Sunday, March 13, 2011

Are Antidepressants Effective? A Review of “The Emperor’s New Drugs” by Irving Kirsch

It’s common knowledge now that antidepressants are no better than placebo for the majority of patients. Only ten years ago, however, this was a very controversial idea. Back then, doctors, patients, the media, and the general public believed that Prozac, Paxil, Zoloft, and other “wonder drugs” helped millions of people overcome their depression by correcting chemical imbalances. It’s the story that drug companies, regulators, and academic psychiatrists told us. Many people still believe this, and doctors write out millions of antidepressant prescriptions, but it’s contrary to evidence. It’s true that antidepressants successfully treat depression. The problem is that sugar pills (“placebos”) also successfully treat depression, and the sugar pills are about as effective as antidepressants, without any of the drugs’ side effects.

Irving Kirsch, a researcher who pioneered the use of meta-analysis in studying antidepressants, writes about the chimera of antidepressant effectiveness in his book The Emperor’s New Drugs: Exploding the Antidepressant Myth. Unlike Robert Whitaker’s book The Anatomy of an Epidemic, which talks about all the major psychiatric disorders and classes of drugs, Kirsch restricts his analysis to depression and antidepressants. Kirsch’s main argument is that placebos are effective treatments for depression, and that antidepressants add very little except side effects.

Before conducting his research project, Kirsch, like most people, believed that antidepressants worked. A clinical psychologist, Kirsch used to refer depressed people to psychiatrists so that they could obtain prescriptions for antidepressants. He trusted the data in the published literature that demonstrated the effectiveness of antidepressants. He changed his view after doing his research.

After analyzing 38 clinical trials involving more than 3000 depressed patients, Kirsch found that only 25% of the benefit of antidepressant treatment was due to the drug effect. The placebo effect, the patient’s hope that he will improve from treatment, was twice as powerful as the drug effect.

When analyzing the data, Kirsch also found that the newer antidepressants (e.g. SSRI’s) were no better than the older antidepressants. Even more surprisingly, he found that sedatives, barbiturates, antipsychotic drugs, stimulants, opiates, and thyroid medications were as effective as antidepressants in treating depression. The only thing that these drugs have in common is that they produce easily noticeable side effects. Kirsch explains that in a clinical trial, patients are randomly assigned to either a treatment (drug) group or a placebo group. If the patient knows that he’s been assigned the drug, he’ll feel more hopeful and optimistic—i.e. he’ll feel less depressed. Since the studies are supposed to be double-blind, the only way the patient can know this is if he gets side effects. If he tells his doctor about the side effects, then the doctor will also know that he’s been assigned the treatment. The doctor may have a different attitude toward the patient if he knows that he’s been assigned the treatment. So the supposedly double-blind study isn’t really double-blind. That’s the reason why the other drugs also were effective for depression. Any drug that causes side effects will make both the patient and doctor more confident and hopeful, since the side effects make them know that the patient is receiving the actual treatment. The placebo effect, not the chemical action of the drug, treats the depression.

Additional evidence for this hypothesis that drugs are only active placebos is that there’s a near-perfect correlation between improvement and the experience of SSRI side effects. The more side effects the patient has, the more he improves on the drug. Another way to interpret this, however, is that patients who actually benefit from the chemical action of the drug also tend to experience more side effects.

As part of his research project, Kirsch used the Freedom of Information Act to obtain unpublished clinical trial studies from the FDA. Combining this data with the published studies, Kirsch found that the drug effect was less than 20%. By contrast, the drug effect for pain medication is about 50%. Kirsch also found that the therapeutic effect of antidepressants, unlike most other medications, is not dose dependent. Higher doses of antidepressants produce more side effects, but don’t reduce the symptoms of depression more than lower doses.

These above-mentioned results were well known by researchers, regulatory agencies, and drug companies, but not by most doctors and patients. Pharmaceutical companies have used some tricks to keep this “dirty little secret” from the general public, including:
  • Withholding negative studies from publication
  • Publishing positive studies multiple times
  • Publishing only some of the results from multi-site studies
  • Publishing data that was different from what they submitted to the FDA

Why were the drugs approved, when they show so little benefit over placebo? Regulators only require two clinical trials having positive results. Negative trials don’t count. Drug companies can conduct as many trials as they want until they find two with positive results. Kirsch calls this “voodoo science.” It makes things too easy for drug companies.

Part of the reason for the popularity of antidepressants is that doctors and patients have been told that depression is a brain disease, a chemical imbalance that can be treated by medication. Kirsch tears apart the chemical imbalance myth. “Not only is the chemical-imbalance hypothesis unproven, but . . . it is about as close as a theory gets in science to being disproven by the evidence” (p. 81). The chemical imbalance theory states that depression is caused by inadequate levels of neurotransmitters in the brain. The two neurotransmitters that are most associated with depression are norepinephrine and serotonin. The theory came about from the supposed successes of antidepressant medications in treating depression. These drugs either block the destruction of norepinephrine and serotonin, or inhibit their reuptake, which result in more of the neurotransmitters in the brain. Additional evidence in favor of the chemical imbalance theory came from studies of a depression-causing drug resperine. These studies found that resperine decreased brain levels of norepinephrine and serotonin.

The problem with the chemical imbalance theory is that it doesn’t fit the data. Reanalysis of the data showed that resperine doesn’t actually cause depression. Antidepressants don’t really help treat depression, either, since most of their effectiveness is due to the placebo effect. Studies have been conducted in which norepinephrine or serotonin is experimentally reduced. This neurotransmitter reduction does not cause depression in healthy volunteers, or depressed people off medication. Rapid depletion of serotonin only triggers depression in patients currently taking SSRI’s. The final nail in the coffin of the chemical imbalance theory is the effectiveness against depression of tianeptine, a new antidepressant that has an opposite chemical effect as that of SSRI’s. Tianeptine is a selective serotonin reuptake enhancer, increasing the amount of serotonin in the brain. Depressed patients respond identically to tianeptine as they do to SSRI’s. Since it has an opposite chemical effect compared to the SSRI’s, any improvement in depression symptoms can’t logically be due to the chemical action of the drug.

In the last three chapters, Kirsch discusses at length the placebo effect. “The word placebo is Latin for ‘I shall please’” (p. 102). Placebo effects are examples of how suggestion can change how people feel and behave. Expectancies are important in placebo effects. If people expect to get better, depending on how strong they believe this, and what kind of disorder they have, there’s a chance that they will get better. Depression and pain are two disorders that respond well to placebos. The way in which the placebo is administered (e.g. pills, injection, or surgery), along with its brand name, color, price, and dosage are factors controlling its effectiveness. Placebos, like drugs, can produce changes in brain activity. For example, both patients given Prozac and those given placebo had reduced brain activity in the limbic system, the area of the brain associated with sadness and depressed mood.

Since placebos work so well for depression, why not prescribe placebo pills to depressed patients instead of medications? Placebo pills are cheaper and don’t have any side effects. Kirsch argues that this is wrong because it involves deception. A better alternative is psychotherapy, especially cognitive-behavioral therapy. Therapy is the “quintessential placebo,” a treatment that utilizes the placebo effect (i.e. the relationship between therapist and client, and the client’s expectancies of getting better), but does so without deception. Psychotherapy has a number of advantages over medication, including no side effects, reduced likelihood of relapse, and less long-term cost.

One problem with this book is that Kirsch seems to think that placebos will effectively treat all kinds of depression, including the more severe kinds. He acknowledges that the placebo response is reduced for the most severe types of depression. In other words, medications are more effective relative to placebos for the most severely depressed. He explains this by saying that because the severely depressed patients are more likely to have been on antidepressant medication before, and have higher dosages prescribed, they can more easily recognize whether they are on the actual drug or placebo. This will reduce the placebo effect for those assigned the sugar pill, which means that the drug effect is really a placebo effect in disguise. I don’t agree with this explanation. I think that some of the severe types of depression are biologically based, not responsive to placebos, but responsive to antidepressant medication.

Another problem is that Kirsch doesn’t once mention bipolar disorder. Would placebos successfully treat symptoms of depression associated with bipolar disorder? I doubt that they would for the majority of people with this disorder. What about seasonal affective disorder? Would placebos treat symptoms of depression for most people with this disorder? I doubt it. Like with severe (unipolar) depression, I think that bipolar disorder and seasonal affective disorder are biologically based, and don’t respond well to placebo. How about OCD, which although is not classified as a type of depression, has been successfully treated with SSRI antidepressants? Having had OCD, I don’t think that my core symptoms would have responded to a placebo pill. I know from experience that my symptoms didn’t respond well to psychotherapy (although I appreciated the advice from one therapist).

In conclusion, The Emperor’s New Drugs is an excellent account of the ineffectiveness of antidepressants, written by a pioneering researcher. It makes one wonder how so many people were fooled for so long into thinking that antidepressants treated patients by correcting chemical imbalances. Its weakness is that the author doesn’t distinguish between the majority of cases of mild to moderate depression in which drugs are no more effective than placebo, and the small number of biologically-based more severe cases in which placebos aren’t effective, but drugs are.