indication

For the treatment of depression.

pharmacology

Trazodone is an antidepressant and hypnotic chemically unrelated to tricyclic, tetracyclic, or other known antidepressant agents. The mechanism of trazodone's antidepressant action in man is not fully understood. In animals, trazodone selectively inhibits serotonin uptake by brain synaptosomes and potentiates the behavioral changes induced by the serotonin precursor, 5-hydroxytryptophan. Cardiac conduction effects of trazodone in the anesthetized dog are qualitatively dissimilar and quantitatively less pronounced than those seen with tricyclic antidepressants. Trazodone is not a monoamine oxidase inhibitor and, unlike amphetamine-type drugs, does not stimulate the central nervous system. In man, trazodone is well absorbed after oral administration without selective localization in any tissue. Since the clearance of trazodone from the body is sufficiently variable, in some patients trazodone may accumulate in the plasma.

mechanism of action

Trazodone binds at 5-HT2 receptor, it acts as a serotonin agonist at high doses and a serotonin antagonist at low doses. Like fluoxetine, trazodone's antidepressant activity likely results from blockage of serotonin reuptake by inhibiting serotonin reuptake pump at the presynaptic neuronal membrane. If used for long time periods, postsynaptic neuronal receptor binding sites may also be affected. The sedative effect of trazodone is likely the result of alpha-adrenergic blocking action and modest histamine blockade at H1 receptor. It weakly blocks presynaptic alpha2-adrenergic receptors and strongly inhibits postsynaptic alpha1 receptors. Trazodone does not affect the reuptake of norepinephrine or dopamine within the CNS.

toxicity

LD₅₀=96mg/kg (i.v. in mice)

biotransformation

Undergoes extensive hepatic metabolism via hydroxylation, N-dealkylation, N-oxidation and splitting of the pyridine ring. Cytochrome P450 (CYP) 3A4 catalyzes the formation of the major active metabolite, m-chlorophenylpiperazine (m-CPP). Metabolites may be further conjugated to glucuonic acid or glutathione. CYP2D6 is responsible for 4'-hydroxylation of m-CPP and the formation of at least one glutathione conjugates of m-CPP, a quinone imine-sulhydryl adduct. Oxotriazolopyridinpropionic acid, an inactive metabolite, and its conjugates account for about 20% of the total excreted oral dose. Less than 1% of the oral dose is excreted unchanged. Approximately 70-75% of the dose is eliminated in urine with the remainder being excreted in feces via biliary elimination.

absorption

Rapidly and almost completely absorbed following oral administration. Food may decrease the rate and extent of absorption.

half life

Undergoes biphasic elimination with an initial phase t_{1/2 α} of 3-6 hours and a terminal phase t_{1/2 β} of 5-9 hours.

drug interactions

Almotriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Aminoglutethimide: The CYP3A4 inducer, Aminoglutethimide, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Aminoglutethimide is initiated, discontinued or dose changed.

Amiodarone: The CYP3A4 inhibitor, Amiodarone, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Amiodarone is initiated, discontinued or dose changed.

Amitriptyline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Amoxapine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Amprenavir: The protease inhibitor, Amprenavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Amprenavir is initiated, discontinued or dose changed.

Aprepitant: The CYP3A4 inhibitor, Aprepitant, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Aprepitant is initiated, discontinued or dose changed.

Atazanavir: The protease inhibitor, Atazanavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Atazanavir is initiated, discontinued or dose changed.

Bosentan: The CYP3A4 inducer, Bosentan, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Bosentan is initiated, discontinued or dose changed.

Bromocriptine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Buspirone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Cabergoline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Carbamazepine: The CYP3A4 inducer, Carbamazepine, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Carbamazepine is initiated, discontinued or dose changed.

Cimetidine: The CYP3A4 inhibitor, Cimetidine, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Cimetidine is initiated, discontinued or dose changed.

Citalopram: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Clarithromycin: The CYP3A4 inhibitor, Clarithromycin, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Clarithromycin is initiated, discontinued or dose changed.

Clomipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Clotrimazole: The CYP3A4 inhibitor, Clotrimazole, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Clotrimazole is initiated, discontinued or dose changed.

Conivaptan: The CYP3A4 inhibitor, Conivaptan, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Conivaptan is initiated, discontinued or dose changed.

Cyclosporine: The CYP3A4 inhibitor, Cyclosporine, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Cyclosporine is initiated, discontinued or dose changed.

Dabigatran etexilate: P-Glycoprotein inducers such as trazodone may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.

Darunavir: The protease inhibitor, Darunavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Darunavir is initiated, discontinued or dose changed.

Delavirdine: The CYP3A4 inhibitor, Delavirdine, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Delavirdine is initiated, discontinued or dose changed.

Desipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dexamethasone: The CYP3A4 inducer, Dexamethasone, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Dexamethasone is initiated, discontinued or dose changed.

Dextromethorphan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dihydroergotamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Diltiazem: The CYP3A4 inhibitor, Diltizem, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Diltiazem is initiated, discontinued or dose changed.

Donepezil: Possible antagonism of action

Doxepin: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Duloxetine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Efavirenz: The CYP3A4 inhibitor and inducer, Efavirenz, may alter Trazodone efficacy/toxicity by altering Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Efavirenz is initiated, discontinued or dose changed.

Eletriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Ergoloid mesylate: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Ergonovine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Ergotamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Erythromycin: The CYP3A4 inhibitor, Erythromycin , may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Erythromycin is initiated, discontinued or dose changed.

Escitalopram: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Fluconazole: The CYP3A4 inhibitor, Fluconazole, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Fluconazole is initiated, discontinued or dose changed.

Fluoxetine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Fluvoxamine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Fosamprenavir: The protease inhibitor, Fosamprenavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Fosamprenavir is initiated, discontinued or dose changed.

Fosphenytoin: The CYP3A4 inducer, Fosphenytoin, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Fosphenytoin is initiated, discontinued or dose changed.

Frovatriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Furazolidone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Galantamine: Possible antagonism of action

Ginkgo biloba: Increased effect and toxicity of both agents

Haloperidol: The CYP3A4 inhibitor, Haloperidol, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. The CYP2D6 inhibitor, Trazodone, may increase the efficacy of Haloperidol by decreasing Haloperidol metabolism and clearance. Monitor for changes in Trazodone and Haloperidol efficacy/toxicity if either agent is initiated, discontinued or dose changed.

Imatinib: The CYP3A4 inhibitor, Imatinib, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Imatinib is initiated, discontinued or dose changed.

Imipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Indinavir: The protease inhibitor, Indinavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism via CYP3A4. Monitor for changes in Trazodone efficacy/toxicity if Indinavir is initiated, discontinued or dose changed.

Isocarboxazid: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Isoniazid: The CYP3A4 inhibitor, Isoniazid, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Isoniazid is initiated, discontinued or dose changed.

Itraconazole: The CYP3A4 inhibitor, Itraconazole, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Itraconazole is initiated, discontinued or dose changed.

Ketoconazole: The CYP3A4 inhibitor, Ketoconazole, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Ketoconazole is initiated, discontinued or dose changed.

Lapatinib: The CYP3A4 inhibitor, Lapatinib, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Lapatinib is initiated, discontinued or dose changed.

Lidocaine: The CYP3A4 inhibitor, Lidocaine, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Lidocaine is initiated, discontinued or dose changed.

Linezolid: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Lithium: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Lopinavir: The protease inhibitor, Lopinavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Lopinavir is initiated, discontinued or dose changed.

Maprotiline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Meperidine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Methylergonovine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Metronidazole: The CYP3A4 inhibitor, Metronidazole, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Metronidazole is initiated, discontinued or dose changed.

Miconazole: The CYP3A4 inhibitor, Miconazole, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Miconazole is initiated, discontinued or dose changed.

Mirtazapine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Moclobemide: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Nafcillin: The CYP3A4 inducer, Nafcillin, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Nafcillin is initiated, discontinued or dose changed.

Naratriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Nefazodone: Increased risk of serotonin syndrome. The CYP3A4 inhibitor, Nefazodone, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for symtpoms of sertonin syndrome and changes in Trazodone efficacy/toxicity if Nefazodone is initiated, discontinued or dose changed.

Nelfinavir: The protease inhibitor, Nelfinavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Nelfinavir is initiated, discontinued or dose changed.

Nevirapine: The CYP3A4 inducer, Nevirapine, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Nevirapine is initiated, discontinued or dose changed.

Nicardipine: The CYP3A4 inhibitor, Nicardipine, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Nicardipine is initiated, discontinued or dose changed.

Norfloxacin: The CYP3A4 inhibitor, Norfloxacin, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Norfloxacin is initiated, discontinued or dose changed.

Nortriptyline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Oxcarbazepine: The CYP3A4 inducer, Oxcarbazepine, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Oxcarbazepine is initiated, discontinued or dose changed.

Paroxetine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Pentobarbital: The CYP3A4 inducer, Pentobarbital, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Pentobarbital is initiated, discontinued or dose changed.

Pergolide: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Phenelzine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Phenobarbital: The CYP3A4 inducer, Phenobarbital, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Phenobarbital is initiated, discontinued or dose changed.

Phenytoin: The CYP3A4 inducer, Phenytoin, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Phenytoin is initiated, discontinued or dose changed.

Posaconazole: The CYP3A4 inhibitor, Posaconazole, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Posaconazole is initiated, discontinued or dose changed.

Primidone: The CYP3A4 inducer, Primidone, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Primidone is initiated, discontinued or dose changed.

Procarbazine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Promethazine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Protriptyline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Quinidine: The CYP3A4 inhibitor, Quinidine, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Quinidine is initiated, discontinued or dose changed.

Rasagiline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Rifabutin: The CYP3A4 inducer, Rifabutin, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Rifabutin is initiated, discontinued or dose changed.

Rifampin: The CYP3A4 inducer, Rifampin, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Rifampin is initiated, discontinued or dose changed.

Rifapentine: The CYP3A4 inducer, Rifapentine, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Rifapentine is initiated, discontinued or dose changed.

Ritonavir: The protease inhibitor, Ritonavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Ritonavir is initiated, discontinued or dose changed.

Rivastigmine: Possible antagonism of action

Rizatriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

S-Adenosylmethionine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Saquinavir: The protease inhibitor, Saquinavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Saquinavir is initiated, discontinued or dose changed.

Selegiline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Sertraline: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Sibutramine: Increased risk of serotonin syndrome. Avoid concomitant therapy.

Sitaxentan: The CYP3A4 inhibitor, Sitaxsenten, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Norfloxacin is initiated, discontinued or dose changed.

St. John's Wort: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Sumatriptan: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Tamoxifen: Trazodone may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Trazodone, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Trazodone is initiated, discontinued, or dose changed.

Telithromycin: The CYP3A4 inhibitor, Telithromycin, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Telithromycin is initiated, discontinued or dose changed.

Tetracycline: The CYP3A4 inhibitor, Tetracycline, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Tetracycline is initiated, discontinued or dose changed.

Tipranavir: The protease inhibitor, Tipranavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Tipranavir is initiated, discontinued or dose changed.

Tramadol: The use of two serotonin modulators, such as trazodone and tramadol, may increase the risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Tranylcypromine: Increased risk of serotonin syndrome. Use caution during concomitant therapy and monitor for symptoms of serotonin syndrome.

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Triprolidine: The CNS depressants, Triprolidine and Trazodone, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Verapamil: The CYP3A4 inhibitor, Verapamil, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Verapamil is initiated, discontinued or dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of trazodone by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of trazodone if voriconazole is initiated, discontinued or dose changed.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and trazodone, may increase the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.