Prozac, Ritalin, Cognitive Enhancement, and the power of a snappy title

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:

Oh well.

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:
dopamine synapse.jpg
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:

Cognitive Enhancement!

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

16 responses so far

  • The field of stimulant addiction research is sort of all over the place, in terms of paying attention to work that's already been done and doing things systematically. I hate to say it, but this sort of thing (leaving out citations, stopping short of really testing your hypothesis, assuming that something is a certain way and thus not controlling for it) seems par for the course. I can't count (well, I probably could) how many papers I've seen on cocaine self-administration that purport to use Koob's escalation model, and have no control groups - just a long-access group.
    On the other hand, the theories of drug addiction that are supported by self-administration and CPP models are themselves somewhat controversial. The way that dopamine, serotonin, and norepinephrine receptor effects interact to create psychostimulant effects (let alone addiction) is far from solved. I can't blame the authors for wanting to only bite off a little piece of the problem at a time. It seems like this study generates at least one testable behavioral hypothesis (that fluoxetine should enhance the "addict-like" behaviors such as self-administration that methylphenidate elicits,) which is useful in itself.
    That said, I also would have preferred that they started on the behavioral end first - it's simply a more direct form of evidence if you want to make claims about addiction, which is ultimately a pattern of behavior.

  • Onat Dalas says:

    Can fluoxetine alone be useful in reducing Adult ADHD symptoms?
    Symptoms being (Indecision, Poor Planning, Procrastination, Lack of focus/ Hyper Focus) in my case..

  • Scicurious says:

    Onat: No, it probably won't work for the ADHD symptoms. In fact, I'm pretty sure it DEFINITELY won't work.
    Mike: I don't know, there are problems associated with starting at the behavioral end. As far as we can tell, rodents just don't get addicted the way humans do (even a fully addicted rat will choose sex over cocaine, for example). In addition, they DID run some locomotor studies. But starting with something like self-administration is certainly better in terms of contingency and things like that, and it would also prove their point that the cocktail is more "addictive" than Ritalin alone.
    Also, with the Koob model, I don't blame a lot of people for skipping out on the control. It's a well established model, and also, just getting enough rats in the long access model is trial enough. If, say, you're testing two groups against each other there, with more than one drug condition, and to do that to ANOTHER two groups in the short access group? That's a lot of extra work, and it's a LOT of extra rats, which seems a lot to tell you the answer of a control we already think we know. And you can "control" for drug motivation via a saline lever in the cage if you want. I mean, it's true it's not well controlled, and people skip that all the time while keeping things like a saline group, but it's not hard to understand why they do it.

  • Brian says:

    This post has made me a bit curious; I suffer from MDD co-morbid with GAD (well, I've had a lot of diagnoses, but that appears the most accurate, so far), and as such, among others, I take Cymbalta (serotonin & norepinephrine), Wellbutrin XL (dopamine & norepinephrine), and buspirone (serotonin, albeit as an agonist, not as a reuptake inhibitor, IIRC).*
    Anyway, would that combination be at all similar to the Prozac / Ritalin duo? It would seem to be (S + N + D), but from my own research of my condition(s) and my studies as a cognitive science undergrad, I've learned that "the answer" is more-often-than-not "well, um, kind of... it's complicated." 😀
    *The "others" for the curious, are clonazepam and Lamictal (for its effects as an off-label adjunct, not as an anticonvulsant); also, if my "inconsistency" in using some label names and some generic names seems confusing, it's just that I've made a habit over time of being as specific as possible in how I refer to my medications, particularly with doctors (though, as an aside, I find it quite sad how many are befuddled by the name "buspirone" and don't understand until I clarify by saying "Buspar").

  • Scicurious says:

    Brian: "well, um, kind's complicated" 🙂
    Honestly, I think what probably matters a lot in situations like these is the RATIO of dopamine to norepinephrine to serotonin, in order to get the effects you need without crossing over into addictive territory. Some studies have shown that higher dopamine to serotonin is more "rewarding", and norepinephrine plays into that, but we're not sure how.
    But also, kudos on being REALLY specific with your meds to your dcotors. That sort of thing can be really confusing, and being as specific as possible (heck, if I'm on meds I bring the bottles WITH me to show people) makes you get the best treatment with the most information. So go you. 🙂

  • Brian says:

    Thanks for the quick reply.
    > Some studies have shown that higher dopamine to serotonin is more "rewarding", and norepinephrine plays into that, but we're not sure how.
    If it's not too much trouble, are there any relevant DOIs (or just authors and dates, if that's easier) you might be able to furnish? GScholar is my friend, of course, but that said, I'm still far from adept at the "keyword game" when seeking out papers.

  • Scicurious says:

    The rather iconic one I'm thinking of is this one:
    But any Pubmed search using keywords like "dopamine serotonin self-administration" should get you some stuff.

  • megan says:

    CAFFEINE and NICOTINE, the last socially acceptable and mostly unregulated stimulants. Billion dollar worldwide markets. It has been theorized that humans have always found and used plant enhancing stimulants and only recently learned how to concentrate the key chemicals and then fabricate them from unnatural sources. Of course big global pharma would love to find a legal method to create a drug prescription version of a cognitive enhancer stimulant for direct profits vs people visiting Starbucks, smoke breaks or brewing a pot. Taking a pill or patch avoids calories and possible organ destruction from the delivery system side effects - ie dehydration and kidney harm from excessive coffee or lung cancer and heart problems from smoking.

  • DrugMonkey says:

    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,
    GlamourMag-ification of science.

  • DN says:

    Regarding mechanisms, Ritalin has many effects beyond reuptake inhibition: dumping internal neuron stores of neurotransmitters (VMAT blocker), directly stimulating some serotonin receptor subtypes (5-HT(2C) at least, resulting in weight loss and sexual effects), blocking certain nicotinic acetylcholine receptor subtypes, and probably others. Inferring a mechanism of synergy is not possible without extensive behavior data and comparisons with other drugs, and ideally a variety of gene knock-out animals.

  • Scicurious says:

    DN: actually, the dumping via VMAT is through reversal, not a blockade necessarily, and appears to only occur at higher doses. In addition, I believe the only 5-HT receptor subtype that Ritalin stimulates directly is the 5-HT1A (Markowitz has some stuff on this), I've never seen anything in the literature to indicate direct 2C effects. While there are certainly interactions with nicotinic systems, Ritalin is not an antagonist there, it's effects are modulated by these receptors, but that's not the same thing. There is, however a great deal of work on the affinities of DAT and SERT inhibitors and their relative rewarding potentials, and while of course more studies need to be done on this, it would seem that acetylcholine is probably not the main player, though 5-HT1A may be bigger than people have realized.

  • iuhiuh says:

    loved it, thanks so much

  • David says:

    I was diagnosed as ADHD with Anxiety and Depression co-morbid.

    I am taking Wellbutrin xl 300 mg and Strattera 80mg. I am 60 and

    that is the reason my psychologist doesnt want me on amphetamines

    Vyvanse etc... I can't find anything that shows any of the ADHD drugs to

    be any heart safer than others. Not seeing any change in my symptoms,

    and Strattera is expensive, do you know of any studies that show any risks

    for old people .. or is it just that speed may raise blood pressure so we dont

    try it so we dont know for sure ? Suspect that CBT is likely a better bet

    than drugs for adhd. thankyou

  • On Prozac says:

    I read your entire article and it was a complete waste of time! There is no conclusion to it but just arousing useless curiosity that is obvious to anyone using these drugs.
    There is no clear reason for this article but to give your hmmm and "I wonder" or " doesn't it make you think" crap that (once again) wasted my time.
    I have to say, the website is remarkable and I do enjoy its layout.
    Also, the images and explanations were magnificent. That part was nice to refresh my memory and stimulate the "I already know that" part of my brain.

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