"Antidepressant drugs don’t work"

The headline above comes from the UK’s Independent. I could have picked number of variants (BBC, “Anti-depressants ‘of little use‘,” Financial Times, “Antidepressants ‘have no impact‘”), but what is interesting is that as of this hour, this study, published by the University of Hull, is getting MSM coverage solely in the UK and Commonwealth countries.

The study was a meta-analysis of 47 published and unpublished clinical trials submitted to the FDA for the most popular category of antidepressants, the selective seratonin reuptake inhibitors (SSRIs), which include Prozac, Paxil, Zoloft, and Efexor. This study did not cover an older type of anti-depressant, bupropion (Wellburtin and Zyban). Bottom line: SSRIs are beneficial only for a very small group, the most severely depressed, and then only to a limited degree.

The cynic in me wonders both about regulatory regimes that allowed such marginal drugs to become blockbusters, and the US media for (as of now) failing to broadcast this finding. Comments from the lead researcher, Professor Irving Kirsch, indicate that it was difficult for him to get the data needed to perform the analysis.

From the Independent:

They are among the biggest-selling drugs of all time, the “happiness pills” that supposedly lift the moods of those who suffer depression and are taken by millions of people in the UK every year.

But one of the largest studies of modern antidepressant drugs has found that they have no clinically significant effect. In other words, they don’t work.

The finding will send shock waves through the medical profession and patients and raises serious questions about the regulation of the multinational pharmaceutical industry, which was accused yesterday of withholding data on the drugs….

In the study, researchers conducted a meta-analysis of all 47 clinical trials, published and unpublished, submitted to the Food and Drug Administration in the US, made in support of licensing applications for six of the best known antidepressant drugs, including Prozac, Seroxat – which is made by GlaxoSmithKline – and Efexor made by Wyeth. The results showed the drugs were effective only in a very small group of the most extremely depressed.

Two drugs were excluded from the study because of incomplete data. A third drug, chemical name nafazodone, has been withdrawn from the market because of side-effects.

Professor Irving Kirsch of the University of Hull, who led the study published in the online journal Public Library of Science (PLoS) Medicine , said the data submitted to the FDA would also have been submitted to the licensing authorities in Britain and Europe. It showed the drugs produced a “very small” improvement compared with placebo of two points on the 51-point Hamilton depression scale…..

Professor Kirsch said: “Given these results, there seems to be little reason to prescribe antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide a benefit. This study raises serious issues that need to be addressed surrounding drug licensing and how drug trial data is reported.”

Five years ago, there were allegations that antidepressant drugs were addictive and could trigger suicides. All but Prozac were banned for children, although a major investigation on the safety of medicines cleared them of causing suicide in adults.

Alternative treatments for depression, such as counselling or physical exercise , should be tried first, Professor Kirsch said. The pharmaceutical companies had withheld data that was available to the licensing authorities so that doctors and patients did not understand the true efficacy, or lack of it, of the drugs.

“This has been the frustration. It has made it very difficult to answer the question of whether the drugs work. The pharmaceutical companies should be obliged when they get a drug licensed to make all the data available to the public. When you analyse all the trials of these SSRIs, both published and unpublished, it leads you to more sober conclusions,” he said.

Tim Kendall, deputy director of the Royal College of Psychiatrists’ research unit, said the findings, if proved true, would not be surprising. As head of the National Collaborating Centre for Nice guidelines on mental health, he said it had proved impossible to get access to unpublished trials in the past.

“The companies have this data but they will not release it. When we were drawing up the guidelines on prescribing antidepressants to children [in 2004] we wrote to all the companies asking for it but they said no. The Government pledged in its manifesto to compel the drug companies to give access to their data but that commitment has not been met.”

The new finding would make doctors “much more cautious about prescribing the drugs,” Mr Kendall added.

GlaxoSmithKline, makers of Seroxat, said the authors of the study had “failed to acknowledge” the very positive benefits of SSRIs and their conclusions were “at odds with the very positive benefits seen in actual clinical practice.” A spokesperson added: “This one study should not be used to cause unnecessary alarm for patients.

Lilly said in a statement: “Extensive scientific and medical experience has demonstrated that fluoxetine [Prozac] is an effective antidepressant.

Wyeth said: “We recognise the need for both pharmacological and non-pharmacological treatments for depression.”

On the new training for therapists, Mr Johnson said the programme signalled a decisive shift away from drugs in favour of non-drug treatments for depression. “We are not taking the decision away from clinicians,” he said.

“For many, medication is successful. But talking therapies can have dramatic effects. We have put a lot of emphasis on medication in the past and it is about time we redressed the balance and put more emphasis on talking treatments.”

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  1. Anonymous

    Just shocking. An entire profession precribing medications to depressed people for decades which have almost no efficacy.

    How could it take this long to expose this? And no coverage in the US media? This seems to be symptomatic of an entire system (or a culture) which has become very broken. Anything for a buck.

  2. Yves Smith

    I imagine the US media will report on this a day late. It’s getting too much traffic in the UK and in the blogsphere to be ignored.

    What really gets to me is my own anecdotal experience that the FDA did know these meds are bunk.

    I’ve suffered on and off from fatigue ever since I had mono as a adult (well after college). Fatigue is one of those conditions modern medicine isn’t very interested in, once they’ve ruled out anemia and low thyroid (which it turns out I have, but taking thyroid hasn’t helped much).

    Say “fatigue” to a US doctor, and his next line of defense is antidepressants. No psych evaluation, mind you, if you are tired and they can’t figure it out quickly, it must be in your head, you need a happy pill.

    I grumbled about this pattern to a good friend, a partner in an FDA law firm (there are only seven that are first tier). She comes from the NIH and big Pharma, and many of her partners are former FDA commissioners. She told me in no uncertain terms not to consider taking SSRIs, her FDA partners wouldn’t touch the stuff, they’d take Valium (which has high risk of addiction) long before they’d take an SSRI.

  3. CrocodileChuck


    I had ChronicFatigueSyndrome several years ago, compounded by depression. I NEVER took SSRI’s-thought they were dangerous and questioned their effectiveness (actually, I was uncomfortable taking anything for 30 days to change my neurochemistry before any purported ‘improvement’). Good to see this coming out-and vindicating my view of modern medicine/pharma NB two family members are MD’s

    Take responsibility for one’s own health!


  4. Anonymous

    You can add in Rumsfeld and his chicken flu vaccine as well, to the list of mis-approved FDA snake oils!

  5. Daniel Newby

    I just skimmed the meta-analysis in question and am skeptical. They do not report the doses and titration schedules used. In other words, they are hiding from us whether the trials were unreported because an insufficient dose had been used.

    They also do not report about confounders like IQ, race, and economic conditions. During adverse social conditions, it is likely that the will be a wave of refractory mild depression.

    Astonishingly, their success/failure criterion is the “clinical significance” standard set by NICE, the British agency in charge of selecting which drugs the public purse will pay for (and given that charge by government-captive interests responsible for cutting costs). This whopping conflict of interest is not disclosed.

    There is no analysis of objective practical criteria, such as personal income, promotions, number of hours spent vegetating in front of the TV, divorce rate, number of children conceived after starting the drug, etc. To conclude that SSRIs are worthless in the absence of practical data is irresponsible.

    There is also the small matter of these being central nervous system drugs. Not only is placebo often a legitimate effective treatment, but small differences from placebo are the norm. The brain can break in dozens of different ways, only a few of which can be fixed by a given drug.

  6. Yves Smith

    daniel newby,

    I sincerely doubt that all or even any of the variables you are asking for are collected in any clinical trial. In addition, many data items would have to be self-reported and would also be unreliable (do you think people are going to answer truthfully about how much money they make? Having done a lot of survey research, the answer is no. Moreover, responses are very much influenced by the design of the survey instrument. Questions would need to be administered in an identical manner, word for word, for them to have the same meaning across studies, Even small changes in phrasing lead to significant differences in responses).

    And even if the data you wanted had been collected in a consistent fashion across all trials, most trials are not terribly large scale. If you know any statistics, you can’t test many variables in regression analyses when you have relatively small samples, and the samples for clinical trials are not large in by statistical standards. So with all due respect, the analysis you are claiming needed to be done can’t possibly be done in any reasonably rigorous manner. They’d be garbage-in, garbage-out exercises.

    And what hypotheses do you have relative to the items you are curious about? Promotions raise stress. For certain individuals, they could initially worsen mood, not improve it. TV? Since TV watching is generally self-reported, I don’t know of any studies linking TV watching to depression or lack of depression (all I know is that TV withdrawal is reported to make people unhappy).

    In general, even the clinical trials that have reported favorable outcomes for SSRI find an efficacy rate of about 50% versus a placebo rate of 30%. That isn’t exactly compelling. So I am not at all surprised that inclusion of less clear cut studies make the results look worse.

    I am sure the US drug industry will have its knives out for this one. I am waiting to see the response from researchers in countries that don’t have a dog in this fight. US medical practice is heavily invested in the use of psychoactive drugs, so I would discount most US views as being biased.

  7. Deborah

    I worked to help people quit smoking and the doctor I worked with liked to use Zyban.

    I couldn’t believe how many of the smokers were taking the line up in this post, and essentially, we couldn’t get them off those anti-depressants, nor did they have a very good success rate. Our success rate with those not taking anti-depressants was actually exceptionally good.

  8. Daniel Newby

    I agree that getting proper data takes work. I would hope there had been at least a few large government-sponsored trials, like the ones they do for heart disease. Alas, a quick search does not turn up anything.

    The data need not be completely bogus. For income, show us your W-2 form or you don’t get the $250 participation payment. Phone bills would be an interesting proxy for social withdrawal. Stamina, as a proxy for inactivity, is trivial to measure with a treadmill. You can get a lot real-world data at a reasonable cost. (Economic data is standard for studying acute migraine treatments; they’re $20/pill and you need something to keep the accountants from flipping out.)

    “So with all due respect, the analysis you are claiming needed to be done can’t possibly be done in any reasonably rigorous manner.”

    That was my point. The extant data does not permit a meaningful meta-analysis. Yet they concluded that SSRIs were definitely ineffective in most users, and the accompanying editorial says they should not be prescribed. Their data also strongly suggests that the placebo effect is doing valuable work, but they cannot come out and say that having a doctor simply try to help is an effective medical treatment.

    “In general, even the clinical trials that have reported favorable outcomes for SSRI find an efficacy rate of about 50% versus a placebo rate of 30%. That isn’t exactly compelling.”

    That’s as good as it gets for a central nervous system drug. Yes, CNS drug development is a total swamp.

    The meta-analysis also ignores whether SSRIs affect the long-term progression of mild depression into major depression. Given the high costs of major depression, this is not a trivial consideration.

  9. Anonymous

    Daniel Newby,

    Keep in mind that, according to the article, the pharmaceutical companies are extremely resistant to releasing data. The issues Yves raises are problem enough, but following your lead would allow the pharmaceutical companies to benefit from their nondisclosure. If there are legitimate doubts, the onus should be on the drug companies to demonstrate that these are effective drugs, rather than allowing them to sell the drugs until someone can definitively prove that they don’t work–after somehow getting the money to do the study.

  10. mmm

    Daniel Newby,

    Per 12:53, the onus IS on the drug companies to prove efficacy. Thus, they should prove that they prevent minor depression from turning into major depression. It shouldn’t be assumed as a possibility, which is what you are saying, in effect, and then the burden on someone else to disprove it.

    And “20% better than placebo rate is as good as it gets” sounds like a poor justification for giving people meds that mess with their brain chemistry. Many of these drugs (SSRIs included) are hard to get off.

    I have a friend who used to work for the NIH and gave up medical research in general disgust with how it is done (too many efforts to draw lines through scatter diagrams that were pretty inconclusive). He said that the FDA was no longer a science based organization. I never got him to explain what he meant, but the research around SSRIs may be the sort of thing he had in mind.

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