Posts Tagged ‘research’

So That’s How Antidepressants Work (in mice)!

September 16, 2010 3 comments

By Rama via Wikimedia Commons

In the September 17 of Science, a new mouse study of SSRI effects finds that there is a microRNA that is upregulated by SSRIs, and which affects expression of serotonin transporters. This is presumably in addition to the direct inhibition of the reuptake pumps by the drug itself. It’s an interesting new piece of info that helps explain how these drugs work, which is surprisingly mysterious given how widely they are used.

Most people, even many psychiatrists, will tell you that they work by increasing the amount of serotonin in the brain (or if they’re really trying to be smart, the amount of serotonin in the synapse). It’s true that these drugs do in fact do this (in the synapse): it makes basic sense that if you stop reuptake, there will be more serotonin left in the synapse. But does this treat depression and anxiety? Are these maladies simply caused by a lack of serotonin in synapses, or perhaps an insensitivity of the post-synaptic cell which then requires extra serotonin to be activated? These common explanations, again, even by some psychiatrists. But they are wrong. If all we needed was more serotonin in the synapses, then these drugs would work immediately. SSRIs would work just as fast as Tensilon and amphetamine, which increase acetylcholine and dopamine in synapses respectively. It’s well-known that SSRIs take 4-6 weeks or more to take effect, and it’s even more well-known that amphetamine works immediately. So it should be obvious that SSRIs have effects that depend on something besides dumping serotonin into our synapses.

I’m not going to tell you exactly how SSRIs work, because I don’t know. And I don’t know anyone who does. It is likely that by increasing the amount of serotonin in the synapse they affect the sensitivity and/or expression of presynaptic receptors (autoreceptors), thereby effecting subtle changes in the sensitivity and overall reactivity of the serotonin networks. This kind of response would in fact be expected to take a few weeks.

But then there’s norepinephrine.

Image courtesy of Odile Kellermann via AAAS

To me, the interesting thing about the current study, even if it’s just in mice, is that the researchers have demonstrated that SSRIs appear to have downstream effects that include promoting expression of serotonin reuptake in noradrenergic neurons. This is mapped out in the cartoon here. I’m not a molecular biologist, so I can’t and won’t get too deep here, but in this mouse model fluoxetine (Prozac) sensitizes noradrenergic neurons this way, and also inhibits GSK3β. Before today I had never heard of GSK3β, and I don’t know if this is truly meaningful, but Dr. Wikipedia says that another drug that inhibits GSK3β is lithium! Another effective drug that we really don’t know what it’s doing. GSK3β appears to have a number of activities, and one that is interesting is phosphorylation of Tau, the protein that is found in the “tangles” of Alzheimer’s.

I once asked an experienced psychiatrist why he prescribed so much Cymbalta. (Cymbalta is an SNRI, so it works directly on both serotonin and norepinephrine.) His answer was that, although he continues to use SSRIs extensively, he feels that the responses from patients are not as robust as he used to see in the days when he prescribed mostly tricyclics. He thought this might have been from the noradrenergic effect of TCAs that was presumably missing from SSRIs. Now that he has Cymbalta available, he often uses it as a first choice and feels the response is better than from SSRIs.

So maybe the effect from SSRIs is really due to this other effect, however weak, on the noradrenergic system. This would be a blow to the Serotonin Hypothesis purists, but not to the utility of the medications and the patients who benefit from them. It’s unlikely, however, that SSRIs work in only this way. There remains abundant evidence that serotonin itself is somehow implicated in mood and anxiety, so norepinephrine can’t be the whole story. Perhaps, however, it’s been serotonin’s silent partner all along. And maybe these mice brains and their microRNA-16s will help norepinephrine get the co-star billing it deserves.

Magic Mushrooms for Anxiety

September 7, 2010 3 comments

By Vaxzine via Flickr

In a study published online yesterday in Archives of General Psychiatry, investigators at UCLA published the results of a pilot study using psilocybin (the active ingredient in “magic mushrooms”) to treat anxiety in cancer patients. This was a small study, with 12 patients who acted as their own controls (each had two sessions, one using the active drug and the other using a niacin placebo). These patients were fairly ill with advanced cancer, in fact only two of the patients were alive at the time of publication. Aside from legion anecdotal reports that using ‘shrooms makes people feel better, which has been accumulating since prior to Woodstock, we know that psilocybin and its active metabolite, psilocin, are potent serotonin agonists like LSD and presumably other psychedelics as well. Not that mushrooms and Paxil are strictly comparable, but we also know that generally upregulating the serotonin system is good for mood and anxiety, so there is a decent pharmacological rationale to think that this treatment might work.

It seems that the purpose of the study was twofold. First, as a proof-of-concept and model for further studies with psychedelic drugs, and second to actually test the efficacy of psilocybin on anxiety. The study does seem to have demonstrated that these drugs can be given in a safe manner and be fairly benign: no adverse reactions (or bad trips) were reported. The authors describe using a fairly low dose of psilocybin compared to the studies done with this drug 40 years ago. It’s not clear to me how this dose actually compares with the recreational doses used by your average illicit consumer, but it was apparently enough to get some typical psychedelic effects.

I’m not familiar with the “5-Dimension Altered States of Consciousness profile,” but it’s apparently a method to assess quality and intensity of experiences, and a good way to scientifically rate and characterize mushroom trips (and presumably other drug experiences as well). The patients described their psilocybin experiences as generally positive, with higher scores in “Positive Derealization” and  “Positive Depersonalization,” compared to the low scores in “Anxious Derealization” and “Fear of Loss of Thought Control,” to name a few of the subscales. It’s not clear whether the “Manialike Experience” item would be considered pleasant or unpleasant, but this one scored high as well.

If there are any criticisms of the study, they would be the small size and the lack of a true placebo (I think the strongest niacin flush in the world would be easily distinguishable from a mushroom trip, and the patients in the study in fact said so). Given that the patients were their own controls in a cross-over design, the long-term results of the drug use isn’t interpretable compared to the placebo anyway, and that wasn’t really the aim of the investigators. So is psilocybin effective for anxiety in cancer patients? Probably. Should we go ahead and recommend it? Probably not.

For the patient experienced with psychedelic use and with access to his or her own supply, I think it would be fair to suggest a trial. But if this study concerned a “regular” prescription drug, we would still be quite a ways off from FDA approval and evidence-based recommendation. Given the complicated legal and social history of psilocybin,  we are still incredibly far from mainstream acceptance of this drug as a treatment, even in critically ill patients.

By Thom via Picasa

But the big news lately is that after a 40-year hiatus, relegated to touring with the Grateful Dead, Phish, and annual appearances at Burning Man, etc., psychedelic drugs are officially re-entering the world of science. As the baby boomers gain control of research budgets, and the generations of academics who feared illicit drug use continue to retire, medicine is perhaps getting over its hang-ups related to these drugs. In the brave new world of  “medicinal” marijuana, it’s important to allow researchers to evaluate the potential of these drugs the same way we investigate the drugs produced by Big Pharma. Why should global corporations be the only ones allowed to tinker with your serotonin system?

Sharpen That Needle? No, I Don’t Think So

September 3, 2010 4 comments

Scott Beale/Laughing Squid

A study out in Archives of Neurology this week has generated a lot of interest. For example, the New York Times had a front-page story with the subhead “100% Accuracy in Test for Alzheimer’s” or something similar. The “100% Accurate” part is what caught my eye, and others too. I doubt that a “10% Accurate” headline would have made it to the front page or that the story would have been covered on the major networks. But is the headline true? My first thought was that no, of course not, otherwise the headline would have been “First-Ever 100%-Accurate Medical Test Developed.” 100% is a number we don’t see too much in medicine, particularly in the ambiguous world of neurological diagnosis. A test like that would be an enormously huge deal.

Does the study live up to the hype? Sadly, no. And it certainly doesn’t justify the an editorial entitled “Sharpen That Needle” which appeared in the same issue, written by two doctors who should know better. There is a 100% result found within the study results, but it isn’t the accuracy of the test exactly. It’s the sensitivity. And not the overall sensitivity, but the sensitive among patients with mild cognitive impairment who went on to develop Alzheimer’s. Now in the next paragraph I’ll explain sensitivity, so those of you who don’t want or need a (very) basic statistics lesson can skip over it.

New York Times Front Page 8/10/10

The “sensitivity” of a test tells us how good it is at finding true cases of what it’s looking for. Of all the people who have a certain disease, say, how many will test positive on our proposed test? If 5% of people with the disease test negative (false negatives) then our test is 95% sensitive. The other basic quality of a test is “specificity.” It tells us how many of the people who come up positive on our test actually have the disease we’re testing for (true positives). So let’s say that 10% of the time our test is positive, it’s wrong. Then we have a 90% specificity. You can’t judge a test based on just one of these elements. As an extreme example, let’s say we check if people are breathing to see whether they have Alzheimer’s. Now since we only test living people, all of the people with Alzheimer’s will have a positive test result: 100% Sensitivity, hooray! But if only 3% of the people we test have Alzheimer’s, then we have a 3% Specificity. Boo! Now the test proposed in the article did a lot better than that, but you get the idea.

If you guessed that the problem with the test is in the specificity, you’d be right. About 36% of the normals in the study also tested positive. So our specificity is down around 64%. This is a problem. It’s a problem because if you use this as a screening test in your office, about 1/3 of the people you inform that they should prepare for Alzheimer’s won’t actually get it. Not good. The other problem is that the “accuracy” of the test is better described by the positive predictive value, which depends on the sensitivity/specificity but also the prevalence of the disease. About 20% of people 75-85 have Alzheimer’s. If we use that as the prevalence, I get a 38% PPV for the test. (This is where my statistics starts to get hazy, so please send corrections if needed). That means that if you test positive on this test, and you live past 75, there’s about a 40% chance you’ll get Alzheimer’s. There are just too many false positives for this test to be a good screen.

andrewacomb via flickr

And the biggest problem with this test for most people won’t even be its accuracy. The big problem will be that it requires a spinal tap. Let me tell you firsthand that lots of people are deathly afraid of taps. They’re really not so bad, but if you think it’s hard to get people in for colonoscopy, forget about spinal taps.

Not to mention the biggest problem of all: if you do get Alzheimer’s there’s not a lot we can do for you anyway. Most doctors would or should question the ethics of testing for an untreatable illness. Now AD isn’t exactly untreatable, but there’s no evidence that the meager treatments we do have change the course of the illness in the long run, or that starting them earlier makes much difference.

If this did become a standard screening test, I’d certainly stand to benefit: as a neurologist I would start a dementia clinic and tap everybody and send lots of big bills to Medicare. And if I thought it would do my patients any good, I’d do just that. In fact, I’d team up with a GI doc and offer a combined colonoscopy/lumbar puncture. It’d be perfect: you’re already lying on your side, sedated, and you won’t feel or remember a thing. Turning 50? Come on in!

But until we have something to offer our Alzheimer’s patients, I’ll postpone sharpening that needle, thanks.

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