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A randomized controlled trial of ganaxolone in posttraumatic stress disorder.

Abstract：

:Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated ganaxolone (a synthetic 3β-methylated derivative of allopregnanolone, a GABAergic neuroactive steroid) for treatment of PTSD in a proof-of-concept, multisite, double-blind, placebo-controlled trial. Veteran and non-veteran participants (n = 112) were randomized to ganaxolone or placebo at biweekly escalating doses of 200, 400, and 600 mg twice daily for 6 weeks. During an open-label 6-week extension phase, the initial ganaxolone group continued ganaxolone, while the placebo group crossed over to ganaxolone. Eighty-six and 59 participants, respectively, completed the placebo-controlled and open-label phases. A modified intent-to-treat mixed model repeated measures analysis revealed no significant differences between the effects of ganaxolone and placebo on Clinician Administered PTSD Symptom (CAPS) scores, global well-being, negative mood, or sleep. Dropout rates did not differ between groups, and ganaxolone was generally well tolerated. Trough blood levels of ganaxolone at the end of the double-blind phase were, however, lower than the anticipated therapeutic level of ganaxolone in >35% of participants on active drug. Pharmacokinetic profiling of the ganaxolone dose regimen used in the trial and adverse event sensitivity analyses suggest that under-dosing may have contributed to the failure of ganaxolone to out-perform placebo. Future investigations of ganaxolone may benefit from higher dosing, rigorous monitoring of dosing adherence, a longer length of placebo-controlled testing, and targeting of treatment to PTSD subpopulations with demonstrably dysregulated pre-treatment neuroactive steroid levels. Clinicaltrials.gov identifier: NCT01339689.

journal_name

Psychopharmacology (Berl)

journal_title

Psychopharmacology

authors

Rasmusson AM,Marx CE,Jain S,Farfel GM,Tsai J,Sun X,Geracioti TD,Hamner MB,Lohr J,Rosse R,Summerall L,Naylor JC,Cusin C,Lang AJ,Raman R,Stein MB

doi

10.1007/s00213-017-4649-y

subject

Has Abstract

pub_date

2017-08-01 00:00:00

pages

2245-2257

issue

eissn

0033-3158

issn

1432-2072

pii

10.1007/s00213-017-4649-y

journal_volume

234

pub_type

杂志文章,多中心研究,随机对照试验

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A randomized controlled trial of ganaxolone in posttraumatic stress disorder.