously promising, delivery of panic disorder treatment.

5. Conclusions

The available empirical and clinical evidence suggests that first-line pharmacotherapies for panic disorder include selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines with the former best accompanied by cognitive behavioral therapy (CBT) and the latter used for short-term management of panic symptoms (Figure 1). In refractory cases, there are second- and third-line pharmacological agents available, however, their use has mixed results and support, possesses less clear treatment regimens and algorithms, and comes with increasing possibility of side effects and adverse interactions. Emerging clinical data from the study of mood disorders, including MDD, suggest that serotonin multimodal drugs and faster acting medications like esketamine may show promise moving forward. One can imagine that the next decade of drug development in the area of panic disorder will represent an amalgam of evidence gleaned from the pharmacological treatment of disorders with which panic is co-morbid, serendipitous findings from the clinic that continue to shed light on new innovations, and a maintenance of the psycho/pharmacotherapy regimen that has shown efficacy for the better part of the past 25 years.

Conflict of interest

The author declares no conflict of interest.