Chronic Unpredictable Mild Stress (CUMS) Model

CUMS (Chronic Unpredictable Mild Stress) Model

• This is a widely used animal model that induces depression-like behaviors in rodents.
• Rodents are exposed to mild, randomized stressors over 4–8 weeks.
• Stressors include food/water deprivation, flashing lights, cage tilting, social isolation, reversed light cycles, tail pinching, and temperature stress.
• The model reliably mimics human stress-induced depression, making it useful for preclinical studies.

Depression-like Behaviors Assessment

• Sucrose Preference Test (SPT) is the gold standard for measuring anhedonia, which is reduced in CUMS-induced depression.
• Forced Swim Test (FST) models hopelessness, with increased immobility time in CUMS.
• Locomotor Activity Test (LAT) models activity level, showing reduced total distance traveled and time moving in CUMS.
• Tail Suspension Test (TST) involves suspending the rodent by the tail, with increased immobility in CUMS.
• Open Field Test (OFT) assesses exploratory behaviors, which are expected to decrease in CUMS.
• Antidepressants should attenuate deficits induced by the CUMS model.

Differences in Mice vs. Rats

• Rats tend to show a stronger reduction in sucrose preference compared to mice.
• Mice are more variable; some strains (e.g., C57BL/6) show a mild response, while others (e.g., BALB/c) exhibit a more pronounced anhedonic response.
• Mice subjected to CUMS increase immobility in TST, indicating behavioral despair.
• Mice are more sensitive to environmental changes, leading to greater variability in behavioral outcomes.

Other Models

• Learned Helplessness involves exposure to inescapable stressors (e.g., repeated foot shocks).
• When given a chance to escape later, the rodents fail, indicating learned helplessness.
• Olfactory Bulbectomy involves surgical removal of olfactory bulbs, leading to hyperactivity, cognitive deficits, aggression, anhedonia, and HPA-axis dysregulation.

Track Record in Drug Development and Criticisms

• The CUMS model is widely used for preclinical antidepressant screening, especially for detecting chronic treatment effects.
• Many approved antidepressants (e.g., SSRIs, SNRIs, ketamine) reverse CUMS-induced deficits.
• Some novel antidepressants (e.g., TNF-α inhibitors like infliximab) that work in CUMS rodents fail in clinical trials.
• Some rodent strains (e.g., Kyoto Wistar rats) display high baseline immobility and stress sensitivity.
• C57BL/6 mice show weaker CUMS responses than BALB/c mice.
• CUMS does not fully model long-term safety concerns of antidepressants.

Detecting Novel Drugs

• CUMS-induced depression-like behaviors respond to drugs beyond SSRIs/SNRIs, such as ketamine.
• CUMS reveals antidepressant effects in TNF-α inhibitors, IL-6 antagonists, and metabolic modulators.
• Complementary models (e.g., learned helplessness, olfactory bulbectomy, social defeat stress) may improve detection of truly novel antidepressants.

Predictive Value of CUMS

• Sucrose preference-related anhedonia is restored with antidepressants (both novel and classical) in rats.
• Individual findings often show non-significant results, even for previously significant drugs.
• Dosing, CUMS protocol, and non-responders are important factors.
• Infliximab restores SPT in rats but does not translate to clinical efficacy.
• Some rodents (e.g., Kyoto Wistar rats) have high baseline immobility, making interpretation difficult.
• CUMS has good predictive validity, as many clinically effective antidepressants reverse CUMS-induced behavioral deficits.
• Methodologies are very important, and CUMS should be used in conjunction with other models.

Forest Plot and Funnel Plot

• 20 classical antidepressants and 18 novel antidepressants were selected from an initial 1,386 papers.
• After removing duplicates and screening titles and papers, 31 papers were included in the meta-analysis.
• One classical drug and one novel drug were pulled from each paper, with the most significant increase in sucrose preference selected.

Results of Forest Plot

• Classical Antidepressants (Fixed-Effects Model)
  • The standardized mean difference (SMD) was -0.8145, indicating a moderate to strong reduction in anhedonia compared to controls.
  • There was substantial heterogeneity (I² = 78.93%), indicating variations in study outcomes.
  • Imipramine and Sertraline were identified as potential outliers.
  • Publication bias was evident, with significant funnel plot asymmetry.
  • Six crossed the line of no effect, showing variability in responses.
• Novel Antidepressants (Random-Effects Model)
  • The SMD was -1.8053, indicating a stronger effect in reducing anhedonia compared to classical antidepressants.
  • Heterogeneity remained high (I² = 71.21%), but no studies were classified as significant outliers.
  • The 95% prediction interval was -3.5315 to -0.0791.
  • Funnel plot asymmetry was significant, suggesting potential publication bias.
• Novel antidepressants showed a stronger effect size than classical antidepressants.
• Heterogeneity was present in both models, suggesting variability in CUMS protocol, methodologies, dosing, or outcome measurements.

Bias in Forest Plot

• There was stronger evidence of publication bias with classical antidepressants.
• The selection of one drug per study based on the strongest result influences findings and indicates selective publication of positive results.

Case Study: Infliximab

• Infliximab is a TNF-alpha targeting monoclonal antibody with a large effect size of -3.67 in a rat model using data from Karson et al in 2013.
• TNF-alpha is an inflammatory cytokine used to treat autoimmune and inflammatory diseases.
• Infliximab is administered via intravenous (IV) infusion, often with immunosuppressants (e.g., methotrexate).
• Clinical trials for treatment-resistant depression or bipolar depression have been conducted.
• Additional rat and mice CUMS models studying efficacy of infliximab in treated depression that used OFT, FST, TST behavioural endpoints.

Mechanism of Action for Infliximab

• Infliximab is a chimeric monoclonal antibody that binds to TNF-α, preventing its pro-inflammatory effects.
• Each molecule binds to two molecules of TNF-alpha.
• It binds to soluble and membrane-bound TNF-α and prevents TNF-α from interacting with TNF receptors.
• It blocks downstream inflammatory signaling, preventing activation of NF-κB, JNK, and MAPK pathways.
• It reduces immune cell activation, suppressing macrophage and T-cell activation.
• It induces apoptosis in TNF-expressing cells.

Involvement in Depression

• TNF-α contributes to stress-induced depression, neuroinflammation, reduced serotonin availability, neurotoxicity and cortisol release.
• Infliximab's pharmacokinetics (IV administration, long half-life of 8–10 days) and its likely to be used in treatment-resistant depression (TRD) and bipolar depression.
• It takes 6 weeks to work, and efficacy is not sustained after treatment cessation.

Preclinical Efficacy and Safety of Infliximab

• Injecting infliximab into the cerebrospinal fluid of CUMS mice decreased immobility in the Forced Swim Test (FST) and Tail Suspension Test (TST) and increased exploratory behavior in the Open Field Test (OFT) and learning and memory improved (Gao et al., 2024).
• Infliximab downregulated TNF-α and IDO (Indoleamine 2,3-dioxygenase) in the cortex and hippocampus, improving depressive symptoms (Fu et al., 2016).
• Chronic infliximab reversed anhedonia (measured by the sucrose preference test) and reduced anxiety-like behaviors (Karson et al., 2013).
• Infliximab blocked stress-induced TNF-α increases and prevented depressive-like behavior (Liu et al., 2015).

Clinical Efficacy and Safety of Infliximab

• Most studies used 5 mg/kg administered intravenously at weeks 0, 2, and 6.
• Studies Supporting Antidepressant Effects
  • Infliximab did not significantly reduce depressive symptoms overall but showed strong antidepressant effects only in TRD patients with high inflammation (CRP >5 mg/L) (Raison et al., 2013).
  • Infliximab significantly reduced anhedonia in patients with CRP >3 mg/L, suggesting a role in reward system dysfunction (Singh et al., 2025).
  • Metabolic factors (cholesterol, glucose regulation) predicted who responded to infliximab, implying inflammation modifies metabolic pathways linked to depression (Mehta et al., 2013).
  • Infliximab did not reduce depressive symptoms overall in bipolar depression but was effective in patients with a history of childhood trauma (McIntyre et al., 2019).
  • Infliximab reduced depressive symptoms in patients with Crohn’s disease, suggesting benefits in inflammation-related depression (Mansur et al., 2020).
• Studies with Limited or No Effect
  • A meta-analysis found no significant reduction in overall depressive symptoms with infliximab in TRD (Bavaresco et al., 2019).
  • No significant effect in bipolar depression, except in subgroups with inflammation/trauma history (McIntyre et al., 2019).
  • Found no improvement in non-inflammatory TRD patients (Raison et al., 2013).
• Inflammation as a Predictor of Response
  • Across multiple studies, higher inflammation (CRP >3–5 mg/L, elevated TNF-α) predicted who responded to infliximab.
  • Biomarker-based precision medicine may be needed to identify patients who would benefit from anti-inflammatory therapy.