A New Generation of Rapid-acting Antidepressants?

/ Author:  / Reviewed by: Joseph V. Madia, MD

Conventional antidepressant treatments generally require three to four weeks to become effective, thus the discovery of treatments with a more rapid onset is a major goal of biological psychiatry.

The first drug found to produce rapid improvement in mood was the N-methyl-D-aspartic acid (NMDA) glutamate receptor antagonist ketamine.

In the new issue of Biological Psychiatry, researchers from the National Institutes of Health report  another medication, scopolamine, also appears to produce replicable rapid improvement in mood. Scopolamine temporarily blocks the muscarinic cholinergic receptor, thought to be overactive in people suffering from depression.

Drs. Wayne Drevets and Maura Furey recruited outpatients with major depressive disorder who were randomly assigned to receive placebo and then scopolamine treatment or vice versa in a double-blind study, so neither the researchers nor the patients knew which treatment they were receiving.

"Scopolamine was found to reduce symptoms of depression within three days of the first administration. In fact, participants reported that they experienced relief from their symptoms by the morning after the first administration of drug," explained Dr. Furey. "Moreover, one-half of participants experienced full symptom remission by the end of the treatment period. Finally, participants remained well during a subsequent placebo period, indicating that the antidepressant effects persist for at least two weeks in the absence of further treatment."

The efficacy of scopolamine is very interesting because the potent blockade of muscarinic receptors was a property of tricyclic antidepressant medications, the oldest type of antidepressants. With these medications, the muscarinic receptor blockade was mostly viewed as the cause of unwanted side effects, such as constipation, sedation and memory impairments. Newer antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), were explicitly designed to avoid blocking muscarinic receptors. Yet the current data raise the possibility this strategy may have increased safety and tolerability of these medications at the expense of providing effective and timely relief for depression symptoms.

Dr. John Krystal, editor of Biological Psychiatry, commented that these findings "have the potential to raise expectations for new antidepressant treatments. Three to six weeks is a long time to wait for depression symptoms to be alleviated. Depressed people describe their emotional state using terms like 'agony' and others compare their condition to 'living in hell.' Further, depression is a life-threatening condition for some, preventing them from performing basic self-care functions or causing them to exhibit self-destructive behavior."

Although these findings open the door to a conceptually different approach to treating depression, it remains to be seen whether rapid-acting antidepressant effects will be viable clinically. One could imagine such medications might mitigate hospitalization in some patients and enhance the overall effectiveness of depression treatment. However, this possibility remains to be demonstrated empirically in studies showing a rapid-acting antidepressant treatment can be smoothly transitioned to definitive long-term treatment for depression.

Maureen Hunter
[email protected]

Reviewed by: 
Review Date: 
September 16, 2010
Last Updated:
September 16, 2010