The fibrinolytic system: A new target for treatment of depression with psychedelics

This hypothesis-building article (2017) proposes that psychedelics such as psilocybin and ketamine exert antidepressant effects by restoring balance to the fibrinolytic system, a network of enzymes in the bloodstream that prevent blood clots from growing and reopen vessels closed by thrombosis. The authors postulate that psilocybin decreases coagulation promoting factors, neuroinflammation, and fibrin deposition in the brain, and restores the 5-HT2a receptor to pre-stress levels.

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.”

Authors: Richard D. Idell, G. Florova, A. A. Komissarov, S. Shetty, R. B. S. Girard & Steven Idell

Summary

Current understanding of the neurobiology of depression includes chronic stress, inflammation and disrupted synaptic plasticity. We propose that an imbalance between tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) and neuroserpin leads to depression by reducing neurogenesis, neuroinflammation, and fibrin deposition.

Introduction

Major depression is among the most common mental health disorders in the United States. There are several novel treatment strategies that have been identified to improve outcomes. The role of cytokine-mediated inflammation, neurogenesis, and the glutamate in the pathogenesis of depression has been extensively studied, but the role of the fibrinolytic system has been comparatively ignored, even though depression is considered to be an independent risk factor for coronary artery disease.

Here we review prior hypotheses on the role of impaired fibrinolysis, aberrant extravascular fibrin deposition and tissue remodeling in the development of depression, and provide new supporting evidence that these mechanisms may occur within the brain parenchyma.

Plasminogen activators and their inhibitors, PAI-1 and neuroserpin, are involved in the pathogenesis of depression. Psilocybin, a 5-ht2A serotonin receptor agonist, may induce positive psychological experiences of high personal significance leading to enduring beneficial changes in mood, thinking, and behavior.

We propose that psilocybin, a serotonergic classic psychedelic, will normalize changes that occur as a result of chronic stress and disruption of the fibrinolytic system in the brain, leading to increased mBDNF production, normalized synaptic plasticity, and resolution of depression.

The linkage between peripheral or cerebral inflammation and suppression of the fibrinolysis in the brain

Evidence from human studies suggests that increased peripheral cytokine levels are associated with depression and suicidality. Increased levels of IL-6 and TNF-a may be biomarkers of treatment responses.

Proinflammatory cytokines may access the central nervous system through several mechanisms, including the vagus nerve, the blood brain barrier, or the circumventricular organs. This may contribute to neuroinflammation, which may suppress normal hippocampal neurogenesis.

Disruption of hippocampal neurogenesis may occur as a result of chronic peripheral inflammation due to medical illness or chronic stress, and may be mediated by suppression of the fibrinolytic system.

Synaptic plasticity, depression, and the fibrinolytic system in the brain

The interplay between inflammation, coagulation, and fibrinolysis may be a key factor in the pathogenesis of depression. Several key elements of the fibrinolytic system are altered during stress, including uPA, which may promote synaptic plasticity in the brain.

Fibrin has been demonstrated to activate microglia, increase neuroinflammation, and potentially depression. Moreover, PAI-1, which is upregulated in alveolar epithelial cells during lung inflammation, may be a biomarker of depression.

The fibrinolytic system plays a key role in the pathogenesis of lung disease, including chronic obstructive pulmonary disease (COPD), acute and chronic lung injuries, and depression.

Stress-induced inflammation may occur in the brain as a result of depression. Fibrinogen, tPA, uPA, uPAR, PAI-1 and neuroserpin may play a role in regulating stress, neural inflammation and mood.

tPA has been shown to influence neural cell functionality and behavior through several mechanisms, including degradation of the extracellular matrix and activation of the NMDA receptor. tPA has also been shown to be involved in memory, learning, and stress dependent behavioral responses.

The literature provides a link between the fibrinolytic system in the brain, BDNF and depression. Exercise, enriched environments, and electro convulsive therapy have been shown to increase mBDNF and tPA levels, suggesting a novel tPA-mediated regulatory mechanism of action.

PAI-1 is minimally expressed in the normal brain, and neuroserpin is the primary inhibitor of tPA. Neuroserpin is expressed in neurons throughout the developing and adult nervous system.

The literature suggests that tPA is a gliotransmitter mediating cross talk between neurons and astrocytes. Excess hypothalamic-pituitary-adrenocortical (HPA) activation leads to activation of microglia and impaired astrocyte reuptake of glutamate, leading to neuro-inflammation and subsequent depression.

Antidepressants, ketamine and psilocybin: established and hypothetical effects on the brain fibrinolytic system and depression

SSRIs, such as fluoxetine, sertraline, and citalopram, inhibit the serotonin transporter, which leaves more serotonin available in the synaptic cleft to increase serotonergic neurotransmission. However, SSRIs exert various side effects that may lead to discontinuation.

In major depressive disorder, neural circuits involved in emotional processing and reward seeking are dysfunctional. Psilocybin and mindfulness meditation have been shown to decrease activity in the default mode network, which may be therapeutic in depression.

Sertraline, an SSRI, has been shown to increase BDNF levels in the prefrontal cortex and hippocampus in rats exposed to chronic unpredictable mild stress.

Additional clinical evidence supports the hypothesis that the activity of the fibrinolytic system is decreased in depression, and that this derangement may be alleviated by psilocybin.

Blockade of serotonin uptake in platelets by SSRis could increase mBDNF levels and promote hippocampal neurogenesis, thereby decreasing depressive symptoms associated with chronic stress.

Ketamine, an NMDA receptor antagonist and fast acting antidepressant, has been shown to modulate the inflammation mediated kynurenine pathway. It is possible that ketamine indirectly affects PAI-1 expression within the brain and may be involved in the pathogenesis of depression.

Psilocybin binds with high affinity to the 5-ht2a subtype of the serotonin receptor and induces psychedelic effects including perceptual changes, labile moods, and cognitive changes. The mystical experience is defined by abstract traits such as transcendence of time/space, unitary being, sense of sacredness, and ineffability.

Recent studies suggest that 5-ht2a receptor modulation may have therapeutic potential in treating depression. This may be because 5-ht2a receptors are downregulated in response to antidepressants and atypical antipsychotic drugs.

C57BL/6J mice with varying degrees of psychological resiliency when exposed to chronic stress showed enhanced expression of 5-ht2a and Cox-1 in the pre-frontal area, and psilocybin could restore 5-ht2a to pre-stress levels with concomitant and potentially critical salutary downregulation of PAI-1 or perhaps neuroserpin.

R-DOI, a potent psychedelic and 5-ht2a agonist, has been demonstrated to have potent anti-inflammatory effects. It may do this via blockade of TNF-a signaling, which could lead to reduction in PAI-1 levels and alleviation of depressive symptoms.

Psilocybin has been shown to normalize limbic hyperactivity in individuals with depressed mood, attenuate amygdala hyperactivity and increase positive affect, and may be useful in reducing predisposing factors to depression. It has also been shown to be well-tolerated in humans in a controlled setting with proper supervision, screening and preparation.

Ketamine and psilocybin may be involved in the regulation of the fibrinolytic system in the brain, and psilocybin may be able to help with weight loss and depression simultaneously by downregulating the 5-ht2a receptor and PAI-1.

Psilocybin can be used to treat depression by reducing neuroinflammation, restoring the fibrinolytic system to baseline, and by restoring tPA activity. This can be tested in wild type mice with depressive behavior.

In vitro studies using astrocytes and clinical studies using mindfulness mediation have shown that psilocybin can alleviate pro-inflammatory, anti-fibrinolytic changes induced in glial cells.

The preponderance of literature suggests that the fibrinolytic system is dysregulated in depression, and that psychedelics may regulate the fibrinolytic system in a salutary manner. Psychedelics may reduce neuroinflammation engendered by chronic stress, and restore serotonergic tone to euthymic mood.

Disclosures

Dr. S. Idell, the University of Texas Horizon Fund, The University of Texas Health Science Center at Tyler and Dr. Shetty have equity positions in Lung Therapeutics, Inc., and all authors have declared conflicts of interest.

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