Doctors don't fully understand biology of depression

Despite major advances in research, between 30 and 40 percent of all people diagnosed with depression don’t respond to standard treatments.

That’s a failure rate that would be unacceptable today for heart disease or high blood pressure, and it shows what a long way doctors have to go in making chronic depression a disorder they can treat simply and effectively.

Part of the reason for the poor rate may be patients failing to stick with medications, but researchers also face more fundamental challenges.

They still don’t fully understand the biology of depression and have only partial answers to which imbalanced brain chemicals and miswired connections are driving the disease.

Ian Cook, a depression researcher at the University of California at Los Angeles, said the understanding of depression is similar to where lung disease was 100 years ago.

In those days, he said, pneumonia was described by the kind of phlegm people produced or the sounds their lungs made — not so different from describing depression today based on people’s symptoms.

“With understanding of what the causes were, this syndrome of pneumonia became understood as tuberculosis pneumonia, pneumococcal pneumonia, viral pneumonia, all of which may require very different treatments,” Dr. Cook said.

“The brain is a lot more complicated. We’ve got trillions of moving parts, all of which connect to each other to give rise to these illnesses, so it’s still a very complicated and humbling set of illnesses to work with.”

And while new brain imaging studies and animal experiments have yielded important discoveries about depression and its cousin disease, bipolar illness, doctors are still struggling to match the correct treatments to the right patients.

Mary Phillips, a brain imaging expert at the University of Pittsburgh, said studies by her team and others around the world are beginning to show the brain mechanisms for different types of depression — but there is not yet a good way to link these “biomarkers” to different treatments.

“It’s very frustrating actually,” she said. “The treatments for depression have developed in the absence of biomarkers, and yet we are now getting neuroimaging results and, somehow, we have to figure out a way to marry these two things.”

Much of the research today is aimed at figuring out the underpinnings of different types of depression and then predicting who will do best with different types of medication, psychotherapy, or more extreme treatments such as electroshock and deep brain stimulation.

Here is a sampling of some of those initiatives.

A key brain location

Helen Mayberg, a leading depression researcher at Emory University in Atlanta, has identified one area of the brain, the right anterior insula, that may help predict who will respond best to medications and who will do better with psychotherapy.

While some studies have shown that medications and psychotherapy are equally effective in treating depression, many researchers believe that some patients do better on one type of therapy or the other.

Dr. Mayberg’s work lends credence to that idea.

Her group did brain imaging of depressed patients and then randomly assigned them to get either cognitive behavioral therapy, which teaches patients how to alter their negative thoughts about themselves, or the drug escitalopram, also known as Lexapro, a common antidepressant.

After charting which patients no longer had symptoms after each therapy, her group then looked back to see if any particular brain area predicted who would do best with each approach. It found that patients who had an overactive anterior insula did best on medication, while those with an underactive insula responded better to the behavioral therapy.

The insula is an important center in the brain for integrating many of our bodily sensations with our emotions. It’s particularly important when people feel “angst, or when you feel disgust or have a queasy feeling,” she said.

It makes sense that medication might help to quiet down this area and lessen negative feelings, she said. But even more intriguing is why the insula might be underactive in the patients who did best on psychotherapy.

There is evidence that depressed people who suffer some kind of childhood trauma respond to that by shutting down their emotional systems, and the low-insula group may include those patients. By helping people recognize what is bothering them, psychotherapy may allow patients to “integrate the insula with other brain systems,” she said.

Dr. Mayberg’s group is now doing a larger study to see if they can replicate these early results. If so, it might provide a way of tailoring the right treatment to the right groups.

“We have very effective treatments,” she said, “but we don’t do a very good job of matching people to the treatment they need. At the end of the day, it’s not good enough to do trial and error. It’s costly, people are out of work, they can’t be involved with their families and some of them kill themselves. And people are using up their [insurance coverage] with treatments that are not effective.”

People who can’t enjoy life

Dr. Phillips is an expert in brain imaging of depressed and bipolar patients, with joint appointments at Pitt and the Institute of Psychiatry in London.

She has taken a particular interest in patients with anhedonia — from the Greek words for “without pleasure.” Unlike depressed patients who are anxious and can’t stop thinking about their problems, people with the anhedonic version are smothered in a gray blanket of numbness.

When the two types of depressed people are examined in a functional magnetic resonance imaging scanner, the anxious ones show an overactive amygdala, an almond-shaped structure that governs emotional reactions, along with too little control of the amygdala by the brain’s executive center in the frontal cortex, she said.

The anhedonia patients, by contrast, have too much frontal control, and it particularly seems to tamp down positive emotions in an area that releases the neurotransmitter dopamine, which has been linked to rewarding feelings.

Her lab is participating in a multi-center study aimed at determining which kinds of treatments will work best for different types of depressed people.

One of the drugs being explored for people with anhedonia, she said, is Wellbutrin, or bupropion, an older medication that boosts dopamine production.

Like other scientists, she wants to find ways to link specific brain activity patterns to effective treatments. Working with colleagues in London, her group has used a technique called machine learning to study the brain scans of young people in Pittsburgh who are vulnerable to depression.

The machine learning algorithms have been able to predict which children will go on to get depression. Eventually, the same technique may reveal which treatments will work best in different groups of people.

Low-cost tools

Brain imaging can be expensive and isn’t routinely covered by insurance for psychiatric care.

That is where some of the low-cost tools being developed by Pitt researcher Greg Siegle may play an important role.

One technique he uses is measuring the dilation of people’s pupils using a simple webcam. “Just about every interesting brain area innervates the pupil,” he said. “If we want to see if someone is going over and over negative things, you can show them negative words and take them away, and depressed people will show increased pupil dilation and it stays wider for maybe 30 seconds.

“So if your goal is to do cheap statistical prediction, we can do pupil dilation with a $100 webcam.”

In patients with the anxious form of depression, brain imaging can show how the prefrontal cortex — the thinking part of the brain — is failing to control the brain’s emotional centers. And while the cost of brain imaging is coming down, he said, researchers are now finding they can use a $350 EEG scan, in which electrodes are attached to the skull, and get good readings of prefrontal cortex function.

He said there also have been some encouraging results from using transcranial direct current stimulation for treating some forms of depression, and the equipment for that is “effectively two sponges and a 9-volt battery.”

In fact, in some cases, just asking a simple question can help determine what type of depression someone has or what treatment might work best, he said.

Patients who can’t enjoy daily life often need different treatment than those who worry excessively. “So we ask, ‘If you have a good meal or have sex, do you feel pleasure?’ and if the person says ‘No,’ that tells us something.”

Another simple screening question: “Have you had a relationship that lasted more than three months?” If someone says they haven’t, it means they probably are not a good candidate for cognitive psychotherapy, because “your first long-term relationship is not going to be with that therapist.”

These new tools mean “the era of consumer neuroscience is upon us,” he said.

“All of these are technologies that can be in the offices of health care practitioners in a few years,” he said, and “better assessment before treatment will allow us to prescribe tailored treatments.”

A new suspect in the brain

Much of the current research is aimed at figuring out which patients are the most likely to respond to existing antidepressants.

The top selling drugs — Zoloft, Celexa, Prozac — are all serotonin reuptake inhibitors, or SSRIs, meaning they make the neurotransmitter serotonin more available in the brain.

Dennis Charney, dean of the Icahn School of Medicine at Mount Sinai Hospital in New York, said there is no doubt in his mind that serotonin plays a role in depression. Not only do the SSRIs make many people feel better, but scientists have given depressed patients a drink that contains all the amino acids except the one that is the precursor of serotonin, and after consuming it, their depression symptoms immediately return.

Still, many researchers believe that serotonin may not be the primary brain chemical that is driving depression.

One new candidate is a neurotransmitter called acetylcholine, said Marina Picciotto, a psychiatry professor at Yale University.

In tests at Yale, researchers gave people a substance that attaches to the same brain receptors as acetylcholine. Much less of the substance bound to those receptors in depressed people, compared to those who had never been depressed, suggesting their brains had more acetylcholine competing to attach to the receptors.

And in experiments with rodents, her group found that when the animals got a substance that blocked the natural breakdown of acetylcholine, they exhibited the rodent form of depression, staying much longer inside a dark chamber.

One set of brain receptors that acetylcholine attaches to are the same ones that attract nicotine, which may explain why smoking is twice as common in people with depression as the rest of the population. By blocking the receptors that acetylcholine acts on, nicotine probably relieves some of the symptoms of the disease, she said.

Her work suggests there may be more than one pathway in the brain causing depression, which shows how complicated the disorder is — but may also lead to new treatments.

Exploring the gender gap

Twice as many women as men experience depression.

Etienne Sibille, a Pitt psychiatry professor, is trying to understand what causes that difference by using mice, which can get a form of depression after being exposed to anxiety-provoking stresses such as disrupted sleep, the smells of predators or being restrained.

Working with postdoctoral student Marianne Seney, his lab has used specially bred male mice that lack male gonads, as well as female mice that have male gonads. That way, they can test whether depression is influenced by the sex chromosomes themselves— XX for females, XY for males — or by the sexual organs releasing hormones.

Surprisingly, they found that the XY male mice who did not have gonads were more susceptible to depression than female mice, while XX female mice with male gonads were protected from depression.

It seems then, that depression “is balanced in adult [animals] by the effects of circulating testosterone, which is known to have anti-anxiety effects.”

That does not mean he would suggest using testosterone supplements for women with depression, though. “If you boost hormones in a context that is not appropriate, you can have great trouble,” he said.

Resetting our internal clocks

David Kupfer, a pioneering depression researcher at Pitt, started his career by focusing on the disturbed sleep cycles many depressed patients experience — hardly sleeping at all, or sleeping excessively.

Today, he still believes that the genes that control our daily, circadian rhythms may hold the key for at least some forms of depression.

For one thing, he said, research has shown that poor sleep makes people vulnerable to conditions like diabetes and obesity, so the disrupted sleep patterns in depression may help explain why people with the disorder have so many accompanying physical ailments.

Beyond that, though, it could be that a distorted circadian clock in the brain may actually trigger depression, he said.

There are several parts of the brain that help regulate the body’s daily rhythms, he said, and many of them also have a role in governing people’s moods. One key center, located in the deep brain structure known as the hypothalamus, helps reset our daily clocks using light signals from the eye.

One possible mechanism of depression, he said, is a lack of coordination among that part of the hypothalamus and other brain areas.

“I liken the hypothalamus to a central train station, and most of the time it operates on pretty good Swiss time. The trains come in and go out on time.

“But what happens if one of the trains begins to be regularly late, and it begins to have an effect on the rest of the trains coming in and going out of that station?

“So suddenly I’m having difficulty sleeping and eating and I’m not moving as quickly as I was, and my sexual interests and activity are all screwed up. So these very basic activities depend on the train station operating in a fairly good way and it’s not helping.”

Some existing treatments for depression seem to “reset” the brain’s clock, he said, including electroshock therapy, the use of the drug lithium in bipolar disease and even forms of talk therapy that emphasize “doing the same thing at the same time every day.”

Straightening out circadian rhythms may not help with every kind of depression, but it may be important for many patients, he said.

“The idea that there is one depression is absurd. And while there may not be thousands of depressions, there could be dozens. And one of those depressions may be related to a real circadian clock gene defect.”

Mark Roth:, 412-263-1130 and on Twitter: @markomar.

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