Lithium Is Regaining Favor Over Anticonvulsants

UCSD

After years of aggressive counter-detailing by the manufacturers of anticonvulsants, there has been a resurgent interest in the use of lithium, as clinicians have come to recognize the limitations of non-lithium mood stabilizers. While divalproex was initially lauded for its ease of administration, issues with thrombocytopenia, hyperammonemia, hypoalbuminenia, and neutropenia have tempered the early enthusiasm. Moreover, large retrospective studies such as the classic paper by Goodwin and his colleagues have demonstrated that lithium possesses superior anti-suicidal properties compared with divalproex.

In recent months, several studies have highlighted the potential benefits of lithium, and the July 2015 issue of the British Journal of Psychiatry included three papers covering important aspects of lithium. One of these papers focused on lithium’s role in neuroprotection, a hypothesis supported by extensive in vitro and in vivo data. Using a large U.S. claims database, researchers examined dementia risk during a mean follow-up of 19 months in a cohort of 41,931 bipolar patients aged 50 and older. The researchers found that the use of lithium for 301 to 365 days was associated with significantly reduced dementia risk (hazard ratio [HR] = 0.77, 95% CI 0.60-0.99), whereas exposure to anticonvulsants was not associated with reduced dementia risk.

The second paper directly compared non-suicide mortality of patients taking lithium with those taking valproate using large balanced cohorts (21,288 patients per group) from a VA database. Both short- and long-term exposure to lithium was associated with decreased non-suicide mortality compared with valproate (for example, 1 year HR = 0.62, 95% CI 0.45–0.84). Supporting the direct action of lithium on this outcome, the investigators found increased mortality risks among patients who discontinued lithium treatment before 180 days (HR = 1.54, 95% CI 1.01–2.37).

The third British Journal of Psychiatrypaper examined the association between natural lithium in drinking water and suicide rates. Previous meta-analyses suggest that higher lithium concentrations in drinking water may be associated with reduced risk of suicide in the general population, and this paper comes to similar conclusions, though this group observed the effect only in males.

Lithium, of course, is not without its own potentially problematic side effects. Polyuria, for example, is not uncommon in patients treated with lithium. The gold standard measure for polyuria, a 24-hour urine collection, can be burdensome and often impractical. In search of alternative tests, a team from Dublin performed a battery of tests on lithium-treated patients and correlated these results with those from a 24-hour urine collection. As the authors described in the August 2015 issue of the Journal of Clinical Psychopharmacology, among the laboratory measures, early morning urine osmolality was able to distinguish those with clinically significant polyuria. This is an easily obtained assay performed from a single specimen, with the only inconvenience being the preference to obtain the specimen in the morning.

However, there is an easier and more reliable screening tool that involves no trip to the laboratory: the 24-hour fluid intake recollection (FIR). The Dublin researchers noted that FIR values of less than 2000 mL in 24 hours were associated with a very low likelihood of polyuria, while those with an intake greater than 3500 mL/24 hours had very high likelihoods of polyuria. The FIR involves no early morning trip to the lab and can be repeated as needed if there is doubt about the validity of a result. Those who screen positive based on the FIR should have a follow-up early morning urine osmolality to provide a biological measure, particularly if there is consideration of an amiloride trial.

Lithium provides many unique benefits, but clinicians must find ways to manage the adverse effects. This simple, elegant study should help establish the standard use of 24-hour FIR as a screening measure for polyuria. Try it out—your patients will thank you for it. ■