Initial trials of low-dose lithium failed to improve long COVID symptoms, but new findings suggest higher doses could offer hope for patients suffering from fatigue and cognitive impairment.

Study: Lithium Aspartate for Long COVID Fatigue and Cognitive Dysfunction. Image Credit: p.ill.i / Shutterstock

A recent study published in the journal JAMA Network Open investigated the effects of lithium aspartate on cognitive dysfunction and fatigue in post-coronavirus disease 2019 (COVID-19) condition (PCC). Long COVID or PCC is the persistence of symptoms for ≥ four weeks after COVID-19 recovery. PCC symptoms can linger for over six months in 10% of patients; cognitive dysfunction, fatigue, and post-exertional malaise are the most common symptoms. PCC remains a major cause of disability, impacting the quality of life of around 65 million individuals worldwide.

Neuroimaging and autopsy data support chronic brain inflammation as a contributor to neurologic symptoms of PCC – cognitive dysfunction and fatigue. Specifically, increased activation in the ventral striatum, dorsal putamen, and thalamus has been linked to these symptoms. Increased astrocyte and microglia activation has been observed in patients with neurologic PCC symptoms, suggesting elevated neuroinflammation. Therapies that suppress glial activation and neuroinflammation could be promising for neurologic PCC.

Lithium has various neuroprotective actions, including neuroinflammation reduction by suppressing astrocyte and microglia activation. In pilot clinical trials involving Alzheimer’s disease patients, 45 mg per day (mg/d) of lithium aspartate was associated with decreases in a neuroinflammation biomarker. As such, lithium might be a potential therapy for cognitive dysfunction and fatigue in PCC.

About the study

In the present study, researchers investigated the effects of lithium aspartate treatment on cognitive dysfunction and fatigue in PCC. This double-blind, randomized, placebo-controlled trial enrolled patients at a neurologic clinic between November 28, 2022, and June 29, 2023. Eligible patients had a positive COVID-19 test with new/worsened symptoms of cognitive dysfunction and fatigue lingering for at least four weeks post-COVID-19 recovery.

Eligible participants were required to have a Beck Depression Inventory (BDI)-II score

The primary outcome was the change in the sum of BFSS and FSS-7 scores. Secondary outcome measures were changes in various questionnaires from baseline. Subjects were randomized to receive lithium aspartate or placebo capsules. They took two capsules daily for the first 10 days; if their symptoms were still bothersome, they were allowed to take three capsules daily for the subsequent 11 days.

At a follow-up visit 21 days post-baseline, patients were provided with a two-week supply of open-label lithium capsules. They were asked to start with two capsules daily in the first week and increase the dosage to three capsules in the second week if they still felt their PCC symptoms were bothersome.

After the trial, a dose-finding study was performed to examine whether lithium aspartate doses up to 45 mg/d were associated with improved BFSS or FSS-7 scores compared to 15 mg/d during the trial. They were instructed to start with two capsules a day (10 mg/d) for the first week and increase one capsule daily every week to a maximum dose of 45 mg/d. The study used an intention-to-treat analysis, adding robustness to the trial’s findings.

Findings

Overall, 52 patients, on average 58.54 years old, were randomized. Of these, 50 completed the trial and entered the open-label lithium phase; outcome data were available for 45 subjects. Ten subjects (six placebo and four lithium aspartate recipients) opted to continue with two capsules per day in the trial. Two and five subjects in the lithium aspartate and placebo groups had adverse events. Importantly, none of the adverse events were attributable to lithium therapy. No adverse events occurred during the open-label lithium phase.

The researchers observed no significant group differences for the primary outcome. On average, the FSS-7 and BFSS scores changed about -17.4 and -14.4, respectively, for all patients reporting much or very much improved symptoms on the patient global impression of change (PGIC) questionnaire. Further, five patients participated in the dose-finding study. Of these, four continued 15 mg/d for 7–12 months after the trial, and only one reported satisfactory benefit from this dosage.

One patient withdrew after no perceived improvements in cognitive dysfunction or fatigue at 40 mg/d. Another patient experienced mild sedation at 45 mg/d, which subsided at 40 mg/d. Among three patients who completed the dose-finding study, 40 – 45 mg/d was associated with a numerically higher reduction in cognitive dysfunction and fatigue.

Conclusions

Taken together, the study showed that 10 – 15 mg/d of lithium aspartate was ineffective for PCC cognitive dysfunction and fatigue. Only five patients from the trial participated in the dose-finding study, and results from three patients suggested that serum lithium levels of 0.18 – 0.49 mEq/L might offer meaningful improvements in fatigue or cognitive dysfunction. However, the study has notable limitations, including a small sample size and the lack of biomarker assessments, which could have helped identify patients more likely to benefit from lithium therapy. As such, another trial will be required to examine the benefits of higher lithium doses to treat neurologic PCC.