Norepinephrine Transporter Blockade, Autonomic Failure (NETAF)

Autonomic failure is a group of rare neurodegenerative disorders that primarily affect the autonomic nervous system. These patients develop neurogenic orthostatic hypotension (OH) because of impaired autonomic reflexes that control cardiovascular and neuro-humoral adaptation to upright posture. The treatment of neurogenic OH is challenging; the therapeutic options are scarce, and some patients are refractory to treatment.

Atomoxetine is a selective norepinephrine transporter inhibitor that increases the availability of norepinephrine in the synapse by blocking its reuptake. Our preliminary data in sixty-five patients with primary autonomic failure and neurogenic OH showed that atomoxetine was more effective than midodrine, standard of care, in improving standing SBP (+7.5 mm Hg). Notably, only atomoxetine and not midodrine induced a significant reduction in OH-related symptoms (lightheadedness and dizziness) compared with placebo. In this proposal, we will test the hypothesis that prolonged administration of the norepinephrine transporter blocker, atomoxetine, improves OH-related symptoms and OH-impact on daily activities compared with placebo in autonomic failure patients. We propose a randomized, double-blind, placebo-controlled, 2x2 crossover study.

Inclusion criteria

• 40 years old or older
• Neurogenic Orthostatic Hypotension (defined by a reduction of ≥20 mmHg drop in SBP within 3 minutes of standing, associated with impaired autonomic reflexes as assessed by autonomic function tests.

Exclusion criteria

• Pregnancy or breastfeeding
• Hypersensitivity to atomoxetine (severe allergic reaction, rash, urticaria, anaphylaxis)
• Use of other norepinephrine transporter inhibitors such as Wellbutrin (Bupropion), Cymbalta (Duloxetine), Effexor (venlafaxine), Pristiq (desvenlafaxine), Savella (milnacipran)
• Previous history (within 14 days prior to enrollment) and current use of monoamine oxidase inhibitors
• Concomitant use of strong CYP2D6 inhibitors such as delavirdine, paroxetine, fluoxetine, quinidine
• Pre-existing sustained severe hypertension (BP ≥ 140/80 mmhg in the sitting position)
• Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >2 x upper limit of normal range)
• Impaired renal function (serum creatinine equal or more than 1.6 mg/dl)
• Myocardial infarction within 6 months prior to enrollment
• Congestive heart failure (LV hypertrophy acceptable)
• History of serious neurologic disease such as cerebral hemorrhage, or stroke
• Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, unlikelihood of completing the study, and mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
• Narrow-angle glaucoma