Caffeine enhances activity of common antidepressants in forced swim test in mice
ncbi.nlm.nih.govThey don't appear to have run a control with caffeine alone. Caffeine is a well-established athletic performance-enhancing drug in its own right. Isn't this a serious flaw with the swim-test portion of this study?
Figure 1 shows that 5,10,20,50 mg/kg caffeine has an effect on the forced-swim test, but not as strong as imipramine. Table 1 shows that the same doses of caffeine don’t make the mice more active in their cage, which might help address your concern.
"Table 1 shows that the same doses of caffeine don’t make the mice more active in their cage"
As a former rat owner, and a former locked-up felon, if a rat (or human) is in a cage, it tends to know and act like it's in one. Caffeine isn't going to make you suddenly more energetic in your cage unless you've got some other underlying issues, so that part of the study is instantly suspect.
Mice will run for miles (literally!) if there’s a treadmill or wheel in their cage. I could certainly imagine there’s some sort of multiplicative effect, where a substances causes (say) a 1.2x increase in activity, but that’s also not really how caffeine hits me: too much and I’m nonspecifically jittery.
Regardless, that could certainly explain the caffeine-only part, but it’s harder to square with the caffeine*anti-depressant effect.
You’re probably right, but that’s an anecdote, not scientific evidence.
I had thousands of other data points in the GP cell right there with me. Plenty of scientific basis for my conclusion, as I had a good 50 weeks to observe.
I was under the impression that this is a pretty known effect. I used to take anti-depressants along with CNS stimulants and this definitely was something that my psychiatrist and my other doctors mentioned to me and considered when choosing an appropriate dosage.
They have spent a lot of money to research the fact that people are less productive when hungover. I guess even known things are targets for scarce research dollars.
It's also important to figure out the magnitude of the effect.
How much less? How does it depend on exactly how much they drank (linear, quadratic)? How much does it differ from person to person? ...?
It is obvious that it has some impact, but not at all obvious how this works in detail.
Can you expound on that? Can you paraphrase the doctor's suggestions?
There isn't much to paraphrase, really. When my doctor was prescribing fluoxetine he offhandedly mentioned that he would start me off with a lower dose than he normally would for a person of my size and issues because I was already taking amphetamines, which meant that I wouldn't need as high a dose. The offhanded way he mentioned it gave me the impression that it was common knowledge and later another doctor also mentioned the same thing to me, but this one was not a psychiatrist but a cardiologist, farther cementing my suspicions.
When I later asked my psychiatrist about this he said that since SSRIs and amphetamines are though to complement each other (even if the science on the matter isn't really decided) the recommendation they get is to adjust the dose of SSRIs down. I'm sure the actual reason is more complex than that, maybe involving fears of serotonin syndrome, but my takeaway from it was that the effect is well known.
No idea about coffee in particular since I wasn't allowed to have any caffeine during that time.
FWIW ssris aren’t dosed by weight anyway, so it was just the amphetamine interaction they were counting on
DAT inhibitors, DA releasers and agonists are effective antidepressants in that they reduce the symptoms of depression. Drugs like Zoloft are DAT inhibitors as well as acting as SSRIs, Wellbutrin is a NET and DAT inhibitor, and MAOIs inhibit the breakdown of serotonin, DA and norepinephrine. Newer antipsychotic medications that are indicated for use as adjunct therapy for depression also have binding action at certain DA receptor sites.
The problem with dopaminergics is that they tend to be addictive, and build tolerance. Both Zoloft and Wellbutrin only inhibit a certain percentage of DAT in areas of the brain related to reward, so they aren't exactly abusable, while something like methylphenidate (which is a potent NET and DAT inhibitor) is.
I hope one day the mice will finally thank us for all the hard work we've done in improving their quality of life.
They're doing the tests on us.
Well, if you look at the results...
X cures cancer in mice
Y increases lifespan in mice
Z improves disease resistance in mice
W reverses cognitive decline in mice
The signs are all there.
I sometimes joke that the NIMH[0] is actually the National Institute for Mouse Health.
[0] Yes, like the rats! It's a real institute (National Institute for Mental Health).
Mrs Frisby has no idea what you're talking about. :D
Jenner, however, is an engineer like the rest of us.
Don't forget your towel!
we could meet in the middle and actually change the human genome to be more like a mouse so we also get these benefits
Full title gives a bit more context: "Caffeine enhances the antidepressant-like activity of common antidepressant drugs in the forced swim test in mice."
My perfect day is 8 hours of caffeine, an hour at the gym, 4 hours of alcohol, SSRI for a nightcap. YMMV
While I never used alcohol, some many number of years ago my drug cocktail used to not be so dissimilar from yours.
All I can say is that, for me personally, and many others, being able to eventually move off that chemical dependency has resulted in richer and healthier days. This isn't a judgement on what works for you, or a suggestion that you do some radical change. Just something to chew on in the back of your mind if the day ever comes where you get sick of it all.
There’s evidence that all of the effectiveness of antidepressants is due to the placebo effect. Contrast this with bipolar or schizophrenia where medications actually seem to benefit vs placebo.
A relative of mine is on a very strong SSRI and stimulant combination; talking to them is almost impossible, they're constantly interjecting and changing the subject. They're a coked up toddler with a particularly large vocabulary.
A lot of SSRIs have the expected mechanism of action of disrupting your executive function. This is usually explained as making you more likely to act. The other is disrupting the linking and creation of long term memories, especially negative ones. You can find research evaluating SSRIs and antidepressents looking for these things. Maybe it's not bad, but long term memory and good executive function are the main components of IQ.
In the above case the stimulants were originally prescribed I think to counteract a loss of focus, they might be worse off without them.
Personally I lost a year and a half to Lexapro. It made me happy (or made me think I was) but completely removed any motivation I had to do anything. In my observations this is typical, and a concern I expressed to the doctors involved. People I've known turned into shells of themselves who never left the house.
What do you mean disrupting the executive function? I have taken citalopram (an SSRI) for years without any impact.
I'd recommend a book that dives into this topic before downvoting: Lost Connections by Johann Harl
It should go without saying that YMMV if you keep that up.
I hope you're exaggerating - that kind of cocktail is going to kill your sleep quality and, in the long-term, quite possibly fry your brain.
Thumbs up on the exercise though.
I usually let these types of comments enable interesting discussion, but given the response and the worry that it validates someone else’s lifestyle, I must say that it was tongue-in-cheek. My perfect day does not imply my everyday. Please don’t drink alcohol for 4 hours every dear reader!
I am glad to hear that you were indeed joking!
I like how this is getting flagged out - but it's 100% true - this dude is going to fry himself with practically 0% REM sleep.
Alcohol induces REM, so, you may not be as airtight as you think, there.
Source? Every result on Google for 'alcohol rem sleep' says it suppresses it during the initial phase of sleep, while the alcohol is still in your system. There is a "rebound effect" later in the night, after the alcohol has been metabolised, but spending the second half of the night in a lighter phase of sleep is not good either.
Basically, alcohol is uncontroversially terrible for sleep quality.
Alcohol eliminates REM. It’s one of the most potent suppressors.
How do you manage long-term drinking?
For example, I myself am about 65 kg and I can easily chug 5-6 pints of beer and be only slightly sleepy the next day.
But I know for sure that my alcohol habits are not sustainable because the next day my stomach (bowels, etc) is having a hurricane. Not sure what would happen if I did this every day (but I did that when I was 22).
I'd strongly recommend L-Theanine if you'd like to not need as much caffeine or alcohol.
I have a similar routine, but with less caffeine and more Ritalin.
If only I were being facetious.
SSRI as a night cap is a bit misleading. It’s not a sleep aid.
Selective serotonin reuptake inhibitors (SSRIs)
boclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825
TIL "forced swim test", right up there with "rapid unscheduled disassembly".
The methodology here is typical for testing antidepressants with animals but many people find it somewhat horrifying:
First the mice are made to be depressed by exposing them to constant sounds of birds screeching and other predators. Next some are given the intervention. The level of depression is then measured by putting the mice in a container of deep water from which there is no escape, and timing how long until the mouse gives up swimming. The mice are not left to drown but are fished out and killed in a presumably more-humane way (chronically depressed mice are not otherwise useful).
A second ethical issue with studies with mice is that occasionally the unfortunate phd student tasked with dispatching the mice will not have been taught any way to do so and will have to try to come up with something on the spot. This can be quite traumatic for both parties.
I’m sorry but I’m having trouble believing the second part. Every university I’ve worked at has extensive training and monitoring for animal research, and there’s no way any of them would have approved what you’re describing. Screwing around with something like this could get the entire university’s federal funding cut off, and so they take compliance very seriously. Secondly, the brains are often collected as part of the experiment, and these samples would absolutely be destroyed by someone “coming up with something on the spot.”
I was so annoyed about 2nd part that I almost forgot to mention that the first part is untrue too. There’s no mention of predator sounds whatsoever in the paper. The standard forced swim test model just looks at how long the mouse actively tries to escape vs just floating too; there’s no drowning involved.
tl;dr: Lies
I understand the parent is wrong and that correcting them was needed, but I find all this hand-wringing about ethics in animal experiments kind of absurd, since it's so obviously fundamentally unethical in the first place (or at least I know of none that aren't unethical). I suspect it's mostly just a defense mechanism to shield the human mind from the trauma of continuously inflicting mass suffering and death, much like how the Nazis established gas chambers as a less traumatic way of perpetrating genocide compared to firing squad units going village to village and potentially developing symptoms of PTSD.
In both cases, zero or less value is attributed to the lives and minds that are being assaulted and extinguished on a loop (though the value is below zero in the Nazi case and sits roughly at zero in the animal experiment case). This isn't entirely fair, since I'm sure most researchers do attempt to prevent animal suffering from being the most utterly barbaric it can be due to ethical rather than selfish reasons, but I think anything that's moderately barbaric or below is still considered justifiable in their minds and I think attempts to "soften" it do mostly fall into the selfish defense mechanism category.
I understand the great benefit to scientific progress afforded by such experiments, but there was some long-term benefit from human experimentation during WWII, as well, and there probably could've been much more future benefit if those regimes had won.
Nonsense.
I don’t know any researcher that likes sacrificing animals though every single one is painfully aware of the moral weight. They also go out of their way to minimize suffering, for ethical reasons, for selfish reasons, and even to improve the quality of the data. The reason I jumped down the parent's throat is because it reinforces the mistaken idea that scientists are okay with “moderately barbaric” things and indifferent to suffering. We aren’t!
And what’s the alternative to animal research? Computational modeling isn’t there yet and in vitro experiments have pretty stark limitations too. In any case, both would need animal data to determine if they’re correct. Waiting for another Nazi regime[0], as you proposed(!), doesn’t seem like a viable—-or ethical—-option.
[0] Incidentally, I have read that most of that “data” was scientifically useless, not just because of its moral provenance, but also because the stuff that was done was more akin to torture than controlled research.
I'll grant that most of them don't like it, but there's a far too high fraction that uses animals even though they do not need to. This is a constant and ongoing point of contention between animal rights groups and large biologically-focused universities. Generally it comes down to budgeting concerns (ie it is cheaper to use animals) or time concerns (ie it is faster to use animals).
Whether or not one of those two arguments is compelling to you is another story.
Can you give some examples?
My impression is that animal work is literally never the cheap or fast option. It's slow, it's labor-intensive, and it's expensive, while career incentives favor doing things that are quick and cheap.
It's certainly true that someone could have run a version of this study where patients with depression were "prescribed" different doses of caffeine and asked to fill out rating scales to quantify its effects on their symptoms. This experiment could reveal its effect on symptoms, the headline of this article, but it wouldn't suffice for understanding the pharmacological mechanisms (see Table 4). I don't think there are PET ligands available for any of those metabolites, and even if there were (and ignoring the animal work needed to develop them), injecting people with radioactive tracers also raises ethical questions.
> The reason I jumped down the parent's throat is because it reinforces the mistaken idea that scientists are okay with “moderately barbaric” things and indifferent to suffering. We aren’t!
I never said they were okay with it. Merely that they're still participating in it regularly, and need a way to justify it.
> A second ethical issue with studies with mice is that often the unfortunate phd student tasked with dispatching the mice will not have been taught any way to do so and will have to try to come up with something on the spot. This can be quite traumatic for both parties.
uhhhhhh are you sure about that?? This strikes me as a flagrant violation of policy. Animal studies are heavily regulated.
In my experience, (and mind you I've only ever worked adjacent to animal labs, not directly in them) there is always a canister of CO2 and a euthanization chamber on standby in experiments where there is a risk of injuring the mice.
While this is standard, it shouldn't be.
Mammals sense CO2 buildup, not oxygen depletion. By smothering with CO2, the mice spend their last moments desperate to breathe and unable to.
If they were to use nitrogen instead, the mice, having no way to know they've been deprived of oxygen, would just pass out and die.
There's a good chance I have that wrong and they use nitrogen. Like I said, I don't work in animal labs, just adjacent to them.
I knew someone who worked with lab rats; her job was to kill them and she had to use CO2.
afaik (second hand) CO2 is used for safety reasons, humans can sense a CO2 poisoning but not an excess of nitrogen.
As for methods here's the list: https://animal.research.uiowa.edu/iacuc-guidelines-euthanasi...
In my work, our approved methods were isoflurane and decapitation. In some types of experiments CO2 will interfere with your result.
Probably should substitute “often” for “occasionally”. I’ve edited the comment.
I suppose there are other factors too, eg the student not thinking to say they don’t know how to kill a mouse and their advisor not thinking to ask.
Ethical horrors aside, I'm a bit confused by their definition of depression here. I think there's a solid gap between 'constantly exposed to predators and thus feeling like there's no chance you'll survive' and 'feeling like life is just a black void of emptiness'. The latter being a very, very rudimentary description of depression that I've heard from friends.
Is there a scientist in the thread who could clear up why a mouse's will to persevere and live is equated with how depressed it is? Do mice just not perceive circumstance as well?
That description of the experiment isn’t correct. They’re not using predator calls or anything to induce depression.
Instead, the readout is how long the mouse spends scrambling to escape vs. floating immobile in the water, usually after a “training run” that demonstrates to it that it can’t escape. You can draw some vague parallel to “coping with adversity”, but the test’s value is mostly that historically, it has predicted drugs that seem to help human patients with depression: mice receiving anti-depressants tend to spend less time immobile.
Ah, okay, that makes sense, thank you for clearing up my confusion. Basically, they're looking for the most effective substances to boost activity, which is one of the things that anti-depressants are supposed to help with.
It’s more that substances boosting activity also help with depression: nobody really knows the causal direction, or even if there really is one.
That said, one way to botch these assays is to do something that just directly increases locomotion. They did look at that in Table 1 though.
This is so wrong I don't know where to start! All of this kind of work is highly scrutinized, you can check it out by starting your own work on reading up on IACUC.
Here are the accepted methods for "dispatching the mice": https://animal.research.uiowa.edu/iacuc-guidelines-euthanasi...
You can decide whether you think this is satisfying to you, or you can consult the bioethicists that helped develop these protocols.
As to your second part, that shouldn’t happen. Animal welfare is highly regulated and monitored. Every university has strict rules about animal tests and every experiment has to be evaluated by a panel to make sure the animals aren’t mistreated AND that any limited suffering is justified by the value of the data.
If any PhD is making up ways to kill their animals, then they either didn’t pay attention or work for a crappy lab.
Sounds like the effect of an open office
We have so little understanding of basically anything about the brain or mental health issues, it's the next big frontier in medicine.
Studies have shown that caffeine in moderation encourages learning.