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Mechanism of Action
US Drug Names
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 general, elderly patients may require lower initial dosage and slower dose titration than younger adults. Maximum daily dosage is 400 mg/day PO for outpatients and 600 mg/day PO for inpatients. Maintenance therapy should be given at the lowest effective dosage.
Data are limited; not considered a first-line agent for treatment of depression 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; if needed, gradually increase dose every 3 to 4 days. 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: 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.
Initially, 150 mg PO once daily on an empty stomach late in the evening, preferably at bedtime. Increase gradually by 75 mg/day PO every 3 days (i.e., may start 225 mg/day on Day 4 of therapy). Thereafter may adjust as tolerated and needed. Max: 375 mg/day PO. 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. Titration from a low initial dose (e.g., 25 to 50 mg) may increase tolerability. Guidelines suggest that there is insufficient or 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 controlled trial which evaluated 50 mg of trazodone and found no clinically significant improvement in sleep outcomes and significantly more side effects with trazodone (e.g., headache, daytime somnolence) than placebo; other studies were considered inadequate for assessment. The British Association for Psychopharmacology guidelines state that antidepressants may be considered for insomnia when there is a co-existing mood disorder and therapeutic 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, further studies are needed to determine long-term safety and efficacy.       
50 to 100 mg PO once daily has been shown to decrease cravings for alcohol, depression and anxious symptoms in patients with alcohol dependence. Pharmacotherapy should be used as a part of a comprehensive management program that includes psychosocial support and treatment.
Initially, 150 mg/day PO in divided doses, increase by 50 mg/day every 3 to 4 days as tolerated and needed. Trazodone 300 mg/day PO in divided doses has decreased symptoms of panic, phobia and anxiety in a small number of patients with panic disorder or agoraphobia. In comparison to imipramine and alprazolam, trazodone was not as effective in the treatment of panic attacks.
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.
For the immediate release tablets, 400 mg/day PO for outpatients and 600 mg/day PO for inpatients; for the 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 some references use a max of 6 mg/kg/day PO; in clinical trials, doses off-label have not exceeded 150 mg/day PO in adolescent patients.
Less than 6 years: Safety and efficacy have not been established.
Patients with hepatic dysfunction may require dosage adjustment of trazodone based upon the severity of hepatic impairment 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.
CrCl 50 mL/minute: No dosage adjustment needed.
CrCl less than 50 mL/minute: Specific guidelines are not available; no dosage adjustments are expected to be needed in initial dosage since less than 1% of a dose appears in the urine unchanged. Titrate according to patient response and tolerance; the manufacturer recommends caution since specific studies in renal dysfunction are not available.
Description: Trazodone is an oral antidepressant, unrelated to tricyclic or tetracyclic antidepressants. It possesses some similarities of action to other antidepressant drugs, however, and also has some action as an anxiolytic. Trazodone is used in the treatment of major depression, generalized anxiety disorder, and insomnia. Trazodone was approved by the FDA in 1981. In February 2010, an extended-release formulation was approved for the treatment of major depression in adults.
In October 2004, the FDA directed manufacturers of all antidepressants to include a Black Box warning, expanded warning statements, and clinical trial results detailing the increased risk of suicidality in children and adolescents. The warning was subsequently revised to include data on the increased risk of suicidality in young adults. A Patient Medication Guide (MedGuide) should accompany all prescriptions for antidepressants.
For storage information, see the specific product information within the How Supplied section.
Adverse psychiatric effects reported in clinical trials for trazodone included akathisia (psychomotor restlessness), 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 predisposed patients during treatment with an antidepressant. Monitor all antidepressant-treated patients for any indication for worsening of depression or the condition being treated and the emergence of suicidal behaviors or suicidal ideation, especially during the initial few 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 increase in the 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. 
Priapism (including clitoral priapism or clitorism) has been reported in a number of patients receiving trazodone. Priapism occasionally results in permanent impairment of erectile function or impotence. Patients should be warned of the possibility and to discontinue the drug at once and consult with the physician if this reaction occurs. Careful consideration should be given before administering the drug to postpubescent male patients. Other sexual abnormalities included: impotence (erectile dysfunction) (< 1%), ejaculation dysfunction (retrograde or no ejaculation) (1.5%), orgasm dysfunction (< 1%), libido increase, and libido decrease (1.3—1.5%).
Hypotension (3.8—7%), including orthostatic hypotension, and syncope (2.8—4.5%), can occur during therapy with trazodone. Patients receiving treatment for hypertension may require a reduction in the antihypertensive dosage. Other cardiovascular-related adverse effects associated with trazodone include: hypertension (1.3—2.1%), shortness of breath (1.3%), dyspnea (> 1%), edema (> 1%), chest pain (unspecified), cardiospasm, congestive heart failure, cerebrovascular accident, conduction block, myocardial infarction, cardiac arrest.
Cardiac arrhythmias (i.e., arrhythmia exacerbation) and palpitations (0—7%) have been reported however, they are not as common during therapy with trazodone as with tricyclic antidepressants. Isolated premature ventricular contractions (PVCs), ventricular couplets and short episodes (3—4 beats) of ventricular tachycardia (0—7%) have occurred in patients with or without preexisting cardiac disease. Bradycardia and atrial fibrillation have been noted in post-marketing reports during therapy with trazodone. Additionally, there have been post-marketing reports of QT prolongation, Torsade de Pointes, and ventricular tachycardia with immediate-release trazodone at doses of 100 mg per day or less.
Drowsiness/somnolence/sedation (23.9—46%) is the most common side effects of trazodone. Other CNS effects include confusion (1—5.7%), dizziness/lightheadedness (19.7—28%), nervousness (6.4—14.8%), fatigue (5.7—15%), headache (9.9—33%), excitement/excitability (1.4—5.1%), memory impairment (<= 1.4%), impaired cognition, migraine (> 1%), amnesia (< 1%), aphasia (< 1%), disorientation (> 1—2.1%), decreased concentration (1.3—2.8%), speech disorder (< 1%), nightmares/vivid dreams/abnormal dreams (< 1—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 during a fasting state may increase the incidence of these effects.
Various musculoskeletal complaints have been reported with trazodone use. Muscle tremor (>= 1 to 5.1%) and musculoskeletal pain (5.1—5.6%) may due to weak skeletal muscle-relaxant activity. Back pain (5%), myalgia (> 1%), muscle twitching (< 1%), incoordination or abnormal coordination (1.9—4.9%), paresthesias (1.4%), hypoesthesia (< 1%), gait disturbance (< 1%), ataxia, weakness, extrapyramidal symptoms, tardive dyskinesia, chills, and numbness have also been reported.
Gastrointestinal adverse reactions have been reported with trazodone use. Xerostomia (14.8—33.8%) is a common side effect during therapy with trazodone and is believed to be due to alpha1-adrenergic blocking effects rather than to anticholinergic action. Of note, increased and hyper-salivation has also been reported with trazodone use. Other GI-related adverse effects include: abdominal pain (> 1%), constipation (7—8%), diarrhea (0—9%), dysgeusia ( >1 to 1.4%), flatulence, gastroesophageal reflux (< 1%), increased amylase, nausea (9.9—21%), and vomiting (> 1—12.7%). Administration with food, which reduces the absorption rate, can reduce manifestations of GI upset.
Blurred vision (5—14.7%) during therapy with trazodone may be an anticholinergic effect. Other ophthalmic effects reported with trazodone use include: red, tired, or itchy eyes (2.8%), visual impairment/disturbance (> 1%), xerophthalmia (dry eye) (< 1 %), ocular pain (< 1 %), and photophobia (< 1%). Patients experiencing ocular changes should have an ophthalmologic examination.
Various skin, skin structure, and subcutaneous tissue adverse reactions have been reported with trazodone use. Photosensitivity was reported in < 1% patients during clinical trials; the mechanism of this reaction is not known. Night sweats (> 1%), acne vulgaris (< 1%), hyperhidrosis (< 1%), alopecia, flushing or vasodilation, psoriasis, rash (unspecified), urticaria, pruritus, leukonychia, hirsutism, and sweating/clamminess (< 1—1.4%) have also been reported.
In cases of trazodone overdose, respiratory arrest, priapism, seizures, and ECG/EKG changes may occur. Significant ingestions may produce hypotension, bradycardia, and respiratory depression in addition to severe manifestations of other adverse effects. Grand mal seizures have been reported with post-marketing use of the drug.
Trazodone blocks the reuptake of serotonin at the presynaptic neuronal membrane. Although unlikely to occur with use of trazodone alone, the coadministration of other medications that potentiate the actions of serotonin could theoretically result in serotonin syndrome.
Hyponatremia may occur in patients taking antidepressants. While the cases were complex, many may have been due to the syndrome of inappropriate antidiuretic hormone (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. The majority of cases have been seen in patients who are elderly, taking diuretics, or volume depleted. 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.
Ear and labyrinth disorders have been reported with trazodone use, including hypoacusis/hearing loss (< 1%), tinnitus (< 1—1.4%), and vertigo (< 1%).
Urinary adverse effects that have been reported with trazodone use include delayed urine flow, increased urinary frequency, urinary incontinence, urinary retention, urinary urgency (> 1%), urinary incontinence (< 1%), bladder discomfort or pain (< 1%), and hematuria.
Hepatic-related adverse event noted with post-marketing reports of trazodone include cholestasis, hyperbilirubinemia, jaundice, and altered hepatic enzymes.
Hematologic lab abnormalities reported with post-marketing use of trazodone include anemia, hemolytic anemia, leukocytosis, and methemoglobinemia.  
Sinus/nasal congestion (2.8—5.7%) and apnea have been reported in patients receiving trazodone. 
Appetite stimulation , weight gain (1.4—4.5%), decreased appetite/anorexia (3.5%), and weight loss (< 1—5.7%) have been reported in patients receiving trazodone.
Adverse effects associated with trazodone use in women include early menses and missed periods (i.e., menstrual irregularity), breast enlargement or engorgement, and lactation.
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, adolescent, 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. 
All effective antidepressants can transform depression into mania or hypomania in predisposed individuals. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. If a patient develops manic symptoms, trazodone should be withheld and appropriate therapy initiated to treat the manic symptoms. Additionally, depression may be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an 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 a course 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 and triptans) and with drugs that impair metabolism of serotonin (including MAOIs, linezolid, or intravenous methylene blue), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms 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). Serotonin syndrome, in its most severe form, 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 the above reactions occur and supportive symptomatic treatment should be initiated. If concomitant treatment with trazodone and an SSRI, SNRI or a serotonin receptor agonist (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 antidepressant drugs (including trazodone) may cause cardiac arrhythmias. Avoid use in patients with known QT prolongation or who are receiving medications known to inhibitors of 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 somnolence or sedation and 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 should be used with caution in patients with hepatic disease; trazodone has not been studied in patients with hepatic impairment. The drug is extensively metabolized in the liver. 
Trazodone should be used with caution in patients with renal impairment. While less than 1% of an oral dose is excreted unchanged in the urine; trazodone's active metabolite and other metabolites are excreted primarily in the urine. Trazodone has not been studied in patients with renal impairment or renal failure. 
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 if possible. Withdrawal symptoms including anxiety, agitation and sleep disturbances, have been reported with trazodone. Clinical experience suggests that the dose should be gradually reduced before completely discontinuing the drug. 
In general, clinical experience with trazodone has not identified differences in response to the drug in elderly 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.      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 may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. Concurrent use of 2 or more antidepressants may increase the risk 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 clinical need of the mother for trazodone and any potential adverse effects on the breastfed infant from trazodone or from the underlying maternal condition. Trazodone is excreted into breast milk; however, limited data from postmarketing reports have not identified trazodone-associated adverse effects on the breastfed child. There are no data regarding the effect of trazodone on milk production.  Patients should advise their physician of their intention to breast-feed. Alternative therapy may be considered. A pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants in breast-feeding mothers.
Mechanism of Action: Similar to fluoxetine, trazodone inhibits the reuptake of serotonin, although trazodone is less potent than fluoxetine in this regard. Trazodone appears to act as a serotonin agonist at higher doses (6—8 mg/kg), yet appears to antagonize serotonin at low doses (0.05—1 mg/kg). Antidepressant activity is believed to be produced by blocking the reuptake of serotonin at the presynaptic neuronal membrane. Long-term therapy also can affect postsynaptic neuronal receptor binding sites. Trazodone has no influence on the reuptake of norepinephrine or dopamine within the CNS. There is some evidence in animals that norepinephrine release is enhanced by trazodone. Trazodone does not inhibit monoamine oxidase.
Anticholinergic activity is lower with trazodone than with the tricyclic antidepressants. It has a sedative effect, which is believed to be produced by the alpha-adrenergic blocking action and modest histamine blockade. Total sleep time is increased, but unlike the tricyclics, trazodone does not affect stage 4 sleep. Trazodone has weak skeletal muscle-relaxant activity and no anticonvulsant activity. Unlike the tricyclics, trazodone has no direct quinidine-like action on the cardiovascular system. Hypotension may be a result of lowered arterial blood pressure caused by the blocking of pressor response to norepinephrine. Trazodone may affect the endocrine system, but results are inconclusive.
Trazodone is administered orally. The drug is highly protein bound (89% to 95%). Distribution occurs without selective localization into any tissue. In vitro studies in human liver microsomes show that trazodone undergoes 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 being 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 a delay in the time taken to reach peak concentrations. Peak levels are achieved 1 hour after dosing in the fasting state and 2 hours after dosing with food following administration of the immediate-release formulation. 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.
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