Outcomes of the State of the Science Summit: Pathophysiology of Posttraumatic Stress Disorder: Rethinking Drug Targets

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Lorraine Robinson
5 years ago
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1 Background and Objectives: In June 2017 the Military Operational Medicine Research Program and U.S. Army Medical Materiel Development Activity hosted the Posttraumatic Stress Disorder State of the Science Summit (PTSD SoSS). Subject-matter experts and stakeholders (academia, industry, government and non-profits) worked together to achieve the following four objectives: (1) To provide a research update on receptor systems and circuits involved in the pathophysiology of PTSD (onset, prevention, chronicity). (2) To streamline and accelerate progress in the development of medication treatments for PTSD by identifying the most promising new drug targets. (3) To examine challenges and innovations in defining clinical endpoints and treatment selection parameters for subpopulations within the overall population of PTSD diagnosed individuals. (4) To provide an opportunity for industry, academia and government to problemsolve and exchange ideas with one another and initiate viable partnerships for future efforts. Following the PTSD SoSS plenary presentations that included pre-clinical and clinical findings for a multitude of pathophysiological domains, 10 working groups (WGs) composed of subject-matter experts met to address six questions focused on addressing the four objectives listed above. The first three questions addressed the domains that, if investigated further, would most likely yield new treatments for PTSD and the most salient attributes for those new treatments. Questions four and six focused on the prioritization of drugs with existing clinical data and the identification of biological subtypes that may be most responsive to specific interventions. Question five requested opinions from attendees about how best to establish private and public partnerships with multiple stakeholders. The WG members were not asked to come to consensus (due to Federal Advisory Committee Act considerations) but to share all of their ideas during discussion. Due to time constraints not all aspects of all questions were able to be addressed. WG chairs provided highlights of their group s discussions and key points during the PTSD SoSS final closing plenary session. Working Group Questions and Summary of Responses: Below is a list of each question addressed during the WG sessions and a summary of the responses. (1) What pathophysiological domains have the most potential for defining a new drug target? Is the target a discrete pathway or focused upon a grouping of symptoms that theoretically share a common etiological origin or does the target encompass a "magic bullet concept" addressing the full disorder? 1

2 (2) What other pathways are potentially important in the pathophysiology of PTSD that have not yet been explored? What types of studies should be done to explore these pathways? Summary of responses to questions one and two: Pathophysiological domain was defined broadly in the plenary presentations but the term was interpreted even more broadly by responders in the WG sessions. The responses encompassed different categories of neurobiological systems, pathways and pathophysiological domains, systemic systems and pathways, and psychological constructs. Many of the groups discussed that PTSD involves multiple domains resulting in the need to focus on or differentiate between co-morbidities, staging of the disease process/treatment timing, drug combinations, interaction/augmentation with psychotherapy, neuronal circuitry, symptom presentation and biomarkers. Domains are listed below, followed by the number of WGs in which they were discussed as having potential for defining a new drug target: Neurobiological Systems/Pathways/Domains Circadian rhythms/sleep (7) Hypothalamic Pituitary Adrenal (HPA) Axis/Steroid Hormones (5) Cannabinoid system (5) o Cannabidiol o FAAH Neuronal circuitry (5) Excitatory/Inhibitory Pathways (4) Opioid System(4) Neuroplasticity (3) Neuropeptides (3) o Vasopressin o Oxytocin (2) o Orexin (2) Dopamine system/reward (2) Monoamines (2) Systemic Systems/Pathways Inflammation (5) Gut Microbiome (4) Angiotensin/Renin (3) mtor pathway(1) Psychological Constructs Reactivation/Propranolol (3) Salience Gating/Arousal (2) Emotion Regulation (1) Fear extinction (1) Dissociation (1) (3) Please discuss desired attributes for drugs to target specific pathophysiological domains. How could this domain be targeted for treatment of PTSD? i.e. Increase or decrease activity at which specific receptor/peptide system? 2

3 Summary of responses to question three: Common themes for drug attributes included known mechanism(s) of action and evidence of target engagement, highly effective with a durable response, rapidly acting (within one to two days), safe with few side effects and unanticipated effects (including negative sexual side effects, hypotension, sedation, cognitive impairment, etc.), easy to administer, taken short-term, low potential for abuse, and short half-life. To keep active military ready and alert it was deemed beneficial if some drugs had positive effects such as improved cognitive performance and fortifying sleep. Using drugs with the potential for abuse was a concern and it was mentioned that registry, supervision and clear protocols for these drugs are needed. The importance of patient preference was also identified. (4) Please consider the drugs on the attached list. [A list of 50 drugs that had data from at least one completed randomized placebo-controlled trial or an open-label trial as of May 1, 2017 was included in the PTSD SoSS information book that was distributed to all participants and is included at the end of the body of this document.] Discuss which drugs should be tested in additional clinical trials as treatments for PTSD. What types of studies should be considered to determine efficacy of these drugs? Do psychiatric co-morbidities (e.g. Major Depression, Substance Use Disorder, etc.) change your thoughts about how to study these drugs? If so, how? Summary of responses to question four: Attendees chose to discuss drugs not included in the summit information book. Specific drugs and broader classes of drugs were also discussed concurrently, however they are listed separately below. Lastly, listed below are drugs or drug classes that attendees thought should not be studied in future clinical trials. Drugs mentioned by more than one WG (followed by the number of WGs in which they were suggested for testing in additional clinical trials as treatments for PTSD) are below. Ketamine (7) Cannabis/Cannabidiol (2) Hydrocortisone (6) Nabilone (2) Eszopiclone (3) Delta 9 THC (2) Prazosin (3) TNX-102SL (2) Mirtazapine (3) DHEA (2) o +sertraline MDMA (2) Drugs mentioned in one WG (as should be tested in additional clinical trials as treatments for PTSD): Acamprosate EPA DHA ALKS 5461 GSK Ayahuasca (A botanical tea) Guanfacine Buprenorphine LSD/Psilocybin Clonidine Methylphenidate Divalproex Memantine 3

4 Mifepristone Minocycline Moclobemide Naltrexone NPY PH10 Phenelzine Ramelteon (Melatonin receptor Drug Classes to study: Orexin-1 and Orexin-2 antagonists (3) GR antagonists (3) Cannabinoids (2) o FAAH Inhibitor (6) o MAGL inhibitor Allopregnanolone NMDAR modulators (2) Sigma 1 agonists (2) agonist) Suvorexant Tianeptine Tolcapone TRH Venlafaxine Vortioxetine SSRI (gender-specific) with better biomarkers(2) Anti-inflammatories (2) Kappa Opioid Antagonists (2) GABA agents NK1 antagonists HDAC 2,3 inhibitors TNF inhibitors Atypical antipsychotics Drugs/Classes to stop studying: Delta 9 THC SSRIs (2) Benzodiazepines Atypical antipsychotics (5) How can the DoD facilitate effective partnerships between academia, industry and government? Are there any additional stakeholders that should be engaged? Please provide examples of relevant partnerships. Summary of responses to question five: There was overall enthusiasm for continued discussion on these topics. Despite intellectual property issues, lack of access to raw data and other barriers, the groups felt public/private partnerships and consortia were important and could help break through those challenges. Some felt that the Veterans Affairs (VA) and DoD would be priority partners with some policy changes needed. Specific examples of successful partnerships were mentioned including the Alzheimer s disease Neuroimaging Initiative (ADNI) and efforts by Dr. Murray Raskind at the Puget Sound VA. Several groups mentioned the need for a pre-competitive platform, working across populations and including advocacy groups and nonprofits/mission-centric foundations as stakeholders. It was mentioned a few times that the government should take the risk to fund initial studies and that the government might consider partnering with small pharmaceutical companies to repurpose current drugs. It was also suggested that publicity and incentives could help facilitate participation of all stakeholders. 4

5 (6) How should clinical and/or biological subtypes of PTSD be identified for the purposes of designing successful clinical trials using newer approaches to patient selection and enrichment (e.g. precision medicine)? Summary of responses to question six: For drug clinical trials, the need to look at stratification and take pre- and postmeasures was highlighted. Possible ways to differentiate subgroups included demographics (sex, education, etc.), duration or severity of illness, co-morbidities (substance abuse, major depression, chronic pain, traumatic brain injury, etc.), trauma type, military status (civilians, Active Duty Service members, and Veterans), physiological markers, biological markers/genetics, cognitive measures and symptomatology. Suggestions of available tools to use for phenotyping participants included the Phen-x toolkit, elevated aggression scales and trauma indexing. The drug trials themselves need to be large and multi-domain, and should carefully bank serum, blood and other biological samples. Objective behavioral and physiological endpoints and patient reported measures were mentioned as possible outcome measures. Overall Summary of SoSS Outcomes: As evidenced by the breadth of topics presented during the summit plenary sessions, PTSD is a complex disorder with a diverse representation of clinical symptomatology (e.g. there are >636,000 ways to arrive at a PTSD diagnosis based on criteria defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) and biological alterations in multiple neurobiological pathways and circuits (e.g. prefrontalamygdala circuits, excitatory and inhibitory neurotransmitter levels and signaling), further complicated by psychosocial stressors and frequently occurring co-morbid conditions (e.g. substance abuse). PTSD is difficult to treat effectively due to this heterogeneity and complexity. Gaining a better understanding of the underlying pathophysiology of neurobiological systems, domains and circuitry will result in the identification of biological subtypes of PTSD and will lead to more targeted, effective treatments. The importance of identifying biological subtypes of PTSD and the need to utilize those subtypes in future clinical trial designs was repeatedly reinforced during the summit. Successful clinical trials using this approach will lead to the successful implementation of precision medicine. Finally, due to the scientific complexity of PTSD and the multiple stakeholders involved in addressing the treatment of the disorder and related conditions, the strategy of working within a private/public partnership model was endorsed. Despite barriers related to intellectual property and limited resources, establishing a public/private partnership was viewed as a way to accelerate understanding of the biology of PTSD and to facilitate development of novel drug treatments for PTSD. Alignment on common scientific questions, inclusion of appropriate stakeholders for each project and use of flexible execution mechanisms were highlighted as key to a successful future partnership. 5

6 Drug List Δ9-THC Alprazolam Amitriptyline Aprepitant Aripiprazole Asenapine Brofaromine Citalopram Desipramine Disulfiram Divalproex D-serine Escitalopram Eszopiclone Fluoxetine Galantamine GR GSK Guanfacine Hydrocortisone Imipramine Inositol Ketamine Lamotrigine Memantine Methylphenidate Mirtazapine Mirtazapine + Sertraline Moclobemide Nabilone N-acetylcysteine Naltrexone Naltrexone + Desipramine Naltrexone + Disulfiram Naltrexone + Paroxetine Nefazodone Olanzapine Paroxetine Phenelzine Prazosin Quetiapine Risperidone Sentra AM + Sentra PM Sertraline Tiagabine Tianeptine TNX-102SL Topiramate Venlafaxine Ziprasidone 6

7 Acronym List ADNI Alzheimer s disease Neuroimaging Initiative DHA Docosahexaenoic Acid DHEA Dehydroepiandrosterone DoD Department of Defense EPA Eicosapentaenoic Acid FAAH Fatty acid amide hydrolase GABA Gamma-Aminobutyric Acid GR Glucocorticoid Receptor HDAC Histone Deacetylase HPA Hypothalamic Pituitary Adrenal LSD Lysergic Acid Diethylamide MAGL Monoacylglycerol lipase MDMA 3,4-Methylenedioxymethamphetamine mtor Mammalian Target of Rapamycin NK1 Neurokinin Receptor 1 NMDAR N-methyl-D-aspartate receptor NPY Neuropeptide Y PTSD Posttraumatic Stress Disorder SSRI Selective Serotonin Reuptake Inhibitor SoSS State of the Science Summit SL Sublingual THC Tetrahydrocannabinol TNF Tumor Necrosis Factor TRH Thyrotropin Releasing Hormone VA Veterans Affairs WG Working Group

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