The fibrinolytic system: A new target for treatment of depression with psychedelics.
R D Idell, G Florova, A A Komissarov, S Shetty, R B S Girard, S Idell
Medical Hypotheses March 2017 DOI: 10.1016/j.mehy.2017.01.013 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Interventions | Psilocybin Ketamine Antidepressants |
| Topics | Depression |
| Key points | Proposes that depression arises partly from an imbalance in the brain's fibrinolytic system, in which inflammation-driven inhibitors PAI-1 and neuroserpin suppress tPA and uPA, reducing proBDNF cleavage, neurogenesis, and synaptic plasticity while promoting fibrin deposition and neuroinflammation. Argues that antidepressants, ketamine, and psilocybin may relieve depressive symptoms by restoring fibrinolytic balance through anti-inflammatory and pro-fibrinolytic effects, including TNF-alpha blockade and decreased PAI-1 activity. |
Abstract
Current understanding of the neurobiology of depression has grown over the past few years beyond the traditional monoamine theory of depression to include chronic stress, inflammation and disrupted synaptic plasticity. Tissue plasminogen activator (tPA) is a key factor that not only promotes fibrinolysis via the activation of plasminogen, but also contributes to regulation of synaptic plasticity and neurogenesis through plasmin-mediated activation of a probrain derived neurotrophic factor (BDNF) to mature BDNF. ProBDNF activation could potentially be supressed by competition with fibrin for plasmin and tPA. High affinity binding of plasmin and tPA to fibrin could result in a decrease of proBDNF activation during brain inflammation leading to fibrosis further perpetuating depressed mood. There is a paucity of data explaining the possible role of the fibrinolytic system or aberrant extravascular fibrin deposition in depression. We propose that within the brain, an imbalance between tPA and urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) and neuroserpin favors the inhibitors, resulting in changes in neurogenesis, synaptic plasticity, and neuroinflammation that result in depressive behavior. Our hypothesis is that peripheral inflammation mediates neuroinflammation, and that cytokines such as tumor necrosis factor alpha (TNF-α) can inhibit the fibrinolytic system by up- regulating PAI-1 and potentially neuroserpin. We propose that the decrement of the activity of tPA and uPA occurs with downregulation of uPA in part involving the binding and clearance from the surface of neural cells of uPA/PAI-1 complexes by the urokinase receptor uPAR. We infer that current antidepressants and ketamine mitigate depressive symptoms by restoring the balance of the fibrinolytic system with increased activity of tPA and uPA with down-regulated intracerebral expression of their inhibitors. We lastly hypothesize that psychedelic 5-ht2a receptor agonists, such as psilocybin, can improve mood through anti- inflammatory and pro-fibrinolytic effects that include blockade of TNF-α activity leading to decreased PAI-1 activity and increased clearance. The process involves disinhibition of tPA and uPA with subsequent increased cleavage of proBDNF which promotes neurogenesis, decreased neuroinflammation, decreased fibrin deposition, normalized glial-neuronal cross-talk, and optimally functioning neuro-circuits involved in mood. We propose that psilocybin can alleviate deleterious changes in the brain caused by chronic stress leading to restoration of homeostatic brain fibrinolytic capacity leading to euthymia.
Comparable studies
Other theoretical and historical papers on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Mindfulness-based cognitive therapy for depression | 2006 | Theoretical or philosophical paper | |
| Psilocybin-assisted therapy of major depressive disorder using Acceptance and Commitment Therapy as a therapeutic frame | 2020 | Theoretical or philosophical paper | |
| The Yale Manual for Psilocybin-Assisted Therapy of Depression (using Acceptance and Commitment Therapy as a Therapeutic Frame) | 2020 | Theoretical or philosophical paper | |
| Neuroinflammation and neuroprogression in depression: Effects of alternative drug treatments | 2022 | Theoretical or philosophical paper | |
| Improving cognitive functioning in major depressive disorder with psychedelics: A dimensional approach | 2021 | Theoretical or philosophical paper |
Citations in the library
Cited by 13
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- A single inhalation of vapor from dried toad secretion containing 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms. Psychopharmacology April 13, 2019
- Rapid-acting antidepressants. Advances in pharmacology (San Diego, Calif.) 2019
- Rapid-Acting Antidepressants Current Pharmaceutical Design October 19, 2018
- What is the clinical evidence on psilocybin for the treatment of psychiatric disorders? A systematic review Porto Biomedical Journal 2021
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Cites 14
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer Archives of General Psychiatry September 7, 2010
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology December 1, 2011
- Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction Journal of Psychopharmacology September 11, 2014
and 9 more in the library