Medication Quickly Lifts Bipolar Depression Symptoms

People with treatment-resistant bipolar disorder were relieved from the symptoms of depression in as little as 40 minutes after an intravenous dose of the anesthetic medication ketamine. The potential for side effects makes ketamine impractical for standard use, but similar compounds may have potential as rapid and effective medications for depression, including bipolar depression.

Bipolar disorder is marked by severe swings in mood, energy and behavior. Episodes of depression alternate with spells of mania. The depressive episodes tend to be more frequent and longer-lasting. Bipolar disorder can be disabling, affecting academic performance and making it hard to keep a job. It's also among the psychiatric disorders with the highest risk of suicide.

Bipolar disorder is usually treated with mood stabilizing medications such as lithium, valproate, carbamazepine or other medications. For depressive episodes, antidepressant medications are often used in addition to a mood stabilizer. However, existing medications typically take weeks to have an effect, and many patients don’t respond adequately to them.

A team led by Dr. Carlos A. Zarate Jr. of NIH's National Institute of Mental Health (NIMH) set out to find faster acting medications to treat bipolar depression. The researchers focused on the brain chemical glutamate. Previous research suggested that altered glutamate signaling between neurons likely plays a role in depression. The anesthetic medication ketamine is known to block NMDA receptors, an important class of receptor for glutamate. In a previous study, the researchers found that ketamine had a rapid antidepressant effect in patients with treatment-resistant major depression.

For the new study, the team enrolled 18 people with bipolar disorder who had been unsuccessfully treated with at least one antidepressant medication and a mood stabilizer. All the patients received maintenance treatment with a mood stabilizer medication. In the first phase of the study, the participants were randomly assigned to receive a single dose of either intravenous ketamine or placebo (saline). After 2 weeks, the treatment was switched. Neither the patients nor those treating them knew whether they were receiving ketamine or placebo. The results appeared in the August 2010 issue of the Archives of General Psychiatry.

The researchers found that, within 40 minutes, more than half of the patients receiving ketamine had at least a 50% reduction in symptoms, with 13% becoming nearly symptom-free. The response to ketamine lasted an average of about a week. By contrast, no patients receiving placebo had declines in symptoms close to that seen with ketamine.

The authors note that the rapid antidepressant response seen in 2 different disorders—major depressive disorder and bipolar disorder—confirms the importance of the NMDA receptor in developing quick-acting treatments. Medications targeting the glutamate system have the potential to bring rapid relief from depression, even in people who have failed to respond to other existing therapies.

Researchers are now focusing on developing NMDA-targeting medications that are suitable for clinical use, both for rapid relief and for long-term maintenance.