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Mechanism of Action
US Drug Names
Initiate at 150 mg/day PO in divided doses; may increase by 50 mg/day every 3 to 4 days as needed based on clinical response. Lower starting doses and slower titration schedules may be better tolerated in geriatric patients or those with risks for orthostatic hypotension and syncope (e.g., antihypertensive therapy). Max: 400 mg/day PO for outpatients and 600 mg/day PO for inpatients. Maintenance therapy should be continued at the lowest effective dose. Periodically reassess for the need for continued treatment and symptom control with current dose. 
Due to limited data, trazodone is not considered a first-line agent in this population. Initially, 25 mg PO once daily at bedtime, then may titrate every 3 to 4 days up to 100 to 150 mg/day, given in divided doses. Alternatively, weight-based dosing has been used: 1.5 to 2 mg/kg/day PO given in divided doses. May gradually increase dose every 3 to 4 days if needed. Max: 6 mg/kg/day PO, given in divided doses.  
Data are limited; not considered a first-line agent for treatment of depression in this population. Weight-based dosing has been used at 1.5 to 2 mg/kg/day PO given in divided doses; if needed, gradually increase dose every 3 to 4 days. Max: 6 mg/kg/day PO, given in divided doses. 
150 mg PO once daily in the evening, preferably at bedtime, and on an empty stomach. May increase gradually by 75 mg/day PO every 3 days (i.e., may start 225 mg/day on Day 4 of therapy) if needed for clinical response and tolerability. Max: 375 mg/day PO. Patients should be maintained on lowest effective dose and monitored for continued need for treatment. Once an adequate response has been achieved, dosage may be gradually reduced with subsequent adjustment depending on therapeutic response.
25 mg to 150 mg PO at bedtime is the usual dose range. Titration from a low initial dose (e.g., 25 to 50 mg) is recommended and may increase tolerability. There is insufficient/limited evidence for efficacy of trazodone for chronic insomnia. The American Academy of Sleep Medicine (AASM) guidelines recommend against trazodone for chronic insomnia based on a short-term trial which evaluated trazodone 50 mg/night and found no clinically significant improvement in sleep outcomes and significantly more side effects (e.g., headache, daytime somnolence) vs. placebo; other studies were considered inadequate for assessment. Antidepressants like trazodone may be considered for insomnia when there is a co-existing mood disorder and therapeutic antidepressant doses are used. Findings from one large systematic review suggest there may be a small improvement in sleep quality during short-term use of low-dose trazodone; however, additional studies are needed to determine long-term safety and efficacy.       
Initially, 150 mg/day PO in divided doses, increase by 50 mg/day every 3 to 4 days as needed; however, slower titration schedules may be better tolerated. In one study, the mean maximum daily effective dose was 255 mg/day. In general, elderly patients may require lower initial dosage and slower dose titration than younger adults. Max: 400 mg/day PO for outpatients or 600 mg/day PO for inpatients. Maintenance therapy should be given at the lowest effective dosage.
Immediate release tablets: 400 mg/day PO for outpatients and 600 mg/day PO for inpatients
Extended-release tablets: 375 mg/day PO.
Safety and efficacy have not been established; in clinical trials, doses off-label have not exceeded 150 mg/day PO.
6 to 12 years: Safety and efficacy have not been established; off-label max: 6 mg/kg/day PO; doses off-label have not exceeded 150 mg/day PO for those 12 years and older.
Less than 6 years: Safety and efficacy have not been established.
Dosage adjustment of trazodone based upon the severity of hepatic impairment may be needed as trazodone is extensively metabolized. However, no quantitative guidelines are available. Titrate according to patient response and tolerance; the manufacturer recommends caution since specific studies in hepatic dysfunction are not available.
Specific guidelines are not available; titrate according to patient response and tolerance. The manufacturer recommends caution since specific studies in renal impairment are not available.
Trazodone is an oral selective serotonin reuptake inhibitor and serotonin type 2 receptor antagonist that is FDA-approved for the treatment of major depressive disorder in adults. Due to its sedating effects related to antagonism at histamine and alpha receptors, it is commonly used off-label at low doses for the treatment of insomnia. It has also been used off-label for the treatment of generalized anxiety disorder. It is available as both an immediate-release and extended release (ER) formulation. Product labels for all antidepressants contain a boxed warning related to an increased risk of suicidality in children, adolescents, and young adults during the initial stages of therapy when treating depression or other conditions; therefore, the necessity of pharmacologic therapy versus the potential risks should be carefully considered in these populations.
For storage information, see the specific product information within the How Supplied section.
Adverse psychiatric effects reported in clinical trials for trazodone included akathisia (less than 2%), agitation (1% or more), anxiety, insomnia (6.4% to 9.9%), hostility (1.3% to 3.5%), and hypomania (more than 1%). Mania can occur in patients predisposed to bipolar disorder during treatment with an antidepressant. Monitor all antidepressant-treated patients for any indication for worsening of depression and the emergence of suicidal behaviors or suicidal ideation, especially during the initial months of drug therapy and after dosage changes. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in the absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. These studies did not show an increased risk of suicidal thoughts and behavior with antidepressant use in patients over 24 years of age; there was a reduction in risk with antidepressant use in patients aged 65 and older. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation during trazodone treatment. 
Drowsiness (23.9% to 46%) is the most common side effect of trazodone. Other CNS effects include confusion (1% to 5.7%), dizziness or lightheadedness (19.7% to 28%), nervousness (6.4% to 14.8%), fatigue (5.7% to 15%), headache (9.9% to 33%), excitement/excitability (1.4% to 5.1%), memory impairment (up to 1.4%), impaired cognition, migraine (less than 1%), amnesia (less than 1%), aphasia (less than 1%), disorientation (up to 2.1%), decreased concentration (1.3% to 2.8%), speech disorder (less than 1%), nightmares or vivid/abnormal dreams (up to 5.1%), malaise (2.8%), diplopia, hallucinations/delusions, impaired speech, paranoid reaction (i.e., paranoia), psychosis, and stupor. Some CNS side effects occur during the first few weeks of therapy, and tolerance can develop after 1 or 2 weeks. Taking trazodone on an empty stomach may increase the incidence of these effects. 
Hypotension (3.8 to 7%), including orthostatic hypotension, and syncope (2.8 to 4.5%), can occur during therapy with trazodone. Patients receiving treatment for hypertension may require a reduction in their antihypertensive dosage when starting trazodone. Other cardiovascular-related adverse effects associated with trazodone include hypertension (1.3 to 2.1%), shortness of breath (1.3%), dyspnea (less than 1%), and edema (less than 1%). Postmarketing reports have also included cases of chest pain (unspecified), cardiospasm, congestive heart failure, cerebrovascular accident (stroke), AV block or other conduction block, myocardial infarction, cardiac arrest. Trazodone should be used with caution in patients with cardiac disease and close monitoring is recommended. 
Cardiac arrhythmias (i.e., arrhythmia exacerbation) and palpitations (up to 7% of outpatients in clinical data) have been reported with trazodone at rates lower than what has been documented with tricyclic antidepressants. Isolated premature ventricular contractions (PVCs), ventricular couplets and short episodes (3 to 4 beats) of ventricular tachycardia have also occurred in patients with or without preexisting cardiac disease. Bradycardia and atrial fibrillation have been noted in postmarketing reports during therapy with trazodone. Additionally, there have been postmarketing reports of QT prolongation, Torsade de Pointes, and ventricular tachycardia with immediate-release trazodone at doses of 100 mg per day or less. 
Various musculoskeletal complaints have been reported with trazodone use. Muscle tremor (up to 5.1%) and musculoskeletal pain (5.1 to 5.6%) may be due to weak skeletal muscle relaxant activity. Back pain (5%), myalgia (more than 1%), muscle twitching (less than 1%), incoordination or abnormal coordination (1.9 to 4.9%), paresthesias (1.4%), hypoesthesia (less than 1%), gait disturbance (less than 1%), ataxia, weakness, extrapyramidal symptoms, tardive dyskinesia, chills, and numbness have also been reported. 
Various skin, skin structure, hypersenstivitiy, and subcutaneous tissue adverse reactions have been reported with trazodone use. Photosensitivity was reported in less than 1% of patients during clinical trials; the mechanism of this reaction is not known. Night sweats (more than 1%), acne vulgaris (less than 1%), hyperhidrosis (less than 1%), alopecia, flushing or vasodilation, psoriasis, rash, urticaria, pruritus, leukonychia, hirsutism, drug eruption, and sweating/clamminess (up to 1.4%) have also been reported. Hypersensitivity has been reported in less than 1% of patients receiving trazodone. 
Gastrointestinal (GI) adverse reactions have been reported with trazodone use. Xerostomia (15% to 34%) is a common side effect during therapy with trazodone and is believed to be due to alpha-1 adrenergic blocking effects rather than to anticholinergic action. Of note, increased salivation and hypersalivation has also been reported with trazodone use. Other GI-related adverse effects include abdominal pain (more than 1%), constipation (7% to 8%), diarrhea (0% to 9%), dysgeusia (up to 1.4%), flatulence, gastroesophageal reflux (less than 1%), increased amylase, nausea (10% to 21%), and vomiting (up to 12.7%). Administration with food slows the absorption rate and may decrease the severity of GI adverse effects. 
Hepatic-related adverse events noted in postmarketing reports of trazodone include cholestasis, hyperbilirubinemia, jaundice, and altered hepatic enzymes. 
Appetite stimulation, weight gain (1% to 5%), and weight loss (up to 6%) have been reported in patients receiving trazodone. 
Blurred vision (5% to 15%) during therapy with trazodone may be related to the anticholinergic effects of the drug. Other ophthalmic effects reported with trazodone use include red, tired, or itchy eyes (2.8%), visual impairment/disturbance (more than 1%), xerophthalmia (less than 1%), ocular pain (less than 1%), and photophobia (less than 1%). Patients experiencing ocular changes should have an ophthalmologic examination. 
Ear and labyrinth disorders have been reported with trazodone use, including hypoacusis/hearing loss (less than 1%), tinnitus (less than 1.4%), and vertigo (less than 1%). 
Urinary adverse effects that have been reported with trazodone use include delayed urine flow, increased urinary frequency (less than 2%), urinary incontinence, urinary retention, urinary urgency (greater than 1%), urinary incontinence (less than 1%), bladder discomfort or pain (less than 1%), and hematuria. 
Priapism (including clitoral priapism or clitorism) has been reported in a number of male patients receiving trazodone. Priapism occasionally results in permanent impairment of erectile function. Male patients should be warned of this possibility and advised to discontinue the drug at once and seek emergency medical care if this reaction occurs. Other sexual dysfunctions included impotence (erectile dysfunction) (less than 1%), ejaculation dysfunction (retrograde or no ejaculation) (1.5%), orgasm dysfunction (less than 1%), libido increase (less than 2%), and libido decrease (1.3 to 1.5%). 
Adverse endocrine effects associated with trazodone use in women include early menses and missed periods (i.e., menstrual irregularity), breast enlargement or engorgement, and breast discharge or lactation. 
Hematologic lab abnormalities reported in controlled clinical trials include anemia (less than 2%). Postmarketing reports of hemolytic anemia, leukocytosis, and methemoglobinemia have also been associated with the use of trazodone. 
Hyponatremia may occur in patients taking antidepressants and is often due to the syndrome of inappropriate antidiuretic hormone (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Patients who are geriatric, taking diuretics, or are volume depleted are at an increased risk. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness. More severe cases may cause hallucinations, syncope, seizures, coma, respiratory arrest, and death. Discontinuation of trazodone may be necessary in those with symptomatic hyponatremia. Grand mal seizures have also been reported during postmarketing use of the drug, and may or may not be related to hyponatremia. 
Sinus/nasal congestion (3% to 6%) and apnea have been reported in patients receiving trazodone. 
Trazodone blocks the reuptake of serotonin at the presynaptic neuronal membrane. Although unlikely to occur with use of trazodone alone, the coadministration of trazodone with other medications that potentiate the actions of serotonin could result in serotonin syndrome. 
Safety and efficacy of trazodone for the treatment of depression have not been established in pediatric patients less than 18 years of age. A boxed warning in the product label describes the risk of suicidality and suicidal ideation in children, adolescents, and young adult patients receiving antidepressants. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of trazodone may be necessary in patients with emerging suicidality or worsening depression. 
Patients with bipolar disorder may initially present with symptoms of a major depressive episode. Treating such an episode with an antidepressant alone may increase the likelihood of precipitating a switch to mania or a hypomanic episode in patients with underlying bipolar disorder. Likewise, complaints of insomnia in a depressed patient are common but could indicate the presence of a mixed episode in a patient with bipolar disorder. If a patient develops manic symptoms, trazodone should be withheld and appropriate therapy initiated to treat the manic symptoms. Patients should be adequately screened for bipolar disorder prior to initiating any antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of drug therapy, or at times of dose changes. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or suicidality. It should be noted that trazodone is not approved for use in treating bipolar depression. 
Due to the risk for serotonin syndrome, it is recommended that trazodone not be used in combination with monoamine oxidase inhibitor therapy (MAOI therapy) or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping trazodone before starting an MAOI. In addition to a risk for serotonin syndrome, limited animal data on the effects of combined use of serotonergic antidepressants and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. The development of a potentially life-threatening serotonin syndrome has been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (e.g., SSRIs, SNRIs, or "triptans") and with drugs that impair metabolism of serotonin (including MAOIs, linezolid, or intravenous methylene blue), or with antipsychotics or other dopamine antagonists. Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Severe forms of serotonin syndrome can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Treatment with trazodone and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if these reactions occur and supportive symptomatic treatment should be initiated. If concomitant treatment with trazodone and an SSRI, SNRI, or a serotonin receptor agonist (such as a "triptan") is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of trazodone with serotonin precursors (such as tryptophan) is not recommended. 
Trazodone prolongs the QT/QTc interval. There are postmarketing reports of isolated PVCs, ventricular couplets, and tachycardia with syncope. Torsade de pointes (TdP), a life-threatening arrhythmia, has also been reported. Some of these events have occurred at doses of 100 mg/day or less. Avoid using trazodone in patients with a history of cardiac arrhythmias or conditions that may increase the risk of TdP and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and congenital long QT syndrome. Trazodone is not recommended for use during the initial recovery phase of an acute myocardial infarction. Use caution and closely monitor patients with cardiac disease during treatment as trazodone may cause cardiac arrhythmias. Avoid use in patients with known QT prolongation or who are receiving medications known to inhibit CYP3A4 or prolong the QT interval. Use trazodone with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Caution is advisable in patients with pre-existing hypotension because orthostatic hypotension and syncope can occur during treatment with trazodone. Conditions that may predispose patients to hypotension, such as hypovolemia and dehydration, should be corrected if possible before starting trazodone therapy. Lower doses may be required in patients at increased risk for hypotension or in patients taking antihypertensive agents.     
Trazodone-induced somnolence or sedation may impair the mental and/or physical ability required for the performance of potentially hazardous tasks. Patients should be warned to use caution when driving or operating machinery until they know how trazodone will affect them. Trazodone may enhance the response to alcohol, barbiturates, and other CNS depressants; use with caution during coadministration with other CNS depressants. Ethanol ingestion should be limited or avoided. 
Trazodone is extensively metabolized in the liver and has not been studied in patients with hepatic impairment. Use with caution in patients with hepatic disease. 
Trazodone has not been studied in patients with renal impairment or renal failure. Since the active metabolite of trazodone is excreted primarily in the urine, trazodone should be used with caution in patients with renal impairment. 
Antidepressants may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 millimoles/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative agent. People 65 years and older, those receiving diuretics or prone to dehydration, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of trazodone, as well as implementation of the appropriate medical interventions. 
Caution is recommended when prescribing trazodone to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated. 
Monitor patients for signs and symptoms of bleeding. Postmarketing data have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal (GI) bleeding. While no association between trazodone and bleeding events, in particular GI bleeding, was shown, platelet aggregation may be impaired by drugs that inhibit serotonin reuptake due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage). Concurrent use of aspirin, non-steroidal antiinflammatory drugs (NSAIDs), anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase this risk. Patients taking trazodone should be should be instructed to promptly report any bleeding events to the practitioner. 
Rare cases of priapism (painful erections greater than 6 hours in duration) were reported in men receiving trazodone. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Men who have an erection lasting greater than 6 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention. 
There is limited experience with trazodone and electroconvulsive therapy (ECT). It is recommended to avoid concurrent use of these therapies.
Abrupt discontinuation of trazodone should be avoided unless clinically necessary. Withdrawal symptoms including anxiety, agitation, and sleep disturbances have been reported with abrupt cessation of trazodone. Clinical experience indicates that the dose should be gradually reduced before complete discontinuation of the drug. 
In general, clinical experience with trazodone has not identified differences in response to the drug in geriatric vs. younger adult patients, but data are limited. Geriatric patients generally require a lower dosage of trazodone and are more susceptible to adverse reactions such as sedation, orthostatic hypotension, QT prolongation, or hyponatremia due to SIADH than younger adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities (LTCFs). According to OBRA, the duration of therapy should be in accordance with pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants like trazodone may cause side effects of dizziness or somnolence, which can increase the risk for falls. Concurrent use of 2 or more antidepressants may increase the risk or severity of side effects; in such cases there should be documentation of expected benefits that outweigh the associated risks and monitoring for any increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated. OBRA also regulates the use of sedative/hypnotics in residents of LTCFs. The OBRA guidelines provide criteria for use and tapering requirements for sedating antidepressants used as sedative/hypnotics, including trazodone.      
Although available studies cannot definitively establish the absence of risk, published prospective cohort studies, case series, and case reports over several decades with trazodone use in pregnant women have not identified any drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. It should be noted that all available studies have methodological limitations, including small sample sizes and inconsistent comparator groups. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than those who continued antidepressants. Consider the risk of untreated depression versus the potential for adverse fetal outcomes when discontinuing or changing treatment with trazodone during pregnancy and postpartum. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to trazodone; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants or by calling 1-866-961-2388 or 1-844-405-6185. 
The developmental and health benefits of breast-feeding should be considered along with the mother's underlying condition, clinical need for treatment, and the risk of adverse effects in the breastfed infant. Trazodone is excreted into breast milk at low levels; however, limited data from postmarketing reports have not identified trazodone-associated adverse effects in the breastfed child. There are no data regarding the effect of trazodone on milk production. Patients should advise their physician of their intention to breastfeed and alternative therapy may be considered. A pooled analysis found that maternal use of sertraline, nortriptyline, and paroxetine usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants for breast-feeding mothers. However, mother's prior antidepressant trials and the risk of symptom relapse during transition to a new medication must also be considered.  
Trazodone has a unique mechanism of action via activity at a variety of receptors, making it distinct from other traditional antidepressant medications. At low doses, trazodone has antagonistic effects at alpha-1 adrenergic receptors and histamine H1 receptors, leading to an increased risk for postural hypotension, syncope, and sedation. Unlike other sedating antidepressants, trazodone has minimal effects on REM sleep while improving sleep efficiency and subjective sleep quality. At increased doses, trazodone exerts antidepressant effects by selectively inhibiting reuptake of serotonin (5-HT) while also acting as an antagonist at 5-HT2 receptors. Trazodone is also a partial agonist at 5-HT1A receptors, providing mild anxiolytic activity.
Trazodone is administered orally and distributed without selective localization into any tissue. The drug is highly protein bound (89% to 95%). In vitro studies in human liver microsomes show that trazodone undergoes metabolism via oxidation to an active metabolite, m-chlorophenylpiperazine (mCPP), by CYP3A4. Other metabolic pathways have not been well described. The mean terminal half-life is about 10 hours. Less than 1% of an oral dose is excreted unchanged in the urine. Elimination is mainly through the urine, with about 70% to 75% of a dose excreted (mainly as metabolites) within 72 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
Trazodone is extensively metabolized in the liver, primarily by CYP3A4. Concurrent use of CYP3A4 inhibitors may necessitate lower dose of trazodone and concurrent use of CYP3A4 inducers may necessitate higher doses of trazodone. Use of potent CYP3A4 inhibitors may increase the risk of trazodone-associated cardiac arrhythmias.
Trazodone is well absorbed after oral administration. Food affects absorption. When taken with or shortly after a meal, there may be an increase in the amount of drug absorbed, a decrease in peak plasma concentrations, and an increase in the time to reach peak concentrations. Peak levels of the immediate-release formulation are achieved 1 hour after dosing in the fasting state or 2 hours after dosing when taken with food. When the extended-release tablets are taken shortly after ingestion of a high-fat meal, Cmax increases by about 86% compared to administration under fasting conditions. However, Tmax is not significantly affected by food.
Trazodone has not been studied in patients with hepatic impairment but is metabolized extensively through the liver. Caution is advised when using in patients with hepatic impairment.
Trazodone has not been studied in patients with renal impairment. The primary route of excretion for trazodone metabolites is via the kidney; caution is advised when using trazodone in patients with renal impairment as accumulation of the active metabolite may occur.
Pharmacokinetic data are not available. Clinical studies have not shown differences in response between geriatric and younger adult patients, but data are limited. Caution is advised when using trazodone in this population due to the potential for increased adverse effects.
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