Panic disorder is characterized by recurrent, unexpected panic attacks accompanied by persistent concern about further attacks and maladaptive behavioral changes [1]. These attacks manifest as abrupt surges of intense fear, typically involving severe physical and cognitive symptoms such as palpitations, shortness of breath, dizziness, and a profound fear of dying or losing control. These acute episodes are highly distressing, often leading patients to seek emergency medical care due to the catastrophic misinterpretation of normal somatic sensations as signs of imminent physical or mental harm [2]. Consequently, the frequent recurrence of these attacks triggers severe anticipatory anxiety and agoraphobic avoidance, causing patients to desperately try to prevent future episodes. Together, these symptoms can lead to substantial functional impairment, restricting mobility, work productivity, and social participation [3]. Epidemiologic studies indicate that panic disorder is relatively common in the general population, with approximately 2%‐3% for 12-month prevalence and 4%‐5% for lifetime prevalence in adults [4]. Given its substantial clinical burden and functional impairment, considerable research has focused on improving treatment strategies for panic disorder, and effective, scalable interventions that can alleviate frequent acute attacks remain an ongoing clinical need [5].

The most common method of treating panic disorder is pharmacotherapy, and selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are widely recommended as a first-line pharmacological option [6]. SSRIs provide effective long-term reduction in panic symptoms and relapse risk with relatively favorable safety, but their clinical benefits are delayed, whereas benzodiazepines produce rapid relief of panic symptoms, but their use is limited by sedation, cognitive impairment, and significant risks of dependence [7]. Despite pharmacotherapy, the remission rate of panic disorder in randomized controlled trials is generally around 30%‐50% [8], meaning that a significant number of patients do not achieve complete remission. Moreover, even for patients who have achieved remission, it takes a considerable amount of time to reach that state. Consequently, many patients in the acute phase of panic disorder continue to experience unpredictable and distressing panic attacks despite receiving active medication. Therefore, there is a need for optimized, accessible adjunctive interventions that can provide immediate support to better manage the recurrence of these acute episodes.

Cognitive behavioral therapy (CBT), provided by a skilled therapist, may be considered one of these interventions and is particularly well-suited to panic disorder, in that it directly targets the maintenance mechanisms that trigger and exacerbate frequent acute panic attacks, namely, catastrophic misinterpretation of bodily sensations, anticipatory anxiety, and avoidance behaviors [9]. The core components of CBT, including psychoeducation, cognitive restructuring, and exposure exercises, systematically reduce safety behaviors and increase adaptive coping, producing durable improvements in both the frequency of acute attacks and functional impairment [10], and the addition of digital content to these therapeutic techniques provides additional benefits to the treatment of panic disorder [11,12]. However, despite robust evidence supporting the effectiveness of CBT for panic disorder, access to adequate CBT in routine practice remains limited. Delivering CBT with sufficient intensity and fidelity typically requires trained therapists, multiple sessions, and sustained engagement, but these resources are often constrained by availability, cost, and scheduling barriers [13]. Consequently, many patients receive only pharmacotherapy and brief psychoeducation without sufficient opportunities for structured skills training, guided exposure, or ongoing reinforcement outside the clinic [14].

In the treatment of panic disorder, patients’ everyday self-management and lifestyle factors are important considerations. Patients often report that panic symptoms are worsened by common, modifiable triggers such as caffeine intake, irregular sleep, alcohol or nicotine use, and physical deconditioning [15-17]. While behavioral changes can support anxiety regulation, it is difficult for patients struggling with unpredictable panic episodes to implement them on their own in daily life. In routine outpatient care, lifestyle counseling is frequently delivered as brief, one-off advice (eg, “avoid caffeine” or “exercise regularly”) during time-limited visits, and clinicians may not be able to address these topics consistently at every visit. Moreover, many relevant behaviors are highly variable between visits and difficult to track without structured tools, making it challenging to provide timely, individualized feedback. As a result, although lifestyle-focused self-management may represent an important, patient-empowering component of care (particularly because it emphasizes skills and behaviors that patients can actively practice) [18], real-world implementation remains constrained in standard clinic-based settings.

To bridge the gap between evidence-based nonpharmacological care and real-world delivery, a range of self-help and technology-assisted strategies have emerged, including bibliotherapy, web-based programs, and app-based interventions [19,20]. In this context, digital therapeutics (DTx) have gained increasing attention as a scalable approach to deliver structured, protocol-driven interventions beyond the constraints of face-to-face therapy. In particular, regarding the effectiveness of CBT, which is a core component of most DTx, self-guided methods using digital technology have been reported to be noninferior to face-to-face methods provided by a therapist in terms of improving various medical conditions [21-23]. By offering standardized content, on-demand access, and the ability to provide repetitive practice and monitoring even outside the clinic, DTx holds promise for expanding the reach of nonpharmacological treatment for panic disorder [24].

However, translating this promise into consistent clinical benefits often requires a multifaceted approach that takes into account the complex, fluctuating nature of panic disorder. Currently available digital interventions tend to excel in specific therapeutic domains. For instance, Freespira, a well-known prescription-based DTx, provides a capnometry-guided respiratory intervention to regulate physiological panic symptoms [25]. Similarly, established transdiagnostic digital CBT programs targeting anxiety disorders, such as Velibra and FearFighter, offer structured cognitive restructuring and exposure modules [26,27], and digital modules specific to panic disorder have also been introduced in the form of exposure therapy and self-guided mindfulness training [28]. While these targeted approaches demonstrate clinical value, managing the full spectrum of panic disorder often invites a more integrated strategy. Existing modular programs may not fully capture the need for real-time, context-responsive support, such as ecological momentary interventions and just-in-time adaptive interventions (JITAIs), which are critical when patients face abrupt anticipatory anxiety or early panic [29-31]. In addition, they have not fully used ongoing opportunities, such as incorporating practical tools for daily lifestyle tracking within self-directed applications [32] or integrating with routine clinical care, including progress reviews and skill reinforcement through the participation of health care professionals [33]. These considerations suggest that DTx for panic disorder may benefit from an integrated framework that combines structured CBT training, ongoing self-management support, context-responsive tools for symptom episodes, and linkage to standard clinical settings.

In line with these considerations, we developed a prescription-based mobile DTx for panic disorder that integrates multiple components within a single protocol [34]. This DTx app was designed based on CBT principles and relevant guidelines [35] and is delivered via a smartphone and a smartwatch. Specifically, this comprises 3 patient-facing services and a clinician-facing management console. The training service provides structured, CBT-oriented modules that include psychoeducation, cognitive restructuring to address catastrophic misinterpretations of bodily sensations, and guided interoceptive and in vivo exposure exercises. The companion service delivers JITAIs offering immediate tools such as paced breathing and grounding techniques during periods of acute symptom escalation or anticipatory anxiety. The care service facilitates daily self-management and lifestyle modifications by allowing patients to monitor mood, sleep patterns, exercise levels, and potential triggers such as caffeine and alcohol intake and by providing individualized feedback based on accumulated data. The management console allows clinicians to monitor patients’ use and adherence to the 3 services in real time, facilitating linkage between digital engagement and routine clinical care.

The purpose of this study was to verify, through a randomized controlled clinical trial, whether this DTx provides additional clinical benefits when added to conventional pharmacotherapy compared with conventional pharmacotherapy alone during an 8-week treatment period in acute-phase patients experiencing frequent panic attacks. The primary outcome of the efficacy evaluation was to assess changes in overall panic symptom severity. Because panic disorder is often accompanied by broader emotional symptoms and fear-related cognitive and somatic processes, secondary outcomes were to assess changes in overall anxiety and depression, panic-related catastrophic cognitions, and the fear of bodily sensations. In addition to the mean symptom change, we aimed to provide a more interpretable measure of treatment benefit by calculating the proportion of patients who achieved a clinically meaningful level of improvement.

This multicenter randomized controlled trial evaluated the efficacy of a prescription-based DTx as an adjunct to pharmacotherapy for acute-phase panic disorder. Changes in overall panic symptom severity for the primary objective of the efficacy evaluation were significantly greater in the DTx group than in the control group. More than half of the participants in the DTx group achieved a clinically meaningful response in overall panic symptom severity, which was nearly 3 times higher than the control group. In the evaluation of the secondary objectives—changes in overall anxiety and depression, panic-related catastrophic cognitions, and the fear of bodily sensations—different results were observed by domain; the DTx group showed significant improvement in overall anxiety and catastrophic cognitions compared to the control group, but such improvement was not observed in depression and the fear of bodily sensations.

The most obvious result regarding the improvement of panic symptoms is that at the primary end point of week 8, the DTx group showed significantly superior results in the reduction of PDSS-SR scores compared to the control group, suggesting that the adjunctive use of DTx provides additional benefits in symptom improvement compared with pharmacotherapy alone. Notably, this therapeutic effect was already observed in week 2, indicating that the benefits of the DTx are evident from the early stage. Beyond panic symptom severity, the clinical benefits of the DTx extended to overall anxiety and panic-related catastrophic cognitions. The DTx group demonstrated significantly greater improvements in these measures at all postbaseline visits, suggesting that the DTx effectively addresses both the core panic symptoms and the broad cognitive-emotional factors that perpetuate the disorder. Taken together, the early-onset efficacy and comprehensive improvement across various symptom domains underscore the potential of this DTx as an efficient tool for managing panic disorder in real-world clinical settings.

Meanwhile, when discussing the effectiveness of DTx use, we must consider that since sham use was not included in the control group, it is difficult to rule out the possibility that the potential influence of expectancy effects of digital participation using the new device or the additional effects of nonspecific treatment factors including increased clinical attention may have been involved in the superior effect in the DTx group. In this regard, we need to discuss the magnitude of the effectiveness. The magnitude of symptom reduction and responder rates observed in this study aligns with the established efficacy of both digital interventions and conventional therapies for panic disorder. Previous meta-analyses evaluating internet-based CBT and mobile health interventions for anxiety have reported comparable symptom reduction and responder rates, typically ranging between 40% and 55% [45-47]. Notably, the effect size observed for the primary outcome in our study (Cohen d=0.80) represents a large effect, which is comparable to or exceeding those reported for clinician-guided digital interventions for panic disorder (Hedges g=0.95) and substantially larger than self-guided formats (Hedges g=0.31) in a recent meta-analysis [24]. Furthermore, the 17.61% symptom reduction and 17.24% (5/29) responder rate observed in our control group are very similar to the modest short-term trajectories reported in previous meta-analyses for treatment-as-usual or placebo conditions in panic disorder trials [39,48]. This consistency shown in the control group may confirm that the group served as a valid comparator representing conventional care, and the unsatisfactory treatment response further highlights the unmet clinical need for adjunctive interventions to address acute panic symptoms.

A challenge for many existing self-directed mobile health apps has been high attrition rates and rapidly declining user engagement, which frequently dilute their clinical impact outside of strictly controlled clinical trials [49]. Our findings demonstrated high patient adherence, achieving high success rates not only in the initial phase but also overall, suggesting that this challenge may be relatively less problematic. We believe that this high level of adherence may be driven by several factors. This was likely facilitated not only by the app’s comprehensive, user-centered design integrating structured CBT training, daily lifestyle self-management, and real-time symptom management support, but also by its prescription-based framework. Rather than relying solely on patient self-motivation, this synergistic approach combines a well-designed digital tool with active integration into the psychiatric treatment workflow. Knowing that their attending clinician monitors their progress via a web-based console likely can make patients feel a sense of accountability in them and strengthen the therapeutic alliance [50,51]. This “clinician-in-the-loop” oversight effectively mitigates the “digital fatigue” commonly reported in prior literature, ensuring that patients consistently engage with the intervention [52]. Although we observed a gradual decrease in phase-specific adherence over time, this pattern is typical in prolonged digital health interventions. Meanwhile, given that there was no significant difference in adherence between responders and nonresponders, high adherence cannot be seen as directly related to therapeutic efficacy, nor can the decrease in adherence over time be attributed to a natural reduction in the need for daily app use following rapid symptom alleviation. However, in making this interpretation, it should be considered that the statistical power of the subgroup analysis regarding the difference in adherence between the 2 groups may have been limited due to the relatively small sample size of this study.

The early and sustained reduction in symptoms, particularly the significant between-group differences observed as early as week 2, suggests that specific therapeutic mechanisms may be active during the initial phase of the intervention. Traditional face-to-face CBT often encounters challenges with skill generalization, as patients frequently struggle to recall and apply coping strategies during unexpected panic episodes in real-life situations [53]. The intervention in the current study appears to mitigate this practical difficulty through the companion service, which delivers JITAIs. By providing immediate, context-responsive tools, such as paced breathing and grounding techniques, at the moment of physiological arousal, the app assists patients in managing their symptoms before they worsen. This real-time intervention appears to have been particularly relevant to rapid improvements in ACQ scores. Catastrophic cognitions in panic disorder tend to persist when autonomic arousal is misinterpreted as an imminent physical or mental threat [54]. Delivering JITAIs via the companion service during these acute moments has the potential to reduce the patients’ feared catastrophic consequences of physiological arousal and to lead to an experience of in vivo cognitive restructuring. This potential experiential learning is more likely to disrupt the “fear-of-fear” cycle more rapidly than delayed reflection in a clinic setting.

Beyond the management of acute panic symptoms, the significant reduction in overall anxiety levels (HADS-Anxiety) observed throughout the 8-week period likely reflects the comprehensive nature of the DTx, particularly the synergy between cognitive-behavioral skill acquisition and daily self-management. While the training and companion services directly target cognitive distortions and acute arousal associated with anticipatory anxiety, the care service addresses underlying physiological vulnerability. Panic disorder is frequently exacerbated by lifestyle factors, such as irregular sleep patterns or excessive caffeine consumption, which heighten baseline physiological arousal [17,55]. By systematically identifying and modifying these daily habits alongside structured CBT practice, patients can actively lower their everyday physiological vulnerability [56]. This continuous, multifaceted self-regulation likely contributed to a steady decline in overall anxiety, providing a stabilizing effect between clinical visits.

While the intervention demonstrated consistent effects on the severity of panic symptoms, overall anxiety, and catastrophic cognitions, changes in other secondary domains, such as depression or fear of bodily sensations, were transient or insignificant, suggesting that its effects may be confined to specific core domains rather than being general. A significant difference in HADS-Depression scores between the DTx and control groups was observed only at week 4, but it is difficult to view this as a result reflecting the therapeutic effect of the DTx, because it appears to be due to a temporary worsening in the control group rather than improvement in the DTx group. The intermittent significance in these scores may reflect the secondary and highly variable nature of mood symptoms in this population. Mild-to-moderate depression often arises as a secondary reaction to psychosocial impairment caused by unpredictable panic attacks, and thus may improve or worsen depending on the immediate severity of panic behaviors [3]. However, in cases of severe depression, recovery from depressive symptoms may be slow even if panic symptoms improve first [57]. Therefore, the 8-week time frame of using DTx seems insufficient to capture stable, long-term modifications in these comorbid mood symptoms. Meanwhile, the lack of significant between-group differences in BSQ scores at all measurement points may reflect the nature of the self-guided approach of the DTx. A previous study reporting improvements in this scale in patients with panic disorder observed the effectiveness of cognitive therapy conducted through a sufficient number of face-to-face sessions with a therapist [58]. Fear of bodily sensations measured by this scale is typically addressed through interoceptive exposure, which often requires repetitive and high-intensity symptom provocation [43]. However, the self-guided approach in a real-world environment may not have allowed for sufficient intensity or dosage of interoceptive exposure required to significantly alter these specific somatic fears. These findings suggest that while the DTx effectively manages acute panic and cognitive appraisals, certain symptom domains may require extended treatment durations or more targeted, therapist-guided exposure components.

While pharmacotherapy is the cornerstone of standard treatment for panic disorder, many patients continue to experience persistent panic symptoms and their aftereffects, particularly anticipatory anxiety and avoidance behaviors, despite such treatment [59]. Our results indicate that the adjunctive use of the DTx provides meaningful additional symptom reduction to an extent that cannot be achieved with pharmacotherapy alone. Notably, these benefits were observed in a naturalistic setting where clinicians adjusted medication regimens according to clinical needs. Because this approach closely mirrors routine outpatient care, the generalizability of our findings can be extended to everyday psychiatric practice. By using a prescription-based digital tool for patients coupled with a monitoring dashboard for clinicians, psychiatrists can provide evidence-based behavioral interventions while efficiently managing patient progress, even within the time constraints of outpatient visits. Furthermore, the observed attrition rate was markedly lower than anticipated during study planning, further supporting the feasibility and acceptability of this multifunctional DTx. Despite integrating multiple therapeutic components within a single protocol, participant retention remained high, suggesting that the comprehensive design did not impose an excessive burden but rather facilitated sustained engagement throughout the intervention period. It must be noted here that the observed low attrition rate may be associated with a selected sample of voluntary participants in the controlled environment of a clinical trial. Therefore, it is uncertain whether this result will be actually maintained in routine clinical practice; thus, verification in real-world clinical settings will be necessary.

Several limitations should be considered when interpreting the results of this study. First, the primary and secondary efficacy end points relied on self-report questionnaires to assess the symptom severity subjectively perceived by patients as an indicator of effectiveness. While these questionnaires are widely validated and used as standards in panic disorder research, they are inherently susceptible to reporting bias. In addition, no adjustment was made for multiple comparisons in analyzing these efficacy end points, as the analyses for variables other than the single primary end-point variable were entirely exploratory; thus, it should be noted that the interpretation of the results cannot be definitive due to the increased risk of type I error. Second, the control group received pharmacotherapy alone without a sham digital intervention, despite consenting to participate in the study. Consequently, in addition to the aforementioned issue regarding the expectancy effects of digital participation and additional nonspecific therapeutic elements in the DTx group, it is possible that the inability to use a sham device also affected the control group in another way. That is, it cannot be entirely ruled out that not only did they fail to obtain a placebo effect from sham use, but the disappointment stemming from their inability to use a novel device also had a negative impact on the symptom assessment. Third, although medication adjustments were permitted based on symptom status at the discretion of clinicians who were unaware of the participants’ group assignments, some potential pharmacological confounding factors may not have been controlled. A post hoc review of concomitant medication records indicated that use duration and dosage changes for all types of psychiatric medications were similar between the 2 groups. However, it was not possible to determine whether there were differences in pharmacological intensity between the groups due to the difficulty in quantifying dosages by type, nor could it be confirmed whether there was any biased use toward specific medications, given the small number of users for each medication due to the use of various ones. Finally, the 8-week trial duration captures only the acute treatment phase. It remains unclear whether the observed symptom reductions achieved through a digital platform and high patient engagement persist over a longer follow-up period, or if symptoms worsen again after the formal intervention. This needs to be clarified through a future study including a posttrial follow-up of 3 or 6 months.

In conclusion, this multicenter randomized controlled trial indicates that our prescription-based DTx is a feasible adjunct to pharmacotherapy for panic disorder, demonstrating particular clinical value for acute-phase patients experiencing frequent panic attacks. The adjunctive use of the DTx resulted in early and sustained symptom reductions across various domains, including panic severity, overall anxiety, and catastrophic cognitions, and demonstrated a clinically meaningful responder rate. This self-guided intervention, which integrates structured CBT, just-in-time context-responsive coping tools, and daily lifestyle tracking, supported sustained patient adherence throughout the 8-week period. Taken together, the results of the current study suggest that this integrated DTx model can serve as a practical complement to routine psychiatric care for patients experiencing frequent panic attacks. Furthermore, this model is expected to present a new framework for establishing a new doctor-patient relationship in the treatment of acute-phase panic disorder by reflecting various aspects related to symptoms manifesting in the patient’s daily life into the clinician’s evaluation and guidance in the clinic. Future large-scale studies with extended follow-up periods are warranted to further establish the long-term utility of this intervention.