Trial Report Lithium Aspartate for Long COVID Fatigue and Cognitive Dysfunction: A Randomized Clinical Trial, 2024, Guttuso et al.

Lithium Aspartate for Long COVID Fatigue and Cognitive Dysfunction: A Randomized Clinical Trial
Thomas Guttuso; Jingtao Zhu; Gregory E. Wilding

IMPORTANCE
Neurologic post–COVID-19 condition (PCC), or long COVID, symptoms of fatigue and cognitive dysfunction continue to affect millions of people who have been infected with SARS-CoV-2. There currently are no effective evidence-based therapies available for treating neurologic PCC.

OBJECTIVES
To assess the effects of lithium aspartate therapy on PCC fatigue and cognitive dysfunction.

DESIGN, SETTING AND PARTICIPANTS
A randomized, double-blind, placebo-controlled trial (RCT) enrolling participants in a neurology clinic from November 28, 2022, to June 29, 2023, with 3 weeks of follow-up, was conducted. Subsequently, an open-label lithium dose-finding study with 6 weeks of follow-up was performed among the same participants enrolled in the RCT. Eligible individuals needed to report new, bothersome fatigue or cognitive dysfunction persisting for more than 4 weeks after a self-reported positive test for COVID-19, Fatigue Severity Scale-7 (FSS-7) or Brain Fog Severity Scale (BFSS) score of 28 or greater, Beck Depression Inventory-II score less than 24, and no history of a condition known to cause fatigue or cognitive dysfunction. All participants in the RCT were eligible for the dose-finding study, except for those who responded to the placebo. Intention-to-treat analysis was used.

INTERVENTION
Lithium aspartate, 10 to 15 mg/d, or identically appearing placebo for 3 weeks followed by open-label lithium aspartate, 10 to 15 mg/d, for 2 weeks. In the subsequent dose-finding study, open-label lithium aspartate dosages up to 45 mg/d for 6 weeks were given.

MAIN OUTCOMES AND MEASURES
Change in sum of FSS-7 and BFSS scores. The scores for each measure range from 7 to 49, with higher scores indicating more severe symptoms. Secondary outcomes included changes from baseline in the scores of additional questionnaires.

RESULTS
Fifty-two participants were enrolled (30 [58%] males; mean [SD] age, 58.54 [14.34] years) and 26 were randomized to treatment with lithium aspartate (10 females) and 26 to placebo (12 female). Two participants assigned to lithium aspartate were lost to follow-up and none withdrew. No adverse events were attributable to lithium therapy. There were no significant intergroup differences for the primary outcome (−3.6; 95% CI, −16.6 to 9.5;P = .59) or any secondary outcomes. Among 3 patients completing a subsequent dose-finding study, open-label lithium aspartate, 40 to 45 mg/d, was associated with numerically greater reductions in fatigue and cognitive dysfunction scores than 15 mg/d, particularly in 2 patients with serum lithium levels of 0.18 and 0.49 mEq/L compared with 1 patient with a level of 0.10 mEq/L.

CONCLUSIONS AND RELEVANCE
In this RCT, therapy with lithium aspartate, 10 to 15 mg/d, was ineffective for neurologic PCC fatigue and cognitive dysfunction. Another RCT is required to assess the potential benefits of higher lithium dosages for treating neurologic PCC.

TRIAL REGISTRATION
ClinicalTrials.gov Identifier:NCT05618587 and NCT06108297


Link | PDF (JAMA Network Open) [Open Access]

 

Perhaps a dose-response study should have been done in the first place.

 

"There are both autopsy and neuroimaging data supporting chronic brain inflammation as a mechanistic contributor to the neurologic PCC symptoms of fatigue and cognitive dysfunction.5-8"

Interesting to see this boldly stated. Is that commonly understood or are these researchers 'over reaching' the evidence?

"The brain glial cells of microglia and astrocytes are primary mediators of neuroinflammation when activated.9 Using 2 different positron emission tomography (PET) ligands, widespread increases in microglial and astrocyte activation are seen in patients with neurologic PCC compared with healthy controls, signifying increased neuroinflammation.7,8 These studies show the greatest increases in inflammation in the ventral striatum, dorsal putamen, and thalamus, which are regions previously implicated in engendering symptoms of fatigue and cognitive dysfunction.10-13 Because inflammation seen on PET imaging is known to localize to brain sites preferentially affected in neurologic diseases, including Alzheimer disease, Parkinson disease, and stroke,14-17 therapies known to suppress glial activation and neuroinflammation in these sites would represent promising therapies for neurologic PCC fatigue and cognitive dysfunction."

"Lithium, in addition to being an effective treatment for bipolar disorder, has a multitude of neuroprotective actions.18 One of these actions is its ability to reduce neuroinflammation by suppressing both microglial and astrocytic activation.19-23"

I'm wondering what other therapeutics could be identified as possibly useful.

Dosage used was 15ml/d and they now think that a dose nearer 45ml/d could be more effective. They did try pts on the 45 dose but only for 3 weeks. Seems quite short time.

 

The author believes in trying lithium for everything and has written a book on how wonderful lithium is. I doubt it has any significant anti-inflammatory effects. Glial activation in people who have had brain damage is not a sign of ongoing oinflammation as much as repair I suspect.

I don't know whether we have reviewed these PET papers here? I will have a look.

 

Of the two papers claiming neuroinflammation, one has never been formally published, the other looked at 20 cases with depression and cognitive problems who had had Covid. The problem here is that if they had any pre-existing brain problems before Covid they are probably more likely to get cognitive problems after covid. So the findings may reflect pre-existing subclinical brain disease. I think we did look t this a year or two ago. Certainly this is very limited and weak evidence for an effect of Covid on glial activity.

 

I know people who are on lithium for life and it’s my understanding we have no idea why it works for bipolar disorders and there are significant side effects and possibility for complications. Seems a very odd thing to be trying here and a lot of reaching by the paper.

 

Forbes: Can A Medicine Used For Bipolar Disorder Help People With Long Covid?

A clinical trial of 52 people with long Covid who were prescribed low doses of lithium aspartate revealed that it failed to treat symptoms like chronic fatigue and brain fog. Despite this finding, researchers say higher doses of the medication might offer some relief from long Covid symptoms.

In a press release, lead author of the study, Thomas J. Guttuso, a professor of neurology at the Jacobs School of Medicine and Biomedical Sciences said: “It’s a negative study with a positive twist.”

“This is a very small number of patients, so these findings can only be seen as preliminary. Perhaps achieving higher blood levels of lithium may provide improvements to fatigue and brain fog in long COVID,” Guttuso added.​

The article continues: https://www.forbes.com/sites/anurad...bipolar-disorder-help-people-with-long-covid/