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A Closer Look at Antidepressants


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I’d like to thank everyone for their comments, both online and “offline” about my recent “Placebos as Effective as Antidepressants” article. Some very good questions were raised in a comment from Stephan, author of the highly recommended Whole Health Blog that I would like to address in today’s article.

The tricky thing about doing scientific research, as I explained in last week’s article, is that conflicts of interest between doctors, researchers and pharmaceutical companies have become so prevalent that the results of even studies published in prominent, peer-reviewed journals cannot be taken at face value.

One must ask: was the study designed properly? Do the author’s conclusions match their own data? Have the authors reported all of the relevant results? Who funded the study, and what role did they have in choosing the subjects, overseeing the methodology and publishing the results?

When looking at a body of research, one must also consider whether there are unpublished studies on the topic and what the effect of those studies might be. This is particularly true in the case of antidepressants, where it has been estimated that approximately 23% of studies have not been published. Why? Because those studies had even less favorable results than those studies that have been published, and the drug companies who paid for them are under no legal obligation (currently – hopefully this might change in the future) to publish study results.

With that in mind, let’s consider Stephan’s comment and each of the points he brings up in turn:

“I fully agree with you about the “chemical imbalance” thing; it’s incredibly dense. They try to spin it like you were born with depression and there’s nothing you can do about it but take a drug. I have a friend who’s into mood disorder research and I’ve talked to him about that meta-analysis showing no significant effect of ADs.

First of all, he has no dog in the fight because his interest in mood disorders is purely academic. I can vouch for his lack of bias toward antidepressants. Here’s what he told me. Basically, what we call “depression” is actually a collection of related disorders. Antidepressants only work on a subset of them.

There are “responders” and “non-responders” in any group of people who receive antidepressants. For responders, antidepressants can be very effective. When you do a meta-analysis where you’re averaging everyone with “depression” together, the effect of an antidepressant will be small or nonexistent because of the heterogeneity. So this is a problem with saying that antidepressants aren’t effective based on that analysis.

I don’t have a problem believing that antidepressants work for some people. They certainly work in animal models of depression, where there is no placebo effect. I don’t think we should banish them from planet Earth. But I do think the fact that we use them so much points to a bigger problem that we should be addressing by other means.”

I want to thank Stephan again for his comment and for raising these important issues.

Let’s start with the parts that I agree with. Certainly, depression has become so broad a term that some have argued that it is an essentially meaningless clinical designation.

Unlike other conditions that have measurable physiological markers, people that are diagnosed as depressed do not usually have any features that categorically distinguish them from other people. The sorts of problems that are diagnosed as depression can vary considerably depending upon which diagnostic criteria are used, the interpretation of those criteria, and cultural and professional attitudes.

In their book The Loss of Sadness, Horwitz and Wakefield point out that the diagnosis of depression has now come to include transient and completely appropriate responses to life such as sadness after the passing of a loved one, disappointment after the loss of a job or anxiety about financial troubles. They argue, very convincingly, that the DSM IV criteria for depression do not adequately distinguish between what they call “normal sadness” and depression, and the result has been the almost complete medicalization of our emotional response to life. I will be writing an article on this very soon, as I believe it’s a critical perspective to understand in our exploration of depression and antidepressants.

Secondly, I certainly cannot argue with the statement that “antidepressants work for some people”. However, the important questions to ask in relation to that statement are:

  • Why do antidepressants work?
  • How do antidepressants work?
  • Whom do they work for?

Why are these questions important? Because if it turns out that antidepressants do not have any specific drug effects (raising serotonin, for example), and work only because people expect or desire them to work (like placebos), or because of non-specific drug effects (such as sedation or stimulation), then the logic behind prescribing antidepressants at all becomes quite tenuous to say the least – especially when their side effects and risks are taken into consideration.

Now let’s consider each point in turn.

“Basically, what we call “depression” is actually a collection of related disorders. Antidepressants only work on a subset of them. There are “responders” and “non-responders” in any group of people who receive antidepressants. For responders, antidepressants can be very effective. When you do a meta-analysis where you’re averaging everyone with “depression” together, the effect of an antidepressant will be small or nonexistent because of the heterogeneity. So this is a problem with saying that antidepressants aren’t effective based on that analysis.”

What Stephan says about the dangers of meta-analysis are true. However, the same danger applies to overestimating the efficacy of antidepressants. There may be some people who are “responders” who have a response to the drug that is significantly higher than placebo; however, there may also be “nonresponders” whose response to the drug was significantly lower than placebo. There is no indication that antidepressants work on a particular subset of people, and no one has identified who this subset is and why they are helped by antidepressants when others are not.

Kirsch’s analysis that antidepressants do not have a clinically meaningful advantage over placebo (“The Emperor’s New Drugs“) has been almost universally accepted within the scientific community. Kirsch and his colleagues invoked the Freedom of Information Act to obtain access to the FDA database of controlled trials used in the initial approval for the most popular antidepressants. According to researcher David O. Antonuccio in his article “Antidepressants: A Triumph of Marketing Over Science?“, it is difficult to imagine a database that would offer a more fair opportunity to evaluate the efficacy of antidepressants.

The fact that Kirsch found that antidepressants were no more effective than placebo is surprising, in a way, because these results come from studies that were underwritten and designed by the drug companies themselves under conditions most favorable to the active drug condition. In other words, the deck was stacked from the start in favor of the drugs, and they still didn’t come out ahead.

Since a drug must be shown to be superior to placebo in order to be approved, placebo effects are incredibly annoying to drug companies and they do everything they can to minimize the impact of placebo in their studies. The fact that the FDA allows them to use these techniques is, in my mind, blatant corruption. Consider the following methods used in the studies Kirsch analyzed (and most studies, for that matter):

  1. Placebo washout period: During the first two weeks of the study, everyone is on a placebo. The subjects that respond best to placebo are eliminated from the study. This potentially removes both antidepressant nonresponders (i.e. those that were on an antidepressant before the study starts who get better when they are taken off of it) and placebo resopnders (i.e. those that are not on antidepressants before the study and who respond to placebo). Imagine the converse: an antidepressant washout procedure that eliminates all of the antidepressant responders before a study begins! Such a procedure would surely be considered bias.
  2. Penetration of the blind: the double-blind in these studies (where neither the patients nor doctors are supposed to know who is taking the drug and who is taking the placebo) is likely to be unintentionally broken because of the pattern of side effects in the active and inactive drug conditions (Greenberg & Fisher, 1997). When efforts are made to ensure the integrity of the blind, drug effects are diminished. For example, a recent review of the Cochrane database of antidepressant studies using “active placebos” (making side effects more difficult to detect) found very small, non-significant differences between drug and placebo, suggesting that trials using inert placebos overestimate drug effects (Moncrieff, Wessely & Hardy, 2001)
  3. Replacement of non-responders: at least six of the studies Kirsch reviewed (of 38) allowed replacement of nonresponders. This means that during the first two weeks of the study, those that were not responding to the drug were removed from the study!
  4. Use of sedative medication: Most studies allowed the prescription of a sedative concurrent with the antidepressant. Since other studies have shown that sedatives are as effective in treating depression as antidepressants, how can we possibly know whether the antidepressant effect obtained (if there was one) in these studies was due to the antidepressant drug or the sedative? There are at least 6 points on the 52-point HAM-D scale that the doctors use to determine whether a patient is depressed or not that are related to sleep and favor medications with sedative properties. Since the mean difference between patients taking drugs and patients taking placebos in the studies Kirsch analyzed was only 2 points, it is entirely possible that this small difference is only due to the effects of the sedatives used in the studies and has nothing to do with a true antidepressant drug effect.
  5. Reliance on clinician ratings: Given that patients tend to report smaller differences than clinicians (Moncrieff, 2001) one certainly wonders how the pattern of results would change using self-report measures like the Beck Depression Inventory.

Frankly, considering the bias against placebo described above, it is simply amazing that placebo still nearly matched the effects of the drug. Imagine what the results might look like if the trials had been performed without these “anti-placebo” measures!

Also, Kirsch et al. pointed out that the overall active drug effects may have been further inflated because mean results were not reported from several studies that found nonsignificant differences between placebo and active drugs.

The advantage to using the FDA database for analysis is considerable. It contains all of the data from initial trials, published or not, and therefore is not subject to the usual publication bias. (As I mentioned earlier in the article, drug companies simply don’t publish negative results. This is known as the “file drawer” phenomenon, since they probably just stuff those studies in some file drawer hoping they will never be found). Antidepressants are significantly more effective than inert placebos in about two-thirds of published trials. However, in the FDA database which includes unpublished trials, Kirsch found that medication outperformed placebo less than half of the time (in 20 of 46 trials).

Although Kirsch’s study is a meta-analyses, he is also looking directly at the results of individual trials. When less than half of individual trials show any advantage for the active drug over placebo, one must really wonder whether these drugs have any specific “antidepressant” effects.

Now on to the next point.

“I don’t have a problem believing that antidepressants work for some people. They certainly work in animal models of depression, where there is no placebo effect.”

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Actually, it’s not the case that antidepressants work in animal models. According to Joanna Moncrieff in her book The Myth of the Chemical Cure, it is rarely mentioned that all animal models of depression produce variable results according to where they are conducted. “In other words,” she says, “they are unreliable.” In addition to this, they fail to select specifically for antidepressants and responses are obtained with drugs that are not generally considered to be antidepressants (i.e. amphetamines, opiates, antihistamines, antipsychotics, atropine, pentobarbital, zinc and antibiotics).

Also, the SSRIs (the most popular class of antidepressant drugs) typically fail to have any response in the forced swim test, which is one of the most common antidepressant screening tests. In this test, rats are placed in a tank of water from which they cannot escape. The time until they give up trying to escape is measured, on the assumption that the state of giving up is akin to depression. It is thought that antidepressants should prolong the time to giving up. However, the SSRIs have no such effect.

Finally, other tests for depression also frequently show that non-antidepressant drugs (sedatives, stimulants, antihistamines, etc) yield “false positive” results.

“I don’t think we should banish them from planet Earth. But I do think the fact that we use them so much points to a bigger problem that we should be addressing by other means.”

I’m not so sure we shouldn’t banish them from planet Earth, to tell you the truth.

Longitudinal follow-up studies (which study the effects of antidepresants over the long term – not just the 6-8 week periods the clinical trials look at) show very poor outcomes for people treated for depression both in the hospital and in the community, and the overall prevalence of depression is rising despite increased use of antidepressants (Moncrieff & Kirsch, 2006). Two studies that assessed outcome in depressed patients treated with and without drugs found that people prescribed antidepressants had a slightly worse outcome than those not prescribed them, even after baseline severity had been taken into account (Ronalds C et al., 1997). No comparable studies exist that show a better outcome in people prescribed antidepressants.

Outside short-term randomized clinical trials there is virtually no evidence that antidepressants have changed the outcome of depression. The evidence that does exist suggests that they may have possibly made it worse.

Depression is more common today than before antidepressants were introduced and the outcome has not improved. Epidemiological trends show that the more antidepressants are prescribed, the more prevalent depression is. Sharply rising levels of antidepressant prescribing since the 1990s have been accompanied by increased prevalence of depressive episodes (Patten 2004) and by rising levels of sickness absence for depression (Moncrieff & Pomerleau 2000).

Finally, there is a growing body of research suggesting that antidepressants worsen the chronicity, if not severity, of depression in many patients. Even relatively short-term exposure to antidepressants has been shown to cause chemical and even anatomical changes in the body and brain that could predispose patients to further depressive episodes (Jackson, “Rethinking Psychiatric Drugs“)

Some might argue that antidepressants are important to stave off suicide in very depressed patients. However, there is no evidence that antidepressants reduce the risk of suicide or suicide attempts in comparison with a placebo in clinical trials (Kahn et al. 2000). In fact, rates have actually increased in some age groups and in some countries despite increased antidepressant prescribing (Moncrieff & Kirsch 2006), and when antidepressant trials have been re-analyzed to compensate for erroneous methodologies, the SSRIs have consistently revealed a risk of suicide (completed or attempted) of between two to four times higher than placebo (Jackson, “Rethinking Psychiatric Drugs“)

And we haven’t even talked about side effects yet! Since this article is already very long, I’ll save that for another day. Suffice to say that these are not harmless drugs and the side effects can be severe and potentially fatal.

So I ask you, fair readers, when you add all of this up, should doctors continue to prescribe antidepressants? Let’s see what researchers who have been studying antidepressants and depression for decades have to say:

The SSRIs produce no effects that look likely to be useful in depression. They cause unpleasant agitation in a proportion of patients and, although it is difficult to prove conclusively, an increase in suicidal and violent tendencies may be associated with this effect. Therefore, I can think of no good reason to prescribe them at all. – Joanna Moncrieff, 2008

Moncrieff has actually suggested that the term “antidepressant” is a misnomer, because the drugs have not been demonstrated to have a consistent and specific effect against depression.

There is no doubt that antidepressants have a biochemical impact on the brain, but the valence of that impact is open for considerable debate, and whether it corrects a chemical imbalance is in grave doubt… One day we may look back and marvel at the stroke of marketing genius that led to calling these medications antidepressants in the first place. Kirsch et al. have demonstrated that just because a pill is called an antidepressant, it doesn’t necessarily make it so. – David Antonuccio, 2002

If antidepressant drugs were the only option for treating depression, one might still be able to make an argument for their use in spite of their lack of efficacy and risks. However, it has repeatedly been shown that aerobic exercise, light therapy, Cognitive Behavioral Therapy, St. John’s Wort, bibliotherapy (prayer) and perhaps acupuncture (more studies are needed) are just as effective for treating depression as antidepressants – with few, if any, adverse effects. In fact, in the case of exercise many of the side effects produced are beneficial (e.g. better overall health and wellness).

Considering that antidepressants are likely no more effective than placebos, have not improved (and perhaps worsened) long-term outcomes, may increase the risk of suicidal and violent behavior and have significant many other significant side effects and risks, including potentially permanent changes in the brain which predispose patients to further depression… and considering that there are well-established alternatives that are just as effective, if not more so, in treating depression with almost no adverse effects and significantly fewer costs, I see no compelling reason to continue prescribing antidepressants.

Obviously many other people are posing this question, particularly in the medical community. Kirsch’s research has been so widely accepted that the debate has not centered around his conclusions, but on the implications of those conclusions. Ironically, it has been suggested by more than one commentator that although we now know that antidepressants aren’t effective, we should continue to prescribe them – if only in an attempt to elicit a placebo effect.

Huh? Let me explain. One major reason people respond to placebo in antidepressant trials is that they expect the drug to work. They expect it to work because of all of the promotion they’ve seen, newspaper and magazine articles they’ve read, and personal testimonials they’ve heard. What would happen if it became known that antidepressants are, in fact, not effective and that they could actually make depression worse. Bye bye placebo effect.

So some researchers and doctors have actually suggested that we should go on promoting the delusion that antidepressants are effective so that people who are taking them will continue to believe that they are working, which of course significantly increases the chance that they will work.

If these drugs were not so potentially dangerous and harmful, and if there were not proven alternatives, I could almost go along with this deception – although it does raise some very interesting ethical questions. However, the drugs are potentially dangerous and harmful, and there are proven alternatives, so I cannot agree with this approach.

In closing, I just want to remind anyone who is currently taking an antidepressant and thinking about stopping that it is essential you do so under your doctor’s supervision. You will have to gradually taper off of your medication – do not stop abruptly!

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Join the conversation

  1. Stephan,

    I came across a study that addresses a question you had earlier in the thread regarding why antidepressants were slightly more effective than placebo with severely depressed patients (in some studies).

    The authors of this study came to this conclusion:

    “Drug-placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.”


  2. Again, the term psychosomatic does not presuppose that the ‘mind’ is totally independent from the ‘body’, only that it is a system with unique properties that it’s useful to define. It’s not incompatible with the idea that the two are interconnected.

    I don’t think the Alzheimer’s example poses any problem for that idea; to the contrary. The initial wound was more on the physical end of the spectrum, and the healing speed was influenced by the mental state.

    At every level of the universe, including our bodies, you can draw distinctions that separate things from one another. A full understanding of a system requires understanding both its uniqueness and its interconnectedness.

  3. Stephan,

    The fact that elements in a system have specialized function does not detract from their interdependence.

    Can you tell me where the mind ends and the body begins, or vice versa? If quantum physics and chaos theory is applied to the study of the body, it quickly becomes clear that the divisions we perceive are not actually divisions at quantum level.

    Certainly there are circumstances in which seemingly gross physical forces (I say seemingly because we know that all matter is energy) cause injury and illness, and others where perhaps the cause is more obviously energetic, psychological or emotional.

    However, even in the case of a “physical” injury or illness the “mind” is always directly involved in how the body responds. Even to say it this way is wrong, because there is no mind apart from the body or body apart from the mind. No one has been able to isolate them from each other.

    Let’s take the example you used above: that someone trips on a stone and scrapes their knee. You claim this is not “psychosomatic”. (I could ask, of course, what was going through the person’s mind and where their attention was when they tripped in the first place – but I’ll let that go for now). You may be right in terms of the initial injury, but the state of the person’s mind and emotions will directly influence how they heal from this injury.

    There are many studies which prove this. For example, there’s a study on caregivers of Alzheimer’s patients that shows they heal from wounds about 3 times more slowly than healthy people. Why? Because taking care of someone with Alzheimer’s is incredibly stressful, and this stress weakens their immune system’s capacity to respond to the injury.

    There have been many studies showing that medical students are 2-3x more likely to catch a cold in the weeks preceding final exams. In that case, someone might claim the sickness is purely physical since the virus is a pathogen; however, it is known that stress depresses immune activity, and this of course made the med. school students more vulnerable to getting sick.

    We can agree to disagree on this, but I just do not see the usefulness (or accuracy) of the term “psychosomatic”. It implies that other illnesses are not related or connected to they psyche, which is just complete B.S.

  4. Well now I do think the term “psychosomatic” is useful. While I acknowledge there’s a big gray zone, some things are more based in the mind than others. If you trip on a stone and fall on your knee, the cause of the scrape is more on the physical side. If you have back pain and tension that disappear from watching a seminar, the cause is more on the mind side.

    Not making the distinction between mind and body is like not making the distinction between lung and kidney. Yes, the body is all one interdependent system. But the same can be said about an organ, a cell, a protein, a society, an ecosystem. Each distinction has its own use in the appropriate situation. Using the term “psychosomatic” does not presuppose that the mind is completely separate from the body, only that it has certain unique qualities.

  5. Stephan,

    I do know Sarno’s work and I’m aware of the lack of correlation between back pain and structural abnormalities. A similar phenomenon exists in Irritable Bowel Syndrome, of course, and quite a few other chronic pain conditions and “functional illnesses”.

    There was a famous “sham surgery” study done by Moseley et al. which showed that arthroscopic knee surgery was no more effective than placebo surgery (a small incision is made but no instruments enter the knee joint)! Now that is a powerful placebo!

    To be frank, I think the term “psychosomatic’ is redundant. ALL illnesses are psychosomatic. The idea that our minds and bodies are somehow separate and operating independently is based in 17th century science. As I’m sure you are aware, there is an entirely new discipline called psychoneuroimmunology that studies the complex interrelationships between the brain, nervous system and immune & endocrine systems.

    A lot of the research has gone into the stress-disease connection, and more recently, the placebo effect. Both are good examples of the interconnectedness of mind and body. We really need to find a different way of talking about this because our words are inadequate.

    It’s interesting to note that in Traditional Chinese Medicine, there is no separate word for “mind” and “body”. They don’t make a clear distinction.

  6. Well said. I bet you’re right about the most powerful healers eliciting the best placebo response. It has worked in practically every culture since the beginning of time, and it continues to work today. I’ll look forward to your posts on the placebo effect.

    I’m going to be posting on something related in the near future, back pain. I believe garden-variety back pain (and most other chronic pain) is psychosomatic. This is based on my reading as well as personal experience. Actually, I bet you’d get a kick out of this. Mainstream back pain treatments, including surgery, are miserable failures. The only thing that really works is heavy-duty pain killers! Furthermore, there seems to be no correlation between vertebral/disc abnormalities and pain. It’s anatomically impossible for garden-variety back pain to result from spinal nerve impingement. Are you familiar with the work of Dr. John Sarno?

  7. Regarding the drug-placebo differences in relation to severity, I’m not entirely sure what to make of that. I know that Kirsch co-authored a paper with Moncrieff in 2006 (four years after the meta-analyses) which I quoted from above in which both authors stated:

    “Thus there seems to be little support for the suggestion that recent failure to find marked differences between antidepressants and placebo is due to recruitment of patients with mild depression that is less responsive to antidepressants.”

    I’ve already quoted the rest of their remarks about this in my previous reply above. What it could mean is that there may be some difference in response in relation to severity within a given study population, but not when taken overall. Since almost all of the studies Kirsch reviewed were done on patients that were severely depressed, it follows that ADs are not more effective than placebos in severely depressed populations.

    Perhaps I’ll contact Moncrieff or Kirsch and see if they can shed some light on that question.

    The placebo effect is evidence of the body’s powerful capacity for self-healing. I will be writing more about this as it has been a subject of intense interest for me for some time now, and I’ve done a lot of research on it. I think Kirsch’s numbers on the effectiveness on pain management are low. Recent studies I’ve looked at have put the placebo effect at closer to 70-75% for pain management. Many researchers believe that between 40-60% of ALL medication effects are due to placebo.

    Unfortunately, there has been little discussion about how to utilize this effect in clinical practice because the pharmaceutical companies can’t see any way to make money off of it. They just want it to go away. All of their research efforts around the placebo effect have been centered on how to identify the type of patient that is likely to respond to placebos so they can eliminate them from their studies and thus give their drugs a better chance of being approved.

    You are right: placebo is powerful. But it is powerful because the innate healing mechanisms of our body are so much more sophisticated than even the most advanced medical treatments available today. The potential exists for the placebo effect to become MORE powerful if people come to understand that their own belief and attitude towards life is perhaps the single greatest contributing factor to their health – or illness.

    Of course this is both empowering and scary, because with that realization the responsibility for our own wellness shifts from doctors and the medical care system to ourselves.

    Witch-doctors are powerful healers! In fact, I believe that the most skilled healers in any modality are those that can elicit the most powerful placebo response. And how can that possibly be considered inferior as a method to the practice of prescribing dangerous drugs with unknown effects or performing invasive, life-threatening surgery?

    I’m not saying there’s anything wrong with drugs and surgery when necessary, but I am saying that these methods are not nearly as sophisticated and desirable as utilizing the body’s natural healing mechanisms. Drugs and surgery should be a last resort, not the first step.

  8. Here’s what I was referring to in the Kirsch abstract:

    Drug–placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category.

    I thought this was pretty neat from the discussion:

    The response to placebo in these trials was exceptionally large, duplicating more than 80% of the improvement observed in the drug groups. In contrast, the effect of placebo on pain is estimated to be about 50% of the response to pain medication [24–26].

    Placebo effect is a powerful thing! I wonder how much of medicine is just witch-doctoring, and if its efficacy will change if people lose faith in it.

  9. I’m not sure exactly what you mean. In the meta-analysis conducted by Kirsch et al. all but one of the trials were conducted in patients with severe to very severe depression according to NICE (National Institute for Health and Clinical Excellence) criteria. And since we know what the results are of that analysis, we also know that – according to that analysis – ADs are not more effective than placebo in severely depressed people.

    Also, another recent meta-analysis found no relation between severity and antidepressant effect, and a meta-analysis of older studies showed that differences between antidepressants and placebo were smaller and less significant in inpatient trials (where people tend to be more severely depressed) than outpatient trials. The NICE meta-analysis failed to find a consistent gradient of effect from “moderate” (HAM-D score 14-18) through “severe” (19-22) to “very severe” depression (>23). In fact, the middle group, which would generally be referred to as “moderately depressed”, tended to show larger effects than either of the other two – but numbers of studies were small.

    As Moncrieff states in a 2006 paper (“Efficacy of Antidepressants in Adults”, in BMJ) “The possibility that patients in the mid-range of severity show a greater antidepressant response, as suggested by the NICE data, would not be expected from a simple biological effect. It may indicate that this group is more susceptible to some methodological artifact such as infringement of the double blind.”

    Thanks again for your participation, Stephan. I’m enjoying the dialogue!


  10. Chris,

    I agree that the burden of proof is on the drug companies to prove their drugs are safe and effective.

    What do you think about the finding in Kirsch et al’s meta-analysis that ADs seem to work better than placebo for severely depressed people?

  11. Stephan,

    Not all of the studies I’m quoting are meta-analyses. As I pointed out, in the FDA database antidepressants only outperformed placebo in 20 of 46 studies reviewed.

    Furthermore, you can bet that all kinds of post-hoc analyses have been performed on these data, and as far as I know there is no analysis suggesting a strong response in a specific subset as you suggest. If there were, I think it highly likely that the drug companies would have identified that subset, defined it, and targeted it in their promotion.

    I didn’t mention this in my post, but contrary to popular belief, antidepressants have not been shown to be any more effective for severely depressed patients than mildly or moderately depressed patients.

    I understand what you mean about averaging, and I agree with you that we can’t rule out a possible effect on a subset of people. But what you haven’t explained is why we should go on prescribing these drugs when there is no evidence to support this possibility? The burden of proof should be on the drug companies to prove this before the drugs are used, not the other way around.

    Again, if the drugs were harmless and if there were no alternatives continuing to prescribe them might make sense for research or diagnostic purposes. But knowing what we DO know about SSRIs (side effects, risks, poor outcomes, potential for increasing frequency and duration of depressive states, costs, etc.), I cannot see the ethical justification for conducting such an experiment on millions of unsuspecting adults and children around the world. It simply doesn’t make sense, when there are so many other ways we could approach this.

  12. Hi Chris,

    I agree that you make a good case for antidepressants not passing the generally accepted criterion for drug efficacy: that they work better than placebo, on average.

    Imagine this hypothetical scenario. You give an SSRI to 100 depressed people, and a placebo to 100 more. In the placebo group, 30 people improve and the rest stay the same. In the SSRI group, 60 people improve, 30 get worse, and the rest stay the same. You will see no difference in average depression score, correct? Yet there’s still a meaningful effect on a subset of patients that can be exploited by a skillful physician. That’s an example of the kind of effect that’s masked by averaging. That’s what I mean when I say the data I’m aware of don’t rule out a possible effect on a subset of people. I’m not claiming that the data support this kind of an effect, simply that they don’t rule it out.

  13. Stephan,

    Thanks again for your comment.

    I don’t agree that this doesn’t address the heterogeneity of depression. It is true that study results vary considerably. Some studies show that antidepressants do outperform placebo, but many others show just the opposite – including some of the largest and best-designed individual trials such as the Medical Research Council Trial and the early National Institute for Mental Health trial.

    What we can say, then, is that in some cases when people take antidepressants they improve. That does not mean, however, that 1) it was the drug that caused the improvement rather than the placebo, or 2) that the drug has a specific effect on depression that other less specific and less dangerous and risky drugs would not have.

    There are no data that I’m aware of which support your idea that ADs work on a specific subset of depressed patients, in the sense that this hypothetical group has been identified or characterized. Of course the lack of proof supporting this notion does not prove it is false, but there’s certainly no reason to believe it’s true.

    The washout period does not get rid of AD responders. It only removes placebo responders and AD nonresponders. There is some convoluted logic behind this, but studies have shown it to be a completely biased and faulty methodology.

    The claim that “physicians know that some people respond well and others don’t” also does not necessarily illustrate that antidepressants are having true drug effects on certain patients and not others. I can certainly see why it would seem so, but studies don’t bear this out.

    Wolf, Doering, Clark & Hagans did a study in the 50s where patients were successfully given seven different treatments for nausea, following which ipecac was administered. Response was defined as blocking the emetic (causing vomiting effects of ipecac. There was substantial variability in response rates. Some participants responded to all treatments, some to none. Most responded to some treatments but not others.

    Thus, the pattern of responding was similar to that observed clinically with antidepressants: patients who did not respond to a given medication often respond to another. In the Wolf et al. study, however, all seven treatments were known to be ineffective for the condition being treated! They were placebos. These data demonstrate that the response to placebo is inconsistent. Thus, finding that patients sometimes respond after switching to a different antidepressant is exactly what one would expect if antidepressants were nothing more than active placebos.

    Then there is the question of whether the SSRIs actually have an antidepressant effect when compared to other drugs that are non-specific for depression.

    Another study (this one very extensive) reviewed 105 clinical trials in which serotonin uptake inhibitors (SSRIs) were compared against other types of antidepressant drugs to find predictors of differential outcomes. Factors considered included age of the patient, measurement scale, method of analysis, dose of the drug, mechanism of action, and sponsorship of the trial. In the end, only one of these factors turned out to be significant: there was a trend towards increased efficacy of the sponsor’s drug! In other words, if a study on a drug was sponsored by the pharmaceutical company that manufactures the drug, that trial is likely to show more positive results. No other factors determined whether one drug was more effective than another for depression.

    Then there are the studies with healthy volunteers in which ADs don’t appear to elevate mood at all. On the other hand, side effects of ADs in patient trials are consistent with those found in healthy volunteers.

    As I mentioned in my previous post, there’s no doubt that SSRIs “work” for some people, if by “work” you mean that when they take the drugs their symptoms improve. But the available clinical research strongly suggests that the effect is due to placebo or regression to the mean in many cases. Even if/when there is a true drug effect, it does not seem to be specific to antidepressants as many other classes of drugs have been shown to relieve depression equally well (or equally poorly, I should say).

    If drugs must be used, older tricyclic ADs could be used to produce short-term sedative effects when necessary (which is how they’ve been used for several years by practitioners), but because of their cardiotoxicity they are probably best avoided. Benzodiazapenes may actually be safer, as long as patients are monitored closely and warned of their addictive potential.

    But why use drugs at all when many other proven remedies are available? I will cover these in more detail in a subsequent article.

    Stephan, you say “there’s no way to know [whether the drug effect is due to placebo] with the available data”. Perhaps that is true on an individual-by-individual basis. But in this country (and most others), the whole basis for the approval of a drug is whether it is more effective than placebo in randomized clinical trials. That’s the point of trials: to estimate based on a statistical sample whether the drug is effective or not. There is no possible way to test the drugs on every single person that would potentially take them, of course, so the trials are the most accurate way we have of assessing drug efficacy and safety.

    What if drug companies didn’t have to go through these trials and they could just make whatever claim they wanted about a drug, sell it to millions of people, and only THEN have to prove that it works? That would not be a very effective system. Unfortunately, that’s analogous to where we find ourselves with antidepressants. The drugs are widely used but it is now being shown that they are not not more effective than placebo or other classes of drugs.

    So, according to the standards of research and drug approval we have set up in this country, there should be no place for the use of antidepressants in treating depression. You could make an argument for using other drugs, but there is little justification for continuing to prescribe SSRIs.

    The only thing that might be nebulous about all of this is why antidepressants continue to be prescribed in light of everything pointed out in this article. But of course the answer to that becomes crystal clear when you consider the $20 billion the pharmaceutical companies make each year selling these drugs.

  14. Hi Chris,

    That’s a lot of information! I would say the most compelling point is the idea that long-term outcomes are worse for people who receive antidepressants (on average), even controlling for initial severity.

    I like the information on drug trial design, that’s pretty sick. If ADs are nothing more than placebo however, wouldn’t the “washout” get rid of AD responders as well?

    I don’t think any of this addresses the heterogeneity of depression. Basically, I’m not aware of any real data one way or the other on whether there’s a positive effect in a subset of depressed patients. The only thing that speaks to that is physicians’ experience. Physicians know that some people respond well and others don’t, and they (should) only continue treatment on someone who is responding well. You could say it’s a placebo effect, and maybe it is, but I’m not aware of any good data to support or disprove that.

    I know several people who have been helped by antidepressants, so it’s hard for me to believe they never work. You could say it’s a placebo, but again, there’s no way to know whether that’s true or not with the available data. So the question remains nebulous in my opinion.