Let it be known that Sci, like many a young, bright-eyed little scientist, tries to keep up on her reading. TRIES is the operative word, but every week Sci gets the Tables of Contents for all the major journals in her field (and all the major ones in her subdisciple) emailed straight to her for her perusal. She scans the title lists, searching for things that are cool in her field, cool to blog, or that might indicate a scoopage of her work (hey, it happens).
And it was in one of these perusals that I came across this article. And this article is on a subject that needs to be blogged. But this article also says a lot about the “selling” of a scientific paper to a high-ranking journal. Biological Psychiatry, the journal in which this paper was published, has a pretty decent impact factor (8.67), and in Sci’s field, is considered to be a pretty hot publication venue.
But before I go into that, let’s take a look at this paper:
Steiner et al. “Fluoxetine potentiates methylphenidate-induced gene regulation in addiction-related brain regions: Concerns for use of cognitive enhancers?” Biological Psychiatry, 2010.
Sci would like to start by noting that doing an image search for “cognitive enhancer” yields some surprisingly boring results. I was really hoping for something like this:
So let’s start with the idea of cognitive enhancement. It’s an extremely vague term. What does “cognitive enhancement” MEAN?! We don’t (yet) have pills that can make you smarter, and we don’t (yet) have pills that will enhance your memory or learning rate. What we DO have is pills like Ritalin, which, though it can’t enhance your memory or make you smarter, WILL make you concentrate. This works for people with and without ADHD. Sometimes, being able to concentrate is enough to get the extra studying in. And for now, it’s drugs like Ritalin that we are calling cognitive enhancers (for more on Ritalin and ADHD, Sci has a post here).
And ever since people realized that Ritalin really does work to increase focus and help those long nights of studying, it, and drugs like it (another drug for this is amphetamine, and various market names for all these stimulants include Ritalin, Concerta, Adderall, Dexedrine, Focalin, and Vyvanse) have become sought after for their cognitive enhancement properties by people who don’t have ADHD. This worries people. Scientists don’t really know the effects of low dose Ritalin given to people without ADHD over the long term. Not only that, methylphenidate (the drug that makes up Ritalin), and amphetamine (the drug that makes up Adderall) are both stimulants, similar to drugs like cocaine. And while we’re giving it out in very low doses that are thought to be safe…are they? And so a lot of work has gone into studies of low dose Ritalin.
And now we will take a minute and talk about Flouxetine. Fluoxetine is marketed as Prozac and is an SSRI (selective serotonin reuptake inhibitor) antidepressant (Sci has a big post on Prozac and another big post on serotonin).
So now we shall put the two drugs together and take a look at mechanisms. Well ok, that’s a lot. Is too much. See links above for full explanations, in the meantime, Sci will sum up. To start:
Ritalin (methylphenidate) is a drug that increases levels of the neurotransmitters dopamine and norepinephrine in your brain. It does this like so:
Alright, what you’re looking at here are two neurons (one on the top and one on the bottom). The top one has little clear bubbles in it. These are vesicles which contain the chemical dopamine or norepinephrine (seen in orange). The dopamine is release into the space between the neurons (called the synapse), and then binds to the receptors on the other side (in blue), which then stimulate the inside of the other neuron to keep a signal going.
But you don’t want the dopamine staying around in the synapse forever, forever stimulating the neuron, so you have those things on the first neuron, in purple. . Those are transporters, and they take the dopamine up and recycle it, bringing it back into the neuron to be broken down or used again.
So where does Ritalin come in? Ritalin BLOCKS the dopamine and norepinephrine transporters, preventing the chemicals from being recycled, and causing them to build up in the synapse. This means that there’s a lot more dopamine and norepinephrine around to stimulate the neurons.
Prozac (fluoxetine) is a very commonly prescribed antidepressant which increases levels of serotonin between your neurons. Use the same picture above, but put in Prozac instead. Serotonin has the same kind of transporters, and Prozac blocks those to increase serotonin in the synpase.
So Ritalin = dopamine and norepinephrine
Prozac = serotonin
COCAINE = dopamine, norepinephrine, AND SEROTONIN.
wait a minnite…
So the idea behind this paper (as far as Sci can tell, was to look at what happens when you put Ritalin and Prozac TOGETHER, and whether you got effects that were more similar to cocaine. To look at this they looked at changes in gene expression in an area of the brain called the striatum, which is an area associated with the rewarding and reinforcing properties of drugs like cocaine. They looked to see whether Ritalin and Prozac, given together, produced increases in genes in the striatum in a pattern similar to that of cocaine.
And here’s what they got:
Above you can see the changes in gene regulation when rats were given saline (white bars), Ritalin (second bar from left in all the graphs), Prozac (third bar from the left in all the graphs) and both together (black bars). They found that the combination of the two produced a big increase in the amount of gene expression in reward related areas, which they say is a more cocaine-like effect. They also looked at behavior in response to both (using locomotor activity) but didn’t really get anything.
They conclude from this that by their powers combined, Prozac and Ritalin have more cocaine-like effects than just Ritalin alone.
All well and good. Well, well enough. Sci’s got some issues with this paper, and she’s going to start with the scientific ones:
1) They say they are getting an effect that is more psychostimulant-like and more cocaine-like when they combined Prozac and Ritalin, but there are no controls for either cocaine or amphetamine (commonly studied psychostimulants in the drug field) to show that. ARE the results just like those of cocaine? I didn’t even see any citations showing studies with cocaine to say they are similar (here, let me show you one). These authors are in fact well known, and have published previous studies on this stuff, so I’m surprised they didn’t do a comparison.
2) They say they are getting an effect that could lead to addiction or is more addictive-like, but there are no addiction studies on this. Do the rats prefer Ritalin or Ritalin and Prozac together? Which do they prefer MORE? This could be done using a carefully done conditioned place preference study, or using a drug discrimination model. Or even just using self-administration to see which was self-administered to higher levels. In fact, let me show you one of these, using cocaine.
3) They used a dose in rats (5 mg/kg) which I think they thought was a clinically relevant dose (the paper is very short and they never explain). This dose seems a bit high, other studies have shown that 2 mg/kg is closer, and some people prefer to work at 1 mg/kg in the rat (the therapeutic dose in humans is 1 mg/kg or lower, but how this translates to a rat is more difficult). Why this high dose? The people using Ritalin for cognitive enhancement do not take higher doses than normal clinical doses.
So those are my main scientific issues. Now lets get to some others.
1) This. This is a paper showing that locomotor activity in rats (which is induced my Ritalin, you’d expect this because it’s a sitmulant) is enhanced by Prozac.
2) This. This is a paper showing that the effects of amphetamine, another stimulant, are increased by treatment with imipramine, another antidepressant.
3) This. This is a paper showing that another antidepressant, citalopram, increases the breakpoints of cocaine, pointing to an increase in subjective effects.
4) This. This is a paper showing that Prozac increases the stimulant effects of cocaine.
I don’t think I need to go on, but I can find more. What Sci is saying here is that this paper…lacks a certain something in original, groundbreaking awesomeness. Sure, it’s measuring gene expression, and looking at Ritalin specifically…but the results were, honestly totally expected. There’s not a lot that is surprising about this paper, and there’s not even a lot of data. So WHY did this paper (which is FINE, and should definitely have been published) end up in the rather high falootin’ journal of Biological Psychiatry?
Sci could go through lots of options like politics, big names (the first author on the paper has done a lot of these studies and has published a lot of similar work), etc. But she thinks the big thing was this:
(BOOGA BOOGA BOOGA!!!)
It’s a phrase that’s really big and very hot right now. It’s clinically relevant. In fact, it’s VERY clinically relevant. A lot of people seeking cognitive enhancement will also be on antidepressants, and that’s a good demographic to look at. Not only that, but the effects of Prozac on Ritalin go the OTHER WAY. Ritalin enhances the antidepressant effects of Prozac. This works so well that a phenomenon has started among doctors of giving drugs like Ritalin along with Prozac in the first two weeks, to tide the patient over and get them through the weeks until the Prozac really kicks in (this is an issue with antidepressants, that they take several weeks to work).
So it’s interesting right now, it’s cool, and it’s clinically relevant. And the title of the paper “Concerns for use of cognitive enhancers?” has a lot of flair. But to be honest, Sci doesn’t see a lot here that advances the field beyond what we already knew (the gene regulation is nice, but that’s really all there was), and “concerns for the use of cognitive enhancers” doesn’t really fly with Sci until you show me a bunch of rats taking the Prozac/Ritalin combo like candy.
So the paper? Fine. Biological Psychiatry worthy? Maybe not. But it says a great deal about the power of a really snappy title.
Steiner, H., Van Waes, V., & Marinelli, M. (2010). Fluoxetine Potentiates Methylphenidate-Induced Gene Regulation in Addiction-Related Brain Regions: Concerns for Use of Cognitive Enhancers? Biological Psychiatry, 67 (6), 592-594 DOI: 10.1016/j.biopsych.2009.10.004