June 2010

Olanzapine Long-Acting Injection
Extended-release injectable olanzapine (Zyprexa Relprevv) appears to be similar in efficacy to oral olanzapine for relapse prevention in patients with schizophrenia.

Preventing Relapse in Bipolar I Disorder: Lithium, Valproate, or the Combination?
In an open-label trial, the combination of lithium and valproate (Depakote and others) was more effective at preventing breakthrough mood episodes than valproate monotherapy in patients with bipolar I disorder.

Choosing among SSRIs: How Does Fluvoxamine Rate?
Fluvoxamine (Luvox and others) is similar to other selective serotonin reuptake inhibitors (SSRIs) in efficacy and overall tolerability for the acute treatment of major depression. Specific side effects vary among antidepressants.

In Brief
"Traditional" Diet Lowers Risk of Depression and Anxiety; ECT Benefits Patients with Chronic PTSD

Green Tea and the Risk of Depression
In a cross-sectional study, increased consumption of green tea was associated with a decreased risk of depression.

Preventing Relapse in Bipolar I Disorder: Lithium, Valproate, or the Combination?

June 2010

In 1949, Australian psychiatrist John Cade first reported on the beneficial effects of lithium in patients with bipolar disorder. Although lithium remains a mainstay of treatment for this condition, newer agents have eclipsed its popularity and use. Lithium has many adverse effects and requires regular blood tests. Also, because lithium is a naturally occurring chemical, it cannot be patented, and pharmaceutical companies actively promote more expensive medicines. Between 1992 and 1999, prescription of lithium for outpatients in the United States fell by about half, while the rate of valproate (Depakote and others) prescribing almost tripled.1 Lithium is sometimes combined with other agents when patients with bipolar disorder fail to respond to a single medication. An international collaborative trial called Bipolar Affective disorder: Lithium/ANtiConvulsant Evaluation (BALANCE) recently compared lithium, valproate, and the combination for maintenance treatment.2

The trial, which took place in the United Kingdom, the United States, Italy, and France between 2001 and 2007, enrolled 330 patients, aged 16 years and older, with bipolar I disorder. Subjects were randomly assigned in open-label fashion to one of the three options for an active run-in phase of 4 to 8 weeks to guarantee tolerance, followed by up to 24 months of maintenance treatment. The target lithium concentration was 0.4 to 1.0 mmol/L. The valproate dose was at least 750 mg/day, with a target daily dose of 1250 mg or the highest dose tolerated and a serum concentration of at least 50 µg/mL.

Patients on combination treatment fared best. Of 110 subjects who received both drugs, 59 (54%) required a new intervention for an emergent mood episode, which was the primary outcome event. By contrast, 65 (59%) of 110 in the lithium monotherapy group and 76 (69%) of the 110 in the valproate group had emergent mood episodes during follow-up.

The principal result of this study is that the combination conferred a 41% relative benefit over valproate alone—an advantage that was irrespective of baseline severity of illness and maintained for up to 2 years. The main benefit of the combination was in preventing manic (rather than depressive) relapses. Combined treatment was 5.5% better than lithium monotherapy, but this was not statistically significant. The 10% advantage of lithium monotherapy compared with valproate monotherapy was statistically significant, but the authors suggest caution in this comparison.

More than half of the participants taking combination therapy required additional treatment during follow-up, underscoring the need for more efficacious treatments for bipolar I disorder. Furthermore, all three study treatments were less efficacious for depressive recurrences than for manic ones, and depressive episodes in bipolar disorder are prevalent and disabling. The authors call for other drug combinations to be studied and the adverse effects of both lithium and valproate to be quantified. They suggest that future guidelines for the treatment of bipolar disorder downgrade valproate from a first-line treatment option and present combination therapy to patients as a superior alternative to valproate alone. They also recommend that patients with frequent relapses during lithium monotherapy be considered for combination therapy before being switched to valproate monotherapy.

In an accompanying comment, Licht notes that data from placebo-controlled studies support the benefit of long-term valproate monotherapy in patients who have responded to valproate in acute therapy.3 He thinks that the suggestion by the BALANCE group that patients who are insufficiently stabilized on long-term lithium alone should be considered for lithium combined with valproate is debatable. He suggests instead that such patients be offered treatment with a medication other than these two drugs.

BALANCE is a good study, albeit with the compromises and limitations that exist in any clinical trial. It adds to knowledge about long-term therapy for this common disorder. Undoubtedly, bipolar disorder is, like all psychiatric conditions, a heterogeneous syndrome with various biological etiologies. Response to a medication like lithium is probably a proxy for biologically distinct pathology, possibly genetically mediated. Thus, a patient who responds to lithium might not respond as favorably to an alternative treatment with a different mechanism of action. That said, as combinations are applied, with medications that are pharmacologically distinct, it is likely that more patients will achieve the sought-for mood stability, albeit at the price of increased adverse effects. There is still great unmet need in the treatment of bipolar disorder.

1Blanco C, Laje G, Olfson M, Marcus SC, Pincus HA: Trends in the treatment of bipolar disorder by outpatient psychiatrists. Am J Psychiatry 2002;159:1005-1010.

2BALANCE investigators and collaborators, Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, Ostacher MJ, Morriss R, Alder N, Juszczak E: Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): A randomised open-label trial. Lancet 2010;375:385-395.

3Licht RW: A new BALANCE in bipolar I disorder. Lancet 2010;375:350-352.