Furthering the SSRI’s bad rap.

(an explanation of another count on the SSRI’s rap of increased risk of suicide can be found here.)

This afternoon, xnera alerted me to a new study advocating that newer-generation anti-depressant medications (SSRIs) are no more clinically effective than placebos. Now, I realize and support the general opinion that anti-depressants are over-prescribed. At this point in the psychological treatment game, I’d even say that most psychoactive medications are over-prescribed. However, this new trend of over-prescribing can be viewed in two different ways—a safe rather than sorry treatment approach, or a too powerful influence of the drug companies over providers. As studies have shown that the medication plus psychotherapy (talk-therapy) approach is more clinically effective than either psychotherapy or medication alone, I’d lean towards the safe rather than sorry approach. Providers using the latest studies and the general proven treatment standards are going to be much better off using the golden standard approach at first, in both terms of success of treatment and for defense against our litigious society.

So I did a read-through of the new study and here are my initial thoughts.

The title of the article is “Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration.”

Remember, this is a meta-study. Meta is something “occurring later than or in succession to” (from Merriam-Webster).

From the Editor’s Summary in the section What Did the Researchers Do and Find?:

Then they showed that there was virtually no difference in the improvement scores for drug and placebo in patients with moderate depression and only a small and clinically insignificant difference among patients with very severe depression. The difference in improvement between the antidepressant and placebo reached clinical significance, however, in patients with initial HRSD scores of more than 28—that is, in the most severely depressed patients. Additional analyses indicated that the apparent clinical effectiveness of the antidepressants among these most severely depressed patients reflected a decreased responsiveness to placebo rather than an increased responsiveness to antidepressants.

The last sentence is important here, as there wasn’t analysis to support (”reflect”) that the most severely depressed patients had a decreased response to the placebo rather than an actual response to the medication. It worked, but it was magic!

“This strategy omits trials conducted after approval was granted.”

From what I’ve read of FDA approval grants, this dropping of post-approval studies eliminates a significant number of efficacy studies. The tests conducted for FDA approval consist of initial safety and beneficial use. They aren’t long studies (longitudinal) studies, which the studies post-approval are (and there are requirements for post-approval studies).

The FDA dataset includes analyses of data from all patients who attended at least one evaluation visit, even if they subsequently dropped out of the trial prematurely.

(emphasis mine)

Which means the efficacy of the drug isn’t properly evaluated, especially considering the treatment schema of SSRIs (as in, it takes up to four weeks to reach a fully effective dose).

Other validity criteria might yield different conclusions.

Well… duh. This is true for all studies. So, while the stats themselves are interesting, there are other meta analysis that could be conducted and part of the issue is that it’s a meta-analysis with bias towards finding that SSRIs aren’t effective.

However, even if an SSRI isn’t better than a placebo, it still benefits the patient, as the studies says that the medication is no more effective than the placebo. So, it’s still effective.

The use of other psychoactive medication was reported in 25 trials. In most trials, a chloral hydrate sedative was permitted in doses ranging from 500 mg to 2,000 mg per day. Other psychoactive medication was usually prohibited but still reported as having been taken in several trials.

So, some trials allowed the use of other psychoactive medication and others didn’t. This muddies the waters quite a bit.

The results in raw metric are presented comparing both groups, but because of the variation of the SDcs, the standardized mean difference was used in moderator analyses in order to attain better-fitting models.

…does that mean numbers/data was changed to better fit the model they wanted to use?

because preliminary analyses also revealed that this trial was an outlier, these two standard deviations were treated as missing and imputed. In total, SDcs were known for 28 groups, could be calculated from other inferential statistics in nine comparisons (18 groups), and were imputed in 12 comparisons (24 groups)

Impute: to credit to a person or a cause. Attribute. (from Merriam-Webster.)

I followed the link to attribute.

Attribute (transitive verb): to explain by indicating a cause (attributed his success to his coach); to regard as a characteristic of a person or thing; to reckon as made or originated in an indicated fashion (from Merriam-Webster.)

So they took away the outlier because it didn’t fit the datasets from the other trials (which is something done in statistical analysis, as an outlier is a bit of data that falls way beyond the norm of the other data). Okay, I can go with that.

However, in others, they use inferential means to give the other studies an SDc score …in other words, it seems they made shit up mathematically and they tweaked the numbers until they found what they wanted to find. Because, you know, the public needed more crap against SSRIs. Also, they say an SSRI is no more effective than a placebo (statistically because of the standard deviation). Yet, it does show that it’s still clinically effective as is the placebo.

“We also find that efficacy reaches clinical significance only in trials involving the most extremely depressed patients, and that this pattern is due to a decrease in the response to placebo rather than an increase in the response to medication.”

…so the clinically significant improvement of the most severely depressed people is due to… what? magic instead of the medication?

If SSRIs are over-prescribed, then of course it’s only going to work (better than a placebo) in the most severely depressed people because at that point, you can really point it to being a persistent neurotransmitter issue rather that a situational and therefore transient neurotransmitter level. Basically, it’s the difference between people who have to take it from 6 months to a year and never have to take it again, and people who have to take it for the rest of their lives.

…thank you for proving the efficacy of SSRIs in depression requiring maintenance treatment. Well, unless it really is magic.

And yes, I do admit to having my own bias for the efficacy of SSRIs and other psychoactive medications.

Categories: commentary