Experimental Drugs for Panic Disorder: An Updated Systematic Review

Abstract

Several effective pharmacological therapies for panic disorder (PD) are available, but they have some drawbacks, and unsatisfactory outcomes can occur. Expanding the variety of anti-panic medications may allow for improving PD treatment. The authors performed an updated systematic review of preclinical and clinical (Phase I–III) pharmacological studies to look for advances made in the last six years concerning novel-mechanism-based anti-panic compounds or using medications approved for nonpsychiatric medical conditions to treat PD. The study included seven published articles presenting a series of preclinical studies, two Phase I clinical studies with orexin receptor (OXR) antagonists, and two clinical studies investigating the effects of D-cycloserine (DCS) and xenon gas in individuals with PD. The latest preclinical findings confirmed and expanded previous promising indications of OXR1 antagonists as novel-mechanism-based anti-panic compounds. Translating preclinical research into clinical applications remains in the early stages. However, limited clinical findings suggested the selective OXR1 antagonist JNJ-61393115 may exert anti-panic effects in humans. Overall, OXR1 antagonists displayed a favorable profile of short-term safety and tolerability. Very preliminary suggestions of possible anti-panic effects of xenon gas emerged but need confirmation with more rigorous methodology. DCS did not seem promising as an enhancer of cognitive-behavioral therapy in PD. Future studies, including objective panic-related physiological parameters, such as respiratory measures, and expanding the use of panic vulnerability biomarkers, such as hypersensitivity to CO 2 panic provocation, may allow for more reliable conclusions about the anti-panic properties of new compounds.

Acute orexin antagonism selectively modulates anticipatory anxiety in humans: implications for addiction and anxiety

“…There is a robust animal literature suggesting the ORX system is involved in arousal-based anxiety and the motivational drive for alcohol use [ 51 , 52 ]. ORX antagonism has been identified as a promising next-generation therapeutic for anxiety and AUD [ 53 , 54 ]. Surprisingly, very few studies on human volunteers have directly probed the ORX system.…”

Evidence-Based Pharmacotherapies for Panic Disorder

“…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).…”

“…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].…”

Transcranial direct current stimulation does not improve clinical and neurophysiological outcomes in panic disorder: A randomized sham‐controlled trial

“…Panic disorder (PD) is a common psychiatric disorder with up to 5% lifetime prevalence 1 and has been associated with remarkable work impairment and frequent medical treatment‐seeking 2 . Notwithstanding distinct pharmacological and psychological treatments that are currently used, 3 mounting evidence suggests that a considerable number of individuals with PD do not attain a complete remission, 4 and a long‐term clinical course of PD is often chronic or remitting‐relapsing 5 . Early worsening of the symptoms and adverse effects that might diminish the quality of life are additional handicaps of the pharmacotherapy of PD 4 .…”

“…To provide a pathway to novel treatment protocol development, a clear understanding of the pathophysiology of PD is essential; however, the neurobiological basis of PD has not yet been fully elucidated. Although molecular mechanisms have usually been the consuetudinary etiologic and pharmacotherapeutic area of interest for PD, 3 numerous other factors such as genetic, psychosocial factors, and cortical activity changes might also play a role 6 . PD has been considered as a chronic stress and fear network disorder 7 and an integrative biopsychosocial‐behavioral model has been conceptualized which associated the top‐down cognitive processes related to the exaggerated interpretation of the environmental stimuli with the deteriorated interplay between limbic structures and prefrontal cortex 6,8,9 .…”