Source: LA Times
Date: 27 March 2006

... but still sad
Antidepressants aren't the magic that millions hoped.
For the first time, prescriptions fall.

By Marianne Szegedy-Maszak
Special to The Times

THE nation's heady romance with antidepressant medication appears to be over.

First came the warning of a possible link between selective serotonin reuptake inhibitors and suicidal thoughts among children and adolescents. Then came a drop in sales — 14% last year compared with the year before. Now research has found that a single medicine typically does not effectively treat depression for most people and that those with depression often stop taking the medicines altogether.

"The problem is not that the drugs don't work. They do. The challenge is we can't predict who will get well with what medicine," says Dr. Andrew Leuchter, vice chairman of the department of psychiatry at the David Geffen School of Medicine at UCLA.

With that increased understanding — of both the illness and the treatment — has come an attempt to craft more balanced, realistic therapies.

As Dr. David Kupfer, chairman of the University of Pittsburgh School of Medicine's psychiatry department, points out: "The problem of not treating is much more dangerous than all the problems we get into by treating the illness."

Clearly, a one-size-fits-all approach will not suffice. Patients who complained to their internists about feeling blue have not been well-served by simply a prescription for an SSRI — and few warnings about side effects or the very real possibility that the drug might not work.

"Depression is no different from epilepsy or diabetes or hypertension: No one treatment is sufficient for a majority of patients in all medical diseases," says Dr. Madhukar Trivedi, the head of a recent study on antidepressants and a psychiatry professor at the University of Texas Southwestern Medical Center in Dallas.

His study, published in the January issue of the American Journal of Psychiatry, found that a single SSRI medication works only for about 30% of chronically depressed patients. For most of the 2,876 outpatients participating in the study, real progress came only with subsequent drugs or with a combination of drugs.

A second study from the same group, published Thursday in the New England Journal of Medicine, looked at the remaining patients who did not respond to the single medication the first time. More than half of this group switched medications completely, and about a quarter of them became symptom-free within 14 weeks. An additional 565 augmented the initial antidepressant with a second medication, and within 14 weeks of treatment, one-third became symptom free.

But many patients have been too shy or too discouraged — and many primary care physicians not up to speed on sophisticated approaches — to pursue this more complex treatment.

Between 70% and 80% of people with depression receive their treatment not from a psychiatrist but from a primary care doctor. And these doctors typically prescribe one medication in the hope that it will work. As these studies reveal, most of the time it doesn't.

"Most depression is treated in primary care. And while they do a good job with a lot of things, they often don't follow up as well as psychiatrists do," says Dr. Thomas Schwartz, a professor of psychiatry at SUNY Upstate Medical University in Syracuse, N.Y. "Part of our job is to come up with alternatives for our patients. Often we end up adding medications so they work together."

Lindsey, a 28-year-old Palm Desert resident, knows this firsthand. Since she was 17, she's been through an alphabet soup of medications, each with various side effects.

Effexor "sucks in terms of your sex life." Zoloft "just didn't work." Wellbutrin triggered urinary incontinence. And the lithium that she was given when her depression was thought to be bipolar disorder caused her to develop jerky movements and gain 50 pounds.

After suicide attempts and dismal reactions to the medication, and a descent into substance abuse that finally led her to the Betty Ford Center, she has found a psychiatrist she trusts — one who has tweaked her Effexor with a low dose of Wellbutrin. After all, repeated research has shown that the most effective treatment for depression is medications along with psychotherapy. With that approach, she is losing weight and has managed to get, and hold down, a job.

"Of course, if I knew then what I know now, so much pain could have been avoided," says Lindsey, who, like the other antidepressant users quoted in this story, did not want her last name used. "I was feeling really hopeless in trying out all these different drugs and not having them work."

As many patients learn, the key to effective treatment for depression — as with most illnesses — is giving the medications time to work and knowing when they aren't.

"What we should be doing is starting from the get-go and telling patients and families, you may not respond to this treatment alone," says University of Pittsburgh's Kupfer. "We think we are allowed to use one drug, one bullet. If we were treating cardiovascular disease or asthma, we would be talking about a treatment strategy over a lifetime."

The newer, more measured view of antidepressants should not have been entirely unexpected, points out Fred Goodwin, the former head of the National Institute of Mental Health and professor of psychiatry at George Washington University. Every drug has a life cycle, he says.

First, it's called a magic bullet that will save the world. Prozac's history can attest to that. As the first SSRI, the green pill was featured on the cover of Newsweek in 1989, and the 1993 book "Listening to Prozac" spent months on the bestseller list.

Then comes the backlash. For antidepressants, that stage reached its peak during the Food and Drug Administration hearings in February 2004 where the message was: These drugs are killing our children.

Finally, it levels off somewhere in between, assuming its more reasonable place in public perception.

Antidepressants now find themselves in that place.

The boom and bust

From 1988, when Prozac (the first SSRI) was introduced in the U.S., to 1998, prescriptions for antidepressants tripled from 40 million to 120 million, fueled largely by the popularity of that "celebrity pill." Radically different from the previous generation of antidepressant medication, mostly because overdosing was unlikely, the SSRIs at one point were seen as so personally transforming that even people who were not clinically depressed took them for a little performance boost.

By 2004, nearly 150 million U.S. prescriptions were written for the drugs, and they represented the third-largest selling class of medicines after cholesterol and ulcer drugs.

But last year, U.S. sales of these medications, while still sixth in the leading classes of therapeutic drugs, dropped sharply, according to IMS Health Inc. a Fairfield, Conn.-based tracker of prescription drug data. And prescriptions for patients 18 and younger have plunged by 20% since 2004 when the suicide issue was raised at FDA hearings, according to NDC Health Corp., an Atlanta healthcare information provider.

Dr. Judith Bucholtz, a psychotherapist in Brentwood, says that several years ago nearly half the people who came to her for psychotherapy were also taking antidepressants. Today, only three of 20 patients are using the drugs. "There seem to be more and more people who are reluctant to take these medications," she says. "There was more confidence in them before the FDA hearings."

The much-publicized hearings focused on the association between antidepressant medication and suicidal thoughts among children and adolescents. The following October, the FDA told makers of antidepressants to place a black-box warning on the drugs stating that antidepressants can cause suicidal actions in children and adolescents. Last year, the FDA modified its warning, saying the drugs "increased the risk of suicidal thinking and behavior in short-term studies of adolescents and children" with depression.

The FDA placed no such warnings about the medications' effects on adults. But in July 2005, the agency nonetheless issued a public health advisory to alert patients and healthcare providers that there may be a possibility of increased suicidal behavior in adults treated with antidepressants.

However, a 10-year study that also appeared in the January issue of the American Journal of Psychiatry looked at the health plan records of more than 65,000 patients and could find no evidence that antidepressants caused suicidal thoughts. In fact, it found that the number of suicide attempts actually fell by 60% in adults during the month after they began taking the medicine.

"The irony and the lost message is that the risk of suicide in depression is very real and very clear," says Leuchter. "But the risk of increasing suicidality in treatment is vanishingly small."

The sheer dimensions of depression illustrate the importance of treatment. A massive study conducted by the World Health Organization, Harvard University School of Public Health and the World Bank, found that by the year 2020, depression will be second only to heart disease in terms of disability caused. In any one-year period, 9.5% of the population, or about 18.8 million American adults, suffer from a depressive disorder, according to the National Institute of Mental Health. And though less than half seek treatment, many try to get help from their primary care physician or, less frequently, a mental health professional.

As currently offered, even treatment is no guarantee that the depression will lift.

Veering off course

Jennifer, a 38-year-old Web designer from Castro Valley, has struggled with depression since 1996. When she was most depressed, the only reason she didn't kill herself was because she simply couldn't summon the energy to do it.

She couldn't think, couldn't work and barely managed to emerge from her bedroom for days on end. When she went out, usually to a therapy appointment, she would shop compulsively, spending money she didn't have. She would then retreat, once again, into the isolation and paralysis of her home. Sometimes more than a week would slip by before she took a shower.

Then her psychiatrist prescribed the antidepressant Trazodone. The depression eventually lifted but she was left "feeling dead," she says.

"I was just blah, as if there were nothing to feel. I didn't get too happy or too sad and my libido was completely gone." She had been a computer programmer, but the medicine left her so addled cognitively that "it didn't make sense any more. It was like being a math whiz and not able to do simple algebra."

For 10 years she would take various medications that her doctors prescribed, then abandon them when the side effects bothered her or the medicine didn't seem to be working after a few days. Being urged to stick with it, or to keep taking the medications even when she felt a bit better, didn't persuade her.

"The side effects are immediate, but the beneficial effects take some time," says SUNY's Schwartz. "So if people don't have a relatively quick response, they give up. These drugs take weeks to be effective but often people think, 'These are mental medicines — they shouldn't have a physical side effect.' "

Psychiatrists have attempted to more completely understand the mysteries of "treatment compliance" or, more simply, why some people will take their medicine while many just stop.

In a 2005 study in the journal General Hospital Psychiatry, researchers attempted to identify what made people continue, discontinue and switch their SSRI medications over a nine-month period.

They looked at 573 patients from primary care practices and found that about a quarter of the patients who took an SSRI for depression stopped it after about three months and did not try anything else. An additional one-fifth of the patients switched, usually after about six weeks, and then half of the switchers stopped altogether within three months.

More than half of those who switched said they did so because the medicine didn't work. But of those who stopped altogether, 73% did so because of the side effects: nausea, anxiety and agitation, insomnia and sexual dysfunction.

A recent study in the American Journal of Psychiatry found that of 829 adults who took antidepressants, 42% discontinued use during the first month and only 27% continued the therapy for more than 90 days. Those who continued the treatment were more likely to do so if they also received psychotherapy, had completed 12 or more years of education, or had private health insurance.

Kupfer of the University of Pittsburgh School of Medicine points out a crucial problem in communication between doctors and patients. In many cases, patients simply do not know what to expect, and then become discouraged with what is happening to them.

In 2001, the National Depressive and Manic Depressive Assn. conducted a major survey of 900 randomly selected primary care physicians and 1,000 patients receiving treatment from them for major depression. The study found that nearly half the patients surveyed reported that they had experienced side effects from the medication and that 17% of them had skipped doses, while 55% stopped taking the medication altogether.

The problem, researchers found, was basic communication. Most doctors — 69% — said that they told their patients about a loss of libido and 47% said they mentioned weight gain. But patients had an entirely different experience: Only 16% said that their doctors had told them about possible side effects, and 34% said that doctors had not warned them about any side effects when prescribing the medication.

For Susan, a teacher and a mother who lives in Oakland, the years that she was on Paxil were the biggest mistake of her life. With her children grown, her marriage unraveling, her mother dying and menopause engulfing her, she had been impelled to seek a psychiatrist. After months of therapy, her psychiatrist suggested that she try an antidepressant, explaining that easing the depression and anxiety would make her therapy more productive.

"I said 'No way, I'm not taking pills,' " she recalls. But eventually she relented. "First of all, I liked it. It … worked for me. It is only in retrospect that I could see how much damage it did."

She described herself as "comfortably numb" for several years until she suddenly became violently ill. She woke up incontinent, developed a primary immune disorder and was given blood intravenously every three weeks. She started falling and was constantly dizzy, particularly frustrating for a former gymnast and dancer. For three years she suffered — receiving a medical-school curriculum of diagnoses, including Addison's disease and the possibility of atypical cancer.

Finally she looked up the side effects of Paxil and saw every single one of her symptoms. She stopped taking the antidepressant and experienced horrible withdrawal. Then, on the advice of another doctor, she tapered her dose over three months. Within three weeks of her last dose, she says, her physical symptoms disappeared.

"Of course, I still battle with some anxiety and mood swings," she says. "But I am me again — yes more anxious, but physically healthy and mentally clear. And I am a lot happier."

A cautionary progress

The enormous complexity of depression as embodied in the lives of Lindsey, Susan and Jennifer illustrate that the single magic pill that will transform a life from depressed to fulfilled is exceedingly rare.

Certainly the medicines are generally safer than antidepressants of the past and can offer enormous improvements in quality of life. On the other hand, they often come at a high — many would say too high — personal cost.

"I think it is a double-edged sword," says Schwartz. He describes some patients who refuse the medicine because they see managing depression as a question of will. Others refuse therapy and simply want to pop a pill to make all their troubles go away. "Some say, 'I saw Tom Cruise; I should never use them.' Others say, 'I saw Brooke Shields, and I should use them all the time.' "

Each year, however, new research produces greater understanding in the treatment of this often-debilitating illness. And physicians are becoming more appreciative of a holistic approach to treating it, using not just therapy but diet and physical activity as well.

"The trouble with being depressed is that it affects your brain and you can really start doubting yourself," says Lindsey. "But you just can't hand over control or all the decision-making to other people. You know yourself the best. You have to be a part of it."

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