Dementia Drug Helpful With Lupus Brain Fog

Cognitive dysfunction in people with systemic lupus erythematosus (SLE) — aka “lupus brain fog” — was significantly relieved with the Alzheimer’s dementia drug memantine in a small placebo-controlled trial.

Twelve weeks of memantine treatment led to a median improvement of 8 points on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), compared with a median 5-point increase with placebo in the 43-patient trial (P=0.032), according to Jillian Rhoads, PhD, of Vanderbilt University in Nashville, Tennessee, and colleagues.

Significantly more patients in the memantine arm gained at least 8 RBANS points — the standard threshold for clinically meaningful improvement — with treatment (12 vs 9 with placebo, P=0.047), the investigators reported in Annals of the Rheumatic Diseases.

“This provides a proof of concept that memantine may be an effective therapeutic for cognitive manifestations of NPSLE [neuropsychiatric SLE],” the team wrote. “Larger trials are needed to confirm these results.”

Neuropsychiatric involvement is common in SLE, seen in up to 80% of cases, with memory and attention deficits, Rhoads and colleagues observed. The exact mechanisms aren’t fully known, but SLE can disrupt the blood-brain barrier, allowing inflammatory elements to enter the central nervous system. In addition, autoantibodies may target structures in the brain, one of them being the N-methyl-D-aspartate (NMDA) receptor family. Moreover, NMDA can be activated with autoantibody binding.

Memantine is an NMDA receptor antagonist, binding the protein in such a way as to prevent its activation. It’s moderately effective in mild to moderate Alzheimer’s dementia (albeit temporarily), leading the researchers to hypothesize that it could help in NPSLE, via some combination of preventing autoantibody binding and, perhaps, other actions to reduce inflammation in the brain.

Rhoads and colleagues noted that memantine had been tried previously in lupus patients without showing a benefit, but that trial, from 2011, wasn’t restricted to patients with NPSLE, and the memantine dose was capped at 20 mg/day (the label-specified maximum for immediate-release formulations).

The current three-center trial, called ClearMEMory, enrolled 56 adults with NPSLE as determined from an initial screening survey followed by in-person exam. Memantine was started at 5 mg twice daily and escalated over 4 weeks to 20 mg twice daily. Patients with intolerable adverse effects during weeks 4-6 could have the dose reduced.

Eight patients assigned to memantine and five randomized to placebo didn’t complete the trial and were dropped from the analysis. In both groups, five patients quit because of adverse effects; two of the other memantine dropouts were for personal reasons and the third was for starting a prohibited additional medication.

Among the 43 who finished the trial, mean age was 43 and more than 90% were women. About one-third were Black and just over half were white. SLE Disease Activity Index 2000 (SLEDAI-2K) scores at baseline averaged 8.0. Mean baseline RBANS scores stood at 76 and 79 in the memantine and placebo arms, respectively.

Interestingly, SLEDAI-2K scores declined quite a bit in the memantine arm, a median of 2.5 points by week 12 (IQR 0-10.0). No real change in this parameter was seen in the placebo arm, but the between-group difference did not reach significance (P=0.17).

RBANS is divided into five domains (visuospatial, language, attention, and immediate and delayed memory), and much of the improvement in total scores with memantine versus placebo derived from the memory components. Language and visuospatial performance changed little in both groups, while attention showed improvement — more with memantine than placebo but not enough to reach statistical significance.

Patients’ self-assessments favored memantine, at least numerically, with 61% of patients in that group reporting some degree of improvement, compared with 36% of the placebo group (P=0.19).

Adverse effects weighed against memantine, however. Not only did five patients in that group quit prematurely because of them, out of 26 originally randomized to the drug, but not even half were able to tolerate the 40-mg/day target. Four patients had to stick with the starting dose of 10 mg/day and three others ended at 20 or 30 mg/day, leaving 11 able to take the maximum dose as planned.

For exploratory purposes, Rhoads and colleagues also stratified participants according to baseline detection of anti-NMDA receptor antibodies, the idea being that seronegative patients might not respond as well as those carrying the antibodies. Just 10 of the original 56 were seropositive for these autoantibodies, however. With such small numbers, no meaningful conclusions could be drawn.

Limitations to the study included the small overall sample (largely due to the COVID-19 pandemic, which forced an early halt to recruitment) and the short duration.