Editorials

Lithium in bipolar mood disorder

Evidence suggests that lithium should still be first choice for prophylactic treatment

Bipolar affective disorder, also called manic depression, is a common condition associated with multiple relapses often leading to unemployment, marital problems, alcohol abuse, and suicide. The lifetime prevalence is more than 1%, and 10-20% of patients commit suicide. Cade was the first to report the anti-manic effect of lithium, and by the late 1960s its role in the prophylaxis of bipolar disorder was established.¹ In the next decade it became widely used on both sides of the Atlantic as the first line of treatment for the condition. Recent prescribing patterns indicate that the use of lithium in the United States is declining relative to its use in European and other countries such as Australia. The evidence, however, suggests that lithium should be the first choice in the prophylactic treatment of most patients with bipolar disorder.

Some American clinicians no longer prescribe lithium because it is too toxic and alternatives are available. Marketing strategies for mood stabilisers such as valproate and a more hostile medicolegal environment than in European countries have also played a role. A recent multicentre study examined prescribing patterns of psychiatrists in the United States treating a large cohort of adult and older psychiatric inpatients with a primary diagnosis of bipolar disorder (WS Edell et al, Third International Conference on Bipolar Disorder, Pittsburgh, 1999). At discharge 60% of adult and 50% of older patients were taking valproate, carbamazepine, or lithium. This shows that in the United States over half of all patients are discharged without a licensed mood stabiliser and only in a minority of patients is lithium the chosen mood stabiliser.

Despite the recent trends in prescribing in the United States, lithium has the largest data set available for any mood stabiliser. Placebo controlled studies show efficacy in both the manic and depressive phases of illness and in the long term prophylaxis. To date there are 12 placebo controlled trials examining the prophylactic value of lithium. When these studies are combined the relapse rate on placebo and lithium is 80% and 35% respectively.²

The study by Bowden et al has undoubtedly had an impact on the use of lithium in the United States.³ It compared the efficacy of valproic acid (semisodium valproate, divalproex), lithium, and placebo as prophylactic treatment in 372 patients over 52 weeks after a manic episode. Valproate was found to be better than lithium in terms of a longer duration of successful prophylaxis and less deterioration in depressive symptoms. However, a recent Cochrane review of this and related valproate studies concludes that the shift of prescribing practice to valproate is not justified by the evidence, which provides equivocal support for the efficacy of valproate.⁴ In contrast, expert consensus guidelines from the United States support the view that either valproate or lithium is the cornerstone choice for both the acute treatment and prevention of mania.⁵ Both are viewed as equivalent and it is suggested that if monotherapy fails a combination of these agents should be used. In the United Kingdom valproate (as the semisodium salt) has recently been licensed for the treatment of manic episodes, but for most clinicians it remains a second choice for long term treatment. However, it may be of particular benefit in the subgroup of patients who present with a mixed state or as rapid cyclers.

Side effects of lithium are a major factor in non-compliance and contribute to its decreased usage in the United States. Most patients who are prescribed lithium experience some adverse effects, though mainly of a minor nature.⁶ However, even within the therapeutic range the impact on thyroid function can be profound. Overt hypothyroidism occurs in 5-10% of patients and 5% develop a goitre. Such effects are related to the dose and duration of therapy. Whether or not lithium results in memory disturbances is unclear, with a few studies reporting an effect but most failing to find any. Surveys show that many patients rightly or wrongly associate lithium with deterioration in their memory.² Significant gain in weight on lithium is often a source of concern for women. Approximately one in four patients prescribed lithium put on weight of 5 kg or more. However, alternatives to lithium have significant side effects for many patients.

Despite declining use, especially in the United States, the evidence base supports the view that lithium should be the first choice prophylactic drug for most patients with bipolar disorder. To date the alternative mood stabilisers have not been as extensively investigated. Valproate or carbamazepine should be confined to second line use in those who do not respond to lithium, or who have significant and unacceptable side effects due to lithium, and in patients with a history of rapid cycling.

Timothy G Dinan, professor. 

Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland (tdinan{at}indigo.ie)

Footnotes

   TD has received research donations for acting as a speaker and consultant and organising educational events for Eli Lilly and Pfizer.