Fasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling

  • Nat Commun. 2018 Jan 16;9(1):4. doi: 10.1038/s41467-017-02244-2.
Josephine Elia  1  2  3 ,  Grace Ungal  4 ,  Charlly Kao  5 ,  Alexander Ambrosini  6 ,  Nilsa De Jesus-Rosario  7 ,  Lene Larsen  7 ,  Rosetta Chiavacci  5 ,  Tiancheng Wang  5 ,  Christine Kurian  8 ,  Kanani Titchen  9  8 ,  Brian Sykes  9  8 ,  Sharon Hwang  9  8 ,  Bhumi Kumar  9  8 ,  Jacqueline Potts  8 ,  Joshua Davis  9  8 ,  Jeffrey Malatack  9 ,  Emma Slattery  8 ,  Ganesh Moorthy  10 ,  Athena Zuppa  10 ,  Andrew Weller  7 ,  Enda Byrne  5 ,  Yun R Li  5  11 ,  Walter K Kraft  8 ,  Hakon Hakonarson  5  10  12
Affiliations
  • 1. Nemours, du Pont Hospital for Children, Wilmington, 19803, DE, USA. [email protected].
  • 2. Department of Pediatrics Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, 19107, PA, USA. [email protected].
  • 3. Department of Psychiatry Sidney Kimmel Medical College of Thomas Jefferson University, 19107, Philadelphia, USA. [email protected].
  • 4. Drexel University College of Medicine, Philadelphia, 19129, PA, USA.
  • 5. The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, 19104, PA, USA.
  • 6. University of Pennsylvania, Philadelphia, 19104, PA, USA.
  • 7. Department of Psychiatry Sidney Kimmel Medical College of Thomas Jefferson University, 19107, Philadelphia, USA.
  • 8. Department of Pediatrics Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, 19107, PA, USA.
  • 9. Nemours, du Pont Hospital for Children, Wilmington, 19803, DE, USA.
  • 10. Department of Pediatrics Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA.
  • 11. Department of Radiation Oncology, Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, 94143, CA, USA.
  • 12. Divisions of Human Genetics and Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, 19104, PA, USA.
PMID: 29339723 DOI: 10.1038/s41467-017-02244-2
Abstract

The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12-17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50-800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks. NFC-1 treatment resulted in significant improvement. Mean Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scores were, respectively, 3.79 at baseline vs. 2.33 at week 5 (P < 0.001) and 4.83 at baseline vs. 3.86 at week 5 (P < 0.001). Parental Vanderbilt scores showed significant improvement for subjects with mGluR Tier 1 variants (P < 0.035). There were no differences in the incidence of adverse events between placebo week and weeks on active drug. The trial is registered at https://clinicaltrials.gov/ct2/show/study/NCT02286817 .

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