5-HT Receptor

Absorption, Distribution and Excretion
Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%.
Less than 1% of an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine as unchanged drug.
A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg.
A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone.
Following oral administration of single doses of 25, 50, or 100 mg of trazodone to healthy, fasted adults in another study, mean peak plasma trazodone concentrations were 490, 860, and 1620 ng/mL, respectively. The areas under the plasma concentration-time curves (AUCs) were 3.44, 5.95, and 11.19 ug-hr/mL, for the 25-, 50-, and 100-mg doses, respectively. Limited crossover data are available comparing AUCs in fasted and nonfasted patients; however, it appears that the presence of food slightly increases the AUC for trazodone.
Following oral administration of a single 25-mg dose of radiolabeled trazodone to healthy adults in one study, mean peak plasma drug concentrations of 650 and 480 ng/mL occurred at 1.5 and 2.5 hours after ingestion, in the fasted and nonfasted state, respectively.
/MILK/ The excretion of breast milk was studied in six lactating women following the oral administration of a single trazodone tablet (50 mg). The milk/plasma ratio of trazodone based on area under the plasma and milk curves was small: 0.142 +/- 0.045 (mean +/- s.d.). Assuming that the babies would drink 500 mL 12 h-1, they would be exposed to less than 0.005 mg kg-1 as compared to 0.77 mg kg-1 for the mothers. It is concluded that exposure of babies to trazodone via breast milk is very small.
Peak plasma concentrations of trazodone occur approximately 1 hour after oral administration when the drug is taken on an empty stomach or 2 hours after oral administration when taken with food. Following oral administration of multiple doses of trazodone (25 mg 2 or 3 times daily), steady-state plasma concentrations of the drug are usually attained within 4 days and exhibit wide interpatient variation.
For more Absorption, Distribution and Excretion (Complete) data for TRAZODONE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been well characterized. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid.
Trazodone is extensively metabolized in the liver via hydroxylation, oxidation, N-oxidation, and splitting of the pyridine ring. A hydroxylated metabolite and oxotriazolopyridinpropionic acid (an inactive metabolite excreted in urine) are conjugated with glucuronic acid. Results of in vitro studies indicate that metabolism of trazodone to an active metabolite, m-chlorophenylpiperazine, is mediated by the cytochrome P-450 (CYP) 3A4 isoenzyme. The manufacturers state that other metabolic pathways involved in metabolism of trazodone have not been well characterized. Results from animal studies indicate that trazodone does not induce its own metabolism.
In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m-chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine.
Approximately 70-75% of an oral dose of trazodone is excreted in urine within 72 hours of administration, principally as metabolites. About 20% of an oral dose of trazodone is excreted in urine as oxotriazolopyridinpropionic acid and its conjugates, and about 10% as a dihydrodiol metabolite; less than 1% of a dose is excreted unchanged. The remainder of an oral dose of the drug is excreted in feces via biliary elimination, principally as metabolites.
Trazodone has known human metabolites that include p-Hydroxytrazodone, Trazodone epoxide, and 1-(3-Chlorophenyl)piperazine.
Undergoes extensive hepatic metabolism via hydroxylation, N-dealkylation, N-oxidation and splitting of the pyridine ring. Cytochrome P450 (CYP) 3A4 catalyzes the formation of the major active metabolite, m-chlorophenylpiperazine (m-CPP). Metabolites may be further conjugated to glucuonic acid or glutathione. CYP2D6 is responsible for 4'-hydroxylation of m-CPP and the formation of at least one glutathione conjugates of m-CPP, a quinone imine-sulhydryl adduct. Oxotriazolopyridinpropionic acid, an inactive metabolite, and its conjugates account for about 20% of the total excreted oral dose. Less than 1% of the oral dose is excreted unchanged. Approximately 70-75% of the dose is eliminated in urine with the remainder being excreted in feces via biliary elimination.
Half Life: Undergoes biphasic elimination with an initial phase t_{1/2 α} of 3-6 hours and a terminal phase t_{1/2 β} of 5-9 hours.

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Biological Half-Life
The plasma elimination half-life was markedly prolonged (13.6 versus 6 hours) elderly volunteers in the fasted state when compared with younger volunteers. Another study of 8 healthy individuals taking a single dose of trazodone indicated a terminal elimination half-life of 7.3 +/- 0.8 hr. A two-phase pattern of trazodone elimination has been reported. Initially, the half-life is reported to range from 3 to 6 hours and the second phase of elimination to range from 5 to 9 hours.
The half-life of trazodone in the initial phase is about 3-6 hours and the half-life in the terminal phase is about 5-9 hours.
... Following IV administration /of trazodone HCl to beagle dogs/, the mean +/- SD elimination half-life /was/ 169 +/- 53 minutes ... . Following oral administration, the mean +/- SD elimination half-life /was/ 166 +/- 47 minutes ... .
In dogs after 8 mg/kg IV, volume of distribution was (all value are means ) 2.53 L/kg, elimination half life 169 minutes, and plasma total body clearance was 11.15 mL/min/kg. After 8 mg/kg PO, bioavailability was 85%, and elimination half life was 166 minutes, peak plasma levels occurred at 445 minutes (mean), but there was wider inter-subject variation (+ or - 271 minutes).

Hepatotoxicity
Liver test abnormalities occur in a proportion of patients on trazodone, but elevations are usually modest and usually do not require dose modification or discontinuation. At least a dozen instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on trazodone. The onset of injury varies from a few days to 6 months and the pattern of serum enzyme elevations is usually hepatocellular, but mixed and cholestatic forms have also been described. Several cases have had immunoallergic features (rash, fever, eosinophilia), but these were not prominent. Autoimmune (autoantibodies) features are uncommon. Rare instances of acute liver failure and death from trazodone have been reported. Nefazodone, an antidepressant similar in structure and mechanism of action to trazodone, was approved for use in 1998, but is currently not commonly used because of multiple reports of acute hepatocellular injury, with a high mortality rate arising 2 weeks to 6 months after starting therapy.
Likelihood score: B (likely but rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that trazodone levels in milk are low and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months or when doses of 100 mg or less are used at bedtime for sleep. A safety scoring system finds trazodone use to be possible to use cautiously during breastfeeding.
◉ Effects in Breastfed Infants
One woman was 6.5 weeks postpartum and taking trazodone 75 mg, venlafaxine 75 mg and quetiapine 75 mg daily before conception, during pregnancy and during breastfeeding. Her breastfed infant's development was tested at 12 months of age with the Bayley Scales. Measurements were within normal limits on the mental, psychomotor and behavior scales.
One infant whose mother took trazodone 200 mg daily for 12 weeks starting at 4 weeks postpartum was followed up at 12 months of age. No adverse effects on growth and development were found.
One exclusively breastfed 15-week-old infant was breastfed during maternal therapy with trazodone 100 mg daily and venlafaxine 150 mg daily. No adverse reactions were reported by the mother or found in the medical records.
A woman took etizolam 1 mg and trazodone 50 mg once daily for 3 months postpartum. Her infant was over 50% breastfed and demonstrated no adverse reactions at the 1- and 3-month checkups. The infant’s Denver Developmental Screening Test II was normal at 6 months of age.
◉ Effects on Lactation and Breastmilk
A nonpregnant woman with depression was treated with citalopram 20 mg daily, then 40 mg daily. Trazodone 50 mg at bedtime was added to treat insomnia and then increased to 100 mg at bedtime. One week later the patient noticed milk leakage from her breasts, which stained her clothing. Her serum prolactin was somewhat elevated, but no other abnormalities were noted. The trazodone dosage was tapered and then discontinued. One month later, the galactorrhea had resolved and her serum prolactin was in the normal range.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking trazodone.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.
◈ What is trazodone?
Trazodone is an antidepressant and sedative that has been used to treat depression and symptoms of insomnia (trouble sleeping). Some brand names for trazodone include Desyrel®, Oleptro®, and Trazorel®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take your medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.Some people may have a return of their symptoms (relapse) if they stop this medication during pregnancy. If you stop taking this medication, it is important to have other forms of support in place (e.g. counseling or therapy) and a plan to restart the medication after delivery, if needed. If you plan to stop this medication, your healthcare provider may suggest that you slowly lower the dose instead of stopping all at once. Stopping this medication suddenly can cause some people to have withdrawal symptoms. It is not known if or how withdrawal might affect a pregnancy.
◈ I take trazodone. Can it make it harder for me to get pregnant?
Studies have not been done to see if trazodone could make it harder to get pregnant. Some conditions, including depression, can make it harder to get pregnant. This makes it hard to know if the medication, the condition being treated, or other factors might affect fertility (ability to get pregnant). For more information on depression, please see our fact sheet at https://mothertobaby.org/fact-sheets/depression-pregnancy/.
◈ Does taking trazodone increase the chance of miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Two studies, with over 200 hundred people, found no increase in miscarriage when trazodone was taken during pregnancy. Some studies have reported a higher chance of miscarriage when depression is left untreated in pregnancy.
◈ Does taking trazodone increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Studies have looked at over 300 pregnancies where trazodone was taken during the first trimester. These studies did not find an increased chance of birth defects above the background risk.
◈ Does taking trazodone in pregnancy increase the chance of other pregnancy-related problems?
One study found no greater chance for preterm delivery (delivery before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth) in babies who had been exposed to trazodone during pregnancy.Another study of over 200 pregnancies found no greater chance for low birth weight but did find a slightly higher chance for preterm delivery. However, research has also shown that when depression is left untreated during pregnancy, there could be an increased chance for pregnancy complications. This makes it hard to know if the medication, the condition being treated, or other factors might increase the chance of pregnancy complications.
◈ I need to take trazodone throughout my entire pregnancy. Will it cause withdrawal symptoms in my baby after birth?
The use of trazodone during pregnancy can cause temporary symptoms in newborns soon after birth. These symptoms are sometimes referred to as withdrawal. Symptoms include jitteriness, breathing problems, or trouble feeding. Not all babies exposed to trazodone will have these symptoms. No withdrawal symptoms were reported in one study of 18 infants exposed to 50 mg/day of trazodone for insomnia in the third trimester. It is important that your healthcare providers know you are taking trazodone so that if symptoms do occur, your baby can get the care that is best for them.
◈ Does taking trazodone in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if trazodone can cause behavior or learning issues for the child.
◈ Breastfeeding while taking trazodone:
Information on the use of trazodone in breastfeeding is limited. Small amounts of trazodone have been found in breast milk. If you suspect the baby has any symptoms (such as being more sleepy than usual), contact the child’s healthcare provider. Be sure to talk to your healthcare provider about all your breastfeeding questions.
◈ If a male takes trazodone, could it affect fertility or increase the chance of birth defects?
Studies have not been done to see if trazodone could affect male fertility (ability to get partner pregnant) or increase the chance of birth defects. People with conditions such as depression may have lower sex drive (desire to have sex), which might make it harder for them to get their partner pregnant. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
The plasma protein binding of trazodone is 89-95% according to in vitro studies.

[1]. Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders. Drugs Aging, 1994. 4(4): p. 331-55.

Trazodone is an N-arylpiperazine in which one nitrogen is substituted by a 3-chlorophenyl group, while the other is substituted by a 3-(3-oxo[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)propyl group. It has a role as an antidepressant, a sedative, an adrenergic antagonist, a H1-receptor antagonist, a serotonin uptake inhibitor and an anxiolytic drug. It is a N-alkylpiperazine, a N-arylpiperazine, a triazolopyridine and a member of monochlorobenzenes.
Trazodone is triazolopyridine derivative from the serotonin receptor antagonists and reuptake inhibitors (SARIs) class of antidepressants. It is used in adults and has been shown to be comparable in efficacy to other drugs such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine receptor inhibitor (SNRIs) in the treatment of depression. A unique feature of this drug is that it does not promote the anxiety symptoms, sexual symptoms, or insomnia, which are commonly associated with SSRI and SNRI therapy. Trazodone acts on various receptors, including certain histamine, serotonin, and adrenergic receptors, distinguishing it from other antidepressants that cover a narrow range of neurotransmitters. It was initially granted FDA approval in 1981.
Trazodone is a Serotonin Reuptake Inhibitor.
Trazodone is a serotoninergic modulating antidepressant that is used in therapy of depression, aggressive behavior and panic disorder. Trazodone therapy can be associated with transient, usually asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.
Trazodone is a synthetic triazolopyridine derivative, antidepressant and sedative Trazodone acts as a serotonin uptake inhibitor, chemically unrelated to tricyclic, tetracyclic, or other antidepressants. It is effective in patients with schizoaffective disorders; major depressive disorders; and depressive disorders associated with insomnia and anxiety. (NCI04)
A serotonin uptake inhibitor that is used as an antidepressive agent. It has been shown to be effective in patients with major depressive disorders and other subsets of depressive disorders. It is generally more useful in depressive disorders associated with insomnia and anxiety. This drug does not aggravate psychotic symptoms in patients with schizophrenia or schizoaffective disorders. (From AMA Drug Evaluations Annual, 1994, p309)
A serotonin uptake inhibitor that is used as an antidepressive agent. It has been shown to be effective in patients with major depressive disorders and other subsets of depressive disorders. It is generally more useful in depressive disorders associated with insomnia and anxiety. This drug does not aggravate psychotic symptoms in patients with schizophrenia or schizoaffective disorders. (From AMA Drug Evaluations Annual, 1994, p309)
See also: Trazodone Hydrochloride (has salt form).

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Drug Indication
Trazodone is indicated for the treatment of major depressive disorder (MDD). It has been used off-label for adjunct therapy in alcohol dependence, and off-label to treat anxiety and insomnia. It may also be used off-label to treat symptoms of dementia, Alzheimer’s disease, schizophrenia, eating disorders, and fibromyalgia due to its effects on various neurotransmitter receptors.

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Mechanism of Action
The mechanism of action of trazodone is not fully understood, however, it is known to inhibit the reuptake of serotonin and block both histamine and alpha-1-adrenergic receptors. Despite the fact that trazodone is frequently considered a selective serotonin reuptake inhibitor, several reports have shown that other mechanisms including antagonism at serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes may occur. The strongest antagonism of trazodone is reported to occur at the serotonin 5-HT21c receptors, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has been shown to inhibit serotonin transporters. The antidepressant effects of trazodone result from the inhibition of receptor uptake, which normally decreases circulating neurotransmitters, contributing to depressive symptoms.
The precise mechanism of antidepressant action of trazodone is unclear, but the drug has been shown to selectively block the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane. The effects of serotonin may thus be potentiated. Unlike other antidepressant agents (e.g., tricyclic antidepressants), trazodone may have a dual effect on the central serotonergic system. Animal studies indicate that trazodone acts as a serotonin agonist at high doses (6-8 mg/kg), while at low doses (0.05-1 mg/kg), it antagonizes the actions of serotonin. Trazodone does not appear to influence the reuptake of dopamine or norepinephrine within the CNS; however, animal studies indicate that trazodone may enhance release of norepinephrine from neuronal tissue. Trazodone does not cause serotonin release in vitro.

C19H23CL2N5O

408.3248

407.127

C, 55.89; H, 5.68; Cl, 17.36; N, 17.15; O, 3.92

25332-39-2

Trazodone-d6 hydrochloride; 1181578-71-1; Trazodone; 19794-93-5

5533

White to off-white crystalline powder

528.5ºC at 760 mmHg

223ºC

273.4ºC

2.94E-11mmHg at 25°C

3.166

0

4

5

26

611

0

0

OHHDIOKRWWOXMT-UHFFFAOYSA-N

InChI=1S/C19H22ClN5O.ClH/c20-16-5-3-6-17(15-16)23-13-11-22(12-14-23)8-4-10-25-19(26)24-9-2-1-7-18(24)21-25;/h1-3,5-7,9,15H,4,8,10-14H2;1H

2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 1.67 mg/mL (4.09 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.67 mg/mL (4.09 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.67 mg/mL (4.09 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)