Clinical evaluation of switching from immediate-release to prolonged-release lithium in bipolar patients, poorly tolerant to lithium immediate-release treatment: A randomized clinical trial

Aim: The effect of switching from lithium immediate release (Li-IR) to lithium prolonged release (Li-PR) on lithium-induced tremor after 1 and 12 weeks of treatment was evaluated in a randomized, multicenter, open trial, in bipolar patients from the participating sites with a tremor severity ≥2 (Udvalg for Kliniske Undersøgelser [UKU] rating scale) despite optimal lithium titration. Methods: The primary endpoint was the evaluation of tremor by means of the UKU scale after 1 week of treatment. Secondary endpoints included manic Young Mania Rating Scale (YMRS) and depressive symptoms (Montgomery-Asberg Depression Rating Scale), a global assessment of the patient's status (Clinical Global Impression), polyuria/polydipsia (UKU item 3.8) and patient-reported outcomes. Results: Owing to difficulties in including suitable patients the enrollment phase was closed when 73 patients were randomized. Notwithstanding the lower number of patients, in the modified intention-to-treat population (n = 70) the primary endpoint was statistically significant: tremor improved after 1 week in 62.9% in Li-PR group against 20.0% of patients in Li-IR group (p = .0006; two-tailed Fisher's exact test). The difference remained statistically significant after 4 (p = .0031) and 12 weeks (p = .0128). The same analysis performed in the PP population confirmed these results. Among the secondary endpoints, only the factor convenience of the treatment satisfaction questionnaire showed a statistically significant difference between groups. There were no apparent differences in the safety profile of the two formulations. Conclusions: This study is the first comparative documentation of a potential benefit of the prolonged-release formulation in reducing the symptom tremor, a well-known adverse effect of lithium therapy. Indeed, the study results should be interpreted taking into account the sample size lower than planned.