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.[38831] [43857]

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.[38831] [43857]

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.[38831] [43857]

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.[38831] [43857]

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.[38831] [43857]

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.[38831] [43857]

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.[38831] [43857]

Hepatic-related adverse events noted in postmarketing reports of trazodone include cholestasis, hyperbilirubinemia, jaundice, and altered hepatic enzymes.[38831] [43857]

Appetite stimulation, weight gain (1% to 5%), and weight loss (up to 6%) have been reported in patients receiving trazodone.[43857] [38831]

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.[38831] [43857]

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%).[38831] [43857]

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.[38831] [43857]

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%).[38831] [43857]

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.[38831] [43857]

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.[43857] [38831]

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.[38831] [43857]

Sinus/nasal congestion (3% to 6%) and apnea have been reported in patients receiving trazodone.[38831] [43857]

The use of SNRIs and SSRIs, including trazodone, can precipitate serotonin syndrome, a potentially life-threatening condition. The coadministration of trazodone with other medications that potentiate the actions of serotonin can increase the risk of serotonin syndrome. Symptoms may include nausea, vomiting, sedation, dizziness, diaphoresis (sweating), facial flush, mental status changes, myoclonia, restlessness, shivering, and elevated blood pressure. If serotonin syndrome becomes evident during treatment, trazodone and any other serotonergic agents should be discontinued and appropriate supportive symptomatic medical treatment should be initiated.[38831] [43857]

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.[38831] [43857]

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.[38831] [43857]

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.[38831] [43857]

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.[28432] [28457] [38831] [43857] [56592] [65180]

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.[38831] [43857]

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.[43857] [38831]

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.[38831] [43857]

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.[38831] [43857]

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.[38831] [43857]

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.[38831] [43857]

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.[38831] [43857]

There is limited data examining the use of trazodone during electroconvulsive therapy (ECT). While limited case reports indicate minimal effect on ECT-related seizure duration with trazodone, there have been reports of reduced seizure threshold and increased risk of serotonin syndrome when other serotonergic agents were given concomitantly with ECT.[70461]

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.[38831] [43857]

Clinical experience with trazodone has not identified differences in response to the drug in geriatric vs. younger adult patients, but data are limited. Geriatric adults may be more susceptible than younger adults to trazodone adverse reactions such as sedation, orthostatic hypotension, or hyponatremia due to SIADH.[43857] [63609] The U.S. Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities (LTCFs). When an antidepressant 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. Dosages and durations of treatment used in the geriatric adult should be in accordance with prescribing labels, published literature recommendations, and expert guidelines.[60742]

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.[38831] [43857]

Data from published literature indicate that 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, the mother's prior antidepressant trials and the risk of symptom relapse during transition to a new medication may preclude the use of alternatives. 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.[38831] [43857] [45642]