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

Major depression imposes a large burden of disability and a substantial fraction of patients do not remit with standard antidepressant treatment. Idell and colleagues place this clinical problem in the context of evolving biological models that extend beyond the monoamine hypothesis to include chronic stress, cytokine-mediated inflammation, glutamate signalling and disrupted synaptic plasticity and neurogenesis. They note that the fibrinolytic system—principally tissue plasminogen activator (tPA), urokinase (uPA), their receptor uPAR, and the inhibitors PAI-1 and neuroserpin—has been little studied in depression despite its known regulation by inflammation in other organs and its mechanistic links to activation of brain-derived neurotrophic factor (BDNF) via plasmin-mediated cleavage of proBDNF to mature BDNF (mBDNF). This paper sets out to synthesise prior literature and experimental observations into a mechanistic hypothesis: peripheral inflammation (notably TNF-α) upregulates fibrinolytic inhibitors (PAI-1 and possibly neuroserpin) which suppress tPA/uPA activity, favour transient extravascular fibrin deposition and reduce plasmin-mediated conversion of proBDNF to mBDNF. The downstream consequences would include impaired hippocampal neurogenesis, altered synaptic plasticity and circuit dysfunction that manifest as depressive behaviour. Idell and colleagues further propose that established and emerging antidepressant interventions—including selective serotonin reuptake inhibitors (SSRIs), ketamine, electroconvulsive therapy (ECT) and serotonergic psychedelics such as psilocybin—may relieve depression in part by anti-inflammatory and profibrinolytic actions that restore tPA/uPA activity and BDNF processing.

The extracted text presents a narrative review and hypothesis paper rather than an original clinical trial or systematic meta-analysis with prespecified methods. Idell and colleagues integrate findings from human biomarker studies, animal experiments, genetic and transgenic mouse models, in vitro observations and selected reports from the authors' own laboratory to build a mechanistic framework linking inflammation, the fibrinolytic system and BDNF processing to depression. No systematic search strategy, study selection criteria, or quantitative synthesis methods are reported in the extracted text. The approach is conceptual: the investigators summarise prior empirical results relevant to fibrinolysis, inflammation and neuroplasticity, highlight animal and human findings that support each link in their proposed chain of causation, and propose experimental and clinical tests (for example, knockout or transgenic mouse studies, in vitro astrocyte experiments, and biomarker assessments during psychological interventions) to evaluate the hypothesis.

Rather than reporting new experimental data, the paper collates evidence supporting each step of the proposed pathway linking inflammation, impaired fibrinolysis and altered BDNF processing to depressive phenotypes. Key empirical observations cited in the text include: elevated peripheral proinflammatory cytokines (interleukin-6 and TNF-α) in depressed patients; increased soluble urokinase receptor (suPAR) as a biomarker associated with depression and suicidality; and associations between inflammatory medical comorbidities (for example inflammatory bowel disease, diabetes, obesity, chronic lung disease) and depressive symptoms. Mechanistic links described include the role of tPA and uPA in converting plasminogen to plasmin, which cleaves proBDNF to mBDNF; proBDNF and mBDNF have opposing effects on neuronal structure and plasticity (proBDNF promotes dendritic retraction and apoptosis while mBDNF supports dendritic growth, survival and long-term potentiation). The authors highlight evidence that enriched environments and exercise increase tPA and mBDNF, and that electroconvulsive therapy increases tPA and mBDNF in animal models. Sertraline has been shown in rats to increase hippocampal tPA and BDNF after chronic stress. Genetic and knockout models also support a role for fibrinolytic components in behaviour: uPAR-deficient mice show increased anxiety, reduced social behaviour and cognitive impairment; uPA-deficient animals demonstrate reduced exploratory activity, exaggerated fear responses and increased neuroinflammation. The review emphasises that PAI-1 and neuroserpin are upregulated by inflammation and inhibit tPA/uPA, potentially promoting transient extravascular fibrin deposition in the brain parenchyma. Fibrin itself binds tPA and plasmin with high affinity, can activate microglia and perpetuate neuroinflammation, and therefore may compete with proBDNF for plasmin-mediated processing, reducing mBDNF availability. The authors note parallels between inflammatory epithelial remodelling in the lung—where PAI-1 upregulation and suppressed uPA accompany fibrosis—and hypothetical remodelling in the brain that could follow chronic stress or inflammation. Regarding therapeutics, Idell and colleagues synthesise data suggesting SSRIs, ketamine, ECT and psilocybin may share anti-inflammatory and profibrinolytic properties. SSRIs may decrease platelet serotonin uptake and thereby reduce PAI-1 release, potentially increasing plasmin activity and mBDNF production; however, effects of SSRIs on systemic or central PAI-1 remain unclear. The effect of ketamine on PAI-1 expression in brain has not been evaluated, though ketamine modulates inflammatory pathways (for example the kynurenine pathway) and treatment response may be predicted by IL-6. For serotonergic psychedelics, the authors cite animal studies and limited human data: certain 5-HT2A agonists (R-DOI) show anti-inflammatory effects and can block TNF-α signalling in mouse models; LSD reduced cortical 5-HT2A expression by 33–66% in rabbits; low-dose psilocybin reduced conditioned fear and showed trends towards increased hippocampal neurogenesis in mice; and small clinical trials and survey analyses have associated psilocybin with reduced anxiety in advanced cancer, decreased substance use, reduced sensitivity to social rejection and preliminary efficacy in treatment-resistant depression. They emphasise, however, that direct evidence demonstrating modulation of fibrinolytic components by psilocybin or ketamine in the brain is lacking and requires empirical testing. Overall, the assembled results generate a coherent model in which inflammation-driven upregulation of PAI-1/neuroserpin and reduced tPA/uPA activity lead to decreased plasmin-mediated conversion of proBDNF to mBDNF, impaired neurogenesis and synaptic plasticity, and potentially transient fibrin deposition that sustains neuroinflammation and depressive circuitry dysfunction. The authors propose that existing and novel treatments may exert beneficial effects in part by reversing these changes.

Idell and colleagues interpret the evidence to argue that dysregulation of the fibrinolytic system is a plausible, underexplored contributor to the pathogenesis of depression and a potential therapeutic target. They position their hypothesis as tying together peripheral inflammation, blood–brain barrier modulation, local inhibition of plasminogen activators by PAI-1 and neuroserpin, transient fibrin deposition with microglial activation, impaired proBDNF processing and consequent reductions in mBDNF, which together impair hippocampal neurogenesis, synaptic plasticity and mood-related neural circuits. The authors suggest that several established and emerging antidepressant modalities could share a final common pathway in restoring fibrinolytic balance: by lowering TNF-α and other proinflammatory mediators, reducing PAI-1 activity or expression, and disinhibiting tPA/uPA to increase plasmin and mBDNF. They present conceptual and preclinical rationale for testing whether psilocybin and other 5-HT2A agonists exert antidepressant effects through anti-inflammatory and profibrinolytic mechanisms, including downregulation of cortical 5-HT2A expression, suppression of TNF-α signalling and secondary reductions in PAI-1. Limitations and uncertainties acknowledged in the text include the absence of direct data demonstrating transient fibrin deposition in the brains of patients with depression, the complex context-dependent roles of tPA and PAI-1 (which can be neurotoxic or neurotrophic depending on concentration and location), and the lack of information on how antidepressant drugs process or modify PAI-1 activity centrally. The authors call for targeted experimental work: animal studies using knockouts or transgenic overexpression of fibrinolytic components, plasminogen-deficient models, in vitro astrocyte assays examining cytokine effects on fibrinolytic regulation and the impact of psychedelics, and clinical biomarker studies in humans receiving psychological or pharmacologic interventions. Finally, they note practical barriers — regulatory scheduling and stigma around psychedelics — that complicate clinical research but argue these should not prevent investigation given the unmet need in treatment-resistant depression.