Sharon Begley has an excellent Newsweek cover story on the rise and fall of anti-depressant medications, or how a class of drugs that were once hailed as medical miracles are now seen as barely better than placebos:

In just over half of the published and unpublished studies, Kirsch and colleagues reported in 2002, the drug alleviated depression no better than a placebo. "And the extra benefit of antidepressants was even less than we saw when we analyzed only published studies," Kirsch recalls. About 82 percent of the response to antidepressants--not the 75 percent he had calculated from examining only published studies--had also been achieved by a dummy pill.

The extra effect of real drugs wasn't much to celebrate, either. It amounted to 1.8 points on the 54-point scale doctors use to gauge the severity of depression, through questions about mood, sleep habits, and the like. Sleeping better counts as six points. Being less fidgety during the assessment is worth two points. In other words, the clinical significance of the 1.8 extra points from real drugs was underwhelming. Now Kirsch was certain. "The belief that antidepressants can cure depression chemically is simply wrong," he told me in January on the eve of the publication of his book The Emperor's New Drugs: Exploding the Anti-depressant Myth.

The 2002 study ignited a furious debate, but more and more scientists were becoming convinced that Kirsch--who had won respect for research on the placebo response and who had published scores of scientific papers--was on to something. One team of researchers wondered if antidepressants were "a triumph of marketing over science." Even defenders of antidepressants agreed that the drugs have "relatively small" effects. "Many have long been unimpressed by the magnitude of the differences observed between treatments and controls," psychology researcher Steven Hollon of Vanderbilt University and colleagues wrote--"what some of our colleagues refer to as 'the dirty little secret.' " In Britain, the agency that assesses which treatments are effective enough for the government to pay for stopped recommending antidepressants as a first-line treatment, especially for mild or moderate depression.

I'm currently working on a longer article on a related subject, so I won't go into detail here, but I think it's worth pointing out that anti-depressants might still prove to be a very useful class of drugs, just not for depression. To understand why, it's important to realize that antidepressants don't work the way the way the big pharm companies tell you they work, at least on their websites.

Their neat little story goes like this: antidepressants increase the brain's supply of serotonin, thus correcting our chemical imbalance. This implies that sadness is simply a lack of chemical happiness. The little blue pills cheer us up because they give the brain what it has been missing.

There's only one problem with this theory of depression: it's almost certainly wrong, or at the very least woefully incomplete. Experiments have since shown that lowering people's serotonin levels does not make them depressed, nor does it worsen their symptoms if they are already depressed. And then there's the "Prozac lag": although antidepressants increase the amount of serotonin in the brain within hours, their beneficial effects are not usually felt for weeks.

But just because antidepressants don't work via some silly and obsolete chemical model of depression doesn't mean the drugs don't trigger important changes in the brain. In recent years, scientists have found that the little blue pills modulate the neural pathways of plasticity, up-regulating trophic factors and neurogenesis. Because they make our mind more malleable - and help counter the the toxic effects of stress - the drugs have potential implications far beyond the treatment of depression.

Consider this 2008 study by Italian researchers, published in the journal Science. The scientists were interested in seeing if fluoxetine, the active ingredient of Prozac, could increase the potential of brain cells in the adult rat. They studied animals with severe cases of "lazy eye," a condition characterized by poor vision in one eye due to underdevelopment of the visual cortex. The scientists showed that fluoxetine gave brain cells the ability to take on new roles and form new connections, which erased the symptoms of the disorder.

Jose Vettencourt, a lead author on this paper, told me that "The drug appears to make brain cells quite young". The scientists are currently repeating the experiment with humans, raising the possibility that fluoxetine might one day be used to treat lazy eye and related conditions.

And then there's this brand new paper:

Widely used antidepressants may help patients recover cognitive functions, such as memory skills, that are damaged following a stroke, according to research released Monday.

Escitalopram, a type of selective serotonin reuptake inhibitor, or SSRI, was linked to improved cognitive functioning in a group of stroke patients who did not have symptoms of depression, scientists found.

Participants were treated within three months of the stroke in one of three ways: a low dose -- 5 to 10 milligrams -- of escitalopram, a placebo pill or problem-solving therapy but no medication. (The standard dose of escitalopram, also known by the brand name Lexapro, for treating depression is 20 milligrams.)

After one year, the group on escitalopram had higher scores on tests assessing thinking, learning and memory functions as well as ones testing verbal and visual memory. The group treated with medication also had greater improvements in activities related to daily living.

The point is that we might still be taking Prozac, et. al. years from now, just not for depression. The pills do something - they just aren't great at cheering us up.


More like this

I am very curious about this topic, for two personal reasons: my wife and myself.

My wife would cry for 2-3 hours at a time on an almost daily basis and be unable to do simple tasks. Once she got on the right pill(and I want to come back to that) she hasn't had that or many of the other problems. And the few times she does have a problem, it is much milder in degree and much shorter in time.

I have/had a real problem with binge eating. I would literally plan my day around times when I would be alone and could simply shove food in my mouth. If I was home alone for an entire day, I would plan how I could go to several different stores to buy food - so no one clerk suspected how much I was eating - after my wife left, eat it all, then throw out the wrappers and clean up before she got home. People also said I was mildly depressed/anxious because I would whenever I wasn't thinking about food, I would imagine I left the door open and our pets would be dead when we got home. I've spent 5 minutes locking the door in the morning and turning around a block from home just to go back and lock it again. I even once got so nervous during the day that I asked a co-worker to drive me home to check that I locked the door.

I've been through prozac and celexa and they had absolutely no effect at all except for headaches on the higher doses.

Wellbutrin has almost done away with all of that. Instead of every day, I'll have an episode once a month or so. Still constantly thinking about death and dying, still hate to leave the house for extended periods, but at least the eating is under more control.

I know anecdotes are data. But something finally clicked for me. If it is the placebo affect, I'm willing to spend the money because I don't care *what* helps me, I just want the help.

You mention prozac specifically and I have seen other similar stories about the other anti-depressants. Could you expand on how they do compared to placebos and what their secondary effects might be? If I'm forming new connections while trying not to binge, maybe the new connections are overwriting or somehow circumventing the "bad" connections.

Any thoughts on some lay-person literature?

I have never been a fan using a pill to treat depression. It seems to me like treating the symptom rather than treating the underlying cause of the issue, or, like the article suggests, just a placebo. I believe that cognitive behavioral therapy is a more effective treatment than medication because you are potentially enabling people to deal with their issues head on (by modifying behavior) rather than suppressing them medically. I spent some time shadowing a physician, and it seemed like the majority of his patients were in the office for a refill of antidepressants or painkillers. It's much easier to take a drug than to make changes in our lives, but I worry that we wind up treating the pain of a disease rather than the cancer causing it.

For Bob; I enjoyed reading Peter D. Kramer's book: "Listening to Prozac." (ISBN: 0670841838) Kramer is a psychiatrist who writes in everyday language that is both understandable and thought provoking. On the subject of Wellbutrin, it seems to have helped a friend in a V A Hospital after a stroke left him largely disabled. Best of luck on your reading.

By OftenWrongTed (not verified) on 03 Feb 2010 #permalink

I'm someone who benefited from Lexapro/Celexa, but prescribed off-label, i.e., not for depression, but as treatment for irritable bowel syndrome. I got relief almost immediately, within the first few days of starting to take it. At the time I assumed that was placebo effect, since my doctor had warned me that it might take 2-3 weeks before I felt anything. Perhaps it was an actual effect from the medication (though the reason for prescribing for IBS is for serotonin management, too).

I eventually got tired of the side effects and went off it, but my bowels had stabilized at that point for over a year and so I did not relapse. Since then I've started taking a probiotic and that's gotten rid of most of my symptoms (though not entirely), even without the SSRI.

Anyway, just my story...

Jonathan-- *sigh*

The only thing I can say to people who think that the brain is some magical organ that never messes up, is why dont you volunteer to test novel anti-anxiety drugs at a local university?

One shot of CCK-4, one anxiety attack, knowing what it feels like to have your brain *screaming* no matter how much you tell it to stop, and I doubt you will tell someone with depression/anxiety/mental health issues to 'suck it up' again.

Have you read "Crazy Like Us: The Globalization of the American Psyche?" I'm curious about how corrupt the field of psychiatry/psychology is and the pharmaceutical industry for the related drug is. Why are doctors prescribing medicine or serving therapies that are not based in science?

By Fouridine (not verified) on 03 Feb 2010 #permalink

@ERV - I am not saying that issues such as anxiety or depression are not legitimate or that people should just "suck it up." I am suggesting that in many cases the cause of such issues is not solely chemical, but a combination of several factors, including behavior or trauma that contributed to chemical changes - especially in the case of depression. If one only treats the chemical changes without addressing the underlying issues, the symptoms might temporarily disappear while the problem remains.

I'm interested to see how antidepressants can influence brain plasticity. It's possible that increased plasticity can help individuals who suffer with these issues to develop new behaviors or thought patterns to get to the root of their problems. I believe the brain has the ability/plasticity to "heal" or restore chemical balances through behavioral changes and/or addressing any trauma suffered.

I've often heard it said that antidepressants are useful not for curing depression directly, but for making it lift enough to help you tackle the underlying problems. Certainly that's the attitude I'm taking to my citalopram (which I think of more as anti-anxiety than antidepressant, but I think the principle still applies).

That said I know quite a few people who are on antidepressants long-term and who attribute a lot of their ups and downs to changes of dosage or medication, so I'm sure it's more complicated than that.

I wonder why the belief that antidepressants never have an immediate effect is so persistent. In not just my own experience, but that of *everyone I know* who was given them for moderate-severe symptoms, they caused an immediate change in behaviour and mood. It's sufficiently apparent that my partner can tell if I've missed a dose in the morning by my behaviour by tea-time. (And when I was first given them, I went from too scared to leave the house without assistance, to shopping in London in the January sales in 48 hours! Not data, but a datum.) I'll believe that your underlying problems don't always shift, especially the habits of thought that you've learned to cope, and that if your response to the drug is minimal it may take a while for the placebo effect to gather steam, but that kind of blanket statement just contributes to the patients' belief that, wrt mental health issues, the medical establishment can't tell bum from breakfast. In particular, it gets very tiresome for your doctor to repeatedly tell you that your own experience cannot be, because a clinical trial said so (kind-of like when your doctor tells you that the side-effects aren't in the book, or are very rare, so can't be caused by the drug!). Doctors really, really need to be looking at their own practice as a giant phase-3 test (poorly controlled, admittedly), rather than allowing the results of limited tests to mask what's actually happening in front of them.

Of course, there are probably many patients for whom antidepressants don't work well. Moving away from the concept that depression is a single condition with a one true treatment would help everyone: both the patients who are getting pills that don't work, and the patients who are having a job to hang onto pills that do work for them; and probably also the doctors who are suffering in reputation because they're failing to help patients.

By stripey_cat (not verified) on 03 Feb 2010 #permalink

Prozac helped bring my stepdaughter back from a psychic meltdown when she was eleven years old. She had been sexually abused as a preschooler and, with onrushing puberty, became suicidal. When she was hospitalized in a unit for children with similar histories, she became feral â refusing to wash herself, comb her hair or communicate, eating only with her hands, etc. She spent the most of the first few days hiding under her bed. But soon after starting Prozac, she returned to a state closer to normal. She remained hospitalized for over a month and continued to improve. My husband and I have been grateful for Prozac ever since.

Three things. First, I don't read the studies as saying that SSRIs aren't any better than sugar pills for depression, period. I think they're really raising a question about diagnosis. In cases of severe depression, the evidence is strong in favor of SSRIs. But it'd very weak for mild to moderate depression. So anti-depressants help people who are really "depressed", not those who are "very sad". There's a huge diagnostic difference, which the average family practice physician doesn't pay much attention to. So if you want to hand out pills like candies, then indeed they may as well be made of sugar.

Second, you're absolutely right about the chemistry. Nobody really knows how or why these things work. Or why they work with some people, but make others (e.g., me) feel worse. Or why other drug classes (anti-psychotics, anti-convulsants, etc.) sometimes work wonders where the SSRIs fail.

Third, the general literature shows that the optimal treatment for depression is usually drugs PLUS some kind of talk therapy. People who are really depressed have a cancer that needs to be extracted. Drugs are the anesthetic.

Jonathan-- I am suggesting that in many cases the cause of such issues is not solely chemical, but a combination of several factors, including behavior or trauma that contributed to chemical changes...

That is precisely what physicians do. Those 'people coming in just to get refills' you were watching are almost certainly also going to psychologists and councilors, who cannot write prescriptions, but are much cheaper (sometimes free) than psychiatrists who can write prescriptions. So patients have to go to their GP to get refills, and thats all they are there for, as other medical illnesses (hyper/hypothyroidism, viral infection, hormonal imbalances, etc) have been ruled out.


I can tell you that antidepressants work wonders for brain injured patients. As a Trauma Nurse, our rehab doctors sometimes start our seriously brain injured patients on "cocktails" before they leave ICU. These include Welbutrin, Prozac, Ritalin among others. These are not all given at once, but different combos have been used.

It's quite fascinating to watch the improvement in cognitive function. It's also amazing to watch Beta-blockers, drugs we have been giving for years for high heart rate and BP calm a patient experiencing neuroleptic attacks.

Nice blog post. It would also be good to mention Tardive dyskinesia, and of course all those pesky suicides. But don't take my word for - Peter Breggin wrote the book on it years ago.

Chalk me up as another person who can attest that anti-depressants have effects almost immediately. In fact, the effect was far more pronounced the day after I started taking Lexapro than it was a few weeks later, presumably because I had developed some form of tolerance for the drug.

Regarding the larger question of whether anti-depressants act mainly as a placebo -- I have no idea. It certainly seems plausible, at least in the case of mild depression.

As I understand it, SSRRI's don't increase the amount of serotonin in the brain; they prolong the availability of existing serotonin in the synaptic cleft. The idea that Prozac drugs INCREASE serotonin is just not true. Please clarify.

"So anti-depressants help people who are really "depressed", not those who are "very sad"."

Agreed. This article shares some numbers about antidepressants:

From the article: "Dr. Ronald Dworkin tells the story of a woman who didn't like the way her husband was handling the family finances. She wanted to start keeping the books herself but didn't want to insult her husband. The doctor suggested she try an antidepressant to make herself feel better."

To me this clearly seems like a case where the pill was absolutely not necessary. This is just a married couple who need to communicate better with each other, but the doctor made it a brain chemistry issue. When all you have is a hammer, everything starts to look like a nail. I admit I don't know the frequency of cases like this vs. legitimate needs of antidepressants, but seeing as they are the most prescribed drugs in the US, I believe that a large number (not all) of these prescriptions are unnecessary.


"She goes running for the shelter
Of her mother's little helper."

And we're back to the medicalization of things that are either communication issues, or feminist ones (depending, in this case, partly on why the woman didn't want to insult her husband).

Ben made the point that the best therapy is a combination of talk + medication. If the mechanism of action of the drug is to make the brain more plastic, perhaps it just gives the brain room to accept the changes in perception that are advanced by the cognitive therapy.

I think it's important here to distinguish between anti-depressants and anti-anxiety drugs. There is no denying the latter work.

Plenty of SSRI positive responders report feeling better in as little as 3 days, even though blood levels of the meds aren't supposed to be high enough by then for anything to happen. If they are still feeling better a year or two later, can we really attribute this rapid and sustained improvement to some sort of perpetual placebo effect?

Y-ellow All.

This is largely anecdotal since I don't have means to formalize this. However it was through reading some related articles here on science blogs that I twigged onto the idea of repurposing SSRIs in my fight against firbromyalgia. One study, (I wish I could quote the source here and now but I'm in a bit snowed under right now.) suggested that serotonin played a part in the brain's ability to repair it self. That this was in fact the reason for the typical 2 week lag. The reason it had an effect on depression (If at all) was that it helped repair cognitive parts of the brain which may not be functioning well. But note that the whole brain is bathed in this stuff when you take it.

Enter another study which was beginning to show that Firbromyalgia may be caused by the motor sections of the brain mis-firing and causing the feed back into the sensory system at some point. Thus when the impulse to move is sent, it returns as pain. This makes sense because firbromyalgia is characterized by arthritic type symptoms but often no describable inflammation. Essentially, it is thought that the motor cortex is not repairing it self properly and eventually malfunctioning.

Having been reduced to a crippled mass of meat, I hardly had the time to wait for anyone else to put two and two together so I organized to get put on sertraline. Officially to treat depression of course. Now this wasn't the entire answer the the problem as you might expect. But interestingly, around 2 weeks later I began to be able to move again. The next step was to get exercise and build up a little strength. Within a month I had bought a bicycle. Within 2 months I was riding between 40 and 60Ks a day and haven't looked back. (Sands for now in writing this.)

The exercise is the real answer of course but bridging that point was the problem the SSRIs solved. Which tallies well with the studies mentioned above. SSRIs had done nothing for depression but they did get me back on my bike as it were. And that in it self made me feel better and thus less depressed in general.

As mooted above. There's probably nothing wrong with the drugs. There's just a better way to use them.

If you want to cure your depression IMHO, you probably need to find a happy world to live in. Good luck with that one.


No discussion of exercise?

From a recent paper (Arch Gen Psychiatry. 2010 Feb;67(2):133-43)": Following exercise training, relative hippocampal volume increased significantly in patients (12%) and healthy subjects (16%), with no change in the nonexercise group of patients (-1%)."

Of course this is related to depression (Science. 2003 Aug 8;301(5634):805-9.): "Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants"

Basically, the data strongly suggests that you NEED TO INCREASE nuerogenesis to get behavioral improvements from anti-depressants and that exercise increases neurogenesis. Of course exercise also reduces your risk for Alzheimerâs, diabetes, cardiovascular disease, colon/breast cancer, and oh yeah risk of death. That is the dirty little secret that big Pharma won't talk about.

I will be curious to see how whether the underwhelming perfomance of anti-depressants on low-moderate depressed individuals is anywhere nearly as effective as exercise in increasing hippocampus neurogenesis.

Do you know of any studies that look at the effect of Prozac (or similar SSRIs) on the plasticity of the brains of people on the autism spectrum? Sounds like it could be promising.

No discussion of exercise?

You only need to get a patient with depression to start doing exercise. On his own.

Good luck with that.

"Big pharma" isn't there to provide advice on healthy living, but medication for the sick. What medication is developped and how it is used depends on demand and strategies adopted by patients. That's how the market is right now - no need to resort to "Big pharma" conspiracy to explain it.

I take an SSNRI, not an SSRI. However, I can attest that my SSNRI of choice is my lifeline. It improves my ability to cope with severe SAD, for one thing. I take a much smaller dosage, or none, in the late spring and summer, ramping up in September to my top dosage by November. If I don't, life gets very, very ugly. I don't need a study to tell me that, without this pill, my life would suck big-time six months out of the year. I would be in bed and unable to function in the smallest way. Clearly there is great individual variance in the amount of depression that anti-depressants alleviate. So don't conclude that antidepressants don't do much good. In my case, they are a godsend. SOME of us have vastly improved quality of life because of them.

To Jonathon, I tend to agree with the idea that too often we take pills to treat the symptoms and not the cause. However, if the approach is correct, one can use antidepressants to treat the cause. For me, I realized on my own that I suffered from depression. I made great progress for a few months then realized that the negative thoughts that come along with depression were hindering my progress. Taking antidepressants helped keep those thoughts at bay so I could continue to improve. After 3.5 years, I ceased the medication and have been much better for about 5 years now.

The approach we need to take is that we may need medication to use as a stop gap to continue the work that needs to be done for us to be better without medication.

I'm going to second Bob on the effects of Wellbutrin (bupropion). I have struggled with depression for the last 20 years. I have been on and off various antidepressants, with varying degrees of success. I even took a break for a couple of years to see if I could manage it with just proper sleep and exercise.

When I managed to sleep right and exercise, I was in a generally good mood, productive, and happy with my life. The problem was sticking with it. Sometimes an emotional event would happen, I'd end up staying up too late, and the next day I'd feel like the world was coming to an end. I couldn't function, I'd have obsessive behaviors, and would go back to the gloom and doom feeling I'd known so well.

When I finally accepted that my depression wasn't something I could handle all on my own (through exercise, willpower, or other), I sought help and got started on Wellbutrin. I felt "normal" again for the first time in years, and the effects were evident in the first week. I was able to handle stress better, and not amplify the seriousness of everyday events.

I was suddenly able to be decisive, a problem I had always struggled with. Perhaps the fact the Wellbutrin is a dopamine agonist (re: "How We Decide") and not an SSRI is the difference. I still have issues, and still have to exercise and get sleep, but they are much more manageable with chemical assistance.

Matt: You said "The data strongly suggests that you NEED TO INCREASE nuerogenesis to get behavioral improvements from anti-depressants and that exercise increases neurogenesis."

This is exactly what I was thinking!! This helps me understand the link between exercise & well-being, especially for mild-moderate depression. I teach psychopathology in my intro psych class and my students are always shocked to find that exercise beats medication in clinical trials (beats talk therapy, too).

I've suffered from bouts of Major Depression since I was 12. You do not understand what the illness is at all. No one who compares Depression with "sadness" does. When you experience sleepless nights of nausea, diarrhea, delusional guilt running through your mind and not be able to shut it out, arguing with yourself in a state of terror over whether or not you should kill yourself, and taking your gun to the police so you don't - then you might realize that Major Depression is not "sadness" or even an extreme on the sadness scale. I have done CBT and drugs. Lexapro kept me from pulling the trigger; Martin Selgiman's theories about "learned helplessness" did not.

I don't think that many psychiatrists who work with patients with psychotic depression, postpartum depression, panic disorder, obsessive-compulsive disorder, bipolar disorder, etc would agree that the SSRIs have no effect.

By @murmur55 (not verified) on 08 Feb 2010 #permalink

This is what I hate about the agenda of modern media. Doing hyperbolic stories about medical breakthroughs to sell newspapers, books & magazines, then years later coming out with hyperbolic denunciations of those same remedies to sell even more.

Some SSRI's significantly help some people with severe depression, especially when combined with talk therapies. That's all the story is, and ever was.

By davidavid (not verified) on 10 Feb 2010 #permalink

Might be interesting to see brain scans done on people treated with SSRI's for posttramatic stress. Is it the neural plasticity that allows their brains to reset to better cope with triggering stimuli?
Great blog, BTW.:)

I think it would be interesting to do long-term follow up studies to see how many cases of mild or moderate depression were later found to be misdiagnosed cases of bipolar II.

I personally found that antidepressants worked on a temporary basis, until they either lost effectiveness or triggered a hypomanic episode. It took some time to figure out the what was happening to me; in part the answer came because there has been a recent shift in thinking about this issue. My experience with a mood stabilizer has been radically different.

I would also like to add my support to the posters who have pointed out the difference between depression and profound sadness. I have experienced both, and did not find them to be at all similar.

Good God. Here's a rule of thumb, any writer, scientist, or doctor (or some combination of the three) who implies that depression is synonymous with "sadness" or that the cure should "cheer us up" does not know what he/she is talking about. Depression is not feeling sad. Depression is being chronically immobilized by persistent negative thoughts. My experience with both SSRIs and amino acid supplements (which unlike SSRI's actually do increase serotonin supply) has convinced me that depression is almost entirely biochemical. But all you people who know better because you felt sad one time and got through it without drugs should continue to weigh in on the SSRI debate, because we really need uninformed opinions like yours.

Jonathan, can you cite and explain further your dismissal of the serotonin model? I wonder if simply measuring the quantity of serotonin (or the other neurotransmitters that various anti-depressants influence) is not a sufficient amount of information, vs. where and how it moves through the brain. I am open to either side of the debate; I'm just gathering info at this point. Also, can anyone speak to the different manifestations of depression as they relate to different neurotransmitters? What symptoms are believed to be related to serotonin vs. dopamine vs. norepinephrine, epinephrine, etc.? It seems that psychiatrists are not there yet, so they give you a pill and if it doesn't work, they give you another. This clearly helps some people, but not all...

I was addressing the previous comment to Jonah (damn auto-complete...). Thanks

Has anyone ever had the experience of a common cold temporarily curing your depression? I suffer with mild to moderate depression where nothing 'feels' good, but everytime I get a cold it seems like by brain chemistry chages and I 'feel' good again. I'm wondering how brain chemistry changes during a cold.