Treatment Research Investigating Depression Effects on Neuroimmune Targets (TRIDENT)

Project Summary
Since the early days of the epidemic, psychoneuroimmunology research established that there is a bi-
directional relationship between depression and HIV pathogenesis. Among people with HIV (PWH), substantial
damage to the gastrointestinal tract occurs during acute HIV infection, which is partially responsible for
dysregulation of the gut microbiome (i.e., dysbiosis) and translocation of inflammatory microbial products into
the periphery. Even among those receiving effective anti-retroviral therapy (ART), these pathophysiologic
alterations in the gut drive persistent immune dysregulation that partially explains amplified risk for depression
and other neuropsychiatric disorders in PWH. An important gap is that no prior clinical research in PWH
receiving effective ART has examined the functional connections between the microbiome, gastrointestinal
tract, immune system, and the brain – the microbiome-gut-brain (MGB) axis. Treatment Research Investigating
Depression Effects on Neuroimmune Targets (TRIDENT) is a randomized controlled trial that leverages an
evidence-based Cognitive-Behavioral Therapy for Adherence and Depression (CBT-AD) treatment as an
experimental probe to advance our understanding of how decreasing depression alters MGB axis pathways in
PWH. TRIDENT will enroll 120 depressed PWH taking an integrase strand transfer inhibitor (INSTI)-based
ART regimen who have an undetectable viral load. TRIDENT will have a brief run-in period (i.e., waiting period
prior to randomization) where potentially eligible participants will be asked to complete a baseline psychosocial
assessment, provide biospecimens, and attend a separate baseline fMRI assessment. A total of 120
participants who complete the run-in period will be randomized to receive either: 1) CBT-AD (n = 60); or
2) a wait-list control (WLC) condition (n = 60). Immediately following randomization, CBT-AD participants will
receive up to 12 individual sessions over 4 months. WLC participants will have the opportunity to receive the
CBT-AD treatment after a 6-month delay. During the intent-to-treat period, follow-up assessments at 2 months
and 4 months (i.e., during and immediately following the delivery of CBT-AD) will characterize changes in the
microbiome, soluble immune markers relevant to HIV pathogenesis, and leukocyte signaling to measure the
conserved transcriptional response to adversity (CTRA). These will be examined as plausible mediators of
CBT-AD related improvements in the primary outcome – resting state activation and connectivity of the
negative valence system at 6 months (assessed via fMRI). Six months after randomization, WLC participants
will crossover and have the opportunity to receive CBT-AD, and all participants (both CBT-AD and WLC) will
complete a final follow-up assessment at 10 months. TRIDENT will have an exceptional impact by providing an
experimental model to advance our understanding of how decreasing depression changes the MGB axis in
PWH. TRIDENT will include multi-level, high dimensional data on the MGB axis to catalyze a new generation
of pharmacologic and behavioral treatments for depression and its neurobehavioral substrates in PWH.

Grant Number: 5R01MH128868-06
NIH Institute/Center: NIH
Principal Investigator: Adam Carrico