Browse the corpus

©2013 UpToDate ® Print Email Antidepressants used in treatment of adults with generalized anxiety disorder Antidepressant Generic available (US) Selected drug interactions and metabolic effects* Advantages Disadvantages • Fluoxetine Yes (capsule, tablet, oral solution) Concurrent use with tamoxifen, pimozide or thioridazine is contraindicated. Fluoxetine is a potent inhibitor and substrate of CYP-2D6 as well as a moderate inhibitor of 2C9, 2C19 and 3A4. Interactions include amiodarone, atomoxetine, digoxin, clozapine, codeine, warfarin and phenytoin. No discontinuation symptoms due to long half-life (tapering is not necessary). Activating. Significant drug interactions. Prolonged half-life and active metabolites require weeks to reach steady-state, prolonging time necessary to evaluate effect of dose adjustment and complicating wash-out and withdrawal. Fluvoxamine Yes (tablet) No (controlled release capsule) Concurrent use with pimozide, thioridazine, alosetron, ramelteon or tizanidine is contraindicated. Fluvoxamine is a potent inhibitor of CYP-1A2 and 2C19 and moderate inhibitor of 2B6, 2C9, 3A4 and 2D6. It may interact with CYP substrates including clozapine, metoprolol, propranolol, methadone, theophylline and warfarin. Fluvoxamine is a substrate of CYP-1A2 and 2D6. Low risk of insomnia. Significant drug interactions. Short half-life associated with discontinuation symptoms in absence of tapering. Paroxetine Yes (tablet, extended release tablet, oral solution) No (paroxetine mesylate tablet) Concurrent use with tamoxifen, thioridazine or pimozide is contraindicated. Paroxetine is a potent inhibitor of CYP-2D6 and 2B6 and substrate of 2D6. Interactions include amiodarone, atomoxetine, desipramine and propranolol. Low risk of insomnia. Moderate half-life with no active metabolites. Weakly anticholinergic. May cause constipation, dry mouth or drowsiness. Associated with more severe discontinuation symptoms in absence of tapering. Sertraline Yes (tablet, oral solution concentrate) Concurrent use with thioridazine or pimozide is contraindicated. Sertraline is a potent inhibitor of CYP-2D6 only at doses ≥200 mg daily. Few significant drug interactions. Intermediate half-life. More frequent gastrointestinal symptoms including diarrhea. Oral solution contains alcohol. Discontinuation symptoms may occur absent tapering. Citalopram Citalopram: Yes (tablet, oral solution)

Concurrent use with thioridazine or pimozide is contraindicated. Sertraline is a potent inhibitor of CYP-2D6 only at doses ≥200 mg daily. Few significant drug interactions. Intermediate half-life. More frequent gastrointestinal symptoms including diarrhea. Oral solution contains alcohol. Discontinuation symptoms may occur absent tapering. Citalopram Citalopram: Yes (tablet, oral solution) Diverse transformations include CYP-2C19, 2D6 and 3A4 metabolism. Moderate inhibitor of CYP-2D6 at high doses. Few significant drug interactions. Low risk of insomnia. Possible elevated risk of cardiac arrhythmia in combination with other agents that cause QTc prolongation and/or increased citalopram concentrations. Δ Mild discontinuation symptoms may occur absent tapering. Escitalopram Escitalopram: Yes (tablet) Diverse transformations include CYP-2C19, 2D6 and 3A4 metabolism. Moderate inhibitor of CYP-2D6 at high doses. Few significant drug interactions. Low risk of insomnia. Mild discontinuation symptoms may occur absent tapering. Venlafaxine Desvenlafaxine Venlafaxine: Yes (extended release tablet and capsule, immediate release tablet) Desvenlafaxine: No (extended release tablet) Metabolism of venlafaxine includes CYP-2D6 transformation to an active metabolite. Applies to both: no known potent effects on CYP. Can antagonize efficacy of antihypertensive drugs. Few significant drug interactions. Activating. Associated with discontinuation symptoms absent tapering. Dose-related elevation in blood pressure. Gastrointestinal symptoms (eg, nausea) may be more prominent with immediate release form. Nefazodone Yes (tablet) Nefazodone is a potent inhibitor of CYP-3A4 and inducer of P-glycoprotein. Nefazodone is contraindicated in combination with numerous drugs including: carbamazepine, cisapride, dronedarone, dabigatran, pimozide or ranolazine. Nefazodone can increase concentrations of drugs metabolized by 3A4 including simvastatin, cyclosporine, everolimus and tacrolimus, necessitating additional monitoring and dose adjustment. A 50 to 75 percent dose reduction of alprazolam or triazolam is suggested if used with nefazodone. Metabolism of nefazodone includes CYP-3A4 and 2D6 transformations and active metabolites. Sedating. Low risk of insomnia and sexual dysfunction. May be taken at bedtime.

Nefazodone is a potent inhibitor of CYP-3A4 and inducer of P-glycoprotein. Nefazodone is contraindicated in combination with numerous drugs including: carbamazepine, cisapride, dronedarone, dabigatran, pimozide or ranolazine. Nefazodone can increase concentrations of drugs metabolized by 3A4 including simvastatin, cyclosporine, everolimus and tacrolimus, necessitating additional monitoring and dose adjustment. A 50 to 75 percent dose reduction of alprazolam or triazolam is suggested if used with nefazodone. Metabolism of nefazodone includes CYP-3A4 and 2D6 transformations and active metabolites. Sedating. Low risk of insomnia and sexual dysfunction. May be taken at bedtime. Not a first-line choice. Numerous drug interactions due to potent CYP-3A4 inhibition. Rare reports of fatal hepatotoxicity leading to market withdrawal in EU, Canada and elsewhere. Duloxetine No (delayed release capsule) Duloxetine is a moderate inhibitor of CYP-2D6 and primarily metabolized by 1A2 and 2D6. Can antagonize efficacy of tamoxifen and concurrent use is not recommended. Contraindicated with thioridazine. Sedating. Low risk of insomnia. Useful for comorbid painful conditions such as diabetic neuropathy or chronic pain. Moderate risk of drug interactions particularly with potent inhibitors of CYP-2D6 and/or 1A2. Mirtazapine Yes (tablet, orally dispersible tablet) Diverse metabolic transformations with weak effects on CYP. Sedating. Low risk of insomnia and sexual dysfunction. Useful for patients who may benefit from increased appetite. Drowsiness, increased appetite and weight gain are disadvantageous in most patients. Rare reports of agranulocytosis. Nortriptyline (and other TCAs) Yes TCAs are inhibitors of several CYP enzymes and glucuronidation. Nortriptyline is an inhibitor of CYP-D6 and 2C19 and metabolized by 2D6. Concurrent use with pimozide, thioridazine, ziprasidone or other agents known to prolong the QTc interval or associated with cardiac conduction abnormalities or arrhythmias may be regarded as contraindicated. Nortriptyline is sedating. May be taken at bedtime. Not a first-line choice. Potentially cardiotoxic, can cause orthostatic hypotension and decrease seizure threshold. Significant anticholinergic effects include dry mouth, constipation, urinary retention or altered vision. Significant drug interactions.◊

TCAs are inhibitors of several CYP enzymes and glucuronidation. Nortriptyline is an inhibitor of CYP-D6 and 2C19 and metabolized by 2D6. Concurrent use with pimozide, thioridazine, ziprasidone or other agents known to prolong the QTc interval or associated with cardiac conduction abnormalities or arrhythmias may be regarded as contraindicated. Nortriptyline is sedating. May be taken at bedtime. Not a first-line choice. Potentially cardiotoxic, can cause orthostatic hypotension and decrease seizure threshold. Significant anticholinergic effects include dry mouth, constipation, urinary retention or altered vision. Significant drug interactions.◊ TCA: tricyclic antidepressant; SSRI: selective serotonin reuptake inhibitor; CYP: cytochrome P-450. * Applies to all: avoid use with monoamine oxidase inhibitors (MAOI). May lower convulsive threshold thereby antagonizing efficacy of anti-epileptic drugs. Applies to all serotoninergic agents: may elevate risk of gastroduodenal bleeding in combination with non-steroidal antiinflammatory drugs or anticoagulants. For additional information refer to topics on NSAIDs and gastroduodenal toxicity. For additional information on drug interactions see Lexi-Interact™ drug interaction application or Lexi-Comp drug information topic, Drug Interactions section. • Additional information on adverse effects are listed in the table "Adverse effects of antidepressants". Δ Maximum recommended dose of citalopram is 20 mg for patients >60 years of age, with significant hepatic insufficiency, or taking interacting medications that can increase citalopram levels. Refer to topics on unipolar depression in adults and selective serotonin reuptake inhibitors (SSRIs). ◊ For additional information refer to topics on tricyclic and tetracyclic drugs for treating depression.