Do antidepressants work?

There is an active debate underway in the popular literature about whether antidepressant medications actually do anything chemically helpful for depressed patients.  No one doubts that many patients report feeling better, and that most evidence less depression on standardized rating scales, following treatment.  But much of that improvement appears to be due to psychological factors, i.e., the placebo effect.  The debate is over how much improvement is not due to the placebo effect.  What beneficial effects can be attributed to the active ingredients in the tablet or capsule?

It’s disconcerting to enter this debate decades after the popularization of antidepressants.  These are among the most common prescriptions in America: In 2010, antidepressants were the second most commonly prescribed class of drugs in the U.S., according to IMS Health.  They are so widely used that Consumer Reports publishes “best buy” recommendations about which ones to try first.  Yet recent reanalyses of efficacy data have called into question whether antidepressants help more than inert pills.  In a twopart piece in the New York Review of Books, Marcia Angell MD, the former editor-in-chief of the New England Journal of Medicine, favorably reviews these skeptical findings.  (I won’t summarize the arguments here, but I do very much recommend her review.)  In the other corner is Peter Kramer MD, author of Listening to Prozac and other books, who offers a spirited defense of antidepressants in his op-ed rebuttal in the New York Times.  The 300 comments that follow the online version of the op-ed also make for fascinating reading: Many are first-person accounts of the lifesaving benefit of antidepressants.

What to make of all this?  Those conversant in research methodology will pick apart the various arguments.  Do the studies have enough statistical “power”?  Does it matter that typical efficacy studies recruit subjects who differ from patients in clinical practice?  How much difference does an “active” placebo make?  Is it preferable to use subjective mood ratings, or ratings from trained observers?  How many weeks or months should subjects be assessed?  Should subjects with co-morbidities, i.e., additional diagnoses, be included or excluded?  Are there advantages to including a third study arm (a known effective intervention) to the usual two (the drug being assessed, and placebo)?

There are many such questions that need to be resolved, and professional researchers are probably in the best position to discuss them.  Meanwhile, the rest of us are left with a seeming paradox.  Thousands — millions? — of individuals claim relief from antidepressant treatment, and virtually any psychiatrist will swear that antidepressants really have helped many of his or her depressed patients.  (This is my own experience, by the way — it’s nearly inconceivable to me that antidepressants are no more than placebos.  I’ve seen too many patients improve before my very eyes.)  Meanwhile, there are also many patients, equally depressed, who obtain little or no benefit from antidepressants, and a large number of carefully conducted studies that find little benefit in the active ingredients of these pills, once placebo effects are factored out.

While I can’t prove it, my sense is that the answer lies in the heterogeneity of depression.  Some patients get dramatically better on antidepressants (in entirely believable ways, as opposed to reactive “flight into health” and the like), some only a little, and others appear not to change at all.  Widely varying responses can easily “average out” in the usual randomized controlled trials used to assess efficacy, and could account for lackluster findings in group studies.  Since I do have some research background and training myself, I’d want to see the scatterplots of individual subject ratings, to see if they cluster into responsive, partly responsive, and unresponsive groups.

Of course, it is not a new idea that some depression responds to medication and some doesn’t.  When I started medical school, psychiatrists distinguished “endogenous” and “exogenous” depression — i.e., depression that originated within the patient chemically, and depression that originated from external stress or loss.  (For a concise summary of the idea, see the first paragraph of this editorial.)  Antidepressants were thought to help the former but not the latter.

Unfortunately, that wasn’t true.  As it turns out, knowing whether an external event precedes a depression doesn’t predict whether an antidepressant will help.  The search has gotten more sophisticated lately, and measurable genetic subtypes may one day tell us who will benefit by antidepressants and who won’t.  But we’re not there yet.   At this point, we cannot predict whether an individual patient will improve with antidepressant medication.

I’ll end this post by noting that the placebo effect, a vexing complication in clinical research, isn’t a bad thing in real life.  If a patient feels better, I don’t worry too much about who or what gets the credit.  Maybe it’s the citalopram or sertraline in the pill.  Maybe it’s the patient’s belief in the pill and in the medical science behind it.  Maybe it’s the fact that I gave the patient something that our culture imbues with symbolic healing powers.  Maybe my words were healing and the prescription was a mere distraction.  Or maybe I had no effect at all, and the patient healed himself or herself.  Usually it’s impossible to know.  In my view, being a psychiatrist in clinical practice requires this kind of agnosticism and humility.

12 comments to Do antidepressants work?

  • KT

    There are so many “what ifs” and “yes, buts” surrounding the topic it’s hard to make a coherent statement about antidepressants. You seem to be saying that ultimately it doesn’t matter all that much how people are being helped by antidepressant medication, as long as they’re being helped.

    If the companies, medical groups, and doctors providing, advertising, and prescribing these medicines were all completely unbiased and free of ulterior motives (like profit), and the drugs themselves were free of side effects (like decreased libido) perhaps that would be true. But is it wise to to blithely accept a widespread placebo effect when there is so much money at stake, not to mention the side effects?

    BTW, I have nothing against a placebo effect, it’s great! I do have problems with huge profits on a placebo effect, however.

    • This is one of those times I wish I’d been a little more careful in wording my original post. Instead of writing that the placebo effect isn’t a bad thing “in real life,” I wish I’d written “in treating a specific patient.” I completely agree that in the real-life world of pharmaceutical marketing, insurance coverage, health care costs, and risk-benefit ratios, whether a medication has more to offer than a sugar pill is vitally important. It is clearly not wise, at this “macro” level, to accept a placebo effect as though it were the result of an active drug — and that’s exactly what the debate is about.

      However, there’s a reason all this talk of placebo effect revolves around group studies and statistics. In an individual, it’s impossible to know what accounts for change. There is always more than one thing happening: medications are swallowed, conversations take place, everyday stresses come and go, time passes. Patients with certain kinds of complaints, e.g., major depression, often do improve while taking medications. No one disputes that. Maybe we’ll learn someday that it’s handling the plastic pill bottles that does the trick. (Consider that plastic pill bottles came into use about the same time as antidepressants, in the 1960s. Whoa.)

      Whatever it is, I’m glad they feel better. And they’re glad they feel better. And we’ll all still be glad even when the serotonin theory of depression is debunked, or when we meekly accept that it was the pill bottles all along.

      Thanks for writing.

  • TK

    Strong blog post, as usual.

    A couple of points worth clarifying.

    That “exogenous” or situational depression you talk about is often not simply in reaction to a prior event — say, a death — but to an ongoing set of circumstances in the patient’s life. Say, a partner is dying, or the patient is sick.

    Secondly, there’s a kicker when it comes to the placebo effect of SSRIs, and you allude to it in your piece. Yet it needs to be underscored. That is, SSRIs are not inactive drugs. When you take them, it is not like taking sugar pills, for which the patient would feel nothing. SSRIs have physical affects apart from whatever they do to serotonin. SSRI patients commonly report wildly vivid dreams, for example. They report dry mouth. They report a whole host of things. When a drug does X or Y to you, and you see X or Y manifest, it’s a lot easier to imagine that it does Z to you. Emphasis on the word “imagine.”

    SSRIs have a statistically significant impact on severe depression. This is not trivial — there are a couple of million severely depressed folks in our country. As for the rest of those who are popping e.g. Paxil? Not so much.

  • Actually, side effects and risks of an unnecessary medication are extremely important beyond the immediate health care costs.

    When patients might benefit just as much from getting more sleep and exercise, and cutting out junk food, how can medicine justify elevating the risk of, let’s say, diabetes, a truly dire disease, by prescribing an antidepressant as a placebo?

    Even slight prolongation of the QT interval — all antidepressants affect this cardiac function — may increase death risk, see

    Why increase the risk of drug-drug interactions by prescribing unnecessary and very powerful medications? Doesn’t anyone care about minimizing medications anymore?

    As usual, I am stunned by a cavalier dismissal of the cost of side effects that may not immediately be apparent to the clinician or patient, not to mention the side effects that are obvious.

    And don’t bring up the red herring of suicidality. Obviously 11% of the US population doesn’t need to be medicated with antidepressants to reduce the .01% suicide rate. It’s debatable widespread antidepressant use has reduced this at all.

    The diabetes death rate is more than twice as high (2007 statistics), and rising.

    Plus, anyone serious about suicide knows to avoid mental health professionals anyway. So what’s the excuse for handing out antidepressants as though they were vitamin C, good for what ails you and if they’re placebos, so what?

    • Hi, Iatrogenia (a truly inspired pseudonym). Taking your points in turn, side effects and risks of medication are always important to consider. The essence of medical practice is to weigh risks and benefits, to advise treatment only when the latter outweigh the former, and to present this recommendation in such a way that the patient can make an informed choice, also considering both potential risks and potential benefits. Patients who come to see me for depression are nearly uniformly too depressed to eat, sleep, or exercise as they normally do, much less do extra. Nonetheless, I always mention and encourage these helpful lifestyle changes.

      You cite an epidemiological study showing QT interval prolongation is associated with increased mortality. However, the average follow-up in that study was nearly 14 years, and the causes of QT prolongation were not studied. Antidepressant treatment for single-episode major depression is only 6-12 months, so that study’s findings may not be relevant to our discussion. And people who suffer recurrent severe depression (and thus take antidepressants for longer durations) may consider the risk worth taking if they achieve significant benefit. Many other common medications, some used chronically, also can cause QT interval prolongation.

      “Doesn’t anyone care about minimizing medications anymore?” Yes, you’re writing to one. I’m sure I’ve simplified, i.e., decreased, more medication regimens over the years than most docs have. My practice is more psychotherapy than prescription writing, and I rarely accept a new medication-only patient anymore. I believe “chemical imbalance” rationales are meaningless in psychiatry, and when it comes to antidepressants we can probably thank the placebo effect for most — maybe even all — of the benefits seen. Despite all of this, I am not anti-medication. Many depressed people suffer terribly, and would accept far greater treatment risks than typical antidepressants carry. Most of the time such patients do feel better, and do not suffer significant side-effects, from antidepressants.

      I’m not cavalier and I don’t “hand them out like vitamin C.” I offer them sparingly, generally in combination with psychotherapy, and with plenty of disclosure about potential drawbacks. If you were my patient you’d certainly be free to say “no thanks.” In fact, I wish more patients did, but it’s not for me to tell them to suffer longer because I can’t explain how the meds work, or because a small minority of former patients had very bad side-effects or discontinuation syndromes.

  • Anonymous

    Thank alot “Tom Cruise”, way to set mental illness back a few decades. There is enough stigma and belief that people can just pull themselves up by the bootstraps and go on. Do you really believe that a placebo effect could stop panic attacks, anxiety and help people heal from depression?

    • Yes. Just as I believe that placebo can decrease physical pain from “real” medical causes. The research bears this out both for pain and for psychiatric conditions. If this reality “sets mental illness back a few decades,” it must do the same for pain management too. It’s regrettable that some people misuse facts to bolster their unfair prejudices, but that’s no argument for denying the facts themselves.

      • aan

        When i finally went to the dotcor about my depression, i knew that i was very unwell, and i wanted drugs- i wanted to take some pills and make it all go away. i walked away from my appointment relieved that it was All Going To Be Okay. But time went on, and it wasn’t. i went back. As i hadn’t responded to ONE trial of ONE baseline dose of generic antidepressant, Nice Mr Doc-Man then told me there was obviously nothing wrong with me. i next saw him when he was summoned in to sign my section papers: the irony was the first thing that had amused me in weeks.Seven years and over eight different presciptions later, my notes reading like a veritable Who’s Who’ of SSRIs, i have to conclude that i am most probably one of the 30-50% of sufferers who are treatment-resistant. i went from drug to drug, hoping, hoping, hoping that it would be The One, but it wasn’t to be. If there had been other options, i wouldn’t have had to force myself onto yet another drug regimen, which would make me sick/ lose/gain a stone/ sleep constantly, generally suck all the life out of me, but there were never other options, it was this tablet, that tablet, or nothing at all. It sucks that there’s no magic pill for me, but i’m old enough and wise enough now to realise that a quick-fix is not going to work for me, that my depression stems from things which need to be worked through, not temporarily numbed. i hate depression, but without the drugs, at least i finally know who and how i am. Now i wait my turn for therapy.And i wait.Too many people fear the judgement of a society which doesn’t accept the ill- which views depressives as weak or lazy- so they dont get help soon enough, and too few agencies focus on the importance of early intervention to help. Too many people aren’t aware of the options they have, or the fact that they have rights to access those options. Ultimately too many people take antidepressants because it is the only option they have; the only hope to cling to in an immediacy which is all too painful, a world that is more and more unforgiving.

    • Hmmm it get’s me thinking.I agree with some of the altrcie, but don’t necessarily believe antidepressants are generally a last resort However I believe more often than not they should be! (especially when it comes to children and young people.)For people with severe depression, I believe that a combination of talking therapy and anti depressants is generally best. However it’s worth pointing out I’m not a huge fan of CBT. It’s usually carried out in a way which is not person centred and often not young person friendly. I realise CBT is beneficial to many people, which is great, I just think far too much emphasis is put on that being the be all and end all’ therapy, when person centred counselling (which can encorporate different therapeutic techniques, including CBT) can be just as helpful.I’ve been on Antidepressants, more or less, for a decade. Some have made me very ill, some seem to have helped a little a benefit I only notice when I stop taking them for a few days (I often run out of meds or forget to take them.) However they have had very little impact compared to therapy but then again I don’t suffer from Depression as such so my experience will vary from someone who does.

    • I believe nidatepressants have saved my life on several occasions, that they have allowed me to function normally Totally agree I had therapy and bbt didn’t work for me lessoned it a little bit but that it the reall change was when I took sertraline and have been them a year and have literally done everything that I wanted to now. I don’t agree they don’t work and it is in your mind if it was then they wouldn’t have worked for me because the whole of te first 6 weeks I believed they wouldn’t work and wanted to come off it!

  • Aside from full, partial, and null responders, there is a fourth study group that no one ever addresses.

    Throughout antidepressant trials, a group of subjects drop out, usually due to intolerable side effects — up to 30% of the study population. Study statistics are then analyzed as though the dropouts never existed.

    Effectively, this is a human population upon which antidepressants have never been tested at length.

    Yet these people are part of the general population who might be prescribed antidepressants. They then go on to have adverse reactions — but the doctor has been trained (if not indoctrinated) to keep the patient on the drug anyway, until it has a chance to “work.”

    Some of these patients never get any benefit from the medication, experiencing years of adverse effects during which their doctors might switch them from drug to drug or add others. Ultimately, medication does them more harm than good.

    (This was seen in Gueorguieva et al 2011 , which inadvertently found about 16% of patients who did stay in clinical trials did worse on antidepressants.)

    Kirsch and other teams did not include dropout counts in their statistical analyses showing antidepressants no more effective than placebo. If true clinical experience were included, more weight would be added to the negative side of the scale.

    In addition, Kirsch and colleagues did not include the incidence of withdrawal symptoms counted as relapse in studies of antidepressant efficacy (no study of efficacy, including STAR*D with 4,000 subjects, ever distinguished between withdrawal and relapse).

    El-Mallakh et al 2012 mention this: “This pattern strongly suggests that the apparent superiority of antidepressants may be due to (i) their ability to prevent recurrence, (ii) antidepressant withdrawal (characterized by depressive symptoms) in patients switched to placebo or (iii) a combination of these phenomena.”

    This suggests “true” effectiveness of antidepressants is substantially less than 50%, which would be even with placebo.

    • The approach for handling non-completers in most well-conducted clinical trials is called Last Observation Carried Forward (LOCF). It’s a conservative statistical maneuver aimed to decrease the apparent effect of the active treatment. If a subject can’t tolerate the study drug and drops out, his or her symptom ratings are “carried forward” from their last measurement to the analysis at the end of the study, often several weeks later. Since people who drop out early haven’t improved, their ratings pull down the average improvement scores in the treatment group. Good studies also look at the non-completers as a group, to see if they differ in obvious ways from completers, and also analyze why they stopped.

      I’m not aware of any study that identifies a distinct subpopulation of subjects who are prone to intolerable side effects across different antidepressants. However, this subpopulation certainly seems to exist in clinical practice. In my experience, these are patients who are not kept on a useless, noxious medication indefinitely. Instead, they report ten different antidepressants they’ve tried in the past, each for a week or two. (In this way, they are a “human population upon which antidepressants have never been tested at length.”) Some aim to try yet another, others seek non-medication alternatives. Unfortunately, most psychiatrists seem more comfortable with the former than the latter, so another intolerable prescription is written…

      Both of the papers you cite are creative and interesting, but I don’t see how they support your point. The first highlights heterogeneity in treatment groups, and proposes a way to analyze this statistically. The study says nothing about side effects, nor about whether doctors keep patients on meds that are making them worse. The second study finds no evidence that prolonged antidepressant treatment prevents relapse, although it does appear to prevent return of the original depressive episode. Again, nothing about side effects, nor about the “true” effectiveness of antidepressants.

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