Psychopharmacology (2017) 234:2245–2257 DOI 10.1007/s00213-017-4649-y ORIGINAL INVESTIGATION A randomized controlled trial of ganaxolone in posttraumatic stress disorder Ann M. Rasmusson1,2 & Christine E. Marx3 & Sonia Jain4 & Gail M. Farfel5,6 & Julia Tsai5 & Xiaoying Sun4 & Thomas D. Geracioti7 & Mark B. Hamner8 & James Lohr4,9 & Richard Rosse10 & Lanier Summerall11 & Jennifer C. Naylor3 & Cristine Cusin12,13 & Ariel J. Lang4,9 & Rema Raman14 & Murray B. Stein4,9 Received: 14 December 2016 /Accepted: 13 May 2017 /Published online: 1 July 2017 # Springer-Verlag Berlin Heidelberg (outside the USA) 2017 Abstract Preclinical and clinical research supports a role for repeated measures analysis revealed no significant differences neuroactive steroids in the pathophysiology of posttraumatic between the effects of ganaxolone and placebo on Clinician stress disorder (PTSD). We investigated ganaxolone (a syn- Administered PTSD Symptom (CAPS) scores, global well- thetic 3β-methylated derivative of allopregnanolone, a being, negative mood, or sleep. Dropout rates did not differ GABAergic neuroactive steroid) for treatment of PTSD in a between groups, and ganaxolone was generally well tolerated. proof-of-concept, multisite, double-blind, placebo-controlled Trough blood levels of ganaxolone at the end of the double- trial. Veteran and non-veteran participants (n = 112) were ran- blind phase were, however, lower than the anticipated thera- domized to ganaxolone or placebo at biweekly escalating peutic level of ganaxolone in >35% of participants on active doses of 200, 400, and 600 mg twice daily for 6 weeks. drug. Pharmacokinetic profiling of the ganaxolone dose regi- During an open-label 6-week extension phase, the initial men used in the trial and adverse event sensitivity analyses ganaxolone group continued ganaxolone, while the placebo suggest that under-dosing may have contributed to the failure group crossed over to ganaxolone. Eighty-six and 59 partici- of ganaxolone to out-perform placebo. Future investigations pants, respectively, completed the placebo-controlled and of ganaxolone may benefit from higher dosing, rigorous mon- open-label phases. A modified intent-to-treat mixed model itoring of dosing adherence, a longer length of placebo- Ann M. Rasmusson and Christine E. Marx share first authorship and are the lead investigators responsible for the design and implementation of the study as submitted for funding and support to the INTRuST Clinical Consortium Coordinating Center. * Ann M. Rasmusson 7 VA Medical Center Cincinnati and University of Cincinnati College [email protected] of Medicine, Cincinnati, OH, USA 8 Ralph H. Johnson VA Medical Center and Medical University of 1 National Center for PTSD-Women’s Health Science Division, South Carolina, Charleston, SC, USA Department of Veterans Affairs, Boston University School of 9 VA San Diego Healthcare System, San Diego, CA, USA Medicine, Boston, MA, USA 10 2 VA Boston Healthcare Center, (116B-3), 150 South Huntington Washington DC VA Medical Center, Washington, DC, USA Avenue, Boston, MA 02130, USA 11 Manchester VA Medical Center and White River Junction VA 3 Durham VA Medical Center, VA Mid-Atlantic MIRECC, Duke Medical Center, White River Junction, VT, USA University School of Medicine, Durham, NC, USA 12 Massachusetts General Hospital, Boston, MA, USA 4 University of California, San Diego, La Jolla, CA, USA 13 5 Marinus Pharmaceuticals, Inc., Radnor, PA, USA Harvard Medical School, Boston, MA, USA 6 Zogenix, Inc., San Diego, CA, USA 14 University of Southern California, Los Angeles, CA, USA 2246 Psychopharmacology (2017) 234:2245–2257 controlled testing, and targeting of treatment to PTSD subpop- associated with anxiety-like behaviors, increased aggression, ulations with demonstrably dysregulated pre-treatment neuro- enhanced contextual fear conditioning, and extinction deficits. active steroid levels. In turn, administration of allopregnanolone, drugs that stimulate Clinicaltrials.gov identifier: NCT01339689. allopregnanolone synthesis, or an SSRI at doses well below that which block serotonin reuptake but that rectify allo- Keywords Multisite clinical trial . Ganaxolone . pregnanolone levels reverse these aberrant behaviors (Pinna Allopregnanolone . GABA receptor agonist . Neurosteroid . et al. 2006; Pibiri et al. 2008; Zhang et al. 2014). Depression . Trauma . PTSD In women with PTSD, cerebrospinal fluid (CSF) levels of allopregnanolone and pregnanolone (the GABAergic 5β stereo- isomer of allopregnanolone) were together decreased to 39% of Introduction levels seen in healthy women, correlated inversely with PTSD re-experiencing symptoms and negative mood, and were lowest Over the past 15 years, strides have been made in defining the in patients with comorbid major depressive disorder (MDD) neurobiological characteristics of PTSD (Pitman et al. 2012). (Rasmusson et al. 2006). The ratio of these GABAergic neuro- Nevertheless, there remain limited efficacious pharmacother- active steroids to the immediate allopregnanolone precursor, 5α- apies for PTSD, either as stand-alone treatment or for augmen- dihydroprogesterone, was also decreased, consistent with a tation of trauma-focused psychotherapies such as Prolonged block in their synthesis. Recent studies demonstrate a similar Exposure or Cognitive Processing Therapy (Resick et al. role for these neuroactive steroids in the pathophysiology of 2014). Medications tested in PTSD have typically shown PTSD in men (Marx 2014; Rasmusson et al. 2016). large effect sizes in small preliminary studies, but smaller Allopregnanolone acts at benzodiazepine-sensitive synap- effects when tested against placebo in large multisite trials. tic GABAA receptors and more potently at benzodiazepine- The serotonin selective reuptake inhibitors (SSRIs) sertraline insensitive, extrasynaptic GABAA receptors (Semyanov et al. and paroxetine, the only two FDA-approved medications for 2004). Of note, Chhatwal et al. (2005) demonstrated down- the treatment of PTSD, showed only moderate effect sizes in regulation of synaptic GABAA receptors in the amygdala after FDA registration trials (Brady et al. 2000; Davidson et al. fear conditioning, thus providing a rationale for the poor effi- 2001;Marshalletal.2001; Tucker et al. 2001). Combat vet- cacy in PTSD of benzodiazepines. In contrast, gabapentin and erans, in particular, appeared to be resistant to SSRIs (e.g., topiramate (which target extrasynaptic GABAA receptors) Friedman et al. 2007), although variability in outcomes across have shown efficacy in several PTSD trials (Bernardy and veteran studies now suggests that ethnicity, age, or other sub- Friedman 2015). Thus, the potential utility of population differences may play a role (Bernardy and allopregnanolone in treating PTSD appears plausible. Friedman 2015). The growing evidence for biological hetero- Although allopregnanolone has been intravenously admin- geneity underlying the PTSD phenotype has therefore pro- istered to healthy humans (Timby et al. 2006; van Broekhoven voked a call for medications that address individually variable et al. 2007), and to patients with traumatic brain injury PTSD-specific pathophysiological processes (Rasmusson and (ClinicalTrials.gov: NCT01673828), Alzheimer’sdisease Abdallah 2015; Friedman and Bernardy 2016). (ClinicalTrials.gov: NCT02221622), and postpartum depres- As discussed below, preclinical and clinical evidence sup- sion (ClinicalTrials.gov Identifier: NCT02942004), an oral ports a role for neuroactive steroids with effects at gamma- formulation of allopregnanolone is not yet available. amino-butyric acid (GABA)A receptors in the pathophysiology Ganaxolone, a synthetic 3β-methylated analog of and treatment of PTSD in at least some subpopulations. Levels allopregnanolone, can be administered orally, however. Like of allopregnanolone, a progesterone metabolite that positively allopregnanolone, ganaxolone is a positive allosteric modula- and potently modulates effects of GABA at GABAA receptors, tor of GABAA receptors and demonstrates anxiolytic and an- increase following administration of SSRIs, and appear to con- ticonvulsant actions in rodent models (Kaminski et al. 2004; tribute to the therapeutic effects of SSRIs (Uzunova et al. 1998; Reddy et al. 2004). The tolerability and safety of ganaxolone Romeo et al. 1998). In healthy humans, increases in serum also has been demonstrated in phase 1 and phase 2 clinical allopregnanolone levels during a study of the effects of preg- trials in patients with refractory epilepsy (Laxer et al. 2000; nenolone (a precursor for allopregnanolone) on emotion regu- Nohria and Giller 2007; Bialer et al. 2010). We therefore de- lation correlated negatively with amygdala activity; further, a cided to investigate ganaxolone for the treatment of PTSD in a higher ratio of allopregnanolone to pregnenolone after pregnen- phase 2, proof-of-concept clinical trial. We hypothesized that olone infusion was positively correlated with dorsomedial pre- ganaxolone would show an advantage over placebo in reduc- frontal cortex-amygdala connectivity, which in turn correlated ing PTSD symptoms and improving well-being. We also ex- negatively with anxiety (Sripada et al. 2013). In contrast, a pected ganaxolone to be well tolerated and that adverse events reduction in the corticolimbic expression of allopregnanolone would not differ between the ganaxolone and placebo in male rodent models (Pibiri et al. 2008; Zhang et al. 2014)is treatments. Psychopharmacology (2017) 234:2245–2257 2247 Methods