Table 1.
Summary of the novel investigation therapeutics for panic disorder
| Novel investigational therapeutic | Pharmacological mechanism | Preclinical study | Clinical study |
|---|---|---|---|
| Modulators of glutamatergic receptors | Modulate the DMH/PeF, DPAG and orexin system | Dose-dependent inhibition of NaLac-induced panic-like response by LY354740 (a selective agonist of the Group II metabotropic receptors) | Tolerability and efficacy of LY354740 in a placebo-controlled double-blind randomized phase II study |
| Induce a balance between glutamatergic and GABAergic tone | Dose-dependent blockade of NaLac-induced panic-like behavior by antagonists of ionotropic NMD A receptors | Efficacy of LY544344 in reducing anxiety responses to cholecystokinin tetrapeptide infusion in healthy subjects | |
| Antagonists of orexin receptors | Modulate the hypersensitive suffocation or chemoception monitor and panic-like responses | Attenuation of NaLac-induced panic-like response by SB334867 or SB408124 (ORX1R antagonists) | No clinical studies |
| Attenuation of anxiety behavior following exposure of 20% CO2 by SB334867 | |||
| Corticotrophin-releasing factor 1-receptor antagonists | Facilitate the escape behaviors in the ETM and the electrical stimulation of the DPAG | Blockade of the increase of escape behaviors by infusion of CRF in DPAG of rats | Effects of R317573 (a non-peptidergic, selective CRF1 receptor antagonist) on 7.5% CO2 inhalation response in healthy subjects in a phase I randomized, double-blind, placebo-controlled study |
| Acute effect in preventing the NaLac-induced panic-like behavior by intraperitoneal pretreatment of JNJ19567470/CRA5626 (a selective, non-peptidergic CRF1 effect) | |||
| Angiotensin II receptoor antagonists | Modulate the respiratory variability, which can be increased in patients with panic disorder | Blockade of the panic-like behavioral and cardiorespiratory NaLac-induced response by injection of losartan (A-II type 1 receptor antagonist) and saralasin (non-specific A-II receptor antagonist) | No clinical studies |
| Modulators of endocannabinoid system | Modulate the release of serotonin, glutamate and GABA implicated in panic disorder | Decrease escape responses induced by electrical stimulation of DPAG, with intra-PDAG administration of capsazepine (TRPV1 receptor antagonist) | No clinical studies |
| Neurokinin 1 receptor antagonists | Modulate the substantial concentration of substance P in the DPAG | Reduce escape behaviors induced by electrical stimulation of the DPAG, with not SB222200 (NK3 receptor antagonist) but spantide (NK1 receptor antagonist) | Efficacy of two NK1 antagonists in blocking the behavioral and physiological panic responses to challenge in a phase I study of 19 healthy subjects |
| Arginine vasopressin VIB receptor antagonists | Modulate the activation of hypothalamopituitary-adrenal axis | Blockade of anxiety-like behavioral response to NaLac infusion by TASP0233278 (V1B receptor antagonist) | No clinical studies |
A-II: angiotensin-II, DMH: dorsomedial hypothalamus, DPAG: dorsal periaqueductal gray, ETM: elevated T-maze, GABA: γ-aminobutyric acid, NaLac: sodium lactate, NK: neurokinin, ORX: orexin, PeF: perifornical, TRPV1: transient receptor potential vanilloid type-1