Macrocyclic Oxindole Peptide Epoxyketones-A Comparative Study of Macrocyclic Inhibitors of the 20S Proteasome.

Peptide macrocycles have recently gained attention as protease inhibitors due to their metabolic stability and specificity. However, the development of peptide macrocycles with improved binding potency has so far been challenging. Here we present macrocyclic peptides derived from the clinically applied proteasome inhibitor carfilzomib with an oxindole group that mimics the natural product TMC-95A. Fluorescence kinetic activity assays reveal a high potency of the oxindole group (IC50 = 0.19 µM) compared with agents lacking this motif. X-ray structures of the ligands with the ß5-subunit of the yeast 20S proteasome illustrate that the installed macrocycle forces strong hydrogen bonding of the oxindole group with ß5-Gly23NH. Thus, the binding of our designed oxindole epoxyketones is entropically and enthalpically favored in contrast to more flexible proteasome inhibitors such as carfilzomib.

Massed vs Intensive Outpatient Prolonged Exposure for Combat-Related Posttraumatic Stress Disorder: A Randomized Clinical Trial.

Importance: Improved, efficient, and acceptable treatments are needed for combat-related posttraumatic stress disorder (PTSD). Objective: To determine the efficacy of 2 compressed prolonged exposure (PE) therapy outpatient treatments for combat-related PTSD. Design, Setting, and Participants: This randomized clinical trial was conducted among military personnel and veterans at 4 sites in Texas from 2017 to 2019. Assessors were blinded to conditions. Data were analyzed from November 2020 to October 2022. Interventions: The interventions were massed-PE, which included 15 therapy sessions of 90 minutes each over 3 weeks, vs intensive outpatient program PE (IOP-PE), which included 15 full-day therapy sessions over 3 weeks with 8 treatment augmentations. The IOP-PE intervention was hypothesized to be superior to massed-PE. Main Outcomes and Measures: Coprimary outcomes included the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) (CAPS-5) and the PTSD Checklist for DSM-5 (PCL-5) administered at baseline and posttreatment follow-ups. Measures ranged from 0 to 80, with higher scores indicating greater severity. Diagnostic remission and reliable change were secondary outcomes. Results: Among 319 military personnel and veterans screened, 234 were randomized (mean [SD] age, 39.20 [7.72] years; 182 [78%] male participants), with 117 participants randomized to IOP-PE and 117 participants randomized to massed-PE. A total of 61 participants (26%) were African American, 58 participants (25%) were Hispanic, and 102 participants (44%) were White; 151 participants (65%) were married. Linear mixed-effects models found that CAPS-5 scores decreased in both treatment groups at the 1-month follow-up (IOP-PE: mean difference, -13.85 [95% CI, -16.47 to -11.23]; P < .001; massed-PE: mean difference, -14.13 [95% CI, -16.63 to -11.62]; P < .001). CAPS-5 change scores differed from 1- to 6-month follow-ups (mean difference, 4.44 [95% CI, 0.89 to 8.01]; P = .02). PTSD symptoms increased in massed-PE participants during follow-up (mean difference, 3.21 [95% CI, 0.65 to 5.77]; P = .01), whereas IOP-PE participants maintained treatment gains (mean difference, 1.23 [95% CI, -3.72 to 1.27]; P = .33). PCL-5 scores decreased in both groups from baseline to 1-month follow-up (IOP-PE: mean difference, -21.81 [95% CI, -25.57 to -18.04]; P < .001; massed-PE: mean difference, -19.96 [95% CI, -23.56 to -16.35]; P < .001) and were maintained at 6 months (IOP-PE: mean change, -0.21 [95% CI, -3.47 to 3.06]; P = .90; massed-PE: mean change, 3.02 [95% CI, -0.36 to 6.40]; P = .08). Both groups had notable PTSD diagnostic remission at posttreatment (IOP-PE: 48% [95% CI, 36% to 61%] of participants; massed-PE: 62% [95% CI, 51% to 73%] of participants), which was maintained at 6 months (IOP-PE: 53% [95% CI, 40% to 66%] of participants; massed-PE: 52% [95% CI, 38% to 66%] of participants). Most participants demonstrated reliable change on the CAPS-5 (61% [95% CI, 52% to 69%] of participants) and the PCL-5 (74% [95% CI, 66% to 81%] of participants) at the 1-month follow-up. Conclusions and Relevance: These findings suggest that PE can be adapted into compressed treatment formats that effectively reduce PTSD symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT03529435.

Cognitive Behavioral Therapy for Veterans With Comorbid Posttraumatic Headache and Posttraumatic Stress Disorder Symptoms: A Randomized Clinical Trial.

Importance: Posttraumatic headache is the most disabling complication of mild traumatic brain injury. Posttraumatic stress disorder (PTSD) symptoms are often comorbid with posttraumatic headache, and there are no established treatments for this comorbidity. Objective: To compare cognitive behavioral therapies (CBTs) for headache and PTSD with treatment per usual (TPU) for posttraumatic headache attributable to mild traumatic brain injury. Design, Setting, and Participants: This was a single-site, 3-parallel group, randomized clinical trial with outcomes at posttreatment, 3-month follow-up, and 6-month follow-up. Participants were enrolled from May 1, 2015, through May 30, 2019; data collection ended on October 10, 2019. Post-9/11 US combat veterans from multiple trauma centers were included in the study. Veterans had comorbid posttraumatic headache and PTSD symptoms. Data were analyzed from January 20, 2020, to February 2, 2022. Interventions: Patients were randomly assigned to 8 sessions of CBT for headache, 12 sessions of cognitive processing therapy for PTSD, or treatment per usual for headache. Main Outcomes and Measures: Co-primary outcomes were headache-related disability on the 6-Item Headache Impact Test (HIT-6) and PTSD symptom severity on the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (PCL-5) assessed from treatment completion to 6 months posttreatment. Results: A total of 193 post-9/11 combat veterans (mean [SD] age, 39.7 [8.4] years; 167 male veterans [87%]) were included in the study and reported severe baseline headache-related disability (mean [SD] HIT-6 score, 65.8 [5.6] points) and severe PTSD symptoms (mean [SD] PCL-5 score, 48.4 [14.2] points). For the HIT-6, compared with usual care, patients receiving CBT for headache reported -3.4 (95% CI, -5.4 to -1.4; P < .01) points lower, and patients receiving cognitive processing therapy reported -1.4 (95% CI, -3.7 to 0.8; P = .21) points lower across aggregated posttreatment measurements. For the PCL-5, compared with usual care, patients receiving CBT for headache reported -6.5 (95% CI, -12.7 to -0.3; P = .04) points lower, and patients receiving cognitive processing therapy reported -8.9 (95% CI, -15.9 to -1.9; P = .01) points lower across aggregated posttreatment measurements. Adverse events were minimal and similar across treatment groups. Conclusions and Relevance: This randomized clinical trial demonstrated that CBT for headache was efficacious for disability associated with posttraumatic headache in veterans and provided clinically significant improvement in PTSD symptom severity. Cognitive processing therapy was efficacious for PTSD symptoms but not for headache disability. Trial Registration: ClinicalTrials.gov Identifier: NCT02419131.

Intensive prolonged exposure therapy for combat-related posttraumatic stress disorder: Design and methodology of a randomized clinical trial.

Combat-related posttraumatic stress disorder (PTSD) is the most common psychological health condition in military service members and veterans who have deployed to the combat theater since September 11, 2001. One of the highest research priorities for the Department of Defense and the Department of Veterans Affairs is to develop and evaluate the most efficient and efficacious treatments possible for combat-related PTSD. However, the treatment of combat-related PTSD in military service members and veterans has been significantly more challenging than the treatment of PTSD in civilians. Randomized clinical trials have demonstrated large posttreatment effect sizes for PTSD in civilian populations. However, recent randomized clinical trials of service members and veterans have achieved lesser reductions in PTSD symptoms. These results suggest that combat-related PTSD is unique. Innovative approaches are needed to augment established evidence-based treatments with targeted interventions that address the distinctive elements of combat-related traumas. This paper describes the design, methodology, and protocol of a randomized clinical trial to compare two intensive prolonged exposure therapy treatments for combat-related PTSD in active duty military service members and veterans and that can be administered in an acceptable, efficient manner in this population. Both interventions include intensive daily treatment over a 3-week period and a number of treatment enhancements hypothesized to result in greater reductions in combat-related PTSD symptoms. The study is designed to advance the delivery of care for combat-related PTSD by developing and evaluating the most potent treatments possible to reduce PTSD symptomatology and improve psychological, social, and occupational functioning.