Bipolar Disorder treatment and role of Lithium
Bipolar disorder (BD) is an episodic illness with a very heterogeneous clinical course. It usually presents as a severe, chronic, and disabling condition characterized by mood alterations between euthymia, major depression, and (hypo-)mania. The estimated lifetime prevalence ranges from 0.6% to 2.4% worldwide. BD is usually a lifelong disease, hence requiring lifelong treatment strategies. One of the major pharmacological agents in the treatment of BD is lithium. It remains the gold standard in preventing recurrences in BD I (mania and depressive episodes) and BD II (hypomania and depressive episodes) and is effective in the treatment of mania. Additionally, the proposed anti-suicide effect of lithium is unique and potentially of high relevance in the treatment of BD over the lifespan, as patients with BD suffer from high suicide rates. Over the last decades, other substances such as second generation antipsychotics (SGA) and anticonvulsants have been prescribed more frequently and there has been a tendency to avoid lithium in the treatment of BD. Reasons may be the overestimation of potential side effects as compared to other substances by professionals and patients alike, despite the highly problematic metabolic profile of antipsychotics (e.g., Olanzapine), particularly over the lifespan.
This narrative review focuses on lithium-treatment over the lifespan in BD and gives a summary of its effectiveness, side effects, and treatment recommendations with regard to specific treatment conditions and subtypes of BD. Furthermore, we discuss the risk of lithium-discontinuation, which is an important topic in the treatment of BD over the lifespan.
The pharmacological treatment of BD has several goals. Lithium is the agent of the “first hour” in the treatment of BD and has been used over decades in all phases of the disease. Lithium treatment aims at the prevention of relapses and is used in the treatment of acute episodes, such as mania, depression, and specific subtypes, such as mood episodes with mixed features or rapid cycling (RC) (see below). Especially with regard to the lifespan, the efficacy of lithium in special treatment conditions, such as BD in paediatric and older aged patients and BD during pregnancy and postpartum are of high relevance.
For each of these conditions, different recommendations are available from different treatment guidelines. The German S3 guidelines also recommends lithium as the first choice of treatment for patients with high risk for suicidality. First, we give a short summary of the general effects of lithium in mania, depression, and maintenance treatment of BD.
Bipolar depression is the predominant pole in BD type I and type II and responsible for a large number of suicides. The suicide rate is 20-times above that of the general-population, which is considerably larger than that of unipolar depression. Bipolar depression is also associated with a high rate of morbidity and mortality due to comorbid somatic disorders. However, treatment of bipolar depression is challenging for clinicians, as the classical treatment strategies of unipolar depression (antidepressants, lithium) show small(er), if any, effects. The lack of effectiveness of antidepressants in BD has been the topic of an ongoing controversy. There is evidence that antidepressants may worsen the course of the disease in patients with mixed symptoms or RC by increasing the switch risk or causing tachyphylaxis after repeated antidepressant drug exposures.
Similarly, the available data strongly doubt the effectiveness of lithium in treating bipolar depression. The large EMBOLDEN I study found that lithium was not more effective than placebo in treating bipolar depression. In an open-label RCT comparing venlafaxine and lithium in bipolar depression in BD type II, lithium was significantly less effective than the antidepressant. However, relatively low lithium serum levels are a possible limitation of this and several other trials investigating lithium in the treatment of bipolar depression. Albeit the lack of evidence supporting lithium monotherapy in the treatment of bipolar depression, there are substantial differences in international treatment guidelines with regard to the role of lithium in bipolar depression. Some guidelines, such as the CANMAT guidelines, still regard lithium as a first line treatment option in bipolar depression. These guidelines argue that lithium should be considered in the acute treatment of bipolar depression due to its central role as a mood stabilizer, its effectiveness in preventing mania and the proposed anti-suicide effect.
These guidelines highlight the low number of studies investigating lithium in bipolar depression and the limitations of these studies. Contrarily, the German S3 guideline does not recommend the use of lithium monotherapy in the treatment of bipolar depression. The WFSBP guideline agrees with that recommendation and emphasizes the combination therapy of lithium with other agents in bipolar depression.
