What is a Serotonin Antagonist?
Serotonin antagonists and reuptake inhibitors are primarily indicated as antidepressant medications but are more commonly used to treat other conditions such as anxiety and insomnia. SARIs are non-narcotic. Studies have shown that medications like trazodone (a popular brand name) are comparable to other drug classes such as serotonin reuptake inhibitors (SSRIs) like Prozac or Zoloft, and serotonin-noradrenaline reuptake inhibitors (SNRIs) such as Cymbalta or Effexor. SARIs may also help individuals bypass certain side effects common with medications like SSRIs, symptoms like insomnia, anxiety, and sexual dysfunction.
Common side effects of serotonin antagonists include drowsiness, headache, dry mouth, dizziness, and blurred vision. Their use is associated with an antidepressant discontinuation syndrome, which means that people may experience certain drug withdrawal symptoms if the medication is stopped suddenly. There is also some risk of drug overdose and drug toxicity with SARIs. Though these drugs have a low potential for abuse, there have been reported cases of misuse in connection with polysubstance abuse.
Serotonin antagonists and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.
The two serotonin antagonist/reuptake inhibitors (SARIs), trazodone and nefazodone, inhibit serotonin reuptake and, to varying degrees, block serotonin 5-HT2A and 5-HT2C receptors. Advantages of SARIs include few sexual side effects and no changes in normal sleep architecture. Adverse effects include sedation, dizziness, nausea, constipation, and headache. Trazodone can also cause orthostatic hypotension and has a rare side effect of priapism.
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Neurotransmitters are chemicals that pass messages in your brain, telling you to feel certain ways. A specific neurotransmitter, serotonin, is thought to be responsible for feelings of well-being and happiness. When an individual suffers from major depressive disorder, their brain experiences decreased serotonin activity, resulting in low self-esteem, low energy, and loss of interest in daily activities.
Neurotransmitter receptors receive the messages from the neurotransmitters resulting in your brain processing these signals. Serotonin antagonists and reuptake inhibitors work by antagonizing or blocking the serotonin receptors from their usual reuptake process, where the neurotransmitters would generally process and then be removed. Instead, the SARIs allow serotonin to remain in the neurotransmitter system for longer periods of time, thus resulting in an elevated mood and an increased pleasure in activities.
Used in combination with therapy, SARIs allow individuals struggling with a major depressive disorder to develop the coping skills necessary to manage their depression. Therapy provides a safe place for people to process their feelings and learn how to handle them in the future. Aided by the increased sense of well-being provided by the serotonin antagonist and reuptake inhibitors, individuals with a major depressive disorder are better able to combat their depression and live a happy, healthy life.
What are Serotonin-Blocking Drugs Used for?
Consumers and health professionals are advised that serotonin syndrome is a newly identified issue associated with products containing the serotonin-blocking medicines classed as 5-HT3 receptor antagonists.
These medicines are used after surgery and in patients undergoing cancer treatment to prevent nausea and vomiting. They work by blocking serotonin from entering certain cells in the nervous system and brain.
Serotonin syndrome has been seen in patients using 5-HT3 receptor antagonists at the same time as other serotonergic medicines. Serotonin syndrome occurs when serotonin accumulates to high levels in the body, as can happen when medicines block the chemical from entering cells. The syndrome is characterized by:
- Altered mental state, e.g. confusion, agitation, restlessness, and excitement
- Autonomic dysfunction, e.g. tachycardia, sweating, shivering, hypertension, and hyperthermia
- Neuromuscular excitation, e.g. hyperreflexia, tremor.
In some cases, serotonin syndrome can lead to loss of consciousness, coma and death.
Serotonin Antagonist Drugs
5-HT3 receptor antagonists (also called serotonin receptor antagonists or serotonin blockers) are a class of medicines used to prevent and treat nausea and vomiting, particularly those caused by chemotherapy, radiation therapy, or postoperatively. 5-HT3 is an abbreviation for serotonin that may also be written as 5-hydroxytryptamine.
Cells lining the gastrointestinal tract release serotonin when damaged by chemotherapy and radiation therapy. This serotonin binds to serotonin receptors on nerves that transmit impulses to the vomiting center within the brain, which in turn stimulates other nerves involved in the vomit reflex. 5-HT3 receptor antagonists prevent serotonin from binding to 5-HT3 receptors in the small intestine, thereby reducing the likelihood of nausea and vomiting.
However, the way 5-HT3 receptor antagonists work to prevent postoperative nausea and vomiting is less well understood. The first-generation 5-HT3 receptor antagonists include dolasetron, granisetron, and ondansetron. Despite variations in their chemical structures and absorption rates, they all work similarly and are well tolerated. In addition, oral formulations are just as effective at preventing nausea and vomiting as intravenous forms.
Palonosetron is a second-generation serotonin blocker. It has a greater affinity for serotonin receptors than first-generation agents, which increases its duration of effect. Palonosetron is also thought to have an effect on 5-HT3 receptors in the vomiting center and chemoreceptor trigger zone as well, not just in the small intestine. It is approved for both acute and delayed chemotherapy-induced nausea and vomiting.
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Zofran (Pro)
Zofran (ondansetron) blocks the actions of chemicals in the body that can trigger nausea and vomiting. Zofran is used to prevent nausea and vomiting that may be caused by surgery, cancer chemotherapy, or radiation treatment.
Zofran ODT
Zofran ODT blocks the actions of chemicals in the body that can trigger nausea and vomiting. Zofran ODT is used to prevent nausea and vomiting that may be caused by surgery, cancer chemotherapy, or radiation treatment.
Sancuso
Sancuso (granisetron) blocks the actions of chemicals in the body that may cause nausea and vomiting. Sancuso skin patches are used to prevent nausea and vomiting caused by cancer chemotherapy.
Kytril
The Kytril brand name has been discontinued in the U.S. If the FDA has approved generic versions of this product, generic equivalents may be available. Kytril (granisetron) blocks the actions of chemicals in the body that can trigger nausea and vomiting.
Aloxi
Aloxi (palonosetron) blocks the actions of chemicals in the body that can trigger nausea and vomiting. Aloxi is used in adults to prevent nausea and vomiting caused by surgery or receive medicine to treat cancer (chemotherapy).
Sustol (injection)
Sustol blocks the actions of chemicals in the body that can trigger nausea and vomiting. Sustol is used to prevent nausea and vomiting caused by medicine to treat cancer (chemotherapy) or after surgery. Sustol is sometimes used together with other anti-nausea medications.
Zuplenz
Zuplenz (ondansetron) blocks the actions of chemicals in the body that can trigger nausea and vomiting. Zuplenz is used to prevent nausea and vomiting that may be caused by surgery, cancer chemotherapy, or radiation treatment.
Anzemet
Anzemet (dolasetron) blocks the actions of chemicals in the body that can trigger nausea and vomiting. Anzemet oral (taken by mouth) is used to prevent nausea and vomiting that may be caused by medicine to treat cancer (chemotherapy).
What are the Side Effects of Serotonin Antagonist and Reuptake Inhibitors
Serotonin antagonists and reuptake inhibitors tend to have fewer side effects than some earlier generation antidepressants such as tricyclics and monoamine oxidase inhibitors (MAOIs) [1].
That said, SARIs can produce some side effects. Commonly experienced side effects of trazodone are:
- Headache
- Dizziness
- Blurred vision
- Drowsiness
- Fatigue
- Dry mouth
- Constipation
Potentially more serious side effects include:
- Erection lasting for more than 6 hours (priapism)
- Orthostatic hypotension (falling blood pressure when rising from a sitting position; increased risk of falls and injuries)
- Syncope (fainting)
- Serotonin syndrome (agitation, hallucinations, poor coordination, trouble walking, rapid heartbeat, nausea, vomiting)
- Low levels of sodium in the blood (hyponatremia)
- Irregular or fast heartbeat
- Unusual bruising or bleeding
Common side effects of nefazodone include:
- Headache
- Dry mouth
- Indigestion
- Nausea
- Vomiting
- Constipation
- Increased appetite
- Sedation
- Orthostatic hypotension
- Dizziness
- Vision problems
- Burning or prickling sensations
- Agitation
- Confusion
- Impaired memory
- Lack of control over muscle movements
- Weakness
Serious but rare side effects of nefazodone include:
- Suicidality
- Liver toxicity
- Liver failure
- Mania
- Seizures
- Priapism
To counter the impact of the side effects, doctors may prescribe a smaller dose of the antidepressant initially and increase the dose as the individual’s body adjusts to the new medication.
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Serotonin Antagonist Uses
Antiemetic 5-HT3 antagonists are used in conditions such as:
- Chemotherapy-induced nausea and vomiting
- Postoperative nausea and vomiting
- Radiation-induced nausea and vomiting
- Hyperemesis gravidarum (an extreme form of morning sickness that causes severe nausea and vomiting during pregnancy)
- Cholestatic pruritus (sensation of itching because of any liver disease)
Can You Overdose from Serotonin Antagonists?
An overdose is possible on SARIs.
Symptoms of a trazodone overdose include:
- Drowsiness
- Vomiting
- Seizures
- Cardiac rhythm disturbances
- Respiratory arrest
- Erection lasting for more than 6 hours (priapism)
Symptoms of a nefazodone overdose include:
- Nausea
- Vomiting
- Over-sedation
- Hypotension (low blood pressure)
- Seizures
Seek emergency attention in the event of an overdose. If you’re with the person who has overdosed, try to find out when the person took the drug and how much they took, and recover the pill bottle, if possible, for the emergency response team.
Treating an overdose usually involves:
- Heart monitoring; frequent, serial vital sign monitoring
- Airway maintenance and breathing support (when needed) via supplemental oxygen or assisted ventilation
- Gastric lavage (stomach pumping)
- Activated charcoal to prevent the digestive tract from further absorbing the medication into the body
Can Serotonin Antagonists be Abused?
A study found that trazodone had less abuse potential than many other prescription drugs used for sleep disorders [2].
These drugs appear to have a low potential for abuse, according to studies.
A 2014 literature review investigated the abuse and misuse of antidepressants and found no published cases of trazodone or nefazodone abuse. Similarly, clinical studies of Oleptro, a former brand-name formulation of trazodone, found no evidence of drug-seeking behavior among participants.
Another study found that trazodone had less abuse potential than many other prescription drugs used for sleep disorders, including zolpidem (Ambien) and triazolam (Halcion). The study recommended it as an alternative to the other drugs in people with histories of alcohol or drug abuse.
However, there have been reported cases of trazodone abuse by people using multiple drugs. One case study looked at an individual who overdosed on trazodone while actively using cocaine and experienced an episode of painful priapism—a side effect of both drugs. The study commented on trazodone’s potential for misuse by polydrug users. Another case study documented an incident of serotonin syndrome in a man who was abusing tramadol (Ultram) while taking both trazodone and sertraline (Zoloft).
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Do They Interact with Other Drugs or Alcohol?
Yes. Both medications can interact with other drugs.
Trazodone can interact with:
- Non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, or anticoagulants: may increase bleeding risk.
- Warfarin (Coumadin): using trazodone with this drug can lead to difficulties with blood clotting.
- Monoamine oxidase inhibitors: may enhance the risk of serotonin syndrome.
- Serotonergic medications: when combined with trazodone, can increase the risk of serotonin syndrome.
- Central nervous system depressants (alcohol and benzodiazepines): may increase certain effects of these drugs, including drowsiness and respiratory depression.
- Digoxin or phenytoin: taking these drugs while on trazodone may lead to increased blood serum levels of the medications. Digoxin toxicity can lead to fatal cardiac arrhythmias. Phenytoin toxicity is associated with a range of neurologic complications.
- CYP3A4 enzyme inhibitors (e.g., clarithromycin, nefazodone, ketoconazole): using these with trazodone may lead to the person requiring a lower dose; this combination may also cause trazodone toxicity at lower doses.
- CYP3A4 inducers (e.g., carbamazepine): using these with trazodone may lead to the person requiring a higher dose of trazodone; the effects of trazodone will also likely be lowered at normal doses.
Nefazodone may interact with:
- Selective serotonin reuptake inhibitors (SSRIs): due to the CYP2D6 enzyme inhibition of these drugs, may increase the risk of nefazodone-related adverse side effects.
- Monoamine oxidase inhibitors: may enhance the risk of serotonin syndrome.
- Alprazolam (Xanax) and triazolam (Halcion): due to nefazodone’s CYP3A4 inhibition, may increase the half-life or duration of action for these drugs and heighten their effects.
- Buspirone: due to nefazodone’s CYP3A4 inhibition, may increase blood plasma concentrations and increase the risk of adverse effects.
- HMG CoA reductase inhibitors: due to nefazodone’s CYP3A4 inhibition, could increase the serum concentration of certain statin drugs and increase the risk of rhabdomyolysis (breakdown of muscle tissue that can lead to kidney damage).
- Haloperidol: when combined with nefazodone, may not be cleared from the body as quickly, necessitating a lower dose.
- Pimozide (Orap): due to nefazodone’s CYP4A4 inhibition, can increase concentrations of the drug in a person’s system, increasing the risk of cardiac arrhythmias.
People taking SARIs should avoid alcohol and other central nervous system depressants (CNS depressants) such as benzodiazepines and barbiturates. Not only can mixing SARIs with alcohol or CNS depressants lead to heightened sleepiness and dizziness, but it can also lead to an overdose. Fatal overdoses have occurred in people who took trazodone while drinking or using other CNS drugs.
While serotonin antagonists or SARIs and other antidepressants can be valuable components of treatment for certain mood disorders and related conditions, they are often prescribed as part of a more comprehensive treatment plan—complete with therapy and overall lifestyle changes to best manage depression.
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Sources:
[1] NCBI – https://pubmed.ncbi.nlm.nih.gov/22232986/
[2] NCBI – https://www.ncbi.nlm.nih.gov/books/NBK470560/