A randomized controlled trial of ganaxolone in posttraumatic stress disorder

被引:46
作者
Rasmusson, Ann M. [1 ,2 ]
Marx, Christine E. [3 ]
Jain, Sonia [4 ]
Farfel, Gail M. [5 ,6 ]
Tsai, Julia [5 ]
Sun, Xiaoying [4 ]
Geracioti, Thomas D. [7 ,8 ]
Hamner, Mark B. [9 ,10 ]
Lohr, James [4 ,11 ]
Rosse, Richard [12 ]
Summerall, Lanier [13 ,14 ]
Naylor, Jennifer C. [3 ]
Cusin, Cristine [15 ,16 ]
Lang, Ariel J. [4 ,11 ]
Raman, Rema [17 ]
Stein, Murray B. [4 ,11 ]
机构
[1] Boston Univ, Sch Med, Dept Vet Affairs, Natl Ctr PTSD,Womens Hlth Sci Div, Boston, MA 02118 USA
[2] VA Boston Healthcare Ctr, 116B-3,150 South Huntington Ave, Boston, MA 02130 USA
[3] Duke Univ, Sch Med, VA Midatlantic MIRECC, Durham VA Med Ctr, Durham, NC USA
[4] Univ Calif San Diego, La Jolla, CA 92093 USA
[5] Marinus Pharmaceut Inc, Radnor, PA USA
[6] Zogenix Inc, San Diego, CA USA
[7] VA Med Ctr Cincinnati, Cincinnati, OH USA
[8] Univ Cincinnati, Coll Med, Cincinnati, OH USA
[9] Ralph H Johnson VA Med Ctr, Charleston, SC USA
[10] Med Univ South Carolina, Charleston, SC USA
[11] VA San Diego Healthcare Syst, San Diego, CA USA
[12] Washington DC VA Med Ctr, Washington, DC USA
[13] Manchester VA Med Ctr, White River Jct, VT USA
[14] White River Junct VA Med Ctr, White River Jct, VT USA
[15] Massachusetts Gen Hosp, Boston, MA 02114 USA
[16] Harvard Med Sch, Boston, MA USA
[17] Univ Southern Calif, Los Angeles, CA USA
关键词
Multisite clinical trial; Ganaxolone; Allopregnanolone; GABA receptor agonist; Neurosteroid; Depression; Trauma; PTSD; DOUBLE-BLIND; ANTICONVULSANT ACTIVITY; GABA(A) RECEPTORS; MAJOR DEPRESSION; ALLOPREGNANOLONE; PLACEBO; VALIDITY; PTSD; VALIDATION; SERTRALINE;
D O I
10.1007/s00213-017-4649-y
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated ganaxolone (a synthetic 3 beta-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.
引用
收藏
页码:2245 / 2257
页数:13
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