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big pharma cartoonA new report due to be published in the May issue of the American Journal of Psychiatry shows that antidepressants aren’t all they’re cracked up to be.

But, faithful readers, you already knew that. Right?

The report is part of the National Institute of Mental Health-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project – the largest study of the treatment of depression conducted in the United States. It showed that findings from clinical studies used to gain FDA approval of antidepressants are not applicable to most patients with depression.

Researchers at the University of Pittsburgh Graduate School of Public Health compared symptoms and outcomes in depressed patients who met phase III study inclusion criteria to those who did not. Phase III studies for antidepressants determine the effectiveness of the drug in comparison to a placebo.

The inclusion criteria for these studies aren’t standardized or subject to any federal guidelines. Typically this means that patients with milder forms of depression, chronic depression, or other psychiatric or medical conditions in addition to short-term depression are excluded from studies.

In other words, the majority of “real world” patients with depression who end up taking antidepressants are excluded from clinical studies. It should be obvious why this is a problem. In a normal, clinical setting many patients with depression do also have other illnesses, such as diabetes, chronic fatigue syndrome or irritable bowel syndrome (IBS). It’s not unusual for them to have anxiety and insomnia, as well. In fact, it wouldn’t be presumptuous to expect that a depressed person might be suffering from a number of conditions that are either contributing to or caused by their illness.

Yet the only people that “qualify” for the clinical trials which determine whether antidepressants get approved by the FDA are those with short-term depression, no history of depression, no other psychiatric conditions such as anxiety, and no physical illnesses like heart disease or diabetes. This is the only subgroup of the general population for which we have any data on the efficacy of antidepressants.

By the same token, this means is that we have almost no clinical data on how antidepressants work for the “real world” patients who are most likely to be taking them. Indeed, after assessing 2,855 patients treated with citalopram (Celexa), the study authors found that fewer than one in four, or 22.2%, of the patients met the usual criteria for inclusion in phase III clinical trials.

According to study lead author, Stephen Wisniewski, Ph.D., professor of epidemiology and co-director of the Epidemiology Data Center, University of Pittsburgh Graduate School of Public Health, “This raises major concerns about whether results from traditional phase III studies can be generalized to most people with depression, who also often suffer from anxiety, substance abuse and other medical and psychiatric problems.”

When Wisniewski and his colleagues looked at the efficacy of antidepressants in those who did not meet phase III inclusion criteria – meaning the majority of people who take the drugs in real life – they found that their outcomes were much worse than those who did qualify for the trials. The depression remission rate in the patients who met the criteria was 34.4 percent, compared to only 24.7 percent in the ineligible group.

So, here’s the bottom line: antidepressants are nowhere near as effective as research suggests.

And that is really bad news for the drug companies, because research already suggests that antidepressants aren’t very effective at all. In fact, as I explained in a previous article, antidepressants are no more effective than placebo for most people. If antidepressants are no more effective than placebo in the patients that do meet phase III criteria, and we know that antidepressants are less effective for patients who don’t meet phase III criteria (the vast majority of “real world” depression patients), then couldn’t we assume that antidepressants are less effective than placebo for most patients?

Yes, we could.

For more information on this topic, check out this index of my articles (as well as selected off-site resources) on depression and antidepressants.

tibetan bowlEach week, it seems, more and more evidence pours in demonstrating the effectiveness of non-drug treatments for depression.

In a study, published December 1, 2008 in the Journal of Consulting and Clinical Psychology, MBCT proved as effective as maintenance anti-depressants in preventing a relapse and more effective in enhancing peoples’ quality of life. The study also showed MBCT to be as cost-effective as prescription drugs in helping people with a history of depression stay well in the longer-term.

Over the 15 months after the trial, 47% of the group following the MBCT course experienced a relapse compared with 60% of those continuing their normal treatment, including anti-depressant drugs. In addition, the group on the MBCT programme reported a higher quality of life, in terms of their overall enjoyment of daily living and physical well-being.

MBCT was developed by a team of psychologists from Toronto (Zindel Segal), Oxford (Mark Williams) and Cambridge (John Teasdale) in 2002 to help people who suffer repeated bouts of depression. It focuses on targeting negative thinking and aims to help people who are very vulnerable to recurring depression stop depressed moods from spiralling out of control into a full episode of depression.

Click here to read the full article.

pills on spoon

THS reader Chad sent in this question:

Antidepressants – effective or placebo?

The use of antidepressant medication has become so widespread and commonly accepted that it seems almost sacrilegious to question it. But alas, questioning is the name of the game here at The Healthy Skeptic!

And what do you know? Antidepressants aren’t all they’re cracked up to be. In fact, a recent meta-review of published studies on the efficacy of antidepressant drugs revealed that selective serotonin reuptake inhibitors (SSRIs), which are the most commonly prescribed drugs to treat depression, have no clinically meaningful advantage over placebo.

What that means is that in most of the trials reviewed, patients who took a sugar pill recovered from depression just as often as those who took the active drug. This study may come as some surprise to both physicians and the general public, whose faith in the efficacy of these drugs has led to over 118 million prescriptions in 2007 and over $16 billion in sales.

But should this really come as a surprise? Antidepressant drugs are thought to act by altering levels of brain neurotransmitters; however, it takes several weeks before these changes can be measured. Yet patients often report symptomatic relief within hours or days of receiving an antidepressant.

Available data suggests, in fact, that SSRIs are no more effective than placebos and have considerable adverse effects and risks, including increased suicidality amongst both children and adults. Sapirstein and Kirsch conducted a meta-analysis of 3,000 patients who received either antidepressants, psychotherapy, placebo or no treatment at all. They found that 27% of therapeutic responses were attributable to drug activities, 50% to psychological factors, and 23% to “non-specific” factors. In other words, 73% of the response to the drug was unrelated to its pharmacological activities – and antidepressants may be no better or more specific than placebos.

This of course raises grave questions about why the National Institute for Health and Clinical Excellence (NICE) still recommends that antidepressants should the be first line treatment for moderate or severe depression. Their message is identical to that of the Defeat Depression Campaign in the early 90s, which contributed to the 253% rise in antidepressant prescribing in 10 years.

In a review published in the British Medical Journal in February of 2006, researchers Joanna Moncrieff and Irving Kirsch point out that the NICE recommendations ignore even their own study data. Although the NICE meta-analysis of placebo controlled trials of SSRIs found statistically significant differences in levels of symptoms, these were so small that the effects were deemed “unlikely to be clinically important.”

After analyzing several published studies and reviews, Moncrieff and Kirsch reached the following conclusions:

Summary points

  1. SSRIs have no clinically meaningful advantage over placebo
  2. Claims that antidepressants are more effective in more severe conditions have little evidence to support them
  3. Methodological artifacts may account for the small degree of superiority shown over placebo
  4. Antidepressants have not been convincingly shown to affect the long-term outcome of depression or suicide rates

The response to a drug or placebo in a clinical trial for depression is often measured using the Hamilton rating scale, a multiple choice questionnaire which doctors use to rate the severity of a patient’s condition. The questionnaire rates the severity of symptoms observed in depression such as low mood, insomnia, agitation, anxiety and weight-loss; it is considered to be a highly reliable physician-rated scale and has been reported to be more sensitive than patient-rated scales to drug/placebo differences. (Murray, 1989)

In the NICE meta-analysis, the difference between drug and placebo groups was one point. The most commonly used 17 item version of the Hamilton scale has a maximum score of 52. It is highly unlikely that a difference of one point on a 52-point scale is clinically significant, a fact that the FDA has admitted in memoranda (Laughren, 1998; Leber, 1998) reviewed by Moncrieff and Kirsch.

Other studies have yielded similar results. A study by Khan et al. found a 10% difference in levels of symptoms between placebo and active drugs in two different meta-analyses. In a more recent review, Kirsch et al. invoked the Freedom of Information (FOA) act to obtain access to previously unpublished studies (the drug companies are under no requirement to publish a study they have sponsored if the results don’t suit them). The overall difference between drugs and placebos in that analyses was 1.7 points on the Hamilton scale.

Moncrieff and Kirsch also point out that the Hamilton scale contains seven items concerning sleep and anxiety, with each item on sleep scoring up to six points. Therefore any drug with some sedative properties, including many antidepressants, could produce a difference of two points or more without exerting any specific antidepressant effect.

Follow-up studies that track patients for a significant length of time have also shown very poor outcomes for people treated for depression both in the hospital and in outpatient settings, and the overall prevalence of depression is rising despite increased use of antidepressants. Suicide rates have increased in some groups and some countries, despite increased prescribing of antidepressant, and there are continuing concerns that SSRIs may increase the risk of suicidal behavior in obht cildren and adults.

In children, the balance of benefits to risks in antidepressant treatment is already recognized as “unfavorable”. The analyses performed by Moncrieff and Kirsch strongly suggests that the same is the case for adults, and that the ongoing uncertainty about the possible risk of increased suicidality as well as the adverse effects of antidepressant drugs warrant a “thorough re-evaluation of our current approach” to treating depression.

I couldn’t agree more. One question the authors failed to pose, which I believe to be at the root of the matter, is why are so many more children and adults depressed now than before? You might not be surprised to learn that I have some thoughts about this. But I’ll save them for another post.

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