Second-generation Antidepressants

A recent article in the prestigious British Medical Journal seems to confirm an increased risk for suicidal behavior among adults taking popular antidepressants. This follows evidence that certain selective serotonin reuptake inhibitors (SSRIs) may have a similar effect among children and adolescents.

As with the controversy over certain painkillers, public policy about the use of Prozac, Paxil, Zoloft and other antidepressants must balance the known benefits with the newly emerging risks. This month’s Facts of Life takes an evidence-based second look at second-generation antidepressants.

Their names—Prozac, Paxil, Zoloft—are familiar ones in a country where about one in five people suffer from depression or similar mental disorders. These so-called “second-generation” antidepressant medications have been the treatment of choice since 1985.

Coming In Second

Second-generation antidepressants include selective serotonin reuptake inhibitors (SSRIs) and other similar drugs that work primarily by increasing the amount of time that the hormone serotonin circulates in the connective gap between nerve cells in the brain. Serotonin helps nerve cells communicate with one another, communication that often lags in depressed brains.

SSRIs like Prozac are called second-generation because they are now prescribed more often than earlier-introduced “first generation” tricyclic antidepressants. Tricyclic drugs work in a similar way to SSRIs, but they are toxic at smaller doses and tend to have more serious side effects.

Taking Stock

The new antidepressants are a success story, an effective treatment for millions and a market winner for many drug companies. But researchers are just beginning to examine the 20 years’ worth of data available for the drugs to answer some pressing questions about their use. Are all second-generation antidepressants equally effective? How often do serious side effects like suicide occur? And should the medications be used sparingly in certain groups, like children and pregnant women?. A review of the cost effectiveness of depression treatment concluded that there are few studies that compare the cost-effectiveness of behavioral and drug-based therapies for depression.1

The Facts:

• Approximately one in five Americans has a mental disorder such as depression, anxiety disorder, bipolar disorder or a similar condition that can be treated with second-generation antidepressant drugs.
• A 2004 meta-analysis of antidepressant medications, including seven SSRI drugs, concluded that the medications had a “modest beneficial effect” on patients with combined depression and substance abuse disorders.
• A new systematic review of studies including 87,650 patients found a twofold increase in suicide attempt rates in SSRI patients compared to those taking a placebo or other therapies than tricyclic antidepressants.
• Second-generation antidepressants may be preferred over older tricyclic drugs as a first line treatment for bipolar depression, according to a 2004 systematic review.
• Most studies of antidepressant treatment for people age 55 and older exclude patients with other serious health problems, making it difficult to conduct medication trials with a large number of study participants.
• Rates of stroke and brain hemorrhage in patients taking SSRI drugs are very low, despite the fact that serotonin can affect blood clotting and blood vessel diameter in the brain.
• The Center for Science in the Public Interest’s review of studies on SSRI treatment for children found that industry-funded studies are 50 percent more likely to report positive treatment outcomes than government or university-funded studies.
• A systematic review of unpublished research on SSRI treatments for adolescents suggest that many SSRIs, with exception of Prozac, are more risky to the health of teens than published data would suggest.
• A meta-analysis of studies of antidepressant treatment for obsessive-compulsive disorder in children found that the older tricyclic antidepressant clomapramine (Anafranil) was significantly more effective in treating the disorder than four SSRI drugs.
• The “best buys” in second-generation antidepressants, based on safety, effectiveness and cost, are generic fluoxetine (Prozac and Sarafem), citalopram (Celexa) and buproprion (Wellbutrin), according to a 2005 Consumers Union report.

Catching the Problem Early:

In November 2004, the Center for Evidence-based Policy at the Oregon Health and Science University released a report on the effectiveness of “second-generation” antidepressant medications. 12 The report included information on how well Prozac, Wellbutrin, Zoloft, Celexa and similar drugs worked for conditions like major depression, social anxiety disorder, obsessive compulsive disorder and premenstrual disorders. But the report’s authors had a more unusual and potentially controversial goal in mind for their work: which one of these drugs worked the best, in head-to-head competition with the others?

For consumers and physicians alike, their findings might be a little unnerving. Report author Richard Hansen, Ph.D., says the evidence is “fair to good” that these second-generation antidepressants “do not differ substantially” among themselves and seem to be equally effective and tolerable.

Hansen, a researcher at the University of North Carolina at Chapel Hill, and colleagues found some small differences in how fast the drugs worked and in the prevalence of certain side effects like sleep disturbances and sexual dysfunction. Most of the few head-to-head studies they analyzed looked at treatment for depression. “For most [other] indications, no head-to-head trials have been conducted,” Hansen says.

Few of the studies analyzed in the report looked at how well the drugs performed in different racial and ethnic groups and special populations like children and older adults, Hansen and colleagues found.

“ Oftentimes companies do not look at subpopulations,” says John Santa, M.D., of the Center for Evidence-based Policy. “It’s too expensive, ethically risky in children, and let’s face it—once the FDA approves the drug (the pharmaceutical companies) can figure out ways to present information regarding various issues to patients and doctors without going through the FDA,”

Santa’s group, which reviews the effectiveness of drugs from beta-blockers to Alzheimer’s disease medications, commissioned the study of antidepressants in part “because antidepressants represent the second largest drug class for Medicaid drug dollars.” Increasing availability of generic versions of the drugs, along with new concerns about higher suicide rates in SSRI users, prompted the review, Santa says.

For the most part, the FDA does not require head-to-head effectiveness comparisons of drugs within a class as part of its determination of whether a new medication should be approved. Without this crucial data, Santa says, drug companies can make claims for their products that justify higher and higher prices.

As systematic reviews like the Oregon report conclude there are few differences between drugs within a class, “it’s much more likely that (drug) manufacturers will also have to compete on the basis of price,” according to Santa.