HNNewShowAskJobs
Built with Tanstack Start
Prozac 'no better than placebo' for treating children with depression, experts(theguardian.com)
93 points by pseudolus 20 hours ago | 79 comments
  • shswkna19 hours ago

    From the article:

    > They can also increase suicidal ideation.

    A very close family member committed suicide, after Prozac dosage adjustments made his brain chemistry go haywire.

    This happened 30 years ago, and it has been known to us that Prozac can cause this, since then.

    The Guardians headline is way, way understating the real situation here.

    • carsoon19 hours ago |parent

      The problem with suicidal depression is that if someone has created the thought pattern that death is best, then removing the symptoms of depression (lethargy, lack of energy, no willpower) now gives the person the ability to actually follow through with the act.

      Medications almost always target symptoms and never address root causes.

      • fragrom19 hours ago |parent

        This is what my psychiatrist more or less warned me about when I went on medication; that a lot of people who are suicidal lack the energy and ability to plan their suicide, and medications can sometimes undo those particular symptoms and people manage to end themselves.

        I'm not sure what kinds of studies have been done about it, but I've had a few therapists same similar ideas. If it's not a studied phenomenon, then it has folks that believe it exists.

        • autumnstwilight18 hours ago |parent

          I'd like to make the point that even if this does occur, it doesn't mean, "therefore this medication shouldn't be used/is worse than doing nothing," just that awareness and caution is needed.

          I went through a frankly terrible few months on my current meds because they removed the emotional numbness before removing the bad feelings. However, once that was over they effectively gave me my life back after 10+ years of continual exhaustion and brain fog.

        • doubled11218 hours ago |parent

          Sometimes willpower improves before mood.

        • DANmode15 hours ago |parent

          Almost like depression is an acute toxicity caused by physiological variance (or infection related) detox inefficiency!

          • DANmode15 hours ago |parent

            This gets even more interesting when you realize many SSRIs are antibacterials.

      • pixelready19 hours ago |parent

        Finding everyone’s cow is expensive and time consuming: https://antidepressantcow.org/2020/02/the-story-of-the-antid...

        But is the only true cure to the suffering. We’d have to undergo a massive reorganization of society (and upset a few hefty profit margins) to prioritize that, so we settle for the messy symptom management we have.

        • cornstalks18 hours ago |parent

          That story doesn’t work for people with depression who otherwise have very good lives.

          I grew up in a stable household with a loving family and both parents present and supportive. I’ve never had financial hardship, either as a kid depending on my parents to provide or as an adult providing for myself and family. I did very well in school, had plenty of friends, never had enemies, never got bullied or even talked bad about in social circles (so far as I know…). I have no traumatic memories.

          I could go on and on, but despite having a virtually perfect life on paper, I have always struggled with depression and suicidal ideation. It wasn’t until my wife sat down and forced me to talk to a psychiatrist and start medication that those problems actually largely went away.

          In other words, I don’t think there’s a metaphorical “cow” that could have helped me. It’s annoying we don’t understand what causes depression or how antidepressants help, and their side effects suck. But for some of us, it’s literally life saving in a way nothing else has ever been.

          • pronouncedjerry5 hours ago |parent

            very interesting. would you be comfortable sharing what therapy uncovered as the cause for you?

          • coffeecat15 hours ago |parent

            Take my baseless speculation for what it's worth, but could it be that you were depressed because your life was too easy? We humans are meant to struggle through adversity. Can you really appreciate your financial security if you've never faced financial insecurity, or appreciate companionship if you've never experienced loneliness?

            • cornstalks13 hours ago |parent

              It’s a reasonable question but I doubt it. We weren’t affluent at all and I worked my butt off for everything. And that’s good, because I agree that if things are too easy it turns into a curse.

          • jrflowers16 hours ago |parent

            > I don’t think there’s a metaphorical “cow” that could have helped me.

            The medication is the cow for you. In this story your support system figured out what would work best for you, which was medication, and facilitated that.

            It’s a story about a doctor that serves patients in rural Cambodia. Help from the local community would look different in Borey Peng Huoth, for example.

          • hirvi7417 hours ago |parent

            First of all, I want to write that I am glad you found something that worked so that you are able to remain here with us.

            Though, I am curious about the, "otherwise have very good lives" part.

            Whose definition are you using? It seems the criteria you laid out fits a "very good life" in a sociological sense -- very important, sure. You could very well have the same definition, and perhaps that is what I am trying to ask. Would you say you were satisfied in life? Despite having a good upbringing, were you (prior to medication) content or happy?

            I am by no means trying to change your opinion nor invalidate your experiences. I just struggle to understand how that can be true.

            As someone that has suffered with deep depressive bouts many times over, I just cannot subscribe to the idea that depression is inherently some sort of disorder of the brain. In fact, I am in the midst of another bout now. One that's lasted about 3 or so years.

            To me, I have always considered emotions/states like depression and anxiety to be signals. A warning that something in one's current environment is wrong -- even if consciously not known or difficult to observe. And if anyone is curious, I have analyzed this for myself, and I believe the etiology of my issues are directly linked to my circumstances/environment.

            > I don’t think there’s a metaphorical “cow” that could have helped me.

            The smart-ass in me can't help but suggest that maybe medication was your cow?

            • cornstalks17 hours ago |parent

              > Whose definition are you using?

              To be honest, I've never really thought about it... I suppose I mean in both a sociological and self fulfillment way.

              > Would you say you were satisfied in life? Despite having a good upbringing, were you (prior to medication) content or happy?

              I would say "yes" overall. Aside from the depression (typically manifesting as a week or two of me emotionally spiraling down to deep dark places every month or so), I was very happy and satisfied. That's what makes the depression so annoying for me. It makes no sense compared to my other aspects of life.

              > In fact, I am in the midst of another bout now. One that's lasted about 3 or so years.

              *fist bump*

              > To me, I have always considered emotions/states like depression and anxiety to be signals. A warning that something in one's current environment is wrong -- even if consciously not known or difficult to observe. And if anyone is curious, I have analyzed this for myself, and I believe the etiology of my issues are directly linked to my circumstances/environment.

              I think that's a great hypothesis so long as it's not a blanket applied to everyone (which I don't think you're doing, to be clear; I mention this only because it is what motivated my original response to the other commenter).

              I don't want to go into private details of family members without their permission, but I will say that given the pervasive depression in my family and mental health issues like schizophrenia and bipolar disorders (neither of which I have, thank goodness), I feel like there's something biologically... wrong (for lack of a better word?)... with us, particularly since you can easily trace this through my mother's side.

              > The smart-ass in me can't help but suggest that maybe medication was your cow?

              Ha fair. I interpreted the story to be about depression being a symptom of your situation (job, health, etc.) and if you just fixed that then there's no need for medication. That definitely makes sense in some (many? most?) situations. But not all, unfortunately.

      • squishington9 hours ago |parent

        My understanding is that the optimal scenario is taking an SSRI in combination with therapy. The SSRI adds flexibility for the brain to respond to therapy and envisage new possibilities. If you don't include therapy, you've just established a new baseline to habituate to.

      • shswkna19 hours ago |parent

        Yes, this is what happens.

        • kittensmittens519 hours ago |parent

          No it's not.

      • kayodelycaon19 hours ago |parent

        Yup. Depression medication can significantly help the emotional symptoms, but that takes longer to be effective.

        I’m bipolar and a lot of the medication I take does not become fully effective for months. For me, my medication slowly became more effective over years as my brain no longer had to compensate for hardware problems.

    • EasyMark15 hours ago |parent

      Isn't that a possibility with a lot of drugs though? I think it depends on the rate and not a "does or does not" type of questions. Now if the drug doesn't help more than a placebo that's clearly a huge negative, but if it has a high rate of success vs placebo then they will make adjustments and watch out for the side-effect (of course) letting patients know it's a possibility and to report if it starts happening.

    • ekianjo19 hours ago |parent

      Suicidal ideation is a risk for many CNS drugs, and not unique to Prozac as far as I know. But yes this is a major risk factor that needs to be taken in account before such kind of treatments.

  • lemming18 hours ago

    Our 11 year old daughter was seriously depressed recently. N=1, but fluoxetine was life changing (and potentially life saving) for her, at least.

    • thebigspacefuck17 hours ago |parent

      Placebo can be life changing

      • biff117 hours ago |parent

        Nocebo can too. Apropos the featured article, I wonder if we should worry about that when we report in the popular media that antidepressants trigger suicides.

    • tcj_phx17 hours ago |parent

      Do you have a plan to get her off, or is she on the maintenance drug for life?

      Sometimes girls get depressed when their periods start. Girls often don't ovulate regularly, which can cause problems until their cycle stabilizes. Sometimes pediatricians don't allow girls' cycles to stabilize. The doctor says to the girl, "you're a woman now, so we're going to regulate your irregular period with birth control."

      Women often get depressed due to the progestins used in all the birth control prescriptions.

      SSRIs never help because of boosting serotonin. When someone benefits, it's from the drug's other physiological effects.

      • lemming14 hours ago |parent

        Do you have a plan to get her off, or is she on the maintenance drug for life?

        It's too early to say. Obviously the idea is to get her off it if possible.

        SSRIs never help because of boosting serotonin.

        That's a hell of a claim, which could use some evidence.

        • 6 minutes ago |parent
        • tcj_phx4 hours ago |parent

          > > SSRIs never help because of boosting serotonin.

          > That's a hell of a claim, which could use some evidence.

          My experience with the chatbots is that they start with the conventional marketing tropes, but if you ask pointed questions they'll dig into the actual research.

          This thread started with a generic question about why ECT seemed to help some patients. It had a really good reasoning about why SSRIs are still the first-line treatment for depression, even though the MAOIs were much better drugs.

          https://chatgpt.com/share/69207aa3-26a0-8005-8dda-8199da153f...

            The Big Picture
          
            SSRIs flood serotonin globally, which can suppress 
            dopamine/norepinephrine and blunt mood.
            
            Anti-serotonin strategies (receptor-specific antagonism, 
            reuptake enhancement, or targeted modulation) often 
            result in cleaner antidepressant effects with fewer 
            side effects.
            
            This supports the criticism you mentioned: SSRIs may 
            “work” only because the brain adapts to the serotonin 
            disruption, whereas directly reducing or modulating 
            serotonin is more therapeutic.
          
          The whole 'conversation' is pretty good, and would provide plenty of search terms for helping you figure out what science has actually figured out about depression.

          A simple pregnenolone supplement can sometimes be magical, because of the steroidogenesis cascade: https://en.wikipedia.org/wiki/Steroid#/media/File:Steroidoge...

          There's a supplement seller that said his pregnenolone powder was made with a newer, cleaner process than is used by most of the pregnenolone supplement vendors, but I don't know if he's still using that supplier. The powders are a much better value than the capsules.

          hth.

      • EasyMark15 hours ago |parent

        Puberty in general can be rough. I (a dude) had all kinds of bad thoughts and moods going through puberty and then one year it was just gone, grades improved dramatically, started making friends again, etc

  • marcus_holmes19 hours ago

    > "But a new review of trial data by academics in Austria and the UK concluded that..."

    > "Mark Horowitz, an associate professor of psychiatry at Adelaide University and a co-author of the study,"

    Austria - cold, has mountains, but not Adelaide University

    Australia - hot, has kangaroos, and Adelaide University

    Is the Grauniad returning to form?

    • aaronbrethorst19 hours ago |parent

      Nature is healing. https://en.wikipedia.org/wiki/The_Guardian#References_in_pop...

  • comex16 hours ago

    I think this is the paper in question?

    https://osf.io/preprints/psyarxiv/wk4et_v3

    Clinical trials of antidepressants are weird because they're usually short-term (6-12 weeks), whereas practical use of antidepressants usually lasts years. I personally suspect that short-term trials show an exaggerated placebo effect, because the novelty doesn't have time to wear off.

  • hirvi7417 hours ago

    I can't bring myself to try an SSRI. I just cannot do it. I've got a prescription for an NDRI on my desk, and I still won't take it. I am not anti-psychiatry either. I take psychiatric medication for a different condition already. But something about anti-depressants just doesn't sit well with me.

    As crazy as it may sound, I think a lot of my depression stems from living a life that is not true to myself and due to countless failed attempts to be someone I cannot never be. As far as I am concerned, depression is just a symptom of my situation and not some true disorder. For the sake of analogy, I would say it's like food poisoning. Yes, the GI issues are awful, but the body is responding appropriately.

    • sundarurfriend16 hours ago |parent

      > I've got a prescription for an NDRI on my desk, and I still won't take it. ... something about anti-depressants just doesn't sit well with me.

      At first it sounded like your antipathy was with SSRIs specifically (which I largely share), but it seems like it's anti-depressants in general.

      FWIW, I used to think similar to you, and roughly agree with the gist of your second paragraph, but I've come to think of antidepressants as useful in a specific way: people say "it's a crutch" as a negative thing (about a lot of things including antidepressants), but a crutch was very useful to me when recovering from a fracture, and helped me enormously with my progress; similarly, even if "depression is just a symptom of my situation", it can and does often lead to a cycle where the depression itself feeds into the situation and in turn sustains itself. An antidepressant that works for you is a good way to be able to see things more clearly, feel the motivation and insight that depression clouds out, and thus be able to break out of the cycle.

      It doesn't have to be a "cure" that counters a disorder, it can be a tool that you use for its purpose and then throw away (and it does sound like you're well-motivated to do that).

    • anuramat8 hours ago |parent

      > not some true disorder

      there's a tool on your desk that might help you solve your problem; what does it matter if the problem is an "appropriate response of your body"? so is pain/anxiety/diarrhea

    • burnt-resistor17 hours ago |parent

      One needs to not work and be able to remain at home for about a week or so to see if the side-effects are manageable. One shouldn't simply continue on with operating machinery or working a job while titrating up a new psychiatric medication. Honestly, employers should offer medical time off for this.

  • monero-xmr19 hours ago

    SSRIs literally saved my life, no question about it. Night and day difference, from daily panic attacks destroying my life, happiness, and career, to being almost completely better in 2 weeks after starting. I tried exercise and diet and meditation and you name it, for years!, before I gave medication a go.

    Do not care what the science says. It 100% worked for me. Please get help if you need it, tens of millions of people use this medicine successfully

    Articles like this are part of the narrative that SSRIs in general are no better than placebo. Absolutely not true for me!

    • fgonzag19 hours ago |parent

      Same here, after struggling for 39 years, glp-1 + SSRI + ADHD meds have made me a normal productive human, and 2 years ago I had pretty much given up on the possibility.

      Having a child forced me to fix my life, and I'm incredibly happy because of it.

      • ipnon19 hours ago |parent

        Pharmacology and chemistry can really make the world a better place.

        • djohnston19 hours ago |parent

          Evidently not for children with depression. But yes chemistry is great.

      • thebigspacefuck17 hours ago |parent

        What’s normal anyway?

        • IAmBroom5 hours ago |parent

          I think that's a shorthand for "not dysfunctional and neurotically impaired".

        • fgonzag2 hours ago |parent

          For me? Not being hyper anxious all day (to the point that I just freeze and procrastinate all day), being able to sort of focus on the most important task (I'm still ADHD with 1000 unfinished projects, but at least I finish the things that have to be finished), eating healthy and enjoying exercising (100 lbs down and got quite good at tennis), not entering into a rage state due to anxiety overflow everytime I fight with my wife, being able to regulate my emotions, I could go on and on honestly.

      • floundy18 hours ago |parent

        Who would have figured that microdosing amphetamines all day leads to increased productivity?

        • hirvi7417 hours ago |parent

          Doctors. That is why they prescribe it.

        • MattRix18 hours ago |parent

          This seems a little snarky. For someone with ADHD it’s not as much about “increased” productivity but rather non-zero productivity.

          • hirvi7417 hours ago |parent

            As someone with ADHD, if your productivity was decreased or did not increase in the slightest, then I doubt a doctor would keep prescribing the medication. Such increases do not have to be astronomically large, but I do believe increasing the productivity of people with ADHD is absolutely part of the benefit.

            • MattRix6 hours ago |parent

              I agree, but I think you’re misunderstanding my comment. I was replying to a snarky comment that seemed to imply that the effect of taking amphetamines is obvious and mundane.

              The point I was trying to make is that the effect on someone with ADHD can be profound and transformative, not like going from 80 to 100 but rather from 0 to 100. You suddenly feel like a functional person (I say this as someone with ADHD).

        • zer00eyz18 hours ago |parent

          See: The dot com boom and its recovery into Web 2.0

          It was so pervasive at the time that the references to it spilled over into SF Bay Area hip hop culture...

          • pessimizer17 hours ago |parent

            Massive amounts of cocaine did the same for the housing bubble in the 2000s.

    • flatline18 hours ago |parent

      I have tried prozac in my teens and zoloft in my 30s. Prozac made me dissociate pretty hard, I found myself between classes not knowing where I was coming from or going. Zoloft did nothing but give me the zaps when I came off it.

      There have been some serious efforts made to reproduce the original groundbreaking results that showed how effective SSRIs were, without much success. Anecdotally, I know plenty of people who have benefited from them, so I would not say they are ineffective as a blanket statement. I do think it’s important to understand that nobody really knows how these drugs will impact any one individual, and it’s trial and error to find something that may help.

    • BlackjackCF19 hours ago |parent

      I think it’s important to note the headline that it’s specifically about children. Maybe Prozac is effective for adults but not kids in that range?

    • funkychicken19 hours ago |parent

      Hopefully people don’t see articles like this (for depression) and think the results are the same for anxiety disorders.

      • IAmBroom5 hours ago |parent

        THIS!

        SSRIs have been proven to be very effective against anxiety disorders, which in many ways mimic depression, but have different pathologies and causes.

        Also, they saved me.

    • chemotaxis17 hours ago |parent

      Placebo works very well for many people too! That's precisely the thing. That's what makes these studies tricky.

      If you're a doctor, and if Prozac helps your patients, then it's obviously excellent. You should keep writing prescriptions.

      If you're a scientist, you obviously want to distinguish between "real" drugs and drugs that help because people believe they should. So, you do these kinds of tests.

      And then, from the perspective of ethics, once you know it's just placebo, you kinda shouldn't keep giving it to people, even if it helps? Maybe? I don't know. That's the weird part.

      • sitharus17 hours ago |parent

        > And then, from the perspective of ethics, once you know it's just placebo, you kinda shouldn't keep giving it to people, even if it helps?

        That's a very big ethical question in the medical field. Placebos _do_ help, but only if people believe they will. So is it ethical to lie to a patient and give them a placebo knowing it's likely to help?

    • thomassmith6519 hours ago |parent

      This seems like bias against the placebo effect.

    • gexla19 hours ago |parent

      Spitballing here. I always understood stuff like this as "the system doesn't care about you, it cares about the masses." If the result is overwhelmingly looking no better than a placebo, then the small number of people it actually helps is sort of irrelevant. The exception might be cases where people are willing to drop a bomb of cash for lifesaving drugs for rare diseases (Pharma Bro got a lot of flack for massively jacking up the price of one of these drugs.) I don't know what implications such a study may have in a complex space. I imagine the drug will still be available for those who want to try, but far less prescribed as a sort of safe default. I doubt drug companies will care much for this, since the patent has long expired.

    • thebigspacefuck17 hours ago |parent

      You should have tried placebo first

  • mhuffman17 hours ago

    They must have been pretty damn confident of the results to give depressed children a placebo.

  • Forgeties7918 hours ago

    This reads to me like over-prescription rather than lack of efficacy but I’m also not a doctor and won’t presume my kneejerk reaction is accurate.

    We saw a similar whiplash with Ritalin after over-prescribing in the 90’s/2000’s. ADHD medication absolutely works, but for a lot of people it didn’t for this reason.

    • hirvi7417 hours ago |parent

      Even for people with legit ADHD, like myself, medication isn't always a home run. I think something like 10%-20% of people do not respond well to any medications. I personally am only a 'partial responder' in that I only really get an improvement in focus/concentration -- not really anything else. But hell, that is still better than life without medication.

      • Forgeties797 hours ago |parent

        Definitely didn’t mean to imply it’s a home run. I’m just saying it clearly and legitimately helps a ton of people.

        My point is if you include more and more people who don’t need it because of over-prescription it’s going to appear as lower overall efficacy while still helping a lot of people in the pool.

        Making up numbers: If only 20 out of 100 people actually have ADHD then out the gate you’ve ruled out helping 80% of the people. So if 15 of the remaining 20 see improvement in their daily lives that means 75% suddenly looks like 15%.

        Diagnosing and treatment is never that clean, there will always be some people who don’t necessarily need a certain medication yet get it prescribed (or don’t when they need it! Especially women with ADHD) because doctors are fallible like anybody else, systemic issues, etc. But with a commonly prescribed medication like Adderall the problem is definitely more pronounced.

        Anyway I’m curious enough to look more closely at the study, this is a very interesting topic. If Xanax is really not helping people that’s pretty serious.

  • tsoukase13 hours ago

    Antidepressants benefit specific populations, those that have a predominant "internal" stress/depression and not due to a profound external trauma. They will not help a child that is continuously bullied, but one that has inherited a depressive trend. This holds for children and adults, barring some differences due to age maturity. Saying "no difference from placebo" for a treatment that is used by hundreds of millions is poor science, if not misinformation and malice.

  • burnt-resistor17 hours ago

    Maybe SSRIs work for some, but Paxil gave me serotonin syndrome and Prozac made my mom psychotically homicidal. I've tried every SSRI titrating on and off (except Paxil), but they all caused deal-breaking side-effects.

    • rrrrrrrrrrrryan15 hours ago |parent

      Homicidal?

      • burnt-resistor11 hours ago |parent

        Yep. My dad recounted that in 1989, he had to restrain her because she (then age 40) had a psychotic episode described as a "murderous impulse" just after starting a brand new "wonder pill", Prozac. This was quite uncharacteristic for a tiny, docile woman who is often described as "sweet" and "nice" who never had any psychiatric symptoms before or since except a couple of brief times of situational depression. There's a lot of FUD and social ills washing in mass media rather than less biased peer-reviewed research that blames individuals, conflates preexisting conditions with medication side-effects, and clouds the issue of whether SSRIs increase suicide and/or violent psychosis or not.

        Check out one of the modern black box warnings of fluoxetine (Prozac) that only addresses a subset of side-effects, suicide in children and young adults: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?set...

        Somehow, I doubt there is much motivation to look for economically inconvenient and unnerving side-effects in some demographics, especially if they're adults who can easily be blamed entirely for all of their own actions because it's "definitely not" due to a (formerly) profitable pill or a pseudoscientific profession that doesn't exactly know how the medications it prescribes work, who would benefit from or be harmed by them, or have any ability to measure the organ or system they're supposed treating.

        • tcj_phx4 hours ago |parent

          Thanks for sharing your mom's experience with big pharma's then-new wonder-drug.

          > Somehow, I doubt there is much motivation to look for economically inconvenient and unnerving side-effects in some demographics,

          Robert Whitaker examined the pharmaceutical industry's ideological capture of conventional psychiatry in his third book, Psychiatry Under the Influence.

          https://robertwhitakerbooks.com/psychiatry-under-the-influen...

          I've written for the Mad in America Foundation's webzine. My latest piece was titled Theodoric of Arizona: State-Sanctioned Pharma-Based Pseudo-Doctor: https://www.madinamerica.com/2024/07/theodoric-arizona/

          This was inspired by the old SNL skit, Theodoric of York, Medieval Barber. The article is structured around my proposal of a Theodoric’s Principle of Medical Advancement, to explain why medical progress is so glacial.

  • cc-d18 hours ago

    The FDA is such a joke.

    • forgetfreeman18 hours ago |parent

      Use more words.

      • khannn18 hours ago |parent

        FDA, what a joke

        • AnimalMuppet18 hours ago |parent

          Um, that's fewer words.

          • khannn31 minutes ago |parent

            FDA = Joke

  • djohnston19 hours ago

    It’s fascinating that otherwise intelligent people have no hesitation pumping their children’s developing brains full of SSRIs and amphetamines at the behest of a professional class who is paid to distribute these medications.

    • mberning17 hours ago |parent

      I used to share your opinion, and in a way I still do, but after having 3 children and seeing how horrible some of these behaviors and habits can get, I completely understand why people cave in to get some relief. The stress of dealing with severe behavioral issues day after day can easily destroy a marriage and family.

    • forgetfreeman18 hours ago |parent

      It's even more fascinating when you have first hand experience with how much unmitigated guesswork goes into selecting psychiatric meds and their dosage.

      • Aeglaecia17 hours ago |parent

        it's somehow even more fascinating when you talk to dozens of people who were medicated as kids and get an idea of the real implications

        • forgetfreeman6 hours ago |parent

          ...or literally watched friends get over-medicated into committing suicide.

  • RickJWagner7 hours ago

    Fortunately, there are well documented lifestyle adaptions that can sharply reduce depression.

    Religion is a good example. https://pmc.ncbi.nlm.nih.gov/articles/PMC3426191/