New strategy for developing antidepressants

Researchers may be able to develop an antidepressant which takes effect almost immediately by directly targeting novel molecules in the brain instead of taking a less direct route, which can lead to longer times for medication to take effect, according to a new study presented at the American College of Neuropsychopharmacology (ACNP) annual meeting.

The antidepressant is also thought to be effective in people for whom previous treatments have been ineffective. This human and rodent research is among the first to examine the effects of rapid antidepressant strategies.

Lead researcher and ACNP member Husseini Manji, M.D., director of the mood and anxiety disorders program at the National Institute of Mental Health (NIMH), says one of the major limitations in existing pharmacological treatments for major depression is the time between starting to take the medication, and when it starts to alleviate the depression, often a period of one month or longer. He adds that strategies that work at much faster rates would have a tremendous impact for Americans who suffer from depression – nearly 21 million annually, according to NIMH.

"Today's antidepressant medications eventually end up doing the same thing, but they go about it the long way around, with a lot of biochemical steps that take time. Now we've shown what the key targets are and that we can get at them rapidly," says Dr. Manji. “This research is leading to some very real possibilities for a whole new generation of antidepressant medications."

The study looked at patients in a “difficult to treat” group, meaning individuals who had not responded to other treatments including psychotherapy, traditional antidepressants or electroconvulsive therapy. This group did not attempt all treatment options, like medication. Researchers treated the depressed patients intravenously with ketamine, a general anesthetic usually used for minor surgical procedures in which muscle relaxation is not required. The doses of ketamine used in this study were considerably lower than when it is used as an anesthetic.

Ketamine produced results much more quickly than traditional antidepressants because it acted directly upon critical molecules in important neuronal circuits instead of having to bypass multiple locations en route to those circuits. Typically, currently available antidepressant medications work via serotonin or norepinephrine, neurotransmitters which act within the brain to help regulate emotion and cognition.

The results showed that patients responded after only two hours, and within 24 hours, 70% had responded. Patients were followed over time, and 35% maintained their response for up to one week. Traditional antidepressants usually take many weeks, or even months, to begin to work. “This is intriguing data which suggests that targeting these important molecules in critical circuits would be extremely helpful in treating depression more quickly, before it worsens and becomes more severe,” Dr. Manji said.

The researchers also studied rodents to determine whether they could get medication to highly responsive brain areas more quickly. By looking at different biomarkers – specific physical features used to measure the progress of a disease or condition – in mice and rats, researchers came closer to identifying at what point in the biochemical process medication might become effective, which would ultimately lead to faster treatment.

Treating patients with rapid strategies is essential since some patients who suffer from depression are tempted to stop their medication if it doesn't work quickly enough.

Ongoing human studies using magnetoencephalography (MEG) are also helping to identify the specific brain circuits through which these rapid antidepressant effects occur. Identifying these precise circuits may lead to the development of molecules with even more precise effects, and therefore fewer side effects.