How Do SSRI's Really Work
November 19, 2019
SSRI's are in the headlines lately especially out of Europe where research is a little more "impartial".
It's interesting that this coincides with a resurgence of research (thank you John Hopkins) looking at psilocybin for anxiety and depression within the last few years.
The last hurrah of SSRIs??
Many of the millions of people prescribed SSRIs do not really know how they work.
In fact, a lot of doctors prescribing them only know what their pharma rep tells them.
The mechanism is actually pretty well established and it's fascinating.
We'll get into all of it below.
We'll cover these topics:
- What do SSRI's do in the brain (and gut)
- An introduction to serotonin and SSRI's
- BDNF - the star of the show for SSRI's
- SSRI's and the microbiome
- How effective are SSRI's for anxiety and depression
- Why does it take a few weeks for SSRI's to work
- Why do SSRI's increase anxiety and depression in the first few weeks
- Are SSRI's addictive?
- Is it hard to come off of SSRI's
- CBD and other alternatives to SSRI's
Let's get into it.
The number of SSRIs prescribed to the elderly doubled in the last year.
We need to know what we're getting into.
What do SSRI's do in the brain (and gut)
SSRI is short for selective serotonin uptake inhibitor
Basically, this class of medications keeps serotonin from being reabsorbed and taken off-line in the nervous system.
The net effect of this is that there is more serotonin available to neurons.
This would address a lack of serotonin which can easily be determined by a test your doctor can give.
Wrong!
There is no good test to determine if you're low in serotonin availability or function.
SSRIs are prescribed based on symptoms...generally anxiety or depression.
When I was prescribed Lexapro for perimenopause anxiety (that story is here), my general practitioner made the prescription based on the fact that I could no longer take benzos (extremely addictive) and SSRI's are the next ticket to pull for anxiety or depression.
That was it!
Also, there was a benzo prescription for the first few weeks as it "takes time for the SSRI's to kick in".
Turns out that's not correct and we'll get into it below.
Now, for people with a genuine serotonin deficiency, SSRI's may help with that.
Temporarily.
So...how many people fall in this category as opposed to the many other causes (see CBD and the mechanism of anxiety for an example)
Do SSRI's work for anxiety and depression?
We get into the studies quite a bit at our CBD versus SSRI for anxiety or CBD and anti-anxiety medications.
Traditionally, SSRI's are more targeted for depression but they work via the same pathway.
Let's look at metadata or large aggregates of many studies.
There's a really impressive examination of 1000's of trials, both published and unpublished (very important) here:
Some interesting points come out of this study...
There's a wide range of both effectiveness and acceptability between the different drugs.
- SSRI's appear to be more effective in people with severe depression
- SSRI's appear to work for about 30% of people who try them
- Placebo effects were very strong as depressive symptoms tend to improve on their own for many participants
- SSRI's effects for severe depression were modest at an approx .3 effect
Another fascinating piece is that the average age was 45 and over 60% were women.
We're not surprised as estradiol (see Estradiol review) and testosterone both direct control over serotonin creation and break-down.
Check out estrogen and mental health or our deep dive on serotonin.
After a forced release of FDA studies that are unpublished, the effects reflect the above points:
The magnitude of benefit of antidepressant medication compared with placebo increases with the severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2253608/
So, severe depression. Notice no mention of anxiety that SSRI's are commonly prescribed for.
I was prescribed Lexapro for anxiety. I didn't have depression until it was a side effect from the SSRI.
In terms of SSRI's for panic attacks, here's a different way to parse out the statistics of all this:
Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit.
https://www.ncbi.nlm.nih.gov/pubmed/29620793
Interestingly, when you reduce serotonin in healthy subjects, it doesn't result in depression:
In healthy participants with no risk factors for depression, tryptophan depletion does not produce clinically significant changes in mood.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471964/
Tryptophan is the precursor for serotonin and depletion drops serotonin.
However, if you do the same thing in people who recovered from depression and have no medications, they see their moods depress as a result.
Tryptophan is the raw material that's turned into serotonin.
Our immune system will starve our brain/nervous system of tryptophan if there's a sign of infection or...inflammation!
Interestingly, if biomarkers of inflammation are high, SSRI's have less effectiveness:
An inflammatory biomarker as a differential predictor of the outcome of depression treatment with escitalopram and nortriptyline.
https://www.ncbi.nlm.nih.gov/pubmed/25017001/
That's a clue we can use for later!
Okay...we'll leave the heavy lifting to our CBD versus SSRI here.
Let's get to the heart of our question...how do they work?
To answer that question, we first need to understand serotonin.
An introduction to serotonin and SSRI's
Spending a few 100's hours researching all facets of anxiety, we're pretty well acquainted with serotonin.
It's commonly referred to as the "feel-good" neurotransmitter but that's misleading.
It doesn't create pleasure...that's Anandamide the "bliss" molecule- an endocannabinoid and opiods.
It's more of a workhorse transmitter in the brain and gut.
A master regulator of ALL human behavior.
See how they just threw all the other stuff in grab-bag heading towards the end:
It has a popular image as a contributor to feelings of well-being and happiness, though its actual biological function is complex and multifaceted, modulating cognition, reward, learning, memory, and numerous physiological processes.
https://en.wikipedia.org/wiki/Serotonin
"Numerous physiological processes".
Vague and yet all-encompassing.
You can take a look at the side-effects of SSRI's to see just how varied here:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021323s047lbl.pdf
Our focus is serotonin as a neurotransmitter.
Most neurotransmitters have pretty defined roles:
- GABA is like a brake pedal
- Glutamate is like a gas pedal
- Dopamine rewards actions
Granted, this is a simplification but it's harder to do with this with Serotonin.
It has its fingers in many pies!
Research is showing that it appears to control the sensitivity and activity of other neurotransmitters and brain areas.
To put a point to it:
The behavioral and neuropsychological processes modulated by serotonin include mood, perception, reward, anger, aggression, appetite, memory, sexuality, and attention, among others. Indeed, it is difficult to find a human behavior that is not regulated by serotonin.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864293/
The keyword there is "modulated".
That's a fancy way to say manage or balance.
This is where SSRI's get into trouble.
Too much serotonin is just as troublesome as too much.
Brand new research is showing that serotonin may have direct "epigenetic" effects...not just relay messages.
Epigenetic is the brave new world of how, when, and where genes are turned on and off.
The difference between your body/brain now and when you were 25 (I'm 49 now) lies in the epigenetics...not the genetics.
My genes haven't changed but which ones are turned on and off have.
Much to my chagrin.
Researchers just found out that serotonin may have a base-level effect at this level:
Epigenetic events relating to serotonin has already been linked to stress, and more broadly, epigenetic aging to mental disorders such as depression and bipolar disorder.
It may not seem earth-shattering but in the world of neuroscience, this new trick is huge!!
Serotonin is a master stress response buffer!
The visual is here:
With serotonin attached, DNA loosens on its spool, allowing for increased gene expression.
https://directorsblog.nih.gov/2019/03/19/mood-altering-messenger-goes-nuclear/
Powerful stuff which explains why serotonin impacts so many seemingly disparate activities.
For example...
The same serotonin pathways that are involved in anxiety have dual uses elsewhere:
For example, anxiety-like behavior is regulated primarily by 5-HT1A and 5-HT2C receptors, among others (14, 15), but the 5-HT2C receptor regulates not only anxiety but also reward processing, locomotion, appetite, and energy balance.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864293/
Okay, before we get lost in the weeds, let's get to serotonin's main effect for anxiety and depression.
Brain repair and growth!
Don't listen to the professionals that say "we don't really know how they work".
New research is zeroing in on it pretty clearly.
As an example:
Multiple studies indicate that 5-HT1A and 5-HT4 receptor signaling in the DG contributes to SSRI-mediated promotion of neurogenesis and increased neurotrophic factors expression.
https://www.frontiersin.org/articles/10.3389/fncel.2017.00142/full
Before your eyes glaze over, let us translate.
Basically, brain growth (neurogenesis) in the hippocampus (powerful mood and memory area of the brain) increased chemicals that are known to repair and rebuild the brain.
This is usually a response to stress, infection, immune response, trauma, or more.
Check out CBD and mechanisms of anxiety or CBD and hippocampus neurogenesis.
How do we know this?
In fact, in studies where they genetically or chemically block this neurogenesis effect, the anti-depressant and anti-anxiety result goes away.
Okay...that's exciting stuff.
We save the best for last (next really).
The last piece of that statement talks about "Neurotrophic factors".
People...the star of this show!
BDNF - the star of the show for SSRI's
You may have heard of serotonin but BDNF probably isn't rolling off your tongue usually.
It will be.
BDNF is part of a family called neurotrophins (literally translate to "brain" "growing").
BDNF is so important for anxiety and depression that we did a full review of CBD and BDNF for neurogenesis.
Why does it matter with SSRIs?
Follow this and geek out with us.
When researchers blocked a pathway of BDNF processing called Trkb, the anti-depressant effect of psychedelics (huge impact on depression and anxiety being studied now) went away.
When cortical cultures were co-treated with ANA-12 (Cazorla et al., 2011), a selective antagonist of BDNF’s high-affinity receptor TrkB, the ability of psychedelics or BDNF to stimulate neuritogenesis and spinogenesis was completely blocked.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082376/
This pathway is not used by serotonin (also spikes with psychedelics) but serotonin increases BDNF activity.
Remember...serotonin governs other sub-systems throughout the brain and nervous system.
We're not done.
Remember the hippocampus effect from serotonin?
Subsequent work showed that a single bilateral infusion of a low dose of BDNF directly into the DG or CA3, but not CA1, region of the hippocampus was sufficient to induce an antidepressant-like effect within three days (Shirayama et al., 2002), suggesting that these regions may be key regions for antidepressant effects acting through BDNF.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763983/
This is the exact area mentioned above.
We really get into the hippocampus at our CBD and hippocampus neurogenesis.
The CA3 area deals with "approach" - taking chances. CA1 counters it and deals with avoiding situations or to put a better way...anxiousness.
Too much stress creates a natural response in the brain to pare back the "risk tolerance" area of the brain.
It's nature's way of saying "slow it down...we're not comfortable with this".
Chronic stress or stress at specific times of brain development can over-play this effect and leave you with anxiety and depression.
We did a huge review of how early trauma or infection (even in utero) can downregulate serotonin later in life!
You have to address this to really get at why serotonin my be out-gunned!
The two tend to travel together (comorbid is the technical term).
What's really weird is that SSRI's usually don't work for weeks. In fact, they can increase anxiety and/or depression!
Keep in mind that if low serotonin was really the issue (the mechanism for SSRI's), we would expect a result right away.
Benzos (which boost GABA) have their effect almost instantly (5-10 minutes) as an example.
This speaks to brain repair via the BDNF pathway as the key.
Finally...how do we know it's the brain remodeling effect of BDNF (our brain's fertilizer) and not just it's increased level on some other mechanism?
Rather surprisingly, this study also noted that BDNF produced an antidepressant effect for up to 10 days after the infusion, well past the time frame of the degradation of the protein, suggesting that BDNF may be triggering a sustained plasticity mechanism to mediate the long-term antidepressant effects.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763983/
Check out CBD and long term anxiety to really look at the tug of war between insults (stress, infection, trauma, etc) and repair (serotonin, BDNF, endocannabinoids, etc).
Look...serotonin appears to be a "promoter" of BDNF (among many other pathways).
You now know more than 99% of the people (including doctors) on how SSRI's actually work.
We'll hit one more stop before looking at how we might access these same pathways without the 3 nights of no sleep and total blunted emotions I felt from Lexapro.
By the way, "blunted emotions" is the Orwellian way Pharma companies have come up with to sugarcoat feeling absolutely nothing.
Zero. Zilch. Or blunted if you will.
Let's now head south. To the Gut Miss Teschmacher! (terrible shout out to the original Superman movie...our apologies).
SSRI's and the microbiome
Most of your serotonin is actually made in the gut.
Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the GI tract, where it regulates intestinal movements.
https://en.wikipedia.org/wiki/Serotonin
Hence, all the GI side-effects with SSRI's.
Needless to say, the gut microbiome or countless bacteria in our gut are intimately intertwined with serotonin function.
And mood!
Check out CBD and probiotics for anxiety as an example.
The connection with serotonin and gut bacteria gets very interesting and these are early days.
For example, one study found that SSRIs directly affect specific gut bacteria which actually signal the serotonin process in the gut itself!
In the presence of serotonin, the bacterium grew to high levels in mice, but when exposed to fluoxetine, the bacterium grew to only low levels in mice.
https://www.sciencedaily.com/releases/2019/09/190906092809.htm
Another study looked at the roughly 1/3rd of patients who do not respond to treatment and/or lose effectiveness over time.
They found that concurrent treatment with probiotics significantly improved their outcomes!
At the end of an 8-week intervention mean changes for depression scores and quality of life in the group were clinically significantly improved.
https://link.springer.com/article/10.1007/s10787-017-0311-x
Afterwards, they were kept on SSRI's but had the probiotics taken away.
They relapsed into depression.
Researchers were able to increase or decrease serotonin levels in the gut simply by adding or removing the SSRI-affected bacteria.
When Hsiao’s team raised mice without the bacteria, more than 50% of their gut serotonin was missing. The researchers then added the bacteria mixture of mainly Turicibacter and Clostridia, and their serotonin increased to a normal level.
https://neurosciencenews.com/ssri-serotonin-microbiome-14877/
The most interesting study showed how one gut bacteria can actually cancel out the mood effects of SSRI's:
Antidepressants affect gut microbiota and Ruminococcus flavefaciens are able to abolish their effects on depressive-like behavior.
https://www.nature.com/articles/s41398-019-0466-x
Here's the key point to this article on exactly how SSRI's work (BDNF brain growth!!).
R. flavefaciens treatment-induced changes in cortical gene expression, up-regulating genes involved in mitochondrial oxidative phosphorylation, while down-regulating genes involved in neuronal plasticity.
Let's translate.
It down-regulated genes involved in neuronal plasticity.
That's just another way to say brain growing and repair!!!
A gut bacteria that hurt brain repair canceled out SSRI's.
Go figure.
These are the early days.
Let's look at some common and intriguing questions so you're a pro at exactly how SSRI's work.
Why does it take a few weeks for SSRI's to work
If serotonin was the missing piece, people would feel the effect right away.
Building a brain takes time.
It's not overnight unless you're looking at psilocybin or other psychedelics which have their effect with an explosion of BDNF.
See CBD and BDNF to look at that research.
Otherwise, we now know that BDNF is the real lever with SSRI's and it's tasked with growing new neural pathways.
Keep in mind, SSRI's probably haven't done much to deal with what's attacking the brain to begin with (chronic stress, neuroinflammation, loss of estrogen, etc).
BDNF is increased but there's still probably something doing the damage to begin with (stress and hyperactive immune response is a big culprit).
This is why it can take some time to get going.
That...however...is half the story during those first few weeks.
The doctor either doesn't know or wants to avoid the following section.
Why do SSRI's increase anxiety and depression in the first few weeks
My doctor basically knocked me out with Klonopin (benzo - see CBD versus benzos for GABA or how I used CBD to get off benzos) for the first few weeks after starting Lexapro.
He said it's because it can take time to work so the benzo will help for now.
Actually, anxiety and depression are known to INCREASE upon starting a new SSRI.
What on earth is this??
We were fascinated and if you've read any of our articles, we rarely take answers at face value.
Remember how SSRI's boost serotonin and serotonin is involved in almost "every human behavior"?
One of those "behaviors" is the fight or flight response.
It turns out that boosting serotonin will also boost the levels of a hormone called corticotropin-releasing factor.
It's the alarm bell in our brain that says, "FIRE!!!!".
Scientists found that boosting serotonin actually increases this signal in the first few weeks.
Check out CBD and corticotropin-releasing factor here since it may be one of the "insults" that BDNF is trying to clean up after.
Let's get into our (least) favorite section.
Are SSRI's addictive?
Technically, no.
Technically, I'm a primate so you can see science can have a wide berth.
Here's the deal...addiction in research usually implies tampering with the dopamine system and impacting the "reward" circuit in the brain.
You know...the classic click on the lever for cocaine over food until a rat starves to death.
SSRIs don't directly juice the dopamine system at a specific area called the nucleus accumbens where this usually occurs with nicotine, opioids, alcohol, etc.
Check out our big review on CBD and addiction to understand this pathway.
That's only part of the answer though.
Enter normalization.
What your doctor may not tell you is that your SSRI will eventually stop working (assuming it does to begin with and you're in the 30% group) at the dose you're on.
You'll need to switch to another drug, another class, a higher dosage, or layer one on top of it.
This is classic "normalization".
It's very important for our decision.
Check out the book Never Enough by Judith Grissel.
It's an amazing explanation of this effect.
Essentially, when we boost important neurotransmitters with outside chemicals, the brain reacts the other way.
It will start to lower it's naturally produced levels to counter this outside influence.
It's trying to establish balance over time:
- Nicotine will reduce acetylcholine
- THC will reduce anandamide
- Benzo's and alcohol will reduce GABA
These addictive chemicals will also reduce naturally produced dopamine as an offset from the spiking of it.
So...if SSRI's are boosting serotonin and they normalize (stop working at the same dose), what does mean if you want to come off of them?
Remember, serotonin is our "feel right" neurotransmitter with its hands on every lever in the nervous system and gut.
Welcome to Hell!
Is it hard to come off of SSRI's
A good doctor will warn you not to miss or come off of SSRI's quickly.
Ideally, they warn you beforehand that this is even an issue if you want to come off but good luck on that one.
We're finally seeing the floodgates open on articles in the media regarding how excruciating if not impossible it is for people to come off of SSRIs.
It's about time!
If you didn't have lower serotonin, to begin with (can't test and most likely didn't), you may very well after coming off of SSRI's.
Put it this way...it can be downright dangerous to stop taking them quickly.
I had to wean off of Lexapro with a little blue pill cutter.
A sliver at a time.
Even then, it was even harder than coming off of benzos.
Check out CBD to wean off SSRI's and CBD to wean off benzos where I walk through the whole process.
So yes...Black Box warning hard to come off of SSRIs.
Are there other ways to get at the BDNF pathway without rolling the dice with the devil (coming off and Serotonin Syndrome here).
CBD and other alternatives to SSRI's
My story is common these days.
A brutal perimenopause which doctors then exploded into two years of trauma.
In many respects, my interaction with Lexapro was both the lowest point in my life (see SSRI and suicidal thoughts) and the reason we found CBD and started to research all of this.
Had it not been for SSRI's, I wouldn't be writing this and you would be at one of the other generic sites that say that SSRI's help with depression and anxiety.
So...what did we find for BDNF...the real effect of SSRI's for anxiety and depression?
These are the tools we found along the way:
- CBD (see CBD for BDNF or CBD for hippocampus neurogenesis)
- Exercise (see Exercise for neurogenesis)
- Mindful Meditation (see meditation for neurogenesis)
- Estradiol or Testosterone (see Estradiol for perimenopause)
That's on the "pro-growth" side.
What about the other end...slow-damage?:
- CBD (see CBD for inflammation or CBD for neuroinflammation)
- Curcumin - powerful anti-inflammatory
- NAC - boost glutathione and anti-oxidation
- Progesterone - for perimenopausal and menopausal women
- Fisetin - great anti-oxidant
- Berberine - powerful gut calming agent
Of course, we're best versed on CBD since it affects both sides of the equation:
- growth - (BDNF, serotonin, etc)
- insult (stress response, immune response, inflammatory response)
We focus on CBD Isolate to avoid histamine issues.
Histamine is excitatory and pro-inflammatory in the brain (see CBD and histamines for anxiety).
We want to avoid the plant material in full-spectrum that might cause histamine responses.
Research is showing that 300 mg of CBD is the best level for neurogenesis (see how many mg of CBD for anxiety).
Beyond that, the neurogenesis effect goes down.
We're really excited that science is finally starting to get to the root of how to address these pathways.
Micro-dosing psilocybin will probably be the new big entry on this front once legalized.
Interestingly, the long term effect for depression for psilocybin were from immune system (inflammation) genes being turned on and off!
This is revolutionary!
Outside of steroidal hormone loss (as we age), really zero in on remodeling the immune system. This is where the current research is!
Early trauma, infection can cause all the issues we discussed above and there are ways to offset this. More at Immune System and Mental Health.
This is about REAL change.
Until then, we have CBD and the actors available in the immune system link above.
Be well. Be informed. Be empowered!
Related Articles:
Deep dive into the process of depression
Pathways of anxiety
The science of brain repair for mental health
The problem with SSRIs
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.