Lithium may be protective of cognitive function in the long term since it promotes neurogenesis in the hippocampus and increases grey matter volume in the prefrontal cortex. Antidepressants Antidepressants are used with caution in bipolar disorder, as they may not be effective and may even induce mania. They are generally not used alone, but may be considered as an adjunct to lithium. A recent large-scale study found that severe depression in patients with bipolar disorder responds no better to a combination of antidepressant medications and mood stabilizers than it does to mood stabilizers alone and that antidepressant use does not hasten the emergence of manic symptoms in patients with bipolar disorder. The concurrent use of an antidepressant and a mood stabilizer, instead of mood stabilizer monotherapy, may lower the risk of further bipolar depressive episodes in patients whose most recent depressive episode has been resolved. However, some studies have also found that antidepressants pose a risk of inducing hypomania or mania, sometimes in individuals with no prior history of mania. Saint John's Wort, a naturally occurring compound, is thought to function in a fashion similar to man-made antidepressants, and there are reports that suggest that it can also induce mania. For these reasons, some psychiatrists are hesitant to prescribe antidepressants for the treatment of bipolar disorder unless mood stabilizers have failed to have an effect, however, others feel that antidepressants still have an important role to play in treatment of bipolar disorder. Side effects vary greatly among different classes of antidepressants. Antidepressants are helpful in preventing suicides in people with bipolar disorder when they go in for the depressive phase. NMDA-receptor antagonists In a double-blind, placebo-controlled, proof-of-concept study, researchers administered an N-methyl-d-aspartate–receptor antagonist (ketamine) to 18 patients already on treatment with lithium (10 patients) or valproate (8 patients) for bipolar depression. From 40 minutes following intravenous injection of ketamine hydrochloride (0.5 mg/kg), the researchers observed significant improvements in depressive symptoms, as measured by standard tools, that were maintained for up to 3 days, an effect not observed in subjects who received the placebo. Five subjects dropped out of the ketamine study; of these, four were taking valproate and one was being treated with lithium. One patient showed signs of hypomania following ketamine administration and two experienced low mood. This study demonstrates a rapid-onset antidepressant effect of ketamine in a small group of patients with bipolar depression. The authors acknowledged the