VA Class:CN609

AHFS Class:

• Serotonin Modulators 28:16.04.24

Generic Name(s):

• traZODone Hydrochloride

Trazodone hydrochloride is a triazolopyridine-derivative antidepressant that is chemically and structurally unrelated to tricyclic or tetracyclic antidepressants or to selective serotonin-reuptake inhibitors.

Major Depressive Disorder

Trazodone is used in the treatment of major depressive disorder. The drug is used in patients who exhibit a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning and is manifested as a change in appetite, psychomotor agitation or retardation, a loss of interest in usual activities, a decrease in sexual drive, increased fatigability, a change in sleep, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and/or suicidal ideation or attempts. Trazodone has been used effectively in the treatment of patients who have major depression with or without prominent anxiety. In addition, trazodone has been used effectively in patients with major depression in hospital, institutional, and outpatient settings. Unlike tricyclic antidepressants, trazodone generally has not been reported to precipitate hypomanic or manic attacks in patients with bipolar disorder; however, further study is needed to determine the safety and efficacy of trazodone when used alone as an antidepressant in these patients.

Trazodone is particularly effective in reducing affective and ideational manifestations of depression, especially anxiety, apathy, irritability, and suicidal thoughts. Somatic signs and symptoms associated with depression, including sleep disturbances and fatigue, are also reduced during trazodone therapy. Most clinical studies have shown that the antidepressant effect of usual dosages of trazodone in patients with moderate to severe depression is about equal to that of usual dosages of amitriptyline, imipramine, or doxepin. However, trazodone has reportedly caused fewer adverse effects (e.g., anticholinergic effects) than these tricyclic antidepressants. (See Cautions: Anticholinergic Effects.) Although trazodone has been reported to have a slightly more rapid onset of action than amitriptyline, desipramine, or imipramine, this has not been established.

Trazodone has been used in patients with major depression who have associated anxiety. Based on limited data, the antidepressant effect of usual dosages of trazodone appears to be greater than that of amitriptyline or imipramine in these patients. Trazodone is particularly effective in reducing anxiety, tension, somatic symptoms, insomnia, and psychomotor retardation in these patients.

For further information on treatment of major depressive disorder and considerations in choosing the most appropriate antidepressant for a particular patient, including considerations related to patient tolerance, patient age, and cardiovascular, sedative, and suicidal risk, see Considerations in Choosing Antidepressants under Uses: Major Depressive Disorder, in Fluoxetine Hydrochloride 28:16.04.20.

Schizophrenic Disorder

Although trazodone has been used in the treatment of schizophrenic disorder†, the drug is less effective than chlorpromazine. Depressive symptomatology may improve during trazodone therapy, but the drug does not appear to relieve psychotic symptoms in most schizophrenic patients. Based on limited data, trazodone has little value when used alone in patients with chronic schizophrenic disorder without depression; however, it may be a useful adjunct to antipsychotic agents (e.g., phenothiazines) in patients with chronic schizophrenic disorder and associated depression. Unlike tricyclic antidepressants, trazodone does not appear to worsen psychotic symptoms in these patients.

Alcohol Dependence

Trazodone has been used in the adjunctive treatment of alcohol dependence†. In a limited number of patients with alcohol dependence, oral (50-75 mg daily) or IV (50 mg twice daily) trazodone has reduced tremor, depression, and anxiety. In one study, trazodone was more effective in patients who had pronounced affective symptomatology during periods of intoxication and abstention than in those who only had affective symptomatology during intoxication. Further study is needed to determine the efficacy of trazodone in the treatment of alcohol dependence.

Erectile Dysfunction

Trazodone has been used in a limited number of patients for the treatment of erectile dysfunction† (ED, impotence);219,220,221,222 however, the American Urological Association (AUA) states that such therapy currently is not recommended.219 Although some studies indicated that trazodone was more effective than placebo for the treatment of erectile dysfunction, 219,220 other comparative studies did not.219,221,222 In addition, pooled analysis of these studies failed to show a statistically beneficial effect of the drug on sexual function,219,220 although subgroup analysis suggested possible benefit in those with psychogenic erectile dysfunction.219

Other Uses

Trazodone may be useful in the treatment of some patients with anxiety states† (anxiety neuroses). In one study, the drug reduced anxiety, tension, somatic symptoms, and insomnia in most of these patients. Based on limited data, trazodone appears to have a greater anxiolytic effect than some other antidepressant agents (e.g., tricyclic antidepressants); however, further study is needed to confirm this finding.

Trazodone has been used in the symptomatic treatment of a limited number of patients with drug-induced dyskinesias†. In one placebo-controlled study in patients with levodopa-induced dyskinesias, oral trazodone (60-120 mg daily) reduced signs and symptoms of dyskinesia by up to 50%. In this study, most patients showed some improvement, with greatest improvement in facial, oro-buccal-facial, and neck dyskinesias. In another study, IV trazodone (50 mg twice daily) eliminated chronic chlorpromazine- and haloperidol-induced tardive dyskinesias in some patients. The decrease in tremor was accompanied by a reduction in anxiety, which may be partly responsible for the favorable effect of trazodone on tremor in these patients. Additional studies are required to determine the efficacy of trazodone in the treatment of drug-induced dyskinesias.

Administration

Trazodone hydrochloride is administered orally. The drug should be taken shortly after a meal or light snack. If drowsiness occurs, a major portion of the daily dose may be given at bedtime or dosage may be reduced.

Dosage

There is a wide range of individual trazodone hydrochloride dosage requirements, and dosage must be carefully adjusted according to individual tolerance and response, using the lowest possible effective dosage.

Patients receiving trazodone should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.212,213,218 (See Cautions: Precautions and Contraindications.)

Major Depressive Disorder

For the treatment of major depressive disorder, the usual initial adult dosage of trazodone hydrochloride is 150 mg daily given in divided doses. Dosage may be increased by 50 mg/day every 3 or 4 days, depending on the patient's therapeutic response and tolerance. The maximum dosage for outpatients usually should not exceed 400 mg daily. Dosages up to 600 mg daily may be required in hospitalized, institutionalized, or severely depressed patients. Dosages up to 800 mg daily have been used in the treatment of some patients with severe depression; however, the manufacturers do not recommend exceeding a dosage of 600 mg daily.

Although symptomatic relief may be seen in some patients during the first week of therapy, optimum antidepressant effect usually occurs within 2 weeks. About 25% of patients who respond to trazodone require up to 4 weeks of therapy to reach optimum response.

To avoid recurrence of depressive symptoms, trazodone therapy may be required for several months following optimum therapeutic response. Dosage during prolonged maintenance therapy should be kept at the lowest effective level; once an adequate response has been achieved, dosage should be gradually reduced and subsequently adjusted according to the patient's therapeutic response and tolerance.

Trazodone hydrochloride apparently causes fewer adverse anticholinergic effects than currently available tricyclic antidepressant agents. Other adverse effects, including cardiovascular effects, also appear to occur less frequently with trazodone than with currently available tricyclic antidepressants.

The incidence and severity of adverse reactions to trazodone in relation to dosage and duration of therapy have not been fully characterized; however, adverse effects appear to occur more frequently at dosages greater than 300 mg/day. Total trazodone hydrochloride dosages up to 800 mg daily have been well tolerated by some patients. Adverse effects appear to be mild to moderate in severity and may decrease after the first few weeks of trazodone therapy. Adverse effects may be obviated by a reduction in dosage or alteration in dosage schedule. Serious reactions requiring discontinuance of therapy are relatively rare.

Nervous System Effects

Adverse nervous system effects occur frequently during the first few weeks of therapy with trazodone. The most frequent adverse effect associated with trazodone therapy is drowsiness, which occurs in 20-50% of patients receiving the drug. Other less frequent adverse nervous system effects of trazodone include dizziness and lightheadedness, nervousness, fatigue, malaise, weakness, heaviness or fullness of the head, headache, and insomnia. Confusion, incoordination, anger or hostility, agitation, decreased concentrating ability, impaired memory, impaired speech, disorientation, hallucinations or delusions, and excitement have also occurred. Hypomania, nightmares or vivid dreams, tonic-clonic seizures, tremors, and paresthesias and akathisia occur rarely.

Anticholinergic Effects

Although bothersome anticholinergic effects commonly occur with tricyclic antidepressants, these effects appear to occur less frequently with trazodone. Dry mouth has been reported in about 15-30% of patients during trazodone therapy; it has been suggested that this effect may result from an α-adrenergic blocking effect rather than an anticholinergic effect of trazodone. In several placebo-controlled studies, the incidence of dry mouth was similar in trazodone- and placebo-treated patients. Other anticholinergic effects such as blurred vision, constipation, and urinary retention have been reported less frequently.

Genitourinary Effects

Trazodone therapy has been associated with priapism, with surgical intervention required in approximately one-third of reported cases; in some cases, permanent impairment of erectile function or impotence has resulted.201 Male patients receiving trazodone who experience prolonged or inappropriate penile erections should immediately discontinue the drug and consult their physician.201 Decreased or increased libido,201,202 retrograde ejaculation,201 impotence, inhibited female orgasm (anorgasmia),203 increased urinary frequency, delayed urine flow, and hematuria have also been associated with trazodone therapy.

GI Effects

Adverse GI effects of trazodone include nausea and vomiting, dysgeusia, and abdominal and gastric disorders. Flatulence and diarrhea have also been reported.

Cardiovascular Effects

Trazodone is thought to be less cardiotoxic than currently available tricyclic antidepressant agents. (See Pharmacology: Cardiovascular Effects.) Hypotension (including orthostatic hypotension) is the most frequent adverse cardiovascular effect of trazodone, occurring in about 5% of patients receiving the drug. In most patients, hypotension is mild and not dose related. Syncope, shortness of breath, chest pain, tachycardia, palpitations, and hypertension have also occurred. Bradycardia has occurred in a few patients during long-term therapy.

Various ECG changes have occurred in patients receiving trazodone. In patients with preexisting cardiac disease, trazodone may be arrhythmogenic. PVCs, ventricular couplets, and short episodes (3 or 4 beats) of ventricular tachycardia have occurred in these patients. Arrhythmias have also been reported in patients without preexisting cardiac disease.201 Cardiac arrest has also been reported.201 Myocardial infarction has been reported, but this effect has not been attributed directly to trazodone.

Hematologic Effects

Occasional decreases in leukocyte and neutrophil counts have occurred in some patients receiving trazodone. These changes were not considered clinically important and did not require discontinuance of the drug. Anemia has also been associated with trazodone therapy in a few patients.

Other Adverse Effects

Musculoskeletal aches and pains have occurred in about 5% of patients receiving trazodone. A few patients have developed muscle twitches. Pruritus, rash, urticaria, acne, photosensitivity, edema, nasal or sinus congestion, eye irritation, sweating or clamminess, early or absent menses, and tinnitus have been reported in some patients receiving trazodone. Allergic reactions and hypersalivation have rarely occurred. Minimal increases in serum concentrations of alkaline phosphatase, AST (SGOT), and ALT (SGPT) have occurred in some patients receiving trazodone.

Precautions and Contraindications

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Cautions: Pediatric Precautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.212,213,218,223 This risk may persist until clinically important remission occurs.212 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.212,213,218 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.212 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.212,213 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.212,213 It currently is unknown whether the suicidality risk extends to longer-term use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.212,213

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.212,213,218 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.212,218

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.212,218 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.212 FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.212 Because of the possibility of comorbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders.212

It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder.212 Therefore, patients should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).212

Patients should be warned that trazodone may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Patients also should be warned that trazodone may enhance their response to alcohol, barbiturates, or other CNS depressants. Since the risk of dizziness or lightheadedness may be increased during fasting conditions, patients should be advised to take trazodone shortly after a meal or light snack. In addition, total drug absorption may be up to 20% greater when the drug is taken with food rather than on an empty stomach. Because priapism has been associated with trazodone therapy, patients should be instructed to discontinue the drug and consult a physician if prolonged or inappropriate penile erection occurs.201

Until additional clinical experience on the safety of trazodone in patients with cardiovascular disease is obtained, it is recommended that these patients be closely monitored, particularly for arrhythmias, while receiving the drug. (See Cautions: Cardiovascular Effects.) It is also recommended that trazodone not be used during the initial recovery phase of myocardial infarction.

Leukocyte and differential counts should be performed in patients who develop fever and sore throat or other signs of infection while receiving trazodone. The drug should be discontinued in patients whose leukocyte or absolute neutrophil count decreases to less than normal levels. (See Cautions: Hematologic Effects.)

Trazodone is contraindicated in patients who are hypersensitive to the drug.

Pediatric Precautions

Safety and efficacy of trazodone in children younger than 18 years of age have not been established.

FDA warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.212,213,218 The risk of suicidality for these drugs was identified in a pooled analysis of data from a total of 24 short-term (4-16 weeks), placebo-controlled studies of 9 antidepressants (i.e., bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine) in over 4400 children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders.212,213 The analysis revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in pediatric patients receiving antidepressants than in those receiving placebo.212,213 The average risk of such events was 4% among children and adolescents receiving these drugs, twice the risk (2%) that was observed among those receiving placebo.212,213 However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.223 No suicides occurred in these pediatric trials.212,213,223

The risk of suicidality in FDA's pooled analysis differed across the different psychiatric indications, with the highest incidence observed in the major depressive disorder studies.212,213 In addition, although there was considerable variation in risk among the antidepressants, a tendency toward an increase in suicidality risk in younger patients was found for almost all drugs studied.212,213 It is currently unknown whether the suicidality risk in pediatric patients extends to longer-term use (i.e., beyond several months).212,213

As a result of this analysis and public discussion of the issue, FDA has directed manufacturers of all antidepressants to add a boxed warning to the labeling of their products to alert clinicians of this suicidality risk in children and adolescents and to recommend appropriate monitoring and close observation of patients receiving these agents.212,213 (See Cautions: Precautions and Contraindications.) The drugs that are the focus of the revised labeling are all drugs included in the general class of antidepressants, including those that have not been studied in controlled clinical trials in pediatric patients, since the available data are not adequate to exclude any single antidepressant from an increased risk of suicidality.212,213,216 In addition to the boxed warning and other information in professional labeling on antidepressants, FDA currently recommends that a patient medication guide explaining the risks associated with the drugs be provided to the patient each time the drugs are dispensed.212,213,218

Anyone considering the use of trazodone in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.212,218,223

Mutagenicity and Carcinogenicity

In vitro tests have not shown trazodone to be mutagenic. No evidence of carcinogenesis was seen in animals receiving oral trazodone dosages up to 300 mg/kg daily for 18 months.

Pregnancy, Fertility, and Lactation

Pregnancy

Trazodone has been shown to be teratogenic in rats and rabbits when given at dosages 15-50 times the maximum human dosage. The drug also caused increased fetal resorption and other adverse fetal effects in rats when given at dosages approximately 30-50 times the suggested maximum human dosage.201 There are no adequate and controlled studies to date using trazodone in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

The effect of trazodone on fertility in humans is not known. Impotence, retrograde ejaculation, and decreased or increased libido have occurred in some individuals during trazodone therapy. Reproduction studies in male and female rats using trazodone dosages up to 150 times the usual human dosage have not revealed evidence of impaired fertility.

Lactation

Because trazodone is distributed into milk, the drug should be used with caution in nursing women.200,201

Drugs Affecting Hepatic Microsomal Enzymes

Results of in vitro studies indicate that metabolism of trazodone is mediated by the cytochrome P-450 (CYP) 3A4 isoenzyme, and the possibility exists that drugs that inhibit or induce this isoenzyme may affect the pharmacokinetics of trazodone.210,211 Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. 210,211

Concomitant use of trazodone with inhibitors of CYP3A4 can result in substantially increased plasma concentrations of trazodone and increase the potential for adverse effects.210,211 In one study, concomitant use of ritonavir (200 mg twice daily for 2 days) and trazodone (a single 50-mg dose) in healthy individuals increased maximum plasma concentrations and decreased clearance of trazodone by 34 and 52%, respectively, and increased area under the plasma concentration-time curve (AUC) and half-life of trazodone by greater than twofold.210,211 Adverse effects (e.g., nausea, hypotension, syncope) also were observed with concomitant use of trazodone and ritonavir.210,211 The manufacturers of trazodone state that a reduction in trazodone dosage should be considered in patients receiving a potent inhibitor of the CYP3A4 isoenzyme (e.g., indinavir, itraconazole, ketoconazole, nefazodone, ritonavir) concomitantly with trazodone.210,211

Concomitant use of trazodone (100-300 mg daily) with carbamazepine (400 mg daily), an inducer of CYP3A4, decreased plasma concentrations of trazodone and an active metabolite, m -chlorophenylpiperazine, by 76 and 60%, respectively.210,211 Patients receiving trazodone and carbamazepine concomitantly should be closely monitored and dosage of trazodone increased if necessary.210,211

Serotonergic Agents

Fluoxetine

Elevated plasma trazodone concentrations and adverse effects possibly associated with trazodone toxicity have been reported occasionally during concomitant trazodone and fluoxetine therapy.205,209 Although the exact mechanism has not been established,204,205,206,207,209 it has been suggested that fluoxetine may inhibit the hepatic metabolism of many antidepressant agents, including trazodone.204,205,206,207,209 In addition, both trazodone and fluoxetine possess serotonergic activity; therefore, the possibility of serotonin syndrome also should be considered in patients receiving trazodone and fluoxetine or other selective serotonin-reuptake inhibitor therapy concurrently. For detailed information on serotonin syndrome, see Drug Interactions: Drugs Associated with Serotonin Syndrome in Fluoxetine Hydrochloride 28:16.04.20 and the Monoamine Oxidase Inhibitors General Statement 28:16.04.12. Further study is needed,205,207,208,209 but current evidence suggests that patients receiving trazodone and fluoxetine concomitantly should be observed closely for adverse effects;206,209 monitoring of plasma trazodone concentrations also should be considered206,207 and trazodone dosage reduced as necessary.204,207

Monoamine Oxidase Inhibitors

It is not known whether interactions between trazodone and monoamine oxidase (MAO) inhibitors can occur. Unlike tricyclic antidepressants, trazodone does not interfere with catecholamine uptake by the adrenergic neuron or the pressor response to tyramine. Therefore, an interaction between trazodone and MAO inhibitors is unlikely. However, both trazodone and MAO inhibitors possess serotonergic activity; therefore, the possibility that serotonin syndrome may occur during concurrent therapy should be considered. For detailed information on serotonin syndrome, see Drug Interactions: Drugs Associated with Serotonin Syndrome in Fluoxetine Hydrochloride 28:16.04.20 and the Monoamine Oxidase Inhibitors General Statement 28:16.04.12. Because of the absence of clinical experience, if MAO inhibitors are discontinued shortly before or are to be given concomitantly with trazodone, it is recommended that trazodone therapy be initiated cautiously and dosage increased gradually until optimum response is achieved.

Other Serotonergic Agents

Trazodone possesses serotonergic activity and rarely has been associated with serotonin syndrome when combined with other serotonergic agents, including buspirone, phenelzine, and dextropropoxyphene. Because severe complications and even fatalities have accompanied the serotonin syndrome, trazodone probably should be used with caution in patients receiving or who recently have received other serotonergic agents. For additional information on potentially serious drug interactions that may occur between trazodone and other serotonergic agents, see Drug Interactions: Drugs Associated with Serotonin Syndrome, in Fluoxetine Hydrochloride 28:16.04.20 and the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.

General Anesthetics

Since little is known about the interaction between trazodone and general anesthetics, it is recommended that trazodone be discontinued for as long as clinically feasible prior to elective surgery.

Electroconvulsive Therapy

Pending further accumulation of clinical data on the concurrent use of trazodone and electroconvulsive therapy (ECT), concurrent use of these therapies should be avoided.

CNS Depressants

Trazodone may be additive with, or may potentiate the action of, other CNS depressants such as opiates or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol. When trazodone is used concomitantly with other CNS depressants, caution should be used to avoid excessive sedation.

Hypotensive Agents

Because trazodone can cause hypotension, including orthostatic hypotension and syncope, concomitant administration of antihypertensive therapy may require a reduction in dosage of the antihypertensive agent(s). Trazodone has been shown to inhibit the hypotensive effect of various antihypertensive agents (e.g., clonidine, methyldopa) in animals; however, this inhibition has not always been reproducible. It is not known whether trazodone can inhibit the hypotensive effect of these agents in humans, and the clinical importance of this potential interaction has not been determined.

Other Drugs

Increased serum digoxin or phenytoin concentrations have reportedly occurred in patients receiving trazodone concurrently with either drug.

Food

The rate and extent of absorption of trazodone are affected by the presence of food. When trazodone is taken shortly after the ingestion of food, there may be a slight increase in the amount of drug absorbed, a decrease in peak plasma concentration of the drug, and a lengthening of the time to reach the peak plasma concentration. Total drug absorption may be up to 20% greater when the drug is taken with food rather than on an empty stomach. In animals, the rate of absorption has been delayed when trazodone was administered concomitantly with food because of a decrease in the rate of transfer of the drug from the stomach to the small intestine.

The effect of food on absorption of trazodone during long-term administration of the drug is not considered clinically important. Concomitant administration of trazodone with food is generally recommended since it appears to decrease the incidence of dizziness or lightheadedness.

Acute Toxicity

Limited information is available on the acute toxicity of trazodone.

Pathogenesis

The acute lethal dose of trazodone in humans is not known. In addition, there is no clearly defined relationship between plasma trazodone concentration and severity of intoxication. The oral LD₅₀ of trazodone is 610 mg/kg in mice, 486 mg/kg in rats, 560 mg/kg in rabbits, and 500 mg/kg in dogs. In animals, lethal doses produced dyspnea, salivation, prostration, and clonic seizures.

Manifestations

One patient who intentionally ingested 7.5 g of trazodone experienced only drowsiness and weakness; the patient was aroused at the time of hospitalization and emesis was induced. Another patient had an uneventful recovery after ingesting 9.2 g of trazodone. There have been several reports of accidental ingestion in children; however, the exact amounts ingested are unknown. Each of these children exhibited only lethargy and drowsiness, and recoveries were uneventful. Fatalities have occurred in adults who intentionally ingested trazodone and other drugs (e.g., alcohol, chloral hydrate, amobarbital, chlordiazepoxide, meprobamate) concurrently.

In general, overdosage of trazodone may be expected to produce effects that are extensions of common adverse reactions; vomiting, drowsiness, and lethargy have been the principal effects reported. Other reported effects associated with acute trazodone overdosage have included orthostatic hypotension, tachycardia, coma, headache, tinnitus, dizziness, dyspnea, shivering, aching muscles, incontinence, and dry mouth. Unlike tricyclic antidepressant overdosage, seizures and arrhythmias do not appear to be associated with trazodone overdosage.

Treatment

Treatment of trazodone overdosage generally involves symptomatic and supportive care; there is no specific antidote for trazodone intoxication. In acute overdosage, the stomach should be emptied immediately by inducing emesis or by gastric lavage. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of vomitus. Although administration of activated charcoal after gastric lavage and/or emesis has been useful in the treatment of acute overdosage with tricyclic antidepressants, the effect of activated charcoal on the absorption of trazodone is not currently known. Appropriate therapy should be instituted if hypotension or excessive sedation occurs. Forced diuresis may be useful in facilitating elimination of the drug. It is not known if trazodone is dialyzable; however, because of extensive protein binding of the drug, hemodialysis is probably not effective in enhancing elimination of trazodone.

Pharmacology

The pharmacology of trazodone is complex and in some ways resembles that of tricyclic antidepressants, benzodiazepines, and phenothiazines; however, the overall pharmacologic profile of trazodone differs from each of these classes of drugs.

Nervous System Effects

The precise mechanism of antidepressant action of trazodone is unclear, but the drug has been shown to selectively block the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane. The effects of serotonin may thus be potentiated. Unlike other antidepressant agents (e.g., tricyclic antidepressants), trazodone may have a dual effect on the central serotonergic system. Animal studies indicate that trazodone acts as a serotonin agonist at high doses (6-8 mg/kg), while at low doses (0.05-1 mg/kg), it antagonizes the actions of serotonin. Trazodone does not appear to influence the reuptake of dopamine or norepinephrine within the CNS; however, animal studies indicate that trazodone may enhance release of norepinephrine from neuronal tissue. Trazodone does not cause serotonin release in vitro.

Although the mechanism of action of antidepressant agents may involve inhibition of the reuptake of various neurotransmitters at the presynaptic neuronal membrane, long-term therapy with antidepressant agents also affects postsynaptic neuronal receptor binding sites, resulting in some adaptive changes in neurotransmission. Long-term administration of trazodone reportedly decreases the number of postsynaptic serotonergic (i.e., serotonin₂) and β-adrenergic binding sites in the brain of animals. Although the clinical importance of these effects is not known, the decrease in binding sites is associated with a functional increase in serotonergic activity and a reduction in the sensitivity of adenylate cyclase to stimulation by β-adrenergic agonists. It has been suggested that postsynaptic receptor modification is mainly responsible for the antidepressant action observed during long-term administration of trazodone. Further study is needed to determine the role of binding site alteration in the antidepressant action of trazodone and other antidepressants.

In animals, trazodone's effect on various avoidance behaviors is similar to that of phenothiazines. Unlike phenothiazines, however, trazodone potentiates the effects of serotonin. Trazodone does not potentiate the actions of levodopa or alter neuronal concentrations of acetylcholine. Trazodone does not inhibit monoamine oxidase, and unlike amphetamine-like drugs, does not stimulate the CNS.

Unlike many currently available antidepressants, trazodone exhibits little, if any, anticholinergic activity in vitro. Clinical studies show a lower incidence of anticholinergic effects (e.g., dry mouth, blurred vision, urinary retention, constipation) associated with trazodone use than with tricyclic antidepressant use. (See Cautions: Anticholinergic Effects.)

Trazodone produces varying degrees of sedation in normal and mentally depressed patients. The sedative effect is thought to result principally from central α₁-adrenergic blocking activity and possibly from a histamine blocking action of the drug. Trazodone may cause EEG changes, including increased slow-wave and alpha-wave activity. Some increase in fast-wave activity also occurs. Trazodone increases total sleep time, decreases the number and duration of awakenings in depressed patients, and decreases rapid eye movement (REM) sleep. Unlike tricyclic antidepressants, trazodone does not increase stage 4 sleep.

Although the exact mechanism of action has not been determined, trazodone has an anxiolytic effect. This finding is supported by animal studies in which trazodone is active in certain antianxiety test systems. In addition, the drug has demonstrated anxiolytic activity in patients with major depression who also have associated anxiety. (See Uses: Major Depressive Disorder.)

Therapeutic dosages of trazodone do not appear to affect respiration; however, the effect of higher dosages of trazodone in patients with ventilatory insufficiency is not known.

Like many other centrally acting agents, trazodone exhibits analgesic activity in a variety of analgesic test systems. Trazodone also has weak skeletal muscle relaxant activity but lacks anticonvulsant effects.

Trazodone possesses potent peripheral α-adrenergic blocking activity in animals following IV administration of 3-10 mg/kg. In addition, in animals, the drug blocks the peripheral effects of serotonin, epinephrine, norepinephrine, and histamine. The peripheral antihistaminic effects of trazodone are weaker than those of tricyclic antidepressants.

Cardiovascular Effects

The cardiovascular effects of trazodone have been studied in animals and to a limited extent in humans. Unlike other antidepressant agents (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), trazodone has been associated with only minimal cardiovascular effects. (See Cautions: Cardiovascular Effects.) The absence of substantial anticholinergic activity and catecholamine-potentiating effects appears to be the principal reason for the general lack of cardiovascular effects of trazodone.

Trazodone exhibits α-adrenergic blocking activity and does not inhibit catecholamine reuptake. Unlike tricyclic antidepressants, trazodone blocks the pressor response to norepinephrine and lowers arterial blood pressure. However, in one study in normotensive patients with endogenous depression, the effect of trazodone on systemic blood pressure was equivocal. Trazodone does not block the neuronal uptake of tyramine; thus, unlike tricyclic antidepressants, the drug has no effect on the pressor response to this sympathomimetic amine.

Although trazodone does not appear to have substantial arrhythmogenic activity, arrhythmias have occurred in some patients with preexisting cardiac disease during trazodone therapy. (See Cautions: Cardiovascular Effects.) In animals, trazodone does not affect intra-atrial, ventricular septal, ventricular free-wall, His-Purkinje, or AV nodal conduction. At doses up to 30 mg/kg in animals, trazodone produces only minimal ECG changes, including prolongation of the QT interval and a decrease in heart rate. Unlike tricyclic antidepressants, trazodone does not exert direct quinidine-like cardiotoxic properties. In addition, trazodone does not exert a negative inotropic effect at therapeutic dosages; the drug may decrease aortic blood flow as a result of a decrease in heart rate.

To date, there have been no published studies comparing the cardiovascular effects of therapeutic dosages of trazodone with those of antidepressants such as mianserin, nomifensine, or zimelidine. Although available data suggest that trazodone is less cardiotoxic than tricyclic antidepressant agents at therapeutic dosages, the cardiovascular effects of trazodone overdosage have not been well described.

Other Effects

Trazodone may affect the endocrine system. Following oral administration of a single 50-mg dose in one study in healthy adults, trazodone caused a decrease in mean serum prolactin concentration. However, in another study in depressed patients, trazodone did not alter mean serum prolactin concentration following oral administration of 200 mg daily for 2 weeks.

Trazodone-induced antagonism of α₂-adrenergic receptors may relax the tissues and enhance arterial inflow in penile vascular and corporal smooth muscle resulting in an erection.219,220

Pharmacokinetics

In all studies described in the Pharmacokinetics section, trazodone was administered as the hydrochloride salt.

Absorption

Trazodone is rapidly and almost completely absorbed from the GI tract following oral administration. The rate and extent of absorption are affected by the presence of food. When trazodone is taken shortly after the ingestion of food, there may be a slight increase (up to 20%) in the amount of drug absorbed, a decrease in peak plasma concentration of the drug, and a lengthening of the time to reach the peak plasma concentration.

Peak plasma concentrations of trazodone occur approximately 1 hour after oral administration when the drug is taken on an empty stomach or 2 hours after oral administration when taken with food. Following oral administration of multiple doses of trazodone (25 mg 2 or 3 times daily), steady-state plasma concentrations of the drug are usually attained within 4 days and exhibit wide interpatient variation. Following oral administration of a single 25-mg dose of radiolabeled trazodone to healthy adults in one study, mean peak plasma drug concentrations of 650 and 480 ng/mL occurred at 1.5 and 2.5 hours after ingestion, in the fasted and nonfasted state, respectively. Following oral administration of single doses of 25, 50, or 100 mg of trazodone to healthy, fasted adults in another study, mean peak plasma trazodone concentrations were 490, 860, and 1620 ng/mL, respectively. The areas under the plasma concentration-time curves (AUCs) were 3.44, 5.95, and 11.19 mcg-h/mL, for the 25-, 50-, and 100-mg doses, respectively. Limited crossover data are available comparing AUCs in fasted and nonfasted patients; however, it appears that the presence of food slightly increases the AUC for trazodone.

The therapeutic range for plasma trazodone concentrations and the relationship of plasma concentrations to clinical response and toxicity have not been established.

Distribution

Distribution of trazodone into human body tissues and fluids has not been determined. Following oral administration of trazodone in animals, the drug and its metabolites are distributed mainly into the liver, kidneys, small intestine, lungs, adrenal glands, and pancreas, with lower concentrations being distributed into adipose tissue, heart, and skeletal muscle. Trazodone crosses the blood-brain barrier in animals, and concentrations of the drug in the brain are higher than those in plasma during the first 8 hours after oral ingestion.

In vitro, trazodone is 89-95% bound to plasma proteins at plasma trazodone concentrations of 100-1500 ng/mL.

Although it is not known if trazodone crosses the placenta in humans, the drug crosses the placenta in animals. Following a single oral dose of 50 mg, trazodone is distributed into milk in concentrations approximately 10% of maternal plasma concentrations, with a milk-to-plasma ratio (based on areas under the plasma and milk concentration-time curves) of about 0.1-0.2.200 Based on these data, it is estimated that a nursing infant would ingest less than 0.1% of the dose.200 It is not known whether trazodone metabolites are distributed into milk.200,201

Elimination

Plasma concentrations of trazodone decline in a biphasic manner. The half-life of trazodone in the initial phase (t_½α) is about 3-6 hours and the half-life in the terminal phase (t_½β) is about 5-9 hours. The clearance of trazodone from the body shows wide interindividual variation. The manufacturers state that the drug may accumulate in plasma in some individuals.

Trazodone is extensively metabolized in the liver via hydroxylation, oxidation, N -oxidation, and splitting of the pyridine ring. A hydroxylated metabolite and oxotriazolopyridinpropionic acid (an inactive metabolite excreted in urine) are conjugated with glucuronic acid. Results of in vitro studies indicate that metabolism of trazodone to an active metabolite, m -chlorophenylpiperazine, is mediated by the cytochrome P-450 (CYP) 3A4 isoenzyme. The manufacturers state that other metabolic pathways involved in metabolism of trazodone have not been well characterized. Results from animal studies indicate that trazodone does not induce its own metabolism.

Approximately 70-75% of an oral dose of trazodone is excreted in urine within 72 hours of administration, principally as metabolites. About 20% of an oral dose of trazodone is excreted in urine as oxotriazolopyridinpropionic acid and its conjugates, and about 10% as a dihydrodiol metabolite; less than 1% of a dose is excreted unchanged. The remainder of an oral dose of the drug is excreted in feces via biliary elimination, principally as metabolites.

Chemistry and Stability

Chemistry

Trazodone hydrochloride is a triazolopyridine-derivative antidepressant. The drug is chemically and structurally unrelated to tricyclic or tetracyclic antidepressants or to selective serotonin-reuptake inhibitors. Trazodone hydrochloride occurs as a white, odorless, crystalline powder with a bitter taste and is freely soluble in water and sparingly soluble in alcohol. The drug has a pK_a of 6.7.

Stability

Commercially available trazodone hydrochloride tablets should be stored at room temperature in tight, light-resistant containers and protected from temperatures greater than 40°C.

200. Verbeeck RK, Ross SG, McKenna EA. Excretion of trazodone in breast milk. Br J Clin Pharmacol . 1986; 22:367-70. [PubMedCentral][PubMed 3768252]

201. Mead Johnson Pharmaceutical. Desyrel^® prescribing information. In: Huff BB, ed. Physicians' desk reference. 40th ed. Oradell NJ: Medical Economics Company Inc; 1986:1123-4.

202. Gartrell N. Increased libido in women receiving trazodone. Am J Psychiatry . 1986; 143:781-2. [PubMed 3717405]

203. Jani NN, Wise TN, Kass E et al. Trazodone and anorgasmia. Am J Psychiatry . 1988; 145:896. [PubMed 3381940]

204. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. Am J Psychiatry . 1988; 145:1478. [PubMed 3263809]

205. Aranow RB, Hudson JI, Pope HG Jr et al. Elevated antidepressant plasma levels after addition of fluoxetine. Am J Psychiatry . 1989; 146:911-3. [PubMed 2787124]

206. Downs JM, Downs AD, Rosenthal TL et al. Increased plasma tricyclic antidepressant concentrations in two patients concurrently treated with fluoxetine. J Clin Psychiatry . 1989; 50:226-7. [PubMed 2785987]

207. Tricyclic antidepressants/fluoxetine. In: Tatro DS, Olin BR, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1990 (Apr):743a.

208. Swerdlow NR, Andia AM. Trazodone-fluoxetine combination for treatment of obsessive-compulsive disorder. Am J Psychiatry . 1989; 146:1637. [PubMed 2589561]

209. Metz A, Shader RI. Adverse interactions encountered when using trazodone to treat insomnia associated with fluoxetine. Int Clin Psychopharmacol . 1990; 5:191-4. [PubMed 2230063]

210. Lewis-Hall FC. Dear healthcare professional: changes to labeling for Desyrel^® (trazodone hydrochloride) tablets. Princeton, NJ: Bristol-Myers Squibb Company; 2004. From the FDA website. [Web]

211. Bristol-Myers Squibb Company. Desyrel^® (trazodone) tablets prescribing information. Princeton, NJ; 2003 Sep.

212. Food and Drug Administration. Antidepressant use in children, adolescents, and adults: class revisions to product labeling. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

213. Food and Drug Administration. FDA news: FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

214. Anon. FDA statement on recommendations of the psychopharmacologic drugs and pediatric advisory committees. Rockville, MD; 2004 Sep 16. From the FDA website. [Web]

215. American Psychiatric Association (APA). APA responds to FDA's new warning on antidepressants. Arlington, VA; 2004 Oct. 15. From the APA website. [Web]

216. American Academy of Child and Adolescent Psychiatry (AACAP). AACAP responds to the new FDA warnings on pediatric antidepressant medications. Washington, D.C; 2004 Oct 15. From the AACAP website. [Web]

217. American Academy of Pediatrics (AAP). Children, antidepressants and a black box warning. Washington, D.C; 2004 Oct. 15. From the AAP website. [Web]

218. Food and Drug Administration. Revisions to medication guide: antidepressant medicines, depression and other serious mental illnesses and suicidal thoughts or actions. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

219. Erectile Dysfunction Guideline Update Panel, American Urological Association Education and Research. Management of erectile dysfunction: An update. 2005. Available at AUA website. Accessed 2005 Oct. 20. [Web]

220. Fink HA, MacDonald R, Rutks IR et al. Trazodone for erectile dysfunction: a systematic review and meta-analysis. Br J Urol . 2003; 92:441-6.

221. Meinhardt W, Schmitz PI, Kropman RF et al. Trazodone, a double blind trial for treatment of erectile dysfunction. Int J Impot Res . 1997; 9:163-5. [PubMed 9315494]

222. Enzlin P, Vanderschueren D, Bonte L et al. Trazodone: a double-blind, placebo-controlled, randomized study of its effects in patients with erectile dysfunction without major organic findings. Int J Impot Res . 2000; 12:223-8. [PubMed 11079363]

223. Bridge JA, Iyengar S, Salary CB. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA . 2007; 297:1683-96. [PubMed 17440145]