Rapamycin as a Means of Interference With Reconsolidation of Posttraumatic Stress Disorder-related Traumatic Memory

Rapamycin as a Means of Interference With Reconsolidation of Posttraumatic Stress Disorder-related Traumatic Memory

mTOR Kinase as a Therapeutic Target in Reconsolidation of Posttraumatic Stress Disorder-related Traumatic Memory

The purpose of the proposed study is to determine if pairing reactivation of a traumatic memory with a single administration of Rapamycin (e.g., Sirolimus) in men with combat-related Posttraumatic Stress Disorder leads to a reduction of the emotional strength of that particular traumatic memory. The following hypotheses will be tested: Traumatic memory reactivation paired with a single dose of Rapamycin will decrease objective measures of stress and self-report of stress during replay of the traumatic memory, relative to, subjects receiving placebo. Pairing administration of Rapamycin with traumatic memory reactivation will decrease symptoms of Posttraumatic Stress Disorder one month and three months later, relative to patients receiving placebo.

Post-traumatic stress disorder (PTSD) is characterized by intrusive memories in the form of unwanted images, nightmares, and flashbacks as the result of being exposed to a traumatic event . Current research efforts have begun to explore the underlying neurochemical changes associated with PTSD. Recently, these efforts have focused on the prevention of PTSD in persons exposed to trauma. For example, preliminary evidence suggests that interference with consolidation of trauma-related memories using the beta-antagonist, propranolol, may prevent PTSD in humans with recent traumas. However, given that as much as 90% of the US population is exposed to at least one traumatic event during their lifetimes, the utility of this treatment is limited by the logistical problems of treating everyone at risk. To date, there have been very few systematic studies on humans that focus on changing the underlying traumatic memory once PTSD has been established. The trauma experience is initially stored in short-term memory, then consolidated into long-term memory. However, the long-term stability conferred by the consolidation process undergoes a period of labiality as follows. Each time a consolidated memory is activated, the memory trace becomes newly labile and must be consolidated again to remain in long-term memory5. This process is called reconsolidation. Reconsolidation therefore offers a biologic window during which long-term memories can be disrupted. Preclinical studies have begun to unravel the biological changes that underlie these processes. Both pharmacological agents, including glucocorticoids, and protein synthesis inhibitors can interfere with memory consolidation and reconsolidation. In preclinical studies, the global protein synthesis inhibitor anisomycin can block reconsolidation, leading to a reduction in strength of traumatic memories. Unfortunately, the toxicity of anisomycin is prohibitive for therapeutic use. Thus, rather than using a global protein synthesis inhibitor, a more effective and selective means of reducing consolidation of an established traumatic memory is to target only a subset of protein translation important for synaptic plasticity. The protein kinase mTOR (mammalian target of rapamycin) is just such a regulator of a subset of protein synthesis critical for synaptic plasticity.

Sirolimus is an FDA approved immunosuppressant drug used to prevent rejection in organ transplantation, and is especially useful in kidney transplants. It is non-toxic to kidneys, unlike other immunosuppressants. In this study, the medication will be administered once to see if it interferes with emotional memory reconsolidation. This is based on the fact that it inhibits the mammalian target of Rapamycin (mTOR) through directly binding the mTOR Complex1 (mTORC1). mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis and transcription. a single dosage of 15mg will be administered during this study.

Clinician administered interview which assesses the symptoms of Posttraumatic Stress disorder at baseline, and then again 1 month posttreatment. The CAPS is a 25 item semi-structured interview that assesses the 17 DSM-IV PTSD criteria as well as social and occupational impairment. For each item the participant can respond with a rating of 0-8 (with 0 indicating no symptom severity and frequency and 8 indicating extreme symptom severity and frequency). The range of total scores on a CAPS is from 0-136, with a greater score indicating greater PTSD symptom severity. The total score is computed by summing the aforementioned 17 items. Additionally, the CAPS assesses for a positive PTSD diagnosis by assessing for the three DSM-IV criteria of B, C, and D. In order to meet a positive screen for each criteria, a person must screen positive for symptoms by reporting a score of 3 or more on the specific symptom criterion.

The CAPS is administered to assess the frequency and intensity of PTSD symptoms at baseline, and then again 3 months posttreatment. The CAPS is a 25 item semi-structured interview that assesses the 17 DSM-IV PTSD criteria as well as social and occupational impairment. For each item the participant can respond with a rating of 0-8 (with 0 indicating no symptom severity and frequency and 8 indicating extreme symptom severity and frequency). The range of total scores on a CAPS is from 0-136, with a greater score indicating greater PTSD symptom severity. The total score is computed by summing the aforementioned 17 items. Additionally, the CAPS assesses for a positive PTSD diagnosis by assessing for the three DSM-IV criteria of B, C, and D. In order to meet a positive screen for each criteria, a person must screen positive for symptoms by reporting a score of 3 or more on the specific symptom criterion.

Self-report instrument which assesses the intensity of Posttraumatic Stress Disorder symptoms. The PCL measures the 17 DSM-IV PTSD criteria in 17 items. For each item the participant can respond with a rating of 1-5 (with 1 indicating not at all bothered 5 indicating extremely bothered by the symptom) The range of total scores on the PCL is from 17-85, with a greater score indicating greater PTSD symptom severity. The total score is computed by summing the aforementioned 17 items.

Self-report instrument which assesses the intensity of Posttraumatic Stress Disorder symptoms. The PCL measures the 17 DSM-IV PTSD criteria in 17 items. For each item the participant can respond with a rating of 1-5 (with 1 indicating not at all bothered 5 indicating extremely bothered by the symptom) The range of total scores on the PCL is from 17-85, with a greater score indicating greater PTSD symptom severity. The total score is computed by summing the aforementioned 17 items.

The QIDS is a 16-item self-report measure that assesses how much a participant endorses each of the DSM-IV-TR symptoms of depression, with each item scored from 0 (no endorsement of symptom) to 3 (endorsement of severe symptomatology). Scores on the QIDS range from 0-27, with higher scores indicating higher depressive symptom severity.

The QIDS is a 16-item self-report measure that assesses how much a participant endorses each of the DSM-IV-TR symptoms of depression, with each item scored from 0 (no endorsement of symptom) to 3 (endorsement of severe symptomatology). Scores on the QIDS range from 0-27, with higher scores indicating higher depressive symptom severity.

Inclusion Criteria: Male Veterans Diagnosis of Posttraumatic Stress Disorder related to combat Exclusion Criteria: Hypersensitivity to Rapamycin Organic brain damage (including unresolved Traumatic Brain Injury sequela) Substance dependence in the last three months On any immunosuppressant therapy Prominent suicidal or homicidal features Medical conditions: systemic infections, congestive heart failure, renal failure, hepatic failure

Blundell J, Kouser M, Powell CM. Systemic inhibition of mammalian target of rapamycin inhibits fear memory reconsolidation. Neurobiol Learn Mem. 2008 Jul;90(1):28-35. doi: 10.1016/j.nlm.2007.12.004. Epub 2008 Mar 7.

Suris A, Smith J, Powell C, North CS. Interfering with the reconsolidation of traumatic memory: sirolimus as a novel agent for treating veterans with posttraumatic stress disorder. Ann Clin Psychiatry. 2013 Feb;25(1):33-40.