- Serotonin: 9 Questions and Answers
- Impacts of Brain Serotonin Deficiency following Tph2 Inactivation on Development and Raphe Neuron Serotonergic Specification
- The dopamine side(s) of depression
- Wondering why you cannot tolerate antidepressants? SSRIs can cause Serotonin Syndrome
- What is an SSRI?
- What is Serotonin Syndrome?
- What causes SSRI intolerance?
- What should you do if you are currently taking an SSRI, but it is not working and you are concerned about adverse side effects?
- What else should you consider?
- Serotonin Fooled Me Once
Serotonin: 9 Questions and Answers
From the WebMD Archives
Serotonin acts as a neurotransmitter, a type of chemical that helps relay signals from one area of the brain to another. Although serotonin is manufactured in the brain, where it performs its primary functions, some 90% of our serotonin supply is found in the digestive tract and in blood platelets.
Serotonin is made via a unique biochemical conversion process. It begins with tryptophan, a building block to proteins. Cells that make serotonin use tryptophan hydroxylase, a chemical reactor which, when combined with tryptophan, forms 5-hydroxytryptamine, otherwise known as serotonin.
As a neurotransmitter, serotonin helps to relay messages from one area of the brain to another. Because of the widespread distribution of its cells, it is believed to influence a variety of psychological and other body functions.
Of the approximately 40 million brain cells, most are influenced either directly or indirectly by serotonin.
This includes brain cells related to mood, sexual desire and function, appetite, sleep, memory and learning, temperature regulation, and some social behavior.
In terms of our body function, serotonin can also affect the functioning of our cardiovascular system, muscles,and various elements in the endocrine system. Researchers have also found evidence that serotonin may play a role in regulating milk production in the breast, and that a defect within the serotonin network may be one underlying cause of SIDS (sudden infant death syndrome).
There are many researchers who believe that an imbalance in serotonin levels may influence mood in a way that leads to depression.
Possible problems include low brain cell production of serotonin, a lack of receptor sites able to receive the serotonin that is made, inability of serotonin to reach the receptor sites, or a shortage in tryptophan, the chemical from which serotonin is made.
If any of these biochemical glitches occur, researchers believe it can lead to depression, as well as obsessive-compulsive disorder, anxiety, panic, and even excess anger.
One theory about how depression develops centers on the regeneration of brain cells — a process that some believe is mediated by serotonin, and ongoing throughout our lives.
According to Princeton neuroscientist Barry Jacobs, PhD, depression may occur when there is a suppression of new brain cells and that stress is the most important precipitator of depression.
He believes that common antidepressant medications known as SSRIs, which are designed to boost serotonin levels, help kick off the production of new brain cells, which in turn allows the depression to lift.
Although it is widely believed that a serotonin deficiency plays a role in depression, there is no way to measure its levels in the living brain.
Therefore, there have not been any studies proving that brain levels of this or any neurotransmitter are in short supply when depression or any mental illness develops.
Blood levels of serotonin are measurable — and have been shown to be lower in people who suffer from depression – but researchers don't know if blood levels reflect the brain's level of serotonin.
Also, researchers don't know whether the dip in serotonin causes the depression, or the depression causes serotonin levels to drop.
Antidepressant medications that work on serotonin levels — SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin and norepinephrine reuptake inhibitors) — are believed to reduce symptoms of depression, but exactly how they work is not fully understood.
It can, but in a roundabout way. Un calcium-rich foods, which can directly increase your blood levels of this mineral, there are no foods that can directly increase your body's supply of serotonin. That said, there are foods and some nutrients that can increase levels of tryptophan, the amino acid from which serotonin is made.
Protein-rich foods, such as meat or chicken, contain high levels of tryptophans. Tryptophan appears in dairy foods, nuts, and fowl. Ironically, however, levels of both tryptophan and serotonin drop after eating a meal packed with protein.
Why? According to nutritionist Elizabeth Somer, when you eat a high-protein meal, you “flood the blood with both tryptophan and its competing amino acids,” all fighting for entry into the brain.
That means only a small amount of tryptophan gets through — and serotonin levels don't rise.
But eat a carbohydrate-rich meal, and your body triggers a release of insulin. This, Somer says, causes any amino acids in the blood to be absorbed into the body — but not the brain. Except for, you guessed it — tryptophan! It remains in the bloodstream at high levels following a carbohydrate meal, which means it can freely enter the brain and cause serotonin levels to rise, she says.
What can also help: Getting an adequate supply of vitamin B-6, which can influence the rate at which tryptophan is converted to serotonin.
Exercise can do a lot to improve your mood — and across the board, studies have shown that regular exercise can be as effective a treatment for depression as antidepressant medication or psychotherapy.
In the past, it was believed that several weeks of working out was necessary to see the effects on depression, but new research conducted at the University of Texas at Austin found that just a single 40-minute period of exercise can have an immediate effect on mood.
That said, it remains unclear of the exact mechanism by which exercise accomplishes this. While some believe it affects serotonin levels, to date there are no definitive studies showing that this is the case.
Studies show that men do have slightly more serotonin than women, but the difference is thought to be negligible.
Interestingly, however, a study published in September 2007 in the journal Biological Psychiatry showed there might be a huge difference in how men and women react to a reduction in serotonin — and that may be one reason why women suffer from depression far more than men.
Using a technique called “tryptophan depletion,” which reduces serotonin levels in the brain, researchers found that men became impulsive but not necessarily depressed.
Women, on the other hand, experienced a marked drop in mood and became more cautious, an emotional response commonly associated with depression.
While the serotonin processing system seems the same in both sexes, researchers now believe men and women may use serotonin differently.
Although studies are still in their infancy, researchers say defining these differences may be the beginning of learning why more women than men experience anxiety and mood disorders, while more men experience alcoholism, ADHD, and impulse control disorders.
There is also some evidence that female hormones may also interact with serotonin to cause some symptoms to occur or worsen during the premenstrual time, during the postpartum period, or around the time of menopause. Not coincidentally, these are all periods when sex hormones are in flux. Men, on the other hand, generally experience a steady level of sex hormones until middle age, when the decline is gradual.
In much the same way that we lose bone mass as we age, some researchers believe that the activity of neurotransmitters also slows down as part of the aging process.
In one international study published in 2006, doctors from several research centers around the world noted a serotonin deficiency in brains of deceased Alzheimer's patients.
They hypothesized that the deficiency was because of a reduction in receptor sites — cells capable of receiving transmissions of serotonin — and that this in turn may be responsible for at least some of the memory-related symptoms of Alzheimer's disease.
There is no evidence to show that increasing levels of serotonin will prevent Alzheimer's disease or delay the onset or progression of dementia. However, as research into this area continues, this could also change.
SSRI antidepressants are generally considered safe. However, a rare side effect of SSRIs called serotonin syndrome can occur when levels of this neurochemical in the brain rise too high.
It happens most often when two or more drugs that affect serotonin levels are used simultaneously.
For example, if you are taking a category of migraine medicines called triptans, at the same time you are taking an SSRI drug for depression, the end result can be a serotonin overload. The same can occur when you take SSRI supplements, such as St. John's wort.
Problems are most ly to occur when you first start a medication or increase the dosage. Problems can also occur if you combine the older depression medications (known as MAOIs) with SSRIs.
Finally, recreational drugs such as ecstasy or LSD have also been linked to serotonin syndrome.
Symptoms can occur within minutes to hours and generally include restlessness, hallucinations, rapid heartbeat, increased body temperature and sweating, loss of coordination, muscle spasms, nausea, vomiting, diarrhea, and rapid changes in blood pressure.
Although not a common occurrence, it can be dangerous and is considered a medical emergency. Treatment consists of drug withdrawal, IV fluids, muscle relaxers, and drugs to block serotonin production.
© 2008 WebMD, LLC. All rights reserved.
Impacts of Brain Serotonin Deficiency following Tph2 Inactivation on Development and Raphe Neuron Serotonergic Specification
Brain serotonin (5-HT) is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age.
To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2).
Tph2 inactivation (Tph2−/−) resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/− mice.
The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT) demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification.
Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons.
Moreover, 5-HT deficiency induces an up-regulation of 5-HT1A and 5-HT1B receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis.
Citation: Gutknecht L, Araragi N, Merker S, Waider J, Sommerlandt FMJ, Mlinar B, et al. (2012) Impacts of Brain Serotonin Deficiency following Tph2 Inactivation on Development and Raphe Neuron Serotonergic Specification. PLoS ONE 7(8): e43157. https://doi.org/10.1371/journal.pone.0043157
Editor: Sophie Mouillet-Richard, INSERM, UMR-S747, France
Received: February 5, 2012; Accepted: July 17, 2012; Published: August 17, 2012
Copyright: © Gutknecht et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by the German research foundation (DFG) (S 581, S TRR 58, KFO 125), IZKF (N-162) and the European Community (NEWMOOD LSHM-CT-2003-503474). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Serotonin (5-hydroxytryptamine, 5-HT), a neuromodulator and neurotransmitter extensively distributed in the brain, is involved in the regulation of a wide range of basic physiological functions including developmental processes, synaptic plasticity as well as metabolic homeostasis, neuroendocrine function, appetite, energy expenditure, respiratory rate or sleep. In addition, the 5-HT system, also through its capacity to modulate the activity of other neuronal networks, shapes and regulates cognition and complex emotional behaviors including in interaction with environmental stressors (Gutknecht et al., unpublished data). It has been implicated in a wide spectrum of human behavioral traits as well as neurodevelopmental and neuropsychiatric disorders. An increasing body of evidence links 5-HT signaling alterations in early development to cognitive deficits, emotional dysregulation, and psychopathology in adult age , . During ontogeny, 5-HT appears long before maturation of the raphe serotonergic neurons, suggesting a fundamental role in embryonic and brain development. Several in vitro and in vivo studies showed a morphogenetic effect of 5-HT on proliferation, migration, differentiation, connectivity and survival of neural cells, including the autoregulation of the development of the 5-HT system itself (reviewed in , ). To further analyze the significance of brain 5-HT in general development, the development and function of the brain and more specifically on the differentiation and specification of the serotonergic system itself, we have generated a mouse model displaying a brain-specific 5-HT deficiency resulting from a genetically driven inactivation of neuronal tryptophan hydroxylase-2 (Tph2, NCBI: protein, NP_775567.2; gene ID, 216343, ). Tph2 is the key enzyme in the synthesis of neuronal 5-HT – and catalyzes the hydroxylation of tryptophan (Trp) to 5-hydroxytryptophan (5-HTP) which is transformed to 5-HT by the amino acid decarboxylase (AADC). Tph2 is specifically expressed in the 5-HT neurons of the brainstem raphe complex and is exclusively responsible for the 5-HT synthesis within the brain , while Tph1 (NCBI: NP_033440) is the peripheral isoform. Tph2 null mutant (Tph2−/−) mice thus lack the ability to synthesize 5-HT specifically in brain and as a consequence have lost the capacity to release 5-HT and to establish serotonergic neurotransmission, while their peripheral 5-HT production is left intact.
Other but different models of genetically driven central 5-HT reduction were previously generated, such as the Tph2 R439H knockin mice , yet, this mutation only induces a 50% reduction of extracellular 5-HT in brain regions .
Mice with inactivation of the Pet1  and Lmx1b ,  genes, coding for transcription factors involved in the specification of serotonergic neurons were also generated. However, both represent modification “upstream” of the specification process rather than a specific inactivation of neuronal 5-HT synthesis.
In Pet1 knockout mice (Pet1 KO), 5-HT deficiency is incomplete with approximately 30% of the differentiated 5-HT neurons remaining in various raphe nuclei .
In conditional Lmx1b knockout mice (Lmx1b cKO), in which the gene deletion is driven specifically in serotonergic neurons, 5-HT neurons are generated but fail to differentiate and survive . In contrast, in Tph2−/− mice, serotonergic neurons and their projections are still present but devoid of 5-HT .
In the present study, we investigated the impact of brain 5-HT deficiency on general and brain development, function of other monoamine neurotransmitters and on the specification and maintenance of the serotonergic system itself with focus on the neurochemical, molecular, cellular, and electrophysiological phenotype.
5-HT is implicated in the regulation of various physiological pathways influencing somatic growth, appetite, energy expenditure and storage.
To evaluate the effect of central 5-HT deficiency on the regulation of these mechanisms, body weight was determined in different Tph2 mutants compared to wildtype (wt) littermates at different ages from 3 weeks up to 2.2 years. First, as visible in Fig.
1, adult Tph2-deficient mice display an overall normal life expectancy. Using age as a covariable, growth retardation and leanness which persists throughout the lifespan was observed in Tph2−/− males (F(2,417) = 11.56, p
The dopamine side(s) of depression
Depression is a disease with a difficult set of symptoms. Not only are the symptoms difficult to describe (how do you really describe anhedonia, before you know the word for it?), symptoms of depression manifest in different ways for different people. One person will eat more, sleep all the time, move slowly.
Another will eat almost nothing, never sleep, and be irritable and nervous. They are both depressed. The only universal symptom is the feeling of…depression, and the need for successful treatment. Treatments which often take several weeks to work, are often ineffective, and which come with a host of side effects.
So I was particularly intrigued when Nature published two papers this week looking at the role of dopamine in depressive- behavior. What I particularly is that these two papers have somewhat opposite results, due to different behavioral methods, something which I think highlights some of the problems associated with studying depression.
Ed Yong covered both of the studies together fabulously over at Not Exactly Rocket Science, but I'd to look at them both separately, to take a deeper look at each one, see what they've achieved, and what other questions they raise.
So I will start with one today, and post the other tomorrow, looking at both sides of dopamine's potential role in depression.
Tye et al. “Dopamine neurons modulate neural encoding and expression of depression- behaviors” Nature, 2012.
While you often hear about serotonin in studies of depression (serotonin is, after all, a target of many current antidepressants), there are many other neurotransmitters and systems that are also under investigation, and many of them are bearing some fruitful results. Ketamine, for example. And of course there is the role of dopamine.
We usually think of dopamine linked more with things reward or drug-addiction, but what dopamine actually does is more complex than that.
Dopamine is involved in movement, for example, but it is also involved in, for lack of a better word, “motivated behavior”.
I often think of dopamine in terms of “salience”, helping to determine how relevant something is to your interests, which encompasses motivated behaviors for food, sex, drugs, etc.
And dopamine could also be important in major depressive disorder.
People with depression often exhibit reduced motivation, anhedonia (a decrease in pleasure from usually enjoyed things), sometimes motor decreases as well. All of these are linked with dopamine.
So targeting the dopamine system is one of the ways in which we can look at potential mechanisms and treatments for depressive behaviors.
For this study, the Deisseroth lab (famed for the development of optogenetics) used their famous approach, combined with behavioral techniques, to look at the role of dopamine in depressive- behaviors in animals. Optogenetics is a fascinating technique.
In it, you insert a gene (usually via a harmless viral vector) for a protein called halorhodopsin. This is a channel that, when activated by light, will inhibit action potentials in a neuron, effectively shutting the neuron “off” from signaling.
When you insert the gene for this channel into a neuron using a virus (and usually targeted for a specific neuron set), it will be expressed, and then when you shine a light into the animal's brain, the channel will be activated.
It's a fast and efficient way to shut down very specific sets of neurons.
In this case, Tye et al aimed for the ventral tegmental area (VTA), a set of dopamine neurons that projects to areas the nucleus accumbens.
This is a system that is very closely related to reward and motivation (as opposed to the other set of dopamine neurons in the substantia nigra, which is more closely related to movement).
Then, when they had expression, they tested the animals for a variety of depressive- behaviors, with the light off (so dopamine neurons were firing normally), or with the light on (activating halorhodopsin and thus turning the dopamine cells “off”).
What you can see here is the result of two of the tests for depressive- behavior, tail suspension and sucrose drinking. Tail suspension (on the left) involves hanging a mouse up by its tail, so that it cannot escape.
The animal will struggle for a while, but then give up, showing what is sometimes termed passive coping behavior. If you give the animal an acute injection of an antidepressant Prozac, the animal will increase struggling.
If you expose an animal to chronic stress, on the other hand, they will show less struggling.
And apparently, this also works if you turn “off” the dopamine neurons in the ventral tegmental area. When the light was on (and the dopamine neurons “off”), the animals showed reduced time spent struggling compared to when no light was present.
Of course, because dopamine has a great deal to do with locomotor activity, they had to check that the decreased struggling wasn't just a side effect of decreased locomotor activity.
So on the top right of that figure, you can see the locomotor effects when the light is off vs when it is on. While there is no statistically significant change, it does look there may be something there (which I will get to later). But the authors also conducted another type of test.
On the bottom right you can see sucrose preference, which is used to test anhedonia, or lack of pleasure. A mouse is placed in a chamber with a bottle for water and one for sucrose (which they very much), and you count how much they lick the sucrose.
You can see that when the light was on (and the dopamine neurons “off”) the animals drank less sucrose, showing an anhedonia- behavior.
Then, the authors decided to look at the dopamine neurons from another direction. In a different set of animals they did another optogenetics experiment, this time using channelrhodopsin.
While halorhodopsin is a channel that turns neurons “off” when activated, channelrhodopsin does the opposite, producing increased activation of the neurons. They then exposed the animals to a paradigm known as chronic mild stress for 8-12 weeks.
This is a series of mild stressors (damp cage bedding, cold environment, disco music, your cage being tilted oddly) that rotate, so the stress is unpredictable, for 8-12 weeks.
Here you can see animals exposed to chronic mild stress, and the effects of the channelrhodopsin.
After chronic mild stress, animals show increased depressive- behaviors, they spend less time struggling in the tail suspension (the left of the figure, see the grey line), and drink less sucrose (bottom right of the figure).
But when the authors turned on the lights and activating the channelrhodopsin, animals that had been stressed began to look unstressed animals, showing more struggle and sucrose drinking (see the blue line).
This shows us that decreasing dopamine cell firing can produce an increase in depressive behaviors, and increasing dopamine cell firing can help prevent depressive- behaviors. This effect required dopamine neurons, and only dopamine neurons, influencing glutamate neurons in the same area had no effect.
So it appears that changing dopamine cell firing from the ventral tegmental area could have a big effect of depressive- behaviors. What is particularly interesting is that these effects were immediate, onset within seconds, as opposed to the weeks required with current antidepressant treatment.
So it opens up the possibility of looking at alterations in dopamine for treatment of depression in humans, something which we've already had some hints about (for example, some doctors use Ritalin to augment antidepressant treatment and make it work faster, and Ritalin has a strong effect on dopamine).
And it provides a nice mechanism for producing changes in depression-related behaviors.
While this is a really interesting and good paper, making great use of coming new techniques with older ones, it also raises some interesting questions for depression related research.
The results of the optogenetics were significant in producing increased activity in the forced swim tests and tail suspension test. While the locomotor effects weren't significant statistically…
it definitely looks something (and the lack of effect could be due to statistics). Dopamine is very closely linked with locomotor activity…and so are the forced swim and tail suspension tests, which can both be disrupted by locomotor activity changes.
So while the locomotor results may not be significant, were they small enough not to influence the test? What does the increased locomotor activity mean for the depressive- behavior?
The same could be said for sucrose drinking, but in a different way. Dopamine signaling is linked to salience and to reward-related behaviors. And sucrose drinking is definitely a reward-related behavior.
While this may actually be an advantage in this case (showing an increase in reward-related behavior may be better for depression research than otherwise), this, and the other depression tests, really make me wonder: will we ever come up with behavioral tests that can avoid all of these potential confounds? Usually scientists get around this by doing several types of test, combining (as in this case), the more locomotor-influenced tests with a more hedonia-influenced test. But, in the case of dopamine, does this really help? What does it mean? These behavioral tests are incredibly important and necessary for finding new potential treatments and the mechanisms behind behaviors, but with all of the potential pitfalls of these tests, we may never really know how well a potential treatment work to treat depression until we can test it in a human (or until we can put a mouse on a couch and understand its problems).
And of course, it also raises more mechanistic questions. What other systems besides dopamine are involves and how much so? When two patients show three constellations of symptoms, how do we know which systems might provide the best avenues of treatment?
The authors themselves put it best:
These results underscore the fact that psychiatric
diseases defined by a constellation of different classes of symptoms can
be influenced by multiple neural circuit processes. The heterogeneity
of mood disorders further complicates the pinpointing of precise circuit
dysfunctions mediating symptoms of depression. In animal
models, tests such as sucrose consumption (when depressed patients
can experience either increased or decreased appetite) and the FST
(which may involve transitions between active and passive coping
strategies) must be interpreted with caution.
But we need to find new treatments, new mechanisms, and they begin with studies these.
Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J, Kim SY, Adhikari A, Thompson KR, Andalman AS, Gunaydin LA, Witten IB, & Deisseroth K (2012). Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature PMID: 23235822
*One of the authors also came up with a great new way to look at forced swim counts, which I did not show here, as they mostly focused on the tail suspension for the main effect. It's the sort of thing you only really get excited about if you're a behaviorist, but it's definitely got me interested.
In a forced swim test, an animal is placed in a tank of water where it cannot touch the bottom, and where it cannot climb out. You record the amount of time spent swimming vs the amount of time spent floating (animals almost never sink in these experiments, they are very good swimmers). The amount of time spent swimming can be influenced by antidepressants.
Usually, when someone runs a forced swim test, they videotape, either from the top of the water tank (looking down on the animal) or from the side (to see the whole animal). The recordings are then scored either automatically (automatic systems often look at velocity from above) or with a videotape and a timer (and large amounts of caffeine).
This means there's some variability present in the measurements, when you're looking from the top you can't actually see the animal's feet all the time, so you can't really see how much they are swimming vs doing the bare minimum to stay up.
But looking from the side, it's hard to see all the forms of motion, you can usually only see one side of the mouse. But this author took all of that out, and instead used a magnetic ring around the tank, and a small magnet on the rat's foot. When the rat's foot kicked, the magnetic ring detected it, resulting in an automated kick score.
While this can't differentiate between swimming and climbing behaviors (which is actually really important for pharmacological classification of drugs), if you're looking just for changes in activity…it's pretty brilliant.
Wondering why you cannot tolerate antidepressants? SSRIs can cause Serotonin Syndrome
Last Updated on September 3, 2019
This blog was originally posted on Nov 17th 2016, and revised and updated.
Many people diagnosed with depression cannot tolerate antidepressants even at low doses. To treat the symptoms of depression, patients often try different medications to no avail; nothing seems to work or they cause intolerable side effects.
In the worst-case scenario, a serious adverse reaction to antidepressants such as commonly prescribed SSRIs can include a potentially fatal condition known as ‘Serotonin Syndrome’.
Here we explain why some people have problems finding optimal treatment for depression, anxiety and other mental health conditions.
What is an SSRI?
SSRI is an acronym for ‘Selective Serotonin Reuptake Inhibitor’, which is a class of drugs for the treatment of mental health conditions that includes some of the most commonly prescribed antidepressants. SSRIs are used to treat depression, anxiety disorders and other conditions such as Obsessive-Compulsive Disorder (OCD).
Serotonin is one of the important chemical messengers of brain cells; it regulates mood, emotion, social behaviour, sleep, memory, learning and other functions. It is thought that people who suffer from depression have lower levels of serotonin in the brain.
SSRIs work by blocking the re-absorption of serotonin, causing the level of serotonin in the brain to increase over time, enhancing communication between neural cells. In general, depression symptoms are relieved once an appropriate level of serotonin is achieved.
This is why it takes several weeks before patients and their doctors can know whether or not a treatment plan is working. However, having too much serotonin in the brain also leads to major mental health problems.
Some patients with bipolar disorder, schizophrenia, or personality disorders have elevated levels of neural transmitters in the brain, including serotonin, leading to severe mood swings and anxiety.
Some patients cannot tolerate even the first few doses of SSRIs.
What is Serotonin Syndrome?
When treated with SSRIs, people may be at risk for a serious drug reaction called Serotonin Syndrome, which can be triggered by use of other drugs and supplements that further increase serotonin levels. Serotonin Syndrome symptoms include:
- rapid heart rate
- agitation / restlessness / panic attacks
- twitching muscles
- loss of muscle coordination
- heavy sweating
- high fever
There can be a range in the severity of symptoms. In the case of mild symptoms, the side effects are usually alleviated once the medication is stopped. Some patients, however, experience severe symptoms which can be fatal if left untreated.
Serotonin syndrome can be triggered by interactions between SSRIs, other types of antidepressants, as well as some supplements.
When switching between different types of antidepressants, the current drug must be slowly tapered down over a few weeks, followed by a washout period before new antidepressants can be started to reduce the risk of Serotonin Syndrome. Consult with your doctor and pharmacist about the best way to start new medications safely.
What causes SSRI intolerance?
The answer is in your genes.
Not all patients experiencing mood swings or depression have abnormally low levels of serotonin in the brain.
Even though they have normally functioning liver enzymes that metabolize SSRIs properly, they are still unable to tolerate these medicines, even at low concentrations, and can experience side effects within a few hours of getting the first doses.
People who experience such symptoms frequently carry a mutation in one of the genes that makes proteins involved in the clearance of serotonin from the body, which results in accumulated high levels of serotonin.
An excess of serotonin is commonly found in patients with bipolar disorder and other inherited mental health conditions which have anxiety and depression as part of the initial clinical presentation. The trouble for these people begins when they start taking an SSRI, in combination with other medications that further elevate serotonin levels.
If you are experiencing worsening of anxiety symptoms, rapid heart beat and difficulty breathing when taking one or two doses of your antidepressant, SSRIs might not be right medication for you.
What should you do if you are currently taking an SSRI, but it is not working and you are concerned about adverse side effects?
- Talk to your doctor, pharmacist or other trusted healthcare provider. Describe your side effects in detail, as well as your family history of mental illness.
- If Serotonin Syndrome is suspected, the recommendation would be to discontinue SSRIs and start a different type of antidepressant that does not have an effect on serotonin.
What else should you consider?
The majority of side effects occur when medication concentration in the bloodstream is too high. This can occur even if you are taking a regular drug dose, but your liver cannot eliminate the drug your body. Most of the commonly used antidepressants are metabolized primarily by two liver enzymes.
If one of these enzymes is not working, i.e. you are a Poor Metabolizer, the level of antidepressant increases in the blood, which leads to significant side effects. If antidepressants work too quickly, i.e.
you are a Rapid or Ultrarapid Metabolizer, the drug is eliminated too fast and it does not achieve a high enough concentration in the blood, to be effective.
our experience with psychiatric patients, we note that most of the patients with bipolar disorder and schizophrenia have normal activity of both enzymes.
The side effects they are experiencing are unrelated to drug metabolism, but rather to different brain activity.
The STAR*D study demonstrated that only one-third of patients respond to the first line of treatment with antidepressants, and the majority of patients with depression have to undergo multiple drug trials to find the most effective medication.
The ultimate goal of Pharmacogenetics is to improve treatment outcomes by predicting a patient’s response to specific drugs – before they are prescribed. This approach allows us to move away from the traditional “trial method” of prescribing medicines and shift towards a more evidence-based, personalized approach.
A Pharmacogenetic (PGx) Test, such as Pillcheck™, can help you know in advance whether or not you are at risk for adverse side effects or if you may not benefit from specific medications due to an inherited altered drug metabolism.
However, many patients with a serotonin imbalance cannot tolerate SSRIs even though their liver enzymes are functioning normally. In other words, patients may experience SSRI-induced side effects even though their Pillcheck report shows that this medication is appropriate for them.
These patients should consider more comprehensive genome analyses which can provide valuable insights on the underlying causes of mental illness.
Knowing how your body processes medications can significantly reduce the time to remission, decrease the risk of adverse side effects, improve drug efficacy and lead to overall better treatment outcomes.
Learn more about role of pharmacogenetics in mental healthhere
Drug-Induced Serotonin Syndrome. Bartlett D et al. Crit Care Nurse. (2017) https://www.ncbi.nlm.nih.gov/pubmed/28148614
Serotonin syndrome (serotonin toxicity) https://www.uptodate.com/contents/serotonin-syndrome-serotonin-toxicity
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512908/
Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. https://www.ncbi.nlm.nih.gov/pubmed/27997040
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Serotonin Fooled Me Once
Since I worked in an ER for 25 years, I thought I had pretty much seen everything in medicine there was to see. But when I started working in jails, I was quickly confronted with clinical scenarios that I had no experience with from my ER days. Here is one such case:
A 46-year-old man came into my jail medical clinic complaining of muscle aches and twitching, which he first noticed 2 days before. He had been booked into the jail 2 weeks previously.
This patient's currently prescribed medications prior to coming to jail were continued (as is our general policy): sertraline 200 mg a day, buspirone 15 mg PO BID, and trazodone 200 mg at bedtime.
He also took lisinopril/hydrochlorothiazide and atorvastatin.
The patient walked into clinic with an odd stiff-legged gait and a noticeable hand tremor. He had a heart rate of 124, a blood pressure of 156/100, and a temperature of 99.4° F. His speech was a bit anxious and pressured. Beads of sweat were visible on his forehead. His patellar reflex was exaggerated, but without clonus.
So, what was going on with this patient? I considered the “usual suspects,” such as infection, metabolic abnormalities ( hyperthyroidism), and methamphetamine intoxication (inmates can, indeed, sometimes get meth and other drugs despite being in jail).
But I was most suspicious of serotonin syndrome — and this turned out to be the right diagnosis.
Serotonin syndrome may be an uncommon or even rare condition in outside medicine (I had never seen a case in my ER career), but I have found it to be pretty common in jails.
Serotonin syndrome is a constellation of symptoms caused by an excess of the neurotransmitter serotonin. It ranges in severity from mild/moderate cases ( the one above) to fatal. Serotonin syndrome is characterized by a trinity of abnormalities:
1. Neuromuscular hyperactivity: muscle twitching, tremor, and hyperreflexia.
2. Autonomic effects: tachycardia, hypertension, hyperthermia, sweating, and shivering.
3. Mental status effects: anxiety, agitation, hypomania, confusion, and hallucinations.
Mild cases of serotonin syndrome may only manifest as tremor, hyperreflexia, tachycardia, and sweating.
Moderately severe patients will additionally have an increased temperature, clonus, and agitation.
Patients with severe serotonin syndrome are typically delirious, hallucinating, and have very high temperatures (sometimes over 106° F), which can lead to all sorts of bad effects, rhabdomyolysis, seizures, renal failure, and yes, death.
Serotonin syndrome is caused by drugs that increase serotonin levels in the brain. These are mostly psychiatric drugs, of course. The big three categories of serotonergic drugs are:
1. Selective serotonin reuptake inhibitors (SSRIs). My patient was taking sertraline (Zoloft), but don't forget fluoxetine (Prozac), citalopram (Celexa), and many others.
2.Tricyclic antidepressants (TCAs), which act by blocking serotonin reuptake as well as norepinephrine reuptake. The ones I see used most are amitriptyline, imipramine, and doxepin.
3. Serotonin-norepinephrine reuptake inhibitors (SNRIs). This group includes trazodone, venlafaxine (Effexor), duloxetine (Cymbalta), and others. My patient was also taking trazodone.
You should memorize that list! However, many other drugs increase serotonin levels besides those in the big three categories. Interesting examples include amphetamines, buspirone, tramadol, and the triptans. My patient was also taking buspirone.
Clinicians inadvertently cause serotonin syndrome in their patients in two main ways. The first is when they prescribe large doses of serotonin drugs, usually an SSRI. A psychiatrist friend of mine told me that when Prozac was first introduced, doctors used to commonly prescribe large doses, 80 mg or even more a day.
As a result, my friend says he used to see lots of mild/moderate cases of serotonin syndrome caused by large doses of Prozac alone. It is less common to see large doses of SSRIs used nowadays, since it has been pretty well established that patients get little, if any, additional benefit from SSRIs by using extra-large doses.
However, I still see large doses of SSRIs prescribed in the community and, in fact, my patient was taking the maximum dose of sertraline.
The second (and more important) cause of serotonin syndrome is when clinicians prescribe two or more different serotonin agents from two different categories. This practice is very common. For example, an SSRI is often prescribed along with trazodone for sleep. SSRIs are also combined with an SNRI or a TCA for severe depression.
My patient was actually taking three serotonin drugs: sertraline, trazodone, and buspirone. I suspect that the practitioner in the community who prescribed all three did not check their drug interactions.
If he had used the drug interaction checker that I generally use myself, a big red stop sign would have popped up saying (approximately): “Major potential drug interaction! Risk of serotonin syndrome! Do you really want to do this?”
Fortunately, my patient only had mild/moderate serotonin syndrome, so I was able to successfully treat him by stopping all three drugs and giving him a little diazepam. He was asymptomatic the next day. However, serotonin syndrome can manifest itself much more rapidly and be much more severe, as I had learned from an earlier patient.
This patient was a middle-aged man in jail who was prescribed both paroxetine (Paxil) and imipramine (Tofranil) by his outside psychiatrist.
A couple of months after his incarceration, he developed agitation, hallucinations, vomiting and within several hours became unresponsive.
At the ER, he had a temperature of 107° F, intense muscle rigidity, and full-blown shock. This case did not turn out well.
This tragic case occurred early in my correctional medicine career. It made me vigilant in looking for evidence of serotonin syndrome — and I subsequently have found several mild/moderate cases since. This case also made me question whether the benefit of combining two serotonergic agents in one patient ever outweighs the risk. I personally don't believe so.
Whether you agree or disagree with this conclusion, please remember the danger of serotonin syndrome when you “max out” the dose of SSRIs or especially if you combine serotonergic agents.
You may have used a particular combination sertraline-trazodone a hundred times and have never seen ill effects, but that does not mean you never will! Consider carefully whether the benefits of combining serotonergic drugs truly outweigh the risk of serotonin syndrome.
Don't get burned I did!
Jeffrey E. Keller, MD, FACEP, is a board-certified emergency physician with 25 years of experience before moving full time into his “true calling” of correctional medicine. He now works exclusively in jails and prisons, and blogs about correctional medicine at JailMedicine.com.