Significant outcomes
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• Inflammatory elements of psychiatric disorders are increasingly accepted, and anti-inflammatory interventions can be effective even in treatment-resistant disorders.
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• Adjunctive and off-label interventions in psychiatry have shown promise and combined with the nascent field of precision psychiatry represents new horizons for clinical translation.
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• Colchicine, a non-steroidal anti-inflammatory drug used to treat gout, mitigates purported inflammatory mechanisms of psychopathology, notably those observed in depressive disorders and bipolar disorder.
Limitations
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• Low doses of colchicine are well tolerated with a favourable safety profile even with extended administrations. However, toxicity from potential drug–drug interactions requires close monitoring and targeted application.
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• Clinical investigations for colchicine in psychiatry are scarce, and randomised controlled trials are necessary. We provide a framework for safe, biomarker-guided research.
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• The pharmacodynamics of colchicine suggest that psychiatric improvement is most likely to work indirectly, adjunctive to other treatments. It also remains to be established if efficacy will be greater in those with baseline inflammation – a premise of the precision framework.
Shifting models: from monoamines to immunoinflammatory depression
Understanding of the biological components of mood disorder pathophysiology has extended from a monoamine neurotransmitter-centric paradigm to the incorporation of an immunoinflammatory model (Dantzer et al., Reference Dantzer, O’Connor, Freund, Johnson and Kelley2008; Miller & Raison, Reference Miller and Raison2015). This transition reflects decades of evidence linking peripheral and central inflammatory processes to mood syndromes (Kouba et al., Reference Kouba, de Araujo Borba, Borges de Souza, Gil-Mohapel and Rodrigues2024). Elevated peripheral markers such as C-reactive protein (CRP) and various cytokines are consistently linked to depression and bipolar severity and their chronicity (Dowlati et al., Reference Dowlati, Herrmann, Swardfager, Liu, Sham, Reim and Lanctôt2010; Goldsmith et al., Reference Goldsmith, Rapaport and Miller2016). A large meta-analysis shows CRP, IL-6, IL-12, IL-18 and TNF-α are significantly higher in those with depression, albeit with limited clinical sensitivity and specificity (Osimo et al., Reference Osimo, Pillinger, Rodriguez, Khandaker, Pariante and Howes2020). Beyond peripheral signals, immunophenotyping work indicates abnormalities across innate and adaptive immune cell populations in major depressive disorder (MDD) (Foley et al., Reference Foley, Parkinson, Mitchell, Turner and Khandaker2023). Central nervous system involvement, including microglial activation and NLRP3 inflammasome dysregulation, further implicates immune pathways (Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015; Roy et al., Reference Roy, Arif Ansari, Choudhary and Singh2023). This ‘immunoinflammatory depression’ framework therefore provides a mechanistic rationale for developing targeted anti-inflammatory interventions aimed at restoring neuroplasticity and improving antidepressant response (Berk et al., Reference Berk, Williams, Jacka, O’Neil, Pasco and Moylan2013; Köhler-Forsberg et al., Reference Köhler-Forsberg, Lydholm, Hjorthøj, Nordentoft, Mors and Benros2019; Rosenblat et al., Reference Rosenblat, Cha, Mansur and McIntyre2014). Instead of the ‘typical’ depressive symptoms like insomnia and appetite loss, this subtype is defined by atypical, energy-related symptoms. These include profound fatigue and lethargy, hypersomnia, hyperphagia, weight gain, leaden paralysis and anhedonia. It is thought to be driven by chronic, low-grade inflammation and is further associated with insulin resistance, obesity, dyslipidaemia and leptin resistance (Milaneschi et al., Reference Milaneschi, Lamers, Berk and Penninx2020; Penninx et al., Reference Penninx, Lamers, Jansen, Berk, Khandaker, De Picker and Milaneschi2025). Several putative anti-inflammatory agents have been studied in depression including aspirin, minocycline, statins, celecoxib and infliximab with results ranging from promising to disappointing (Berk et al., Reference Berk, Mohebbi, Dean, Cotton, Chanen and Dodd2020a; Berk et al., Reference Berk, Woods, Nelson, Shah, Reid and Storey2020b; Zazula et al., Reference Zazula, Husain, Mohebbi, Walker, Chaudhry and Khoso2021; Kavakbasi et al., Reference Kavakbasi, Sampson, Mills, Hori, Schwarte and Hohoff2024).
Colchicine: an established anti-inflammatory candidate for repurposing
Colchicine, a plant-derived alkaloid with centuries of clinical use (Slobodnick et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2015), exerts potent anti-inflammatory effects primarily by disrupting microtubule assembly and inhibiting leukocyte chemotaxis (Dalbeth et al., Reference Jiao, Lin, Deng, Ji, Liang and Wei2014; Leung et al., Reference Leung, Yao Hui and Kraus2015). Its therapeutic applications extend beyond gout and familial Mediterranean fever to include the prevention of recurrent pericarditis and major cardiovascular events (Tardif et al., Reference Tardif, Kouz, Waters, Bertrand, Diaz and Maggioni2019; Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020). These cases reflect clinical potency and tolerability both in short-and long-term use of the agent. However, average to high doses (1 mg or higher) have a limited tolerability profile, and overdose risks serious toxicity outcomes. These issues appear less pertinent at the fixed low dose of 0.5 mg utilised in recent extant randomised controlled trials for utility in the secondary prevention of major adverse cardiac events, and indication for which low-dose colchicine has recently won cardiac best practice guidelines level approval (Samuel et al., Reference Samuel, Berry, Dubé, Koenig, López-Sendón, Maggioni and Tardif2025).
Low-dose colchicine (fixed at 0.5 mg daily) has recently received major regulatory endorsement: in June 2023, the US FDA-approved its use to reduce myocardial infarction, stroke, coronary revascularisation and cardiovascular death in adults with established atherosclerotic cardiovascular disease (Robinson et al., Reference Robinson, Terkeltaub, Pillinger, Shah, Karalis and Karatza2022; Nidorf et al., Reference Nidorf, Ben-Chetrit and Ridker2024). This landmark decision marked the first FDA approval of a purely anti-inflammatory agent for long-term cardiovascular prevention, reinforcing the potential of chronic use of low-dose anti-inflammatory strategies (Robinson et al., Reference Robinson, Terkeltaub, Pillinger, Shah, Karalis and Karatza2022; Nidorf et al., Reference Nidorf, Ben-Chetrit and Ridker2024).
Given its affordability, well-defined pharmacokinetic profile and extensive safety record established through large cardiovascular trials (Leung et al., Reference Leung, Yao Hui and Kraus2015; Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020; Robinson et al., Reference Robinson, Terkeltaub, Pillinger, Shah, Karalis and Karatza2022), colchicine is a promising candidate for therapeutic repurposing in psychiatry. Its mechanism of action – attenuation of systemic and central inflammation through inhibition of the NLRP3 inflammasome – aligns closely with current models positioning mood disorders as immune-neural dysregulation syndromes. The drug’s predictable bioavailability, low cost and accessibility worldwide further support its potential as an adjunctive intervention for treatment-resistant depression (TRD) and bipolar disorder (BD) (Bhatt et al., Reference Bhatt, Devadoss, Jha, Baidya, Gupta and Chellappan2022).
Core hypothesis: colchicine-mediated neuroinflammation attenuation
We hypothesise that fixed low-dose colchicine (0.5 mg daily) may serve as an effective augmentation strategy in at least a subgroup of people with treatment-resistant mood disorders by attenuating central neuroinflammation and maladaptive microglial activity (Berk et al., Reference Berk, Williams, Jacka, O’Neil, Pasco and Moylan2013; Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015). Through inhibition of the NLRP3 inflammasome and downstream cytokine cascades (Dalbeth et al., Reference Dalbeth, Lauterio and Wolfe2014; Leung et al., Reference Leung, Yao Hui and Kraus2015; Roy et al., Reference Roy, Arif Ansari, Choudhary and Singh2023), colchicine may restore neuroplasticity, normalise monoaminergic signalling and alleviate some of the behavioural and cognitive symptoms of chronic inflammation (Rosenblat et al., Reference Rosenblat, Cha, Mansur and McIntyre2014; Haroon & Miller, Reference Haroon, Miller, Dantzer and Capuron2016).
This hypothesis positions colchicine as a mechanistically distinct adjunctive therapy acting beyond monoaminergic modulation. By interrupting immune–neural crosstalk and dampening pro-inflammatory cytokine signalling, the drug may mitigate key pathophysiological processes underlying treatment resistance. Its well-characterised safety profile at low doses and ability to modulate both peripheral and central inflammation make it a promising candidate for translational testing in biomarker-defined subgroups of depression and BD. Risk of toxicity in overdose will be a relative consideration for some patients, and issues that could be managed with limited dispensing of colchicine in patients deemed at elevated risk of overdose.
Supporting evidence for further investigation of colchicine: from systemic inflammation to specific molecular targets
Preclinical data
The direct link between inflammation and behaviour is robustly supported by preclinical models (Dantzer et al., Reference Dantzer, O’Connor, Freund, Johnson and Kelley2008; Miller & Raison, Reference Miller and Raison2015). Inhibition of the NLRP3 inflammasome in stress-induced murine models successfully normalises depressive-like behaviours and restores hippocampal neurogenesis (Zhang et al., Reference Zhang, Liu, Liu, Shen, Wu and Zhang2015; Kaufmann et al., Reference Kaufmann, Costa, Ghisleni, Diaz, Rodrigues, Peluffo and Kaster2017). Studies using colchicine in animal models demonstrate reduced levels of pro-inflammatory cytokines and improved spatial memory (Bhatt et al., Reference Bhatt, Devadoss, Jha, Baidya, Gupta and Chellappan2022). The neuroprotective effects of colchicine are not limited to acute inflammatory models; investigations in chronic neurodegenerative disease models, such as Alzheimer’s (Liu et al., Reference Penninx, Lamers, Jansen, Berk, Khandaker, De Picker and Milaneschi2025) and Parkinson’s (Salama et al., Reference Salama, Ellaithy, Helmy, El-Gamal, Tantawy and Mohamed2012), have shown reduced microglial activation and measurable enhancement in cognitive outcomes. These comprehensive findings lend significant support to the notion of a plausible neuroprotective and psychotropic mechanism realised through the central suppression of inflammatory pathways (Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015; Liu et al., Reference Liu, Zhai, Ma, Wang, Wang, Hu and Tang2025).
Mechanistic rationale: targeting immune–neural crosstalk
Inflammatory cytokines and neuroplasticity disruption
Chronic low-grade inflammation impairs key neurobiological processes that regulate mood, cognition and emotional resilience (Dantzer et al., Reference Dantzer, O’Connor, Freund, Johnson and Kelley2008; Miller & Raison, Reference Miller and Raison2015). Elevated pro-inflammatory cytokines-IL-6, TNF-α and IL-1β-suppress the expression of brain-derived neurotrophic factor (BDNF) (Dowlati et al., Reference Dowlati, Herrmann, Swardfager, Liu, Sham, Reim and Lanctôt2010), thereby disrupting hippocampal neurogenesis and increasing vulnerability to glutamate-mediated excitotoxicity (Haroon & Miller, Reference Haroon, Miller, Dantzer and Capuron2016).
Sustained inflammatory activity alters dendritic architecture and synaptic pruning, contributing to the grey matter reductions and associated cognitive symptoms that are consistently observed in chronic depressive illness (Berk et al., Reference Berk, Kapczinski, Andreazza, Dean, Giorlando, Maes, Yücel, Gama, Dodd, Dean and Magalhães2011; Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015). Peripheral immune activation, triggered by chronic metabolic or infectious stress, communicates bidirectionally with the CNS through vagal afferents, humoral cytokine transport across compromised blood–brain barrier regions (Banks, Reference Banks2012) and direct immune cell infiltration (Kohler et al., Reference Kohler, Krogh, Mors and Eriksen Benros2016; Maes & Carvalho, Reference Maes and Carvalho2018).
These processes promote microglial priming and a shift toward a chronically activated, pro-inflammatory state (Rosenblat et al., Reference Rosenblat, Cha, Mansur and McIntyre2014; Roy et al., Reference Roy, Arif Ansari, Choudhary and Singh2023). Once activated, microglia amplify oxidative stress and release additional cytokines, establishing a self-perpetuating neuroinflammatory loop that may undermine synaptic plasticity and antidepressant responsiveness (Dantzer et al., Reference Dantzer, O’Connor, Freund, Johnson and Kelley2008; Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015). A recent comprehensive review further corroborates this mechanistic nexus: ‘The immunological perspective of major depressive disorder’ describes how dysregulated cytokine signalling, microglia/astrocyte dysfunction and neuroinflammation collectively disrupt neurotransmission and neuroplasticity in depression (Jiao et al., Reference Jiao, Lin, Deng, Ji, Liang and Wei2025).
The NLRP3 inflammasome: a central regulator of mood pathology
The NLRP3 inflammasome is a cytosolic complex that links peripheral immune activation to central neuroinflammatory signalling (Kaufmann et al., Reference Kaufmann, Costa, Ghisleni, Diaz, Rodrigues, Peluffo and Kaster2017; Roy et al., Reference Roy, Arif Ansari, Choudhary and Singh2023). When triggered by stress signals-such as ATP, reactive oxygen species or mitochondrial damage (Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015). NLRP3 activates caspase-1, promoting the maturation of interleukin-1β (IL-1β) and interleukin-18 (IL-18) (Kouba et al., Reference Kouba, Gil-Mohapel and Rodrigues2022). These cytokines intensify glial activation and synaptic dysfunction, disrupting neuroplasticity. Post-mortem and clinical studies show increased NLRP3 expression and higher circulating IL-1β and IL-18 levels in individuals with MDD, correlating with treatment resistance and illness chronicity (Kaufmann et al., Reference Kaufmann, Costa, Ghisleni, Diaz, Rodrigues, Peluffo and Kaster2017; Kouba et al., Reference Kouba, Gil-Mohapel and Rodrigues2022). Aberrant inflammasome activity also contributes to oxidative stress and mitochondrial impairment – core features of neuroprogressive mood disorders (Jiao et al., Reference Jiao, Lin, Deng, Ji, Liang and Wei2025). Collectively, these findings identify NLRP3 as a pivotal link between systemic inflammation and disrupted neural homeostasis, and a promising target for interventions aimed at restoring neuroimmune balance.
Oxidative stress
Oxidative stress, marked by increased ROS generation and compromised mitochondrial function (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010), is both a critical cause and consequence of chronic neuroinflammation (Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015). Mitochondrial deficits are strongly implicated in treatment-refractory symptoms of mood disorders such as profound fatigue, cognitive impairment and anhedonia (Berk et al., Reference Berk, Kapczinski, Andreazza, Dean, Giorlando, Maes, Yücel, Gama, Dodd, Dean and Magalhães2011; Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015). By indirectly reducing the inflammatory-driven ROS generation and preserving mitochondrial integrity (Liu et al., Reference Liu, Zhai, Ma, Wang, Wang, Hu and Tang2025), animal studies have indicated that colchicine improves antioxidant capacity and reduces lipid peroxidation in neuroinflammatory models (Salama et al., Reference Salama, Ellaithy, Helmy, El-Gamal, Tantawy and Mohamed2012; Liu et al., Reference Liu, Zhai, Ma, Wang, Wang, Hu and Tang2025).
Meta-analytic support for anti-inflammatory agents
The broader field of immunopsychiatry has demonstrated the therapeutic potential of anti-inflammatory strategies in mood disorders (Rosenblat et al., Reference Rosenblat, Cha, Mansur and McIntyre2014; Köhler-Forsberg et al., Reference Köhler-Forsberg, Lydholm, Hjorthøj, Nordentoft, Mors and Benros2019). Meta-analyses consistently report small-to-moderate reductions in depressive symptoms following treatment with anti-inflammatory agents (Kappelmann et al., Reference Kappelmann, Lewis, Dantzer, Jones and Khandaker2016; Kohler et al., Reference Kohler, Krogh, Mors and Eriksen Benros2016; Du et al., Reference Du, Dou, Wang, Wang, Yan and Fan2024). Importantly, their efficacy appears greatest among patients with elevated baseline inflammatory biomarkers (Raison et al., Reference Raison, Rutherford, Woolwine, Shuo, Schettler and Drake2013; Strawbridge et al., Reference Strawbridge, Young and Cleare2017; Du et al., Reference Du, Dou, Wang, Wang, Yan and Fan2024). This finding is foundational to the concept of precision psychiatry, reinforcing that future colchicine trials should ideally adopt a biomarker-guided design, targeting patients most likely to exhibit inflammation-driven pathophysiology (Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015; Kappelmann et al., Reference Kappelmann, Lewis, Dantzer, Jones and Khandaker2016; Bhatt et al., Reference Bhatt, Devadoss, Jha, Baidya, Gupta and Chellappan2022).
Colchicine’s pleiotropic mechanism of action
Colchicine exerts its clinical effects through multi-level immunomodulation (Leung et al., Reference Leung, Yao Hui and Kraus2015; Slobodnick et al., Reference Slobodnick, Shah, Pillinger and Krasnokutsky2015). Its primary mechanism involves binding to tubulin, which inhibits microtubule polymerisation, thereby preventing NLRP3 assembly (Dalbeth et al., Reference Dalbeth, Lauterio and Wolfe2014; Leung et al., Reference Leung, Yao Hui and Kraus2015). The relevance of this mechanism to chronic disease is well established. In the cardiovascular context, low-dose colchicine has been shown to reduce circulating levels of the inflammatory mediators IL-1β, IL-18 and CRP (Liu et al., Reference Liu, Zhai, Ma, Wang, Wang, Hu and Tang2025), a finding consistently demonstrated in major cardiovascular trials (COLCOT (Tardif et al., Reference Kavakbasi, Sampson, Mills, Hori, Schwarte and Hohoff2019); LoDoCo2 (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020). Importantly, contemporary research confirms that colchicine possesses the capacity to cross the BBB (Leung et al., Reference Leung, Yao Hui and Kraus2015), where it can suppress the activity of primed microglia and astrocytes, offering a direct mechanism for reducing central neuroinflammation (Liu et al., Reference Liu, Zhai, Ma, Wang, Wang, Hu and Tang2025). Specific in vitro studies support this, showing that colchicine downregulates Caspase-1 activation, restricts mitochondrial ROS generation and modulates autophagy (Liu et al., Reference Liu, Zhai, Ma, Wang, Wang, Hu and Tang2025). Microglia, the resident immune cells of the CNS, exist on a functional continuum between destructive pro-inflammatory (M1) states and restorative anti-inflammatory (M2) states (Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015; Roy et al., Reference Roy, Arif Ansari, Choudhary and Singh2023). Chronic M1 activation is characteristic of mood disorders whereas M2 phenotypes are necessary for restorative neurogenesis (Berk et al., Reference Liakou, Kontochristopoulos, Agiasofitou, Tsantes, Papadakis and Marnelakis2011). Preliminary evidence suggests that colchicine may actively promote a beneficial M2-like phenotypic shift, reducing the expression of destructive inducible nitric oxide synthase while increasing the activity of arginase-1 (Liu et al., Reference Liu, Zhai, Ma, Wang, Wang, Hu and Tang2025). This glial reprogramming capability represents a powerful mechanism for facilitating long-term synaptic remodelling and emotional recovery (Haroon et al., Reference Leung, Yao Hui and Kraus2016; Berk et al., Reference Liakou, Kontochristopoulos, Agiasofitou, Tsantes, Papadakis and Marnelakis2011). These combined actions can facilitate the synaptic repair hypothesised in the neuroplastic restoration model of depression (Leung et al., Reference Leung, Yao Hui and Kraus2015; Berk et al., Reference Liakou, Kontochristopoulos, Agiasofitou, Tsantes, Papadakis and Marnelakis2011).
Pharmacokinetics and central nervous system access
While colchicine is orally bioavailable (Slobodnick et al., Reference Slobodnick, Shah, Pillinger and Krasnokutsky2015), its pharmacological profile presents challenges related to its narrow therapeutic window (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010). Colchicine is metabolised primarily by the cytochrome P450 3A4 (CYP3A4) enzyme system, and its distribution is strongly influenced by P-glycoprotein (P-gp) efflux pump (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010). Colchicine’s status as a substrate for both CYP3A4 and P-gp is responsible for risk of clinically significant drug–drug interactions (DDIs), as potent inhibitors of either system can drastically elevate colchicine plasma levels and increase the risk of systemic toxicity (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010). In this regard, colchicine has a narrow therapeutic index (Stamp et al., Reference Stamp, Horsley, Te Karu, Dalbeth and Barclay2024).
For therapeutic use in mood disorders, colchicine must achieve adequate concentration within the brain. While animal studies confirm BBB penetration (Banks, Reference Banks2012), the human access is potentially influenced by inflammatory states that compromise BBB integrity (Kohler et al., Reference Maes and Carvalho2016). Any pharmacological intervention aiming for chronic psychiatric use must meticulously manage these pharmacokinetic factors, ensuring that central efficacy is achieved without crossing the threshold for systemic toxicity (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010). Future advancements in drug delivery, such as advanced lipid-based or polymer nanoparticles, are currently being investigated to optimise CNS targeting, potentially overcoming current limitations imposed by systemic toxicity and restricted bioavailability (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010). The multifaceted mechanistic actions of colchicine, summarised in Table 1, target the central pillars of the neuroinflammatory hypothesis of refractory mood disorders (Miller & Raison, Reference Berk, Kapczinski, Andreazza, Dean, Giorlando, Maes, Yücel, Gama, Dodd, Dean and Magalhães2015; Berk et al., Reference Dowlati, Herrmann, Swardfager, Liu, Sham, Reim and Lanctôt2013).
Proposed mechanism of low-dose colchicine in neuroinflammation and mood regulation
Table 1. Long description
The table has four columns: Target site/system, Molecular/cellular effect of colchicine, Supporting evidence, and Predicted psychiatric outcome. It contains four rows of data. Row 1: Target site/system, Microtubule assembly; Molecular/cellular effect of colchicine, Inhibition of tubulin polymerisation; disruption of cytoskeletal integrity necessary for inflammasome scaffolding, neutrophil mobility and trafficking; Supporting evidence, Reference Jiao, Lin, Deng, Ji, Liang and Wei2025; Kappelmann et al., Reference Kappelmann, Lewis, Dantzer, Jones and Khandaker2016; Predicted psychiatric outcome, Reduced systemic inflammation; potential stabilisation of the BBB. Row 2: Target site/system, NLRP3 inflammasome; Molecular/cellular effect of colchicine, Suppressed assembly; reduced Caspase-1 activation and resultant cleavage of pro-IL-1x1D6FD Undefined and pro-IL-18; Supporting evidence, Roy et al., Reference Dantzer, O’Connor, Freund, Johnson and Kelley2023; Kouba et al., Reference Miller and Raison2024; Kaufmann et al., Reference Kaufmann, Costa, Ghisleni, Diaz, Rodrigues, Peluffo and Kaster2017; Predicted psychiatric outcome, Decreased production of pro-inflammatory cytokines (IL-1x1D6FD Undefined, IL-6); mitigation of neurotoxic cascades. Row 3: Target site/system, Microglia & astrocytes; Molecular/cellular effect of colchicine, Potential promotion of M2 anti-inflammatory phenotype; suppression of M1 pro-inflammatory state; Supporting evidence, Roy et al., Reference Dantzer, O’Connor, Freund, Johnson and Kelley2023; Liu et al., Reference Penninx, Lamers, Jansen, Berk, Khandaker, De Picker and Milaneschi2025; Predicted psychiatric outcome, Enhanced neurogenesis and synaptic remodelling; improvement in mood and cognitive symptoms. Row 4: Target site/system, Oxidative stress & mitochondria; Molecular/cellular effect of colchicine, Inhibition of mitochondrial trafficking; reduced ROS generation driven by inflammation; Supporting evidence (Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015; Liu et al., Reference Penninx, Lamers, Jansen, Berk, Khandaker, De Picker and Milaneschi2025); Predicted psychiatric outcome, Preservation of mitochondrial integrity; mitigation of fatigue and anhedonia.
Safety, tolerability and pharmacologic considerations
Low-dose safety in chronic use: lessons from cardiovascular medicine
Historical concerns regarding colchicine toxicity stem largely from its narrow therapeutic window (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010) and the high doses traditionally used to treat acute gout flares (Slobodnick et al., Reference Slobodnick, Shah, Pillinger and Krasnokutsky2015). However, the use of low-dose colchicine in chronic conditions has recalibrated its risk profile (Robinson et al., Reference Robinson, Terkeltaub, Pillinger, Shah, Karalis and Karatza2022). Extensive long-term cardiovascular and rheumatologic trials, encompassing tens of thousands of participants (Tardif et al., Reference Tardif, Kouz, Waters, Bertrand, Diaz and Maggioni2019; Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020), demonstrate that the 0.5 mg/day regimen is generally well tolerated (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020), with no significant increase in mortality or serious adverse events compared to placebo (Nidorf et al., Reference Nidorf, Ben-Chetrit and Ridker2024). The most common adverse effect is mild gastrointestinal (GI) upset, typically diarrhoea, which is dose-dependent and transient, often resolving shortly after initiation (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020; Robinson et al., Reference Robinson, Terkeltaub, Pillinger, Shah, Karalis and Karatza2022). At this low dose, there is minimal evidence of increased risk for myelosuppression, myotoxicity or cancer, even in patients concurrently taking statins (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020). This robust safety profile in chronic disease management significantly de-risks repurposing colchicine for chronic psychiatric care (Robinson et al., Reference Robinson, Terkeltaub, Pillinger, Shah, Karalis and Karatza2022; Nidorf et al., Reference Nidorf, Ben-Chetrit and Ridker2024). The caveat is risk of overdose which is omnipresent in depression and may require specific prescription and dispensing safeguards.
Drug–drug interactions (CYP3A4/P-gp) and monitoring requirements
Despite its favourable overall safety at low doses, meticulous patient selection and monitoring remain essential due to colchicine’s unique metabolism. As detailed earlier, colchicine is a substrate for both CYP3A4 and P-gp (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010). Co-administration with potent inhibitors of these pathways, which include common medications such as macrolide antibiotics (e.g. clarithromycin), cyclosporine, specific antifungals (e.g. ketoconazole, fluconazole), calcium channel blockers (e.g. verapamil) (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010) and numerous psychotropic medications, can significantly elevate colchicine plasma levels, leading to risk of dangerous systemic toxicity (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010).
Consequently, stringent screening for drug interactions is non-negotiable (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010). When using low-dose colchicine alongside antidepressants, carefully screen for strong CYP3A4 and P-glycoprotein (ABCB1) drug interactions, especially with psychotropics like fluvoxamine, which can elevate colchicine toxicity risks. Baseline and periodic complete blood counts, renal and hepatic panels are essential. Educate patients to promptly report early toxicity signs, such as severe GI distress or muscle weakness, and adjust dosages if renal function declines. In addition to the laboratory monitoring schedule, we have highlighted the necessity of screening for CYP3A4/P-gp inhibitors specifically within the psychotropic pharmacopoeia and have added the requirement for caregiver education regarding early signs of toxicity, such as severe diarrhoea.
Additionally, combining colchicine with statins requires vigilance for increased myotoxicity risk (Stamp et al., Reference Stamp, Horsley, Te Karu, Dalbeth and Barclay2024). Furthermore, colchicine elimination requires adequate renal and hepatic function; low-dose colchicine must not be used in patients with an estimated glomerular filtration rate below 45 mL/min/1.73 m2 (Robinson et al., Reference Robinson, Terkeltaub, Pillinger, Shah, Karalis and Karatza2022) or in those with advanced liver dysfunction (Robinson et al., Reference Robinson, Terkeltaub, Pillinger, Shah, Karalis and Karatza2022). Monitoring renal and hepatic function every 6–12 months is sufficient for chronic use in appropriate patients (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020; Robinson et al., Reference Robinson, Terkeltaub, Pillinger, Shah, Karalis and Karatza2022). Table 2 synthesises the comparison of colchicine dosing across clinical contexts.
Comparison of colchicine dosing, safety and clinical precedent
Table 2. Long description
A table comparing colchicine dosing, safety, and clinical context across different conditions. The table has three rows and four columns. The columns are labeled Indication/context, Daily dose (mg), Safety/tolerability, and Clinical context. Row 1: Indication/context, Acute gout flare; Daily dose (mg), 1.2 mg loading dose, then 0.6 mg after 1 hour; Safety/tolerability, High incidence of dose-limiting gastrointestinal (GI) upset. Narrow therapeutic index; Clinical context, Historical perspective; highlights the risk of high-dose, short-term use. Row 2: Indication/context, Established CAD (Chronic prevention); Daily dose (mg), 0.5 mg daily (fixed dose); Safety/tolerability, Excellent long-term safety comparable to placebo; serious adverse events remain rare; Clinical context, Primary Safety Anchor: FDA-approved status validates chronic use based on anti-inflammation. Row 3: Indication/context, Proposed psychiatric augmentation; Daily dose (mg), 0.5 mg daily (fixed dose); Safety/tolerability, Requires stringent baseline screening for renal (eGFR < 45 mL/min/1.73 m^2) and hepatic impairment. Meticulous DDI management is mandatory; Clinical context, Dosing minimizes toxicity while aligning with successful long-term cardiovascular protocols.
*Low-dose (0.5 mg/day) colchicine demonstrates a consistent safety margin across chronic indications, supporting translational exploration in psychiatry. Pertains to column 2 row 3 of table.
Risk mitigation strategies for overdose in psychiatric populations
Intentional overdose is a necessary consideration for any psychotropic agent, particularly one with a narrow therapeutic window (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010). Colchicine toxicity can precipitate life-threatening multi-organ failure (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010). For patients identified as being at high suicidal risk, structured dispensing protocols, such as supervised administration or weekly dispensing limits – strategies already successfully employed for medications like lithium (Malhi et al., Reference Malhi, Tanious, Das and Berk2012) and clozapine (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010) – are essential to mitigate this risk. Comprehensive patient and caregiver education, alongside robust pharmacovigilance protocols, are required to ensure safe implementation (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020; Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010).
Clinical and translational observations
Randomised psychiatric trials examining colchicine in depression are currently absent. However, substantial translational evidence exists from large, long-term observational studies conducted in cardiovascular and rheumatologic populations. Major cardiovascular outcomes trials, such as COLCOT (Tardif et al., Reference Kavakbasi, Sampson, Mills, Hori, Schwarte and Hohoff2019) and LoDoCo2 (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020), confirm that the 0.5 mg daily regimen is highly effective at suppressing systemic inflammation (Leung et al., Reference Leung, Yao Hui and Kraus2015).
Importantly, post-hoc analyses of patient-reported outcomes from long-term colchicine users in the LoDoCo2 trial noted self-reported non-diagnostic improvements in fatigue and other proxies for somatic/vegetative cluster symptoms for depression (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020). The landmark LoDoCo2 trial evaluated daily low-dose colchicine in 5,522 patients with chronic coronary disease. Over a median follow-up of 28.6 months, 0.5 milligrams of colchicine significantly reduced the risk of cardiovascular death, myocardial infarction, ischaemic stroke or ischaemia-driven revascularization by 31 percent compared to placebo, establishing anti-inflammatory therapy as an effective secondary prevention strategy. It is unclear if this might also map to reduce rates of neuropsychiatric conditions, but a plausible hypothesis meriting testing exists toward this conjecture. The observed benefit appears linked to chronic prevention; a small, acute study of STEMI patients treated for only 40 days showed no significant difference in outcome (Tong et al., Reference Tong, Quinn, Nasis, Hiew, Roberts-Thomson and Adams2020).
While non-specific to depression and explicitly non-psychiatric, this subjective vitality improvement strongly suggests a positive impact on core somatic symptoms that are intimately linked to underlying inflammatory or mitochondrial dysfunction in mood disorders (Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015; Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020). This underlines that the therapeutic benefit of colchicine in chronic inflammatory diseases, like refractory depression, is likely derived from long-term modulation rather than acute intervention (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020).
Additional support derives from quality-of-life (QoL) measures in long-term studies. Most studies report correlation coefficients (r) between –0.4 and –0.7 for QoL measures such as the SF36 and depression measures like the MADRS (Elliott et al., Reference Elliott, Renier and Palcher2003). Colchicine use has been associated with improved QoL in several studies providing indirect and preliminary support in depression (Deftereos et al., Reference Deftereos, Giannopoulos, Efremidis, Kossyvakis, Katsivas and Panagopoulou2014; Liakou et al., Reference Liakou, Kontochristopoulos, Agiasofitou, Tsantes, Papadakis and Marnelakis2021).
Health economic and public health relevance
The economic burden of TRD and BD is immense, driven by lost productivity and sustained healthcare utilisation (Greenberg et al., Reference Greenberg, Fournier, Sisitsky, Simes, Berman, Koenigsberg and Kessler2021). Given colchicine’s low cost and global availability (Saxena et al., Reference Saxena, Thornicroft, Knapp and Whiteford2007; Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020), even modest improvements in remission rates among refractory patients could generate substantial cost savings and a strong return on investment for healthcare systems (Saxena et al., Reference Saxena, Thornicroft, Knapp and Whiteford2007; Greenberg et al., Reference Greenberg, Fournier, Sisitsky, Simes, Berman, Koenigsberg and Kessler2021). Its simple oral administration and minimal need for specialised monitoring make it well suited for incorporation into existing primary care and telepsychiatry infrastructures (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020). If efficacy is confirmed in clinical trials, colchicine could represent the first affordable and scalable immunomodulatory augmenting agent for low-and middle-income countries, helping to close a critical gap in global mental health equity (Saxena et al., Reference Saxena, Thornicroft, Knapp and Whiteford2007; Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020).
Immunopsychiatry and translational implications
Colchicine as a pharmacologic probe
The rise of immunopsychiatry reframes mood disorders as systemic illnesses integrating neurological, immunological and metabolic processes (Dantzer et al., Reference Dantzer, O’Connor, Freund, Johnson and Kelley2008; Miller & Raison, Reference Miller and Raison2015; Maes & Carvalho, Reference Maes and Carvalho2018). Colchicine – a selective NLRP3 inflammasome inhibitor (Berk et al., Reference Berk, Williams, Jacka, O’Neil, Pasco and Moylan2013; Leung et al., Reference Leung, Yao Hui and Kraus2015; Roy et al., Reference Roy, Arif Ansari, Choudhary and Singh2023) – provides a rigorous pharmacologic probe to test this model (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020). Demonstrated efficacy in TRD would not only introduce a novel therapeutic pathway but validate NLRP3 as a critical psychiatric target (Kaufmann et al., Reference Kaufmann, Costa, Ghisleni, Diaz, Rodrigues, Peluffo and Kaster2017; Kouba et al., Reference Kouba, Gil-Mohapel and Rodrigues2022; Roy et al., Reference Roy, Arif Ansari, Choudhary and Singh2023). Moreover, differential response patterns could help distinguish inflammatory subtypes from non-inflammatory depression, refining diagnosis and enabling biomarker-guided interventions across psychiatric spectra (Berk et al., Reference Berk, Williams, Jacka, O’Neil, Pasco and Moylan2013; Strawbridge et al., Reference Strawbridge, Young and Cleare2017; Bhatt et al., Reference Bhatt, Devadoss, Jha, Baidya, Gupta and Chellappan2022).
Future research directions
Future research should extend beyond confirming short-term antidepressant effects (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020) to determine whether long-term colchicine use can attenuate progressive mood disorder deterioration associated with recurrent inflammation (Berk et al., Reference Liakou, Kontochristopoulos, Agiasofitou, Tsantes, Papadakis and Marnelakis2011). Longitudinal structural and functional neuroimaging may clarify whether it preserves hippocampal and prefrontal integrity, which are typically reduced in chronic depression (Berk et al., Reference Liakou, Kontochristopoulos, Agiasofitou, Tsantes, Papadakis and Marnelakis2011).
Design of a randomised, biomarker-guided adjunctive trial
A rigorous randomised, placebo-controlled adjunctive trial is the necessary next step (Table 3) (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020). The study should stratify patients based on objective inflammatory markers (Raison et al., Reference Raison, Rutherford, Woolwine, Shuo, Schettler and Drake2013; Strawbridge et al., Reference Strawbridge, Young and Cleare2017), randomise them to receive either fixed low-dose colchicine (0.5 mg/day) or placebo for a minimum duration of 24 weeks (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020). This fixed, low dose aligns precisely with the regimen proven safe in chronic cardiovascular prevention trials and standard psychotropic protocols (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020; Robinson et al., Reference Robinson, Terkeltaub, Pillinger, Shah, Karalis and Karatza2022)
Suggested design elements for a biomarker-guided adjunctive colchicine trial
Table 3. Long description
A table with six rows and four columns detailing design elements for a clinical trial. The columns are labeled Design element, Specific recommendation, Rationale/connection to mechanism, and Translational/Biomarker Endpoint. Row 1: Design element is Trial duration; Specific recommendation is 24 weeks minimum; fixed dose 0.5 mg/day; Rationale/connection to mechanism is Aligns with chronic anti-inflammatory protocols used in cardiovascular trials; Translational/Biomarker Endpoint is Longitudinal tracking of C R P and cytokine trajectories. Row 2: Design element is Statistical design; Specific recommendation is Randomised, double-blind, placebo-controlled; biomarker-stratified analysis; Rationale/connection to mechanism is Ensures robust causal inference and biomarker validation; Translational/Biomarker Endpoint is Sensitivity analyses by baseline inflammation level. Row 3: Design element is Study population; Specific recommendation is Adults (18-65 years) with treatment-resistant M D D or B D (depressive phase); Rationale/connection to mechanism is Focus on established treatment resistance to maximise potential effect size; Translational/Biomarker Endpoint is Baseline inflammatory markers (C R P, I L-6, I L-1 beta) for stratification. Row 4: Design element is Inclusion criteria; Specific recommendation is Documented non-response to >= 2 adequate antidepressant or mood-stabiliser trials plus elevated inflammatory biomarker (e.g. hsC R P > 3 mg/L or raised I L-6/I L-1 beta); Rationale/connection to mechanism is Anti-inflammatory agents show efficacy mainly in high-inflammation phenotypes; Translational/Biomarker Endpoint is Serum cytokine change (I L-6, I L-1 beta, T N F-alpha) pre- vs post-treatment. Row 5: Design element is Exclusion criteria; Specific recommendation is e G F R < 45 m L / min / 1.73 m^2; significant liver dysfunction; use of strong C Y P 3 A 4 or P-gp inhibitors; Rationale/connection to mechanism is Derived from long-term cardiovascular safety data; Translational/Biomarker Endpoint is Monitoring of creatinine, liver enzymes and drug levels. Row 6: Design element is Primary outcome; Specific recommendation is Change in M A D R S or H A M-D score at 24 weeks; Rationale/connection to mechanism is Standard index of symptomatic improvement; Translational/Biomarker Endpoint is Clinically significant reduction in symptoms. Row 7: Design element is Secondary outcomes; Specific recommendation is Fatigue Severity Scale (F S S); cognitive battery; quality-of-life measures; Rationale/connection to mechanism is Addresses somatic and cognitive symptoms linked to neuroinflammation and mitochondrial dysfunction; Translational/Biomarker Endpoint is C S F inflammasome activity (Caspase-1, I L-1 beta). Sensitivity sub study of T S P O-P E T change in microglial activation density. C S F and T S P O-P E T endpoints are optional mechanistic substudies, not routine requirements.
Combination studies pairing colchicine with neurotrophic or synergistic anti-inflammatory agents, such as omega-3 fatty acids, N-acetylcysteine (NAC) or lithium (Malhi et al., Reference Malhi, Tanious, Das and Berk2012), could optimise therapeutic outcomes (Berk et al., Reference Berk, Williams, Jacka, O’Neil, Pasco and Moylan2013; Bhatt et al., Reference Bhatt, Devadoss, Jha, Baidya, Gupta and Chellappan2022). Genomic and proteomic analyses may help identify responder subgroups defined by inflammasome-related polymorphisms or baseline immune profiles, advancing precision psychiatry (Berk et al., Reference Berk, Williams, Jacka, O’Neil, Pasco and Moylan2013; Rosenblat et al., Reference Rosenblat, Cha, Mansur and McIntyre2014; Strawbridge et al., Reference Strawbridge, Young and Cleare2017). Finally, innovations in drug-delivery technology derived from cardiology (Kaufmann et al., Reference Kaufmann, Costa, Ghisleni, Diaz, Rodrigues, Peluffo and Kaster2017) could enable next-generation formulations with improved CNS penetration and safety, supporting wider psychiatric applications (Banks, Reference Banks2012; Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020).
Conclusion
Low-dose colchicine represents a biologically plausible candidate for testing for treatment-resistant mood disorders (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020). By targeting NLRP3 inflammasome activity and modulating microglial and mitochondrial pathways (Leung et al., Reference Leung, Yao Hui and Kraus2015; Vaváková et al., Reference Vaváková, Ďuračková and Trebatická2015; Roy et al., Reference Roy, Arif Ansari, Choudhary and Singh2023), it aligns with contemporary models positioning depression and BD as incorporating immune–neural dysregulation pathways (Dantzer et al., Reference Dantzer, O’Connor, Freund, Johnson and Kelley2008; Miller & Raison, Reference Miller and Raison2015).
Its well-documented long-term safety at 0.5 mg/day (Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020; Robinson et al., Reference Robinson, Terkeltaub, Pillinger, Shah, Karalis and Karatza2022), established through cardiovascular trials and regulatory approval, mitigates prior clinical concerns (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010). Combined with affordability and scalability (Saxena et al., Reference Saxena, Thornicroft, Knapp and Whiteford2007; Nidorf et al., Reference Nidorf, Fiolet, Mosterd, Eikelboom, Schut and Opstal2020), colchicine is a viable candidate for translational investigation. Nonetheless, its narrow therapeutic index may necessitate fixed low dosing, limited dispensing, biomarker-guided patient selection and vigilant monitoring (Finkelstein et al., Reference Finkelstein, Aks, Hutson, Juurlink, Nguyen and Dubnov-Raz2010; Strawbridge et al., Reference Tardif, Kouz, Waters, Bertrand, Diaz and Maggioni2017).
Data availability statement
No data were analysed for this article.
Acknowledgements
First draft was by A Singh then iterated by AI then iterated by co-authors. All references have been manually cross-checked by the human authors.
Author contributions
For research articles with several authors, a short paragraph specifying their individual contributions must be provided. The following statements should be used Conceptualisation, A.S.; investigation, A.S., D.S., J.L. and M.B.; writing - original draft preparation, A.S., D.S., J.L. and M.B; writing- review and editing, A.S., D.S., J.L. and M.B. All authors have read and agreed to the published version of the manuscript.
Funding statement
This research received no external funding.
Competing interests
The authors declare no conflicts of interest.
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