The value of using antidepressants to treat mild to moderate depression came under fire recently after a study in the Journal of the American Medical Association found that the drugs didn’t work much better than a placebo in those with mild to moderate depression. These findings were widely reported because with 164 million prescriptions written and $10 billion in sales in 2008, according to IMS Health, these antidepressants (called SSRIs) were the third most popular class of therapeutics sold in the U.S.

Companies are promoting an ever-increasing arsenal of SSRI’s and a whole new class of drugs—the atypical antipsychotics—for treating depression and other mental disorders. But despite their widespread use, the JAMA study adds to an emerging body of research that raises more questions than it answers about the safety and efficacy of using current drugs in treating moderate or mild depression. Though sometimes extremely helpful, it has becoming increasingly clear that these drugs are no panacea for many patients, and may even cause harm.

To many practitioners who treat or study depression, there have long been signs that current drugs are fickle allies in addressing symptoms. They can be enormously valuable in alleviating depression in some patients; can be somewhat effective after trial-and-error with several different formulations in other patients, and patently ineffective in still others. And then there are the side effects: Antidepressants have been linked with suicidal thoughts, sexual dysfunction, birth defects and a life-threatening neurological disorder. In 2004, the Food and Drug Administration began requiring a black box, the most serious type of warning for prescription drugs, to be added to the labels of all antidepressants to warn about the increased risk of suicidal thoughts and behavior in children and adolescents being treated with the medications.

The efficacy problem essentially stems from the fact that depression is a mental health disorder that spans an enormously wide spectrum of disability: from temporary melancholy to the unrelenting depths of despair. As Andrew Solomon, author of the ground-breaking book, “The Noonday Demon: An Atlas of Depression” puts it;  “If one imagines a soul of iron that weathers with grief and rusts with mild depression, then major depression is the startling collapse of a whole structure.”

Its causes too, are varied; genetics seems to play a role, as do environmental stressors, brain chemistry and hormones. There are even signs that genetics may play a role in determining why some people respond to SSRIs and others don’t. In work published in the Jan 14 issue of Neuron, researchers attempt to identify differences at the receptor level in the brain that might help determine who responds to antidepressants and who doesn’t. The emerging picture is complex, say the authors.

"Unfortunately, more than half of all depressed patients fail to respond to their first drug treatment," explains senior study author Dr. Rene Hen, from Columbia University. "The reasons for this treatment resistance remain enigmatic. Elucidating the exact nature of both the factors predisposing to depression and the mechanisms underlying treatment resistance remains an important and unmet need."

Depression also stands out as an illness that is at once over-treated with prescription drugs and under-diagnosed and under-treated at its most serious stages.  Because insurers are far more likely to pay for antidepressants or other psychiatric drugs than they are for “talk therapy,” primary care providers use them as first-line treatment for mild or moderate depression in adults and increasingly, in children. Recent studies have shown, for example, that children covered by Medicaid are prescribed psychiatric drugs at a rate of four times higher than those covered by private insurers.

But in a survey conducted in 2008, the Centers for Disease Control found that among people who report symptoms of depression “only 29 percent of respondents with depression symptoms reported contacting a mental health clinician in the prior year. In a subset of respondents with severe depression scores, only 39 percent made contact with a psychiatrist, psychologist, psychiatric nurse, or clinical social worker,” according to the American Psychiatric Association .

So how exactly should patients and doctors use the findings of this recent JAMA study? The authors refrained from advising doctors to stop prescribing antidepressants—they instead asked that patients consider other options as well. Robert J. DeRubeis of the University of Pennsylvania, one of the authors of the study, tells the New York Times;  “The message for patients with mild to moderate depression is, ‘Look, medications are always an option, but there’s little evidence that they add to other efforts to shake the depression — whether it’s exercise, seeing the doctor, reading about the disorder or going for psychotherapy.’”

Daniel Carlat, a practicing psychiatrist who writes The Carlat Psychiatry Blog, has two interesting posts Part I and Part 2 on the study findings that highlight the difference between how patients respond to drugs in a controlled, double-blind study on depression (where the study subjects are vetted and don’t know if they are receiving an antidepressant or a placebo) versus how they respond in a clinical setting. The key, it seems, is the belief many patients have that pills will work.

“So this is the crux of the issue,” writes Carlat, “Response rates are always lower in randomized controlled trials than they are in the real world of the office, where our patients know exactly what they are taking. Thus, when I read about the measly outcome results of antidepressants in these trials, I take it with a big grain of salt. I interpret it in light of many other studies that have indeed shown antidepressants to be more effective than placebo in conditions as diverse as severe depression, anxiety disorders, and eating disorders. Rather than concluding that these meds don't work, I conclude that they do work, but that there is a large placebo component.”

Writing in the Mind blog at the New York Times; Dr. Richard A. Friedman, a psychiatrist at Cornell Weill takes a less nuanced stance toward the JAMA study findings—urging readers to not give up on antidepressants. That may be good professional advice as going cold-turkey with antidepressants can be dangerous. But Friedman goes on to essentially dismiss the study out of hand when he says:

“Every once in a while, a landmark study comes along and overturns everyone’s cherished ideas about a particular treatment. But the current study is not one of them. So it would be a shame if it discouraged depressed patients from taking antidepressants.

“Experts may disagree about what constitutes the best treatment for depression, and for whom. But there is no question that the safety and efficacy of antidepressants rest on solid scientific evidence.”

Actually, the scientific evidence backing up the safety and efficacy of antidepressants is far from solid. In fact, this JAMA study was hardly the first to raise questions about the drugs, especially in treating people with mild or moderate depression. A meta-analysis of the efficacy of popular antidepressants as compared to placebo was published in the open-access journal Plos Medicine and concluded that;

“[T]he new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication.”

There are two fundamental problems with discerning just how well pharmaceuticals work in those suffering from mild to moderate depression. The first is that most drug testing is do
ne on those with the more severe form of the condition. The second problem is that this published “body of evidence” has been discovered to be quite biased, due to selective reporting of trial results by drug companies. In this study in the January 17, 2008 New England Journal of Medicine researchers reported;

“Among 74 FDA-registered studies, 31%, accounting for 3449 study participants, were not published. Whether and how the studies were published were associated with the study outcome. A total of 37 studies viewed by the FDA as having positive results were published; 1 study viewed as positive was not published. Studies viewed by the FDA as having negative or questionable results were, with 3 exceptions, either not published (22 studies) or published in a way that, in our opinion, conveyed a positive outcome (11 studies). According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that 51% were positive. Separate meta-analyses of the FDA and journal data sets showed that the increase in effect size ranged from 11 to 69% for individual drugs and was 32% overall.”

In reporting on this NEJM study, the Times’ Benedict Carey wrote:

“Taken together, previous studies have painted a confusing picture. On one hand, industry-supported trials have generally found that the drugs sharply reduce symptoms. On the other, many studies that were not initially published, or were buried, showed no significant benefits compared with placebos.”

So where does this leave us?

The fact that antidepressants don’t work for many patients means that doctors are always looking for new drugs to help alleviate symptoms. We’ve seen this most recently with increased use of atypical antipsychotics which racked up $14.6 billion in sales in 2008—surpassing even sales of antidepressants. These drugs were originally approved by the FDA to treat schizophrenia, but one, aripiprazole (Abilify, made by Bristol-Myers Squibb), has been approved for use in patients who suffer major depression that’s resistant to antidepressants alone. In December another, Seroquel (sold by AstraZeneca), was approved as an “add-on,” not a first-line treatment, for this same type of resistant depression.

Despite the limited approvals for these two atypical antipsychotics, they and others in their class are increasingly being prescribed for bouts of depression that might not be considered “major,” just resistant to treatment with standard antidepressants. These drugs are also being used to treat anxiety, sleep problems and attention deficit disorder—especially in children.

In some cases, doctors report that patients specifically ask for Abilify—following the advice they received from the drug’s widespread advertising campaign: “Approximately two out of three people being treated for depression still have unresolved symptoms," according to the Abilify ad. “If your anti-depressant alone isn't enough; talk to your doctor. One option you may consider is adding Abilify.”

An article by Melissa Healy in The Los Angeles Times cites a report by the consulting firm Decision Resources that found that the makers of atypical antipsychotics spent $993 million in 2006 on ads like these to promote the drugs to doctors and patients. Healy also reports that “roughly 60% of prescriptions for atypical antipsychotics have been written off-label.”

Meanwhile, the article explains, “a 2008 study on Abilify found it was little better at banishing depressive symptoms than a placebo.”  The drugs also have significant side effects; including weight gain that can be serious enough to cause diabetes and an irreversible movement disorder that causes involuntary tics and jerking movements in patients. This all adds up to a “questionable balance between safety and effectiveness” for the atypical antipsychotics, Dr. Steven Nissen, chairman of the Cleveland Clinic's cardiovascular medicine department tells the L.A. Times, and should stand as a warning to expanded use of these drugs in treating depression.

“‘The story's pretty clear, and pretty embarrassing for the profession of psychiatry, which has allowed itself to be led by marketing,’ says Robert Rosenheck, a psychiatrist at Yale University who has studied the effectiveness and expanded use of the atypical antipsychotics. ‘We know now what these companies' strategies are: The number of people with schizophrenia is limited, so the road to profitability goes through soccer moms. They need to market these drugs to ordinary people who have dissatisfactions in life.’"

Ultimately, the latest findings on antidepressants are controversial because they challenge yet another of our commonly-held beliefs about medicine. This newest class of antidepressants, the SSRIs, was hailed as “revolutionary” in treating depression—mainly because their milder side-effects than previous drugs made them more palatable to a far larger population of sufferers. They have been prescribed to tens of millions of Americans—from preschool age all the way up to the oldest among us. To suggest that these drugs may stop short of effectively treating depression in many patients leaves doctors at a loss for options. Realistically, it’s unlikely that public or private insurers will increase coverage for talk therapy—one of the most effective treatments for mild to moderate depression. And although placebos seem to work just as well as drugs in some people, how really can we justify giving patients sugar pills?

The flip side is that there are people—witnessed by the surge in anecdotes from people who depend on antidepressants to keep them functioning—who are greatly helped by the drugs. Instead of attacking research, which has clearly reached a critical mass, why not use it as notification that we need more insight into the underpinnings of depression. Rather than pretending that SSRIs or atypical antipsychotics are one-size-fits-all drugs and using massive marketing campaigns to sell them to a wider and wider population, we should be pursuing more research on genes and other factors that actually identify who might best be helped by these and newer-generation psychiatric drugs. It’s only by accepting the shortcomings of current treatment that we can fully begin to address the terrible toll of depression.