Why Depression Still Mystifies Us

J. Raymond DePaulo, Jr. M.D., professor of psychiatry at Johns Hopkins University School of Medicine, has called the study of depression “my ﬁrst love.” He is an active clinician, teacher, and researcher, whose genetic studies have added to our knowledge of one of depression’s most bafﬂing manifestations: bi-polar disorder. He is the author of a well-known book for laymen, How to Cope With Depression.

Dr. DePaulo has described depression as “a mystery disease,” a paradoxical characterization of an illness for which brain science has produced an array of usually effective medications. No one is more sensitive to that paradox than Dr. DePaulo. In this interview, he shows how research has overturned our beliefs about childhood depression, the prevalence of bipolar disorder, the genetics of depression, and the role of depression in alcoholism and smoking, bringing both new knowledge and bafﬂing new questions. Here is a relentlessly realistic look at the rugged landscape ahead for researchers on depression.

Lumpers and Splitters

Cerebrum: At a recent meeting on Capitol Hill, where you spoke on progress in brain research, you said that depression was something of a “mystery disease.” Is that because there are many varieties of depression?

Dr. DePaulo: No, it’s because we understand very little, if anything, about its mechanism. In one sense, even the term “major depression” is ambiguous. It’s not easy to distinguish major depression from other forms of depression, as if they had different causes. In the early days, when people were starting to use antidepressants, the term for what we would now call major depression (although the two terms aren’t entirely overlapping) was “endogenous depression.” That was supposed to contrast to “reactive depression.” An endogenous depression was supposedly a kind of disease; a reactive depression was supposed to be just a strong reaction to a stressful stimulus. In fact, in most endogenous depressions you can ﬁnd as many stressors as in reactive depressions. And if you treat people who present clinically with what used to be called reactive depression, a majority will improve on antidepressants.

Now, do I think that depression is three diseases? Four diseases? One disease with gradations of severity? It’s probably several diseases, each with gradations of severity.

I make residents read a wonderful paper written in 1938 by the great British psychiatrist, Aubrey Lewis, called The Classiﬁcation of Depressions. He went through every dichotomy: it’s endogenous, it’s reactive; it’s neurotic, it’s psychotic; it’s mild, it’s severe. And he concluded that none of them ﬁt all patients.

Cerebrum: That was 1938. In 2000 has it become clearer?

Dr. DePaulo: We’ve decided that those distinctions are less important. We just count the symptoms and measure the impairment, and that’s probably as good as we can do. I’m not a fan of algorithms to make diagnoses. That only paints by the numbers; it doesn’t teach how to examine patients or how to differentiate one condition from another.

Cerebrum: Are you viewing depression as a single complicated syndrome and talking only about the number and severity of symptoms?

Dr. DePaulo: At least for working purposes, we’re going to do that for now. It’s not that we necessarily believe that’s how it will work out in the long run. It’s a bit like the scientiﬁc debate between the lumpers, who seek broad categories, and the splitters, who go for ever-increasing levels of distinction. Eventually, the splitters always win. The problem, though, comes if a splitter has gotten a wrong idea. Then, if the ﬁeld accepts that wrong idea, it can’t get there from here. So my view is: okay, split, but if it doesn’t work, at least have the courtesy to lump it back together so that the world can try it again. We do think there are some splits. There are probably three categories that most people would accept: bipolar depression, unipolar depression (major depression), and dysthymia [persistent but less severe depression].

But the splitters can get carried away. An associate of mine, Dr. Francis McMahon, now at the University of Chicago, did grand rounds on the evolving Diagnostic and Statistic Manuals (DSM). He pointed that in DSMII there were four categories (or something like that) of affective disorders. By DSMIII, there were about 25. By DSMIII(R), there were 200. And by DSMIV, there were 2,200. He says, “This is a Roach Motel. You can only get in, you can’t get out.”

It’s ﬁne if somebody can show me that they’ve got groups that differ based on clinical response or in some other way that is valid and useful, even if they can’t tell me the basis.

Treatment That Never Cures

Cerebrum: For all the difﬁculty of ﬁnding the cause of depression, haven’t psychiatrists been quite successful in treating it?

Dr. DePaulo: Yes, although treatment is not nearly as successful as we’d like. We can’t come close to how well we treat pneumococcal pneumonia. Penicillin for pneumococcal pneumonia still cures more than 90 percent of the cases, probably 95 percent.

Over a two-year period, about 80 percent of the people treated for major depression get well. We’re not talking about the specialized population that comes to Johns Hopkins. We’re talking about people who walk into a general clinic, perhaps not knowing they have depression, and say, “Doctor, I’m feeling bad, please treat me.”

Cerebrum: But when you say “get well,” it’s not necessarily in the sense of curing pneumococcal pneumonia. How can you be sure that the depression has been cured?

Dr. DePaulo: Even when one seems well, we assume that it has not. We assume that we put the patient into remission. How long will the remission last? You guess, based on his past history. Even then, we know that there’s a slight tendency for past history to yield an overly conservative estimate of how soon he’ll relapse. And past history gets revised as the patient learns more about the illness. A patient who knows nothing about the illness will tell you, “Gee, this is the ﬁrst time I’ve ever had it.” Six months later, when he understands, when he’s thoroughly in remission, he’ll say, “Oh, you know, there was this time when I was eighteen. And there was the time after my daughter was born.”

Cerebrum: You would never pronounce a depression cured?

Dr. DePaulo: No.

Cerebrum: So the state of the art today would say that depression is a life-time chronic disease, which can be well treated, which often goes into remission, and which can be controlled if the patient cooperates?

Dr. DePaulo: And if the patient is fortunate enough to get the right treatment.

Cerebrum: There’s a certain amount of lore that if you have been successfully treated on antidepressants for awhile, it has reset your thermostat. If you go off, there has been some actual change. Is that your understanding?

Dr. DePaulo: It’s a nice idea; I think somebody ought to test it. But the data say that, in fact, you’ll relapse at the same rate as you did before, once you’ve taken away that protection. People have an illness that will return at a somewhat predictable rate.

A woman came in here at age 66. I saw her and said, yes, it’s a major depression, and treated her. She did well on short tricyclic antidepressant treatment. I treated her for a year and, during that time, the rest of her history came out. She had had an episode of major depression at age 44 and one at age 22. So I thought: take her off the antidepressant and tell her to come back when she’s 87 so we can avoid the next relapse, which will arrive on schedule when she’s 88. Ultimately we’re pragmatists. If I really believed that she was going to have her next episode at 88, I would tell her to come at 87 and pretreat her, but of course I’m not really sure at all. I did think, with her history of every 20 years, that she might go 10 ten years this time. Did she really need the antidepressant to do that?

She had a most unusual history, though. Most people who have had two or three relapses over a short period of time ﬁnd the illness devastating to their lives. If they could take a medicine that they tolerated and that kept them out of depression, they’d be helping their lives enormously. And yet, they tend to be reluctant to do it. But if you ask their family members, “Do you think your wife, your mom, you sister should stay on medication?” “Oh, yes!” Especially where there’s a good chance she’ll relapse.

Cerebrum: When the diagnosis of depression is solid and the response to treatment has been good, should you continue medication indeﬁnitely?

Dr. DePaulo: Yes, if they’ve had multiple episodes. If they’ve had a single episode of depression, I think the current opinion is you should stay on it 12 months. That’s not magical, why we picked 12 and not 11 and not 13. It’s just our best guess.

Cerebrum: What if a patient comes to you at 44 and has had three or four depressions. Would you put him permanently on an antidepressant?

Dr. DePaulo: I’m going to consider it a big part of my job to help you see that it’s in your interest to take one antidepressant or another for the rest of your life.

One in Six Thousand

Cerebrum: About 10 years ago, when you wrote How to Cope With Depression, you devoted one paragraph to this new drug called Prozac. And you said, well, there’s not much new except that it’s probably going to do better on the side effects; on the other hand, it might have some drawbacks. What was it about this drug that enabled it to become a superstar?

Dr. DePaulo: One thing was the lack of perceived side effects. Half of the patients who take it feel as though they’re taking nothing more than a vitamin pill.

Cerebrum: And that was not true with the tricyclics?

Dr. DePaulo: No. In general, when you’re taking a tricyclic, although the side effects may be trivial, and you may be thrilled to make the trade of a little dry mouth and a little constipation for not being depressed, you know you’re taking it. And many patients have a bit more side effects than that. But they’re good drugs. They are equally efﬁcacious, equally potent, against depression. This is important. Some of the managed-care people want to say therefore that you should choose the cheapest drug, because it is true, none of the new drugs works better than Imipramine, the original antidepressant. They’re all equally efﬁcacious.

But besides the side-effect improvement, the other thing about Prozac that was nice was that one pill a day was the right dose. You didn’t have to ﬁddle with the dosing. That made it simple to use. The other very important thing is that Prozac, and other drugs that followed it, like Zoloft, is much safer in overdose. Tricyclics are not safe in overdose, and unfortunately, because we’re treating people with depression, that’s got to be a consideration—especially since only two-thirds of them are going to get well on any particular medication.

Cerebrum: It’s been suggested that until development of the selective serotonin reuptake inhibitors (SSRIs) there had not been a “rational” drug for depression. In other words, the early antidepressants had been discovered by accident, but SSRIs were developed based on a theory. True?

Dr. DePaulo: I’ve heard that there were several accidents along the way to Prozac, too. Eli Lilly & Company may have had the drug before they decided to tie it to the theory. That was my understanding when I visited Lilly while they were developing Prozac. They said, in effect, we told our chemists in 1975 that we wanted a pure norepinephrine reuptake inhibitor (because that was one of the theories), and we wanted a pure serotonin reuptake inhibitor. Their idea was that there were two types of depression, one a norepinephrine depletion depression, the other a serotonin depletion depression. On the serotonin side alone, they went through six thousand compounds. I think that’s actually worth pointing out. They went through ﬁve thousand nine hundred and ninety seven compounds in animal testing to provide to the company only three compounds that looked safe enough to give to humans, and which did what they wanted it to do. Of the three, they picked one because it looked, I think, a lot safer. And thus was born Prozac.

When I looked at the clinical trials, they were not overly impressive. Prozac beat placebo about the same way that Imipramine would. It had a list of side effects, and if you just looked at the list, you’d say, well, dry mouth here is replaced by nausea there. Because 20 to 25 percent of patients would complain of nausea. But it turns out that was very transient and much milder than you would think, looking at it there on the piece of paper. If you look in the Physician’s Desk Reference, you’ll still see nausea as a 20-25 percent side effect. I can tell you that it turns out it was a trivial one, though there are occasional patients for whom it’s not trivial. And more side effects have been discovered, including orgasmic dysfunction as a signiﬁcant one. That was way underestimated initially, because they didn’t know to look for it.

Cerebrum: Doesn’t that effect on potency turn out to be an inhibition to patients to continue on Prozac?

Dr. DePaulo: It does. But, again, one that is manageable, depending on the length of time, the efﬁcacy of the drug, and the severity of the depression. As William Styron says, very eloquently, in his memoir called Darkness Visible, his conclusion was that his outpatient doctor knew nothing about depression when he hesitated to give him a monamine oxidase inhibitor because it might cause erectile dysfunction. He says, “If he thought I was more interested in a little carnal fun, the man knew nothing at all about what I was going through!” When people are in a depression, and you say, “Look, you might lose some sexual pleasure,” I can tell you that 95 percent say, “So what’s that? Get me well, we’ll ﬁgure that one out later.” And, by the way, about a year after they get better, if they do have that side effect (about 20 percent of them), then you start asking how to manage this, and then sometimes you do switch drugs.

My patients really get quite annoyed with me when I talk of “mild depression.” They point out that a little hopelessness goes a long way. Just mild hopelessness, you know!

Cerebrum: So the story is one of trial and error in developing these drugs?

Dr. DePaulo: Yes. Prozac elevates the indices of serotonin function in people who’ve failed to respond to it just as it elevates the indices in people who do respond to it. So, although it was designed with that mechanism in mind, we still don’t know why it works when it works or why it fails when it fails.

Cerebrum: Lithium is not used for ordinary depression, is it?

Dr. DePaulo: That’s not true. Lithium has been stigmatized. I see patients every day who think lithium has only one use. (It’s the way we think of orange juice, you can only drink it at breakfast). The evidence (there are very few studies) is that lithium alone may have antidepressive properties. Certainly in bipolar patients there are two effects: it prevents depression as well as mania. It also prevents unipolar depression. When it is added to another antidepressant, it is the additive medication most likely to make an antidepressant work after that antidepressant has failed alone, including in unipolar patients. So lithium, like all the other antidepressant drugs, is a mysterious treatment. We have even fewer clues as to how it works. But it certainly would be wrong to limit it to the bipolar patient.

Cerebrum: Doesn’t lithium also carry the stigma that, when you take it, you must be a psychotic?

Dr. DePaulo: You’ve got it. That’s what I have to ﬁght through with lots of very intelligent people.

When Nothing Works

Cerebrum: Are there people who just don’t respond to any antidepressant?

Dr. DePaulo: Somewhere in the 20 percent range.

Cerebrum: Are they an eclectic group of leftovers? Or do they share some important characteristics?

Dr. DePaulo: You mean, are there characteristics that predict poor response? Yes, probably there are a few things, but they’re not sufﬁcient. Chronicity is a predictor of poor response to any of our treatments. Somebody who has had a clinical depression for 10 years is more likely to show up in that 20 percent than somebody who’s had an acute depression for six months.

I was going to name severity, but severity is funny. Response according to severity follows a kind of inverted normal curve. People with the mildest depressions may not get speciﬁc beneﬁts from antidepressants because they sometimes get well soon after you sit down and talk with them, ﬁnd out what’s troubling them, give them some encouragement, and tell them to come back in a couple of weeks. People toward the other extreme, with severe—but not cataclysmically severe—depression are the best candidates for medication. But the ones with delusional depression, which would be at the most extreme end, will respond poorly to medications.

In drug studies, if you take the delusional depressions out, you can ferret out relationships between blood levels and treatment response much better, because the majority of patients with delusional depression don’t respond to simple antidepressants. That’s why I suggest that there’s something bafﬂing about severity. They do respond quite well to electroconvulsive therapy, called ECT. Unfortunately, ECT is a short-lived beneﬁt. People talk about its side effects, but those are short-lived, too. The negative side effects on memory disappear and, unfortunately, so do the good effects.

Cerebrum: But once you’ve jolted somebody out of the depths with ECT, can you continue the progress with medication?

Dr. DePaulo: We have certainly tried that. You can show that after ECT the patients do better on antidepressants than if you leave them off or put them on placebos.

Cerebrum: So the group of nonresponders that might be most signiﬁcant and most likely to share some characteristics are what you call the cataclysmically depressed?

Dr. DePaulo: And the chronically depressed.

Cerebrum: Is there evidence that longer depression tends to have some effect on part of the brain, like the hippocampus?

Dr. DePaulo: You could argue that. You’re talking about the work from people looking at the steroid cortisol. If you have high levels of steroids in your body for long enough, does that change the brain? There’s pretty good support for that possibility. The problem is that many people with chronic depression don’t have high cortisol to start with. It is on the acute side, with inpatients, that you have large numbers of people with high cortisol.

Biological Psychiatry: “Fumbling in the Dark?”

Cerebrum: Elliot Valenstein in his book Blaming the Brain, says that biological psychiatrists and drug companies have developed these drugs that obviously work, are helping patients, but now they’re reasoning backward to imply that they understand the cause of illnesses. He suggests that biological psychiatry is fumbling along in the dark.

Dr. DePaulo: Yes, we’re fumbling along, but we’re fumbling in the right direction. I would not disagree in principle that what we’ve got here are drugs that people are trying to reason backwards about, and that that is a very iffy proposition. If it were not an iffy proposition, we’d know a hell of a lot more by now. Whenever I hear a psychiatrist say, “Oh, well, this works, therefore…” I immediately say, “Be careful.” Even the brilliant neuroscientists will tell you that anybody who tries to reason past two synapses needs to see a psychiatrist.

Unfortunately, these ideas of biology versus psychology, or drug therapy versus psychotherapy, are still there. Both seem to miss what’s fundamental to our ﬁeld: the patients and their experiences, and how to evaluate them. You know, a patient who comes in complaining of a shoulder pain, but who turns out to have depression— diagnosing that is the essential skill, in my opinion. Putting a patient on Prozac is not a big skill. Giving her appropriate counseling, whether or not we want to call it cognitive or interpersonal, is a skill, although I don’t think it’s rocket science. I do think that there’s an essential skill of eliciting the patient’s history: being able to cross-examine patients in a way that they’ll tolerate and get you more precise information. And then developing and maintaining a relationship with them so that they will stick with you even through a difﬁcult course of treatment. Those are the clinical skills, in my opinion, that are crucial.

Cerebrum: When you wrote How to Cope With Depression, about a decade ago, you gave pride of place to viewing depression as a disease and treating it pharmacologically. Are you still of that opinion?

Dr. DePaulo: Not more, not less. I had a patient, back in the days when we didn’t have all these drug options, who would lose all of her white blood cells—literally all of them—whenever we gave her an antidepressant. So we couldn’t do it. Well, I didn’t abandon her. I said, “Let’s work on those things that seem to moderate your depressions, those environmental things.”

With this lady, who is still my patient, her relationship with her mother seemed to be the number one thing on her mind at the time of her depressions. So we worked on that and she says, to this day, that was a very helpful thing to do. I thought it was the right thing to do. But I wouldn’t do it alone, as the treatment of choice, in someone with major depression.

I’ll use the analogy of people who are able to treat their diabetes with diet and exercise, as opposed to oral antihypoglycemic drugs and insulin. I don’t doubt that that spectrum exists. I don’t doubt the skeptics who would say that, for many patients out there in the community, almost anything you did for them in treatment would help, including just making a diagnosis. The interview, making the diagnosis and talking to them for one session, may be sufﬁcient for the mildest of them. But most of them—by the way some 70 or 80 percent are not in treatment of any kind—will need more than that.

There is no doubt in my mind that with depression, as with asthma, there is an environmental contribution. It’s just that we’re more ignorant of it because we don’t know the mechanism of brain action in depression the way we know the mechanism of lung action in asthma. You can demonstrate how most of these environmental factors actually trigger an asthma attack. But asthma is every bit as inherited as depression and bipolar disorder are, perhaps more so.

Psychotherapy, Psychoanalysis, and Nothing at All

Cerebrum: Now when you say “psychotherapy”?

Dr. DePaulo: I mean cognitive therapy and interpersonal therapy, although I think that several other forms may be just as efﬁcacious.

Cerebrum: Are there practitioners trying to treat depressed patients with outmoded approaches? For example, if there’s a classic psychoanalyst who has a seriously depressed patient and is trying to treat that patient with standard psychoanalytic methods, is that outmoded?

Dr. DePaulo: As a treatment for major depression, yes. As an experience that two people have decided to engage in, many ﬁnd it extremely useful and may, in fact, ﬁnd it useful for depression. But as a treatment for depression, it’s never been shown to be effective and it is very expensive. And, like any other therapy, it’s not without risks.

You should know, however, that psychoanalysis is not the big public health problem in treating depression in this country. The big problem is that we don’t recognize people with depression and don’t give them any treatment.

First off, patients themselves don’t recognize it. Only a bare majority seek help. Of those, unfortunately, fewer than half get diagnosed when they see a non-psychiatric clinician, usually the person they see initially. Then, among those whose depression is recognized, most of them have been given—in the old days, before the SSRIs—treatments that couldn’t beat placebo. These inappropriate treatments ranged from Valium, because they were not sleeping well, to 25 milligrams of Elavil. Often they were kept on these medications because of the notion: We’ve treated the biological part because you’re sleeping now, Mrs. Jones, and the rest of it is up to you.

There was also an effect of years and years of psychoanalytic treatment, which created the sense that depression was an expected part of the human condition. Dr. Paul Kettle, the chairman of psychiatry at Penn State, was giving a lecture on the psychotherapy of older people and talking about all the biases that people had. He said that most doctors, including maybe psychiatrists, tend to view depression in elderly people as just to be expected. If we viewed arthritis that way, a patient might come in and say, “Doctor, I’m in terrible pain,” and the doctor would reply, “I’ll bet you are”!

That just doesn’t cut it. But, unfortunately, many people who are making those kinds of interpretations are not psychiatrically trained people. What’s outmoded, unfortunately, in many ways, is the education we’ve given to the non-psychiatric clinicians out there.

Cerebrum: What are some other biases keeping people from being treated?

Dr. DePaulo: Certainly among patients and their families it’s the difﬁculty of accepting the formulation that the patient has a disease that’s affecting his moods and that he will take a pill that will affect these moods—and maybe take it for the rest of his life. I hope they will read Kay Jamison’s wonderful book, An Unquiet Mind. She was a world expert on bipolar disorder at the time she started getting treated for it, yet she talked about going off and being tempted to go off the medication more than once.

In 1986, there was a Roper poll that asked which conditions would you be willing to take pills for? I don’t remember the speciﬁc ﬁgures, but it was like—headache, 70 percent; muscle ache, 65 percent; and depression 12 percent. I assume that’s changed now, but I’m also sure we’re still not nearly up there with headaches and muscle aches.

Personality and G22-355

Cerebrum: In Listening to Prozac, published in 1993, Dr. Peter Kramer worried that Prozac might alleviate feelings like guilt or remorse, which at times may be appropriate. Has that proved to be the kind of concern presented there?

Dr. DePaulo: That’s a very good question, and it’s one that was raised about antidepressants in 1957, when the ﬁrst English-language paper was written on Imipramine. I have my residents read that paper. At that time, Imipramine was known as G22-355 (“G” for Geigy Company). Apparently the Vatican was interested in whether or not it would relieve guilt, and concern for the problems of the world, and so forth. The reassuring experience of Dr. Roland Kuhn was that he had treated 500 people with Imipramine and concluded that it did not have that effect. Imipramine relieved the guilt of depression, but it did not turn people into sociopaths.

Dr. Kramer is a very talented writer, and posed an interesting question. I just wish he’d have read “listening to G22-355.”

Now, having said that, it doesn’t answer the question whether or not it might, in some ways, modify what we construe to be personality. First off, what is personality? It is as hard to deﬁne as the concept of disease. If you ask a physician what disease is, he’ll probably say, “Come on, why ask about that? I can tell you about pneumonia, tell you about tuberculosis, tell you about cancer—‘disease’ is just an abstraction.” Well, it is, but it’s a powerful abstraction. Also, its meaning has changed over the centuries. It used to mean “dis-ease,” now it means something different. It means that there’s an abnormal body part that’s creating symptoms and impairment, which are usually amenable to treatment—if not today, then tomorrow—if we come to understand it in some rational way.

Understanding personality is equally problematic. It has constituents ranging, in all likelihood, from inborn, temperamental features to traits that over time become tendencies to respond in particular ways to particular kinds of stimuli. Now if you ask if psychoactive drugs change any of that, well, they might. But if I ask my patients, by and large they will say, no, drugs don’t change personality. If I ask their families, they will say, no, they do not.

Where does personality end and apathy begin, for example, if you give too much of any SSRI? Patients can become very apathetic, which can be a clinical problem because you’re not sure if that is the depression or the drug-induced apathy. Is that a change in personality? I think it’s just a side effect; but there are also people who say, “Wow, on this antidepressant it isn’t just that the depression’s gone, I feel like a new person.” And it’s not just a little hypomania; this is really the way they feel going forward. I used to get that from patients taking Imipramine and Nortripyline and Nardil. Again, it gets back to what you mean by personality. We don’t know where their syndrome begins and ends; we don’t know the lower boundary, especially. So I’d say it’s a very interesting question, but difﬁcult. What’s a disease and what’s a personality?

Cerebrum: But this question has been raised about pharmaceuticals even while the other treatment of choice for depression, cognitive therapy, sets out explicitly—cold bloodedly—to change the patient’s fundamental view of things.

Dr. DePaulo: Right, cognitive therapy often gets a little softball treatment, while we throw pharmacology hardballs.

The Elusive Causes of Depression

Cerebrum: What has been so confounding about the causes of depression?

Dr. DePaulo: There are a couple of fundamental problems. When we talk about cardiac disease, we can look in the heart and see a basic thing that happens. The heart contracts and pumps. As you look from the organ to the cell, to the subcellular organelle, you see the same thing. There’s a unity. You can get to the deepest level of function using linear logic.

The heart fails for a limited number of reasons, all of which could be understood in terms of the pumps and the pipes. In the pipes the resistance is too high, or the pump isn’t strong enough, or it isn’t pumping effectively. Aside from that, there are no other reasons for the heart to fail.

So now how do we go from depressed mood to the brain? There’s no way to translate. Nor do we know in principle if it’s even possible for someone a lot smarter than we are to translate a mental event into a physical event directly, or to do the reverse.

I try to pose this to medical students. They seem absolutely ﬂabbergasted. They think it’s silly, and that as soon as they ﬁnish with the pharmacology course they’re going to know how to translate it and then they’ll come back and tell me. I ask: No matter how much you know about dopamine, can you possibly hope for your understanding of dopamine, serotonin, or GABA to explain how you’re going to feel when you look at a picture of your mother? How could you do that? Here’s a slice done by brain imaging through the brain and it tells you, yes, he’s looking at a picture of his mother and he’s having this complicated set of feelings, tinged with guilt, love, devotion. Okay, thanks Sigmund Freud, we don’t need you any more.

Cerebrum: Is anything about the causes of depression more confounding than with other psychiatric disorders?

Dr. DePaulo: There’s one thing, although I don’t think it’s as fundamental as the mind-brain problem. We all have moods. When I wake up feeling lousy, I don’t intuit that my serotonin is down. I intuit that something’s bugging me, and it doesn’t take long to ﬁnd a dozen candidates.

The term “affective disorder” is much better than “mood disorder,” because these disorders affect more than mood. They are all those presenting complaints that may have to do with emotions or moods, but also to do with vitality, motivation and drive, and vegetative functions. In England, if somebody says “affective disorders,” they mean unipolar depression, bipolar disorder, or anxiety disorders of the severe sort.

But because we all have moods, we can all empathize with depression. That is both the strength of the psychological method and the danger of a purely psychological method.

Cerebrum: Whereas we don’t all have auditory hallucinations or think that we’re Henry VIII.

Dr. DePaulo: Right. So those are helpful symptoms in that sense. They are helpful because you say, wait a minute, now, that’s not like my day-to-day problems. But with affective disorders, how happy is happy? How sad is sad?

Enter Anxiety

Cerebrum: What’s the correlation between anxiety and depression?

Dr. DePaulo: Basically, you ﬁnd lots of anxiety in people with depression. The only time it lessens is when they get well or get so depressed that they can’t get out of bed. People with any moderate to moderately severe form of depression are going to have lots of anxiety symptoms, not always in the form of obsessive-compulsive disorder (OCD) or panic attacks, or the like.

I teach young doctors that the word “depression” is not terribly useful to describe this condition that we treat. Only about half of the people presenting with the illness will agree, even if you ask them, that depression is what they are experiencing. What do they say? They’ll describe their mood—this is translating and distilling down—as down or sad or apathetic or not caring. Depression, anxiety, apathy, and numbness of mood are the four basic ways that “depression” presents to us.

William Styron, in Darkness Visible, says that he had no clue that he was depressed. What he felt was fundamentally just this terror inside, without knowing where to put this feeling that some impending calamity was about to happen. Anxiety times four. What to do with it? How to understand it? He couldn’t ﬁgure it out.

The book came out of a talk he gave at a symposium here. He was our ﬁrst “celebrity depressive,” and gave as pointed and humorous an account of the word “depression” as he does in the book. In the book, he edited out a few choice words he said here, blaming the ﬁrst Chief of Psychiatry at Johns Hopkins for the word “depression.” That was Adolph Meyer, who was well known for not being very good with written English. Styron said that Meyer had a tin ear for the language.

He makes a very good point. “Depression” is not a good description of what depressed people feel. Take the syndrome itself. How come so many people with clinical depression have panic disorder, OCD, phobias, and social phobias? Those are the other major anxiety syndromes. I don’t know the answer, but I interpret these as almost overlapping lesions. In other words, you can see them separately, or you can see them together. One interesting study by one of my fellows used a couple of anxiety and depression rating scales on patients in this hospital. One day he surveyed my clinic, which is for depression, and the next week he surveyed the anxiety disorders clinic. He discovered that my patients had higher anxiety ratings than patients in the anxiety disorders clinic. Anxiety is a fundamental part of depression.

Cerebrum: Is the connection known?

Dr. DePaulo: No. You see anxiety by itself, but you see almost no depression by itself. In other words, you certainly see people with panic attacks who don’t seem to have depressive syndromes. Most people, whether bipolar or unipolar, have more panic attacks, more social phobias, and more OCD when they are depressed. But plenty of them will have those problems between episodes of depression, as well.

In our family studies here, Dr. Dean MacKinnon has seen an interesting relationship between panic disorder and bipolar disorder. Some of our families seemed to have lots of panic disorder; and in those families, the panic disorder was only in the bipolar family members, not the rest of the family. Other families had very little of it. Dr. McKinnon looked for some way to track this out. He took the families where the identiﬁed patient had depression and panic disorder and compared that set of families with the set of families where the identiﬁed patient was bipolar but did not have panic disorder. What he found was that those families differed clinically in lots of different ways. But the families with panic disorder—lots of panic disorder—also had less alcoholism and less drug abuse, which was counterintuitive.

My initial question was: Is this a gender effect? Women have more panic attacks than men do, just as they have more depression, but they have less alcoholism and drug abuse. But the answer is no. The study has been repeated with a second population, and the observation seems to hold; it’s not a gender effect.

It’s probably worth mentioning that antidepressants, as long as the patient isn’t bipolar, are as good a treatment for anxiety disorders as they are for depression. And they’re as good as the benzodiazopines are in the long term.

Genetics: Discovering What Isn’t True

Cerebrum: You said, when you wrote How to Cope With Depression, that the most important aspect of explaining depression would be genetic. Does that still seem true?

Dr. DePaulo: It’s certainly going to be a fundamental aspect of the explanation, but I don’t think that depression is all genetic.

If you can nail down one end of the tent, however, it’s easier to ﬁgure out by stretching out the rest of the tent what it should look like and reason out what is in the environment that will make it worse.

Cerebrum: Over the 10 years since your book, what kind of progress has been made in understanding the genetics?

Dr. DePaulo: We’ve learned about what is not the case. We have learned that there are not one or two genes that explain most or all of depression or manic depressive illness. We had hoped that there might be; then it would make life simpler because we could get straight to treatment in a more direct way.

There’s no doubt about the genetic contribution. You can estimate it from twin studies and comparing concordance rates in identical and nonidentical twins and between twins and the general population. But it now appears that there are many genes, each of which may cause a small percentage of the cases or, more likely, that there are somewhere between a few and several genes, some combination of which creates a genetic susceptibility to the disease in the majority of people who get it. That would mean that each of those genes could be a risk factor for depression. Some of the genes will probably be ones that inﬂuence our response to environmental cues.

Cerebrum: Do any of these genetic differences seem related to gender?

Dr. DePaulo: Women have more depression, and women who have bipolar disorder have more episodes of depression, as part of that disorder, than do men. Women’s depressions are likely to be less responsive to medication, although men and women are equally responsive to ECT—we don’t know why. So far, we cannot explain it based on genetics. It used to be thought that the sex chromosome was important, and maybe it is; but it certainly does not appear to be more important than any other places in the genome in causing depression. Not that we can tell.

Perhaps there will turn out to be an indirect genetic effect. Just to take a possible example, perhaps women’s brains come under the inﬂuence of the X-chromosome through hormonal features. In this scenario, given the same amount of other genetic loading, and the same environmental stressors, women’s brains would be more likely to respond with a clinical depression than men’s.

Cerebrum: What about evolutionary explanations for depression? Maybe depression favored survival because it prevented a defeated individual from going back too soon for a rematch.

Dr. DePaulo: It’s all speculation. There are as many different theories as theorists. The interesting theories relate to things we see in the clinic. Take seasonal affective disorder, or SAD, the hibernating bear idea. With the absence of light, some people go into a depression every October or November and come out every March or May. These tend to be people with a mild form of bipolar disorder who may overeat, oversleep, and feel lethargic during their depression. Is this some sort of entrainment to light that we had in the distant past, and that is no longer as adaptive? That may well be. One experiment suggests that men living in urban areas have lost sensitivity to light, but women living in urban areas have not.

Cerebrum: What have we learned about differences among cultural or ethnic groups?

Dr. DePaulo: We know quite a bit, even from the time of Emil Kraepelin. He was a brilliant clinician-investigator who went to Java to see if people were different there. He decided that fundamentally they were not. There were about the same rates of depression—“melancholia,” he would have called it—and it presented in fundamentally the same way.

In Search of the Truly Depressed Rat

Cerebrum: Is there any indication that depression is present in animals other than humans? Is there an animal model of depression?

Dr. DePaulo: Is there an animal model that’s valid? There are lots of investigators who say they are going to make an animal model for depression, but how do you know when you’ve succeeded? You don’t.

There’s another approach via animals. Robert Robinson of the University of Iowa looked at people who got depressed following a stroke. After all, those might well be nongenetic cases of depression. These were patients who did not have family histories of depression but, if they got the stroke in the left frontal part of the brain, were very likely to get a major depression that was likely to last about a year, which is the length of time that an average depression lasts. Robinson has now been able to show that it responds to antidepressant treatment in the same way that my patients with familial forms of depression respond.

He said: I’m not going to look for a depressed rat; I’m going to try to lesion the areas in the rat brain that would be the same regions damaged by stroke in the human beings. At least I’ll have a model in the rat of the pathology of one form of depression, which we can manipulate. So, with Floyd Bloom, Robinson created artiﬁcial strokes in rats. They used surgery to tie off the middle cerebral artery, which was the area they were interested in from the human stroke studies.

Now they say: We were lucky we did the right side ﬁrst. If we’d done the left side, we would have concluded there was nothing to our idea and gone on to the next experiment. They did the right side ﬁrst, however, and the animal developed a ten-day syndrome, a kind of hyperactivity. And you could measure in the animal that there was a whole brain—not just unilateral —depletion in catecholamines. Then Robinson pre-treated the rats with antidepressants, tricyclics, and found that he prevented the syndrome from developing. Then he did the lesion on the left, and found that the rats had no behavioral response, although they still had some catecholamine depletion. Not as much as they’d had on the right.

Well, was what happened on the right a depression? If so, why in humans is it on the left? Give me a break—we’re going from rats to humans. Maybe that thing on the right in rats was mania, but then why would it be prevented by antidepressants? There are lots of things we haven’t ﬁgured out.

Since then, more data have supported Robinson’s idea. He looked for where, particularly, the lesion was in people who get depression after a stroke, and where there were no lesions in those who don’t get depression. He had to answer critics who said, if you had a stroke, you’d be depressed too. But 50 percent of patients didn’t have any depression. He talked to them two days after their stroke, and they said, “Yes, I’m very lucky. My husband’s been very supportive, the nurses here are wonderful. I’m already getting better.” You can’t call that a depression. You could say, “Ma’am, you’re in denial, you know.” But she’s getting better. At any rate, after some additional studies, now everybody agrees that there’s something important about the connection between injuries to the frontal lobes and depression.

A very interesting story came out last year in the New England Journal of Medicine. In France, they were treating Parkinson’s disease with deep brain electrodes. They would stimulate the patient and his Parkinson’s disease would get better. Well, they misplaced one of the electrodes by two millimeters, and gave the stimulus. A patient who had not been depressed at all, started weeping and telling people that she didn’t want to live, she was disgusted with life, that she was an awful person, et cetera. It took about ﬁve minutes for this to come on after they started. Then they stopped the stimulus. They were blown away by this. As she came out of it, she got giggly and kind of ﬂirtatious, started pulling the doctor’s tie, and then was back to herself. She could remember the whole thing, that it was awful and strange. But this was only one case.

Discovering the Depressed Child

Cerebrum: What about depression in children?

Dr. DePaulo: Certainly depression occurs in children. When we started the affective disorders clinic in the Hopkins Division of Child Psychiatry in four years of rounds every week, I learned that I could make a diagnosis of depression in kids as young as ﬁve or six. The key issue, as with adults, is eliciting the information. Once you get them to tell you the story, and you understood their slant or lingo, the story is the same in adults and children. I remember to this day a small child from East Baltimore, who looked me square in the eyes, when I started interviewing him—he was in the ﬁrst grade—and said “When I was in kindergarten, I had plenty of energy, I was able to do my work, able to read, and I had a lot of friends. Now, in the ﬁrst grade, I can’t do it, I have no energy, and I don’t have any friends.” Well, I just kind of shrugged my shoulders and said to myself, if he doesn’t have depression, then it just doesn’t exist in children. The doctor put him on antidepressants. When he came back into those rounds, about three weeks later, he said, “I’m much better now. I’m like my old self.”

I can tell you conﬁdently, based not only on him, but on hundreds of other children, that depression exists in prepubertal children. But if you look at the rate of depression by age, it clearly is very, very low before puberty, and then jumps up at puberty. Interestingly, it appears that before puberty there’s no difference between the sexes. The pubertal period throws the females way ahead of the males, so it’s age and gender that interact there. Male rates go up in puberty, too, but they don’t go up anything like they do in females during the menarche.

Does depression manifest differently in children, in general? Fewer kids come in complaining of sadness with depression— although only 50 percent of adults do. With kids, you mostly see it in their behavior. It’s not so much a complaint as you see something wrong. You see a lot of irritability. You see evidence that they’re not concentrating well. You see them withdrawing into their room and, if you’re able to get in the room, you see them either up all night or sleeping all the time—during the day. That kind of thing.

Another sign of depression might be that grades go down in school, although it’s surprising to me how many young kids, particularly perfectionistic young kids, will maintain their grades when they’re depressed. They may lose their friends, stop playing hockey or lacrosse, and have all kinds of other signs that they’re depressed, but they maintain their grades. Or some kids will maintain their competition horseback riding, but lose everything else, including their grades. For the parents, this can be tricky, because they will say, “It’s not as though she’s lost interest. She’s still getting straight As,” or “She’s still riding in competitions.” It depends on the child’s inclinations.

Cerebrum: Do you think that’s one of the reasons that depression wasn’t acknowledged in children for so long?

Dr. DePaulo: I think there are all kinds of reasons. One is that affective disorders in general were neglected in adults and children. In the United States, in particular, we were taught that even a little craziness was schizophrenia. Period. There wasn’t much emphasis on differential diagnoses. If a person wasn’t schizophrenic, then he was neurotic. If they were seeing things or hearing voices, they were schizophrenic. So in children, hey, guess what? We didn’t see any depression.

It was the same with manic-depressive illness or bipolar disorder. At one time, we would only very occasionally see an adult and say this was manic-depressive illness. The whole year before I went to the Maudsley Hospital in the United Kingdom to train, I diagnosed only one person as bipolar. The Maudsley had done a research study showing that the same patients were being diagnosed as schizophrenic in the United States and as depressive or manic depressive in the U.K. I came back and read my notes on admissions I had done, diagnoses I had made, and decided that fully half the patients that I had called schizophrenic had had bipolar disorder. It was obvious once I knew what to look for and how to ask the right questions. I knew when I was over there that I had learned something about diagnosing bipolar disorder and affective disorders generally, and that I had missed it in many, many cases.

The day I came back I was walking down the hospital corridor and some woman with ﬁery red hair spied me from way down the corridor, came tearing down the hallway, threw her arms around me, and gave me a kiss. Oh, my God! And this was one of my old patients, whom I’d called schizophrenic! Now it was obvious to me she was manic—very manic.

So there are all kinds of reasons that we’ve missed children with depression, and one is that we neglected the diagnosis altogether. Also, it didn’t ﬁt with some theories that you had to get to a certain level of development before you were capable of becoming depressed.

Age, Depression, and Suicide

Cerebrum: What about the elderly patient? Does depression more often manifest itself there as somatic complaints?

Dr. DePaulo: It appears that when they get depressed there’s more expression of it in their whole bodies. I would suppose that linking depression with bodily complaints may not be directly an effect of age, but because when you get older there are more physical problems to hang onto if you want to explain your depression.

The other thing about elderly people is that when they get depressed they are at higher risk for suicide than younger people, by and large. In most studies, the suicide rate is very low before age about 14. Then it goes up. Depending on time and place, it goes up almost immediately or gradually, and then goes straight across the life span, and then starts upward again in the late seventh decade of life and the eighth. Is that due to age? Not age per se—it probably does have to do with the likelihood of living alone and other factors that increase with old age.

Cerebrum: Is a high incidence of suicide shifting to different age groups?

Dr. DePaulo: Yes, this is the issue of a cohort effect. Again, this is a mystery. I can’t tell you what to make of it, but the data is there. It appears that people born in 1940 to 1960, as compared to people born since 1960, have a lower rate of depression, and if they get a depression it comes on later in life. Whereas people born later than 1960 seem on average to have more depression, and when it comes on, it comes on earlier in life. In the group born 1920 to 1940, you had an even lower rate and with an even older age of onset.

There are several possible explanations. One explanation is that this is an artifact. Most of the studies that generated this data were done with cross-sectional interviews, where you ask persons in different age groups to recall their depressions. But the longer ago an episode of depression occurred, the less likely you are to remember it; and you are more likely to remember the age of onset as later. That’s called the “Bo Peep phenomenon.” That is, the experience that you’re recalling seems to follow behind you at about the same distance. As you get older, it gets later.

Cerebrum: Has the suicide rate been rising in young people?

Dr. DePaulo: Yes, particularly in young males, and in young white males in the 15 to 24 age range. Also even a bit in the 10 to 14 range. Now, again, we don’t know what to make of that. These are tough epidemiologic ﬁndings; how do you interpret them?

One question has been, is this reaching some sort of new high, or is it returning to a previous level? There was some evidence, adduced by skeptics, suggesting that suicide rates were just going back up to the rates that we saw in the 1930s. It’s very interesting. I think if we knew for sure what depression was, what the phenomenon was, it would be easier to form theories about it.

Cerebrum: The suicide rate in bipolar illness has been relentlessly high—more so than in unipolar depression?

Dr. DePaulo: Yes. People with bipolar disorder have more severe depressions, more of them, are more likely to attempt suicide, will need more hospitalizations, will need more ECT—all the indices of severity and impairment. We think of bipolar as mania, in one sense, but in fact the depressions are more severe, as well. This is not if you simply count symptoms according to the DSMs, because almost everybody will have all of them. If you take the severe unipolars in the hospital, they’ll have all nine symptoms. If you take the severe bipolars, they’ll have all nine symptoms. But if you look at things that differentiate them, those are things that suggest more severity in the bipolars.

From Heart Attack to Alcoholism: Depression’s Traveling Companions

Cerebrum: There’s a whole cluster of questions around depression and its association with other conditions. It’s as if depression were somehow of the essence of illness.

Dr. DePaulo: The association with heart disease is intriguing because the arrows showing cause can go in both directions. We now see that depression predisposes to heart attacks. When people have a heart attack, and then they get depressed, it is not surprising. Most of them had preexisting histories of depressive episodes or at least family histories of depressive episodes, and aspects of the heart disease itself may contribute to depression.

The other factor is the prognosis of the patient with a heart attack, which seems to be related to depression. You’re somewhere between two and four times more likely to get a heart attack if you’ve had depression in the past. If you get a heart attack and you’re depressed, you’re three or four times more likely to die from the heart attack.

People ﬁrst had to understand that depression was an important disease, not just a bad day at the ofﬁce, for these kinds of studies to come of age.

Cerebrum: Would you expect more major diseases to turn out to be connected with depression?

Dr. DePaulo: Let’s talk about the ones we know about. Cushing’s disease, thyroid disease—those are well known causes of depression. Also, people with Alzheimer’s may have a higher rate of depression early in their illness. It’s not simply that you get Alzheimer’s and then get depression. But if you get Alzheimer’s and have some genetic predisposition to depression, you may get depression under the inﬂuence of Alzheimer’s.

Probably 40 percent of Huntington’s disease patients and 40 or 50 percent of Parkinson’s disease patients have depressions early in the course of their illness. Those diseases involve the brain generally— the basal ganglia, which turn out to be important in the stroke lesions we discussed earlier. About half of those with Huntington’s disease will have a bipolar form of depression. When James Huntington from Long Island described the illness, he said that there were three characteristic features: a movement disorder, a dementia, and “that form of insanity that leads to suicide.” Okay? He wrote that more than a century ago, and it’s only been recently that people have picked up that these people have an affective disorder, not schizophrenia. A few of them have schizophrenia, but the major association is with “that form of insanity that leads to suicide.” We should keep reading the Old Masters.

Alcoholism is a disorder connected with depression. I don’t call alcoholism a disease because thinking of it as a disease like pneumococcal pneumonia leaves out important information. I’m sympathetic with AA. I agree with everything they say, except that label. They don’t need it because they say things that would tell you that this is not a disease in the traditional sense, including that you need a lot of support and a powerful will to get over it, which isn’t what’s required in pneumococcal pneumonia. What’s required is to take your medicine and stop falling down in the gutter and aspirating.

So, I see alcoholism as an addictive behavior. The choice to take a drink initially is simply a choice. But once you’ve taken enough, and if you’re a vulnerable person, which you might well be—genetically vulnerable—drinking still remains a choice, but it’s not free in the same sense as it is for somebody else

I don’t believe that self-medication is a sufﬁcient explanation in many depressed people for abuse of alcohol. In many people who have depression, alcohol and depression cross, and once they have crossed they often get stuck together. Either the alcohol elevates the mood or it anesthetizes the mood. Either of which is desirable for some people.

Most males in our society drink alcohol, so in door-to-door surveys you ﬁnd no particular relationship in males between the diagnosis of depression and the diagnosis of alcoholism. You do in females, however, because females in our culture, on average, are not as unrestricted in their drinking. There are many more male alcoholics than there are female alcoholics. I see more women who will have something like a self-medication picture, even if that’s not a sufﬁcient explanation.

Cerebrum: What about other addictive behaviors?

Dr. DePaulo: Craving is a central experience for a lot of different behaviors, not just alcoholism, and many of those behaviors have an interesting relationship to affective disorders. Two other addictive behaviors that interest me are eating disorders and cigarette smoking. They have different relationships to depression.

With the eating disorders, I think our culture has been the powerful mover. (Of course, it moves a lot in alcohol too.) But in eating disorders, the cultural emphasis on thinness has undoubtedly promoted the behavior among young women. It is estimated that from 40 to as high as 80 percent of young women at some time experiment with anorexic or bulimic behavior. Well, again, this experimentation, and ﬁnding the vulnerable individuals, may predict who gets really attached to it. If you’ve got depression and you’re looking for something to get your life under control, and you experiment with keeping your weight under rigid control, you may discover that it gives you a sense of control over your life. That’s what a lot of young women say to us. When alcoholics stop drinking, or when you put anorexic women in the hospital and basically make them eat, their depression gets worse initially because you’ve taken away the thing that was helping temporarily. Now, in the long run, stopping the behavior will help—even if you don’t treat the depression—because the long-term effects of the behavior are extremely negative. But those people tend to beneﬁt with treatment of depression as well.

You don’t want to make the mistake, however, of treating the depression and thinking that you are also treating alcoholism or anorexia nervosa with antidepressant medication. I’m not saying that it may not help in some way, but these are behaviors. The key for the patient is to stop them somehow.

Cerebrum: You mentioned smoking. What is known about cigarettes and depression?

Dr. DePaulo: I had never appreciated that there was any signiﬁcant relationship, except that people who were smokers, when they got depressed, smoked more. On my ward, it was very hard for them to stop smoking when the rules prohibiting smoking in public places came along.

There was a drug company that wanted to know if a medicine would be useful in nicotine withdrawal. This was going to be challenging; there were a lot of arguments about what it would take to show this. So the company asked a very good, very exacting scientist to select a highly refractory population of people who smoked cigarettes and to see if its drug would be useful. This scientist was going to do a double-blind, placebo-controlled study of the drug and nicotine withdrawal.

The ﬁndings came out before they ever got to testing the drug. This scientist required, as a condition of enrollment in the study, that a man or woman had failed three professional attempts at withdrawing. What he found was that 60 percent of the people he enrolled had major depression. He was blown off his wheels by that, and I was too. Others have conﬁrmed this work. So, again, this suggests that here is a common behavior that has a particularly powerful impact on a reservoir of vulnerable people out there.

It would be the same thing if I talked about suicide. There’s unemployment, marital separation, bereavement, and a lot of other factors that do increase suicide rates in the community. But it turns out that they do so almost exclusively in that ﬁve to ten percent of the world that has clinical depression.

Three Promising Avenues

Cerebrum: What do you see as the avenues of research on depression that seem most promising?

Dr. DePaulo: Genetics, brain imaging, and neuropharmacology. They are going to have to work together, though, because no one of them alone will be sufﬁciently explanatory. We’re not going to be satisﬁed that we’ve validated these syndromes, that we really know what they are, until we know their anatomy, physiology, and origins. We will pursue the origins through genetics, of course, and pursue anatomy and physiology, at least in part, through brain imaging and neuropharmacology. So those are the fundamentals, no matter how the ﬁeld develops.

Cerebrum: What are other promising directions?

Dr. DePaulo: There are many—for example, more sophisticated knowledge of brain systems in terms of the multiple neurotransmitters coming from each neuron. There isn’t a serotonin neuron versus a norepinephrine neuron. Most neurons probably produce multiple neurotransmitters.

Also, we’ve known for a while that there are many more types of receptors. For types of serotonin receptors, we’re probably at 15 and still counting. So now, researchers are trying to ﬁgure out the difference between receptors. Many of the differences have to do with the subunits—the proteins—that come together to make a receptor. This is now a whole ﬁeld of study.

Then, we’re looking at second-messenger systems. It’s one thing to have a receptor, but once you load the receptor with the particular neurotransmitter, and the gun goes off, what happens? There’s a lot to be sorted out in the neuropharmacology. Most of what we’re learning there is basic, not clinical.

At the clinical level, in terms of neuropharmacology, there are two things. One is our recent ability, our progressive ability, to link neuropharmacology and imaging. This still has a ways to go before it lives up to its promise, but with imaging you are literally following the populations of receptors as they react to the pharmacological substance. The other is to manipulate the neuropharmacology of the brain, which can be combined with imaging. Those manipulations can be psychological as well. This is brain mapping, where they get people to look at happy faces and sad faces and then see how the brain lights up differently. So clearly, there’s already a pretty strong linkage between imaging and neuropharmacology. I think that’s going to have a great future.

Also, I think we are getting good at looking at how genes express in the brain. In fact, many people will say that in medicine today there is only one basic science: molecular biology. Having said that, you have to start looking at organs, as well, and sooner rather than very much later to look at organisms. But that’s where I see things going. The technologies are going to grow together.

The number one cause of disability in the world today is unipolar depression. The number six cause is bipolar. Five of the top 10 causes of disability are psychiatric disorders. By the year 2020, it is estimated by the World Health Organization that the leading disease burdens worldwide— economic and social—will be heart disease and depression. If you look at the research dollars going into coronary artery disease— I think they’re well justiﬁed —and compare them with the amount that goes into depression, which costs exactly the same amount per year to the economy, it’s very, very different. And we don’t need just money. We must have really good, committed people. With them, we can bring closer the day when the confusion dissipates and we can free people from this extraordinarily painful and common disorder.

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Why Depression Still Mystifies Us

An Interview with J. Raymond DePaulo, Jr., M.D.

Lumpers and Splitters

Treatment That Never Cures

One in Six Thousand

When Nothing Works

Biological Psychiatry: “Fumbling in the Dark?”

Psychotherapy, Psychoanalysis, and Nothing at All

Personality and G22-355

The Elusive Causes of Depression

Enter Anxiety

Genetics: Discovering What Isn’t True

In Search of the Truly Depressed Rat

Discovering the Depressed Child

Age, Depression, and Suicide

From Heart Attack to Alcoholism: Depression’s Traveling Companions

Three Promising Avenues

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Poverty and the Developing Brain

Managing Pain

The Miracle of Light

Sleep’s Dark and Silent Gate

Poetry of the Brain

Mental Health for Refugees

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