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DO ANTIDEPRESSANTS REALLY WORK?

 

Modern western psychiatry relies heavily on antidepressants to treat depression and presents it as the most scientific, effective approach to the illness. However, based strictly on the available research, the evidence is pretty mixed. Researchers still have not concluded definitively that antidepressants are more effective than placebo. And in the case of children and adolescents, may do more harm than good.

The placebo effect

The heart of the controversy is the placebo effect – the well-established phenomena of experiencing benefits because the user believes in a particular outcome. A placebo is an inert substance that has no therapeutic effect, used as a control in testing new drugs. One way its effects can be tested is by dividing participants, who share a medical condition, into two groups. One group is treated with a placebo (they are told they are trying a promising new treatment) and one group receives no treatment. Typical results from such an experiment would see an improvement in symptoms in the placebo group, with no change in the group given no treatment. The placebo effect is well documented in clinical trials for antidepressants. The question is what percentage of users will experience real benefits versus those believing they’re experiencing benefits from a placebo?

Much of the past evidence suggesting antidepressants are no more effective than placebo comes from the work of Irving Kirsch, associate director of the Program in Placebo Studies at Harvard Medical School. Kirsch’s 2008 meta-analysis showing antidepressants are no more effective than placebo included data sent by pharmaceutical companies to the Food and Drug Administration (FDA) to approve various antidepressants, which Kirsch obtained through the Freedom of Information Act. The FDA requires pharmaceutical companies to provide data on all the clinical trials they sponsor—including unpublished trials. “This turned out to be very important,” wrote Kirsch in a 2014 paper. “Almost half of the clinical trials sponsored by the drug companies have not been published.” In other words, pharmaceutical companies test new drugs but only publish the studies that show positive results. Any studies that show negative results are buried. All of the results have to be reported to the FDA, but the only information made public will be that which is published – usually by the company sponsoring the studies. What Irving Kirsch did was analyze ALL of the data turned over to the FDA. And much of that data showed as much effectiveness from the placebo groups as in the drug treatment groups.

The other side of the debate

Scientists on both sides of the debate have published various meta-analyses claiming to conclusively show that antidepressants are or are not more effective than placebo – and neither accepts the other’s evidence. There have been findings that counter Kirsch’s work and show antidepressants are truly effective, which Kirsch in turn rejected through his own research.

A recent paper published in The Lancet shows that, according to a meta-analysis of 522 trials, 21 commonly used antidepressants are all more effective than placebo. The meta-analysis includes data on 116,477 patients total, from double-blind, randomized controlled trials published between 1979 and 2016. The researchers found that antidepressants led to a greater reduction in depressive symptoms than placebo over the first eight weeks of treatment.

Pharmaceutical companies fund the majority of studies on antidepressants, and they have a clear financial interest in the success of these drugs. Of the 522 trials in the newly published meta-analysis, 409 were funded by pharmaceutical companies. “Forty-six (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low,” note the authors. There were also signs of “novelty” bias: Antidepressants seemed to perform better when they were newly released in the market but seemed to lose efficacy and acceptability in later years. In other words, this study provides evidence that when people are found to have acute major depression, treatment with antidepressants works to improve outcomes in the first two months of therapy.

This exhaustively researched analysis was interpreted by some commentators to be the final word on the antidepressant controversy. For instance, Prof. Carmine Pariante, spokesperson for the Royal College of Psychiatrists in the U.K., commented:

“This meta-analysis finally puts to bed the controversy on antidepressants, clearly showing that these drugs do work in lifting mood and helping most people with depression.”

“Importantly,” Prof. Pariante adds, “the paper analyzes unpublished data held by pharmaceutical companies, and shows that the funding of studies by these companies does not influence the result, thus confirming that the clinical usefulness of these drugs is not affected by pharma-sponsored spin.”

The review does acknowledge that the short-term benefits of antidepressants are, on average, modest, but it concludes that all of the 21 antidepressants studied are more effective than placebo for the treatment of major depressive disorder in adults.

Some drugs were shown to be more effective than others. Escitalopram (Lexapro), mirtazapine (Remeron), paroxetine (Paxil, Brisdelle, Pexeva), agomelatine (Valdoxan), and sertraline (Zoloft) all had a higher response rate and lower dropout rate than other antidepressants, the researchers report.

Further complicating the issue is that different patients respond very differently to the same drug. There is no one-size-fits-all antidepressant. If there were, we wouldn’t need so many different antidepressants. This may in part be because so many symptoms fall under the rather large umbrella labeled “depression”; many people are classified as having the same disorder, even if the underlying biological and social influences causing the illness vary considerably. And the degree to which different people experience this broad range of symptoms also varies greatly.

“Some people really respond, some don’t respond at all, and everything in between,” Steve Hyman, director of the Stanley Center for psychiatric research at the Broad Institute of MIT and Harvard, previously said in an interview with Quartz.

Finally, there’s the issue of long-term effectiveness. The latest meta-analysis only looks at eight weeks of treatment. There are several studies showing that though antidepressants produce strong results in the short-term, non-medication-based treatment options have better effects in the long-term.

In 2008, a group of researchers made this point by doing a meta-analysis of antidepressant trials that were registered with the FDA as evidence in support of approvals for marketing or changes in labeling. Again, these were ALL of the study results, not just the ones cherry-picked for journal publication. The researchers found 74 studies, with more than 12,500 patients, for drugs approved between 1987 and 2004. About half of these trials had “positive” results, in that the antidepressant performed better than a placebo; the other half were “negative.” But if you looked only in the published literature, you’d get a much different picture. Nearly all of the positive studies are there. Only three of the negative studies appear in the literature as negative. Twenty-two were never published, and 11 were published but tweaked so that they appeared positive.

A second meta-analysis published that year also used FDA data instead of the peer-reviewed literature, but asked a different question. Researchers wondered if the effectiveness of a study was related to the baseline levels of depression of its participants. The results suggested yes. The effectiveness of antidepressants was limited for those with moderate depression, and small for those with severe depression.

Studies of adults with moderate or severe depression showed:

  • Without antidepressants: About 20 to 40 out of 100 people who took a placebo noticed an improvement in their symptoms within six to eight weeks.
  • With antidepressants: About 40 to 60 out of 100 people who took an antidepressant noticed an improvement in their symptoms within six to eight weeks.

In other words, antidepressants improved symptoms in about 20 more people out of 100 than did a placebo.

What about preventing a recurrence?

Studies involving adults show that taking commonly used antidepressants lowers the risk of relapses, but cannot completely prevent them.

  • Without preventive treatment: About 50 out of 100 people who took a placebo had a relapse within one to two years.
  • With preventive treatment: About 23 out of 100 people who took an antidepressant had a relapse within one to two years.

In other words, taking an antidepressant for a longer period successfully prevented a relapse in an average of 27 out of 100 people.

Children and adolescents

Children and adolescents with major depression do not benefit from most antidepressant medications, and some of these drugs may do more harm than good. This is the conclusion of a study published in The Lancet.

Major depression, or major depressive disorder, is estimated to affect around 2.8 percent of children aged 6-12 years and 5.6 percent of adolescents aged 12-18 years in the United States, according to the study authors.

For children and adolescents with major depression, most clinical guidelines recommend cognitive behavioral therapy (CBT) and other psychological therapies as the first-line treatment.

However, lead study author Dr. Andrea Cipriani, of the University of Oxford in the United Kingdom, and colleagues note that an increasing number of youngsters with major depression are being prescribed antidepressants.

For their study, the researchers set out to investigate whether the benefits of antidepressant use outweigh the risks for young people with major depression.

The team conducted a systematic review and meta-analysis of all unpublished and published double-blind, randomized controlled trials up to May 2015 that assessed the treatment of major depression among children and adolescents.

The trials included in the analysis assessed the effects of 14 antidepressant medications, and the team ranked the effectiveness of each medication using four criteria:

  • Efficacy – determined by changes in depressive symptoms and response to treatment
  • Tolerability – whether medication use was discontinued due to adverse events
  • Acceptability – whether medication use was discontinued due to any cause
  • Associated serious harms – whether the medication increased suicidal thoughts or events, or other harms.

The researchers accounted for the quality of each study using the Cochrane risk of bias, and they also assessed the overall quality of the evidence from each study using the GRADE framework.

In 34 of the trials – including 5,260 participants of average age 9-18 years – the researchers identified only one antidepressant, fluoxetine, for which the benefits outweighed the risks when it came to efficacy and tolerability.

“The balance of risks and benefits of antidepressants for the treatment of major depression does not seem to offer a clear advantage in children and teenagers, with probably only the exception of fluoxetine.” Study co-author Prof. Peng Xie, The First Affiliated Hospital of Chongqing Medical University, China, says.

Looking at the long-term

Because we lack good data, we still do not know how well antidepressants work for those with milder symptoms that fall short of major depression, especially if patients have been on the drugs for months or even years. Many people probably fall into that category, yet are still regularly prescribed antidepressants for extended periods. We don’t know how much of the benefit received from such use is a placebo effect.

It is estimated that around 1 in 10 U.S. adults now take antidepressants, and with the incidence of depression on the rise, it seems unlikely that these numbers will reverse any time soon.

We have evidence to suggest that antidepressants may help some people, at least in the short term. While it is true that antidepressants won’t do much to alleviate the environmental circumstances that cause situational depression, they can help alleviate symptoms of major depression enough to enable a person to make lifestyle changes like diet and exercise, support groups, and counseling techniques that may be more effective in the long-term. Even if a person benefits from the placebo effect, what matters is that there is a positive effect in some cases. Cognitive-behavior therapy can help a person identify toxic relationships and other situations that may be contributing to depression. Feeling better, getting proper nutrition, increasing activity levels, and connecting to a good support network can help a person feel empowered to make other healthy life changes.

The risk factors for children and teenagers continue to be a concern. Rather than the first-line treatment that antidepressants are for many adults, the evidence we have so far suggests it may be better to try other alternatives first. Children can benefit from improved diet, increased activity, and mental health therapy. An antidepressant, fluoxetine specifically, might best be considered only after other interventions have been implemented.

If you are currently taking an antidepressant, do not stop taking it without consulting with your doctor. But if you are taking an antidepressant, or are thinking of taking one, you might think of it as a stepping-stone to making some beneficial lifestyle changes. Nutrition plays a major role in depression. Making changes in your diet can reap immediate and lasting benefits and in some cases can even make an antidepressant more effective.

Depression is a serious, sometimes even debilitating condition. Alleviating symptoms is the first order of business. Getting out from under the dark cloud of depression allows us to identify contributing factors and implement changes that can further improve our mood and prevent relapse over the long-term. The jury is still out as to whether antidepressants bring improvement or whether the belief in them brings improvement.  Either way, feeling better is the goal and knowing all of the options and tapping into all beneficial resources will help ensure success for a happier and healthier life.

 

 

 

 

 

 

3 Responses to “DO ANTIDEPRESSANTS REALLY WORK?”

  1. Dena Nichols says:

    Since antidepressants produce strong results in the short-term, perhaps an intermittent schedule, (8-12 weeks on, 8-12 weeks off), rather than a schedule that is long term/open ended would be beneficial. Titration would need to be closely monitored. (Discuss with prescribing professional.) Diet, exercise, environmental circumstances, and having a strong support network should continue to be advocated. “Cherry picking” studies always makes decisions a challenge on many levels. Thank you for sharing your findings on this important topic!

    • admin says:

      We certainly need to do something better. The incidence of depression continues to rise in spite of a plethora of pharmaceuticals to choose from. I like your idea of an intermittent schedule. This would provide an opportunity to get the most benefit and encourage the lifestyle changes as soon as symptoms are diminished enough to do so. The antidepressant could then be used to reinforce those changes for as long as needed. This also provides an opportunity to see when and if it is no longer needed. We don’t currently have a good mechanism for that determination.
      Thanks for your feedback!

    • admin says:

      Just one more point to be clear, research shows that antidepressants have “modest” results more than “strong” results. It would be more accurate to say that we see their strongest results in the first 8 weeks of treatment.

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