Effect of desipramine on patients with breathing disorders in RETT syndrome

Abstract

Objective: Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced the number of apneas in Mecp2-deficient mice, a model of RTT. We planned a phase 2 trial to test its efficacy and its safety on breathing patterns in 36 girls with RTT.

Methods: The trial was a 6-month, multicenter, randomized, double-blind, placebo-controlled study registered with ClinicalTrials.gov, number NCT00990691. Girls diagnosed according to clinical examination and confirmed by genotyping were randomly assigned in a 1:1:1 ratio to receive 2-3 mg/kg Desipramine per day (high Desipramine), 1-2 mg/kg Desipramine per day (low Desipramine), or a placebo. The primary outcome was the change of apnea hypopnea index (AHI), defined by the number of apnea and hypopnea events per hour, assessed at 6 months from baseline. Intention-to-treat analysis was applied.

Results: The median change in AHI from baseline to 6 months was -31 (IQR: -37 to -11) for the high Desipramine, -17.5 (IQR: -31 to 13) for the low Desipramine, and -13 (IQR:-31 to 0) for the placebo group. We did not find any significant difference in these changes between the groups (P = 0.781). A significant inverse correlation between Desipramine plasma concentration and AHI (r = -0.44; P = 0.0002) was underlined.

Interpretation: This first clinical trial of desipramine did not show clinical efficacy. Although required further studies, the significant correlation between Desipramine concentrations and improvement of AHI provided additional and relevant reasons to test the noradrenergic pathway in RTT.

Figures

Figure 1

Trial profile. modified intention‐to‐treat, including randomized patient with valid respiratory assessment. *Adverse events were hypersensitivity (2 weeks), prolonged QTc interval (2 weeks) and constipation (5 weeks) in high dose DMI and status epilepticus (2 weeks), insomnia (2 weeks), and motor dysfunction (9 weeks and 3 months) in low dose DMI.

Figure 2

Relation between AHI measured with Apnealink® and AHI measured with polysomnography. AHI, Apnea‐Hypopnea Index.

Figure 3

AHI at Baseline, 3 months, and 6 months (A), in the boxplot, the “+” sign represents the mean) and individual patient's change at 6 months (B).

Figure 4

DMI plasmatic concentration (ng/mL) at each time point by treatment group.

Figure 5

Relation between DMI plasma concentration (ng/mL) and AHI (events/h) on all time points including 6 months (r = −0.44, P = 0.0002), in insert: data at 6 months solely (r = −0.42, P = 0.19) (A) and correlation between the change of AHI from baseline to 6 months (events/h) in DMI groups and AHI (events/h) at Baseline. Spearman's correlation coefficient r = −0.72 (P = 0.0126) (B).