SSRIs: Too much—or too little—of a good thing?
Experts say a 'one-dose-fits-all' approach does not work with antidepressants
By Deborah Gesensway
While a debate rages over whether adolescents and children should receive antidepressants, experts in depression care say their key concern lies with how primary care physicians are using the drugs to treat adults. The problem? Too many patients are receiving both too much—and too little—of a good thing.
On one hand, experts say that many physicians tend to be too quick to prescribe selective serotonin reuptake inhibitors (SSRIs) without considering other options—or even if they are needed in the first place.
"It's like in the '60s and '70s, when stressed people would go to the doctor's office and get a prescription for Valium," said Wayne J. Katon, MD, professor of psychiatry at Seattle's University of Washington and one of the nation's leading researchers on depression care. While most physicians no longer view diazepam as a magic bullet for what ails patients, he said, too many doctors today take that same view of SSRIs for patients who are down or stressed. Physicians often overtreat minor depression or adjustment disorders with medication, while they undertreat major depression.
The rush to prescribe comes despite a lack of evidence that the drugs actually help patients with minor depressive symptoms. And while many physicians may be quick to prescribe an SSRI, too many also take a laissez-faire attitude when it comes to following up with more severely depressed patients to make sure the drugs are actually helping. While many patients with mental health issues need more than just a pill and an occasional follow-up appointment, those interventions are all that some receive in the new age of SSRIs.
Because internists and other primary care physicians write more than two-thirds of all SSRI prescriptions in the United States, these common mistakes can add up to big problems for people suffering from debilitating depression. These range from needlessly prolonged bouts of un- and undertreated depression to severe loss of sexual libido and perhaps a higher risk of suicide. (See "Are SSRIs dangerous? Physicians weigh in on the debate")
The solution? Closer follow-up, and a willingness to deal with side effects up-front.
When physicians first prescribe SSRIs, Dr. Katon said, patients should at a minimum receive three checkups in 90 days to adjust dosages, deal with side effects, get education and to make sure they are improving. Without that close follow-up, he added, the therapy needlessly fails too many patients.
The fact that many physicians don't follow up after prescribing SSRIs may stem from a "one-dose-fits-all" label the drugs received early on. Experts now know that the drugs require a certain amount of adjustment—and that they are most effective when physicians provide thorough follow-up.
According to Kurt Kroenke, MACP, professor of medicine at the Regenstrief Institute for Health Care and Indiana University in Indianapolis, one popular misconception arises from the notion that researchers have found no differences among the three most popular SSRIs—paroxetine (Paxil), fluoxetine (Prozac) and sertraline (Zoloft)—in terms of effectiveness, side effects or discontinuation rates. However, patients often respond to one SSRI, but not to another for reasons that are not clear.
"That's really no different from treating high blood pressure," Dr. Kroenke explained. "We have many classes of medicine. No single medicine has been proven more effective than another, but one size doesn't fit all."
If patients don't start responding to an SSRI after two or three weeks, Dr. Kroenke said, physicians should increase the dose. If the patient has failed to improve substantially in a month—he defines improvement as "at least 50% better"—you should consider changing medicines altogether.
However, when patients don't respond to treatment, noncompliance is often the problem, not dose or choice of drug.
"The No. 1 reason for an antidepressant failing is that the patients don't take it," explained James L. Levenson, MD, professor of psychiatry, medicine and surgery at the Virginia Commonwealth University School of Medicine in Richmond, Va., and editor of the book, "Depression: Key Diseases Series," from ACP.
In the first two weeks of treatment, about 20% of patients stop taking antidepressants, explained John W. Williams Jr., FACP, associate professor of medicine and psychiatry at Duke University School of Medicine. Three months into therapy, he added, about 45% of patients will have stopped treatment, and at four months, about 60% of patients are no longer taking their medications.
"It's a huge issue that people don't stay on SSRIs," said Dr. Williams, who is co-chair of the MacArthur Foundation's initiative on depression and primary care.
Because SSRIs cause fewer adverse effects than older tricyclic-type antidepressants (TCAs), many experts thought that patients would need little encouragement to take the drugs. In reality, Dr. Williams said, patient compliance with SSRI therapy is only slightly better than compliance with TCA treatments.
In part, noncompliant patients may be taking their cues from physicians, many of whom don't give symptoms of depression the same attention as other conditions. While internists are much better at picking up on signs of major depression than even 10 years ago, said Dr. Katon, many internists still haven't made the cognitive leap to managing depression as aggressively as other chronic diseases.
'When we diagnose someone with diabetes, we don't tell that person to take insulin and send him on his way. It's the same with depression. It's not just enough to start an antidepressant.'
--Kurt Kroenke, MACP
"When we diagnose someone with diabetes, we don't tell that person to start taking insulin and send him on his way," Dr. Kroenke explained. "We know we have to monitor him. It's the same with depression. It's not just enough to start an antidepressant. We have to monitor it closely, just like we do with blood pressure and diabetes."
To do that, experts recommend that internists find a therapeutic tool they like. The MacArthur Foundation has created a Web site that contains a tool kit for primary care doctors trying to provide better care for their depressed patients, with different screening questions, assessment checklists, patient questionnaires and monitoring recommendations.
Dr. Williams said that patient scores on instruments like Pfizer's patient health questionnaire (PHQ-9)—included on the MacArthur site—can help measure how much patients are or aren't improving. According to Dr. Williams, patient scores on the PHQ-9 should decrease five points or more during each follow-up visit—and physicians should aim for clinical remission, which is a score under five.
Warning patients about side effects upfront can also go a long way toward helping patients stay the course long enough to get better, experts say.
Two side effects—sexual dysfunction and weight gain—typically cause patients to stop taking SSRIs. While some patients don't notice any side effects, and some actually see their sex drive improve and their weight drop initially, many others experience just the opposite.
With this in mind, Dr. Kroenke suggested a strategy of preemptive strikes. "You have to tell people about the common side effects and explain that patients often think about stopping their medicines. And then you have to say, 'If you are thinking that, you should give me a call first, and we'll talk about it.' We want to reduce the number of people spontaneously quitting."
Many common side effects of SSRIs—gastrointestinal distress, sleep disturbances, headaches, feeling jittery—tend to go away by themselves after a few weeks. To help patients through this period, Dr. Williams said that some practices have a nurse regularly call patients within the first week they're taking an SSRI to help them "tough out" episodes of upset stomachs and diarrhea.
And to help patients cope with longer term side effects, particularly sexual dysfunction, Dr. Williams said, he recommends talking to patients about this problem up-front. Research has shown that patients won't typically raise the issue themselves.
While there is no clear-cut answer to sexual dysfunction from SSRIs, a study in the Jan. 1, 2003, issue of the Journal of the American Medical Association found that giving sildenafil (Viagra) to men taking SSRIs helped. In a commentary in the September-October 2003 ACP Journal Club, Dr. Williams noted that there currently are no medications to help women with antidepressant-associated sexual dysfunction.
As for weight gain, experts again say that patients need to be counseled up-front, with recommendations on what patients can do to counteract the side effect. Weight gain is another reason, physicians say, to monitor patients closely, so you can stop prescribing SSRIs when patients are finished with their treatment.
Just as no single drug fits all patients, drug therapy may not always be the right choice. With mild to moderate depression, which Dr. Kroenke said is the most common form of the disease seen by internists, "psychotherapy and antidepressants are both equally effective, and patient preferences play a big role," he explained. "Some patients don't want to take a pill, and some patients don't want to talk. Presenting both options makes sense."
Duke's Dr. Williams pointed out that soliciting—and respecting—patient preferences can improve adherence with all sorts of therapies, and that SSRIs are no exception. In fact, when it comes to caring for depression, he said, data show that some preferences break down along lines of race and ethnicity.
"African-Americans, for instance, overwhelmingly want psychological treatments and not antidepressant medications," he explained.
For patients suffering from mild to moderate depression, Dr. Kroenke suggested considering "watchful waiting" for a period of three to six weeks. In the interim, he said, physicians can help patients make simple lifestyle changes that might help, such as scheduling a pleasurable activity. "There is some evidence that this kind of 'activation therapy' is useful," he said, "but it's easier said than done."
Joseph P. Glenmullen, MD, a clinical instructor of psychiatry at Harvard Medical School and author of "Prozac Backlash," a critical look at SSRIs, said his main criticism lies not with the drugs themselves, which he regularly prescribes to patients. Instead, his beef is that SSRIs are being overused, for everything from the "everyday stresses of life and grief to nail-biting and hair-pulling."
Making matters worse, he added, too many primary care physicians fail to understand and counsel their patients about withdrawal. Dr. Glenmullen said he often sees patients whose primary care physicians have mistakenly concluded that they relapsed after discontinuing antidepressant therapy. In many of these cases, he said, the patient simply experienced a withdrawal reaction.
"The patient goes back on the medicine unnecessarily," he said, adding that he often sees patients who have been on the drug for a year or more and are far out from the acute episode.
"There is a good chance they no longer need the drug, but both they and their doctor mistakenly conclude that when they tried to go off the medication, they had a relapse," he added. "Then the patients suffer more years of weight gain and sexual dysfunction because they have been on the drug when they no longer needed it."
Deborah Gesensway is a freelance health care writer living in Glenside, Pa.
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.
Since fluoxetine (Prozac) first stormed the market more than 15 years ago, critics have charged that the entire group of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) can cause people to get worse—and sometimes become suicidal.
While most U.S. physicians and drug regulators say that clinical trials and anecdotal experience have shown SSRIS to be safe and effective, concerns about the drugs' downside have reached a new level. The British government last summer warned doctors and patients about the risks of pediatric and adolescent patients diagnosed with major depressive disorder using paroxetine (Paxil) and venlafaxine (Effexor).
FDA officials responded to the British action by telling drug manufacturers to turn over all data related to the issue of children and suicidality. At a public hearing last month, the FDA announced that it found a link in clinical trial data between antidepressant use in young patients and a higher risk of suicide. (At press time, the FDA had taken no regulatory action.)
Where do doctors weigh in on the debate? While few have real concerns about the safety of SSRIs, they say the conflicting views underscore the need for physicians to take great care when prescribing the latest wonder drug.
Some, for example, say they have witnessed the occasional terrifying reaction to an antidepressant. "These drugs are safe, but not completely safe," explained David O. Brody, MD, professor of medicine at Drexel University College of Medicine in Philadelphia.
Just recently, he reviewed the case of a patient taking Prozac where the drug may have contributed to the man's suicide. That potential risk is the reason why, Dr. Brody explained, physicians should never just prescribe an antidepressant without also putting in place a system of close monitoring during the first few weeks of therapy.
How much of the suicide risk is due to the treatment and how much is due to the disease is at the crux of the SSRI safety debate. While the No. 1 risk factor for suicide is depression, the data are not clear. Not everyone who attempts suicide is depressed, for example, and not all depressed people ever consider suicide.
Suicide occurs in up to 15% of patients with depression, and studies have shown that between 40% and 70% of people who commit suicide have been diagnosed with depression.
Despite anecdotes to the contrary from physicians like Dr. Brody, studies of suicidal adults taking SSRIs have shown time and again that depressed adults fare better on antidepressants than placebos. Experts say the fact that some patients attempt suicide in the early weeks of antidepressant therapy may ironically be proof that the drugs are working.
The fact that many patients may attempt suicide in early antidepressant therapy may be proof that the drugs make patients feel well enough to act on their own thoughts.
"In the early stages of treatment, people are still depressed, but now they may have enough energy to do something about it," Dr. Brody explained. "They now can act on their thoughts. Is that the drug? A drug side effect? Or is it a drug-related factor? I don't know."
A study in the April 2003 American Journal of Psychiatry that looked at "completed suicides" reported in FDA summary reports for nine modern FDA-approved antidepressants found no difference in the risk of suicide when depressed patients were taking SSRIs, other types of antidepressants or placebo medications. (An abstract is online.)
Other studies, however, have been interpreted as evidence that depression treatment is an important tool in suicide prevention. For example, an article published in the May 10, 2003, issue of British Medical Journal found an association between increased antidepressant prescribing and reduced suicide rates in Australia from 1991 to 2000—especially in the elderly.
Banned in Britain
Despite data that give SSRIs a good review, the British government warned physicians not to prescribe antidepressants—with the exception of Prozac—to children and adolescents.
British officials added, however, that the drugs do seem to work for some children, and that physicians should continue SSRI treatment for those children. However, officials also recommended that these children be followed by specialists, not general practitioners. (A summary of the British warning is online. )
Russell Katz, MD, director of the FDA's division of neuropharmacological drug products, which is part of the Center for Drug Evaluation and Research, noted that the studies can be difficult to interpret because they have neither shown nor not shown whether SSRIs work for depressed children or teens. (Prozac is the one exception; the FDA has approved that drug for use in children with major depressive disorder.)
"If we knew for a fact that [the drugs] didn't work, that signal of suicidality wouldn't even be an issue," Dr. Katz said. "We would just say, 'Don't use it.' We are not saying that. Just because we don't have evidence that they do work doesn't mean they are ineffective. It just means we don't know yet."
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