The vast majority of studies evaluating antidepressant efficacy for the treatment of anxiety disorders that are judged by the US Food and Drug Administration (FDA) as positive are published. However, it's a different story for nonsignificant studies, results of a new meta-analysis show.
Investigators at the University Medical Center Groningen, the Netherlands, found that trials that the FDA deemed positive were five times more likely to be published compared with trials deemed not positive. Furthermore, they found evidence for study publication bias (P < .001), outcome reporting bias (P = .02), and spin (P = .02).
The findings, investigators say, provide a skewed view of antidepressant efficacy.
"Antidepressants have value in treating anxiety disorders, but they are not 'miracle drugs,' and there is less evidence to support their efficacy than what appears from the published studies," Annelieke Roest, PhD, told Medscape Medical News in written correspondence.
"It is important that physicians have a realistic view of the efficacy of these drugs so they can make a well-justified decision when prescribing these medications," she said.
The findings were published online March 25 in JAMA Psychiatry.
Skewed View?
The investigators note that there is "strong evidence that significant results from randomized clinical trials are more likely to be published than non-significant studies.
"As a consequence, published studies, including meta-analyses, may overestimate the benefits of treatments while underestimating their harms, thus misinforming physicians, policy makers, and patients."
The researchers examined reporting biases in double-blind, placebo-controlled trials on the pharmacologic treatment of anxiety disorders and quantified the extent to which these biases inflate estimates of drug efficacy.
They identified phase 2 and 3 double-blind, placebo-controlled trials registered with the FDA and conducted in pursuit of marketing approval of second-generation antidepressants for the treatment of generalized anxiety disorder, panic disorder, social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder.
Studies involving seven selective serotonin reuptake inhibitors and two serotonin norepinephrine reuptake inhibitors were evaluated.
Of the 57 trials identified by researchers, findings from 41 of them (72%) were judged to be positive by the FDA.
However, 43 of 45 (96%) of the articles published in the literature were positive (P < .001).
This suggests that trials the FDA determined to be positive were five times more likely to be published in agreement with that determination compared with trials determined to be not as positive by the FDA (risk ratio, 5.20; 95% confidence interval, 1.87 - 14.45; P < .001).
Sixteen of the 57 trials identified by investigators (28%) were not judged to be positive by the FDA, and seven of these trials (44%) were not published. Continue Reading
In contrast, only one of the 41 positive trials (2%) was not published. The difference between the not-positive and positive trials was significant (P < .001)
Of the 16 not-positive trials, only 3 (19%) were published in agreement with the FDA, investigators add ― in other words, they were published without a positive conclusion in the literature.
Importantly, in 3 of the 16 not-positive trials, effects were reported as statistically significant in the journal article, leading to a positive conclusion that conflicted with the FDA review of the study.
"By contrast, outcome reporting bias was found in none of the 41 FDA-positive trials," investigators add. The difference between the not-positive and positive trials was statistically significant (P = .02).
Spin was present in an additional 3 of 16 (19%) of the not-positive trials as well; it was not present for any of the positive trials.
Each of these three trials reported that the primary endpoint was nonsignificant in the results section of the articles in which they were published, but in the abstract, it was concluded that the trial was positive, the investigators note.
The FDA classified one of these three trials as "questionable" and the other two as "negative."
When investigators compared the overall treatment effect from a meta-analysis of the literature to the treatment effect from a meta-analysis of the FDA reviews, there was an overestimation of the treatment effect of 15%, as determined on the basis of the literature analysis, a difference that was not statistically significant.
This is in contrast to a previous study (N Engl J Med. 2008;358:252-260) that showed a larger overestimation ― one of 32% ― for the efficacy of antidepressants in the treatment of depressive disorder, as determined on the basis of literature reports.
"These medications have been shown to have an overall meaningful effect on anxiety, as has been shown for nonpharmacological treatments, like cognitive behavior therapy, as well," Dr Roest said.
"But they will not have a positive effect on all individuals, and physicians should carefully consider and discuss the various treatment options with their patients in order to determine the best treatment effect for each of them."
Antidepressants Not Very Useful
Asked by Medscape Medical News to comment on the study, Irving Kirsch, PhD, associate director, Program in Placebo Studies and the Therapeutic Encounter, Harvard Medical School, Boston, Massachusetts, disagreed with Dr Roest's statement that antidepressants have "an overall meaningful effect" on anxiety.
"In fact," he said, "the overall effect size reported in the study [0.38; 95% CI, 0.33 - 0.42] is very small and may not even be detectable by treating physicians."
At the same time, Dr Kirsch felt that the Dutch group's data were reliable, because they mirrored the effect size (0.27) that he and his colleagues found in a pre- and postmarketing study of paroxetine (multiple brands) in the treatment of anxiety.
"This is an effect size that one sees for these drugs in the treatment of depression," Dr Kirsch observed.
"And they are much smaller than what the National Institute of Clinical Health and Excellence has suggested would be a clinically meaningful effect size, which they have posited should be 0.5," he said.
"So antidepressants are as useful in anxiety disorders as they are in depression, which is not very."
The study was supported by a grant from the Dutch Brain Foundation. Dr Roest and Dr Kirsch report no relevant financial relationships.
JAMA Psychiatry. Published online March 25, 2015. Abstract
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imagine that! follow the money...
Antidepressant and antianxiety meds have very soft endpoints and placebo effect which make it very easy for drug companies to manipulate the true effect, since these are chronic meds there are potentially billions of dollars in profit at risk. Possible negative effects (GI bleed, rage response, increased falls, EKG changes, increased dementia risk) and long term effects are ignored or sometimes hidden. These can be very useful medications. But they should be used with care and for the indications, length of time, and age range for which they have been studied.
Your author has misstated the conclusion of the JAMA article.
You have reported that "The findings... provide a skewed view of antidepressant efficacy."
This is exactly what the findings of the metanalysis in JAMA did NOT do!.
Here is the accurate quote from JAMA:
"Conclusion ...reporting biases were present for trials on the efficacy of FDA-approved ...antidepressants for anxiety disorders. ALTHOUGH THESE BIASES DID NOT SIGNIFICANTLY INFLATE ESTIMATES OF DRUG EFFICACY, [caps my own], reporting biases led to significant increases in the number of positive findings in the literature."
It is worth repeating: ... "these biases ...did NOT significantly inflate estimates of drug efficacy. "
May I make a plea for more accurate reporting?
This is irresponsible journalism: publishing misinformation and biassed conclusions of the author that pose as "analysis". It does a great disservice to your readership and to the larger scientific community.
Please, if you are going to pretend to be a medical journal, hire editors who can accurately read a scientific article and get it right!
I remember a study I read as an undergraduate in the 50's about psychology experiments. The statistical tests used all had the assumption that the experiments were to repeated to make the conclusions valid. Almost none ever were. And I believe that negative results wer much less likely to be reported or published. Things don't change much.
This is scary but does not suprise me..Its all about money. Everything is about money.
I found this article very interesting. I, personally, did not find the observations made in the article all that surprising, however. The bias of publication of positive results versus negative results will likely be found in about any serious publication. I think it would be more interesting to look at the reason for the bias.
Scientists, like myself, are motivated to publish results for a set of reasons. Many of those reasons are not satisfied by publication of work that is inconclusive or negative regarding the purpose of the study. If we do publish the work we likely will spin the results in a positive light. It' human nature.
Lies! Damned lies and statistics!
Its not that they just don't work - they do so much harm! Apart, that is, for the shareholder dividends.
A case of the Emperor's New Cloths - think about it!
@P S I disagree. They do work. I am living proof. Sure, there are problems. I hate taking the stuff but I would be DEAD if I didn't. Yes, they do not get to the root cause and no one said they did (if they are honest).
Is this surprising? The FDA's funding is dependent on the pharmaceutical companies. Less and less funding comes from government, so the jobs of government employees at the FDA are increasingly dependent on industry funding.
There is also a possibility, that people think no positive finding means that there's no need to report it, but the result is that people don't know of the number of tests that failed to find an effect.
Is this concerning? Yes. People have learned to see the FDA as a scientific organisation, unbiased by commercial interests and acting in the role of consumer protection. There would now appear to be some conflicts of interest.
No wonder doctors believe in these drugs even though the evidence suggests that they are of little use, and in fact can cause extreme harm over both the short and long term. We all know that they don't cure the problems, just mask them for a while. Once the drug is ceased, the problem returns only bigger, as the person has depended on the drug to cope, instead of learning better problem-solving and coping skills.
The problem with the marketing of antidepressants is that they are always portrayed as magic bullets for the relief of depressive symptoms. That, of course, is incredibly simplistic and is deliberately designed to fool even the most astute Physician that just one pill will fit the bill.
But the brain & body are far more sophisticated than that. Hence, the high placebo levels.
SSRIs & SNRIs are useful drugs, as part of an overall treatment strategy. But they should NEVER be used alone. These days, such prescribing should virtually amount to medical malpractice.
Major depression demands thorough clinical investigation to uncover the underlying causes.
For example, does the patient have hypothyroidism (TSH > 3.0) or suffer from iron deficiency (ferritin < 50)
Are they in renal failure with an eGFR < 60 or worse; or do they have a malabsorption syndrome so that available amino acid precursors (tyrosine, phenylalanine, tryptophan) are simply not available in sufficient quantities for dopaminergic & serotonergic neurotransmission respectively. What about testing for polymorphisms in COMT, resulting in elevated norepinephrine levels with accompanying anxiety. What about testing salivary cortisols x4 over a 16hr time frame. One can even measure the six major neurotransmitters in urine and determine which pathways actually need metabolic support.
If you don't do the right tests, you don't get the right answers and your patient will suffer the consequences.
Refreshing resume. It timely reminder as one see in clinical practice;considering the patient's well-being is paramount !