Randomized, Placebo-Controlled Trial of the Angiotensin Receptor Antagonist Losartan for Posttraumatic Stress Disorder

Stein, Murray B.; Jain, Sonia; Simon, Naomi M.; West, James C.; Marvar, Paul J.; Bui, Éric; He, Feng; Benedek, David M.; Cassano, Paolo; Griffith, James L.; Howlett, Jonathan G.; Malgaroli, Matteo; Melaragno, Andrew; Seligowski, Antonia V.; Shu, I-Wei; Song, Suzan J.; Szuhany, Kristin L.; Taylor, Charles T.; Ressler, Kerry J.; Beg, Nuzhat; Sun, Xiaoying; Shaikh, Farah; Spangler, Patricia T.; Dempsey, Catherine L.; Eakley, Rachel; Kaufmann, Milissa L.; Murphy, Beth L.; Merker, Julia

doi:10.1016/j.biopsych.2021.05.012

Cited by 26 publications

(7 citation statements)

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“…The central renin angiotensin II system - in particular AT1R-mediated signaling - has received considerable interest as regulator of mental processes and highly promising treatment target for mental and neurological disorders. 2,25,44 However, the lack of an overarching biologically informed framework currently limits mechanistic and translational progress. Here we combined transcriptomic mapping with meta-analytic functional decoding and a randomized placebo controlled pharmacological resting state fMRI strategy in two independent samples to characterize the AT1R signaling pathways and their functional engagement and interaction with other transmitter systems comprehensively and systematically.…”

Section: Discussionmentioning

confidence: 99%

“…10,24 While these results underscore a highly promising therapeutic potential of the AT1R, a recent multi-center randomized controlled clinical trial failed to determine treatment effects of an AT1R antagonist on PTSD symptomatology. 25 This underscores the need for an overarching and biologically-informed overarching framework for the regulatory role of the central AT1R in human cognition and emotion to facilitate generation and testing of precise translational hypotheses. Some of the complex neurofunctional effects of the AT1R may emerge in interaction with other neural signaling systems, with recent evidence suggesting that interactions with the corticotrophin releasing hormone, dopaminergic, opioid, and vasopressin systems mediating AT1R regulation in some emotional and cognitive domains.…”

Section: Introductionmentioning

confidence: 99%

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The central renin angiotensin II system – a genetic pathway, functional decoding and selective target engagement characterization in humans

Chen

Zhou

et al. 2023

Preprint

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The brain renin angiotensin II system plays a pivotal role in cognition and neuropathology via the central angiotensin II type 1 receptor (AT1R), yet the lack of a biologically informed framework currently impedes translational and therapeutic progress. We combined imaging transcriptomic and meta-analyses with pharmaco-resting state fMRI employing a selective AT1R antagonist in a discovery-replication design (n=132 individuals). The AT1R was densely expressed in subcortical systems engaged in reward, motivation, stress, and memory. Pharmacological target engagement suppressed spontaneous neural activity in subcortical systems with high AT1R expression and enhanced functional network integration in cortico-basal ganglia-thalamo-cortical circuits. AT1R-regulation on functional network integration was further mediated by dopaminergic, opioid and corticotrophin-releasing hormone pathways. Overall, this work provides the first comprehensive characterization of the architecture and function of the brain renin angiotensin II system indicating that the central AT1R mediates human cognition and behavior via regulating specific circuits and interacting with classical transmitter systems.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The central renin angiotensin II system – a genetic pathway, functional decoding and selective target engagement characterization in humans

Chen

Zhou

et al. 2023

Preprint

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“…Medications targeting the renin-angiotensin system (e.g., ACE-inhibitors, beta-blockers) have demonstrated efficacy in rodent models, but research in humans with PTSD has been mixed. 50, 51 A next step in this line of work is to determine if existing cognitive-behavioral and pharmacological treatments actually reduce CVD risk in PTSD, and to determine if they are more efficacious for individuals with high genetic risk for both PTSD and CVD. An additional and more immediate next step is to include PTSD as an indicator of CVD risk in routine care (e.g., during hypertension screening).…”

Section: Discussionmentioning

confidence: 99%

Leveraging large-scale genetics of PTSD and cardiovascular disease demonstrates robust shared risk and improves risk prediction accuracy

Seligowski

Misganaw

Duffy

et al. 2022

Preprint

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Individuals with posttraumatic stress disorder (PTSD) are significantly more likely to be diagnosed with cardiovascular disease (CVD; e.g., myocardial infarction, stroke). The evidence for this link is so compelling that the National Institutes of Health convened a working group to determine gaps in the current literature, including the need for large-scale genomic studies to identify shared genetic risk. The current study used a large healthcare biobank dataset of N = 36,412 individuals, combined with GWAS summary statistics from publicly available, large-scale PTSD and CVD studies. We found significant genetic correlations between PTSD and CVD (rG=0.24, S.E.= 0.05982, p=5.09E-05), and Mendelian randomization analyses indicated a potential causal link from PTSD to hypertension (β=0.20, S.E.= 0.04, p=5.97e-6), but not the reverse. PTSD summary statistics significantly predicted PTSD diagnostic status (R2=0.27%, p=5.31E-08), and this was significantly improved by incorporating summary statistics from CVD and major depressive disorder (R2=1.30%, p=2.16E-32). Further, pathway enrichment analyses indicated that genetic variants involved in shared PTSD-CVD risk included those involved in postsynaptic structure (p=0.00001), synapse organization (p=0.0001), and interleukin-7 (IL-7) mediated signaling pathways (p=0.0002). While additional research is needed to determine the clinical utility of these findings, these data further support the biological shared risk for stress-related disorders of mental health and cardiovascular illness.

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“…Specifically, use of ACE-Is/ARBs (but not other antihypertensive medications) has been associated with lower PTSD symptoms [ 163 , 164 ], with some evidence of moderation by genetic variation or sex [ 164 , 165 ]. However, there was no evidence for clinical benefit of ARB use for PTSD in a 10-week randomized, placebo-controlled trial [ 166 ].…”

Section: Biological Mechanisms Linking Trauma With Cvd Riskmentioning

confidence: 99%

Psychological and biological mechanisms linking trauma with cardiovascular disease risk

et al. 2023

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Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and experiences of psychological trauma have been associated with subsequent CVD onset. Identifying key pathways connecting trauma with CVD has the potential to inform more targeted screening and intervention efforts to offset elevated cardiovascular risk. In this narrative review, we summarize the evidence for key psychological and biological mechanisms linking experiences of trauma with CVD risk. Additionally, we describe various methodologies for measuring these mechanisms in an effort to inform future research related to potential pathways. With regard to mechanisms involving posttraumatic psychopathology, the vast majority of research on psychological distress after trauma and CVD has focused on posttraumatic stress disorder (PTSD), even though posttraumatic psychopathology can manifest in other ways as well. Substantial evidence suggests that PTSD predicts the onset of a range of cardiovascular outcomes in trauma-exposed men and women, yet more research is needed to better understand posttraumatic psychopathology more comprehensively and how it may relate to CVD. Further, dysregulation of numerous biological systems may occur after trauma and in the presence of posttraumatic psychopathology; these processes of immune system dysregulation and elevated inflammation, oxidative stress, mitochondrial dysfunction, renin-angiotensin system dysregulation, and accelerated biological aging may all contribute to subsequent cardiovascular risk, although more research on these pathways in the context of traumatic stress is needed. Given that many of these mechanisms are closely intertwined, future research using a systems biology approach may prove fruitful for elucidating how processes unfold to contribute to CVD after trauma.

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Randomized, Placebo-Controlled Trial of the Angiotensin Receptor Antagonist Losartan for Posttraumatic Stress Disorder

Cited by 26 publications

References 50 publications

The central renin angiotensin II system – a genetic pathway, functional decoding and selective target engagement characterization in humans

The central renin angiotensin II system – a genetic pathway, functional decoding and selective target engagement characterization in humans

Leveraging large-scale genetics of PTSD and cardiovascular disease demonstrates robust shared risk and improves risk prediction accuracy

Psychological and biological mechanisms linking trauma with cardiovascular disease risk

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