Serotonin Toxicity: A Review

By: Duke Quach, Kelsey Homan & Lauren Witty

Background
Serotonin (5-hydroxytryptamine or 5-HT) is a ubiquitous neuroendocrine monoamine with both
neurotransmitter and hormone properties, including autocrine, paracrine, and endocrine signaling.1 The
physiological effects of 5-HT are highly variable, such that the degree of response varies not only
between individuals of the same species, but between successive tests on the same individual as well.2
5-HT has a wide range of physiological effects throughout the body. 5-HT plays a role in controlling body
temperature and regulating sleep and circadian rhythms through the 5-HT7 receptor.3 Pathways of 5-HT
in the central nervous system can affect posture and movement, as well as behavioral responses to
arousing stimuli.4 Activation of the carotid and aortic chemoreceptors by 5-HT influences respiration by
temporarily increasing the respiratory minute volume.2 Additionally, 5-HT may also have opposing
effects on the cardiovascular system, either causing vasoconstriction or vasodilation, depending on the
particular vessels influenced.2 Modulation of 5-HT transmission is also considered in numerous CNS
diseases including depression, anxiety, schizophrenia, obsessive-compulsive disorders, addiction,
Parkinson’s disease, and Alzheimer's disease. 5 While many effects of 5-HT have been identified, it’s
overall or total role throughout the body remains elusive and many experiments continue to test effects of
serotonin today.

Serotonin toxicity, also known as serotonin syndrome (SS) is a largely iatrogenic, or drug-induced,
disorder characterized by the overconcentration of free 5-HT or overactivation of 5-HTRs.6 Generally,
severe SS is only seen in individuals taking 2 or more serotonergic drugs.6 However, the syndrome can
occur with the use of a single serotonergic drug in a particularly susceptible individuals.6 SS has been
documented as far back as 1085 C.E. related to ergot alkalosis (a type of grain contaminant), and
continues to be seen in all age groups.6 Today, SS most often occurs when certain antidepressant agents,
particularly selective serotonin reuptake inhibitors (SSRIs), are taken concurrently with other drugs that
manipulate synaptic serotonin levels, including recreational drugs such as ecstasy.7, 8 Symptoms of SS
include a combination of changes in mental status, neuromuscular hyperactivity, and autonomic
hyperactivity due to the effects of 5-HT in both the peripheral and central nervous systems.9 Presentation
of SS is extremely variable, ranging from mild to life-threatening symptoms, that usually begin within 24
hours of the addition or increased dose of a serotonergic agent.9 Mild SS will usually present with
hypertension, tachycardia, mydriasis, diaphoresis, shivering, tremor, myoclonus, and hyperreflexia.9
Moderate SS will present with the symptoms included for mild SS as well as hyperthermia (40°C),
hyperactive bowel sounds, horizontal ocular clonus, mild agitation, hypervigilance, and pressured
speech.9 Severe cases exhibit previously mentioned symptoms as well as hyperthermia greater than
41.1°C, dramatic swings in pulse rate and blood pressure, delirium, and muscle rigidity.9 Severe
cases may also result in complications such as seizures, rhabdomyolysis, myoglobinuria,
metabolic acidosis, renal failure, acute respiratory distress syndrome, respiratory failure, diffuse
intravascular clotting, coma, and death.9

Diagnosis
Due to the large variability in symptoms, the actual incidence of SS is unknown and likely much greater
than the actual number of reported cases.9 However, the incidence of SS and adverse drug reports with
SSRIs has continued to increase as more serotonergic drugs become widely available.7 Additionally,
reporting of cases of SS continues to rise due to increasing awareness of the syndrome.9 No single
diagnostic test is able to confirm the diagnosis of SS.10 The diagnosis of SS is entirely clinical, relying on
the patient’s history, including serotonergic drug use, as well as physical examination.9 The “gold
standard” for SS diagnosis is diagnosis by a medical toxicologist using the Hunter Serotonin Toxicity
Criteria.9, 11 The Hunter Serotonin Toxicity Criteria is intended to be more sensitive to SS and less likely
to yield false positives than other SS criteria based on a retrospective analysis of prospectively collected
data.11

Normal Serotonin Synthesis and Release

Serotonin, more formally known as 5-hydroxytryptamine (5-HT), is synthesized in the brainstem midline.
The precursor to 5-HT is the essential amino acid L-
tryptophan, and it must undergo various reactions to be
converted to 5-HT. The rate limiting step in serotonin
synthesis involves the conversion of L-tryptophan to
5-hydroxytryptophan (5-HTP), and if manipulated, can
lead to a great increase or decrease in serotonin
concentration.12

Once synthesized, serotonin is packaged within the

neuron into vesicles and released into the synaptic cleft
due to calcium-regulated exocytosis. Then, serotonin is
able to bind to the corresponding 5-HT receptor on the
postsynaptic cleft, initiating the desired signal within the
postsynaptic neuron. Once the signal has been sent,
serotonin is sent back into the synaptic cleft and
transferred to the presynaptic neuron by serotonin
reuptake transporters (SERTs). Thus, serotonin is either
repackaged and stored or degraded in order to prevent
continuous serotonin signals.12

Mechanisms of Serotonin Toxicity

In the case of serotonin toxicity, there is over activity of
the 5-HT receptors, leading to continuous serotonin signaling. This stimulation of the 5-HT receptors can
be caused by numerous mechanisms, and the exact pathophysiology of serotonin toxicity is still an active
area of research. So far, researchers have defined the following mechanisms of serotonin toxicity:

1. Inhibition of Serotonin Uptake: with serotonin circulating within the synaptic cleft, it can
continuously bind to 5-HT receptors, causing an increase in serotonin signaling
2. Decreased Serotonin Metabolism: when MAO, the enzyme responsible for the degradation of
serotonin within the presynaptic neuron, is inhibited, more serotonin accumulates within the
presynaptic neuron, which increases the amount of 5-HT released into the synaptic cleft, leading
to over-activity of 5-HT receptors
 3. Increased serotonin synthesis: an increase in the concentration of L-tryptophan can lead to
increased serotonin concentrations, which causes over-activity of 5-HT receptors
4. Increased serotonin release: amphetamines can cause vesicles containing 5-HT to exocytose
without the proper calcium signals, leading to an increase in serotonin concentration within the
synaptic cleft, and over-activity of 5-HT receptors.
5. Activation of serotonergic receptors: certain drugs can bind to 5-HT receptors and cause
continuous signaling
6. Inhibition of CYP450 Enzymes (Specifically CYP2D6 and CYP3A4): CYP450 enzymes are
used to degrade certain drugs that promote serotonergic activity. However, when CYP450
enzymes are inhibited by drugs such as SSRIs, degradation of these drugs stops, and serotonergic
receptor activity increases.9

Usually, in order to cause severe symptoms

of SS, a combination of drugs will
invoke two or more of the
mechanisms above to increase
serotonin response. SSRIs, a
common antidepressant, have
numerous roles, but mainly inhibits
the activity of SERT, increasing
serotonin concentration within the
synaptic cleft.13 Combining a SSRI
with a MAO inhibitor (inhibits the
degradation of serotonin in the
presynaptic neuron) is the
combination most likely to lead to
SS, as the concentration of
serotonin remains high and is not
metabolized in the presynaptic
neuron. While this is the most
dangerous combination of drugs,
any combination of the drugs in
Table 1 can lead to an increased
risk for SS or a development of
more severe symptoms. With the
increase in opioid use and
serotonergic drug prescriptions, SS
prevalence has greatly increased
and is now a large public health
burden within the US.

Continued Research on the

Causes and Mechanism of Serotonin
Toxicity
Current research has attempted to pinpoint the specific receptor responsible for serotonin toxicity. While
this is still an area of active research, scientists have seen a correlation between severe serotonin toxicity
symptoms and over-activity of the 5-HT2A receptor. Additionally, elevated levels of norepinephrine,
dopamine and glutamate have been observed in the hypothalamus of serotonin toxicity patients,
suggesting that GABA and NMDA receptors may also be involved in the pathogenesis of SS in some
capacity.12

Finally, drug use is not the only cause of serotonin toxicity. Genetic polymorphisms within the T102C site
of the 5-HT21 receptor gene have been linked to a predisposition for developing serotonin toxicity.
Individuals with these polymorphisms have also been implicated in antidepressant therapy failure for a
variety of neuropsychiatric disorders.14 This genetic aspect of serotonin toxicity increases the complexity
of this disorder and opens the door for more research within this subject.

Treatments

First line of defense: Preventative treatment.

Avoid using two drugs that significantly increase serotonin levels. A list of common drugs that are taken
can be seen in figure 2.17 Taking accurate drug history from the physician's side. It is necessary to have an
accurate patient history when prescribing medicine. This prevents any additive or synergistic effects of
potential existing drugs. Prescribing the lowest effective dose and checking up on the patient regularly.
This is so that if there are multiple drugs that the patient is taking that affects serotonin, it is closely
monitored. The regular checkup is to see if there are any problems with the drugs and to see if the
prescribed drugs are having any effect.15

Figure 2.
Second line of defense: Palliative care and medicative intervention

Post diagnosis: Identifying and discontinuing potential drugs that may be causing the effects. Supportive
care is then put into action. Depending on how severe and what symptoms present, certain actions will be
taken. In cases of hyperthermia, cooling of the body is attempted by having external cooling and
administering benzodiazepines which lower the CNS which subsequently lowers HR and body
temperature13. With myoclonus (spasms of muscles) and hyperreflexia (increased response to reflexes), IV
and fluids are placed to prevent secondary effects of potential rhabdomyolysis and kidney dysfunction.15
In cases of severe SS, serotonin inhibitors such as antihistamine cyproheptadine can be used to treat
moderate to severe cases.16 Cyproheptadine is an FDA approved antihistamine used to treat allergic
reactions. Efficacy of this drug is not clinically proven as there have been no randomized trials in humans
which is why there is no FDA approval. It has been demonstrated within animal models to improve
serotonin syndrome.18 Cyproheptadine acts as a serotonin antagonist and it has shown some effect on
blocking the vasopressor effects and controlling the spasmogenic effects of serotonin. This can only be
administered orally which presents a potential problem regarding the rate at which it can take effect19. In
case studies of cyproheptadine, most patients respond within 1 to 2 hours with one 8mg dose.20
Author Contribution Statement
Kelsey Homan is responsible for all of the research and written content presented in the Background and
Diagnosis sections. Lauren Witty wrote the “Mechanisms of Serotonin Toxicity” and the “Current
Research on the Causes and Mechanism of Serotonin Toxicity” sections. All figures and tables within
those two sections were taken from other sources and are properly cited in both the sections and our
bibliography. Finally, Duke Quach is responsible for the entire “Treatments” section, including both the
primary and secondary line of defense treatment paragraphs. All figures used in this section are
referenced in the body paragraphs and cited within our bibliography.

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