I think no. My very vague impression is that this is usually recommended against because of serotonin syndrome, but people are constantly overestimating the risk of serotonin syndrome and I don't know if this can really cause it. I will continue to err on the side of not doing it until I know more.
Scott, I find that I don't tolerate many SSRIs and related antidepressant meds well, getting high nausea, "pasty face (my SO calls it), etc. Is there research on why these meds cause such side effects? I.e., is it intrinsic to their mode of activity or are they binding to unrelated receptors, enzymes, etc.?
It's the increase in serotonin concentration in the synaptic cleft (roughly, serotonin floating around in the brain) that causes these side effects. MAOIs, which cause a similar increase in serotonin in the synaptic cleft (but by a different mechanism), also cause nausea, vomiting, headache, and a bunch of other common SSRI side effects (as confirmed by Medscape). It's worth noting that other side effects are also common with MAOIs because they're generally not as well tolerated, but all these side effects mediated by serotonin are still there. 5-HTP, which by yet another mechanism causes a similar increase in serotonin in the synaptic cleft, has similar side effects as well (as confirmed by some Reddit thread I read a long time ago), as do serotonergic psychedelics such as LSD (as confirmed by Wikipedia), which mimic the action of serotonin. Looked at differently, escitalopram, as was mentioned in the article, is well over 1000-fold selective for the serotonin transporter over any other biological action (perhaps by whatever mechanism by which it causes torsades? That part doesn't make a lot of sense to me), but still causes these side effects - so, as you put it, it's intrinsic to their mode of activity and not from binding to unrelated receptors or enzymes. (This isn't the case for some other SSRIs like paroxetine though - it causes weight gain and sedation at a higher rate, for example, because of its other actions.)
I was just going to comment "here's the post I first saw that profile pic from", and then the pic's creator himself (you) shows up. One of those cool moments.
I'm convinced by Kirsch et al's arguments that antidepressants are – at best – marginally better than placebos. But I might be biased, because I tried a number of different ones, and the only effects I noticed were weight gain and fatigue (OK, that was mostly from Paxil, but the other ones didn't work any better). Aside from lack of effectiveness, another problem with antidepressants is that they may actually worsen the long-term outcomes from your depression. So they're worse than useless. Robert Whitaker wrote a whole book about the long-term, negative effects of antidepressants and other psychotropic drugs ("Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America"). See also his article on antidepressant-induced chronic depression: https://www.psychologytoday.com/us/blog/mad-in-america/201106/now-antidepressant-induced-chronic-depression-has-name-tardive-dysphoria
'The reason that antidepressants may have a “prodepressant effect,” El-Mallakh writes, is that “continued drug treatment may induce processes that are the opposite of what the medication originally produced.”'
If this is Whitaker's hypothesis, it seems in tension with Kirsch's idea that they just don't do very much (to which I am also sympathetic.) If the reason they make you more depressed over the long-term is because they have the opposite long-term effect to the effect they have in the short term, that is at least very suggestive, even if not proof, that their short-term effect is real and positive.
I don't think anyone claims that antidepressants are physiologically inert. They clearly have an effect on your neurochemistry. The question (in my mind) is the size of the short-term effect on your mood – whether the effect is positive but small (as compared to placebo), or whether it's essentially zero.
Right, but unless the physiological brain chemistry changes they cause in the short term positively effect mood, why would the opposite of those changes depress mood? There might be a good answer to this, but it's not what one would expect.
David Nutt, one of the co-authors of the citalopram stereochemistry paper (but much better known for being fired from his career as chair of the British Advisory Council on the Misuse of Drugs after he wrote a paper determining that ecstasy was less dangerous than horse-riding), was discussed on SSC a few years ago as the founder of a start-up called GABA Labs, which hoped to create safe alternatives to alcohol (...though as of 2019 they were apparently working with benzodiazepine derivatives, which, uh, yikes).
Anyway, I'm here to report that as of January 2021, GABA Labs actually has an alcohol replacement product on the market called Sentia: https://www.sentiaspirits.com/
But I think I personally would be a bit scared to try it (at least until I know how it compares with MDMA use or horseback riding), since when I went to the FAQ section of the website to determine what exactly Sentia is, the FAQ unhelpfully non-informed me that "Sentia is made through a unique, proprietary series of production methods that preserve the plants’ functional compounds and nutrients, giving you more of what the plants have to offer." https://www.sentiaspirits.com/faq (2nd question)
Going off first impressions, they need to get a better graphic designer. That barefoot lassie clutching a bottle of Sentia looks more like "I used to get quietly hammered at home on cheap supermarket vodka, but since the government cracked down on alcohol promotions, now I get all my needs to get blitzed filled by this stuff (hic)".
Also, this is pure bollocksology (excuse the crude language):
"But unlike alcohol, Sentia is entirely from plants (not a drop of ethanol in sight)."
Uhhhh - conventional alcohol *is* "entirely [derived] from plants" - beer from cereal grains, wine from grapes, clear spirits from distillation of alcohol from fermented grains, and so on. So already I am feeling very doubtful about this new wonder product which will get you to "a moment when you’re drinking where everything just ‘clicks’". Yeah, right; maybe the target market for this is people who want the Dionysian revelation experience, but most people just want to get bloothered.
Okay, that's somewhat harsh of me. The ultimate aim seems to be for the company/companies behind this to develop something they can sell to the drinks industry as an ingredient for creating new, non-ethanol based drinks, and this is more a proof of concept item:
"GABA Labs’ active botanical ingredient, known as “ABI”, will feature in a drink to be released in January 2021 by Sentia Spirits".
There's an awful lot of foofawraw about the publicity, but at the same time I get that they are trying to keep their trade secrets secret. If they flat-out said "we brew this out of lawn clippings and seaweed", everyone else will be trying to get in on the game.
However, the unfortunate side-effect of that is that this looks like it's targeted to appeal to the women who buy Jo Malone candles. To really hit the mass-market, they need to appeal to men (and women who don't buy Jo Malone).
"Sentia is the first alcohol alternative created with proprietary 'Botanical GABAergic Ingredients' from Prof. David Nutt's Team at GABA Labs and developed into the complex Sentia liquid by Plant Alchemist and Product Designer Vanessa Jacoby, to offer the ultimate choice - NOT HAVING TO CHOOSE AT ALL."
'Plant Alchemist' is terribly "candles and crystals amateur witch" kind of associations.
"What makes Sentia effective?
Sentia is crafted by The Social Drinks Company with propriatory 'Botanical Tech' from its partners at GABA Labs:
These Active Botanical Ingredients (ABI®) are pure plants, used for millenia by Herbalists and Plant Crafters for many varied purposes."
Yeah, well, before I neck a bottle of this stuff, I'd like to know what it's based on or off. We already know that with conventional alcoholic drinks. Now, the blah is all about "GABAergic affects" and once I hack my way through the Wikipedia article on GABA, we get to this:
"GABAergic pro-drugs include chloral hydrate, which is metabolised to trichloroethanol, which then acts via the GABAA receptor.
Skullcap and valerian are plants containing GABAergic substances. Furthermore, the plant kava contains GABAergic compounds, including kavain, dihydrokavain, methysticin, dihydromethysticin and yangonin.
...GABA is also found in plants. It is the most abundant amino acid in the apoplast of tomatoes."
So, given that they talk about "Sentia is crafted by The Social Drinks Company with propriatory 'Botanical Tech' from its partners at GABA Labs:
These Active Botanical Ingredients (ABI®) are pure plants, used for millenia by Herbalists and Plant Crafters for many varied purposes." and "organic herbs", and given what is said above about kava being banned in the UK, and given the general "Laura Ashley" vibe this site gives off, I'm going to guess that amongst the ingredients are indeed valerian, which is recommended for insomnia and anxiety as a herbal remedy, lemon balm (for the flavour at least) and skullcap which by looking it up is also a traditional remedy for anxiety and used as a sedative. So those are three herbs/plants used for mood enhancement and would be good candidates for at least some of the "secret ingredients". Maybe some tomato extracts as well!
My guess would be that it's harmless, and works mainly on the placebo effect (non-alcoholic drinks are well known to work similarly if the imbiber doesn't know).
Yes, but can you explain why the floating drunkards in the second picture are wearing formal shoes with no socks ? What happened to their socks ? Did the non-alcohol dissolve them ? I must know !
Clearly they are selling the socks off their feet in order to purchase more Sentia. Next will be the shirts and dresses off their backs. This is why gin was called "Strip-and-go-naked" when it was the hot new drinks sensation, people would sell even their clothing to buy more of it. (I see by Googling that some idiot - I mean, inspired person, has invented a 'cocktail' by mixing beer and vodka with lemonade, others throw in gin as well).
That has to be the stupidest FAQ I've read in some time. Pulling a raw plant from the ground is a method that preserves all functional compounds and nutrients. They misspell "propiatary" in the next question. How the hell did they manage to register a trademark on "Active Botanical Ingredients"? (Note here from prior discussion why it makes sense to put the punctuation outside of the quote? Because what I am quoting was not itself a question.)
This one is also amusing:
> Some of its ingredients require Sentia to be classified as a Food Supplement and these
> ingredients have a recommended daily intake (RDA).
Surely it is either recommended daily allowance or RDI? Who proofreads this stuff?
I've been looking forward for a decade to Nutt's Alcarelle being available to try. Unfortunately this is not it. From a Vice article linked on the Sentía site:
"About 15 years ago, Professor Nutt [developed] Alcarelle, a non-harmful alternative to alcohol that supposedly gives you the positive effects of booze – feeling chatty, relaxed and sociable – without the negatives, like becoming aggy, forgetful and hungover.
"Nutt says he knows the substance works because he’s tested it on himself. But because it’s a “novel synthetic chemical” it needs to go through rigorous safety testing, which will take two years and cost around £20 million.
"In the meantime, he’s developed a non-alcoholic botanical spirit called Sentia. This side project for Nutt’s company, GABA Labs, is mainly to raise the capital to help bring Alcarelle to market, but also to ease the general public into the idea of alcohol alternatives."
I'm not sure whether not being able to control ones facial expression is a desirable effect. I have a picture of someone desperately trying to stop smiling in my head now.
That their answer is something other than a resounding "no" tells me that this product is not meaningfully analogous to alcohol. Or maybe they're just being incredibly irresponsible.
Oy, this thing (Sentia) has snake oil written all over it. As the other replies here point out, you can tell from the (shoddy) FAQ that it has zero pharmacological/psychoactive effects. Also I like how they try to pretend it's sugar-free and low-calorie by quoting the number of calories per 20mL. It works out to about twice as much sugar as Coke or Pepsi.
As far as psychoactive infusions of traditional Chinese and Indian botanicals whose exact preparation techniques are a jealously guarded secret are concerned, I think I'll stick to drinking tea.
Here's the link to the ingredients label: https://www.sentiaspirits.com/product-page/sentia-50cl . It's literally just some B vitamins, GABA, 5-HTP, and a few herbs. The only even remotely unusual ingredient is Damiana, an herb with anxiolytic properties. All of these ingredients can be gotten by one stroll down the health food store supplement and bulk herbs & teas aisle.
Yes. There is. After a health crisis 2 years ago (that involved multiple surgeries) my GP prescribed that dose for me and I've been taking it ever since.
I got it, which blew my mind, since I’m not a scientist and almost failed chem in high school. But enantiomers are cool! Did you know the reverse of the porcupine’s distinctive musk smells like coconut? Now you do.
Those last studies mentioned had no control group, but I sometimes wonder why they can’t compare themselves to some sort of “standard” control group. Should we at some point just collect data on a very large control group (without having an active intervention), and then let studies for the next five years compare their active treatment arm of their antidepressant medication or whatever to this “standard” control group? It seems like it would make trials cheaper, potentially more ethical, and would avoid these sorts of problems. If you have a control group and a treatment group for every trial, then you need to make sure that both of them aren’t abnormal, which seems harder than having one very big control group that you measure every five years which you match for demographics/whatever, and then let every study for five years compare their work to that
You'd have to make all your study groups conform to the control group in terms of age, race, etc., and they could still end up different from your controls in some illegible way.
> you have to make sure that both of them aren't abnormal
I think it's actually the opposite of that. The "randomized" part of "randomized controlled trial" is specifically to ensure that abnormality in your study population (as a whole) doesn't impact results, by ~evenly distributing it between intervention and control population.
If you accept that basically every study population and context will be "abnormal" in some way, then a general control group will never be an effective control. It's easy to imagine time of year impacting study results on depression. What if this year is particularly rainy, or I'm running my study in a colder city, or a region with more air pollution, or I accidentally recruit my study population from one particular university, or I'm a really friendly doctor and so the patients in my study are just happier, or... or... or...
It's just never going to be possible to exactly match your study population to a general control group. Your idea might be a good one to increase the usefulness of studies that can't have control groups, but it'll never actually be as good as a study that's controlled internally.
Note that I say "never" instead of "it would be very difficult" because even if a sufficiently competent experimenter could actually match their study well enough to the control group, that's then asking for the scientific community to put *a lot* of faith in them, and so even if they did successfully adjust their study to match the generic control group, there's no real way to prove that fact to the community.
This designation is based on the direction the compound rotates polarized light that's shined upon it. If it rotates the light clockwise, it's dextrorotatory, and it's referred to as right-handed. Counterclockwise = levorotatory = left handed. It's important in biochem, not only because biological systems tend to differentiate between the two, but also because certain biomolecules tend to be consistently either left-handed or right-handed. As a result, organic poisons evolved by utilizing biomolecues of the opposite handedness, since some of these can successfully bind to proteins without being metabolized, thereby blocking them. You might find it useful in your own life to pay attention to the L- and D- designations on certain supplements, some of which separate the two stereoisomers, and others of which are sold as a 50/50 mix. For some supplements, one steroisomer works better than the other, which means you'll get more benefits from taking the more expensive version where the better one has been isolated.
If I'm understanding this correctly, then yes, with supplements like L-glutamine or L-theanine, sometimes sketchy brands will sell Glutamine or Theanine without specifying and I think it's been later determined they are not 100% the handedness that's needed for efficacy.
I don't know anything about chemistry and so don't understand if it's extra work for a lab to make or isolate only the L-kind of something.
Sorry about the questions, fellow non-chemist, but how do consumers get this information if they don't write which one it is on the package? For that matter, how could I find out which one is the better one for a given supplement?
In the U.S. anyway, the whole supplement market is not well regulated so anyone going down that road is to a certain extent self-experimenting. You do the things you can to be an informed self-experimenter -- talk to doctors or nutritionists you trust, do research online (I mean like studies, not like health magazine articles), and buy brands that suggest they are somewhat diligent about quality control.
For supplements, I don't think you have to worry about toxicity- if the supplement is sold as a blend of stereoisomers, toxicity has probably been ruled out.
On the subject of getting the more effective stereoisomer... What I remember from my organic chemistry days is that, when synthesizing chiral molecules, you'll often end up with a 50/50 blend of stereoisomers because the chemical reaction you're using doesn't favor one isomer over the other. Separating the stereoisomers takes extra work. So that's probably why you see cheaper supplements with no L- or D- designation. They probably contain both.
I'm not sure where you could find more information on products that don't specify chirality. When I'm looking for a supplement at the grocery store, I just make sure that the label gives the same name as my best source of information on it. That way, I know I'm getting the right thing.
The common prescription asthma medication albuterol (Ventolin) is racemic, but there's also a one-handed version levalbuterol (Xopenex HFA) which I managed to score a prescription for. I've found it to be (as I expected) twice as effective with half the side effects, but Wikipedia says -
A 2013 systematic review of the drug's use as a treatment for acute asthma found that it "was not superior to albuterol regarding efficacy and safety in subjects with acute asthma." The review concluded: "We suggest that levalbuterol should not be used over albuterol for acute asthma."
Then again, my asthma is not acute. Also, as expected, levalbuterol costs more.
First paragraph says the FDA claimed studies don't show any increase in intended effect going above 10 mg, but the studies you cited here all show that. Is the FDA lying or was that statement true at one time and they never updated it when more studies were conducted? Or were they extrapolating from the experience with Celexa without having any studies at all?
The studies I cite here are terrible, and the FDA only accepts good studies. Also, they only accept studies done specifically for them. Also, the studies I cite here are later.
What is wrong with Jakubovski et al Dose-Response Relationship Of Selective Serotonin Reuptake Inhibitors?
1. The curves Scott shown in his post (from figure 2) make no sense.
a) In clinical trials, you usually see the improvement rate, largest at 2-4 weeks, peter out and plateau by 8-10 weeks. To the contrary, in Jakubovski et al improvement continues almost linearly beyond 8-10 weeks
b) In clinical trials, the patients improve less and less with each increasing dose of antidepressant. It basically follows the diminishing return law, where, for example, 100 mg helps a lot of patients, 200 mg helps slightly more people, 300 mg makes no difference in comparison to 200 mg. To the contrary, in Jakubovski et al the step between 100 mg and 200 mg improves depression as much as the step between 200 mg and 300 mg and as much as the following step 300-400 mg.
Jakubovski et al dress their model into a lot of fine words: “Previous research has demonstrated that a logarithmic model provided the best fit for the time course of SSRI response” and “The effects of SSRI were modeled using an autoregressive variance function, and the model with the lowest values on the Akaike Information Criterion was selected (14)”, etc. But, in my view, the matter is simple: if your model does not correspond to real life – discard the model.
2. Scott puts a lot of faith in Jakubovski et al, but this is based on a misapprehension. Scott believes that Jakubovski et al. “tries to figure out which doses of which antidepressants are equivalent to each other, and comes up with the following suggestion … 100 mg of imipramine=120 mg of sertraline=100 mg of fluvoxamine=20 mg of paroxetine or fluoxetine=33.3 mg of citalopram=16.7 mg of escitalopram” That is not so!
Jakubovski et al postulate (in other words, conjure from thin air) these ratios as the condition of their model. They try to disguise this choice as something objective: “Dose of SSRI was converted into imipramine equivalents based on previously defined methodology based on the therapeutic dose range of each medication (10, 15)… For SSRI analysis, the dose equivalents were as follows: 100 mg of imipramine=120 mg of sertraline=100 mg of fluvoxamine=20 mg of paroxetine or fluoxetine=33.3 mg of citalopram=16.7 mg of escitalopram.” But description of the dose equivalence choice is too short and perfunctory to be reproducible, thus revealing it as mostly discretional. By the way, this also renders all the subsequent analyses in Jakubovski et al worthless, because the dose equivalency choice, to a significant degree, determines the outcome of their analyses of imipramine dose equivalence v. efficacy, imipramine dose equivalence v. dropouts, etc.
High-Dose Citalopram and Escitalopram and the Risk of Out-of-Hospital Death
The incidence of sudden unexpected death ranged from 27.2 per 10,000 person-years for sertraline to 58.8 per 10,000 person-years for escitalopram. The incidence of all deaths ranged from 50.3 per 10,000 person-years for sertraline to 84.9 per 10,000 person-years for paroxetine.
Lexapro and Celexa are selective serotonin reuptake inhibitors (SSRIs). Both drugs are used to treat depression. Lexapro is also used for anxiety. In 2018, the drugs’ labels included a black box warning for an increased risk of suicide. Other side effects include birth defects.
Nausea, dry mouth, trouble sleeping, constipation, tiredness, drowsiness, dizziness, and increased sweating may occur. If any of these effects persist or worsen, tell your doctor promptly.
Your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
Rarely, males may have a painful or prolonged erection lasting 4 or more hours. If this occurs, stop using this drug and get medical help right away, or permanent problems could occur.
Great read, Scott. Can you comment on whether the dual action of Lexapro could explain the most difficult side effects related to lower sexual desire and sexual (dys)function? This is the most difficult part of taking a higher dose (30 mg) for me.
Scott is mistaken here: “Sometime around 2011, the FDA freaked out that high doses of citalopram might cause a deadly heart condition called torsade de pointes, and lowered the maximum dose to prevent this… When escitalopram was invented, it inherited its parent chemical's unusually-low maximum dose, and remains at that level today.”
Escitalopram was approved in 2002, which was before 2011 when the FDA freaked out about torsade de pointes. In the original, 2002, label of escitalopram the maximum dose is 20 mg and is based on the lack of improvement at the higher dose, not on torsade de pointes (see the 2002 label here https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-440.pdf_Lexapro_Prntlbl.pdf p.20): “The recommended dose of Lexapro™ is 10 mg once daily. A fixed dose trial of Lexapro™ demonstrated the effectiveness of both 10 mg and 20 mg of Lexapro™, but failed to demonstrate a greater benefit of 20 mg over 10 mg (see Clinical Efficacy Trials under Clinical Pharmacology). If the dose is increased to 20 mg, this should occur after a minimum of one week.”
However, the good news is that based on the data from this review https://sci-hub.se/10.1007/s40263-014-0196-9 40 mg escitalopram would have QTc prolongation slightly higher than 40 mg of citalopram, and thus should be safe: Change in the mean QTc interval from baseline was 8.5 ms with citalopram 20 mg/day, 18.5 ms with citalopram 60 mg/day … 4.5 ms with escitalopram 10 mg/day, and 10.7 ms with escitalopram 30 mg/day.
Scott's response to this in the text of the main post:" [edit: I got the timing messed up, see here]". I think not only the timing, but whole paragraph is messed up. The 20 mg maximum dose of escitalopram has always been based on efficacy, no on QTc prolongation. If it were based on QTc prolongation it would have been 40 mg since 40 mg of escitalopram have about the same QTc prolongation effects as 40 mg (max dose) of citalopram.
To be honest, half of Scott's post is messed up since it is based on misunderstanding of what Jacubovski et al were studying, and Jacubowski et al itself is pretty much trash.
Have antidepressants or any other psychiatric medications been shown to increase sex drive or romantic/social interest? Or is it mainly a mood fix. What about energy levels?
Yes, I've long suspected that my asexuality is at least in part because I was on Zoloft from ages 16-24, and most of the asexuals I've talked to have reported being on anti-depressants. I'm curious if anyone is researching it.
Maybe that's just because a lot of people have been on anti-depressants? I was interested in girls long before 16, and the anti-depressants I took didn't change anything as far as I can remember.
I wanted to mention Wellbutrin as well. Wellbutrin is not an SSRI, but an NDRI -- it works on norepinephrine and dopamine instead of serotonin. Like Lexapro, it got a bad rap in early studies that's gone on to limit how it's used. There was early concern that it was associated with an increased risk of seizure. I gather later studies largely corrected this or at least determined that the increased risk was overstated.
I don't understand why Wellbutrin isn't prescribed first-off as often as the SSRIs because it has fewer side effects and for some people is associated with weight loss, increased libido, and increased motivation/energy when so many people report the opposite with SSRIs on all three accounts.
I gather too that it doesn't produce the severity of discontinuation syndrome that the SSRIs do.
My understanding is that the main limitation of Wellbutrin is that for people who also have anxiety, it can be too activating. But it seems like by titrating up gradually, it would be possible to catch early on the folks it's likely to wind up too much and others seem like would be grateful to not have to deal with the very common sexual side effects, weight gain, and sleepiness.
I'd love to hear from psychiatrists why it's not prescribed more often.
From what I gather, energy levels can go either way but usually up (low energy being itself a symptom of depression). Bupropion is a stimulant and some claim fluoxetine to be on the more activating side, too.
This is only tangentially related to the article, but I assume as a psychiatrist you have experience with fluvoxamine. What's your take on the studies showing fluvoxamine prevents cytokine storms in COVID-19 patients drastically reducing the risk of death or hospitalization? My read is the FDA and CDC have been predictably stupid in not authorizing and recommending it's use, but I'd be interested in your thoughts on the safety efficacy tradeoff
A double-blind controlled study found that fluvoxamine may prevent clinical deterioration in outpatients with symptomatic COVID-19. The study had important limitations: it was run fully remotely; it had a small sample size (150) and short follow-up duration (15 days).[26] The accompanying editorial noted that, although this study is important enough to choose out of more than 10,000 other COVID-19 related submissions, it "presents only preliminary information [and] the findings should be interpreted as only hypothesis generating; they should not be used as the basis for current treatment decisions."[27] Similarly, the study authors themselves cautioned that "the trial's results should not be treated as a measure of fluvoxamine's effectiveness against COVID-19 but as an encouraging indicator that the drug warrants further testing."[28] A prospective open-labelled cohort study showed similar results.[29]
I was prescribed escitalopram at 20mg for several years. I did score better on the phq-9 compared to untreated, but was still unable to participate normally in life. After five years, it just stopped working - I crashed like a truck going off a cliff. With the help of a new psychiatrist, I switched to sertraline at a much higher dose (titrated, with serum checks) and finally got to moderate functionality. The persistent caution about higher doses of escitalopram, even in patients with stubborn depression, has caused years of my life to be lost in the weeds. This is combined with the fact that most MHPs I've met have been reluctant to change medications, and seem to choose Lex as their first choice. Given the imposed ceiling on dosage, I'm at a loss as to why it's so popular.
My understanding is that most of what determines how these drugs will be metabolized is the genetics of your liver enzymes, not your weight. But I don't know how weight may mediate the function of your liver enzymes.
This is not my expertise by a long shot, but this article for instance -- https://www.sciencedirect.com/science/article/pii/S0022354920306195 -- suggests that at least in some cases, more weight may mean less effective liver metabolism. That one was studying obesity though.
"I will add my own anecdotal evidence here, which is that I had a patient who spent a year pretty depressed, got very modestly better on Lexapro 20 mg, and agreed to let me experiment with higher doses of Lexapro on him. He got better still at 30 mg, and even better when we increased to 40 mg. I am relatively confident these were real effects."
How can you distinguish that from "remission needed a long time, and you kept raising their Lexapro dose while they waited"?
In my experience, research has this annoying feature where you have some observation of an effect, and it's pretty clear. But then you do an experiment and the data still shows an effect. And then you do the stats and it looks marginal.
And then you do a fuck-ton of experiments and more stats and it still looks pretty shit. And your paper eventually gets published but looks worse than those of people who do much less.
I'm reasonably convinced that it's the inherent nature of a supposedly 'fair test' experiment to
give poor-looking effect levels on results which are individually convincing.
I can't perfectly distinguish, but, for example (can't remember exact numbers), suppose the patient was on Lexapro 20 mg for a year with no improvement, then after increasing to 40 improved within a week. If you assume every week has an equal chance of coincidental remission, there's only a 1/52 chance that the coincidental remission would choose that week, and so you should increase your prior of high-dose Lexapro working by 52x.
You've treated one patient in this way, and got an apparently real effect. They probably did that too, first, but can only allude to it. "There is evidence [...] that clinicians are using escitalopram at doses considerably higher than the recommended maximum[...]"
But as soon as you're doing a proper trial, you get various confounding factors. The stats get diluted down by noise, and whatever generic test you've defined doesn't capture the entirety of the situation.
I think your calculation above is risky, even for a back-of-the-envelope. You don't factor in other experiments which didn't help.
So why didn't they have a control group? I wouldn't be so harsh on them for not having one. They probably wern't allowed to have one for ethical reasons or something. Remember the research you failed to get done because of bureaucracy?
At least two other factors may participate in the phenomenon analyzed here: 1) GI absorption differences and 2) changes in intestinal microbial ecosystem.
1) Different SSRIs have different gastrointestinal absorption. In this paper, “Clinical Pharmacokinetics of Selective Serotonin Reuptake Inhibitors” (https://tinyurl.com/w6zc5mep), Table III shows GI absorption differences between, for example, Fluoxetine, Paroxetine and Citalopram of 80%, >= 64% and ~100%, respectively. The primary datasets analyzed and referenced above use the by-mouth dose instead of plasma levels of the different SSRIs. OTOH, the graph above labeled “(a) Drug (SERT occupancy)” uses a dosing method of micro dialysis. This means a microprobe was inserted into the interstitial area of a rodent brain to administer and/or measure directly the SSRI available to the main targeted site of the serotonin transporter. There are serotonin receptors in the epithelia of the GI tract where by-mouth dosing of SSRIs also interact. The micro dialysis method validates the targeted SSRI effect but doesn’t measure the GI tract serotonin receptor effects.
2) There is increasing evidence that the gut microbiome influences/participates in/?causes? psychiatric effects both “good’” and “bad”. Different antidepressants have demonstrated different antimicrobial effects. See “Unravelling the antimicrobial action of antidepressants on gut commensal microbes” (https://tinyurl.com/yfu3zeeh). Those antidepressants with less GI absorption travel throughout the length of the GI tract influencing the microbial ecosystem and its outputs along the way. The outputs of the microbial ecosystem include neurotransmitters, SCFA and many other small molecules that get absorbed and influence the host health. These phenomenon may cause sufficient GI distress that the patient stops taking the SSRI. The effect on the microbiome is still present even if there is no overt GI distress.
"I hope the three of you who understand stereochemistry appreciate that title as much as it deserves." I understand stereochemistry and I fucking loved that title.
I'd be surprised if the original title of this post wasn't something to the effect of "Oh, the places you'll go, when you're dosing Lexapro". I wonder why it got the more dry title
1/4 of the "minimal dose" of Sertraline worked for me.
I was given the tablets with the lowest dose available and told to split them to ramp up to the minimal therapeutic dose with was 1 tablet. Being the very careful person that I am, I didn't see why I shouldn't ramp up even more gently than that and split the tablet into fourths. I stayed at that dose, because it worked. My psychiatrist mocked me, calling it homeopathy. But I had the antidepressant effect with side effects and everything. Anyways, that "therapeutic relationship" didn't last for some reason.
Basically the same occurred years later with Mirtazapine. I feel lucky, because Mirtazapine is a very effective antidepressant and I managed to dodge the side effects. Considering that during the first week I almost fell asleep at work (on 1/4 of the "minimal dose") I understand why it gets lousy patient reviews. I definitively feel low dose Mirtazapine should be prescribed more.
Also, pet peeve: the lowest therapeutic dose of psychiatric medication is way lower than conventionally believed. Because psychiatric diseases are often several things lumped together you will always have responders and non responders (or less responsive responders). So you need to give a high enough dose that the effect on the responders gives you a statistical signal even though the other half (or something) is not responding. But in clinical practice you try an SSRI and if that doesn't work, Wellbutrin, so you are matching people with "their" antidepressant.
Have you ever been checked for variations in enzyme activity that might explain it? (Although, Wikipedia suggests that the relevant enzymes are different for sertraline vs mirtazapine. But Wikipedia isn't a super authoritative source; and I don't know if mutations in different ones might correlate or something.)
No. But I understand that both of these vaguely hit the same system, so it doesn't really seem that mysterious to me.
There could also be a difference in attitude/expectations: I don't need to be bludgeoned over the head with an effect to think the drug is working. I know that a relatively subtle effect in terms of better mood or less anxiety can guide you towards the influence of the "not depressed" attractor. I would call that "my antidepressant is working". Many patients might not have this level of self awareness. This would cause a correlation between antidepressants regardless of the exact molecular mechanism.
I do think some mutations affect multiple groups of CYPs liver enzymes and so people can be poor metabolizers of multiple classes of drugs.
I share idiosyncratic patient's frustration that dosages are not more flexible downwards and that most psychiatrists are not willing to start with very low doses and move more slowly. I get that everyone is responding to averages, but there's a significant minority of folks who are outliers and never get the benefit that may be had because the initial starting dose is bigger and with more side effects than they need or will tolerate.
I also find it puzzling that more psychiatrists don't seem willing to find the lowest effective dose and then when needed, enhance it with things that don't have big side effects. Fish oil and Deplin (L-methylfolate) have pretty good evidence as augmenters of SSRIs. Why wouldn't you push fish oil or Deplin as far as you can before resorting to a dosage increase of the thing that has all the side effects?
Hi. This is strange because low doses of mirtazapine are more sedating due to prevalent antihistamine action and higher doses more stimulating due to added norepinephrine increase. What do you think about that?
In my case I respond tremendously well to 10mg of fluoxetine with no side effects, but if I take 20mg I get constant headaches. It has a much longer half-life than all the others which probably makes it safer in terms of accidentally missing or accidentally doubling doses and easier to get off of. If the other SSRIs are roughly equivalent in terms of efficacy, has the world benefitted at all from other SSRIs existing? Is it just a bunch of rent-seeking pharma companies making me-too drugs that are no better than prozac except for having a patent?
this lancet systematic review and meta-analysis says fluoxetine was better tolerated but slightly less effective than some newer SSRIs, but I strongly suspect most of the underlying studies were funded by pharma companies trying to sell newer drugs, so I'm still less than 75% convinced that there's any difference in efficacy. Also most studies tend to be very short term, and fluoxetine would need an extra two weeks to reach maximum concentration because of the long half-life. If a pharma company wanted to design a trial to favor their newer, shorter half-life drug, all they'd have to do is make it short.
"But the details here are really confusing and seem to mostly involve differences in the placebo group that don't make sense."
I wonder if this could be explained by a difference in the mechanics of a fixed-dose placebo vs. a variable dose placebo. A fixed-dose placebo is simple, but a variable-dose placebo involves potentially repeated conversations with the care provider that result in changing the "dose" of the placebo. It seems at least possible that this interaction could result in an increased chance of a placebo being suspected, which could result in a decreased placebo effect, which could result in an increased difference between treatment and placebo groups. Although if this story is correct, I think that would mean that variable-dose is no more effective than fixed-dose.
* * *
"I hope the three of you who understand stereochemistry appreciate that title as much as it deserves."
While I appreciate the flattery, I'm betting a lot more than three of us got the joke.
Forgive me for being confused, but if the FDA says that 20mg is the maximum safe dose of Lexapro, how are Scott and others able to prescribe higher doses?
Why do most studies use intention-to-treat despite the problems Scott details above?
It's to avoid issues with selection bias. If you only count patients that actually take the drug instead of people who quit after day 1, you bias the results because there might be some fundamental underlying difference between quitters and non-quitters. For instance, people who successfully follow instructions tend to have better health results across the board, so if you only measure outcomes for those who don't quit, it will tend to make your treatment look more effective than it actually is.
Using ITT makes it harder to detect a real result, but in exchange when we do have a result we are more confident that there's actually a causal relationship.
Come. The obvious explanation is the stereochemistry. With racemic citalopram, for example, half the drug you're getting gives you all the side effects (and burden on drug clearance pathways) with no benefit at all. For a real hair-raising illustration of how *important* stereochemistry is to biochemistry, just compare the effects of R- and S-thalidomide.
I started with 20mg Lexapro and found that it cured much of my Autism: my social reflexes moved so fast I could actually keep up with a conversation involving more than 2 people! I could turn into a total motormouth at times, thinking of interesting things to say faster than I could say them. I had the sort of verbal intelligence and wit that I otherwise have only had while being very angry.
This effects went away, so I increased the dose to 20mg. The pattern repeated. I didn't increase the dose beyond that, I just kept taking this pointless pill for a few years because quitting made me irritable. I eventually quit cold turkey, which turned out to be a lot easier than I expected.
I often feel like a character on a sitcom where the you can have wacky plotlines for one episode - In this episode, my life doesn't suck! - but everything has to go back to normal in time for the end credits. I get just a glimpse into the world of normal people.
I have also discovered that increasing the dose of lexapro up to 30 will often work in patients for whom 20mg has stopped working. I have never tried going higher than that, but maybe I will now that I see it's reasonably well tolerated. However, I have also noticed in my practice that lexapro causes more sexual dysfunction than other SSRIs, which could be related to it's slightly different mechanism of action. Lexapro has been my go-to starting SSRI for depression/anxiety because it seems to have pretty high pt satisfaction, and I will often just switch pts if they experience sexual side effects. However between the sexual side effects and the withdrawal I do wonder if I should just be starting most people on zoloft or prozac and switching if they don't work. *shrug*
Second that. It seems that sexual side effects of escitalopram (specifically, anorgasmia) are much higher than of the equivalent dose of sertraline. But then sertraline has disadvantages in some - headaches, overstimulation.
I think TSC is right about the timing and approval of Lexapro dosing; it had nothing to do with Citalopram FDA debacle which came much later. Scott, I think you can add support to you argument (in addition to the collective clinical experience and some questionable effectiveness studies you cited) from the receptor binding site literature:
In short, the paper seems to support the notion that increasing to a high dose of an SSRI is a valid strategy in patients who haven't responded to a lower dose; that is, in some patients, high-dose SSRIs are better than low-dose SSRIs.
The title of the paper is "Double-Blind Study of High-Dose Fluoxetine Versus Lithium or Desipramine Augmentation of Fluoxetine in Partial Responders and Nonresponders to Fluoxetine", which pretty much says it all. In a sample comprising an equal mix of nonresponders and partial responders to fluoxetine 20mg/day, patients were randomized to high-dose fluoxetine (increasing to 40-60mg/day), or adding lithium or desipramine (two common strategies for patients who haven't responded to an SSRI). There were no significant differences in response rates between the three groups, though there was a nonsignificant trend toward fluoxetine being superior.
I do notice that their dose of desipramine was, in my (unqualified) opinion, too low, and their lithium blood levels were definitely on the low end. This is a limitation of this study, but probably not enough to entirely impeach the result.
I was prescribed anti depressants - after a week I felt awful so I quit taking them. When my brain de-fogged, I changed jobs, left my husband and joined a sports club. Sometimes drugs are not the answer.
Hi Scott, thanks for this. Furukawa is really interesting!
Just to be clear, there are zero randomised trials comparing head-to-head different doses of Escitalopram? If that's right, then I think Furukawa is the best evidence we have.
Notable that in Figure 1 of the appendix, Citalopram plateaus at ~30mg not ~20mg. This fact, plus the idea that the only _downside_ of a higher dose seems to be the higher risk of side effects, would imply that at least trying Escitalopram 30mg or 40mg is a great idea.
I wish Furukawa gave us scatterplots in addition to the splines, the absence of scatterplots feels a tad suspicious (am I misundertanding something? I only skimmed). I might try to make the scatter plots based on the table in the appendix myself.
Another thing that would be really cool is a Bayesian hierarchical model of SSRIs dose-response schedules, to generalise this idea of learning from one SSRI and, if approrpriate, transfering to another. I'm pretty sure this specific idea hasn't been done. [Added a few minuted later] Holy Shit it _has_ been done, first page of Google: "A Bayesian dose–response meta-analysis model: A simulations study and application" (Hamza, Cipriani, Furukawa, Egger, Orsini, and Salanti, 2021) [1]. My reading of Figure 3 is they don't extend the x-axis beyond 30mg fluoxtetine-equivalents for Escitalopram, which makes this pointless for answering our question? 🙄
Thank you very much for this article, it's very interesting. I've been on 20mg Lexapro for a long time, along with Welbutrin to counter some of the side effects. I have had a manic episode before so I'm definitely cautious about using too high a dosage. I've tried 40mg for just a few days and don't recall notice anything much, but it may not have been long enough to tell.
How long was your patient on 30mg and subsequently 40mg before they noticed differences?
Ignorant related question: Have there been any laboratory studies of supplementing SSRIs with serotonin precursors, such as 5-HTP?
I think no. My very vague impression is that this is usually recommended against because of serotonin syndrome, but people are constantly overestimating the risk of serotonin syndrome and I don't know if this can really cause it. I will continue to err on the side of not doing it until I know more.
Scott, I find that I don't tolerate many SSRIs and related antidepressant meds well, getting high nausea, "pasty face (my SO calls it), etc. Is there research on why these meds cause such side effects? I.e., is it intrinsic to their mode of activity or are they binding to unrelated receptors, enzymes, etc.?
It's the increase in serotonin concentration in the synaptic cleft (roughly, serotonin floating around in the brain) that causes these side effects. MAOIs, which cause a similar increase in serotonin in the synaptic cleft (but by a different mechanism), also cause nausea, vomiting, headache, and a bunch of other common SSRI side effects (as confirmed by Medscape). It's worth noting that other side effects are also common with MAOIs because they're generally not as well tolerated, but all these side effects mediated by serotonin are still there. 5-HTP, which by yet another mechanism causes a similar increase in serotonin in the synaptic cleft, has similar side effects as well (as confirmed by some Reddit thread I read a long time ago), as do serotonergic psychedelics such as LSD (as confirmed by Wikipedia), which mimic the action of serotonin. Looked at differently, escitalopram, as was mentioned in the article, is well over 1000-fold selective for the serotonin transporter over any other biological action (perhaps by whatever mechanism by which it causes torsades? That part doesn't make a lot of sense to me), but still causes these side effects - so, as you put it, it's intrinsic to their mode of activity and not from binding to unrelated receptors or enzymes. (This isn't the case for some other SSRIs like paroxetine though - it causes weight gain and sedation at a higher rate, for example, because of its other actions.)
Thanks, that makes sense!
IANAC but I love a good chirality joke!
IAAC and do appreciate it.
IAACE and even I can appreciate it
It was indeed a good joke
I do too, but on the other hand...
As a chemist I appreciate it and will pass it around to my cronys...
You are not achiral?
Anyone know our best, easy to interpret evidence that SSRIs are not just placebo?
Our host has a rather extended essay on the topic at his old site here
https://slatestarcodex.com/2014/07/07/ssris-much-more-than-you-wanted-to-know/
Cool profile picture ;)
I was just going to comment "here's the post I first saw that profile pic from", and then the pic's creator himself (you) shows up. One of those cool moments.
I'm convinced by Kirsch et al's arguments that antidepressants are – at best – marginally better than placebos. But I might be biased, because I tried a number of different ones, and the only effects I noticed were weight gain and fatigue (OK, that was mostly from Paxil, but the other ones didn't work any better). Aside from lack of effectiveness, another problem with antidepressants is that they may actually worsen the long-term outcomes from your depression. So they're worse than useless. Robert Whitaker wrote a whole book about the long-term, negative effects of antidepressants and other psychotropic drugs ("Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America"). See also his article on antidepressant-induced chronic depression: https://www.psychologytoday.com/us/blog/mad-in-america/201106/now-antidepressant-induced-chronic-depression-has-name-tardive-dysphoria
'The reason that antidepressants may have a “prodepressant effect,” El-Mallakh writes, is that “continued drug treatment may induce processes that are the opposite of what the medication originally produced.”'
If this is Whitaker's hypothesis, it seems in tension with Kirsch's idea that they just don't do very much (to which I am also sympathetic.) If the reason they make you more depressed over the long-term is because they have the opposite long-term effect to the effect they have in the short term, that is at least very suggestive, even if not proof, that their short-term effect is real and positive.
I don't think anyone claims that antidepressants are physiologically inert. They clearly have an effect on your neurochemistry. The question (in my mind) is the size of the short-term effect on your mood – whether the effect is positive but small (as compared to placebo), or whether it's essentially zero.
Right, but unless the physiological brain chemistry changes they cause in the short term positively effect mood, why would the opposite of those changes depress mood? There might be a good answer to this, but it's not what one would expect.
I would be interested in a similar explanation but for ADHD medication (ie how long until it stops working, and how to maximize that time)
David Nutt, one of the co-authors of the citalopram stereochemistry paper (but much better known for being fired from his career as chair of the British Advisory Council on the Misuse of Drugs after he wrote a paper determining that ecstasy was less dangerous than horse-riding), was discussed on SSC a few years ago as the founder of a start-up called GABA Labs, which hoped to create safe alternatives to alcohol (...though as of 2019 they were apparently working with benzodiazepine derivatives, which, uh, yikes).
Anyway, I'm here to report that as of January 2021, GABA Labs actually has an alcohol replacement product on the market called Sentia: https://www.sentiaspirits.com/
But I think I personally would be a bit scared to try it (at least until I know how it compares with MDMA use or horseback riding), since when I went to the FAQ section of the website to determine what exactly Sentia is, the FAQ unhelpfully non-informed me that "Sentia is made through a unique, proprietary series of production methods that preserve the plants’ functional compounds and nutrients, giving you more of what the plants have to offer." https://www.sentiaspirits.com/faq (2nd question)
Wow.
That is not a confidence-inspiring FAQ, for sure. I wonder if it’s got kava in it.
Kava is banned in the UK I believe.
I didn't know that! Thanks!
Going off first impressions, they need to get a better graphic designer. That barefoot lassie clutching a bottle of Sentia looks more like "I used to get quietly hammered at home on cheap supermarket vodka, but since the government cracked down on alcohol promotions, now I get all my needs to get blitzed filled by this stuff (hic)".
Also, this is pure bollocksology (excuse the crude language):
"But unlike alcohol, Sentia is entirely from plants (not a drop of ethanol in sight)."
Uhhhh - conventional alcohol *is* "entirely [derived] from plants" - beer from cereal grains, wine from grapes, clear spirits from distillation of alcohol from fermented grains, and so on. So already I am feeling very doubtful about this new wonder product which will get you to "a moment when you’re drinking where everything just ‘clicks’". Yeah, right; maybe the target market for this is people who want the Dionysian revelation experience, but most people just want to get bloothered.
Okay, that's somewhat harsh of me. The ultimate aim seems to be for the company/companies behind this to develop something they can sell to the drinks industry as an ingredient for creating new, non-ethanol based drinks, and this is more a proof of concept item:
"GABA Labs’ active botanical ingredient, known as “ABI”, will feature in a drink to be released in January 2021 by Sentia Spirits".
There's an awful lot of foofawraw about the publicity, but at the same time I get that they are trying to keep their trade secrets secret. If they flat-out said "we brew this out of lawn clippings and seaweed", everyone else will be trying to get in on the game.
However, the unfortunate side-effect of that is that this looks like it's targeted to appeal to the women who buy Jo Malone candles. To really hit the mass-market, they need to appeal to men (and women who don't buy Jo Malone).
"Sentia is the first alcohol alternative created with proprietary 'Botanical GABAergic Ingredients' from Prof. David Nutt's Team at GABA Labs and developed into the complex Sentia liquid by Plant Alchemist and Product Designer Vanessa Jacoby, to offer the ultimate choice - NOT HAVING TO CHOOSE AT ALL."
'Plant Alchemist' is terribly "candles and crystals amateur witch" kind of associations.
"What makes Sentia effective?
Sentia is crafted by The Social Drinks Company with propriatory 'Botanical Tech' from its partners at GABA Labs:
These Active Botanical Ingredients (ABI®) are pure plants, used for millenia by Herbalists and Plant Crafters for many varied purposes."
Yeah, well, before I neck a bottle of this stuff, I'd like to know what it's based on or off. We already know that with conventional alcoholic drinks. Now, the blah is all about "GABAergic affects" and once I hack my way through the Wikipedia article on GABA, we get to this:
"GABAergic pro-drugs include chloral hydrate, which is metabolised to trichloroethanol, which then acts via the GABAA receptor.
Skullcap and valerian are plants containing GABAergic substances. Furthermore, the plant kava contains GABAergic compounds, including kavain, dihydrokavain, methysticin, dihydromethysticin and yangonin.
...GABA transaminase inhibitors: gabaculine, phenelzine, valproate, vigabatrin, lemon balm (Melissa officinalis).
...GABA is also found in plants. It is the most abundant amino acid in the apoplast of tomatoes."
So, given that they talk about "Sentia is crafted by The Social Drinks Company with propriatory 'Botanical Tech' from its partners at GABA Labs:
These Active Botanical Ingredients (ABI®) are pure plants, used for millenia by Herbalists and Plant Crafters for many varied purposes." and "organic herbs", and given what is said above about kava being banned in the UK, and given the general "Laura Ashley" vibe this site gives off, I'm going to guess that amongst the ingredients are indeed valerian, which is recommended for insomnia and anxiety as a herbal remedy, lemon balm (for the flavour at least) and skullcap which by looking it up is also a traditional remedy for anxiety and used as a sedative. So those are three herbs/plants used for mood enhancement and would be good candidates for at least some of the "secret ingredients". Maybe some tomato extracts as well!
My guess would be that it's harmless, and works mainly on the placebo effect (non-alcoholic drinks are well known to work similarly if the imbiber doesn't know).
Yes, but can you explain why the floating drunkards in the second picture are wearing formal shoes with no socks ? What happened to their socks ? Did the non-alcohol dissolve them ? I must know !
It's laundry day.
Clearly they are selling the socks off their feet in order to purchase more Sentia. Next will be the shirts and dresses off their backs. This is why gin was called "Strip-and-go-naked" when it was the hot new drinks sensation, people would sell even their clothing to buy more of it. (I see by Googling that some idiot - I mean, inspired person, has invented a 'cocktail' by mixing beer and vodka with lemonade, others throw in gin as well).
With a name like GABA Labs, is it any surprise they are working with benzodiazepine derivatives?
That has to be the stupidest FAQ I've read in some time. Pulling a raw plant from the ground is a method that preserves all functional compounds and nutrients. They misspell "propiatary" in the next question. How the hell did they manage to register a trademark on "Active Botanical Ingredients"? (Note here from prior discussion why it makes sense to put the punctuation outside of the quote? Because what I am quoting was not itself a question.)
This one is also amusing:
> Some of its ingredients require Sentia to be classified as a Food Supplement and these
> ingredients have a recommended daily intake (RDA).
Surely it is either recommended daily allowance or RDI? Who proofreads this stuff?
I too came to the conclusion that quoted text should contain the original punctuation (and no other)!
I've been looking forward for a decade to Nutt's Alcarelle being available to try. Unfortunately this is not it. From a Vice article linked on the Sentía site:
"About 15 years ago, Professor Nutt [developed] Alcarelle, a non-harmful alternative to alcohol that supposedly gives you the positive effects of booze – feeling chatty, relaxed and sociable – without the negatives, like becoming aggy, forgetful and hungover.
"Nutt says he knows the substance works because he’s tested it on himself. But because it’s a “novel synthetic chemical” it needs to go through rigorous safety testing, which will take two years and cost around £20 million.
"In the meantime, he’s developed a non-alcoholic botanical spirit called Sentia. This side project for Nutt’s company, GABA Labs, is mainly to raise the capital to help bring Alcarelle to market, but also to ease the general public into the idea of alcohol alternatives."
Oh well that explains a lot! He's making vitamin-herbal water to raise capital.
Ahh I'll wait for that then. Thanks for clarifying that.
The customer testimonials on this site are quite something.
“I can’t stop smiling…”
— Jill, Advertising Executive
“Wow, just wow… this is incredible.”
— Giovanna, Holistic Practitioner
I'm not sure whether not being able to control ones facial expression is a desirable effect. I have a picture of someone desperately trying to stop smiling in my head now.
"Is it safe to drive after consuming Sentia?"
That their answer is something other than a resounding "no" tells me that this product is not meaningfully analogous to alcohol. Or maybe they're just being incredibly irresponsible.
They should have called in synthehol.
Oy, this thing (Sentia) has snake oil written all over it. As the other replies here point out, you can tell from the (shoddy) FAQ that it has zero pharmacological/psychoactive effects. Also I like how they try to pretend it's sugar-free and low-calorie by quoting the number of calories per 20mL. It works out to about twice as much sugar as Coke or Pepsi.
As far as psychoactive infusions of traditional Chinese and Indian botanicals whose exact preparation techniques are a jealously guarded secret are concerned, I think I'll stick to drinking tea.
Strether, is that you?
Here's the link to the ingredients label: https://www.sentiaspirits.com/product-page/sentia-50cl . It's literally just some B vitamins, GABA, 5-HTP, and a few herbs. The only even remotely unusual ingredient is Damiana, an herb with anxiolytic properties. All of these ingredients can be gotten by one stroll down the health food store supplement and bulk herbs & teas aisle.
The rest is a huge amount of fluffy words and pseudo-science marketing-speak.
I've been on 40mg of Lexapro for the past two years. I think it has been the optimal dose for me.
Any story behind how that happened?
Yes. There is. After a health crisis 2 years ago (that involved multiple surgeries) my GP prescribed that dose for me and I've been taking it ever since.
I think you underrate your readership to think only 3 of us got the chirality joke. Maybe even more than 3% of us did!
I did!
I got it, which blew my mind, since I’m not a scientist and almost failed chem in high school. But enantiomers are cool! Did you know the reverse of the porcupine’s distinctive musk smells like coconut? Now you do.
And I make more than 3. Though I required Scott's nudge to notice the stereochemistry entendre.
Those last studies mentioned had no control group, but I sometimes wonder why they can’t compare themselves to some sort of “standard” control group. Should we at some point just collect data on a very large control group (without having an active intervention), and then let studies for the next five years compare their active treatment arm of their antidepressant medication or whatever to this “standard” control group? It seems like it would make trials cheaper, potentially more ethical, and would avoid these sorts of problems. If you have a control group and a treatment group for every trial, then you need to make sure that both of them aren’t abnormal, which seems harder than having one very big control group that you measure every five years which you match for demographics/whatever, and then let every study for five years compare their work to that
You'd have to make all your study groups conform to the control group in terms of age, race, etc., and they could still end up different from your controls in some illegible way.
> you have to make sure that both of them aren't abnormal
I think it's actually the opposite of that. The "randomized" part of "randomized controlled trial" is specifically to ensure that abnormality in your study population (as a whole) doesn't impact results, by ~evenly distributing it between intervention and control population.
If you accept that basically every study population and context will be "abnormal" in some way, then a general control group will never be an effective control. It's easy to imagine time of year impacting study results on depression. What if this year is particularly rainy, or I'm running my study in a colder city, or a region with more air pollution, or I accidentally recruit my study population from one particular university, or I'm a really friendly doctor and so the patients in my study are just happier, or... or... or...
It's just never going to be possible to exactly match your study population to a general control group. Your idea might be a good one to increase the usefulness of studies that can't have control groups, but it'll never actually be as good as a study that's controlled internally.
Note that I say "never" instead of "it would be very difficult" because even if a sufficiently competent experimenter could actually match their study well enough to the control group, that's then asking for the scientific community to put *a lot* of faith in them, and so even if they did successfully adjust their study to match the generic control group, there's no real way to prove that fact to the community.
Okay, maybe one day it will be useful for me to know that two mirrored stereoisomers are called "left-handed" and "right-handed" by scientists.
This designation is based on the direction the compound rotates polarized light that's shined upon it. If it rotates the light clockwise, it's dextrorotatory, and it's referred to as right-handed. Counterclockwise = levorotatory = left handed. It's important in biochem, not only because biological systems tend to differentiate between the two, but also because certain biomolecules tend to be consistently either left-handed or right-handed. As a result, organic poisons evolved by utilizing biomolecues of the opposite handedness, since some of these can successfully bind to proteins without being metabolized, thereby blocking them. You might find it useful in your own life to pay attention to the L- and D- designations on certain supplements, some of which separate the two stereoisomers, and others of which are sold as a 50/50 mix. For some supplements, one steroisomer works better than the other, which means you'll get more benefits from taking the more expensive version where the better one has been isolated.
That is actually does seem useful, thanks. There aren't any bad supplements which accidentally have isolated the wrong stereoisomer, I hope?
If I'm understanding this correctly, then yes, with supplements like L-glutamine or L-theanine, sometimes sketchy brands will sell Glutamine or Theanine without specifying and I think it's been later determined they are not 100% the handedness that's needed for efficacy.
I don't know anything about chemistry and so don't understand if it's extra work for a lab to make or isolate only the L-kind of something.
Sorry about the questions, fellow non-chemist, but how do consumers get this information if they don't write which one it is on the package? For that matter, how could I find out which one is the better one for a given supplement?
In the U.S. anyway, the whole supplement market is not well regulated so anyone going down that road is to a certain extent self-experimenting. You do the things you can to be an informed self-experimenter -- talk to doctors or nutritionists you trust, do research online (I mean like studies, not like health magazine articles), and buy brands that suggest they are somewhat diligent about quality control.
For supplements, I don't think you have to worry about toxicity- if the supplement is sold as a blend of stereoisomers, toxicity has probably been ruled out.
On the subject of getting the more effective stereoisomer... What I remember from my organic chemistry days is that, when synthesizing chiral molecules, you'll often end up with a 50/50 blend of stereoisomers because the chemical reaction you're using doesn't favor one isomer over the other. Separating the stereoisomers takes extra work. So that's probably why you see cheaper supplements with no L- or D- designation. They probably contain both.
I'm not sure where you could find more information on products that don't specify chirality. When I'm looking for a supplement at the grocery store, I just make sure that the label gives the same name as my best source of information on it. That way, I know I'm getting the right thing.
And you're welcome. It's been a while since I studied biochem, but some of it still comes in handy.
oops- I answered this a step below your question. Look under Radar's next comment.
The common prescription asthma medication albuterol (Ventolin) is racemic, but there's also a one-handed version levalbuterol (Xopenex HFA) which I managed to score a prescription for. I've found it to be (as I expected) twice as effective with half the side effects, but Wikipedia says -
A 2013 systematic review of the drug's use as a treatment for acute asthma found that it "was not superior to albuterol regarding efficacy and safety in subjects with acute asthma." The review concluded: "We suggest that levalbuterol should not be used over albuterol for acute asthma."
Then again, my asthma is not acute. Also, as expected, levalbuterol costs more.
First paragraph says the FDA claimed studies don't show any increase in intended effect going above 10 mg, but the studies you cited here all show that. Is the FDA lying or was that statement true at one time and they never updated it when more studies were conducted? Or were they extrapolating from the experience with Celexa without having any studies at all?
The studies I cite here are terrible, and the FDA only accepts good studies. Also, they only accept studies done specifically for them. Also, the studies I cite here are later.
What is wrong with Jakubovski et al Dose-Response Relationship Of Selective Serotonin Reuptake Inhibitors?
1. The curves Scott shown in his post (from figure 2) make no sense.
a) In clinical trials, you usually see the improvement rate, largest at 2-4 weeks, peter out and plateau by 8-10 weeks. To the contrary, in Jakubovski et al improvement continues almost linearly beyond 8-10 weeks
b) In clinical trials, the patients improve less and less with each increasing dose of antidepressant. It basically follows the diminishing return law, where, for example, 100 mg helps a lot of patients, 200 mg helps slightly more people, 300 mg makes no difference in comparison to 200 mg. To the contrary, in Jakubovski et al the step between 100 mg and 200 mg improves depression as much as the step between 200 mg and 300 mg and as much as the following step 300-400 mg.
Jakubovski et al dress their model into a lot of fine words: “Previous research has demonstrated that a logarithmic model provided the best fit for the time course of SSRI response” and “The effects of SSRI were modeled using an autoregressive variance function, and the model with the lowest values on the Akaike Information Criterion was selected (14)”, etc. But, in my view, the matter is simple: if your model does not correspond to real life – discard the model.
2. Scott puts a lot of faith in Jakubovski et al, but this is based on a misapprehension. Scott believes that Jakubovski et al. “tries to figure out which doses of which antidepressants are equivalent to each other, and comes up with the following suggestion … 100 mg of imipramine=120 mg of sertraline=100 mg of fluvoxamine=20 mg of paroxetine or fluoxetine=33.3 mg of citalopram=16.7 mg of escitalopram” That is not so!
Jakubovski et al postulate (in other words, conjure from thin air) these ratios as the condition of their model. They try to disguise this choice as something objective: “Dose of SSRI was converted into imipramine equivalents based on previously defined methodology based on the therapeutic dose range of each medication (10, 15)… For SSRI analysis, the dose equivalents were as follows: 100 mg of imipramine=120 mg of sertraline=100 mg of fluvoxamine=20 mg of paroxetine or fluoxetine=33.3 mg of citalopram=16.7 mg of escitalopram.” But description of the dose equivalence choice is too short and perfunctory to be reproducible, thus revealing it as mostly discretional. By the way, this also renders all the subsequent analyses in Jakubovski et al worthless, because the dose equivalency choice, to a significant degree, determines the outcome of their analyses of imipramine dose equivalence v. efficacy, imipramine dose equivalence v. dropouts, etc.
Oh man, looks like a total misreading of Jakubovski from Scott. Scott do you want to comment?
High-Dose Citalopram and Escitalopram and the Risk of Out-of-Hospital Death
The incidence of sudden unexpected death ranged from 27.2 per 10,000 person-years for sertraline to 58.8 per 10,000 person-years for escitalopram. The incidence of all deaths ranged from 50.3 per 10,000 person-years for sertraline to 84.9 per 10,000 person-years for paroxetine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916769/
Lexapro and Celexa are selective serotonin reuptake inhibitors (SSRIs). Both drugs are used to treat depression. Lexapro is also used for anxiety. In 2018, the drugs’ labels included a black box warning for an increased risk of suicide. Other side effects include birth defects.
https://www.drugwatch.com/ssri/lexapro-celexa/
https://www.webmd.com/drugs/2/drug-63990/lexapro-oral/details
Nausea, dry mouth, trouble sleeping, constipation, tiredness, drowsiness, dizziness, and increased sweating may occur. If any of these effects persist or worsen, tell your doctor promptly.
Your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
Rarely, males may have a painful or prolonged erection lasting 4 or more hours. If this occurs, stop using this drug and get medical help right away, or permanent problems could occur.
Great read, Scott. Can you comment on whether the dual action of Lexapro could explain the most difficult side effects related to lower sexual desire and sexual (dys)function? This is the most difficult part of taking a higher dose (30 mg) for me.
Scott is mistaken here: “Sometime around 2011, the FDA freaked out that high doses of citalopram might cause a deadly heart condition called torsade de pointes, and lowered the maximum dose to prevent this… When escitalopram was invented, it inherited its parent chemical's unusually-low maximum dose, and remains at that level today.”
Escitalopram was approved in 2002, which was before 2011 when the FDA freaked out about torsade de pointes. In the original, 2002, label of escitalopram the maximum dose is 20 mg and is based on the lack of improvement at the higher dose, not on torsade de pointes (see the 2002 label here https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-440.pdf_Lexapro_Prntlbl.pdf p.20): “The recommended dose of Lexapro™ is 10 mg once daily. A fixed dose trial of Lexapro™ demonstrated the effectiveness of both 10 mg and 20 mg of Lexapro™, but failed to demonstrate a greater benefit of 20 mg over 10 mg (see Clinical Efficacy Trials under Clinical Pharmacology). If the dose is increased to 20 mg, this should occur after a minimum of one week.”
However, the good news is that based on the data from this review https://sci-hub.se/10.1007/s40263-014-0196-9 40 mg escitalopram would have QTc prolongation slightly higher than 40 mg of citalopram, and thus should be safe: Change in the mean QTc interval from baseline was 8.5 ms with citalopram 20 mg/day, 18.5 ms with citalopram 60 mg/day … 4.5 ms with escitalopram 10 mg/day, and 10.7 ms with escitalopram 30 mg/day.
Scott's response to this in the text of the main post:" [edit: I got the timing messed up, see here]". I think not only the timing, but whole paragraph is messed up. The 20 mg maximum dose of escitalopram has always been based on efficacy, no on QTc prolongation. If it were based on QTc prolongation it would have been 40 mg since 40 mg of escitalopram have about the same QTc prolongation effects as 40 mg (max dose) of citalopram.
To be honest, half of Scott's post is messed up since it is based on misunderstanding of what Jacubovski et al were studying, and Jacubowski et al itself is pretty much trash.
Have antidepressants or any other psychiatric medications been shown to increase sex drive or romantic/social interest? Or is it mainly a mood fix. What about energy levels?
Welbutrin can increase sex drive as one of its side effects, but most of the SSRIs are known to destroy libido.
Possibly permanently in some cases. Reports of this are only anecdotal as far as I can tell though.
Yes, I've long suspected that my asexuality is at least in part because I was on Zoloft from ages 16-24, and most of the asexuals I've talked to have reported being on anti-depressants. I'm curious if anyone is researching it.
Maybe that's just because a lot of people have been on anti-depressants? I was interested in girls long before 16, and the anti-depressants I took didn't change anything as far as I can remember.
I wanted to mention Wellbutrin as well. Wellbutrin is not an SSRI, but an NDRI -- it works on norepinephrine and dopamine instead of serotonin. Like Lexapro, it got a bad rap in early studies that's gone on to limit how it's used. There was early concern that it was associated with an increased risk of seizure. I gather later studies largely corrected this or at least determined that the increased risk was overstated.
I don't understand why Wellbutrin isn't prescribed first-off as often as the SSRIs because it has fewer side effects and for some people is associated with weight loss, increased libido, and increased motivation/energy when so many people report the opposite with SSRIs on all three accounts.
I gather too that it doesn't produce the severity of discontinuation syndrome that the SSRIs do.
My understanding is that the main limitation of Wellbutrin is that for people who also have anxiety, it can be too activating. But it seems like by titrating up gradually, it would be possible to catch early on the folks it's likely to wind up too much and others seem like would be grateful to not have to deal with the very common sexual side effects, weight gain, and sleepiness.
I'd love to hear from psychiatrists why it's not prescribed more often.
Same reason some doctors still recommend a low fat, whole-grain diet.
Bupropion (Wellbutrin) increases libido only in women. At greater doses >= 300 mg it also affects erection like all norepinephrine reuptake inhbitors.
From what I gather, energy levels can go either way but usually up (low energy being itself a symptom of depression). Bupropion is a stimulant and some claim fluoxetine to be on the more activating side, too.
Sex drive C MN handled already.
Testosterone and other androgens reliably increase sex drive, sometimes to a disturbingly strong degree.
Hi Scott,
This is only tangentially related to the article, but I assume as a psychiatrist you have experience with fluvoxamine. What's your take on the studies showing fluvoxamine prevents cytokine storms in COVID-19 patients drastically reducing the risk of death or hospitalization? My read is the FDA and CDC have been predictably stupid in not authorizing and recommending it's use, but I'd be interested in your thoughts on the safety efficacy tradeoff
I know about fluvoxamine for OCD and depression but I don't have any special insight on it for COVID.
https://jamanetwork.com/journals/jama/fullarticle/2773108
A double-blind controlled study found that fluvoxamine may prevent clinical deterioration in outpatients with symptomatic COVID-19. The study had important limitations: it was run fully remotely; it had a small sample size (150) and short follow-up duration (15 days).[26] The accompanying editorial noted that, although this study is important enough to choose out of more than 10,000 other COVID-19 related submissions, it "presents only preliminary information [and] the findings should be interpreted as only hypothesis generating; they should not be used as the basis for current treatment decisions."[27] Similarly, the study authors themselves cautioned that "the trial's results should not be treated as a measure of fluvoxamine's effectiveness against COVID-19 but as an encouraging indicator that the drug warrants further testing."[28] A prospective open-labelled cohort study showed similar results.[29]
I saw a really interesting "60 Minutes" episode (see below) about fluvoxamine / Luvox® as a possible treatment for Covid. It surprises me that this drug has received much less hype than hydroxychloroquin. https://www.cbsnews.com/news/fluvoxamine-antidepressant-drug-covid-treatment-60-minutes-2021-03-07/
I was prescribed escitalopram at 20mg for several years. I did score better on the phq-9 compared to untreated, but was still unable to participate normally in life. After five years, it just stopped working - I crashed like a truck going off a cliff. With the help of a new psychiatrist, I switched to sertraline at a much higher dose (titrated, with serum checks) and finally got to moderate functionality. The persistent caution about higher doses of escitalopram, even in patients with stubborn depression, has caused years of my life to be lost in the weeds. This is combined with the fact that most MHPs I've met have been reluctant to change medications, and seem to choose Lex as their first choice. Given the imposed ceiling on dosage, I'm at a loss as to why it's so popular.
Does body weight affect dosage? If I'm twice as big, do I need twice as much?
For some medications yes, but apparently not for Lexapro.
Note that this likely just means it hasn't really been studied. It's not like we have compelling evidence that body weight doesn't matter.
Hasn't it? We check serum levels of the drug to determine whether body size is a factor is dosage.
My understanding is that most of what determines how these drugs will be metabolized is the genetics of your liver enzymes, not your weight. But I don't know how weight may mediate the function of your liver enzymes.
Wouldn't big people have bigger livers? I don't think getting fat would make your liver bigger, but some people are just big aside from that.
This is not my expertise by a long shot, but this article for instance -- https://www.sciencedirect.com/science/article/pii/S0022354920306195 -- suggests that at least in some cases, more weight may mean less effective liver metabolism. That one was studying obesity though.
This article maybe explains better: https://www.nytimes.com/2018/06/08/well/drug-dose-weight-size-doctors-prescriptions-medications.html .
"I will add my own anecdotal evidence here, which is that I had a patient who spent a year pretty depressed, got very modestly better on Lexapro 20 mg, and agreed to let me experiment with higher doses of Lexapro on him. He got better still at 30 mg, and even better when we increased to 40 mg. I am relatively confident these were real effects."
How can you distinguish that from "remission needed a long time, and you kept raising their Lexapro dose while they waited"?
In my experience, research has this annoying feature where you have some observation of an effect, and it's pretty clear. But then you do an experiment and the data still shows an effect. And then you do the stats and it looks marginal.
And then you do a fuck-ton of experiments and more stats and it still looks pretty shit. And your paper eventually gets published but looks worse than those of people who do much less.
I'm reasonably convinced that it's the inherent nature of a supposedly 'fair test' experiment to
give poor-looking effect levels on results which are individually convincing.
I can't perfectly distinguish, but, for example (can't remember exact numbers), suppose the patient was on Lexapro 20 mg for a year with no improvement, then after increasing to 40 improved within a week. If you assume every week has an equal chance of coincidental remission, there's only a 1/52 chance that the coincidental remission would choose that week, and so you should increase your prior of high-dose Lexapro working by 52x.
I'm not sure you entirely got my point above.
You've treated one patient in this way, and got an apparently real effect. They probably did that too, first, but can only allude to it. "There is evidence [...] that clinicians are using escitalopram at doses considerably higher than the recommended maximum[...]"
But as soon as you're doing a proper trial, you get various confounding factors. The stats get diluted down by noise, and whatever generic test you've defined doesn't capture the entirety of the situation.
I think your calculation above is risky, even for a back-of-the-envelope. You don't factor in other experiments which didn't help.
So why didn't they have a control group? I wouldn't be so harsh on them for not having one. They probably wern't allowed to have one for ethical reasons or something. Remember the research you failed to get done because of bureaucracy?
At least two other factors may participate in the phenomenon analyzed here: 1) GI absorption differences and 2) changes in intestinal microbial ecosystem.
1) Different SSRIs have different gastrointestinal absorption. In this paper, “Clinical Pharmacokinetics of Selective Serotonin Reuptake Inhibitors” (https://tinyurl.com/w6zc5mep), Table III shows GI absorption differences between, for example, Fluoxetine, Paroxetine and Citalopram of 80%, >= 64% and ~100%, respectively. The primary datasets analyzed and referenced above use the by-mouth dose instead of plasma levels of the different SSRIs. OTOH, the graph above labeled “(a) Drug (SERT occupancy)” uses a dosing method of micro dialysis. This means a microprobe was inserted into the interstitial area of a rodent brain to administer and/or measure directly the SSRI available to the main targeted site of the serotonin transporter. There are serotonin receptors in the epithelia of the GI tract where by-mouth dosing of SSRIs also interact. The micro dialysis method validates the targeted SSRI effect but doesn’t measure the GI tract serotonin receptor effects.
2) There is increasing evidence that the gut microbiome influences/participates in/?causes? psychiatric effects both “good’” and “bad”. Different antidepressants have demonstrated different antimicrobial effects. See “Unravelling the antimicrobial action of antidepressants on gut commensal microbes” (https://tinyurl.com/yfu3zeeh). Those antidepressants with less GI absorption travel throughout the length of the GI tract influencing the microbial ecosystem and its outputs along the way. The outputs of the microbial ecosystem include neurotransmitters, SCFA and many other small molecules that get absorbed and influence the host health. These phenomenon may cause sufficient GI distress that the patient stops taking the SSRI. The effect on the microbiome is still present even if there is no overt GI distress.
How do you decide whether a post like this will be posted here or on the pysch blog (Lorien?)?
Lorien is for patients, so the stuff there is what Scott's pretty sure of. This blog is for stuff he's still figuring out.
"I hope the three of you who understand stereochemistry appreciate that title as much as it deserves." I understand stereochemistry and I fucking loved that title.
I'd be surprised if the original title of this post wasn't something to the effect of "Oh, the places you'll go, when you're dosing Lexapro". I wonder why it got the more dry title
You may mean Lexapro(TM)... a comment and a possible reason.
1/4 of the "minimal dose" of Sertraline worked for me.
I was given the tablets with the lowest dose available and told to split them to ramp up to the minimal therapeutic dose with was 1 tablet. Being the very careful person that I am, I didn't see why I shouldn't ramp up even more gently than that and split the tablet into fourths. I stayed at that dose, because it worked. My psychiatrist mocked me, calling it homeopathy. But I had the antidepressant effect with side effects and everything. Anyways, that "therapeutic relationship" didn't last for some reason.
Basically the same occurred years later with Mirtazapine. I feel lucky, because Mirtazapine is a very effective antidepressant and I managed to dodge the side effects. Considering that during the first week I almost fell asleep at work (on 1/4 of the "minimal dose") I understand why it gets lousy patient reviews. I definitively feel low dose Mirtazapine should be prescribed more.
Also, pet peeve: the lowest therapeutic dose of psychiatric medication is way lower than conventionally believed. Because psychiatric diseases are often several things lumped together you will always have responders and non responders (or less responsive responders). So you need to give a high enough dose that the effect on the responders gives you a statistical signal even though the other half (or something) is not responding. But in clinical practice you try an SSRI and if that doesn't work, Wellbutrin, so you are matching people with "their" antidepressant.
Have you ever been checked for variations in enzyme activity that might explain it? (Although, Wikipedia suggests that the relevant enzymes are different for sertraline vs mirtazapine. But Wikipedia isn't a super authoritative source; and I don't know if mutations in different ones might correlate or something.)
No. But I understand that both of these vaguely hit the same system, so it doesn't really seem that mysterious to me.
There could also be a difference in attitude/expectations: I don't need to be bludgeoned over the head with an effect to think the drug is working. I know that a relatively subtle effect in terms of better mood or less anxiety can guide you towards the influence of the "not depressed" attractor. I would call that "my antidepressant is working". Many patients might not have this level of self awareness. This would cause a correlation between antidepressants regardless of the exact molecular mechanism.
I do think some mutations affect multiple groups of CYPs liver enzymes and so people can be poor metabolizers of multiple classes of drugs.
I share idiosyncratic patient's frustration that dosages are not more flexible downwards and that most psychiatrists are not willing to start with very low doses and move more slowly. I get that everyone is responding to averages, but there's a significant minority of folks who are outliers and never get the benefit that may be had because the initial starting dose is bigger and with more side effects than they need or will tolerate.
I also find it puzzling that more psychiatrists don't seem willing to find the lowest effective dose and then when needed, enhance it with things that don't have big side effects. Fish oil and Deplin (L-methylfolate) have pretty good evidence as augmenters of SSRIs. Why wouldn't you push fish oil or Deplin as far as you can before resorting to a dosage increase of the thing that has all the side effects?
Hi. This is strange because low doses of mirtazapine are more sedating due to prevalent antihistamine action and higher doses more stimulating due to added norepinephrine increase. What do you think about that?
In my case I respond tremendously well to 10mg of fluoxetine with no side effects, but if I take 20mg I get constant headaches. It has a much longer half-life than all the others which probably makes it safer in terms of accidentally missing or accidentally doubling doses and easier to get off of. If the other SSRIs are roughly equivalent in terms of efficacy, has the world benefitted at all from other SSRIs existing? Is it just a bunch of rent-seeking pharma companies making me-too drugs that are no better than prozac except for having a patent?
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32802-7/fulltext
this lancet systematic review and meta-analysis says fluoxetine was better tolerated but slightly less effective than some newer SSRIs, but I strongly suspect most of the underlying studies were funded by pharma companies trying to sell newer drugs, so I'm still less than 75% convinced that there's any difference in efficacy. Also most studies tend to be very short term, and fluoxetine would need an extra two weeks to reach maximum concentration because of the long half-life. If a pharma company wanted to design a trial to favor their newer, shorter half-life drug, all they'd have to do is make it short.
"But the details here are really confusing and seem to mostly involve differences in the placebo group that don't make sense."
I wonder if this could be explained by a difference in the mechanics of a fixed-dose placebo vs. a variable dose placebo. A fixed-dose placebo is simple, but a variable-dose placebo involves potentially repeated conversations with the care provider that result in changing the "dose" of the placebo. It seems at least possible that this interaction could result in an increased chance of a placebo being suspected, which could result in a decreased placebo effect, which could result in an increased difference between treatment and placebo groups. Although if this story is correct, I think that would mean that variable-dose is no more effective than fixed-dose.
* * *
"I hope the three of you who understand stereochemistry appreciate that title as much as it deserves."
While I appreciate the flattery, I'm betting a lot more than three of us got the joke.
Forgive me for being confused, but if the FDA says that 20mg is the maximum safe dose of Lexapro, how are Scott and others able to prescribe higher doses?
Why do most studies use intention-to-treat despite the problems Scott details above?
It's to avoid issues with selection bias. If you only count patients that actually take the drug instead of people who quit after day 1, you bias the results because there might be some fundamental underlying difference between quitters and non-quitters. For instance, people who successfully follow instructions tend to have better health results across the board, so if you only measure outcomes for those who don't quit, it will tend to make your treatment look more effective than it actually is.
Using ITT makes it harder to detect a real result, but in exchange when we do have a result we are more confident that there's actually a causal relationship.
That's such a beautiful title for a paper...
Come. The obvious explanation is the stereochemistry. With racemic citalopram, for example, half the drug you're getting gives you all the side effects (and burden on drug clearance pathways) with no benefit at all. For a real hair-raising illustration of how *important* stereochemistry is to biochemistry, just compare the effects of R- and S-thalidomide.
I started with 20mg Lexapro and found that it cured much of my Autism: my social reflexes moved so fast I could actually keep up with a conversation involving more than 2 people! I could turn into a total motormouth at times, thinking of interesting things to say faster than I could say them. I had the sort of verbal intelligence and wit that I otherwise have only had while being very angry.
This effects went away, so I increased the dose to 20mg. The pattern repeated. I didn't increase the dose beyond that, I just kept taking this pointless pill for a few years because quitting made me irritable. I eventually quit cold turkey, which turned out to be a lot easier than I expected.
I often feel like a character on a sitcom where the you can have wacky plotlines for one episode - In this episode, my life doesn't suck! - but everything has to go back to normal in time for the end credits. I get just a glimpse into the world of normal people.
I have also discovered that increasing the dose of lexapro up to 30 will often work in patients for whom 20mg has stopped working. I have never tried going higher than that, but maybe I will now that I see it's reasonably well tolerated. However, I have also noticed in my practice that lexapro causes more sexual dysfunction than other SSRIs, which could be related to it's slightly different mechanism of action. Lexapro has been my go-to starting SSRI for depression/anxiety because it seems to have pretty high pt satisfaction, and I will often just switch pts if they experience sexual side effects. However between the sexual side effects and the withdrawal I do wonder if I should just be starting most people on zoloft or prozac and switching if they don't work. *shrug*
Second that. It seems that sexual side effects of escitalopram (specifically, anorgasmia) are much higher than of the equivalent dose of sertraline. But then sertraline has disadvantages in some - headaches, overstimulation.
I think TSC is right about the timing and approval of Lexapro dosing; it had nothing to do with Citalopram FDA debacle which came much later. Scott, I think you can add support to you argument (in addition to the collective clinical experience and some questionable effectiveness studies you cited) from the receptor binding site literature:
https://pubmed.ncbi.nlm.nih.gov/17497139/
https://academic.oup.com/ijnp/article/10/6/777/804783
https://www.sciencedirect.com/science/article/pii/S0925492715301335?casa_token=Zp9WEOeEQc0AAAAA:sCIUMuc2CZpeqsAvRSVsnXMcuM3RDn3x-j5XWAYbjv1z0duZOxFKy1tgihPhRyoJAG-62JUbjQ5w
Intro to use of PET for drug development if needed:
https://onlinelibrary.wiley.com/doi/full/10.1002/npr2.12084
This post made me think of this paper, by Fava et al (paywalled, but can be found elsewhere for free): https://journals.lww.com/psychopharmacology/Abstract/2002/08000/Double_Blind_Study_of_High_Dose_Fluoxetine_Versus.8.aspx
In short, the paper seems to support the notion that increasing to a high dose of an SSRI is a valid strategy in patients who haven't responded to a lower dose; that is, in some patients, high-dose SSRIs are better than low-dose SSRIs.
The title of the paper is "Double-Blind Study of High-Dose Fluoxetine Versus Lithium or Desipramine Augmentation of Fluoxetine in Partial Responders and Nonresponders to Fluoxetine", which pretty much says it all. In a sample comprising an equal mix of nonresponders and partial responders to fluoxetine 20mg/day, patients were randomized to high-dose fluoxetine (increasing to 40-60mg/day), or adding lithium or desipramine (two common strategies for patients who haven't responded to an SSRI). There were no significant differences in response rates between the three groups, though there was a nonsignificant trend toward fluoxetine being superior.
I do notice that their dose of desipramine was, in my (unqualified) opinion, too low, and their lithium blood levels were definitely on the low end. This is a limitation of this study, but probably not enough to entirely impeach the result.
I was prescribed anti depressants - after a week I felt awful so I quit taking them. When my brain de-fogged, I changed jobs, left my husband and joined a sports club. Sometimes drugs are not the answer.
Hi Scott, thanks for this. Furukawa is really interesting!
Just to be clear, there are zero randomised trials comparing head-to-head different doses of Escitalopram? If that's right, then I think Furukawa is the best evidence we have.
Notable that in Figure 1 of the appendix, Citalopram plateaus at ~30mg not ~20mg. This fact, plus the idea that the only _downside_ of a higher dose seems to be the higher risk of side effects, would imply that at least trying Escitalopram 30mg or 40mg is a great idea.
I wish Furukawa gave us scatterplots in addition to the splines, the absence of scatterplots feels a tad suspicious (am I misundertanding something? I only skimmed). I might try to make the scatter plots based on the table in the appendix myself.
Another thing that would be really cool is a Bayesian hierarchical model of SSRIs dose-response schedules, to generalise this idea of learning from one SSRI and, if approrpriate, transfering to another. I'm pretty sure this specific idea hasn't been done. [Added a few minuted later] Holy Shit it _has_ been done, first page of Google: "A Bayesian dose–response meta-analysis model: A simulations study and application" (Hamza, Cipriani, Furukawa, Egger, Orsini, and Salanti, 2021) [1]. My reading of Figure 3 is they don't extend the x-axis beyond 30mg fluoxtetine-equivalents for Escitalopram, which makes this pointless for answering our question? 🙄
[1] https://journals.sagepub.com/doi/10.1177/0962280220982643
Thank you very much for this article, it's very interesting. I've been on 20mg Lexapro for a long time, along with Welbutrin to counter some of the side effects. I have had a manic episode before so I'm definitely cautious about using too high a dosage. I've tried 40mg for just a few days and don't recall notice anything much, but it may not have been long enough to tell.
How long was your patient on 30mg and subsequently 40mg before they noticed differences?