Much Ado About Area 25

An estimated 16 percent of the American population will suffer from major depressive disorder at some point during life. The disease strikes down nearly 19 million Americans each year, and it’s likely to happen more than once. A whopping 50 percent will experience an encore performance within two years of their initial depressive “episode,” and the stats get even worse after the second recurrence.

What does this mean? It means that if you’re wired for depression, you’ll likely spend most of your adult life on some form of antidepressant–a fate that many do not relish given the side effects and philosophical ramifications. And that’s discounting entirely the 30 percent of depression sufferers who get no relief from the current crop of antidepressants. All of which explains why breakthroughs in our understanding of depression make for such good headlines. Millions of Americans are waiting for a quick fix for depression and the media wants to give them good news.

The current superstar of depression research is area 25. (See The New York Times, Scientific American Mind, NPR–the list goes on and on.)Yes, I know. It doesn’t sound very sexy. But trust me, it is. Here’s why: if current findings prove correct, area 25 may one day be the key to curing depression. Not managing depression, or blunting depression, or masking depression – as many argue the current crops of drugs do – but curing it.

For those who don’t spend their time geeking out over breakthroughs in mental health, allow me to explain. After years of researching the mechanics of depression, Emory University Neurologist Helen Mayberg noticed something unusual. If you looked at fMRI scans of depressive’s brains next to scans of healthy people’s brains, the depressed people’s showed two things: reduced activity in the frontal cortex, and hyperactivity in an obscure section of the brain known as area 25. Mayberg grew curious, so she did some scans of depressed people pre- and post-treatment. As she predicted, once the patient’s medications took effect, normal frontal cortex activity was restored, and area 25 showed decreased activity.

Mayberg’s began to suspect that area 25 served as gateway of sorts–the bridge between the part of the brain responsible for negative rumination (the frontal cortex) and the seat of anxiety and fear (the limbic system). She wondered whether psychiatric drugs worked because they unintentionally reduced activity in area 25. To test her thesis, she decided to perform an experiment on 12 subjects whose chronic depression had stubbornly withstood drugs, talk therapy, and frequent bouts of electroconvulsive therapy.

The only way to test her theory was to bore two holes into the skulls of her subjects and insert electrodes directly into their brains–a stark reminder that neuroscience is still in its infancy. Yes, it sounds barbaric, but Mayberg’s hope was that delivering a small jolt of electricity to this site would effectively reboot it. And it looks like she was right. Eight of her 12 subjects experienced relief, some instantaneously. Their melancholy evaporated as if by magic and it has yet to return. A quick shock to area 25 appears to lower the gateway between negative thoughts and painful feelings, effectively eliminating both the emotional and physiological components of depression.

All of this is good news and certainly worthy of note. If area 25 proves to be the conductor of depressive thoughts, learning how to regulate it could eventually render SSRIs and the like obsolete. But when The New York Times Magazine runs a cover story called the “The Depression Switch?” people are likely to jump to the conclusion that a cure for depression is just around the corner. And this is patently untrue. Even if Mayberg’s theory is born out in future studies, the average depression sufferer will have to wait years to reap the benefits.

Why? Because, at present, the only way to target area 25 is through invasive brain surgery. And, let’s face it, few among us would be willing to let a neurologist drill a hole in our heads and feed wires directly into our brains. Even if you were game, the odds of being admitted into one of Mayberg’s studies are very, very slight. So, the vast majority of depression sufferers will have to bide their time and wait for a drug capable of:

1) Overcoming the blood brain barrier, and
2) Effectively regulating activity in area 25.

To say that this is a Herculean task is a huge understatement. Right now, the only way scientists have found to breech the blood brain barrier (the barricade between the blood stream and the brain) is to design drugs that act like carpet bombs. SSRIs, for example, work by bathing the brain in serotonin. This has proven effective in alleviating depression in many people, but it also impacts the functioning of systems better left untouched (i.e., the dopamine pathways that control libido).

A drug capable of making a beeline for area 25 is going to be a long time coming. So while Mayberg’s findings offer hope to many, they won’t deliver relief for years to come.

**Virtual Endnote: I don’t mean to be a Gloomy Gus. Here’s some good news. There are more than 40 new antidepressants/anti-anxiety medications in development, a few of which are scheduled for release over the next 2-3 years. Many of these appear to have fewer sexual and physiological side effects than SSRIs. Neurontic will run a short piece on some of the most promising candidates at a future date.