Antidepressants: Clinical Trials versus Real Life

In a recent post, I argued that no-one knows how well antidepressants work. Although there have been a huge number of clinical trials conducted on a variety of antidepressant drugs, it is impossible to know what the results of these trials mean in terms of real benefits for real patients.

I'm not the only skeptic. A paper just out in the American Journal of Psychiatry adds to growing case against contemporary antidepressant trials (almost all of which are industry-sponsored) and should give everyone cause for thought.
The article, Can Phase III Trial Results of Antidepressant Medications Be Generalized to Clinical Practice? A STAR*D Report, is one of the many spin-offs from STAR*D. STAR*D was a large and ambitious study designed to investigate the effectiveness of antidepressants in a realistic setting. The results were rather difficult to interpret (and some are yet to be published), but this report is certainly amongst the most interesting.

One of the things that made STAR*D different from the average trial was the recruitment criteria. Most trials require a volunteer to tick numerous boxes before they can be enrolled - for example, it's common to exclude anyone showing signs of suicidal thoughts or behaviours, people with any problems other than depression, such as addictions, and anyone whose depression is rated as "insufficiently severe" using a depression rating scale such as the HAMD.

The majority, probably the vast majority, of people who suffer from depression don't fit such narrow criteria. So antidepressants end up being tested on no more than a small select group of the people who are likely to end up taking them when and if they hit the market. And because criteria can differ between trials, two trials might end up testing the same drug on two quite different types of people - although on paper they are both a trial of the drug for the exact same thing, "major depression".

To be fair, some criteria are necessary to protect the safety of volunteers (you don't want someone who is suicidal getting their hands on an experimental and potentially dangerous drug), but the whole situation is far from ideal. People have been complaining about it for a while. The new paper adds to the list of complaints. The authors took advantage of the fact that STAR*D did not have restrictive entry criteria, and simply compared those patients who did happen to fit the bill for a "typical" antidepressant trial vs. those who didn't.

First off, just under a quarter (22.2%) of patients met the typical criteria. That's really not very many. And, as you'd expect, this minority of patients were rather different from the rest. Amongst many other things they were slightly younger, a lot richer (mean monthly income $3050 vs. $2163), much less likely to be unemployed or to have no medical insurance, and less likely to be black or Hispanic (this was an American sample).

Such differences might seem unimportant - if someone is suffering from a disease, and they're given a medication to treat it, does the size of their paycheque really matter? Yes it could - the patients who met the criteria for a typical antidepressant trial reported on average more improvement, and fewer side effects, compared to the others. (They were all given citalopram, a popular and pretty decent SSRI).

Does this mean that rich white people really get more benefit from citalopram? Or do they just tend to report more benefit? Or do they experience larger placebo effects? It's impossible to say. The authors, who include some big names in antidepressant research, conclude that:

...a patient sample that meets the inclusion criteria for a phase III clinical trial is not representative of depressed patients seen in typical clinical practice, and phase III trial outcomes may be more optimistic than results obtained in practice.

Although it's also possible that trial outcomes could be more pessimistic, in terms of finding smaller drug-placebo differences than they otherwise would. Only one thing is certain - antidepressant trials are far removed from the real world, and the results of such trials have to be taken with a large pinch of salt.

Wisniewski, S., Rush, A., Nierenberg, A., Gaynes, B., Warden, D., Luther, J., McGrath, P., Lavori, P., Thase, M., Fava, M., & Trivedi, M. (2009). Can Phase III Trial Results of Antidepressant Medications Be Generalized to Clinical Practice? A STAR*D Report American Journal of Psychiatry DOI: 10.1176/appi.ajp.2008.08071027