2-Minute Neuroscience: Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Serotonin-Norepinephrine Reuptake Inhibitors, or SNRIs, are a common treatment for depression and a variety of other ailments like anxiety disorders and chronic pain. In this video, I discuss how SNRIs work in the brain and how they are proposed to be able to treat the symptoms of depression.
TRANSCRIPT:
Serotonin-norepinephrine reuptake inhibitors, or SNRIs, first appeared on the market in 1993 with the introduction of venlafaxine. Several others, like duloxetine, would be introduced in the following decades. Most SNRIs were primarily developed for the treatment of depression, but some are now also used to treat a variety of other conditions like anxiety and chronic pain. The development of SNRIs was guided by research that suggests neurotransmitters like serotonin and norepinephrine play a role in depression. Specifically, this research suggests that low levels of these neurotransmitters might contribute to the symptoms of depression.
SNRIs work primarily by inhibiting a mechanism called reuptake. In reuptake, a protein called a transporter transports excess neurotransmitter molecules out of the synaptic cleft, typically back into the neuron that released them. SNRIs inhibit the reuptake of serotonin and norepinephrine. When the removal of serotonin and norepinephrine from the synaptic cleft is inhibited, this causes levels of these neurotransmitters in the synaptic cleft to rise. These increases in serotonin and norepinephrine levels have been hypothesized to be the mechanism by which SNRIs can treat the symptoms of depression. It should be noted, however, that research suggests the neurobiological mechanism of depression is more complex than a simple neurotransmitter deficiency. Thus, it may be that increasing serotonin and norepinephrine levels leads to other effects that can alleviate the symptoms of depression, or that the drugs have other mechanisms that contribute to their effectiveness.
Studies have found SNRIs to be comparable to other popular antidepressants, like SSRIs, in terms of effectiveness. SNRIS are also generally well-tolerated, with problems like nausea, sweating, and loss of appetite being some of the commonly reported side effects---although different snri drugs have different side effect profiles.
REFERENCES:
Brunello N, Mendlewicz J, Kasper S, Leonard B, Montgomery S, Nelson J, Paykel E, Versiani M, Racagni G. The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. Eur Neuropsychopharmacol. 2002 Oct;12(5):461-75. doi: 10.1016/s0924-977x(02)00057-3. PMID: 12208564.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JPA, Geddes JR. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018 Apr 7;391(10128):1357-1366. doi: 10.1016/S0140-6736(17)32802-7. Epub 2018 Feb 21. PMID: 29477251; PMCID: PMC5889788.
Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol. 2015 Feb;23(1):1-21. doi: 10.1037/a0038550. PMID: 25643025; PMCID: PMC4428540.
Lambert O, Bourin M. SNRIs: mechanism of action and clinical features. Expert Rev Neurother. 2002 Nov;2(6):849-58. doi: 10.1586/14737175.2.6.849. PMID: 19810918.
Sansone RA, Sansone LA. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innov Clin Neurosci. 2014 Mar;11(3-4):37-42. PMID: 24800132; PMCID: PMC4008300.

[@af02271]

I started taking Strattera a few months ago for ADHD after never pursuing medication until my 20s. I can confidently say every single facet of my life has exponentially improved. Best decision of my life

[@petiesjogren1614]

I just started taking Strattera for my ADHD 3 days ago and was extremely ill yesterday with vomiting and intense abdominal pain. I’m gonna try to stick to Strattera and hopefully those side effects go away. I can’t take stimulants and this is the first non stimulant I’ve tried. Did you have any side effects with Strattera at first?

[@nawnie8615]

@@petiesjogren1614 not sure if you stuck with ut day 1 and 2 had me so mentally ill I had to stay home from work and get a baby sitter for a kid, day 3 was the first peaceful day I've had in years

[@Richannplayshop]

@@nawnie8615 @Petie Sjogren @Andrew Feagins I just started taking Straterra today for a possible ADD and / or Bi-polar diagnosis. I just got my preliminary diagnosis a couple of days ago. I'm in my late 50s. For the first 2 to 2 and half hours, I had all the general reported side-effects: slight nausea, mild clammy-sweats, a mild head ache, decreased appetite, low motivation, slightly depressed and the worst was the abdominal pain which wasn't intolerable and felt a lot like constipation. Fortunately, I didn't have any pressing responsibilities and am at home. And, now, 4 hours later, all those symptoms have alleviated quite a bit. I believe I'm feeling calmer or slightly more slowed down than usual. I'm planning to stick with it for a few days and evaluate closely. I sure am hoping that it has some positive effects particularly, for me, in helping me to concentrate and access memory, short and long, and slow down surge of thoughts, and order my thoughts better. I appreciate you all sharing your experience. I'm glad to hear that it greatly improved both Andrew and Nawnie's life. Pete, I hope you are doing well now with it or found something that works better for you. It'd be great to have an update from any or all of you. Thanks

[@nawnie8615]

@@Richannplayshop still helping alot, I was diagnosed adhd as a kid and may start back on a low dose of a stimulate based med, but I believe strattera is what my treatment in the past was missing very optimistic

[@Richannplayshop]

@@nawnie8615 Great to hear and glad for you. Thanks for replying. My first day has been interesting. I was feeling pretty good than suddenly experienced an emotional dis-regulation - I've learned that's what it is just recently. Straterra definitely effected my appetite, hence I didn't eat timely, which normally is never a problem. And then I didn't eat and I started to feel my levels were off, and I've already got low blood pressure, so I ate. I had to make myself eat. But then, I crashed shortly after. I needed to lie down and I napped, which I never normally could or would do. And it was a great nap - ah, so unusually peaceful. I then felt better. I'm a bit confused though; If Norepenephrine is our "get up and go" why did I feel much less of that today than usual. I'm usually hyper-focused most of the day and have very little problem with "get up and go." Patience. It's too early to really tell what's going on - I'm sure I must give myself time to regulate.

[@alex.x_x.]

Love to see you share new content! My neuroscience and drugs, alcohol & the brain students love these videos :)

[@sarahgillies7162]

This channel is so helpful! Thank you for all your hard work

[@antoniomele436]

Thank you! I love your videos. Keep up the great work!

[@allibystarDN514]

I am a med student and I am taking my USMLE Step 1 test next month and your videos are coming in clutch for refreshing my memory! THANK YOU soooo much from all of us med students :D

[@neurochallenged]

Good luck!!

[@nicolehernandez8349]

This video clarified my confusion WOW thank you!

[@Mr_R00k]

Origany I was on an ssri called sertraline aka zoloft and it "zombified" me. I felt nothing but when I changed to a snri aka venlafaxine it quieted "upstairs" and am still able to feel things and I'm able to focus on work more clearly and the extreme sadness and randomly crying have mellowed right out. I think for me snri's work better for me

[@alnicholson4344]

That's really promising to hear. I have tried several ssri's including Sertraline and found the dam he. I was like the walking dead for 3 weeks until I came off it. I'm about to start an SNRI as desperate to feel better. Reading about the withdrawal symptoms is a bit scary though. I hope your meds are still really helping you.

[@sandraihdz1790]

When my new doctor prescribed the snri and tapered me off from fluoxetine, Clonazepam and olanzapine, my life changed, Akathisia symptoms subsided and I was myself again.

[@alnicholson4344]

That's reassuring. I've been having to take clonazapam recently for really bad anxiety. I'm about to start an SNRI as never tried them before. I like to try and do things holistically but right now I'm in crisis point and need to function again.

[@kukhtoviktar372]

Super interesting and helpful!! Thanks.

[@alexgilbert3657]

Love these videos!!

[@user-ts6yy9qu7d]

感激分享，祝福平安喜年來。

[@uknown_system]

It’s good for you it helps you it actually chills you out

[@Aladayle]

Like another commenter I take Strattera for ADHD and while it helps the attention issues what it really helps with is the anxiety and rushing thoughts. I'm happier while on it, and wondered why. I didn't know it was originally for depression.

[@unapologeticallyamy9031]

I really enjoyed this video! May I make a suggestion? Next time would you consider making a video regarding SNRI Discontinuation Syndrome? A lot of patients feel as though they’re stuck on the SNRI medication because both the physical and mental withdrawal symptoms are incredibly difficult to endure. Patients can start to experience withdrawal symptoms as soon as 1 hour after a missed dose.

[@angierox6964]

I was going to comment the same thing! I was thinking recently that had somebody discussed the extreme difficulty of discontinuing SNRI’s, due to severe withdrawals that linger for many years, would I have chosen to take it regardless? People making that decision are generally in a place of desperation. If they are able to seriously consider the consequences of taking SNRI’s then most likely they don’t need this medication. I’m try to stop this medication but the withdrawals feel so awful! Even minuscule tapering is noticeable with many people reporting the symptoms lasting for up to 5 years.

[@stacknsat]

You can have them take cold shower for 2-3 mins

[@Peter_van_bjork]

+1

[@muhammedcagrkartal9954]

I really enjoy all your content please keep up the good work. It would relly help for you to tell how to induce the chemicals in a natural way

[@LindaengelustrupBlogspot]

Nor-epinephedrine is apperently transformed into dopmaine, hence the effeciancy against ADHD. The weird thing about it is why it allways gives so much nightmares at night but at daytime it makes me more calm and gives me time to think before I speak. I wish I knew why this was happening. When it comes to withdraw symptoms I suggest the doc gives an emergency package for storage which is to be used for when holidays suddely accures without the ADHD person having noticed this, the ADHD peron still neds the meds but the doc has gone on holiday. I bet this would prevent a ton of people quitting effexor because of hell of withdraw symptoms

[@taneshiao9337]

Can you do a video on SNDIs "Serotonin-norepinephrine disinhibitors"

[@toekneesee]

Amazing as ever! Putting in a request for 2MN vid on BDNF, pleeeez

[@ryanmchale5795]

Yes please!

[@rickharold7884]

Awesome

[@oceansoflorewi]

Ok but what about NDRI. Can't find the comparison to Wellbutrin & the common SSRI & this one.

[@desiredecove5815]

#Sharingiscaring Excellent quick education

[@jessehobart6871]

“SSRI’s stop the re-uptake of serotonin back into the neuron, increasing the amount of serotonin in the synaptic gap” I hear and read this all of th time. My question is how? How does the substance in this pill stop the re-uptake of serotonin? what is the active substance in this pill and where does it come from or was originally discovered/synthesized? Can anyone help answer these questions for me?

[@Vectorman2X]

antagonist of serotonin?could be the binding of the site of the receptors trick the brain to believe that had not enough serotonin to the receptors so the result is to produce more serotonin in the long run.

[@vaykoden793]

How reuptake inhibitors work is they mimic the structure of a neurotransmitter enough to go into the transporter protein but it gets wedged in there thus blocking reuptake of neurotransmitters.

[@CommonLoganist]

i know u made this comment 2yr ago but how i understand it was the drugs stop(inhibit) the brain from re-absorbing(reuptaking) the norepinephrine and serotonin so now there's more in ur brain that u can actually use. Hope this explanation is a bit simpler!!

[@dos7325]

What soft you use to make these videos?

[@sergiosanchezpadilla6941]

0:46 So inhibiting reuptake helps keep a higher density of serotonin and norepinephrine in the synaptic cleft. BUT what are those original "neurons that released them"? Are these latter bad? Or is it just a strategy to keep a higher concentration of serotonin and norepinephrine in synaptic clefts available for other neurons? Or a combination or both? Or something else?

[@neurochallenged]

Serotonin and norepinephrine are neurotransmitters that are commonly used in normal neuronal communication, so neurons that release them aren't bad, and they're not trying to achieve any goal other than communicate with other neurons. Inhibiting reuptake alters neuronal signaling because it causes these neurotransmitters to remain in the synaptic cleft longer (and gives them more time to interact with receptors on other neurons).

[@madelinemorgan5692]

So, apparently norepinephrine plays a big role in stress response, triggering fight-or-flight symptoms like faster breathing and heartrate. My question is, why would having more of that stuff in the synaptic cleft help to treat anxiety symptoms??

[@jayton580]

Exactly what I’m trying figure out

[@adlopeezz]

No idea but it for sure works!! Venlafaxine worked way better for my anxiety than any SSRI. I feel like SSRI’s made it worse.

[@egregiousfilmin4842]

Exact thing I'm wondering. Anxiety and elevated blood pressure are possible known side effects of the medication too. I truly believe some people's initial symptoms of anxiety/overstimulation are caused by overproduction rather than underproduction of neurotransmitters and that's why certain people have such severe adverse effects from these meds. There's no way to measure neurotransmitters, all of this"information" is unproven theories. It's annoying whenever people say "oh they DEFINITELY work" because after 20+ years as a medical guinea pig and my body literally starting to shut down from serotonin syndrome - I know these meds don't help everyone. Not to say they're completely ineffective or whatever but there's definite holes in the logic of why these meds are capable of causing the same symptoms they're supposed to treat.

[@CommonLoganist]

dont forget it also interacts with serotonin(happy/camling) and if you think about when u are in fight or flight, ur not really stressing ur more just physically responding to ur environment. so there for if u dont have the ability to fight to fly cuz of low adrenalin you shut down and start to worry cuz your body cant respond you your environment, so its kinda an action v reaction the way i understand it. also the video suggests that noradrenaline and serotonin help assist in unknown functions that help treat anxiety, depression, adhd ect. as opposed to being the fix themselves, hope this helps!!

[@egregiousfilmin4842]

I'm curious... How much have researchers/scientists considered the possibility of people having high, rather than low, levels of serotonin/norepinephrine?? Considering these medications theoretically CAUSE anxiety/high blood pressure by raising the levels too much or too quickly - isn't it also possible that anxiety/hyperactivity could also be caused by higher than normal levels of these neurotransmitters in the first place? I'm only wondering this because I'm one of the minority of people who experiences worsening anxiety/depression when taking these medications and Drs have yet to offer any explanation or alternative treatments. These medicines can not possibly be a one-size-fits-all solution, I wish researchers would focus more on other possibilities.

[@alnicholson4344]

I think now that is why so much research is being done on plant medicines such as psilocybin, Mdma and ketamin as since the 90s the scientists haven't come up with anything else that works and as we know we are now experiencing a mental health crisis worldwide.

[@1_Handle_1]

I'm curious on snri mixed with alcohol from what I got its possible for internal bleeding an that scares me an alcohol is too amazing

[@Jess-TheMess]

I'm now on Duloxetine and it's only been 3 days and I've forgotten to eat for 2 and 1/2 days. No appetite Kinda sucks

[@George-pz6mj]

Has anyone here gone from SSRI to SNRI? My doc is on the fence about moving me over to SNRI cos there's more side effects. I currently take 10mg Lexapro for chronic anxiety and depression I've had. I noticed Lexapro has been great generally but I find this time around on my 3rd stint with Lexapro my anxiety is a little higher. Don't know if I should increase to say 20mg of Lexapro or go on an SNRI. My doc recently put me on a 2 week only dose of Olanzapine 2.5mg to help augment Lexapro. It has worked wonders. My sleep is great, mood is lifted and my anxiety is soooo much better. So I'm starting to think if my issue is not just serotonin but dopamine as well which I think SNRI help with. Would love to hear your experiences ❤️

[@allenkendall3412]

I moved from an ssri to venlefaxine. After finding out I have adhd my doctor started me on norephinephrine as well. It gives me extra energy so far. It hasn't caused me any anxiety. Adhd and depression seem to run in pairs with some people. Food for thought...

[@Otto-mq8lg]

Does sertraline help symptoms of depression in humans with epilepsy?

[@nidhalbenkhalfa4935]

But, I need to know more how SNRI work as SSRI at a lower dose and an SNRI at a larger dose ?

[@nidhalbenkhalfa4935]

@@joepopelas Thank you, I mean what mecanism make Effexor be a Norepinephrine reuptake inhibitor at higher dose(>150mg) and when we lower the dose(75mg) it work on Serotonin only ?

[@Vectorman2X]

@@joepopelas you are on point about effexor,its a great drug when you are on,but when you quit hell comes to you.I speak from personal experience,16 months clean from effexor,trying to stay at my foot again.

[@Peter_van_bjork]

It is very difficult to find the right dosage according to my experience. The medicine does good things but also has many unwanted side effects. Either too high or too low and never quite perfect. quite far from good actually.

[@AliAlexRG]

What's the difference between ssri and snri

[@neurochallenged]

SSRIs selectively target serotonin reuptake, while SNRIs affect the reuptake of serotonin and norepinephrine.

[@darrenmulvaney7286]

You left out the part where a 70 percent plus report by users said they had sexual issues.

[@angierox6964]

What happens to the brain when one stops taking this medication?

[@heinz-georgschneider3567]

The brain is fucked up by these chemicals, withdrawal effects take place, symptoms of chronic brain impairment come up (tiredness, agitation, nerve pain etc.) as the system wants to get the normal homeostasis and natural balance of neurotransmitters back....

[@MomoIsMyHero]

i am on ssri, but still not feeling great so my doctor suggested switching to an snri. i'm still not sure what the practical difference is... anyone in the comments section have experience?? thanks

[@B3arAbl3]

Why did the neurotransmitter apply for a job as a DJ? Because it wanted to keep the party going in the brain! 🎧

[@jdulast]

Duloxetine gave me permanent genital and emotional numbness

[@dailydoseofmedicinee]

Venlafaxine can make you feel less hungry than usual, so you may lose weight when you start taking it. Some people might find they gain weight👍

[@Robmanian]

I hope I'll lose weight, not gain more

[@Lazymath007_]

Are beta blockers NRIs? Please answer

[@neurochallenged]

Their primary mechanism of action is blocking beta-adrenergic receptors. I'm not aware of any effect on reuptake.

[@Lazymath007_]

@@neurochallenged I know nothing about neurology. I am just trying to apply from what I understand so far. From what I know, if a neurotransmitters is blocked from binding to another receptor it stays in the synapse which should logically increase its reuptake? Does that not mean that beta blockers increase norepinephrine?

[@neurochallenged]

Beta-blockers block receptors, which prevents norepinephrine from having a target to act at. But they don't affect reuptake, so reuptake can continue at its normal rate. The end result of beta-blockers is less norepinephrine activity at beta-adrenergic receptors, which leads to lower blood pressure etc.

[@Lazymath007_]

@@neurochallenged I am taking beta blockers for adhd. Adhd is a lack of norepinephrine. That means I must be screwing my symptoms more?

[@neurochallenged]

@@Lazymath007_ I was able to find some research that looked into the use of beta-blockers to treat ADHD. They were found to have little effect on cognitive symptoms, but perhaps some benefit in treating behavioral symptoms such as angry outbursts (see here: www.ncbi.nlm.nih.gov/pmc/articles/PMC3000197/). ADHD is much more complex than just a lack of norepinephrine. If I were you, I would just ask my doctor what the rationale behind prescribing the beta-blockers is. There might be a specific reason why he/she thinks they will benefit you.

[@holdenmcgroin8917]

Teach me.how to pronounce Norepinephrine

[@probablynot2123]

nore (rhymes with door) ehp pin nef frin (rhymes with chin)

[@mathuedoi]

I think maybe it's time to stop using the monoamine hypothesis as a simplified explanation for the MOA of antidepressant /anxiolytic reuptake inhibitors. It's counterproductive.

[@VilyaGustavsson-xv7ib]

Why dont you explain how SNRI make People commit crimes ?

[@madness198648]

Key words "might work" lol

[@vincentschmitt392]

the low serotonin level causing depression slogan is known to be wro,g. So this video is bs

[@elburto5387]

Is this similar to cocaine?

[@anonymousguest9290]

@@joepopelas What would be a therapeutic dosage of cocaine?

[@anonymousguest9290]

@@joepopelas What about chewing on a coca leaf? I've read that its original use was in an unrefined form.

[@anonymousguest9290]

@@joepopelas So basically its the original "feel good" plant that has been demonized, refined and heavily pushed on the black markets. Pharma would lose too much on its patented chemical crap and so lobby to have this plant, amoung others I can think of, proclaimed "illegal". Does this sound about right to you?

[@desmomotodesmomoto2033]

Don't take drugs! Find the reason for your depression.

[@alnicholson4344]

I agree with you and have been having trauma therapy which has brought up some really deep stuff. I now need some medication to get my functioning again so I can continue dealing with the trauma.

[@desmomotodesmomoto2033]

@@alnicholson4344 don't take meds! Meds change the biochemistry of your brain. don't do it. Try high saturated animal fat carnivore diet, or animal base raw primal diet. Call me crazy, but many have seen great results. Your brain needs nutrition to be able to function properly.

[@purgatoriumlaboribus1047]

This stuff is hot garbage don't take it.

[@chrisslate1506]

Does this in any way affect dopamine?