Path: /clinical-trials/lithium-psp-phase-2-nct05297202 NCT ID: NCT05297202 Phase: Phase 2 Status: Recruiting Sponsor: Academic/NIH-funded Study Start: 2022
This Phase 2 clinical trial evaluates low-dose lithium as a potential disease-modifying treatment for Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS). Both are 4R-tauopathies characterized by tau pathology, and lithium's GSK-3beta inhibition targets the shared tau hyperphosphorylation mechanism underlying neurodegeneration in these conditions.
Path: /clinical-trials/lithium-psp-phase-2-nct05297202 NCT ID: NCT05297202 Phase: Phase 2 Status: Recruiting Sponsor: Academic/NIH-funded Study Start: 2022
This Phase 2 clinical trial evaluates low-dose lithium as a potential disease-modifying treatment for Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS). Both are 4R-tauopathies characterized by tau pathology, and lithium's GSK-3beta inhibition targets the shared tau hyperphosphorylation mechanism underlying neurodegeneration in these conditions.
The trial represents a critical test of the hypothesis that GSK-3beta inhibition can slow disease progression in pure tauopathies, building on previous mixed results from lithium trials in Alzheimer's disease. By targeting patients earlier in disease progression and focusing on PSP/CBS as "pure" tauopathies without significant amyloid co-pathology, this trial addresses key limitations of prior studies.
This Phase 2 clinical trial evaluates low-dose lithium as a potential disease-modifying treatment for progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), both representing devastating 4R-tauopathies characterized by progressive tau pathology, neuronal loss, and relentless clinical decline. The trial leverages lithium's well-established activity as a glycogen synthase kinase-3 beta (GSK-3beta) inhibitor to target the fundamental tau hyperphosphorylation mechanism that drives neurofibrillary tangle formation in both conditions.
The rationale for this trial stems from decades of research establishing GSK-3beta as a central kinase responsible for pathological tau phosphorylation. By inhibiting GSK-3beta activity, lithium may reduce tau phosphorylation at multiple canonical sites, decrease tau aggregation propensity, and potentially slow the progression of tau-mediated neurodegeneration. Importantly, this approach targets a shared mechanism across PSP and CBS, offering the potential for a therapy that addresses the underlying pathophysiology common to both disorders.
PSP is a distinct clinical syndrome classified as a 4R-tauopathy due to the predominant accumulation of 4-repeat tau isoforms in neurofibrillary tangles. The disease was first described by John Steele, Jerzy Olszewski, and John Richardson in 1963, hence the alternative name Steele-Richardson-Olszewski syndrome.
Core Clinical Features:
Variants:
CBS represents the clinical manifestation of corticobasal degeneration (CBD), another 4R-tauopathy. The syndrome features:
Shared 4R-Tauopathy: Both conditions are classified as 4R-tauopathies, characterized by elevated inclusion of the four-repeat tau isoform in neurofibrillary tangles. This is distinct from Alzheimer's disease, which involves both 3R and 4R tau isoforms.
Common Tau Pathology Mechanism: In both PSP and CBS, the tau protein undergoes hyperphosphorylation at multiple serine and threonine residues, mediated in large part by GSK-3β. This hyperphosphorylation reduces tau's ability to bind microtubules, promotes tau misfolding, and drives the formation of toxic oligomers and filaments.
GSK-3β Overactivity: Multiple lines of evidence suggest that GSK-3β activity is increased in the brains of patients with PSP and CBS, contributing to the observed tau pathology. This provides a mechanistic rationale for therapeutic intervention.
Unmet Medical Need: Both PSP and CBS lack disease-modifying therapies. Current treatments address only symptoms and do not slow disease progression. The development of a tau-directed therapy represents a critical unmet need.
Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase with diverse physiological functions in the central nervous system:
This Phase 2 clinical trial evaluates low-dose lithium as a potential disease-modifying treatment for Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS). Both are 4R-tauopathies characterized by tau pathology, and lithium's GSK-3β inhibition targets the shared tau hyperphosphorylation mechanism underlying neurodegeneration in these conditions[@forlenza2023].
The trial represents a critical test of the hypothesis that GSK-3β inhibition can slow disease progression in pure tauopathies, building on previous mixed results from lithium trials in Alzheimer's disease. By targeting patients earlier in disease progression and focusing on PSP/CBS as "pure" tauopathies without significant amyloid co-pathology, this trial addresses key limitations of prior studies.
PSP is a distinct clinical syndrome classified as a 4R-tauopathy due to the predominant accumulation of 4-repeat tau isoforms in neurofibrillary tangles. The disease was first described by John Steele, Jerzy Olszewski, and John Richardson in 1963, hence the alternative name Steele-Richardson-Olszewski syndrome.
Core Clinical Features:
Variants:
CBS represents the clinical manifestation of corticobasal degeneration (CBD), another 4R-tauopathy. The syndrome features:
Glycogen Synthase Kinase-3 beta (GSK-3β) is a serine/threonine kinase that plays a central role in tau phosphorylation. In tauopathies, GSK-3β activity is upregulated, leading to hyperphosphorylation of tau at multiple disease-relevant epitopes:
Major Phosphorylation Sites:
Beyond GSK-3β inhibition, lithium exerts multiple beneficial effects relevant to neurodegeneration:
Autophagy Enhancement:
Lithium activates autophagy through multiple mechanisms:
The trial uses low-dose lithium (target serum level 0.6-0.8 mEq/L) rather than standard mood-stabilizing doses (0.8-1.2 mEq/L) based on several considerations:
The LITAGE trial (Phase 2, 2012-2015) used low-dose lithium (0.5-0.8 mEq/L) in AD patients[@litage2015]:
Several factors suggest PSP may respond better to lithium:
| Trial | Disease | Phase | Dose | N | Outcome |
|-------|---------|-------|------|---|---------|
| LITAGE | AD | RCT | 0.5-0.8 mEq/L | 45 | No cognitive benefit, biomarker changes |
| ADNI Lithium | MCI/AD | RCT | 0.5-0.8 mEq/L | 80 | Safe, reduced p-tau181 |
| Lithium 4RT (this trial) | PSP/CBS | Phase 2 | 0.6-0.8 mEq/L | 120 | Ongoing |
Inclusion Criteria:
Exclusion Criteria:
| Arm | Intervention | Dose | Titration |
|-----|--------------|------|-----------|
| Active | Lithium carbonate tablets | Target 0.6-0.8 mEq/L | Gradual over 4-6 weeks |
| Placebo | Matching placebo tablets | N/A | Identical schedule |
Neuroimaging:
| Week | Serum Target | Typical Dose | Monitoring |
|------|--------------|--------------|------------|
| 1-2 | 0.3-0.4 mEq/L | 150 mg daily | Weekly lithium level |
| 3-4 | 0.4-0.5 mEq/L | 300 mg daily | Weekly lithium level |
| 5-6 | 0.5-0.6 mEq/L | 300-450 mg daily | Bi-weekly level |
| 7+ | 0.6-0.8 mEq/L | 300-600 mg daily | Monthly level |
Target serum level: 0.6-0.8 mEq/L
Laboratory Monitoring:
| Adverse Event | Frequency | Severity | Management |
|---------------|-----------|----------|------------|
| Tremor | 20-30% | Mild-moderate | Dose reduction, propranolol |
| Diarrhea | 15-20% | Mild-moderate | Dose reduction, loperamide |
| Sedation/fatigue | 5-10% | Mild | Usually transient |
| Hypothyroidism | 5-8% | Moderate | Levothyroxine replacement |
| Weight gain | 5-10% | Mild | Monitor |
| Thirst/urination | 10-15% | Mild | Supportive |
Serious adverse events (rare): lithium toxicity at >1.2 mEq/L requires immediate intervention.
Multiple academic medical centers in the United States:
Metabolic Regulation: GSK-3β was originally characterized as a key regulator of glycogen synthase activity, hence its name. It plays roles in glucose metabolism and cellular energy homeostasis.
Neuronal Signaling: GSK-3β is involved in numerous signaling pathways including Wnt, PI3K/AKT, and NMDA receptor signaling. It modulates synaptic plasticity, learning, and memory processes.
Protein Synthesis: Through regulation of eukaryotic initiation factor 2B (eIF2B), GSK-3β influences protein translation rates in neurons.
Cell Cycle and Survival: GSK-3β participates in cell cycle regulation and programmed cell death pathways, with complex roles in neuronal survival decisions.
In Alzheimer's disease, PSP, CBS, and other tauopathies, GSK-3β activity becomes dysregulated:
Hyperphosphorylation of Tau: GSK-3β phosphorylates tau at over 40 known sites, including critical residues such as Ser199, Ser202, Thr205, Thr231, Ser396, and Ser404. When these sites are phosphorylated, tau loses its ability to stabilize microtubules and instead becomes prone to aggregation.
Increased Kinase Activity: Post-mortem studies of PSP and CBS brain tissue demonstrate increased GSK-3β activity or expression compared to age-matched controls. This may result from:
Synaptic Dysfunction: GSK-3β overactivity contributes to synaptic loss and cognitive decline through effects on synaptic proteins and dendritic morphology.
The centrality of GSK-3β in tau pathogenesis has made it an attractive drug target:
Direct Kinase Inhibitors: Small molecule inhibitors like lithium, tideglusib, and AR-014418 directly inhibit GSK-3β activity.
Indirect Modulation: Other approaches target upstream regulators of GSK-3β, including Akt/PI3K pathway modulators.
Substrate-Targeting Approaches: Alternative strategies aim to reduce tau availability or enhance tau clearance rather than inhibiting the kinase directly.
Lithium is an alkali metal that has been used for decades as a mood stabilizer in bipolar disorder. Its neuroprotective effects are mediated through multiple mechanisms:
Direct GSK-3β Inhibition: Lithium directly inhibits GSK-3β by competing with magnesium ions required for kinase activity. This inhibition is relatively specific at therapeutic concentrations.
Inhibitory Phosphorylation: Lithium promotes inhibitory phosphorylation of GSK-3β at Ser9, providing an additional mechanism of enzyme suppression.
Inositol Depletion: Lithium inhibits inositol monophosphatase, reducing intracellular levels of phosphatidylinositol (4,5)-bisphosphate (PIP2) and downstream signaling through various receptors.
Neurotrophic Effects: Lithium increases levels of brain-derived neurotrophic factor (BDNF) and promotes neuronal survival through Akt signaling.
Anti-apoptotic Effects: Lithium activates pro-survival pathways and protects neurons from various toxic insults.
The inhibition of GSK-3β by lithium leads to several beneficial effects on tau pathology:
Reduced Phosphorylation: Decreased GSK-3β activity results in reduced phosphorylation of tau at canonical GSK-3β sites. This restores microtubule binding and reduces aggregation propensity.
Enhanced Clearance: Less heavily phosphorylated tau may be more readily degraded by the ubiquitin-proteasome system and autophagy pathways.
Reduced Aggregation: Tau with fewer phospho-epitopes has reduced tendency to form oligomers and filaments.
Preserved Synaptic Function: By reducing tau-mediated toxicity, lithium may help preserve synaptic connections and cognitive function.
Achieving therapeutic concentrations in the central nervous system while avoiding peripheral side effects presents a challenge:
Serum Levels: The trial targets serum lithium levels of 0.6-0.8 mEq/L, a range lower than typically used for bipolar disorder (0.8-1.2 mEq/L).
CNS Exposure: Lithium readily crosses the blood-brain barrier, and CSF levels approximate 30-40% of serum levels.
Titration Strategy: Starting at low doses and titrating gradually minimizes the risk of acute neurological side effects while allowing assessment of individual response.
Lithium has been evaluated in several previous clinical trials for neurodegenerative diseases:
Alzheimer's Disease Trials: Multiple trials have evaluated lithium in AD, with mixed results:
Frontotemporal Dementia: Smaller studies evaluated lithium in FTD variants with variable results.
Previous trials informed the design of the current PSP/CBS trial:
Dose Optimization: Lower doses than traditionally used for bipolar disorder may provide optimal risk-benefit.
Patient Selection: Trials in earlier disease stages may show greater benefits.
Biomarker Integration: Including biomarker endpoints helps assess target engagement.
Combination Approaches: Lithium may be more effective as part of combination therapy.
The trial enrolls patients with clinically diagnosed PSP or CBS:
Age: 40-85 years
Diagnosis: Probable PSP (any subtype) or CBS per established clinical criteria
Disease Severity: PSP Rating Scale (PSPRS) score of 15-60, indicating mild to moderate disease
Functional Status: Able to swallow tablets and comply with study procedures
Concomitant Medications: Stable on allowed medications
Key exclusion criteria include:
Prior Lithium Exposure: Current lithium use or history of lithium intolerance
Medical Contraindications: Significant renal disease (creatinine >1.5x upper limit), thyroid disease, or cardiac disease
Psychiatric Contraindications: Bipolar disorder requiring lithium treatment
Neurological Procedures: Prior thalamotomy or deep brain stimulation
Other Conditions: Active malignancy, severe infection, or other conditions precluding participation
Design: Randomized, double-blind, placebo-controlled
Allocation: 1:1 randomization to lithium or placebo
Blinding: Subjects, investigators, and outcome assessors blinded to treatment assignment
Lithium Dosing:
Efficacy: Change in PSP Rating Scale (PSPRS) score from baseline to 12 months
Safety: Incidence and severity of adverse events, serious adverse events, and discontinuations due to adverse events
Neuroimaging: MRI brain volumetry to assess regional brain atrophy rates
CSF Biomarkers:
As of early 2026, the trial is actively recruiting at multiple sites in the United States.
Lithium treatment is associated with several common side effects:
Neurological: Tremor, sedation, fatigue, headache
Gastrointestinal: Nausea, diarrhea, abdominal discomfort
Renal: Polyuria (increased urination), polydipsia (increased thirst)
Thyroid: Hypothyroidism, goiter
Weight: Weight gain
Toxicity at High Levels: Serum lithium >1.5 mEq/L can cause severe toxicity including confusion, seizures, and coma
Renal Effects: Long-term lithium use can cause interstitial nephritis and reduced renal function
Thyroid Effects: Chronic lithium use can cause hypothyroidism requiring hormone replacement
Teratogenicity: Lithium is contraindicated in pregnancy (Category D)
The trial incorporates rigorous safety monitoring:
Regular Serum Testing: Lithium levels checked frequently during titration and periodically during maintenance
Renal Function: Creatinine, BUN, and calculated clearance monitored
Thyroid Function: TSH and T4 measured regularly
Neurological Assessment: Standardized examinations for signs of toxicity
Several factors support hope for this trial's success:
Strong Biological Rationale: GSK-3β inhibition addresses the core tau pathology mechanism
Human Genetics: GWAS data implicate GSK-3β pathway variants in tauopathy risk
Preclinical Data: Animal models show lithium reduces tau phosphorylation and improves behavior
Prior Human Data: Some clinical data support cognitive benefits in neurodegeneration
Unmet Need: No disease-modifying therapies exist for PSP or CBS
Several uncertainties remain:
Clinical Translation: Even with biomarker effects, will clinical outcomes improve?
Disease Stage: Are early-stage patients more likely to benefit?
Endpoint Sensitivity: Are standard scales sensitive enough to detect treatment effects?
Magnitude of Effect: Will lithium's effects be clinically meaningful?
Therapeutic Window: The margin between effective and toxic doses may be narrow
Long-term Safety: 12 months may not be sufficient to assess long-term safety
Individual Variability: Response varies significantly between individuals
| Approach | Mechanism | Stage | Pros | Cons |
|----------|-----------|-------|------|------|
| Lithium | GSK-3β inhibitor | Phase 2 | Well-characterized, CNS-penetrant | Moderate potency |
| Tideglusib | GSK-3β inhibitor | Phase 2/3 | More selective | Limited CNS penetration |
| Lithium + Minocycline | Combined | Phase 1/2 | Synergistic mechanism | Complexity |
| Antibodies | Anti-tau | Various | Direct targeting | Peripheral delivery |
A positive trial would:
A negative trial would:
Beyond lithium, several GSK-3β-targeted approaches are in development:
Selective Inhibitors: Tideglusib, AR-014418, and other more selective inhibitors
Combination Therapies: GSK-3β inhibitors combined with anti-amyloid or anti-tau antibodies
Protein-Protein Interaction Inhibitors: Agents targeting tau-tau aggregation
Gene Therapy Approaches: Vectors delivering GSK-3β regulatory proteins
Recruiting as of March 2026. The trial is actively enrolling patients at sites across the United States.
Estimated completion: 2027-2028
For patient eligibility and enrollment information, contact the study coordinators at participating sites or visit ClinicalTrials.gov.
| Drug | Company | Mechanism | Phase | Status |
|------|---------|-----------|-------|--------|
| Lithium (this trial) | Academic | GSK-3β inhibitor | Phase 2 | Recruiting |
| Tilavonemab (ABBV-8E12) | AbbVie | Tau antibody | Phase 2 | Completed (negative) |
| IONP-02 | Ionis | Antisense oligonucleotide | Phase 1 | Recruiting |
| LMTM (TRx0237) | TauRx | Tau aggregation inhibitor | Phase 3 | Failed |
| AADvac1 | Axon Neuroscience | Tau vaccine | Phase 2 | Completed |
This trial is MODERATELY RELEVANT to the Personalized Treatment Plan for atypical parkinsonism: