February 27, 2008
Meta-Analysis Finds No Benefit From SSRI Antidepressants
A Plos Medicine meta-analysis of studes on 4 antidepressant drugs finds no benefit from their use for all but the most severely depressed. The 4 drugs are the selective serotonin reuptake inhibitors (SSRI) fluoxetine (Prozac), paroxetine (Seroxat, Paxil), venlafaxine (Effexor), and nefazodone (Serzone). Do these big name SSRIs really fail to help people?
What Did the Researchers Do and Find?
The researchers obtained data on all the clinical trials submitted to the FDA for the licensing of fluoxetine, venlafaxine, nefazodone, and paroxetine. They then used meta-analytic techniques to investigate whether the initial severity of depression affected the HRSD improvement scores for the drug and placebo groups in these trials. They confirmed first that the overall effect of these new generation of antidepressants was below the recommended criteria for clinical significance. 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.
So then why do some people swear by the benefits they've gotten from Prozac and Paxil? Are they just lucky they started taking an SSRI just as their depression was about to lift? Or do SSRIs lift depression for short periods of time?
The researchers analyzed data from 35 clinical trials.
The dataset comprised 35 clinical trials (five of fluoxetine, six of venlafaxine, eight of nefazodone, and 16 of paroxetine) involving 5,133 patients, 3,292 of whom had been randomized to medication and 1,841 of whom had been randomized to placebo.
If you click through on the link you can read the full original paper. Plos Medicine is an open source scientific journal.
The SSRI drug makers find fault with this paper and claim it does not use more recent studies. However, the researchers who did this analysis claim they used the least biased among the available studies.
The more troubling question concerns what kind of data is appropriate for analyzing a drug's efficacy. The companies are correct in claiming there is far more data available on SSRI drugs now than there was 10 or 20 years ago. But Kirsch maintains that the results he and colleagues reviewed make up "the only data set we have that is not biased."
One point: The problem is that SSRIs seem to deliver a benefit but one not much better than placebos. Well, doctors can't get away with prescribing a placebo. So they might as well get their patients on SSRIs and get that beneficial placebo effect.
This relates back to that "PLoS Medicine - Why Most Published Research Findings Are False" right?
Well... I don't know of their effectiveness in reducing depression - especially over time - but I do believe they do reduce anxiety..
I have not personally tried any of these but my girlfriend in college became a non-sexual zombie under the influence of Paxil - cleared her anxiety right up.
She was such an intelligent and creative person that I interceded against her families wishes and had her discontinue use after a 10 month trial (long enough to fairly evaluate it's effects imho)
We then both undertook a more disciplined and intensive exercise regimine and it seemed to both positively effect her depression and my add /ocd.
I know several co-workers (and sadly a few close friends) who currently take Effexor, and I would, as a layman, say that they do seem to be under the placebo effect - as I have not noticed their behavior change nor anxiety decrease - but they do seem more self confident and this has led several of them to take up more extensive exercise programs which I believe will help alleviate their chemical imbalances.
I'm sure we will one day create an effective Soma - and it will become as common as the multi-vitamin in the average American's household.
I can't truly decide if this is any worse than the known hypnotic effect of the TV - and if it leads to less discusion about American Idol - well maybe it's not all bad.
I take Paxil, and I don't believe the effects are the result of a placebo. It reduces my anxiety and depression, got rid of my insomnia (I had the kind where one wakes up and can't get back to sleep), and takes much of the prickliness out of my personality. It also seems to increase the vividness of my dreams and the amount of pleasure I get from things that are pleasurable. On the downside, it seems to make me a bit more drowsy through the day.
Now, none of the above is anything more than anecdotal evidence, but I just don't buy that it could all be a placebo effect. Perhaps it helps some people and not others, so that on average it doesn't look like it does much.
Paxil was a six month nightmare for me, weight gain, constipation, random "zaps" in my brain causing twitching, nightmares with extremely vivid levels of reality and being *unable* to have an orgasm. That's right kids, everything worked fine down there but nothing my girl and I did would do it. Eventually my sex drive shut off completely. Coming off paxil was horrible and took a month, including several days of 24x7 vertigo, I staggered everywhere like Keith Richards on a bender and couldn't keep any food down.
I stayed off drugs for the next few years and in 2005 spent 12 months weight training which turned my depression around but when my mother was diagnosed with cancer I stopped exercising and began to slide back. I took her advice and tried lexapro just over a year ago and I intend to stay on it until I can get back into training again at which point I will begin to stop taking it. I've had no detrimental side effects from it at all save for some weirdness in the first few weeks as brain chemical levels began to shift, but nothing particularly unpleasant, in fact for the first few weeks my sex drive increased and I noticed MDMA like effects, especially in the first week, which were quite welcome during sex. Long term I have managed to return to my lowest BMI since I stopped training, about 15%, my chronic insomnia has been better and I've been less prone to some extremes of spending and appetite than I used to be.
I tend towards high-highs and low-lows, hovering around low for the most part and lexapro has stabilized me, without the numbing effect of the paxil. I can say I would not have been able to deal with my mother's death without the drug but I don't intend to remain on it long term. Like I said, the effects of 3x30 minute weight training sessions a week for a year, improving my nutrition and getting out of a bad long term relationship did way more for me than any of the drugs ever did and so I'm starting to work out again. If I forget to take the pill (20mg, by the way) by that evening I will begin to notice a floaty feeling in my head that can be a little weird at times.
Interesting side-note for those curious, and because I couldn't find much info on it at the time; it seems to have no interactions with marijuana, MDMA or LSD, all seem to work just as well with as without. I smoke weed to deal with my remaining anxiety issues, and of course because it is enjoyable. I had been prescribed xanax for that but I reacted... badly... to it. I overused it in combination with ambien and alcohol during the weeks my mother was dying and it caused *huge* out of character mood swings combined with *total* amnesia which resulted in waking up a few times from a seemingly sound nights sleep to find I had caused mayhem all around me. So yeah, I will smoke a bowl every now and again but I will *never* allow another molecule of xanax into my system. I just don't trust myself with it and it left me feeling groggy and hung over even when I would take one.
One man's experience, for consideration.
I think the message from these types of stories is that treatment with brain drugs needs to be individualized.
Lono's experience tallies with mine - I've seen a lot of people recover on SSRIs, but a lot of people not, and I'm not sure those who did wouldn't have got the same out of anything that gave them a bit of hope. However, he then says some people took up "exercise programs which I believe will help alleviate their chemical imbalances".
My quibble is that these "chemical imbalances" (e.g. supposed depletion of intrasynaptic 5HT/serotonin) are precisely what drug companies used in the 1990s to market their products as anti-depressants, despite the lack of evidence that such differences between depressed and non-depressed people exist - they were just a hypothesis to explain how earlier antidepressants worked. For example, antidepressants are tested using a "reserpine suppression test", to see how much they counteract the anti-serotonergic effects of reserpine. The surprising thing then is that the first drug to pass a randomised control trial for depression was... reserpine! So perhaps when they do work, it's not correcting any "imbalance" but giving a kind of shock to the brain that actually creates an imbalance but might, just possibly, shake someone out of the automatic thoughts and vicious circles of depression.
A lot of this is documented by David Healy in his histories of psychopharmacology, particularly _The Antidepressant Era_, where he concludes that the serotonic hypothesis is more marketing than science. He also explains that the drug companies would have actually marketed them as anti-anxiety drugs, but because of people's fears of benzodiazepines this wasn't possible.