Ways to Treat Depression That Aren't Antidepressants

By Matt McMillen
WebMD Health News

Reviewed by Brunilda Nazario, MD

Feb. 27, 2015 -- There may be hope for hard-to-treat depression as scientists explore novel ways to help people who have the often crippling condition.

Recently, a number of studies have suggested the benefits of Botox, ketamine, and certain sometimes-unexpected means of treating depression.

"I'm excited in general, and I'm curious," says Peter D. Kramer, MD, author of Listening to Prozac and Against Depression.

Each year, around 16 million U.S. adults battle major depression. Many of them benefit from antidepressants. But as many as a third get depressive symptoms despite medication. And side effects, which can include weight gain, nausea, and insomnia, are troublesome for some patients. That leaves many people with depression searching for alternatives.

But if Kramer is hopeful about the newer, novel ways to treat the condition, he's also cautious. The studies backing those treatments aren't conclusive, and none of the approaches have been approved by the FDA to treat depression (though some, such as ketamine, have been approved for other uses).

"Things are merely hopeful until they are demonstrated [safe and effective]," Kramer says. "It's always hard to tell what's going on, but it's a very interesting time, and I think some of them will come through."

Here's a closer look at what might be used to help treat depression in years to come.

Ketamine. Already in use in certain clinics and in some emergency departments around the country, ketamine is an anesthetic most often used during surgery. It's given through an IV, and it quickly eases symptoms of depression, often in a matter of hours. The benefit is temporary, though.

One recent study found it to be very good at helping curb suicidal thoughts in severely depressed people. But it's expensive, still experimental as a depression treatment, and can cause hallucinations and other side effects.

"Some people are very uncomfortable with the side effects," says Alan Manevitz, MD, a psychiatrist who specializes in treatment-resistant depression at Lenox Hill Hospital in New York City.

Nitrous oxide, or laughing gas. This is an anesthetic commonly used by dentists. A small study published last December reports that nitrous oxide improved depression symptoms within less than 2.5 hours.

Unlike ketamine, though, nitrous oxide had few side effects. The benefits lasted from 24 hours to a full week in some of the 10 people in the study. Much more research needs to be done on the safety and effectiveness of nitrous oxide, but Manevitz says it's promising.

"For people who are in suicidal despair or crisis, it may, like ketamine, temporarily relieve that person and act as a bridge until other treatments start working," he says.

Botox. Best known for temporarily erasing frown lines and crow's feet, onabotulinumtoxinA (Botox) has recently attracted interest as a novel means of lifting major depression. The theory is simple: If you can't frown, you won't be sad. And some research has borne this out.

A single Botox injection into the facial "frown muscles" provided lasting relief from depression symptoms, according to a study published last spring in the Journal of Psychiatric Research. Another study found similar effects following Botox injections into frown lines around the eyebrows. Many questions remain, though.

"The Botox is very interesting, and the best evidence [it helps] is as an add-on to antidepressants, but what's going on?" asks Kramer. "Is it really feedback to the brain, that if you can't frown, do you feel more resilient? Or is it that people respond to you differently?"

Anti-inflammatory medications. Inflammation has been linked to depression for several years now, says Brown. A recent review of studies, published in JAMA Psychiatry, further backs up the connection. The researchers found that painkillers such as celecoxib, ibuprofen, and naproxen reduced depression symptoms. Another class of anti-inflammatory drugs, called cytokine inhibitors, also showed some benefit.


Depression is a(n) __________ . See Answer

The authors of the review call their findings "proof of concept," meaning that their results are strong enough to encourage further research. Another recent study reports that omega-3 fatty acids, which have anti-inflammatory properties, helped treat depression linked to chronic hepatitis C.

"If you could actually treat depression symptoms along these lines, that would be interesting," Kramer says. "Some of the antidepressants are also anti-inflammatories, and some people have thought that maybe it's just coincidence that they work on [the brain chemicals] serotonin and norepinephrine, and that the real effect is anti-inflammatory."

Uncertain Future

The treatments listed above aren't the only ones being tested.

Nasal sprays that have protein peptides or small molecules have shown some promise, Kramer and Manevitz say. A method called transcranial direct current stimulation, which uses electricity to change brain activity, is also being tested.

Mindfulness meditation is another promising addition to depression treatment, and exercise is known to help relieve symptoms, too.

If some of the newer treatments seem far-fetched, Manevitz points out that the same was said just a few years ago about transcranial magnetic stimulation (TMS), a non-invasive therapy that uses magnets to affect parts of the brain linked to mood.

"People looked at me cross-eyed and thought it sounded wacky," he says. "Now, it's an FDA-approved treatment for depression, and it's used around the world."

Which, if any, of these treatments prove effective is anybody's guess at this point. Researchers have a lot of work ahead of them before any make it to patients in the clinic.

"So many medicines get lost in the pipeline," Kramer says. "Either it's hard to engineer them in ways that are not going to harm the kidneys or the liver, or the actual principle under which they are working turns out not to be right. It's hard to give your heart to any one of them because they tend to disappoint."

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SOURCES: Peter D. Kramer, MD, clinical professor of psychiatry and human behavior, Brown University; author, Listening to Prozac, Penguin Books, 1997, and Against Depression, Penguin Books, 2006. Alan Manevitz, MD, psychiatrist, Lenox Hill Hospital, New York. FDA: "Understanding Antidepressant Medications." Finzi, E. Journal of Psychiatric Research, April 1, 2014. Ballard, E. Journal of Psychiatric Research, August 2014. Nagele, P. Biological Psychiatry, December 2014. Wollmer, M. Frontiers in Psychiatry, March 2014. Kohler, O. JAMA Psychiatry, October 2014. Su, K-P. Biological Psychiatry, October 2014. NIMH: "Director's Blog: Antidepressants: A complicated picture." Johns Hopkins Medicine: "Meditation for Anxiety and Depression?" The New York Times: "How Exercise May Protect Against Depression."

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