Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine.

PURPOSE: Guanfacine is an α2A-adrenergic receptor agonist, FDA-approved to treat attention-deficit hyperactivity disorder and high blood pressure, typically as an extended-release formulation up to 7 mg/day. In our dysautonomia clinic, we observed that off-label use of short-acting guanfacine at 1 mg/day facilitated symptom relief in two families with multiple members presenting with severe generalized anxiety. We also noted anecdotal improvements in associated dysautonomia symptoms such as hyperhidrosis, cognitive impairment, and palpitations. We postulated that a genetic deficit existed in these patients that might augment guanfacine susceptibility. METHODS: We used whole-exome sequencing to identify mutations in patients with shared generalized anxiety and dysautonomia symptoms. Guanfacine-induced changes in the function of voltage-gated Na+ channels were investigated using voltage-clamp electrophysiology. RESULTS: Whole-exome sequencing uncovered the p.I739V mutation in SCN9A in the proband of two nonrelated families. Moreover, guanfacine inhibited ionic currents evoked by wild-type and mutant NaV1.7 encoded by SCN9A, as well as other NaV channel subtypes to a varying degree. CONCLUSION: Our study provides further evidence for a possible pathophysiological role of NaV1.7 in anxiety and dysautonomia. Combined with off-target effects on NaV channel function, daily administration of 1 mg short-acting guanfacine may be sufficient to normalize NaV channel mutation-induced changes in sympathetic activity, perhaps aided by partial inhibition of NaV1.7 or other channel subtypes. In a broader context, expanding genetic and functional data about ion channel aberrations may enable the prospect of stratifying patients in which mutation-induced increased sympathetic tone normalization by guanfacine can support treatment strategies for anxiety and dysautonomia symptoms.

Microwave Thermolysis Reduces Generalized and Social Anxiety in Young Adults With Axillary Hyperhidrosis.

BACKGROUND AND OBJECTIVE: Hyperhidrosis (HH) is associated with impairments in quality of life (QOL) and elevated anxiety. Microwave thermolysis is a newer treatment that reduces sweating, yet effects on QOL and emotional symptoms have not been examined. Two treatment sessions are recommended to achieve 80% amelioration of clinical HH. We hypothesized that microwave thermolysis would reduce sweat severity, improve QOL, and reduce anxiety in young adults suffering from axillary HH in a prospective clinical trial. STUDY DESIGN/MATERIALS AND METHODS: We enrolled 24 young adults (mean age = 23.57 years, 54% female) with elevated scores on the Hyperhidrosis Disease Severity Scale. All participants received one session of microwave thermolysis, and 83% received two sessions. Participants completed measures of sweat severity, QOL, generalized anxiety, social anxiety, social avoidance, and anxious/depressive mood symptoms at baseline; post-first treatment; and following second treatment. RESULTS: At baseline, all participants had severe sweating; 87.5% had impaired QOL, 75% had elevated social anxiety, 50% with generalized anxiety, 48% with social avoidance, and 38% with anxious/depressed mood. Paired samples t tests indicated significant improvements from baseline to first procedure, including decreased sweating (t(21) = 5.68, P < 0.001), improved QOL (t(23) = 4.97, P < 0.001), and decreased generalized anxiety (t(23) = 8.11, P < 0.001), social anxiety (t(22) = 4.55, P < 0.001), mood symptoms (t(21) = 3.81, P = 0.001), and social avoidance (t(22) = 3.12, P = 0.005). After second treatment, further improvements were noted in sweating (t(18) = 3.28, P = 0.004) and QOL (t(18) = 3.83, P = 0.003), and a marginal trend for generalized anxiety (t(19) = 1.96, P = 0.064). CONCLUSION: There were significant improvements in sweat severity, skin-specific QOL, generalized anxiety, social anxiety, anxious/depressive symptoms, and social avoidance. The majority of the psychosocial benefit appears to emerge after one treatment of microwave thermolysis, whereas the level of sweat severity and QOL continued to show further improvements after a second treatment. Results would suggest that although two microwave thermolysis sessions are needed for maximal treatment optimization of axillary HH, patients may experience significant benefits in improving psychosocial functioning after just one session. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.