Neurocognitive changes in lithium-treated older adult bipolar patients on antipsychotics

Lithium is the gold-standard mood stabilizer in bipolar disorder (BD) showing putative neuroprotective effects, but its association with cognition in older adults with BD (OABD) remains unclear.

To examine the association of long-term lithium treatment with cognitive performance in euthymic OABD.

Forty outpatients aged 50-70 years with BD-I, without dementia or lifetime substance use disorder, completed a comprehensive neuropsychological battery. Participants were classified as lithium- (n = 19) or non-lithium-treated (n = 21). Test scores were converted to age- and education-adjusted Z-scores. We used t-tests/Mann-Whitney U tests, and Person's correlations were Bonferroni-corrected. A principal component analysis-generated general cognitive factor was entered into logistic regression models predicting lithium status, with sequential adjustment for various covariates.

Lithium-treated patients showed large, widespread cognitive advantages in attention/working memory (Digit Symbol Forward Test (DSFT), d = 1.481; DSBT, d = 1.519), verbal learning and memory (Rey's Auditory Verbal Learning Test (RAVLT) recognition, d = 1.803), processing speed (Symbol Digit Modalities Test (SDMT), d = 2.147), executive function (Trail Making Test - Part B, d = 1.330), and verbal fluency (Controlled Oral Word Association Test (COWAT), d = 1.423). Higher lithium levels correlated with better DSFT and SDMT performance after correction. Antipsychotic dose was strongly and negatively correlated with Mini-Mental State Examination, particularly in the non-lithium group. The general cognitive factor distinguished lithium from non-lithium patients (R² = 0.70), and its effect remained large and mostly significant across six adjusted models.

In euthymic OABD, chronic lithium treatment is associated with markedly better global cognition, independent of mood, illness severity, and polypharmacy. Our findings provide support for the role of lithium in cognitive preservation and are worthy of further investigation in larger longitudinal studies.