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Why is severe depression so hard to treat? Why are its causes so hard to determine?

February 8, 2012 1:13 p.m.

Guest: Sidney Zisook, M.D., Department of Psychiatry, UCSD

Related Story: Experts Discuss The Mystery Of Severe Depression


This is a rush transcript created by a contractor for KPBS to improve accessibility for the deaf and hard-of-hearing. Please refer to the media file as the formal record of this interview. Opinions expressed by guests during interviews reflect the guest’s individual views and do not necessarily represent those of KPBS staff, members or its sponsors.

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CAVANAUGH: This is KPBS Midday Edition. I'm Maureen Cavanaugh. What causes serious depression most people familiar with the drugs used to treatment depression would tell you it's a chemical imbalance in the brain, most likely low serotonin. For the past 20 years, many people have been successfully treated by drugs that increase those levels. But a fascinating report broadcast recently on KPBS morning edition introduced new theories about the causes of depression and new treatment options. Joining us to talk about depression and its many treatments is my guest, doctor Sid Zisook, professor of psychiatry, UC San Diego medical center. Welcome to the show.

ZISOOK: Thank you. Pleasure being here.

CAVANAUGH: Now, I think most of us believe we know what depression is. But if you were to make a diagnosis of severe depression, what signs would you look for?

ZISOOK: By severe depression, there are criteria. When depression hits, it affects the way we think, the way we feel, the way we behave, the way we view ourselves, the world around us. The cardinal symptoms. Severe depression would be persistent unhappiness regardless of the situation we're in, the inability to enjoy anything or experience pleasure. Again, even things that are normally very pleasurable for us. Very often, an individual with severe depression doesn't feel worthy of feeling happy or good. In some cases, even not worthy of living. And that's where feelings of suicide or that they would be better off dead or that the only way to escape the pain they're in is through dying or even the misguided feeling that people who love them would be better off if they weren't there. So it's I -- serious depression is a brain disease that affects everything that the brain does, and that's thinking, feeling, behaving, and all other functions.

CAVANAUGH: Now, many of us know what it's like to be depressed because of the death of a loved one or severe setback of something. It seems to set you off into a spiral where you become very sad for a long period of time. Is that serious depression? What's the difference between those two?

ZISOOK: Well, we think of depression with a small D, and that's what you describe, sadness and sadness that can last for a period of time. But usually it's intermixed with periods where you can feel okay, where you can be comforted by people around you, where you can still function. The sadness that occurs with depression is unending, unrelenting. So depression with a capital D is sadness that just different go away and is accompanied by a number of other sign, symptoms, and behaviors. So it's not just sadness. It's sadness and inability to function, to sleep well, to eat effectively, inability to feel good about ONE'S self.

CAVANAUGH: I want to invite our listeners to join the conversation if you have a question or a comment you'd like to share about depression, our number is 1-888-895-5727. There have been a lot of famous people that have suffered from depression, haven't there?


CAVANAUGH: Can you tell us who that might be?

ZISOOK: Well, Abraham Lincoln's depression is well known. He probably had a bipolar disorder, probably started early in life, and at times was severe enough for him to think that life wasn't worth living. I've read that Winston Churchill that suffered from depression. Dick Cabot has been open about his treatments of depression. Many famous writers, Virginia Plath.

CAVANAUGH: Sylvia Plath.

ZISOOK: Sylvia Plath, yes. Ultimately, her depression killed her. So lots and lots of people. And many very high-function people who have suffered with depression and maybe overcome some of the worst consequences of it want.

CAVANAUGH: You mentioned Abraham Lincoln. My producer gave me a quote about his depression. "If what I feel were equally distributed to the entire human race, there would not be one cheerful face left on earth."

ZISOOK: Yeah, that says a lot about the sense of misery that people who have a serious depression go through. And one of the problems with it is the sense of time is distorted. So in the throws of the kind of depression he was talking about, your sense is you have always been depressed, and you always will be, so a sense of hopelessness overtakes the soul.

CAVANAUGH: What is the current thinking on causes? Let me preface this by saying people who heard a series of reports on NPR recently heard that there is some thinking now about challenging the idea that chemical imbalance, low serotonin levels alone are the a serious depression. So what are scientists and researchers thinking about now when it comes to what causes depression?

ZISOOK: Well, are the -- unfortunately, we don't know. The bottom line is there are lots of theories and there probably is no one simple cause. There are many. We think of it as what's called a biopsychosocial disease, mean there are biological factor, psychological factors, and social factors. When all three of them are in a depressive direction, that's a perfect storm. And it's a time when depression is likely to surge. When two of the three are there, that may be enough. We know for example that people born with a particular genetic variant, the technical term is the serotonin property gene. If they have two short alleles of one particular chromosome, they're more prone to depression. Of in the context of stress, they're much more vulnerable to respond to that stress with a major depression. If that same person has been in their early childhood abused, sexually, physically, many even psychologically, the likelihood of them getting a depression in their adulthood under the same kinds of stresses is each much greater. So there's myriad causes. Maybe ten, 15 years ago, the leading theory biologically was a serotonin deficiency, or dope mean deficiency, or norepinephrine. Those are chemicals in the brain that help nerve cells communicate with each other. That's oversimplified. That's not the cause, although those imbalances of those chemicals still may be factors. We know that there's something called brain derived neurotropic factors. Kind of brain fertilizer. It's a totally different hormone, is deficient in a lot of people who are depressed. And with appropriate, good treatment, medication or even psychotherapy that works, that particular chemical can increase in its levels and the brain can regenerate itself to some extent. We know the thyroid can sometimes be implicated in depression. We know that the hypothalamic pituitary Adrenal axis is misregulate, and team with depression have hyper activity of their adrenals, increased cortisol levels that doesn't decrease. So lots of factor it is.

CAVANAUGH: So the more we learn, the more complicated it gets.

ZISOOK: The more questions we have, and we're just not there yet. Eventually, we'll have a much better understanding of the genetics of depression, but I don't think in my lifetime or even yours we'll have a really clear cut cohesive story of even the genetics.

CAVANAUGH: I'm inviting our listeners to join the conversation. Maria is calming from Escondido. Hi, Maria, welcome to the program.

NEW SPEAKER: Hello. It's such a great topic that you guys are discussing. And I thank you guys. This is a big favor to the community because probably if we knew what depression is and what -- when a person comes out of it, how reassured they are, like I was right now I'm 57 years old, and when I was 27 years old, I went through a very deep depression. And now I know what it is and I know I'll never go through it again. And I know a lot of people that are in depression right now probably don't think they could come out of it.

CAVANAUGH: But you did and you didn't receive any medication at that time?

NEW SPEAKER: No. But what I -- what I did was, I went to the doctor and they could not find out what it was for a while. But it started with I malnutrition. It started -- I wasn't having -- back then, I studied full-time in college. I was in business administration, four-year college back then. My second year. And I had a full-time job so I could afford it. So I was overworking and over-studying. And I had a month, I went through months, and I got problem with my stomach. So I could not eat for two weeks, I could not eat anything.

CAVANAUGH: Maria, I'm so glad that you were able to come out of that, and thank you for sharing your experience with depression with us. I want to take another call. Andrew is calling from Ocean Beach. Welcome to the beach. Are you there? Well, he has a great question. Is employment affecting depression?

ZISOOK: Probably. The stress is one of the factors that in a vulnerable person can precipitate a depression. So a lot of unemployed people don't have a serious, major depression. Although certainly sadness or depression with a small D is common. But unemployment can trigger it. And everything that goes with unemployment. And with feeling like a failure, with feeling like you're not able to provide for your family, like not being able to take care of yourself, get appropriate medical checkups because you lose your insurance. So absolutely. And also unemployment is probably one of the reasons we're seeing greater suicide rates than at any time in the recent past.

CAVANAUGH: This actually sets up a great example for the question that I wanted to ask you, and that is if someone is depressed and that depression started because they became unemployed and they go see a medical professional about the way they feel, would the first course of action be putting them on one of these drugs that we've heard so much about on TV in recent years, Zoloft or -- now I can't remember of the other one. Prozac, of course. Would that be the first course of treatment for someone or do you have to have a criteria of treatment before you go on medication?

ZISOOK: Well, unemployment itself probably isn't a cause. It's one of the factors that may trigger a depression. Again, in a vulnerable person. But if the -- and we think of making the diagnosis of depression only when they have had a cluster of symptoms with the unhappiness, the lack of pleasure, sleep problems, eating problems, for at least two weeks. Once we think of this as being a depression that might require treatment, then the decision is between medications or psychotherapy or some combination. Psychotherapy is about equally effective for most depressions. If somebody can afford it, if they prefer it, if there's someone available that has -- that can do the kinds of therapy that have been shown effect itch for depression. That's a very reasonable first choice. Antidepressant medications can also be a reasonable first choice. The more severe the depression, the more complicated it is, the more likely it is that combinations of both medications and psychotherapy are going to be the most effective treatment of all.

CAVANAUGH: We have had people on the show talking about how these prescription drugs, these medications for severe depression have changed their life. And there are many success stories associated with these drugs. But I'm wondering, over the long-term how successful is it in taking a pill like Zoloft every single day to keep someone out of depression?

ZISOOK: It can be life-saving. We know that depression tends to be both a chronic and recurring disease. The first caller said her depression got better spontaneously, although it sounds like it took years. That happens. And depression does get better without treatment. The more severe it is, the less likely that is to occur. And treatment can help people get better faster and more thoroughly. For people that have recurrent depressions, two, or three, or more in their life style, sometimes they need to stay on active treatment for years if not a lifetime. And medications have been found to be very effective not only to treat an acute depression but also to prevent further depressions down the road.

CAVANAUGH: What are the downsides of prescription drug enforce depression?

ZISOOK: Well, there are side effects. Some people can't tolerate. They're really not addicting medications. People know the difference between depression and being better when they choose to get off of them. There really are not terrible, long-term effects, other than side effects which generally can be managed. Some people main weight. And that can be depressing in and of itself when you're fat and can't do anything about it. Sexual dysfunction can be a problem with maybe as high as 30% of people, taking SSRIs will have some difficulties with their sexual function. For some people, increased anxiety. Some people have GI disturbances. But usually these are mild and manageable. And sometimes they require either lower doses or shifting treatments or somebody simply can't tolerate medications or is having some of those effects, switching to psychotherapy might be a very reasonable approach.

CAVANAUGH: I don't want to let you go before we at least mention the drug that was featured in the NPR report on depression. Ketamine. I understand UC San Diego is doing some trials on this drug for depression. It's supposed to work faster than some of the prescription drugs that we know now. What are the trials telling you? Anything so far?

ZISOOK: Well, it seems to be a remarkable drug in that it's used primarily IV. My father-in-law is a veterinarian used to talk about the words of Ketamine as a great an synthetic. It doesn't work in the same way as the other depressants. It's a so called NMMA DNA antagonist. But people can have a very propound change in their depression, and the improvement can last for several days. One very interesting study being done in San Diego is the San Diego hospice when they're trying an oral formulation, and people at hospice don't have weeks to wait before an antidepressant may start working. And something that can work within minutes to hours can have a very good benefit. There are side effects. It's an hallucinogenic. It has addicting potential. So it's not going to be a perfect drug. But there's lots of really good studies around the country now looking at alternatives to Ketamine, Ketamine-like drugs that will be easier to give to patients, more tolerable, and may alter the way we treat depression.

CAVANAUGH: Thank you so much. Thanks for coming in and speaking with us.

ZISOOK: Thank you so much.