5-HT Receptor
Trazodone HCl (AF-116; KB-831) is a multi-target agent with high affinity for 5-hydroxytryptamine 2A (5-HT₂A) receptors (rat cortical membranes, Ki = 3.1 nM), moderate affinity for 5-HT₁A receptors (Ki = 82 nM) and histamine H₁ receptors (Ki = 17 nM), and weak affinity for α₁-adrenergic receptors (Ki = 240 nM) [1]
- Trazodone HCl (AF-116; KB-831) inhibits the 5-HT transporter (SERT) in rat brain synaptosomes with an IC₅₀ of 380 nM, showing lower potency for noradrenaline transporters (NET, IC₅₀ > 10,000 nM) and no activity on dopamine transporters (DAT, IC₅₀ > 10,000 nM) [1]

In rat cerebral cortical membrane preparations, Trazodone HCl (AF-116; KB-831) (10⁻¹⁰ to 10⁻⁶ M) concentration-dependently displaces [³H]-ketanserin (a selective 5-HT₂A ligand) binding, with a maximum displacement of 95% at 10⁻⁶ M; it has no significant effect on [³H]-diazepam (GABA-A ligand) binding at concentrations up to 10 μM [1]
- In rat brain synaptosomal 5-HT uptake assays, Trazodone HCl (AF-116; KB-831) (100–5000 nM) dose-dependently inhibits [³H]-5-HT uptake: 380 nM reduces uptake by 50% (IC₅₀), and 5000 nM achieves maximum inhibition (88%). It does not affect [³H]-noradrenaline uptake at concentrations up to 10,000 nM [1]
- In human platelet 5-HT₂A receptor binding assays, Trazodone HCl (AF-116; KB-831) (10⁻⁹ to 10⁻⁵ M) displaces [³H]-spiperone binding with a Ki of 4.5 nM, consistent with its affinity for rat 5-HT₂A receptors [1]

In male ICR mice subjected to the forced swim test (FST, a model of depression), oral administration of Trazodone HCl (AF-116; KB-831) (10, 30, 100 mg/kg) 60 min before testing dose-dependently reduces immobility time: 100 mg/kg decreases immobility by 62% compared to vehicle controls, with no effect on locomotor activity (open-field test) [1]
- In male Sprague-Dawley rats with learned helplessness (a depression model induced by inescapable foot shocks), daily oral administration of Trazodone HCl (AF-116; KB-831) (20, 40 mg/kg) for 14 days reverses helplessness behavior: 40 mg/kg increases escape latency success rate from 25% (vehicle) to 78% [1]
- In male Wistar rats, intraperitoneal (i.p.) administration of Trazodone HCl (AF-116; KB-831) (5, 15 mg/kg) 30 min before testing reduces exploratory behavior in the elevated plus maze (EPM) by decreasing open-arm entries (15 mg/kg: 45% reduction vs. vehicle), indicating anxiolytic-like effects [1]

Rat Cortical 5-HT₂A Receptor Binding Assay: Rat cerebral cortex was homogenized in ice-cold Tris-HCl buffer (50 mM, pH 7.4, containing 120 mM NaCl, 5 mM KCl) and centrifuged at 48,000 × g for 15 min. The membrane pellet was resuspended, and 50 μg of membrane protein was incubated with [³H]-ketanserin (0.5 nM) and various concentrations of Trazodone HCl (AF-116; KB-831) (10⁻¹¹ to 10⁻⁶ M) at 25°C for 60 min. Non-specific binding was defined as binding in the presence of 10 μM mianserin. Reactions were terminated by filtration through GF/B filters pre-soaked in 0.1% polyethyleneimine, and filters were washed 3 times with ice-cold buffer. Radioactivity was counted via liquid scintillation spectrometry, and Ki values were calculated using the Cheng-Prusoff equation [1]
- Rat Brain Synaptosomal SERT Uptake Assay: Rat whole brain (excluding cerebellum) was homogenized in ice-cold sucrose buffer (0.32 M) and centrifuged at 1000 × g for 10 min. The supernatant was centrifuged at 17,000 × g for 20 min to isolate synaptosomes. Synaptosomes (0.5 mg protein/mL) were incubated in Krebs-Ringer-HEPES buffer (KRH: 125 mM NaCl, 4.8 mM KCl, 1.2 mM CaCl₂, 25 mM HEPES, pH 7.4) with [³H]-5-HT (10 nM) and Trazodone HCl (100–5000 nM) at 37°C for 15 min. Uptake was stopped by adding ice-cold KRH, and samples were centrifuged at 17,000 × g for 10 min. The pellet was dissolved in 0.1 M NaOH, and radioactivity was measured via liquid scintillation counting to calculate IC₅₀ [1]

Human Platelet Isolation: Fresh human blood was collected in EDTA-containing tubes and centrifuged at 200 × g for 15 min to separate platelet-rich plasma (PRP). PRP was centrifuged at 1000 × g for 10 min, and the platelet pellet was resuspended in Tyrode’s buffer (137 mM NaCl, 2.7 mM KCl, 1.8 mM CaCl₂, 1 mM MgCl₂, 5.6 mM glucose, 10 mM HEPES, pH 7.4).
- Binding Reaction: Platelet membranes were prepared by homogenizing platelets in ice-cold Tris-HCl buffer (50 mM, pH 7.4) and centrifuging at 40,000 × g for 15 min. 100 μg of membrane protein was incubated with [³H]-spiperone (0.3 nM) and Trazodone HCl (AF-116; KB-831) (10⁻⁹ to 10⁻⁵ M) at 25°C for 90 min. Non-specific binding was determined with 10 μM ketanserin. Reactions were terminated by filtration through GF/C filters, and radioactivity was counted via liquid scintillation spectrometry. Ki values were derived from concentration-response curves [1]

Mouse Forced Swim Test (FST): Male ICR mice (20–22 g) were acclimated to the test environment for 3 days. Mice were randomly divided into 4 groups (n=10/group): Vehicle (0.5% methylcellulose, p.o.), Trazodone HCl 10 mg/kg (p.o.), 30 mg/kg (p.o.), 100 mg/kg (p.o.). Sixty minutes after oral gavage, each mouse was placed in a transparent cylinder (20 cm diameter, 30 cm height) filled with water (25±1°C, 15 cm depth) for 6 min. Immobility time (time spent floating without active swimming) was recorded during the last 4 min. Locomotor activity was measured in an open-field arena (40×40×30 cm) 24 h later to exclude non-specific effects [1]
- Rat Learned Helplessness Model: Male Sprague-Dawley rats (250–280 g) were subjected to inescapable foot shocks (0.8 mA, 10 s duration, 60 shocks/day) for 2 days to induce helplessness. Rats were then randomized into 3 groups (n=8/group): Vehicle (0.5% methylcellulose, p.o.), Trazodone HCl 20 mg/kg (p.o.), 40 mg/kg (p.o.). Drug was administered once daily for 14 days. On day 15, rats were tested in a shuttle box (two compartments separated by a door) with escapable shocks (0.5 mA). Escape latency and success rate (percentage of shocks avoided within 30 s) were recorded [1]

Absorption, Distribution and Excretion
Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability of 63-91% and an AUC0-t of 18193.0 ng·h/mL. The effect of food on absorption varies from person to person and can sometimes lead to a decrease in the Cmax of trazodone. In 8 healthy volunteers, the Cmax was 1.47 ± 0.16 μg/mL after eating and 1.88 ± 0.42 μg/mL after fasting. The mean Tmax after a single 300 mg dose was 8 hours. Food can increase absorption by up to 20%. Less than 1% of the oral dose is excreted unchanged in the urine. In a pharmacokinetic study, approximately 60-70% of the radiolabeled drug was excreted in the urine within 48 hours. Approximately 9-29% of the drug was excreted in the feces within 60 to 100 hours. According to FDA medical review, the kidneys are responsible for 70% to 75% of trazodone excretion. Approximately 21% of trazodone is excreted in feces, and 0.13% of the unchanged drug is excreted unchanged in urine. A single-dose pharmacokinetic study in eight volunteers taking trazodone determined its volume of distribution to be 0.84 ± 0.16 L/kg. The FDA's medical review report on trazodone indicates a volume of distribution ranging from 0.47 to 0.84 L/kg. Compared to younger volunteers, older volunteers showed a lower total apparent clearance in a fasting state (5.1 L/h vs. 10.8 L/h). Another pharmacokinetic study determined that the total clearance of trazodone after a single dose in eight healthy subjects was 5.3 ± 0.9 L/h. In another study, the mean peak plasma concentrations of trazodone after oral administration of 25, 50, or 100 mg in healthy fasting adults were 490, 860, and 1620 ng/mL, respectively. The areas under the plasma concentration-time curve (AUC) for the 25 mg, 50 mg, and 100 mg dose groups were 3.44, 5.95, and 11.19 μg·hr/mL, respectively. Currently, cross-correlation data on AUC in fasting and non-fasting patients are limited; however, the presence of food appears to slightly increase the AUC of trazodone. In one study, after a single oral dose of 25 mg radiolabeled trazodone in healthy adults, the mean peak plasma drug concentrations were reached at 1.5 hours and 2.5 hours post-administration, respectively, in fasting and non-fasting states, at 650 ng/mL and 480 ng/mL. /Breast Milk/ A study investigated breast milk excretion after oral administration of a single trazodone tablet (50 mg) in six lactating women. Based on the areas under the plasma and breast milk concentration curves, the breast milk/plasma ratio of trazodone was small: 0.142 ± 0.045 (mean ± standard deviation). Assuming an infant drinks 500 mL of breast milk every 12 hours, the amount of trazodone ingested through breast milk is less than 0.005 mg/kg, while the mother's intake is 0.77 mg/kg. Therefore, it can be concluded that the amount of trazodone ingested by the infant through breast milk is very small. After oral administration of trazodone on an empty stomach, peak plasma concentrations occur approximately 1 hour after administration; when taken with food, peak plasma concentrations occur approximately 2 hours after administration. Steady-state plasma drug concentrations are typically reached within 4 days after oral administration of trazodone (25 mg each time, 2 or 3 times daily), but there is considerable inter-individual variability. For more complete data on the absorption, distribution, and excretion of trazodone (8 types), please visit the HSDB record page.

---

Metabolism/Metabolites
Trazodone is primarily metabolized and activated in the liver by the enzyme CYP3A4 to the active metabolite m-chlorophenylpiperazine (mCPP). The complete metabolic process of trazodone has not been fully elucidated. Other identified metabolites include dihydrodiol metabolites and carboxylic acids. Trazodone is extensively metabolized in the liver via hydroxylation, oxidation, N-oxidation, and pyridine ring cleavage. The hydroxylated metabolite and oxotriazopyridinepropionic acid (an inactive metabolite excreted in urine) are conjugated with glucuronic acid. In vitro studies indicate that the metabolism of trazodone to the active metabolite m-chlorophenylpiperazine is mediated by cytochrome P-450 (CYP) 3A4 isoenzymes. The manufacturer states that other metabolic pathways involved in trazodone metabolism are not fully elucidated. Animal studies indicate that trazodone does not induce its own metabolism. In vitro human liver microsomal studies show that trazodone is oxidatively cleaved by CYP3A4 to the active metabolite m-chlorophenylpiperazine (mCPP). Other metabolic pathways that may be involved in trazodone metabolism are not fully elucidated. Trazodone is extensively metabolized; less than 1% of the oral dose is excreted unchanged in the urine. Following oral administration of trazodone, approximately 70-75% of the dose is excreted in the urine within 72 hours, primarily as metabolites. About 20% of the oral trazodone is excreted in the urine as oxotriazopyridine propionic acid and its conjugates, and about 10% as dihydrodiol metabolites; less than 1% is excreted unchanged. The remaining portion of the oral drug is excreted primarily as metabolites via bile and in feces. Known metabolites of trazodone include p-hydroxytrazodone, epoxide trazodone, and 1-(3-chlorophenyl)piperazine. Trazodone is metabolized in the liver primarily through hydroxylation, N-dealkylation, N-oxidation, and pyridine ring cleavage. Cytochrome P450 (CYP) 3A4 catalyzes the formation of the major active metabolite, m-chlorophenylpiperazine (m-CPP). The metabolite can further bind with glucuronic acid or glutathione. CYP2D6 is responsible for the 4'-hydroxylation of m-CPP, generating at least one glutathione conjugate of m-CPP, namely a quinone imine-thiol adduct. The inactive metabolite oxotriazopyridine propionic acid and its conjugates account for approximately 20% of the total oral excretion. Less than 1% of the oral dose is excreted unchanged. Approximately 70-75% of the dose is excreted in the urine, with the remainder excreted in the bile. Half-life: 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. Biological half-life: Compared with younger volunteers, the plasma elimination half-life in elderly volunteers under fasting conditions was significantly prolonged (13.6 hours vs. 6 hours). Another study involving 8 healthy subjects with a single dose of trazodone showed a terminal elimination half-life of 7.3 ± 0.8 hours. Trazodone elimination has been reported to follow a biphasic pattern. The initial phase half-life is 3 to 6 hours, and the second phase half-life is 5 to 9 hours. The initial phase half-life of trazodone is approximately 3-6 hours, and the terminal phase half-life is approximately 5-9 hours. …After intravenous administration of trazodone hydrochloride to dogs, the mean elimination half-life ± standard deviation was 169 ± 53 minutes…After oral administration, the mean elimination half-life was 166 ± 47 minutes. After intravenous administration of 8 mg/kg in dogs, the volume of distribution (all values are averages) was 2.53 L/kg, the elimination half-life was 169 minutes, and the total plasma clearance was 11.15 mL/min/kg. After oral administration of 8 mg/kg, the bioavailability was 85%, the elimination half-life was 166 minutes, and the peak plasma concentration occurred at 445 minutes (mean), but there was significant inter-individual variability (± 271 minutes).

---

Oral absorption: In healthy volunteers (n=6), after oral administration of trazodone hydrochloride (AF-116; KB-831) (100 mg), the peak plasma concentration (Cmax) was 450 ng/mL, and the time to peak concentration was 1.5–2.5 hours (Tmax). Due to first-pass metabolism in the liver, the absolute oral bioavailability is 30%–60%[1]
- Distribution: Trazodone hydrochloride (AF-116; KB-831) has a large volume of distribution (human Vd = 1.2–1.8 L/kg) and easily crosses the blood-brain barrier. One hour after oral administration (50 mg/kg) to rats, the brain-to-plasma concentration ratio was 2.3[1]
- Metabolism: The drug is mainly metabolized in the liver by cytochrome P450 enzymes CYP3A4 (major) and CYP2D6 (minor). The main metabolites include m-chlorophenylpiperazine (m-CPP, active, 5-HT agonist) and hydroxytrazodone (inactive). The half-life of m-CPP (6-8 hours) is longer than that of the parent drug [1]
- Excretion and half-life: In humans, the terminal elimination half-life (t₁/₂) of trazodone hydrochloride (AF-116; KB-831) is 3-6 hours. Approximately 70% of the administered dose is excreted in the urine as metabolites within 72 hours, and less than 1% of the drug is excreted unchanged [1]

Hepatotoxicity
Some patients taking trazodone may experience abnormal liver function, but the elevation is usually small and generally does not require dose adjustment or discontinuation. At least a dozen patients taking trazodone have experienced acute, clinically significant liver injury with significantly elevated liver enzymes, with or without jaundice. The onset of injury ranges from a few days to 6 months. The pattern of serum enzyme elevation is usually hepatocellular, but mixed and cholestatic patterns have also been reported. Some cases have shown immune allergic reactions (rash, fever, eosinophilia), but these symptoms are not prominent. Autoimmune manifestations (autoantibodies) are uncommon. Rare cases of trazodone causing acute liver failure and death have been reported. Nefazodone, an antidepressant with a similar structure and mechanism of action to trazodone, was approved for marketing in 1998, but is now rarely used due to numerous reports of acute hepatocellular injury. These acute hepatocellular injuries have a high mortality rate and usually occur within 2 weeks to 6 months after the start of treatment. Probability Score: B (Probably but rarely causes clinically significant liver injury).

---

Effects during pregnancy and lactation
◉ Overview of medication use during lactation
Limited information suggests that low concentrations of trazodone in breast milk are not expected to have any adverse effects on breastfed infants, especially when the infant is older than 2 months or when a dose of 100 mg or less is taken at bedtime. A safety rating system found that trazodone can be used with caution during lactation.
◉ Effects on breastfed infants
A woman 6.5 weeks postpartum took 75 mg of trazodone, 75 mg of venlafaxine, and 75 mg of quetiapine daily before conception, during pregnancy, and during lactation. Her breastfed infant underwent a developmental assessment using the Bayley Scales of Infant Development at 12 months of age. Measurements on the psychomotor and behavioral scales were all within the normal range.
A mother started taking 200 mg of trazodone daily 4 weeks postpartum for 12 weeks, and her infant was followed up at 12 months of age. No adverse effects on growth and development were observed. A 15-week-old exclusively breastfed infant was breastfed while the mother was receiving daily treatment with 100 mg trazodone and 150 mg venlafaxine. The mother reported no adverse reactions, and no adverse reactions were recorded in the medical records. A woman was taking 1 mg estazolam and 50 mg trazodone once daily for 3 months postpartum. Her infant was over 50% breastfed, and no adverse reactions were observed at the 1-month and 3-month checkups. The infant's Denver Developmental Screening Test II results were normal at 6 months of age. Effects on lactation and breast milk: A non-pregnant woman with depression received citalopram treatment at 20 mg daily, later increased to 40 mg daily. For insomnia, 50 mg trazodone was added at bedtime, later increased to 100 mg at bedtime. One week later, the patient experienced breast milk leakage, staining her clothes. Her serum prolactin level was slightly elevated, but no other abnormalities were found. The dosage of trazodone was gradually reduced and eventually discontinued. One month later, the galactorrhea symptoms disappeared, and serum prolactin levels returned to normal. An observational study investigated the outcomes of 2859 women who took antidepressants in the two years prior to pregnancy. Compared to women who did not take antidepressants during pregnancy, mothers who took antidepressants in all three stages of pregnancy were 37% less likely to breastfeed at discharge. Mothers who took antidepressants only in late pregnancy were 75% less likely to breastfeed at discharge. Mothers who took antidepressants only in early and mid-pregnancy were not less likely to breastfeed at discharge. The specific antidepressants used by the mothers were not specified. A retrospective cohort study analyzed hospital electronic medical records from 2001 to 2008, comparing women who took antidepressants in late pregnancy (n = 575), women with mental illness but not taking antidepressants (n = 1552), and mothers who were not diagnosed with mental illness (n = 30,535). The results showed that women who had taken antidepressants were 37% less likely to breastfeed at discharge than women who had not been diagnosed with mental illness, but there was no significant difference in the likelihood of breastfeeding compared to mothers with untreated mental illness. None of the mothers were taking trazodone. A study of 80,882 Norwegian mother-infant pairs between 1999 and 2008 showed that 392 women reported starting antidepressants postpartum, and another 201 women reported starting antidepressants during pregnancy. Compared to the control group that had not been exposed to antidepressants, taking antidepressants in late pregnancy was associated with a 7% lower rate of breastfeeding initiation, but had no effect on the duration of breastfeeding or the rate of exclusive breastfeeding. Compared to the control group that had not been exposed to antidepressants, starting or restarting antidepressants postpartum was associated with a 63% lower rate of breastfeeding as the primary source at 6 months, a 51% lower rate of breastfeeding of any form, and a 2.6-fold increased risk of abrupt cessation of breastfeeding. No specific antidepressants were mentioned in the text. What is trazodone? Trazorel is an antidepressant and sedative used to treat symptoms of depression and insomnia (difficulty sleeping). Some brand names for trazorel include Desyrel®, Oleptro®, and Trazorel®. Sometimes, when people find out they are pregnant, they consider changing how they take the medication or even stopping it completely. However, it is essential to talk to your healthcare provider before changing how you take the medication. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating it during pregnancy. Some people may experience a relapse of symptoms if they stop taking this medication during pregnancy. If you stop taking this medication, be sure to schedule other forms of support (such as counseling or treatment) and develop a plan to restart the medication if necessary after delivery. If you plan to stop taking this medication, your healthcare provider may advise you to gradually reduce the dose rather than stopping it all at once. Abruptly stopping this medication may cause withdrawal symptoms in some people. It is currently unclear whether and how withdrawal symptoms affect pregnancy. ◈ I am taking trazorel. Will it make it harder for me to get pregnant? There are currently no studies confirming whether trazorel affects fertility. Some conditions, including depression, can make conception more difficult. Therefore, it is difficult to determine whether medications, treated conditions, or other factors affect fertility (the ability to conceive). For more information on depression, please see our fact sheet: https://mothertobaby.org/fact-sheets/depression-pregnancy/.
◈ Does taking trazodone increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. Two studies involving more than 200 people found that taking trazodone during pregnancy did not increase the risk of miscarriage. Some studies report that the risk of miscarriage is higher if depression during pregnancy is left untreated.
◈ Does taking trazodone increase the risk of birth defects?
There is a 3-5% risk of birth defects in every pregnancy, known as background risk. Some studies investigated more than 300 pregnancies in which trazodone was taken in early pregnancy. These studies did not find a higher risk of birth defects than background risk.
◈ Does taking trazodone during pregnancy increase the risk of other pregnancy-related problems? One study found that infants exposed to trazodone during pregnancy did not have an increased risk of preterm birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]). Another study of more than 200 pregnancies found no increased risk of low birth weight, but a slightly increased risk of preterm birth. However, studies also suggest that not treating depression during pregnancy may increase the risk of pregnancy complications. Therefore, it is difficult to determine whether the medication, the condition being treated, or other factors increase the risk of pregnancy complications. ◈ I need to take trazodone throughout my pregnancy. Will it cause withdrawal symptoms in my baby after birth? Taking trazodone during pregnancy may cause temporary symptoms in newborns shortly after birth. These symptoms are sometimes called withdrawal reactions. Symptoms include irritability, difficulty breathing, or feeding difficulties. Not all infants exposed to trazodone will experience these symptoms. A study of 18 infants who took 50 mg/day of trazodone for insomnia in late pregnancy showed that none of the infants experienced withdrawal symptoms. It is important to inform your healthcare provider that you are taking trazodone so that your baby can receive the best care if symptoms occur.
◈ Will taking trazodone during pregnancy affect my child's future behavior or learning?
There is currently no research indicating that trazodone causes behavioral or learning problems in children.
◈ Breastfeeding while taking trazodone:
Information is limited regarding the use of trazodone while breastfeeding. Small amounts of trazodone have been detected in breast milk. If you suspect your baby is experiencing any symptoms (such as being more sleepy than usual), contact your baby's healthcare provider. Be sure to consult your healthcare provider about all questions regarding breastfeeding.
◈ Will taking trazodone affect fertility or increase the risk of birth defects in the fetus?
There is currently no research exploring whether trazodone affects male fertility (the ability to impregnate a partner) or increases the risk of birth defects. People with conditions such as depression may have a lower libido, which may make it more difficult for them to impregnate a partner. Generally, medications that the father or sperm donor is exposed to are unlikely to increase the risk of pregnancy. For more information, please refer to MotherToBaby’s “Father Exposure” Fact Sheet at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

---

Protein Binding
According to in vitro studies, the plasma protein binding rate of trazodone is 89-95%.

---

Plasma protein binding: The plasma protein binding rate of trazodone hydrochloride (AF-116; KB-831) in human plasma (as determined by ultrafiltration) is 85-95% in the concentration range of 100-1000 ng/mL, and there is no concentration-dependent variation [1]
-Acute toxicity: In male ICR mice, the oral LD₅₀ of trazodone hydrochloride (AF-116; KB-831) is >2000 mg/kg; in male Sprague-Dawley rats, the oral LD₅₀ is >1500 mg/kg. In rats, no death or serious toxicity (convulsions, respiratory depression) was observed at doses up to 1000 mg/kg [1] - Chronic toxicity: In a 28-day repeated oral toxicity study in rats (dose: 50, 150, 450 mg/kg/day), the No Adverse Effect Level (NOAEL) was observed at 150 mg/kg/day. Mild sedation and a 10% increase in liver weight (without histopathological changes) were observed at a daily dose of 450 mg/kg [1] - Adverse reactions and drug interactions: In clinical trials, common adverse reactions to trazodone hydrochloride (AF-116; KB-831) (100–400 mg/day, orally) included somnolence (32%), dizziness (18%), dry mouth (12%), and nausea (8%); these adverse reactions were mild to moderate and resolved with continued treatment. Concomitant use with monoamine oxidase inhibitors (MAOIs) increases the risk of serotonin syndrome (hyperthermia, confusion), and concomitant use with sedatives (benzodiazepines) enhances central nervous system depression [1]

[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 compound, in which one nitrogen atom is replaced by a 3-chlorophenyl group and the other nitrogen atom is replaced by a 3-(3-oxo[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)propyl group. It possesses a variety of pharmacological effects, including antidepressant, sedative, adrenergic antagonist, H1 receptor antagonist, serotonin reuptake inhibitor, and anxiolytic activity. It belongs to the N-alkylpiperazine, N-arylpiperazine, triazolopyridine class of compounds, and is also a monochlorobenzene class of compounds. Trazodone is a triazolopyridine derivative of serotonin receptor antagonists and reuptake inhibitors (SARIs) antidepressants. Trazodone is used to treat adult depression, and its efficacy is comparable to other drugs such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine receptor inhibitors (SNRIs). The unique feature of this drug is that it does not cause side effects such as anxiety, sexual dysfunction, or insomnia like SSRIs and SNRIs. Trazodone acts on multiple receptors, including certain histamine receptors, serotonin receptors, and adrenergic receptors, which distinguishes it from other antidepressants that act on a narrower range of neurotransmitters. Trazodone was initially approved by the FDA in 1981. Trazodone is a serotonin reuptake inhibitor. Trazodone is a serotonergic modulating antidepressant used to treat depression, aggressive behavior, and panic disorder. Trazodone treatment may cause a transient increase in serum transaminase levels, usually asymptomatic, and has been associated with rare cases of clinically significant acute liver injury. Trazodone is a synthetic triazolopyridine derivative with antidepressant and sedative effects. Trazodone is a serotonin reuptake inhibitor whose chemical structure is independent of tricyclic, tetracyclic, or other antidepressants. It is effective in patients with schizoaffective disorder, major depressive disorder, and depression accompanied by insomnia and anxiety. (NCI04)
Trazodone is a serotonin reuptake inhibitor used as an antidepressant. It has been shown to be effective in patients with major depressive disorder and other subtypes of depression. It is generally more effective in depression accompanied by insomnia and anxiety. This drug does not worsen psychotic symptoms in patients with schizophrenia or schizoaffective disorder. (From JAMA Drug Evaluation Annals, 1994, p. 309)
A serotonin reuptake inhibitor used as an antidepressant. It has been shown to be effective in patients with major depressive disorder and other subtypes of depression. It is generally more effective in depression accompanied by insomnia and anxiety. This drug does not worsen psychotic symptoms in patients with schizophrenia or schizoaffective disorder. (From JAMA Drug Evaluation Annals, 1994, p. 309)
See also: Trazodone hydrochloride (salt form).

---

Drug Indications
Trazodone is indicated for the treatment of major depressive disorder (MDD). It has also been used off-label for adjunctive treatment of alcohol dependence, as well as for the treatment of anxiety and insomnia. Due to its action on multiple neurotransmitter receptors, trazodone can also be used to treat symptoms of diseases such as dementia, Alzheimer's disease, schizophrenia, eating disorders, and fibromyalgia (off-label use).

---

Mechanism of Action
The mechanism of action of trazodone is not fully understood, but it is known to inhibit serotonin reuptake and block histamine receptors and α1-adrenergic receptors. Although trazodone is often considered a selective serotonin reuptake inhibitor, several studies suggest that its mechanism of action may also include antagonism of serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes. Trazodone has been reported to have the strongest antagonistic effect on the serotonin 5-HT21c receptor, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has also been shown to inhibit serotonin transporters. The antidepressant effect of trazodone stems from its inhibition of receptor uptake, which typically reduces circulating neurotransmitter levels, thereby exacerbating depressive symptoms. The exact mechanism of trazodone's antidepressant effect is unclear, but studies have shown that the drug selectively blocks the reuptake of serotonin (5-HT) on the presynaptic neuronal membrane. Therefore, the effect of serotonin may be enhanced. Unlike other antidepressants (such as tricyclic antidepressants), trazodone may have a dual effect on the central serotonergic system. Animal studies have shown that high doses (6-8 mg/kg) of trazodone act as a serotonin agonist, while low doses (0.05-1 mg/kg) antagonize the effect of serotonin. Trazodone does not appear to affect the reuptake of dopamine or norepinephrine in the central nervous system; however, animal studies suggest that trazodone may enhance the release of norepinephrine in nerve tissue. Trazodone does not induce serotonin release in vitro. Trazodone hydrochloride (AF-116; KB-831) is a triazolidine antidepressant developed in the 1970s. It differs from tricyclic antidepressants (TCAs) in that it does not have significant anticholinergic, cardiotoxic, or orthostatic hypotension effects at therapeutic doses.[1] - Mechanism of action: Its antidepressant effect is attributed to a dual action: 1) inhibiting the presynaptic 5-HT transporter (SERT) to increase synaptic 5-HT levels; 2) antagonizing postsynaptic 5-HT₂A receptors, thereby reducing 5-HT₂A-mediated overstimulation and improving mood.[1] - Indications for treatment: Approved for the treatment of major depressive disorder (MDD) in adults. It has also been used off-label for the treatment of insomnia (due to its sedative effect via H₁ receptor antagonism) and anxiety disorders (e.g., generalized anxiety disorder) [1]
- Clinical efficacy: In a 6-week randomized controlled trial (n=240 patients with MDD), trazodone hydrochloride (AF-116; KB-831) (150–400 mg/day, orally) reduced Hamilton Depression Rating Scale (HDRS) scores by 52%, compared to 28% in the placebo group. The response rate (≥50% reduction in HDRS score) was 68% in the treatment group and 32% in the placebo group [1]

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.

---

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.

---

View More

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.

---

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