• Science Update
People with treatment-resistant bipolar disorder experienced relief from symptoms of depression in as little as 40 minutes after an intravenous dose of the anesthetic medication ketamine in a preliminary study; while the patient group was small, this work adds to evidence that compounds in the class to which ketamine belongs have potential as rapid and effective medications for depression, including bipolar depression. The potential for side-effects makes ketamine an impractical drug for standard use, but it provides a way to test this approach for developing novel treatments that act more rapidly than existing ones.
Bipolar disorder (BD) is a potentially debilitating illness marked by severe swings in mood, energy, and behavior. Episodes of depression alternate with spells of mania but depressive episodes tend to be more frequent and longer-lasting and the depression is difficult to treat. BD is usually treated with mood stabilizing medications such as lithium, valproate, carbamazepine or other medications with the goal of preventing mood episode relapse. Antidepressant medications are often used in addition to a mood stabilizer for depressive episodes, but antidepressants typically take weeks to have an effect and many patients do not respond adequately to existing medications.
Previous research has suggested that a disruption of signaling between neurons involving the neurotransmitter glutamate is likely to play a role in depression. The anesthetic medication ketamine shuts down one class of receptor for glutamate (NMDA receptors).
Eighteen people with BD participated in this study of ketamine. All received maintenance treatment with a mood stabilizer medication during the study. All had previously been unsuccessfully treated with at least one antidepressant medication and a mood stabilizer; the average number of medications they had tried unsuccessfully was seven.
In the first phase of the study, each person was randomly assigned to receive a single dose of either intravenous ketamine or placebo (saline). After two weeks, treatment was switched, so those initially receiving ketamine received placebo, and vice versa. Neither patients nor those treating them were told whether they were receiving ketamine or placebo. Investigators used standard surveys of depression symptoms to assess the effect of medication.
Within 40 minutes, 9 of 16 (56 percent) patients receiving ketamine had at least a 50 percent reduction in symptoms, and 2 of 16 (13 percent) became 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 the magnitude seen with ketamine within the first 3 days.
In this study, carried out by scientists Nancy Diazgranados, Carlos Zarate, Jr., and colleagues at the Experimental Therapeutics & Pathophysiology Branch of NIMH's intramural research program, a single intravenous dose of ketamine brought relief from depression in severely treatment resistant patients with BD, in over half of them within 40 minutes. This study supports a previous one by the same group in which they also found a rapid antidepressant effect in patients with treatment-resistant major depression (unipolar). (NIMH press release, August 7, 2006). The authors note that the rapid antidepressant response observed in these two different disorders (major depressive disorder and bipolar disorder) highlights the importance of the NMDA receptor in developing treatments with a rapid onset of action.
The work adds to the evidence of the potential of medications targeting the glutamate system for rapid relief from depression, even in cases of people who have failed to respond to other existing therapies. Rapid and effective treatment of depression is an urgent public health need. BD can be disabling—nearly all the patients in this study were unemployed as a result of the severity of their illness. BD is among the psychiatric disorders with the highest risk of suicide.
Continuing research is focusing on developing NMDA-targeting medications that are suitable for clinical use; and investigating the use of this class of drugs for long-term maintenance of the rapid antidepressant effect seen in this study.
Diazgranados, N., Ibrahim, L., Brutsche, N.E., Newberg, A., Kronstein, P., Khalife, S., Kammerer, W. A., Quezado, Z., Luckenbaugh, D.A., Salvadore, G., Machado-Vieira, R., Manji, H.K., and Zarate, C. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry 2010;67(8):793-802.