ANTIDEPRESSANTS




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Citalopram (Celexa®)

Dosage forms

Tablet
  • 10 mg
  • 20 mg
  • 40 mg

Dosing

Depression
  • Starting: 20 mg a day
  • Maintenance: 20 - 40 mg a day
  • Max: 40 mg a day
  • May take without regard to food
  • Max dose of 20 mg a day recommended for patients > 60 years old, and patients with liver disease
  • For patients who are poor CYP2C19 metabolizers, and patients taking CYP2C19 inhibitors, the maximum daily dose is 20 mg. See CYP2C19 for more.

Generic / Price

- YES/$

Mechanism of action

  • Selective serotonin reuptake inhibitor (SSRI)
  • The mechanism of action of citalopram hydrobromide as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake.

FDA-approved indications

- Depression

Side effects



Side effect Citalopram Placebo
Nausea 21% 14%
Dry mouth 20% 14%
Somnolence 18% 10%
Insomnia 15% 14%
Increased sweating 11% 9%
Ejaculation disorder 6% 1%


Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Pimozide (Orap®) - DO NOT COMBINE
  • Drugs that prolong the QT interval - DO NOT COMBINE
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • CYP2C19 inhibitors - may increase citalopram levels. Maximum citalopram dose is 20 mg a day.

Contraindications / Precautions

  • Prolonged QT syndrome - citalopram should be stopped in patients with persistent QTc longer than 500 ms
  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Angle-closure glaucoma - SSRIs may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Low sodium (hyponatremia) - SSRIs and SNRIs may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - SSRIs, including citalopram, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction (see Side effects above), and females may experience decreased libido and delayed or absent orgasm.
  • Poor CYP2C19 metabolizers - max dose 20 mg a day
  • Liver disease - maximum dose is 20 mg a day
  • Kidney disease
    • CrCl ≥ 30 ml/min: no dose adjustment necessary
    • CrCl < 30 ml/min: use caution

Escitalopram (Lexapro®)

Dosage forms

Tablet
  • 5 mg
  • 10 mg
  • 20 mg

Dosing - Depression

Adults
  • Starting: 10 mg once daily
  • Maintenance: 10 - 20 mg once daily
  • Max: 20 mg once daily
  • Liver disease: 10 mg once daily
  • Elderly: 10 mg once daily
  • May take without regard to food
  • Increase dose after a minimum of one week
Adolescents (12 - 17 years)
  • Starting: 10 mg once daily
  • Maintenance: 10 - 20 mg once daily
  • Max: 20 mg once daily
  • May take without regard to food
  • Increase dose after a minimum of three weeks

Dosing - GAD

Adults
  • Starting: 10 mg once daily
  • Maintenance: 10 - 20 mg once daily
  • Max: 20 mg once daily
  • Liver disease: 10 mg once daily
  • Elderly: 10 mg once daily
  • May take without regard to food
  • Increase dose after a minimum of one week

Efficacy


Generic / Price

- YES/$

Mechanism of action

  • Selective serotonin reuptake inhibitor (SSRI)
  • The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).

FDA-approved indications

  • Depression
  • Generalized anxiety disorder

Side effects



Side effect Escitalopram Placebo
Nausea 15% 7%
Insomnia 9% 4%
Ejaculation disorder (delay) 9% <1%
Diarrhea 8% 5%
Somnolence 6% 2%


Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Pimozide (Orap®) - DO NOT COMBINE
  • Drugs that prolong the QT interval - may potentiate QT prolongation
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • CYP2D6 substrates - escitalopram is a weak CYP2D6 inhibitor

Contraindications / Precautions

  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Angle-closure glaucoma - SSRIs may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Low sodium (hyponatremia) - SSRIs and SNRIs may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - SSRIs, including escitalopram, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction (see Side effects above), and females may experience decreased libido and delayed or absent orgasm.
  • Liver disease - recommended dose is 10 mg a day
  • Kidney disease
    • CrCl ≥ 30 ml/min: no dose adjustment necessary
    • CrCl < 30 ml/min: use caution

Fluoxetine | Prozac® | Prozac weekly™ | Sarafem® | Symbyax® (fluoxetine + olanzapine)

Dosage forms

Fluoxetine capsule
  • 10 mg
  • 20 mg
  • 40 mg
Fluoxetine tablet
  • 10 mg
  • 20 mg
  • 60 mg
Fluoxetine solution
  • 20 mg/5 ml
  • Comes in bottle of 120 ml
Prozac Weekly®
  • 90 mg capsule
Sarafem® tablet
  • 10 mg
  • 15 mg
  • 20 mg
Symbyax® capsule
  • Olanzapine - Fluoxetine
    • 3 mg - 25 mg
    • 6 mg - 25 mg
    • 6 mg - 50 mg
    • 12 mg - 25 mg
    • 12 mg - 50 mg

Dosing - Prozac®

Depression (Adults)
  • Starting: 20 mg once daily
  • Maintenance: 20 - 40 mg once daily
  • Max: 80 mg once daily
  • May take without regard to food
Depression (Children and adolescents)
  • Starting: 10 - 20 mg once daily
  • Maintenance: 10 - 20 mg once daily
  • Max: 20 mg once daily
  • Lower weight children may only require 10 mg/day
  • In trials, children as young as 8 years old were included
  • May take without regard to food
OCD (Adults)
  • Starting: 20 mg once daily
  • Maintenance: 20 - 60 mg once daily
  • Max: 80 mg once daily
  • May take without regard to food
OCD (Adolescents and higher weight children)
  • Starting: 10 mg once daily for 2 weeks, then 20 mg once daily
  • Maintenance: 20 - 60 mg once daily
  • Max: 60 mg once daily
  • In trials, children as young as 7 years old were included
  • May take without regard to food
OCD (Lower weight children)
  • Starting: 10 mg once daily
  • Maintenance: 20 - 30 mg once daily
  • Max: 30 mg once daily
  • In trials, children as young as 7 years old were included
  • May take without regard to food
Bulimia nervosa (Adults)
  • Target dose: 60 mg once daily
  • Max: 60 mg once daily
  • In trials, only the 60 mg dose was superior to placebo
  • May take without regard to food
Panic disorder (Adults)
  • Starting: 10 mg once daily
  • Maintenance: 10 - 60 mg once daily
  • Max: 60 mg once daily
  • May take without regard to food

Dosing - Prozac weekly®

Depression (Adults)
  • 90 mg once a week
  • May take without regard to food

Dosing - Sarafem®

Premenstrual dysphoric disorder (Adults)
  • Continuous dosing: 20 mg once daily
  • Intermittent dosing: 20 mg once daily starting 14 days before menstruation through first full day of menses
  • May take without regard to food

Dosing - Symbyax®

Depression with Bipolar I and treatment-resistant depression (Adults)
  • Starting: 6/25 mg once daily in the evening
  • Maintenance: 6/25 mg - 12/50 mg once daily
  • Max: 18/75 mg once daily
  • May take without regard to food
  • See olanzapine for more
Depression with Bipolar I (10 - 17 years)
  • Starting: 3/25 mg once daily in the evening
  • Maintenance: 6/25 mg - 12/50 mg once daily
  • Max: 12/50 mg once daily
  • May take without regard to food
  • See olanzapine for more

Efficacy


Generic / Price

  • Prozac® (tablet and solution) - YES/$
  • Prozac weekly™ - YES/$$-$$$
  • Sarafem­ - NO/$$$$
  • Symbyax™ - YES/$$-$$$$

Other

  • Switching from daily Prozac to Prozac weekly - start Prozac weekly 7 days after last daily dose
  • Full effect of medication may not be seen for 4 weeks

Mechanism of action

  • Selective serotonin reuptake inhibitor (SSRI)
  • Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin

FDA-approved indications

Prozac®
  • Depression
  • Obsessive-Compulsive Disorder (OCD)
  • Bulimia Nervosa
  • Panic disorder
  • Premenstrual dysphoric disorder
Sarafem®
  • Premenstrual dysphoric disorder
Symbyax®
  • Depression associated with Bipolar 1
  • Treatment resistant depression

Side effects



Side effect Placebo
Nausea 22% 9%
Headache 21% 19%
Insomnia 19% 10%
Nervousness 13% 8%
Fatigue 11% 6%
Diarrhea 11% 7%
Decreased appetite 10% 3%
Abnormal ejaculation 7% 1%


Drug interactions

  • Thioridazine - DO NOT COMBINE
  • Pimozide (Orap®) - DO NOT COMBINE
  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Drugs that prolong the QT interval - fluoxetine may prolong the QT interval. Use caution with other drugs that prolong the QT interval.
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • CYP2D6 substrates - fluoxetine is a strong CYP2D6 inhibitor
  • Tamoxifen - tamoxifen is metabolized by CYP2D6 to its active form. Some studies have found that tamoxifen is not as effective when taken with CYP2D6 strong inhibitors. Other studies have found no effect. See tamoxifen studies for more.

Contraindications / Precautions

  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Angle-closure glaucoma - SSRIs may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Low sodium (hyponatremia) - SSRIs and SNRIs may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - SSRIs, including fluoxetine, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction (see Side effects above), and females may experience decreased libido and delayed or absent orgasm.
  • Liver disease - use lower or less frequent dose. Manufacturer makes no specific dosage recommendations.
  • Kidney disease - no dose adjustment necessary

Fluvoxamine | Luvox® | Luvox® CR

Dosage forms

Luvox® tablet
  • 25 mg
  • 50 mg
  • 100 mg
Luvox CR® capsule
  • 100 mg
  • 150 mg

Dosing - Luvox®

OCD (Adults)
  • Starting: 50 mg once daily at bedtime
  • Maintenance: 100 - 300 mg/day
  • Max: 300 mg/day
  • Doses > 100 mg should be given in 2 divided doses
  • Increase in increments of 50 mg/day every 4 - 7 days
OCD (Children 8 - 17 years)
  • Starting: 25 mg once daily at bedtime
  • Maintenance: 50 - 200 mg/day
  • Max: 300 mg/day
  • Doses > 50 mg should be given in 2 divided doses
  • Increase dose in increments of 25 mg/day every 4 - 7 days

Dosing - Luvox® CR

OCD (Adults)
  • Starting: 100 mg once daily at bedtime
  • Maintenance: 100 - 300 mg once daily
  • Max: 300 mg once daily
  • Increase in increments of 50 mg/day every 7 days

Generic / Price

  • Luvox® - YES/$
  • Luvox® CR - YES/$$-$$$

Other

  • May take without regard to food
  • Because of the potential for drug interactions, fluvoxamine is not widely used

Mechanism of action

  • Selective serotonin reuptake inhibitor (SSRI)
  • The mechanism of action of fluvoxamine maleate in obsessive compulsive disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons. Fluvoxamine has been shown to be a potent inhibitor of the serotonin reuptake transporter in preclinical studies, both in vitro and in vivo.

FDA-approved indications

- Obsessive-Compulsive Disorder (OCD)

Side effects



Side effect Fluvoxamine Placebo
Nausea 40% 14%
Somnolence 22% 8%
Headache 22% 20%
Insomnia 21% 10%
Fatigue 14% 6%
Dry mouth 14% 10%
Nervousness 12% 5%
Dizziness 11% 6%
Diarrhea 11% 7%
Delayed ejaculation 8% 1%


Drug interactions

  • Alosetron (Lotronex®) - DO NOT COMBINE
  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Pimozide (Orap®) - DO NOT COMBINE
  • Thioridazine - DO NOT COMBINE
  • Tizanidine (Zanaflex®) - DO NOT COMBINE
  • Drugs that prolong the QT interval - may potentiate QT prolongation
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • Zolpidem (Ambien®) - fluvoxamine may inhibit zolpidem metabolism and increase zolpidem blood levels
  • CYP1A2 substrates - fluvoxamine is a strong CYP1A2 inhibitor
  • CYP3A4 substrates - fluvoxamine is a strong CYP3A4 inhibitor
  • CYP2C19 substrates - fluvoxamine is a strong CYP2C19 inhibitor
  • CYP2C9 substrates - fluvoxamine is a moderate CYP2C9 inhibitor

Contraindications / Precautions

  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Angle-closure glaucoma - SSRIs may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Low sodium (hyponatremia) - SSRIs and SNRIs may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - SSRIs, including fluvoxamine, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction (see Side effects above), and females may experience decreased libido and delayed or absent orgasm.
  • Liver disease - clearance is decreased. Dose may need to be decreased. Manufacturer makes no specific dosage recommendations.
  • Kidney disease - kidney disease does not appear to affect clearance

Paroxetine | Paxil® | Paxil CR® | Brisdelle™ | Pexeva®

Dosage forms

Paxil® tablet
  • 10 mg
  • 20 mg
  • 30 mg
  • 40 mg
  • Paxil® is paroxetine HCL
Paxil® suspension
  • 10 mg/5 ml
  • Comes in 250 ml bottle
  • Store at room temperature
  • Paxil® is paroxetine HCL
Paxil CR® tablet
  • 12.5 mg
  • 25 mg
  • 37.5 mg
  • Paxil CR® is paroxetine HCL
Pexeva® tablet
  • 10 mg
  • 20 mg
  • 30 mg
  • 40 mg
  • Pexeva® is paroxetine mesylate
Brisdelle™ capsule
  • 7.5 mg
  • Brisdelle® is paroxetine mesylate

Dosing - Paxil®

Depression
  • Starting: 20 mg once daily
  • Maintenance: 20 - 50 mg once daily
  • Max: 50 mg once daily
  • Increase in increments of 10 mg/day every 7 days
  • Liver and kidney disease - initial dose 10 mg a day. Do not exceed 40 mg a day.
OCD
  • Starting: 20 mg once daily
  • Target: 40 mg once daily
  • Max: 60 mg once daily
  • Increase in increments of 10 mg/day every 7 days
Panic disorder
  • Starting: 10 mg once daily
  • Target: 40 mg once daily
  • Max: 60 mg once daily
  • Increase in increments of 10 mg/day every 7 days
Social anxiety disorder
  • Starting: 20 mg once daily
  • Maintenance: 20 - 60 mg once daily
  • Max: 60 mg once daily
  • Increase in increments of 10 mg/day every 7 days
Generalized anxiety disorder
  • Starting: 20 mg once daily
  • Target: 20 once daily
  • Max: 50 mg once daily
  • Increase in increments of 10 mg/day every 7 days
Posttraumatic stress disorder
  • Starting: 20 mg once daily
  • Target: 20 mg once daily
  • Max: 50 mg once daily
  • Increase in increments of 10 mg/day every 7 days

Dosing - Pexeva®

Depression
  • Starting: 20 mg once daily
  • Maintenance: 20 - 50 mg once daily
  • Max: 50 mg once daily
  • Increase in increments of 10 mg/day every 7 days
  • Liver and kidney disease - initial dose 10 mg a day. Do not exceed 40 mg a day.
OCD
  • Starting: 20 mg once daily
  • Target: 40 mg once daily
  • Max: 60 mg once daily
  • Increase in increments of 10 mg/day every 7 days
Panic disorder
  • Starting: 10 mg once daily
  • Target: 40 mg once daily
  • Max: 60 mg once daily
  • Increase in increments of 10 mg/day every 7 days
Generalized anxiety disorder
  • Starting: 20 mg once daily
  • Target: 20 once daily
  • Max: 50 mg once daily
  • Increase in increments of 10 mg/day every 7 days

Dosing - Paxil CR®

Depression
  • Starting: 25 mg once daily
  • Maintenance: 25 - 62.5 mg once daily
  • Max: 62.5 mg once daily
  • Increase in increments of 12.5 mg/day every 7 days
  • Liver and kidney disease - initial dose 12.5 mg a day. Do not exceed 50 mg a day.
Panic disorder
  • Starting: 12.5 mg once daily
  • Maintenance: 12.5 - 75 mg once daily
  • Max: 75 mg once daily
  • Increase in increments of 12.5 mg/day every 7 days
Social anxiety disorder
  • Starting: 12.5 mg once daily
  • Maintenance: 12.5 - 37.5 mg once daily
  • Max: 37.5 mg once daily
  • Increase in increments of 12.5 mg/day every 7 days
Premenstrual dysphoric disorder
  • Continuous: 12.5 - 25 mg once daily
  • Intermittent: 12.5 - 25 mg once daily during the luteal phase (days 14 - 28 of the menstrual cycle with day 1 being the first day of menses)

Dosing - Brisdelle™

Vasomotor symptoms associated with menopause
  • 7.5 mg once daily at bedtime

Generic / Price

  • Paxil® tablet - YES/$
  • Paxil® suspension (250 ml) - YES/$$-$$$
  • Paxil® CR - YES/$
  • Pexeva® - NO/$$$$
  • Brisdelle™ - YES/$$-$$$

Other

All
  • May take without regard to food
Paxil® CR
  • Do not crush or chew tablet

Mechanism of action

  • Selective serotonin reuptake inhibitor (SSRI)
  • The mechanism of action of paroxetine in the treatment of MDD, SAD, OCD, PD, GAD, and PTSD is unknown, but is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin.

FDA-approved indications

Paxil®
  • Depression
  • Panic disorder
  • Social anxiety disorder
  • Generalized anxiety disorder
  • Posttraumatic stress disorder (PTSD)
Paxil® CR
  • Depression
  • Panic disorder
  • Social anxiety disorder
  • Premenstrual dysphoric disorder
Pexeva®
  • Depression
  • Obsessive-Compulsive Disorder (OCD)
  • Panic disorder
  • Generalized anxiety disorder
Brisdelle™
  • Vasomotor symptoms in menopause

Side effects



Side effect Paroxetine Placebo
Nausea 26% 9%
Somnolence 23% 9%
Headache 18% 17%
Dry Mouth 18% 12%
Fatigue 15% 6%
Constipation 14% 9%
Dizziness 13% 6%
Insomnia 13% 6%
Ejaculatory delay 13% 0%
Diarrhea 12% 8%
Sweating 11% 2%
Other male sexual dysfunction 10% 0%


Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Pimozide (Orap®) - DO NOT COMBINE. May increase risk of QT prolongation.
  • Thioridazine - DO NOT COMBINE. May increase risk of QT prolongation.
  • Cimetidine (Tagamet®) - may increase paroxetine levels
  • Risperidone (Risperdal®) - may increase risperidone levels
  • Tricyclic antidepressants (TCA) - may increase TCA levels
  • Fosamprenavir/Ritonavir - may decrease paroxetine levels
  • Drugs that prolong the QT interval - may potentiate QT prolongation
  • Highly protein-bound drugs - paroxetine is highly bound to plasma proteins and use with other drugs that are highly protein bound (e.g. warfarin) may increase free levels of paroxetine or the other drug. Monitor for adverse reactions when combining.
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • CYP2D6 substrates - paroxetine is a strong CYP2D6 inhibitor and may increase exposure to CYP2D6 substrates
  • Tamoxifen - tamoxifen is metabolized by CYP2D6 to its active form. Some studies have found that tamoxifen is not as effective when taken with CYP2D6 strong inhibitors. Other studies have found no effect. See tamoxifen studies for more.

Contraindications / Precautions

  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Pregnancy - pregnancy category D. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy may have an increased risk of congenital malformations, particularly cardiovascular malformations. Exposure to paroxetine in late pregnancy may lead to an increased risk for persistent pulmonary hypertension of the newborn (PPNH) and/or neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.
  • Angle-closure glaucoma - SSRIs may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Bipolar or other manic disorders - SSRIs may precipitate mania in patients with bipolar or other manic disorders
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Low sodium (hyponatremia) - SSRIs and SNRIs may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - SSRIs, including paroxetine, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction (see Side effects above), and females may experience decreased libido and delayed or absent orgasm.
  • Bone fractures - in some observational studies, patients on antidepressants, including SSRIs, have had a higher risk of fracture. It is unknown if a true causal link exists.
  • Liver disease
    • Paxil, Pexeva
      • Severe (Child-Pugh C): starting - 10 mg/day; do not exceed 40 mg/day
    • Paxil CR
      • Severe (Child-Pugh C): starting - 12.5 mg/day; do not exceed 50 mg/day
    • Brisdelle
      • No dose adjustment necessary
  • Kidney disease
    • Paxil, Pexeva
      • CrCl 30 - 60 ml/min: paroxetine levels increase 2-fold; use caution
      • CrCl < 30 ml/min: starting - 10 mg/day; do not exceed 40 mg/day
    • Paxil CR
      • CrCl 30 - 60 ml/min: paroxetine levels increase 2-fold; use caution
      • CrCl < 30 ml/min: starting - 12.5 mg/day; do not exceed 50 mg/day
    • Brisdelle
      • No dose adjustment necessary

Sertraline (Zoloft®)

Dosage forms

Tablet
  • 25 mg
  • 50 mg
  • 100 mg
Oral concentrate
  • 20 mg/ml
  • Comes in 60 ml bottle
  • Contains 12% alcohol

Dosing

Depression
  • Starting: 50 mg once daily
  • Maintenance: 50 - 200 mg once daily
  • Max: 200 mg once daily
  • May take without regard to food
  • Increase dose at intervals of ≥ 1 week
OCD (Adults)
  • Starting: 50 mg once daily
  • Maintenance: 50 - 200 mg once daily
  • Max: 200 mg once daily
  • May take without regard to food
  • Increase dose at intervals of ≥ 1 week
OCD (Children and adolescents)
  • Starting (6 - 12 years old): 25 mg once daily
  • Starting (13 - 17 years old): 50 mg once daily
  • Maintenance: 50 - 200 mg once daily
  • Max: 200 mg once daily
  • May take without regard to food
  • Increase dose at intervals of ≥ 1 week
Panic disorder, PTSD, Social anxiety disorder
  • Starting: 25 mg once daily
  • Maintenance: 50 - 200 mg once daily
  • Max: 200 mg a day
  • May take without regard to food
  • Increase dose at intervals of ≥ 1 week
Premenstrual dysphoric disorder
  • Continuous: 50 - 150 mg once daily
  • Intermittent: 50 - 100 mg once daily during the luteal phase (days 14 - 28 of the menstrual cycle with day 1 being the first day of menses)
  • May take without regard to food
  • Increase dose at the onset of each new cycle
  • For 100 mg/day intermittent dosing, use 50 mg/day for first 3 days of each new cycle

Efficacy


Generic / Price

  • Tablet - YES/$
  • Concentrate (60 ml) - YES/$

Other

Oral concentrate
  • Must be diluted before use. Just before taking, use the dropper provided to remove the required amount and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. Do not mix with anything other than the liquids listed. The dose should be taken immediately after mixing. Do not mix in advance.
  • At times, a slight haze may appear after mixing; this is normal
  • The dropper contains dry natural rubber. Use caution in patients with latex allergy.

Mechanism of action

  • Selective Serotonin Reuptake Inhibitor (SSRI)
  • Sertraline potentiates serotonergic activity in the central nervous system through inhibition of neuronal reuptake of serotonin (5-HT)

FDA-approved indications

  • Depression
  • Obsessive-Compulsive Disorder (OCD)
  • Panic disorder
  • Posttraumatic Stress Disorder (PTSD)
  • Premenstrual Dysphoric Disorder
  • Social Anxiety Disorder

Side effects



Side effect Sertraline Placebo
Nausea 25% 11%
Headache 25% 23%
Insomnia 21% 11%
Diarrhea 20% 10%
Ejaculation failure 14% 1%
Dry Mouth 14% 8%
Somnolence 13% 7%
Dizziness 12% 7%
Fatigue 12% 7%


Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Pimozide (Orap®) - DO NOT COMBINE
  • Drugs that prolong the QT interval - may potentiate QT prolongation
  • Warfarin (Coumadin®) - may increase effect of warfarin
  • Carbamazepine (Tegretol®) - may reduce sertraline levels
  • Cimetidine (Tagamet®) - may increase sertraline levels
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • CYP2D6 substrates - sertraline is a weak CYP2D6 inhibitor

Contraindications / Precautions

  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Angle-closure glaucoma - SSRIs may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Low sodium (hyponatremia) - SSRIs and SNRIs may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - SSRIs, including sertraline, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction (see Side effects above), and females may experience decreased libido and delayed or absent orgasm.
  • Liver disease - clearance is decreased. Use caution. Decrease dose or frequency.
  • Kidney disease - no dose adjustment necessary



Desvenlafaxine | Pristiq® | Khedezla™

Dosage forms

Desvenlafaxine succinate (Pristiq®) extended-release tablet
  • 25 mg
  • 50 mg
  • 100 mg
Desvenlafaxine (Khedezla™) extended-release tablet
  • 50 mg
  • 100 mg

Dosing

Depression (Pristiq® and Khedezla™)
  • Starting: 50 mg once daily
  • Maintenance: 50 - 400 mg once daily
  • Max: 400 mg once daily
  • Pristiq and Khedezla are not considered therapeutically equivalent and cannot be substituted for each other

Generic / Price

  • Pristiq® - YES/$
  • Khedezla™ - YES/$

Other

Pristiq®, Khedezla™
  • May take without regard to food
  • Take at approximately the same time every day
  • Do not cut, crush, or chew tablet
  • In trials, no additional benefit was seen at doses greater than 50 mg a day

Mechanism of action

  • Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)
  • The exact mechanism of the antidepressant action of desvenlafaxine is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have shown that desvenlafaxine is a potent and selective SNRI.

FDA-approved indications

- Depression

Side effects



Side effect Desvenlafaxine 100 mg/day Placebo
Nausea 26% 10%
Dry Mouth 17% 9%
Insomnia 12% 6%
Sweating 11% 4%
Dizziness 10% 5%
Constipation 9% 4%
Ejaculation delay 5% < 1%
Erectile dysfunction 6% 1%
  • Orthostatic hypotension - 8% of patients ≥ 65 years
  • Elevated blood pressure - desvenlafaxine may cause an increase in blood pressure. Effect is typically small. Average SBP increase of 2 - 4 mmHg.
  • Elevated cholesterol - desvenlafaxine may raise cholesterol levels (4 - 10% of patients)


Drug interactions

  • MAO inhibitors - DO NOT COMBINE. Do not start an MAO inhibitor within 7 days of stopping desvenlafaxine . Do not start desvenlafaxine within 14 days of stopping an MAO inhibitor.
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - desvenlafaxine may increase bleeding risk when taken with drugs that affect hemostasis
  • CYP2D6 substrates - desvenlafaxine is a weak CYP2D6 inhibitor. When taking desvenlafaxine 400 mg a day, may need to halve dose of sensitive CYP2D6 substrates.
  • CYP3A4 strong inhibitors - desvenlafaxine is a minor substrate of CYP3A4. Strong CYP3A4 inhibitors may increase desvenlafaxine levels.

Contraindications / Precautions

  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Hypertension - may raise blood pressure
  • Angle-closure glaucoma - SNRIs may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Low sodium (hyponatremia) - SSRIs and SNRIs may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - SNRIs, including desvenlafaxine, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction (see Side effects above), and females may experience decreased libido and delayed or absent orgasm.
  • Liver disease
    • Moderate-severe disease (Child-Pugh B and C): recommended dose is 50 mg/day; do not exceed 100 mg/day
  • Kidney disease
    • CrCl 30 - 50 ml/min: max dose is 50 mg a day
    • CrCl < 30 ml/min: max dose is 25 mg every day or 50 mg every other day

Duloxetine | Cymbalta® | Drizalma Sprinkle™

Dosage forms

Capsule, delayed-release (Cymbalta®)
  • 20 mg
  • 30 mg
  • 40 mg
  • 60 mg
Capsule, delayed-release (Drizalma Sprinkle™)
  • 20 mg
  • 30 mg
  • 40 mg
  • 60 mg

Dosing

Depression (adults)
  • Starting: 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given once daily or 30 mg twice daily)
  • Maintenance: 40 - 60 mg/day
  • Max: 120 mg/day
  • For some patients, starting with 30 mg once daily for 1 week may be desirable
  • There is no evidence that doses > 60 mg/day confer any additional benefits
  • May take without regard to food
Generalized anxiety disorder
  • Children 7 - 17 years
    • Starting: 30 mg once daily for at least 2 weeks before considering increasing
    • Maintenance: 30 - 60 mg once daily
    • Max: 120 mg/day
    • Increase dose in increments of 30 mg/day
    • May take without regard to food
  • Adults (< 65 years old)
    • Starting: 60 mg once daily
    • Maintenance: 60 mg once daily
    • Max: 120 mg once daily
    • For some patients, starting with 30 mg once daily for 1 week may be desirable
    • There is no evidence that doses > 60 mg/day confer any additional benefits
    • May take without regard to food
  • Adults (≥ 65 years old)
    • Starting: 30 mg once daily for at least 2 weeks before considering increasing
    • Maintenance: 30 - 60 mg once daily
    • Max: 120 mg/day
    • Increase dose in increments of 30 mg/day
    • May take without regard to food
Diabetic peripheral neuropathy (adults)
  • Starting: 60 mg once daily
  • Target: 60 mg once daily
  • Max: 60 mg once daily
  • A lower starting dose may be considered in some patients
  • There is no evidence that doses > 60 mg/day confer any additional benefits
  • May take without regard to food
Fibromyalgia
  • Adults
    • Starting: 30 mg once daily for 1 week
    • Target: 60 mg once daily
    • Max: 60 mg once daily
    • There is no evidence that doses > 60 mg/day confer any additional benefits
    • May take without regard to food
  • Children 13 - 17 years
    • Dosing: 30 mg once daily
    • May increase to 60 mg once daily if necessary
    • May take without regard to food
Chronic musculoskeletal pain (adults)
  • Starting: 30 mg once daily for 1 week
  • Target: 60 mg once daily
  • Max: 60 mg once daily
  • There is no evidence that doses > 60 mg/day confer any additional benefits
  • May take without regard to food

Generic / Price

  • Cymbalta® - YES/$
  • Drizalma Sprinkle™ - NO/$$$$

Other

Cymbalta
  • Do not open, crush, or chew capsule
Drizalma Sprinkle
  • Capsules may be opened and contents sprinkled over applesauce. Applesauce should be swallowed immediately.
  • May be given via NG tube

Mechanism of action

  • Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)
  • Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.

FDA-approved indications

  • Depression in adults
  • Generalized anxiety disorder in adults and pediatric patients ≥ 7 years
  • Diabetic peripheral neuropathy in adults
  • Fibromyalgia in adults and pediatric patients ≥ 13 years
  • Chronic musculoskeletal pain in adults

Side effects



Side effect Duloxetine Placebo
Nausea 23% 8%
Dry Mouth 14% 6%
Headache 14% 14%
Constipation 9% 4%
Diarrhea 9% 6%
Fatigue 9% 5%
Somnolence 9% 3%
Insomnia 9% 5%
Erectile dysfunction 4% 1%
Ejaculation delay 2% 1%
Elevated liver enzymes (> 3X upper limit of normal) 1.25% 0.45%
  • Elevated blood pressure - duloxetine may cause a slight increase in blood pressure. In trials, the average increase in SBP and DBP was 0.5 mmHg and 0.8 mmHg, respectively, in duloxetine-treated patients compared to a decrease of 0.6 mmHg and 0.3 mmHg in placebo-treated patients.
  • Orthostatic hypotension - may occur in some patients


Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Thioridazine - DO NOT COMBINE
  • CYP1A2 strong inhibitors - DO NOT COMBINE
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • CYP2D6 strong inhibitors - may increase duloxetine levels
  • CYP2D6 substrates - duloxetine is a moderate CYP2D6 inhibitor. It may increase CYP2D6 substrate levels.
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.

Contraindications / Precautions

  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Hypertension - duloxetine may cause a slight increase in blood pressure. In trials, the average increase in SBP and DBP was 0.5 mmHg and 0.8 mmHg, respectively, in duloxetine-treated patients compared to a decrease of 0.6 mmHg and 0.3 mmHg in placebo-treated patients. Susceptible patients should monitor their blood pressure after starting duloxetine.
  • Angle-closure glaucoma - SNRIs may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Decreased gastric motility - may affect absorption
  • Low sodium (hyponatremia) - SSRIs and SNRIs may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - SNRIs, including duloxetine, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction (see Side effects above), and females may experience decreased libido and delayed or absent orgasm.
  • Liver disease - do not use in patients with significant liver disease
  • Kidney disease
    • CrCl ≥ 30 ml/min: no dose adjustment necessary
    • CrCl < 30 ml/min: DO NOT USE

Levomilnacipran (Fetzima™)

Dosage forms

Extended-release capsule
  • 20 mg
  • 40 mg
  • 80 mg
  • 120 mg
Titration pack:
  • 20 mg capsule X 2
  • 40 mg capsule X 26

Dosing

Depression
  • Starting: 20 mg once daily for 2 days, then 40 mg once daily
  • Maintenance: 40 - 120 mg once daily
  • Max: 120 mg once daily
  • Increase in increments of 40 mg/day at intervals of ≥ 2 days
  • May take without regard to food
Dosing in kidney disease
  • CrCl ≥ 60 ml/min: no dose adjustment necessary
  • CrCl 30 - 59 ml/min: do not exceed 80 mg a day
  • CrCl 15 - 29 ml/min: do not exceed 40 mg/day
  • CrCl < 15 ml/min: not recommended
Dosing with strong CYP3A4 inhibitors
  • Do not exceed 80 mg a day
  • See CYP3A4 for more

Generic / Price

- NO/$$$$

Other

  • Do not open, chew, or crush capsule

Mechanism of action

  • Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)
  • The exact mechanism of the antidepressant action of levomilnacipran is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of reuptake at serotonin and norepinephrine transporters. Non-clinical studies have shown that levomilnacipran is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).

FDA-approved indications

- Depression

Side effects



Side effect Fetzima Placebo
Nausea 17% 6%
Constipation 9% 3%
Excessive sweating 9% 2%
Erectile dysfunction 6% 1%
Rapid heart beat 6% 2%
Urinary hesitancy / retention 5% 0%
Ejaculation disorder 5% <1%
Vomiting 5% 1%
Palpitations 5% 1%
Testicular pain 4% <1%
Hot flush 3% 1%
Orthostatic hypotension 3% 1%
Decreased appetite 3% 1%
  • Elevated blood pressure - levomilnacipran may cause an increase in blood pressure. Effect is typically small. Average SBP increase of 3 - 4 mmHg, average DBP increase 3 mmHg.
  • Increase in heart rate - levomilnacipran may cause an increase in heart rate. Average increase of 7-9 bpm in studies



Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Alcohol - alcohol may accelerate drug release from the levomilnacipran capsule. It is recommended that it not be taken with alcohol.
  • CYP3A4 strong inhibitors - levomilnacipran is a CYP3A4 sensitive substrate. The dose of levomilnacipran should not exceed 80 mg a day when taken with CYP3A4 strong inhibitors
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.

Contraindications / Precautions

  • Uncontrolled narrow-angle glaucoma - DO NOT USE
  • Angle-closure glaucoma - SNRIs may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Urinary retention (e.g. BPH) - levomilnacipran may worsen urinary retention in certain conditions
  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Hypertension - may raise blood pressure
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Low sodium (hyponatremia) - SSRIs and SNRIs may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - SNRIs, including levomilnacipran, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction (see Side effects above), and females may experience decreased libido and delayed or absent orgasm.
  • Liver disease - no dose adjustment necessary
  • Kidney disease
    • CrCl ≥ 60 ml/min: no dose adjustment necessary
    • CrCl 30 - 59 ml/min: do not exceed 80 mg a day
    • CrCl 15 - 29 ml/min: do not exceed 40 mg/day
    • CrCl < 15 ml/min: not recommended

Venlafaxine |Effexor® | Effexor XR®

Dosage forms

Effexor® tablet
  • 25 mg
  • 37.5 mg
  • 50 mg
  • 75 mg
  • 100 mg
Effexor XR® extended-release capsule
  • 37.5 mg
  • 75 mg
  • 150 mg
Effexor XR® extended-release tablet
  • 37.5 mg
  • 75 mg
  • 150 mg
  • 225 mg

Dosing - Effexor®

Depression
  • Starting: 75 mg a day
  • Maintenance: 75 - 225 mg a day
  • Max: 375 mg a day
  • Give in 2 to 3 divided doses
  • Increase dose in increments of up to 75 mg/day at intervals of ≥ 4 days
  • Doses higher than 225 mg a day have not been extensively studied
  • Take with food to help reduce nausea

Dosing - Effexor XR®

Depression
  • Starting: 37.5 - 75 mg once daily
  • Maintenance: 75 - 225 mg once daily
  • Max: 225 mg once daily
  • Increase dose in increments of up to 75 mg/day at intervals of ≥ 4 days
  • Take with food to help reduce nausea
Generalized anxiety disorder
  • Starting: 37.5 - 75 mg once daily
  • Maintenance: 75 - 225 mg once daily
  • Max: 225 mg once daily
  • Increase dose in increments of up to 75 mg/day at intervals of ≥ 4 days
  • Take with food to help reduce nausea
Social anxiety disorder
  • Target: 75 mg once daily
  • There is no evidence that higher doses are beneficial
  • Take with food to help reduce nausea
Panic disorder
  • Starting: 37.5 once daily
  • Maintenance: 75 - 225 mg once daily
  • Max: 225 mg once daily
  • Increase dose in increments of up to 75 mg/day at intervals of ≥ 7 days
  • Take with food to help reduce nausea
Migraine prevention (off-label)
  • 75 - 150 mg/day
Diabetic neuropathy (off-label)

Efficacy


Generic / Price

  • Effexor® - YES/$
  • Effexor XR® capsule - YES/$
  • Effexor XR® tablet - YES/$$

Other

Effexor®
  • May cause false-positive urine drug tests for phencyclidine (PCP) and amphetamines
Effexor XR®
  • May cause false-positive urine drug tests for phencyclidine (PCP) and amphetamines
  • Capsules may be opened and sprinkled on applesauce. Do not chew contents.
  • Do not crush, cut, or chew tablet
Switching brands
  • When switching between Effexor® and Effexor XR®, keep total daily dose the same

Mechanism of action

  • Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)
  • The exact mechanism of the antidepressant action of venlafaxine in humans is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have demonstrated that venlafaxine and its active metabolite are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

FDA-approved indications

  • Depression
  • Generalized anxiety disorder
  • Social anxiety disorder
  • Panic disorder

Side effects



Side effect Venlafaxine Placebo
Nausea 35% 12%
Dizziness 16% 11%
Dry Mouth 16% 6%
Insomnia 15% 10%
Somnolence 14% 8%
Fatigue 12% 8%
Ejaculation delay/abnormal 11% < 1%
Constipation 10% 4%
Sweating 10% 3%
  • Elevated blood pressure - venlafaxine may cause an increase in blood pressure. The effect increases with higher doses.
  • Elevated cholesterol - venlafaxine may raise cholesterol levels (5.3% of patients)

Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Cimetidine (Tagamet®) - may increase venlafaxine levels
  • Haloperidol (Haldol®) - may increase haloperidol levels
  • Desipramine - may increase desipramine levels
  • Metoprolol - may increase metoprolol levels
  • Risperidone (Risperdal®) - may increase risperidone levels
  • Indinavir (Crixivan®) - may decrease indinavir levels
  • Drugs that prolong the QT interval - may potentiate QT prolongation
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • CYP2D6 inhibitors and substrates - venlafaxine is a CYP2D6 sensitive substrate and CYP2D6 weak inhibitor
  • CYP3A4 inhibitors - may increase venlafaxine levels

Contraindications / Precautions

  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Hypertension - may raise blood pressure
  • Angle-closure glaucoma - SNRIs may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Low sodium (hyponatremia) - SSRIs and SNRIs may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - SNRIs, including venlafaxine, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction (see Side effects above), and females may experience decreased libido and delayed or absent orgasm.
  • Liver disease
    • Effexor, Effexor XR
      • Mild-moderate disease (Child-Pugh A/B): reduce dose by 50%
      • Severe (Child-Pugh C): reduce dose by 50% or more
  • Kidney disease
    • Effexor
      • CrCl 30 - 90 ml/min: reduce dose by 25%
      • CrCl < 30 ml/min: reduce dose by 50%
    • Effexor XR
      • CrCl 30 - 90 ml/min: reduce dose by 25% - 50%
      • CrCl < 30 ml/min: reduce dose by 50% or more



Bupropion | Wellbutrin® | Wellbutrin SR® | Wellbutrin XL® | Zyban® | Aplenzin® | Forfivo XL™ | Contrave®

Dosage forms

Wellbutrin® tablet
  • 75 mg
  • 100 mg
Wellbutrin SR® tablet
  • 100 mg
  • 150 mg
  • 200 mg
Wellbutrin XL® tablet
  • 150 mg
  • 300 mg
Forfivo XL™ tablet
  • 450 mg
Zyban® tablet
  • 150 mg
Aplenzin® tablet
  • 174 mg
  • 348 mg
  • 522 mg
  • Aplenzin® is bupropion hydrobromide
Contrave®

Dosing - Depression

Wellbutrin®
  • Starting: 100 mg twice a day for 3 days
  • Maintenance: 100 mg three times a day
  • Max: 450 mg a day
  • May take without regard to food
Wellbutrin SR®
  • Starting: 150 mg once a day for 3 days
  • Maintenance: 150 mg twice a day
  • Max: 200 mg twice a day
  • May take without regard to food
Wellbutrin XL®
  • Starting: 150 mg once daily
  • Maintenance: 300 mg once daily
  • Max: 450 mg once daily
  • Increase dose at intervals ≥ 4 days
  • May take without regard to food
Aplenzin®
  • Starting: 174 mg once daily for 4 days
  • Maintenance: 348 mg once daily
  • Max: 522 mg once daily
  • May take without regard to food
  • Aplenzin-Wellbutrin XL equivalence:174 mg = 150 mg, 348 mg = 300 mg, 522 = 450 mg
Forfivo XL™
  • Starting: use another form of bupropion to initiate therapy
  • Maintenance: 450 mg once daily
  • Max: 450 mg once daily
  • May take without regard to food

Dosing - SAD

Wellbutrin XL®
  • Starting: 150 mg once daily
  • Target: 300 mg once daily
  • Max: 300 mg once daily
  • Increase dose at intervals ≥ 7 days
  • May take without regard to food
Aplenzin®
  • Starting: 174 mg once daily
  • Target: 348 mg once daily
  • Max: 348 mg once daily
  • Increase dose at intervals ≥ 7 days
  • May take without regard to food
  • Aplenzin-Wellbutrin XL equivalence:174 mg = 150 mg, 348 mg = 300 mg, 522 = 450 mg

Dosing - Smoking cessation

Zyban®
  • Starting: 150 mg once daily for 3 days
  • Maintenance: 150 mg twice a day
  • Max: 150 mg twice a day
  • May take without regard to food

Dosing - Weight loss

Contrave® (naltrexone + bupropion)

Efficacy


Generic / Price

  • Wellbutrin® - YES/$
  • Wellbutrin SR® - YES/$
  • Wellbutrin XL® - YES/$
  • Forfivo XL™ - NO/$$$$
  • Aplenzin® - NO/$$$$
  • Zyban® - YES/$-$$

Other

All
  • May take without regard to food
  • Do not crush, cut, or chew tablets
  • May cause false-positive urine drug tests for amphetamines
Switching brands
  • When switching between Wellbutrin®, Wellbutrin SR®, and Wellbutrin XL®, keep total daily dose the same

Mechanism of action

  • Norepinephrine-Dopamine Reuptake Inhibitor
  • The exact mechanism of the antidepressant action of bupropion is not known but is presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.

FDA-approved indications

  • Depression
  • Seasonal affective disorder
  • Smoking cessation

Side effects



Side effect Bupropion Placebo
Agitation 32% 22%
Dry mouth 28% 18%
Constipation 26% 17%
Headache 26% 22%
Nausea 23% 19%
Excessive sweating 22% 15%
Dizziness 22% 16%
Tremor 21% 8%
Insomnia 19% 16%
Blurred vision 15% 10%
Rapid heart beat 11% 9%
  • Increased blood pressure - may increase blood pressure. Incidence is unknown.


Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • CYP2B6 inhibitors and inducers - bupropion is a CYP2B6 sensitive substrate
  • CYP2D6 substrates - bupropion is a CYP2D6 strong inhibitor
  • OCT2 substrates - bupropion is an OCT2 inhibitor
  • Amantadine - may increase side effects
  • Clopidogrel (Plavix®) - clopidogrel is a CYP2B6 inhibitor and may raise bupropion levels. Bupropion doses may need to be decreased when taken with clopidogrel.
  • Digoxin - bupropion may decrease digoxin levels. Monitor digoxin levels when combining.
  • Levodopa (Sinemet®) - may increase side effects
  • Drugs that increase dopaminergic or noradrenergic activity - may increase risk of hypertension
  • Ritonavir, Lopinavir, and Efavirenz - ritonavir, lopinavir, and efavirenz are CYP2B6 inducers and may lower bupropion levels to subtherapeutic levels
  • Tamoxifen - tamoxifen is metabolized by CYP2D6 to its active form. Some studies have found that tamoxifen is not as effective when taken with CYP2D6 strong inhibitors. Other studies have found no effect. See tamoxifen studies for more.

Contraindications / Precautions

  • Seizure disorder - DO NOT USE. Bupropion carries the highest seizure risk of all the antidepressants.
  • Bulimia or anorexia nervosa - DO NOT USE. These patients have a higher risk of seizure.
  • Alcohol/benzodiazepine/barbiturate withdrawal - DO NOT USE. These patients have a higher risk of seizure.
  • Antiepileptic drug withdrawal - DO NOT USE. These patients have a higher risk of seizure.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Angle-closure glaucoma - bupropion may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Liver disease
    • Wellbutrin
      • Mild (Child-Pugh A): consider dose/frequency reduction
      • Moderate-severe (Child-Pugh B/C): do not exceed 75 mg a day
    • Wellbutrin SR
      • Mild (Child-Pugh A): consider dose/frequency reduction
      • Moderate-severe (Child-Pugh B/C): max dose is 100 mg a day or 150 mg every other day
    • Wellbutrin XL, Zyban
      • Mild (Child-Pugh A): consider dose/frequency reduction
      • Moderate-severe (Child-Pugh B/C): max dose is 150 mg every other day
    • Aplenzin
      • Severe (Child-Pugh C): max dose is 174 mg every other day
    • Forfivo XL
      • Liver disease not recommended since only one dose
  • Kidney disease
    • CrCl < 90 ml/min: consider dose/frequency reduction
    • Forfivo XL is not recommended since only one dose



Amitriptyline (Elavil®)

Dosage forms

Tablet
  • 10 mg
  • 25 mg
  • 50 mg
  • 75 mg
  • 100 mg
  • 150 mg

Dosing

Depression
  • Starting: 25- 50 mg once daily
  • Maintenance: 50 - 100 mg once daily
  • Max: 150 mg once daily
  • May take without regard to food
Migraine prevention (off-label)
  • 25 - 150 mg/day
  • May take without regard to food
Diabetic neuropathy (off-label)
  • Starting: 10 - 25 mg once daily
  • Target: 25 - 100 mg/day
  • May take without regard to food
  • See diabetic neuropathy for more

Efficacy


Generic / Price

- YES/$

Mechanism of action

  • Tricyclic antidepressant
  • Inhibits norepinephrine and serotonin reuptake by neurons

FDA-approved indications

- Depression

Side effects

NOTE: Side effect profile not well-defined. Clomipramine is another TCA. It has the most extensive side effect information available. (see clomipramine for more)
  • Dry mouth - > 50% of patients in some trials
  • Drowsiness - common
  • Blurred vision
  • Constipation
  • Urinary retention
  • Postural hypotension

Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Anticholinergic medications - may potentiate side effects
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • CYP2D6 inhibitors - may increase levels of amitriptyline
  • CYP1A2 substrates - amitriptyline is a moderate CYP1A2 inhibitor
  • CYP2C19 substrates - amitriptyline is a strong CYP2C19 inhibitor
  • Topiramate - topiramate may increase amitriptyline levels
  • Valproic acid - valproic acid may increase amitriptyline levels
  • Clonidine - amitriptyline may decrease the effectiveness of clonidine
  • Drugs that prolong the QT interval - may potentiate QT prolongation

Contraindications / Precautions

  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Angle-closure glaucoma - amitriptyline may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Urinary retention - may worsen
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Liver disease - use caution
  • Kidney disease - use caution

Clomipramine (Anafranil™)

Dosage forms

Capsule
  • 25 mg
  • 50 mg
  • 75 mg

Dosing

Obsessive compulsive disorder
  • Starting: 25 mg a day
  • Maintenance: 100 mg a day
  • Max: 250 mg a day
  • When initiating, increase to 100 mg a day over the course of 2 weeks
  • May be given in divided doses to decrease gastrointestinal side effects
  • Take with food to limit GI side effects

Generic / Price

- YES/$$-$$$

Other

  • Gradually increase dose. May give twice a day when initiating to limit side effects.

Mechanism of action

  • Tricyclic antidepressant
  • Inhibits norepinephrine and serotonin reuptake by neurons

FDA-approved indications

- Obsessive-compulsive disorder (OCD)

Side effects



Side effect Clomipramine Placebo
Dry mouth 84% 17%
Somnolence 54% 16%
Tremor 54% 2%
Dizziness 54% 14%
Headache 52% 41%
Constipation 47% 11%
Ejaculation failure 42% 2%
Nausea 33% 14%
Increased sweating 29% 3%
Insomnia 25% 15%
Libido change 21% 3%
Impotence 20% 3%
Weight gain 18% 1%
Abnormal vision 18% 4%
Nervousness 18% 2%
Urinary retention 14% 2%
Diarrhea 13% 9%
Myalgia 13% 9%
Muscle twitching 13% 0%
Increased appetite 11% 2%
  • Orthostatic hypotension
  • Elevated liver enzymes - 1 - 3% of patients


Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Anticholinergic medications - may potentiate side effects
  • Methylphenidate (Ritalin®, Concerta®) - may increase clomipramine levels
  • Haloperidol (Haldol®) - may increase clomipramine levels
  • Phenobarbital - may increase phenobarbital levels
  • Carbamazepine - may increase clomipramine levels
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • CYP2D6 inhibitors - may increase clomipramine levels
  • CYP1A2 inhibitors - may increase clomipramine levels
  • CYP2C19 inhibitors and substrates - clomipramine is a CYP2C19 strong inhibitor and substrate
  • CYP3A4 inhibitors - may increase clomipramine levels
  • Valproic acid - valproic acid may increase clomipramine levels
  • Clonidine - clomipramine may decrease the effectiveness of clonidine
  • Drugs that prolong the QT interval - may potentiate QT prolongation

Contraindications / Precautions

  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Angle-closure glaucoma - clomipramine may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Urinary retention - may worsen
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Liver disease - use caution
  • Kidney disease - use caution

Desipramine (Norpramin®)

Dosage forms

Tablet
  • 10 mg
  • 25 mg
  • 50 mg
  • 75 mg
  • 100 mg
  • 150 mg

Dosing

Depression
  • Starting: 50 mg/day
  • Maintenance: 100 - 200 mg/day
  • Max: 300 mg/day
  • May be given once daily or in divided doses
  • May take without regard to food

Generic / Price

- YES/$

Mechanism of action

  • Tricyclic antidepressant
  • Inhibits norepinephrine and serotonin reuptake by neurons

FDA-approved indications

- Depression

Side effects

NOTE: Side effect profile not well-defined. Clomipramine is another TCA. It has the most extensive side effect information available. (see clomipramine for more)
  • Dry mouth - > 50% of patients in some trials
  • Drowsiness - common
  • Blurred vision
  • Constipation
  • Urinary retention
  • Postural hypotension

Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Anticholinergic medications - may potentiate side effects
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • CYP2D6 inhibitors - may increase levels of desipramine
  • OCT2 substrates - desipramine is an OCT2 inhibitor
  • Clonidine - desipramine may decrease the effectiveness of clonidine
  • Drugs that prolong the QT interval - may potentiate QT prolongation

Contraindications / Precautions

  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Angle-closure glaucoma - desipramine may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Urinary retention - may worsen
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Liver disease - use caution
  • Kidney disease - use caution

Imipramine | Tofranil™ | Tofranil-PM™

Dosage forms

Tofranil™ tablet
  • 10 mg
  • 25 mg
  • 50 mg
Tofranil-PM™ capsule
  • 75 mg
  • 100 mg
  • 125 mg
  • 150 mg

Dosing - Depression

Tofranil™
  • Starting: 75 mg a day
  • Maintenance: 50 - 150 mg a day
  • Max: 200 mg a day
  • May be given once daily or in divided doses
  • May take without regard to food
Tofranil PM™
  • Starting: 75 mg a day
  • Maintenance: 75 - 150 mg a day
  • Max: 200 mg a day
  • May be given once daily or in divided doses
  • May take without regard to food

Dosing - Enuresis (≥ 6 years old)

Tofranil™
  • Starting: 25 mg one hour before bedtime
  • Maintenance:(6-11 years) 25 - 50 mg at night (≥ 12 years) 25 - 75 mg at night
  • Max: 2.5 mg/kg/day or 75 mg a day, whichever is less
  • For early bedwetters, a divided dose of 25 mg given midafternoon and repeated at bedtime may be more effective
  • May take without regard to food

Generic / Price

  • Tofranil™ - YES/$
  • Tofranil PM™ - YES/$$$$

Mechanism of action

  • Tricyclic antidepressant
  • Inhibits norepinephrine and serotonin reuptake by neurons

FDA-approved indications

Tofranil™
  • Depression
  • Childhood enuresis (bedwetting)
Tofranil PM™
  • Depression

Side effects

NOTE: Side effect profile not well-defined. Clomipramine is another TCA. It has the most extensive side effect information available. (see clomipramine for more)
  • Dry mouth - > 50% of patients in some trials
  • Drowsiness - common
  • Blurred vision
  • Constipation
  • Urinary retention
  • Postural hypotension

Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Anticholinergic medications - may potentiate side effects
  • Methylphenidate (Ritalin®, Concerta®) - may increase imipramine levels
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • CYP2D6 inhibitors - may increase levels of imipramine
  • CYP2C19 substrates - imipramine is a strong CYP2C19 inhibitor
  • CYP1A2 substrates - imipramine is a moderate CYP1A2 inhibitor
  • OCT2 substrates - imipramine is an OCT2 inhibitor
  • Clonidine - imipramine may decrease the effectiveness of clonidine
  • Drugs that prolong the QT interval - may potentiate QT prolongation

Contraindications / Precautions

  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Angle-closure glaucoma - imipramine may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Urinary retention - may worsen
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Liver disease - use caution
  • Kidney disease - use caution

Nortriptyline (Pamelor™)

Dosage forms

Capsule
  • 10 mg
  • 25 mg
  • 50 mg
  • 75 mg

Dosing

Depression
  • Starting: 25 mg a day
  • Maintenance: 25 - 100 mg a day given in 1 - 4 divided doses
  • Max: 150 mg a day
  • May take without regard to food
Herpes zoster neuralgia (off-label)
  • Starting: 25 mg at bedtime
  • Max: 150 mg a day
  • Increase by 25 mg daily every 2–3 days as tolerated
  • May take without regard to food
  • Dosing recommendation from the Infectious Disease Society of America

Generic / Price

- YES/$

Other

  • When taking doses > 100 mg a day, plasma levels of nortriptyline should be monitored. Ideal plasma level is 50 - 150 ng/ml.

Mechanism of action

  • Tricyclic antidepressant
  • Inhibits norepinephrine and serotonin reuptake by neurons

FDA-approved indications

- Depression

Side effects

NOTE: Side effect profile not well-defined. Clomipramine is another TCA. It has the most extensive side effect information available. (see clomipramine for more)
  • Dry mouth - > 50% of patients in some trials
  • Drowsiness - common
  • Blurred vision
  • Constipation
  • Urinary retention
  • Postural hypotension

Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Anticholinergic medications - may potentiate side effects
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • CYP2D6 inhibitors - may increase levels of nortriptyline
  • Clonidine - nortriptyline may decrease the effectiveness of clonidine
  • Valproic acid - valproic acid may increase nortriptyline levels
  • Drugs that prolong the QT interval - may potentiate QT prolongation

Contraindications / Precautions

  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Angle-closure glaucoma - nortriptyline may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Urinary retention - may worsen
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Liver disease - use caution
  • Kidney disease - use caution



Trazodone (Desyrel®)

Dosage forms

Trazodone tablet
  • 50 mg
  • 100 mg
  • 150 mg
  • 300 mg
Oleptro® ER tablets (Discontinued)
  • 150 mg
  • 300 mg

Dosing - Depression

Trazodone
  • Starting: 150 mg a day given in divided doses
  • Maintenance: 150 - 400 mg a day given in divided doses
  • Max: 400 mg a day
  • Increase dose by 50 mg/day every 3 - 4 days
  • When taken after a meal or light snack, absorption is increased
Oleptro™ (discontinued)
  • Starting: 150 mg once daily
  • Maintenance: 150 - 300 mg once daily
  • Max: 375 mg once daily
  • Increase dose by 75 mg/day every 3 days
  • Oleptro™ should be taken on an empty stomach, preferably at bedtime

Dosing - Insomnia (off-label)

Trazodone
  • Starting: 50 mg at bedtime
  • Maintenance: 50 - 150 mg at bedtime
  • When taken after a meal or light snack, absorption is increased

Generic / Price

  • Trazodone - YES/$
  • Oleptro™ - NO/$$$

Other

Trazodone
  • Trazodone tablets are scored and can be broken in half
Oleptro™
  • Oleptro™ tablets are scored and can be broken in half. Tablets should not be crushed or chewed.

Mechanism of action

  • The mechanism of trazodone’s antidepressant action is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS. Trazodone is both a selective serotonin reuptake inhibitor (SSRI) and a 5HT 2 receptor antagonist and the net result of this action on serotonergic transmission and its role in trazodone’s antidepressant effect is unknown.

FDA-approved indications

- Depression

Side effects



Side effect Trazodone Placebo
Drowsiness 41% 20%
Dry mouth 34% 20%
Dizzy / Lightheaded 28% 15%
Headache 20% 16%
Blurred vision 15% 4%
Nausea 13% 10%
Decreased libido 1.3% < 1%
Other - incidence not well-defined
  • Orthostatic hypotension
  • Priapism (erection lasting > 6 hours)


Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • CYP3A4 inducers and inhibitors - may affect levels of trazodone
  • Drugs that prolong the QT interval - may potentiate QT prolongation

Contraindications / Precautions

  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Prolonged QT syndrome - may worsen QT prolongation
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Low sodium (hyponatremia) - trazodone may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Angle-closure glaucoma - trazodone may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Liver disease - use caution
  • Kidney disease - use caution

Vilazodone (Viibryd®)

Dosage forms

Tablet
  • 10 mg
  • 20 mg
  • 40 mg
Starter kit:
  • 10 mg X 7
  • 20 mg X 7
  • 40 mg X 16

Dosing

Depression
  • Starting: 10 mg once daily for 7 days, then 20 mg once daily for 7 days, then 40 mg once daily
  • Maintenance: 40 mg once daily
  • Max: 40 mg once daily
  • Take with food. Food increases absorption.
When taken with CYP3A4 strong inhibitors
  • Dose should not exceed 20 mg a day
When taken with CYP3A4 moderate inhibitors
  • Dose should not exceed 20 mg a day in patients with significant side effects
When taken with CYP3A4 strong inducers
  • Consider doubling the dose
  • Viibryd® dose should not exceed 80 mg/day

Generic / Price

- NO/$$$$

Mechanism of action

  • The mechanism of action of vilazodone in the treatment of major depressive disorder is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS through selective inhibition of serotonin reuptake. Vilazodone is also a partial agonist at serotonergic 5-HT1A receptors; however, the net result of this action on serotonergic transmission and its role in vilazodone’s antidepressant effect are unknown.

FDA-approved indications

- Depression

Side effects



Side effect Vilazodone Placebo
Diarrhea 28% 9%
Nausea 23% 5%
Dizziness 9% 5%
Dry mouth 8% 5%
Insomnia 6% 2%
Decreased libido 4% < 1%
Delayed ejaculation 2% 0%


Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • CYP3A4 inducers and inhibitors - may affect levels of vilazodone. See Dosage for dosing recommendations
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.

Contraindications / Precautions

  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Angle-closure glaucoma - vilazodone may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Low sodium (hyponatremia) - vilazodone may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - serotonin modulators, including vilazodone, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction (see Side effects above), and females may experience decreased libido and delayed or absent orgasm.
  • Liver disease
    • Mild-moderate (Child-Pugh A/B): no dose adjustment necessary
    • Severe (Child-Pugh C): has not been studied
  • Kidney disease - no dose adjustment necessary



Mirtazapine | Remeron® | Remeron Soltab®

Dosage forms

Remeron® tablet
  • 7.5 mg
  • 15 mg
  • 30 mg
  • 45 mg
Remeron Soltab® orally disintegrating tablet
  • 15 mg
  • 30 mg
  • 45 mg

Dosing

Depression
  • Starting: 15 mg once daily at bedtime
  • Maintenance: 15 - 45 mg once daily at bedtime
  • Max: 45 mg once daily
  • Increase dose at intervals of no less than 1 - 2 weeks
  • May take without regard to food

Efficacy


Generic / Price

- YES/$ (tablet and ODT)

Other

Soltabs®
  • Soltabs® are placed on the tongue where they dissolve and are swallowed. Water is not necessary.
  • Do not break Soltabs®
  • Use Soltabs® immediately after removing from blister pack. They cannot be stored.

Mechanism of action

  • The mechanism of action of mirtazapine for the treatment of major depressive disorder, is unclear. However, its efficacy could be mediated through its activity as an antagonist at central presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity.
  • In preclinical studies, mirtazapine acts as an antagonist at α2-adrenergic inhibitory autoreceptors and heteroreceptors and as an antagonist at serotonin 5-HT2 and 5-HT3 receptors. Mirtazapine has no significant affinity for the 5-HT1A and 5-HT1B receptors.
  • Mirtazapine also acts as an antagonist of histamine (H1) receptors, peripheral α1-adrenergic receptors, and muscarinic receptors. Actions at these receptors may explain some of the other clinical effects of mirtazapine (e.g., its prominent somnolent effects and orthostatic hypotension may be explained by its inhibition of histamine (H1) receptors and peripheral α1-adrenergic receptors, respectively).

FDA-approved indications

- Depression

Side effects



Side effect Mirtazapine Placebo
Somnolence 54% 18%
Dry mouth 25% 15%
Increased appetite 17% 2%
Elevated cholesterol / triglycerides 15% 7%
Constipation 13% 7%
Weight gain 12% 2%
Dizziness 7% 3%
Elevated liver enzymes 2% 0.3%
  • Sexual side effects are comparable to placebo in trials
  • Orthostatic hypotension may occur


Drug interactions

  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. In general, MAO inhibitors and antidepressants should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
  • Mirtazapine is a CYP2D6, CYP1A2, and CYP3A substrate
  • CYP2D6 inhibitors and inducers - may affect mirtazapine levels
  • CYP1A2 inhibitors and inducers - may affect mirtazapine levels
  • CYP3A4 inhibitors and inducers - may affect mirtazapine levels
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Phenytoin - may decrease mirtazapine levels by 45%
  • Carbamazepine - may decrease mirtazapine levels by 60%
  • Warfarin - mirtazapine may increase warfarin levels
  • Cimetidine - may increase mirtazapine levels by more than 50%
  • Ketoconazole - may increase mirtazapine levels by more than 50%
  • Alpha blockers - mirtazapine may potentiate the effect of alpha blockers
  • Anticholinergic medications - may potentiate side effects

Contraindications / Precautions

  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Low white blood cells - agranulocytosis has occurred in rare cases in patients taking mirtazapine
  • Angle-closure glaucoma - mirtazapine may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Low sodium (hyponatremia) -mirtazapine may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Liver disease - clearance is decreased. No specific recommendations given. Use caution.
  • Kidney disease
    • CrCl 11 - 39 ml/min: clearance is decreased 30%
    • CrCl < 10 ml/min: clearance is decreased 50%; use caution

Vortioxetine (Trintellix®)

Dosage forms

Tablet
  • 5 mg
  • 10 mg
  • 15 mg
  • 20 mg

Dosing

Depression
  • Starting: 10 mg once daily
  • Maintenance: 20 mg once daily
  • Max: 20 mg once daily
  • May take without regard to food
When taken with CYP2D6 strong inhibitors
  • Reduce dose by half
CYP2D6 poor metabolizers
  • Maximum dose is 10 mg once daily
When taken with CYP3A4 strong inducers
  • Consider increasing the dose
  • Dose should not exceed three times the original dose

Generic / Price

- NO/$$$$

Other

  • Brand name was changed from Brintellix to Trintellix in 2016 to avoid confusion with Brilinta

Mechanism of action

  • The mechanism of the antidepressant effect of vortioxetine is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS through inhibition of the reuptake of serotonin (5-HT). It also has several other activities including 5-HT3 receptor antagonism and 5-HT1A receptor agonism. The contribution of these activities to vortioxetine's antidepressant effect has not been established.

FDA-approved indications

- Depression

Side effects



Side effect Vortioxetine Placebo
Nausea 32% 9%
Dizziness 9% 6%
Dry mouth 8% 6%
Constipation 8% 3%
Sexual dysfunction 5% 2%


Drug interactions

  • Anticoagulant / Antiplatelet meds - drugs that interfere with serotonin reuptake can inhibit platelet function and increase bleeding risk. Use caution when combining with aspirin, P2Y12 inhibitors, NSAIDs, warfarin, and other anticoagulants.
  • CYP2D6 strong inhibitors - vortioxetine is a CYP2D6 sensitive substrate, and concomitant CYP2D6 strong inhibitors can increase vortioxetine exposure. Vortioxetine dose should be reduced by half when taken with a CYP2D6 strong inhibitor. After stopping a CYP2D6 inhibitor, increase vortioxetine dose to the original level.
  • CYP strong inducers - CYP strong inducers (e.g. rifampin, carbamazepine, phenytoin) can decrease exposure to vortioxetine. Consider increasing the vortioxetine dose when taken with a CYP enzyme inducer for > 14 days. The maximum dose is not recommended to exceed three times the original dose. After stopping a CYP enzyme inducer, vortioxetine doses should be reduced to the original level within 14 days.
  • Drugs with high protein binding - vortioxetine is highly bound to plasma proteins. When taken with other highly protein-bound drugs, free concentrations of vortioxetine or other protein-bound drugs may be increased. Use caution and monitor for adverse effects.
  • Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. Do not start a MAO inhibitor within 21 days of stopping vortioxetine, and do not start vortioxetine within 14 days of stopping a MAO inhibitor.
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome

Lab interactions

  • Methadone assays - false positive results in urine enzyme immunoassays for methadone have been reported in patients taking vortioxetine. An alternative analytical technique (e.g. chromatographic methods) should be considered to confirm positive methadone urine drug screen results.

Contraindications / Precautions

  • CYP2D6 poor metabolizers - vortioxetine exposure is increased in CYP2D6 poor metabolizers, and the maximum dose in these patients should not exceed 10 mg a day.
  • Serotonin syndrome - antidepressants that block the reuptake of serotonin may increase the risk of serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. Risk is increased when antidepressants are taken with other serotonergic agents.
  • Seizures - antidepressants may lower the seizure threshold and increase the risk of seizures. Use caution in patients with a history of seizure disorder.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis, angioedema, and urticaria have been reported
  • Angle-closure glaucoma - vortioxetine may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
  • Suicidal thoughts and behaviors - in placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.
  • Bipolar - antidepressants may precipitate mania in bipolar patients. Use caution in patients with bipolar or a history of mania.
  • Abnormal bleeding - drugs that interfere with serotonin reuptake may inhibit platelet function and increase the risk of bleeding. Concomitant NSAIDs, P2Y12 inhibitors, and anticoagulants may enhance the risk.
  • Low sodium (hyponatremia) - vortioxetine may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) which can lead to hyponatremia. Elderly patients, patients taking diuretics, and volume-depleted patients may be at greater risk. Symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness.
  • Abrupt discontinuation - abrupt discontinuation may cause nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. When possible, antidepressants should be tapered when discontinuing (see recommendations for stopping antidepressants below).
  • Sexual dysfunction - serotonergic antidepressants, including vortioxetine, may cause sexual dysfunction in some patients. Males may experience ejaculatory delay or failure, decreased libido, and erectile dysfunction, and females may experience decreased libido and delayed or absent orgasm (see Side effects above).
  • Liver disease
    • Mild-moderate (Child-Pugh A/B): no dose adjustment necessary
    • Severe (Child-Pugh C): has not been studied
  • Kidney disease - no dose adjustment necessary






  • Including active metabolite
  • References [1,2]
Antidepressant half-lives
Drug Half-life
SSRIs
Citalopram (Celexa) 35 hours
Escitalopram (Lexapro) 27 - 32 hours
Fluoxetine (Prozac) 4 - 16 days
Fluvoxamine (Luvox and Luvox CR) 15 - 17 hours
Paroxetine (Paxil) 21 hours
Paroxetine (Paxil CR) 15 - 20 hours
Sertraline (Zoloft) 26 hours
SNRIs
Desvenlafaxine (Pristiq) 11 hours
Duloxetine (Cymbalta) 12 hours
Levomilnacipran (Fetzima) 12 hours
Venlafaxine (Effexor and Effexor XR) 11 hours
Other
Bupropion (Wellbutrin IR, SR, XL) 21 hours
Mirtazapine (Remeron) 20 - 40 hours
Trazodone 7 hours
Vilazodone (Viibryd) 25 hours
Vortioxetine (Trintellix) 66 hours
TCAs
Amitriptyline (Elavil) 9 - 25 hours
Clomipramine (Anafranil) 54 - 77 hours
Desipramine (Norpramin) 14 - 25 hours
Imipramine (Tofranil) 10 - 16 hours
Nortriptyline (Pamelor) 18 - 35 hours



  • These recommendations do not apply to MAO inhibitors, which require complete drug discontinuation and a wash-out period when switching
  • References [3,5]
Direct switch
Method
  • Current antidepressant is stopped and the second one is started the very next day
Advantages
  • There is no period where the patient is without treatment
  • The method does not require any tapering
  • In the studies listed below, this method was well-tolerated
Disadvantages
  • This method increases the risk of drug interactions between the first antidepressant and the second. It takes 4 - 5 half-lives for a drug to be cleared from the body, so the first drug will still be present during this time. Drugs with longer half-lives (e.g. fluoxetine) will pose the greatest risk (see antidepressant half-lives above).
  • Patients may experience withdrawal symptoms from the first antidepressant. It takes about 5 half-lives for a drug to reach steady-state, and during this time, withdrawal symptoms from the first drug may occur; this is particularly true for drugs with shorter half-lives.
Conservative switch
Method
  • Current antidepressant is tapered and stopped. Second antidepressant is started after the taper ends or following a washout period where no drug is given.
Advantages
  • This method limits the potential for drug interactions
Disadvantages
  • Patient goes a period without treatment
  • Patient may experience withdrawal symptoms during taper
Cross-taper switch
Method
  • Current antidepressant is tapered, while the second one is introduced at some point during the taper at a low dose. Second antidepressant is then titrated to full dose.
Advantages
  • Patient does not have a period without treatment
  • This method may limit withdrawal symptoms from the current antidepressant
Disadvantages
  • This method increases the risk of drug interactions


Pregnancy safety studies

Association of Maternal Antidepressant Prescription During Pregnancy With Standardized Test Scores of Danish School-aged Children, JAMA (2021) [PubMed abstract]
  • Design: Retrospective cohort study (N=575,369) of children born in Denmark between January 1, 1997, and December 31, 2009, attending public primary and lower secondary school
  • Exposure: Maternal prescription fill for antidepressants during pregnancy vs None
  • Primary outcome: The difference in standardized scores between children with and without maternal prescription fill for antidepressants in mathematics and language tests
  • Findings: In this study of public schoolchildren in Denmark, children whose mothers had filled prescriptions for antidepressants during pregnancy, compared with children whose mothers did not fill prescriptions for antidepressants during pregnancy, had a 2-point lower standardized test score in mathematics, a difference that was statistically significant, but had no significant difference in language test scores. The magnitude of the difference in the mathematics test score was small and of uncertain clinical importance, and the findings must be weighed against the benefits of treating maternal depression during pregnancy.

Associations Between Maternal Depression, Antidepressant Use During Pregnancy, and Adverse Pregnancy Outcomes, Obstet Gynecol (2021) [PubMed abstract]
  • Design: Meta-analysis (N=215 studies) of studies examining associations of depression, depressive symptoms, or use of antidepressants during pregnancy with gestational age, birth weight, SGA, or Apgar scores
  • Exposure: Depressive symptoms vs None and Antidepressant use vs None
  • Findings: Depressive symptoms or a clinical diagnosis of depression during pregnancy are associated with preterm birth and low Apgar scores, even without exposure to antidepressants. However, SSRIs may be independently associated with preterm birth and low Apgar scores.

Antidepressant use during early pregnancy and risk of selected birth defects, JAMA Psychiatry (2020) [PubMed abstract]
  • Design: Case-control study (N=42,108) in mothers of infants who were born with (cases) and without birth defects (controls)
  • Exposure: Self-reported antidepressant use in early pregnancy vs None
  • Primary outcome: Birth defects
  • Findings: We found some associations between maternal antidepressant use and specific birth defects. Venlafaxine was associated with the highest number of defects, which needs confirmation given the limited literature on venlafaxine use during pregnancy and risk for birth defects. Our results suggest confounding by underlying conditions should be considered when assessing risk. Fully informed treatment decision-making requires balancing the risks and benefits of proposed interventions against those of untreated depression or anxiety.

Antidepressant use during pregnancy and the risk of gestational diabetes mellitus: a nested case-control study, BMJ (2019) [PubMed abstract]
  • Design: Nested, case-control study (N=229,955) in pregnant women
  • Exposure: Antidepressant vs None
  • Primary outcome: Gestational diabetes after week 20 of pregnancy
  • Results:
    • Primary outcome: Antidepressant exposed vs None, Odds ratio 1.19, 95%CI [1.08 to 1.30]
  • Findings: The findings suggest that antidepressants and specifically venlafaxine and amitriptyline were associated with an increased risk of gestational diabetes

Association Between Serotonergic Antidepressant Use During Pregnancy and Autism Spectrum Disorder in Children - JAMA (2017) [PMID 28418480]
  • Design: Retrospective cohort study (N=35,906 pregnancies)
  • Exposure: Serotonergic antidepressant exposure defined as 2 or more consecutive maternal prescriptions for an SSRI or SNRI between conception and delivery
  • Primary outcome: Child autism spectrum disorder identified after the age of 2 years
  • Findings: In children born to mothers receiving public drug coverage in Ontario, Canada, in utero serotonergic antidepressant exposure compared with no exposure was not associated with autism spectrum disorder in the child. Although a causal relationship cannot be ruled out, the previously observed association may be explained by other factors.

Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring - JAMA (2017) [PMID 28418479]
  • Design: Retrospective cohort study (N=1,508,629 offspring)
  • Exposure: Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations
  • Primary outcome: Preterm birth (<37 gestational weeks), small for gestational age (birth weight <2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring
  • Findings: Among offspring born in Sweden, after accounting for confounding factors, first-trimester exposure to antidepressants, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder

Neonatal Morbidity After Maternal Use of Antidepressant Drugs During Pregnancy. (Pediatrics 2016) [PubMed abstract]
  • Design: Cohort registry study
  • Results: Maternal use of antidepressants during pregnancy was associated with increased neonatal morbidity and a higher rate of admissions to the NICU. The absolute risk for severe disease was low, however.

Association of SSRI Exposure During Pregnancy With Speech, Scholastic, and Motor Disorders in Offspring. (JAMA Psychiatry 2016) [PubMed abstract]
  • Design: Cohort registry study
  • Results: Exposure to SSRIs during pregnancy was associated with an increased risk of speech/language disorders. This finding may have implications for understanding associations between SSRIs and child development.

Pregnancy Complications Following Prenatal Exposure to SSRIs or Maternal Psychiatric Disorders (Am J Psychiatry 2015) [PubMed abstract]
  • Design: Cohort registry study
  • Results: In a large national birth cohort, treatment of maternal psychiatric disorders with SSRIs during pregnancy was related to a lower risk of preterm birth and cesarean section but a higher risk of neonatal maladaptation. The findings provide novel evidence for a protective role of SSRIs on some deleterious reproductive outcomes, possibly by reducing maternal depressive symptoms. The divergent findings suggest that clinical decisions on SSRI use during pregnancy should be individualized, taking into account the mother's psychiatric and reproductive history.

Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous reports. (BMJ 2015) [PubMed abstract]
  • Design: Bayesian case-control study
  • Results: These data provide reassuring evidence for some SSRIs but suggest that some birth defects occur 2 - 3.5 times more frequently among the infants of women treated with paroxetine or fluoxetine early in pregnancy.

Antidepressant use late in pregnancy and risk of Persistent Pulmonary Hypertension of the Newborn (PPHN) (JAMA 2015) [PubMed abstract]
  • Design: Cohort registry study
  • Results: Evidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However, the absolute risk was small, and the risk increase appears more modest than suggested in previous studies.

SSRIs and venlafaxine in early pregnancy and risk of birth defects (BMJ 2015) [PubMed abstract]
  • Design: Cohort registry study
  • Results: In this large Nordic study no substantial increase was found in prevalence of overall cardiac birth defects among infants exposed to SSRIs or venlafaxine in utero. Although the prevalence of septal defects and right ventricular outflow tract defects was higher in exposed infants, the lack of an association in the sibling controlled analyses points against a teratogenic effect of these drugs.

Tamoxifen interaction studies

Risk of mortality with concomitant use of tamoxifen and SSRIs: multi-database cohort study. (BMJ 2016) [PubMed abstract]
  • Design: Retrospective registry cohort study (N=14,532 | length = median 2.2 years) in women with breast cancer taking tamoxifen and SSRIs
  • Exposure: Potent CYP2D6 Inhibitors (paroxetine and fluoxetine) vs Other SSRIs
  • Primary outcome: All cause mortality in each cohort in women taking SSRIs that are potent inhibitors of CYP2D6 (paroxetine, fluoxetine) versus other SSRIs
  • Results:
    • Primary outcome: Potent CYP2D6 inhibitors - 58.6/1000 person years, Other SSRIs - 57.9/1000 persons years (HR 0.96, 95%CI [0.88 - 1.06])
  • Findings: Concomitant use of tamoxifen and potent CYP2D6 inhibiting SSRIs versus other SSRIs was not associated with an increased risk of death

Tamoxifen and Antidepressant Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors (J Natl Cancer Inst 2015) [PubMed abstract]
  • Design: Retrospective registry cohort study (N=16,887 | length = median 6 years) in breast cancer survivors taking tamoxifen
  • Exposure: Antidepressant vs No Antidepressant
  • Primary outcome: Risk of subsequent breast cancer
  • Results:
    • We did not find a statistically significant effect on subsequent breast cancer with any antidepressant use in the multivariable Cox regression models
    • None of the adjusted hazard ratios of subsequent breast cancer corresponding with a 25%, 50%, and 75% overlap of concomitant antidepressant and tamoxifen use (one to five years) demonstrated a statistically significant effect
  • Findings: Using the comprehensive electronic health records of insured patients, we did not observe an increased risk of subsequent breast cancer in women who concurrently used tamoxifen and antidepressants, including paroxetine

Resistant depression studies

Bupropion SR vs Sertraline vs Venlafaxine XR After Failing Citalopram in MDD, NEJM (2006) [PubMed abstract]
  • Design: Randomized controlled trial (N=727, length = 14 weeks) in patients with MDD who did not respond to citalopram or could not tolerate it
  • Treatment: Bupropion SR up to 400 mg/day vs Sertraline up to 200 mg/day vs Venlafaxine XR up to 375 mg/day
  • Primary outcome: Symptom remission, defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of the study
  • Results:
    • Primary outcome: Bupropion - 21.3%, Sertraline - 17.6%, Venlafaxine - 24.8% (p=0.16)
  • Findings: After unsuccessful treatment with an SSRI, approximately one in four patients had a remission of symptoms after switching to another antidepressant. Any one of the medications in the study provided a reasonable second-step choice for patients with depression.

Switch to Bupropion vs Add Bupropion vs Add Antipsychotic in Resistant MDD, JAMA (2017) [PubMed abstract]
  • Design: Randomized, controlled trial (N=1522, length = 12 weeks) in patients with MDD who were failing SSRI, SNRI, or mirtazapine therapy
  • Treatment: Switch to Bupropion 300 - 400 mg/day vs Add Bupropion 300 - 400 mg/day vs Add aripiprazole 5 - 15 mg/day
  • Primary outcome: Remission during the acute treatment phase of 12 weeks
  • Results:
    • Primary outcome: Switch to bupropion - 22%, Add bupropion - 27%, Add aripiprazole - 29% (add aripiprazole vs switch to bupropion p=0.02)
  • Findings: Among a predominantly male population with MDD unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.

Addition of Aripiprazole vs Placebo to MDD resistant to Venlafaxine (Lancet 2015) [PubMed abstract]
  • Design: Randomized, controlled trial (N=468, length = 12 weeks) in adults older than 60 with MDD who were failing venlafaxine 150 - 300 mg/day
  • Treatment: Aripiprazole (target dose 10 mg/day) vs Placebo
  • Primary outcome: Remission (defined as an MADRS score of ≤ 10 and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits
  • Results:
    • Primary outcome: Aripiprazole - 44%, Placebo - 29% (p=0.03)
  • Findings: In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism.

Stopping vs Continuing Antidepressant in Patients with a History of Depression who are Stable, NEJM (2021) [PubMed abstract]
  • The trial enrolled 478 patients in England with a history of depression who were stable on their current antidepressant (sertraline, citalopram, fluoxetine, or mirtazapine)
Main inclusion criteria
  • ≥ 2 prior episodes of major depression OR taking antidepressant for > 2 years
  • On stable dose of antidepressant for ≥ 9 months
  • Patient feels well enough to stop antidepressant
Main exclusion criteria
  • Current depressive episode
  • History of bipolar, psychosis, or dementia
Baseline characteristics
  • Average age 54 years
  • Female sex - 73%
  • Using antidepressant for ≥ 3 years - 71%
  • ≥ 3 previous episodes of depression - 93%
  • Current antidepressant
    • Sertraline - 16%
    • Citalopram - 47%
    • Fluoxetine - 33%
    • Mirtazapine - 4%
Randomized treatment groups
  • Group 1 (238 patients): Continue antidepressant
  • Group 2 (240 patients): Discontinue antidepressant
  • Only patients taking sertraline 100 mg/day, citalopram 20 mg/day, fluoxetine 20 mg/day, or mirtazapine 30 mg for at least 9 months were enrolled
  • During the first month in the discontinuation group, patients who were taking citalopram, sertraline, or mirtazapine at baseline received the medications at half their regular dose. In the second month, they received half-dose antidepressants and placebo on alternate days. Starting in the third month, they received placebo only.
  • Patients who were taking fluoxetine at baseline received 20 mg of fluoxetine and placebo on alternate days in the first month. Starting in the second month, they received placebo only, since fluoxetine has a long half-life.
Primary outcome: First relapse of depression during the 52-week follow-up, as determined by components of a modified retrospective Clinical Interview Schedule–Revised (CIS-R). CIS-R is a computerized, self-administered, structured interview that asks about depressive symptoms during the previous 12 weeks.
Results

Duration: 52 weeks
Outcome Continue Discontinue Comparisons
Primary outcome 39% 56% HR 2.06, 95%CI [1.56 to 2.70], p<0.001
  • Adverse events were rare (4%) and similar between groups
  • By the end of the trial, 39% of the patients in the discontinue group had returned to taking an antidepressant

Findings: Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy.

Antidepressant vs placebo studies

Escitalopram vs Placebo in Patients with Acute Coronary Syndrome and Depression, JAMA (2018) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=300, length = 24 weeks) in patients with acute coronary syndrome and depression
  • Treatment: Escitalopram 5 - 20 mg/day vs Placebo
  • Primary outcome: A composite of all-cause mortality, myocardial infarction (MI), and percutaneous coronary intervention (PCI)
  • Results:
    • Primary outcome: Escitalopram - 41%, Placebo - 53.6% (p=0.03)
  • Findings: Among patients with depression following recent acute coronary syndrome, 24-week treatment with escitalopram compared with placebo resulted in a lower risk of major adverse cardiac events after a median of 8.1 years. Further research is needed to assess the generalizability of these findings.

Escitalopram vs Placebo in Patients with Heart Failure and Depression , JAMA (2016) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=372, length = 24 months) in patients with heart failure and depression
  • Treatment: Escitalopram 10 - 20 mg/day vs Placebo
  • Primary outcome: Composite of time to all-cause death or hospitalization
  • Results:
    • Primary outcome: Escitalopram - 63%, Placebo - 64% (p=0.92)
  • Findings: In patients with chronic heart failure with reduced ejection fraction and depression, 18 months of treatment with escitalopram compared with placebo did not significantly reduce all-cause mortality or hospitalization, and there was no significant improvement in depression. These findings do not support the use of escitalopram in patients with chronic systolic heart failure and depression.

Sertraline vs Placebo in Patients with Chronic Kidney Disease and Depression, JAMA (2017) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=201, length = 12 weeks) in patients with chronic kidney disease and depression
  • Treatment: Sertraline 50 - 200 mg/day vs Placebo
  • Primary outcome: Improvement in depressive symptom severity from baseline to 12 weeks
  • Results:
    • Primary outcome (change in score): Sertraline -4.1, Placebo -4.2 (p=0.82)
  • Findings: Among patients with non-dialysis-dependent CKD and MDD, treatment with sertraline compared with placebo for 12 weeks did not significantly improve depressive symptoms. These findings do not support the use of sertraline to treat MDD in patients with non-dialysis-dependent CKD.

Fluoxetine vs Placebo for Functional Outcomes after Acute Stroke, Lancet (2019) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=3127 | length = 12 months) in patients with acute stroke and focal neurological deficit at the time of randomisation
  • Treatment: Fluoxetine 20 mg once daily vs Placebo for 6 months
  • Primary outcome: Functional status, measured with the modified Rankin Scale (mRS), at 6 months
  • Results:
    • Primary outcome: The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (p=0.44)
  • Findings: Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function

Fluoxetine vs Placebo for OCD in Children with Autism, JAMA (2019) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=146 | length = 16 weeks) in children and adolescents with autism spectrum disorder and OCD
  • Treatment: Fluoxetine 4 - 30 mg/day vs Placebo
  • Primary outcome: Total score on the CYBOCS-PDD (scores range from 0-20; higher scores indicate higher levels of maladaptive behaviors; minimal clinically important difference, 2 points) at 16 weeks postrandomization
  • Results:
    • Primary outcome: Fluoxetine - 3.72 point decrease, Placebo - 2.53 point decrease (p=0.03)
  • Findings: In this preliminary study of children and adolescents with autism spectrum disorders, treatment with fluoxetine compared with placebo resulted in significantly lower scores for obsessive-compulsive behaviors at 16 weeks. Interpretation is limited by the high dropout rate, null findings of prespecified analyses that accounted for potentially confounding factors and baseline imbalances, and CIs for the treatment effect that included the minimal clinically important difference.

Smoking cessation studies

Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders, Lancet (2016) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=8144, length=24 weeks)
  • Treatment: Nicotine patch vs Varenicline vs Bupropion vs Placebo
  • Primary outcome: 1. Incidence of a composite measure of moderate and severe neuropsychiatric adverse events 2. Biochemically confirmed continuous abstinence for weeks 9 - 12
  • Results:
    • Primary outcome (neuropsychiatric events in nonpsychiatric cohort): Varenicline - 1.3%, Bupropion - 2.2%, Nicotine patch - 2.5%, Placebo - 2.4%
    • Primary outcome (neuropsychiatric events in psychiatric cohort): Varenicline - 6.5%, Bupropion - 6.7%, Nicotine patch - 5.2%, Placebo - 4.9%
    • Primary outcome (tobacco abstinence weeks 9 - 12): Varenicline - 33.5%, Bupropion - 22.6%, Nicotine patch - 23.4%, Placebo - 12.5%
  • Findings:The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo.



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  • $$$ = $101 - $150
  • $$$$ = > $151
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