ANTIDEPRESSANTS




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Citalopram (Celexa®)

Dosage forms

Tablet
  • 10 mg
  • 20 mg
  • 40 mg
Capsule
  • 30 mg
Solution
  • 10 mg/5 ml
  • Comes in 240 ml bottle
  • Store at room temp

Dosing

Depression
  • Starting: 20 mg a day
  • Maintenance: 20 - 40 mg a day
  • Max: 40 mg a day
  • May take without regard to food
  • For patients > 60 years old, the maximum recommended dose is 20 mg once daily
  • For patients with liver disease, the maximum recommended dose is 20 mg once daily
With CYP2C19 inhibitors and CYP2C19 poor metabolizers
  • For patients who are taking concomitant CYP2C19 inhibitors, the maximum recommended daily dose is 20 mg
  • For patients who are CYP2C19 poor metabolizers, the maximum recommended daily dose is 20 mg
  • See CYP2C19 for more
Kidney disease
  • CrCl ≥ 30 ml/min: no dose adjustment necessary
  • CrCl < 30 ml/min: has not been studied. Use caution.
Liver disease
  • Maximum recommended dose is 20 mg/day

Generic / Price

  • Tablets: YES/$
  • Capsule: NO/$$$
  • Solution: YES/$-$$

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.
  • Drugs that prolong the QT interval - DO NOT COMBINE. Citalopram causes dose-dependent QT interval prolongation.
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Pimozide (Orap®) - DO NOT COMBINE. Citalopram increases pimozide exposure, and this may increase the risk of QT prolongation.
  • CYP2C19 inhibitors - citalopram is a CYP2C19 sensitive substrate, and CYP2C19 inhibitors may increase its exposure. When citalopram is taken with CYP2C19 inhibitors, the maximum recommended dose is 20 mg once daily.
  • 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

  • Prolonged QT syndrome - citalopram causes dose-dependent QT interval prolongation, which can lead to Torsade de Pointes, ventricular tachycardia, and sudden death, all of which have been reported in the postmarketing setting. Because of this, doses greater than 40 mg/day are no longer recommended. Citalopram should be avoided in patients with congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute myocardial infarction, and/or uncompensated heart failure unless the benefits outweigh the risks. At-risk patients should have their potassium and magnesium levels monitored along with periodic ECGs. Citalopram should be stopped in patients with persistent QTc measurements > 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/day
  • Liver disease - maximum recommended dose is 20 mg/day
  • Kidney disease
    • CrCl ≥ 30 ml/min: no dose adjustment necessary
    • CrCl < 30 ml/min: has not been studied. 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
  • Elderly: 10 mg once daily
  • May take without regard to food
  • Increase dose after a minimum of one week
Depression (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
Generalized anxiety disorder (adults)
  • Starting: 10 mg once daily
  • Maintenance: 10 - 20 mg once daily
  • Max: 20 mg once daily
  • Elderly: 10 mg once daily
  • May take without regard to food
  • Increase dose after a minimum of one week
Kidney disease
  • CrCl ≥ 30 ml/min: no dose adjustment necessary
  • CrCl < 30 ml/min: use caution
Liver disease
  • Recommended dose is 10 mg/day

Efficacy

Escitalopram vs Placebo Escitalopram vs Psilocybin

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/day
  • Kidney disease
    • CrCl ≥ 30 ml/min: no dose adjustment necessary
    • CrCl < 30 ml/min: use caution

Fluoxetine | Prozac® | Prozac weekly™ | 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
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
Kidney disease
  • No dose adjustment necessary
Liver disease
  • Exposure is increased. Use a lower or less frequent dose and monitor for adverse effects.

Dosing - Prozac weekly®

Depression (adults)
  • 90 mg once a week
  • May take without regard to food
Kidney disease
  • No dose adjustment necessary
Liver disease
  • Exposure is increased. Use a lower or less frequent dose and monitor for adverse effects.

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
Kidney disease
  • No dose adjustment necessary
Liver disease
  • Exposure is increased. Use a starting dose of 3/25 mg or 6/25 mg and titrate slowly.

Efficacy

Generic / Price

  • Prozac® (tablet and solution) - YES/$
  • Prozac weekly™ - YES/$$-$$$
  • 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
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 - exposure is increased. Use a lower or less frequent dose and monitor for adverse effects.
  • 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
  • May take without regard to food
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
  • May take without regard to food
Kidney disease
  • No dose adjustment necessary
Liver disease
  • Exposure is increased. Lower initial doses and slower titration may be appropriate.

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
  • May take without regard to food
Kidney disease
  • No dose adjustment necessary
Liver disease
  • Exposure is increased. Slower titration may be appropriate.

Efficacy

Generic / Price

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

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 - exposure is increased. Lower initial doses and slower titration may be appropriate.
  • Kidney disease - no dose adjustment necessary

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
  • 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
  • May take without regard to food
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
  • May take without regard to food
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
  • May take without regard to food
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
  • May take without regard to food
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
  • May take without regard to food
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
  • May take without regard to food
Kidney disease
  • CrCl < 30 ml/min: starting dose is 10 mg once daily. Do not exceed 40 mg/day.
Liver disease
  • Severe (Child-Pugh C): starting dose is 10 mg once daily. Do not exceed 40 mg/day.

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.
  • Do not crush or chew tablet
  • May take without regard to food
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
  • Do not crush or chew tablet
  • May take without regard to food
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
  • Do not crush or chew tablet
  • May take without regard to food
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)
  • Do not crush or chew tablet
  • May take without regard to food
Kidney disease
  • CrCl < 30 ml/min: starting dose is 12.5 mg once daily. Do not exceed 50 mg/day for MDD and panic disorder and 37.5 mg/day for SAD.
Liver disease
  • Severe (Child-Pugh C): starting dose is 12.5 mg once daily. Do not exceed 50 mg/day for MDD and panic disorder and 37.5 mg/day for SAD.

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
  • May take without regard to food
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
  • May take without regard to food
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
  • May take without regard to food
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
  • May take without regard to food
Kidney disease
  • CrCl < 30 ml/min: starting dose is 10 mg once daily. Do not exceed 40 mg/day.
Liver disease
  • Severe (Child-Pugh C): starting dose is 10 mg once daily. Do not exceed 40 mg/day.

Dosing - Brisdelle™

Vasomotor symptoms associated with menopause
  • 7.5 mg once daily at bedtime
  • May take without regard to food
Kidney disease
  • No dose adjustment necessary
Liver disease
  • No dose adjustment necessary

Generic / Price

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

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 - see Dosing above
  • Kidney disease - see Dosing above

Sertraline (Zoloft®)

Dosage forms

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

Dosing

Depression (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 (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 (adults)
  • 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 (adults)
  • 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
Kidney disease
  • No dose adjustment necessary
Liver disease
  • Child-Pugh A: use half the recommended dose
  • Child-Pugh B or C: DO NOT USE

Efficacy

Generic / Price

  • Tablet: YES/$
  • Capsule: 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.
Capsules
  • Swallow whole. Do not open, crush, or chew.

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 (adults)
  • Obsessive-Compulsive Disorder (adults and children ≥ 6 years)
  • Panic disorder (adults)
  • Posttraumatic Stress Disorder (adults)
  • Premenstrual Dysphoric Disorder (adults)
  • Social Anxiety Disorder (adults)

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
    • Child-Pugh A: use half the recommended dose
    • Child-Pugh B or C: DO NOT USE
  • 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 in adults (Pristiq® and Khedezla®)
  • Starting: 50 mg once daily
  • Maintenance: 50 - 400 mg once daily
  • Max: 400 mg once daily
  • 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/day
  • May take without regard to food
  • Pristiq and Khedezla are not considered therapeutically equivalent and cannot be substituted for each other
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
Liver disease
  • Moderate-to-severe disease (Child-Pugh B or C): recommended dose is 50 mg/day. Do not exceed 100 mg/day.

Generic / Price

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

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 in adults

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/day, doses of sensitive CYP2D6 substrates may need to be halved.
  • 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 / discontinuation syndrome - 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). There have been case reports of serious discontinuation symptoms with desvenlafaxine, including suicide, suicidal thoughts, and aggressive behavior. Other symptoms including visual changes and increased blood pressure have been reported. If severe symptoms occur, dosing may be resumed, or a more gradual taper should be considered.
  • 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-to-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™)
  • 30 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
Kidney disease
  • CrCl ≥ 30 ml/min: no dose adjustment necessary
  • CrCl < 30 ml/min: DO NOT USE
Liver disease
  • Exposure is increased. Do not use in patients with chronic liver disease or cirrhosis.
Administration
  • Cymbalta capsules should not be opened, crushed, or chewed
  • Drizalma Sprinkle may be opened and contents sprinkled over applesauce. Applesauce should be swallowed immediately.

Efficacy

Nonspecific low back pain Hip and knee pain

Generic / Price

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

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 - exposure is increased. Do not use in patients with chronic liver disease or cirrhosis.
  • 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 (adults)
  • 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
  • Do not open, chew, or crush capsule
  • May take without regard to food
Dosing with strong CYP3A4 inhibitors
  • Do not exceed 80 mg/day
  • See CYP3A4 for more
Dosing in kidney disease
  • CrCl ≥ 60 ml/min: no dose adjustment necessary
  • CrCl 30 - 59 ml/min: do not exceed 80 mg/day
  • CrCl 15 - 29 ml/min: do not exceed 40 mg/day
  • CrCl < 15 ml/min: not recommended
Liver disease
  • No dose adjustment necessary

Generic / Price

- NO/$$$$

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 in adults

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 (adults)
  • Starting: 75 mg/day
  • Maintenance: 75 - 225 mg/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
Kidney disease
  • CrCl 30 - 89 ml/min: reduce dose by 25%
  • Hemodialysis: reduce dose by 50%
Liver disease
  • Mild-moderate disease (Child-Pugh A or B): reduce dose by 50%
  • Severe (Child-Pugh C): reduce dose by 50% or more
Switching between Effexor and Effexor XR
  • When switching between Effexor® and Effexor XR®, keep the total daily dose the same or as close as possible

Dosing - Effexor XR®

Depression (adults)
  • 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 (adults)
  • 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 (adults)
  • Target: 75 mg once daily
  • There is no evidence that higher doses are beneficial
  • Take with food to help reduce nausea
Panic disorder (adults)
  • 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)
Diabetic neuropathy (off-label)
Kidney disease
  • CrCl 30 - 89 ml/min: reduce dose by 25% - 50%
  • CrCl < 30 ml/min: reduce dose by 50% or more
Liver disease
  • Mild-moderate disease (Child-Pugh A or B): reduce dose by 50%
  • Severe (Child-Pugh C): reduce dose by 50% or more
Switching between Effexor and Effexor XR
  • When switching between Effexor® and Effexor XR®, keep total daily dose the same if possible or use nearest equivalent dose
Administration
  • Capsules may be opened and sprinkled on applesauce. Do not chew contents.
  • Tablets should not be crushed, cut, or chewed

Efficacy

Generic / Price

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

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 in adults
  • Generalized anxiety disorder in adults
  • Social anxiety disorder in adults
  • Panic disorder in adults

Side effects



Side effect Effexor XR
(N=3558)		 Placebo
(N=2197)
Nausea 30.0% 11.8%
Insomnia 17.8% 9.5%
Dizziness 15.8% 9.5%
Somnolence 15.3% 7.5%
Dry mouth 14.8% 5.3%
Asthenia 12.6% 7.8%
Sweating (including night sweats) 11.4% 2.9%
Abnormal orgasm (men) 9.9% 0.5%
Anorexia 9.8% 2.6%
Constipation 9.3% 3.4%
Diarrhea 7.7% 7.2%
Nervousness 7.1% 5.0%
Impotence (men) 5.3% 1.0%
Libido decreased 5.1% 1.6%
Tremor 4.7% 1.6%
Vomiting 4.3% 2.7%
Abnormal vision 4.2% 1.6%
Yawn 3.7% 0.2%
Vasodilatation 3.7% 1.9%
Anorgasmia (men) 3.6% 0.1%
Hypertension 3.4% 2.6%
Abnormal dreams 2.9% 1.4%
Paresthesia 2.4% 1.4%
Palpitation 2.2% 2.0%
Anorgasmia (women) 2.0% 0.2%

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.
  • CYP2D6 inhibitors and substrates - venlafaxine is a CYP2D6 sensitive substrate, and CYP2D6 inhibitors may increase its exposure. Venlafaxine is a weak CYP2D6 inhibitor and may increase the exposure of concomitant CYP2D6 substrates. Consider reducing the dose of the substrate when combining.
  • CYP3A4 inhibitors - CYP3A4 plays a minor role in venlafaxine metabolism, and CYP3A4 inhibitors may increase venlafaxine exposure. Consider reducing the venlafaxine dose when combining.
  • 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.
  • Cimetidine (Tagamet®) - cimetidine may increase venlafaxine exposure. No dose adjustment is necessary for most people, but patients with hypertension, liver disease, and the elderly should use caution.
  • Haloperidol (Haldol®) - venlafaxine may increase haloperidol exposure by up to 70%
  • Desipramine - venlafaxine may increase desipramine exposure
  • Metoprolol - venlafaxine may increase metoprolol exposure by 30 - 40%
  • Risperidone (Risperdal®) - venlafaxine may increase risperidone exposure
  • Indinavir (Crixivan®) - venlafaxine may decrease indinavir exposure by 28%
  • Weight loss drugs - venlafaxine has not been studied with weight loss agents, including phentermine, and their combination is not recommended

Lab interactions

  • Urine drug screen - false-positive urine immunoassays for phencyclidine (PCP) and amphetamine have been reported in patients receiving venlafaxine. If a false-positive result is suspected, gas chromatography/mass spectrometry testing can be used to distinguish between venlafaxine and PCP or amphetamine.

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 - venlafaxine may raise blood pressure. In studies, average SBP and DBP increased by as much as 2.93 mmHg and 3.56 mmHg, respectively, in venlafaxine-treated patients. Blood pressure increases were dose-dependent, with higher doses causing greater increases. Monitor blood pressure before and during therapy, especially in patients with hypertension.
  • 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 / discontinuation syndrome - 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). There have been case reports of serious discontinuation symptoms with venlafaxine, including suicide, suicidal thoughts, and aggressive behavior. Other symptoms including visual changes and increased blood pressure have been reported. If severe symptoms occur, dosing may be resumed, or a more gradual taper should be considered.
  • 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.
  • Interstitial lung disease and eosinophilic pneumonia - cases of interstitial lung disease and eosinophilic pneumonia have been reported in venlafaxine-treated patients. If unexplained pulmonary symptoms develop (e.g. shortness of breath, cough, chest discomfort), consider these diagnoses and discontinue venlafaxine.
  • Pediatric patients - in pediatric studies, venlafaxine-treated patients had slower height velocity, more appetite suppression, and greater weight loss than placebo-treated patients. Venlafaxine is not approved for use in pediatric patients.
  • Liver disease - see Dosing above
  • Kidney disease - see Dosing above


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

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® (naltrexone + bupropion)

Dosing - Wellbutrin

Depression (adults)
  • 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
  • Do not crush, cut, or chew tablets
Kidney disease
  • CrCl < 90 ml/min: consider reducing the dose and/or frequency
Liver disease
  • Mild (Child-Pugh A): consider reducing the dose and/or frequency
  • Moderate-to-severe (Child-Pugh B or C): do not exceed 75 mg/day
Switching brands
  • When switching between Wellbutrin, Wellbutrin SR, and Wellbutrin XL, keep the total daily dose the same or as close as possible

Dosing - Wellbutrin SR

Depression (adults)
  • Starting: 150 mg once a day for 3 days
  • Maintenance: 150 mg twice a day
  • Max: 200 mg twice a day
  • Do not crush, cut, or chew tablets
  • May take without regard to food
Kidney disease
  • CrCl < 90 ml/min: consider reducing the dose and/or frequency
Liver disease
  • Mild (Child-Pugh A): consider reducing the dose and/or frequency
  • Moderate-severe (Child-Pugh B or C): max dose is 100 mg/day or 150 mg every other day
Switching brands
  • When switching between Wellbutrin, Wellbutrin SR, and Wellbutrin XL, keep the total daily dose the same or as close as possible

Dosing - Wellbutrin XL

Depression (adults)
  • Starting: 150 mg once daily
  • Maintenance: 300 mg once daily
  • Max: 450 mg once daily
  • Increase dose at intervals ≥ 4 days
  • Do not crush, cut, or chew tablets
  • May take without regard to food
Seasonal affective disorder (adults)
  • Starting: 150 mg once daily
  • Target: 300 mg once daily
  • Max: 300 mg once daily
  • Increase dose at intervals ≥ 7 days
  • Do not crush, cut, or chew tablets
  • May take without regard to food
Kidney disease
  • CrCl < 90 ml/min: consider reducing the dose and/or frequency
Liver disease
  • Mild (Child-Pugh A): consider reducing the dose and/or frequency
  • Moderate-to-severe (Child-Pugh B or C): maximum dose is 150 mg every other day
Switching brands
  • When switching between Wellbutrin, Wellbutrin SR, and Wellbutrin XL, keep the total daily dose the same or as close as possible

Dosing - Aplenzin

Depression (adults)
  • Starting: 174 mg once daily
  • Target: 348 mg once daily
  • Max: 522 mg once daily
  • Increase dose at intervals ≥ 4 days
  • Do not crush, cut, or chew tablets
  • May take without regard to food
  • Aplenzin-Wellbutrin equivalence:174 mg = 150 mg, 348 mg = 300 mg, 522 = 450 mg
Seasonal affective disorder (adults)
  • Starting: 174 mg once daily
  • Target: 348 mg once daily
  • Max: 348 mg once daily
  • Increase dose at intervals ≥ 7 days
  • Do not crush, cut, or chew tablets
  • May take without regard to food
  • Aplenzin-Wellbutrin equivalence:174 mg = 150 mg, 348 mg = 300 mg, 522 = 450 mg
Kidney disease
  • CrCl < 90 ml/min: consider reducing the dose and/or frequency
Liver disease
  • Mild (Child-Pugh A): consider reducing the dose and/or frequency
  • Moderate-to-severe (Child-Pugh B or C): maximum dose is 174 mg every other day

Dosing - Forfivo XL

Depression (adults)
  • Starting: use another form of bupropion to initiate therapy
  • Maintenance: 450 mg once daily
  • Max: 450 mg once daily
  • Forfivo can be used in patients who are receiving 300 mg/day of another bupropion formulation for at least 2 weeks, and require a dosage of 450 mg/day
  • Do not crush, cut, or chew tablets
  • May take without regard to food
Kidney disease
  • Forfivo is not recommended because there is only one dose
Liver disease
  • Forfivo is not recommended because there is only one dose

Dosing - Zyban

Smoking cessation
  • Starting: 150 mg once daily for 3 days
  • Maintenance: 150 mg twice a day
  • Max: 150 mg twice a day
  • Do not crush, cut, or chew tablets
  • May take without regard to food
Kidney disease
  • CrCl < 90 ml/min: consider reducing the dose and/or frequency
Liver disease
  • Mild (Child-Pugh A): consider reducing the dose and/or frequency
  • Moderate-to-severe (Child-Pugh B or C): maximum dose is 150 mg every other day

Efficacy

ADHD Methamphetamine abuse Resistant depression Smoking cessation

Generic / Price

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

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.

Lab interactions

  • Urine drug screen - false-positive urine immunoassays for amphetamine have been reported in patients receiving bupropion. If a false-positive result is suspected, gas chromatography/mass spectrometry testing can be used to distinguish between bupropion and amphetamine.

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 - see Dosing above
  • Kidney disease - see Dosing above


Amitriptyline (Elavil®)

Dosage forms

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

Dosing

Depression (adults)
  • Starting: 75 mg/day in divided doses or 50 - 100 mg at bedtime
  • Maintenance: 50 - 100 mg/day
  • Max: 150 mg/day
  • Elderly: lower doses are recommended. Start with 50 mg/day given in divided doses.
  • When dividing the daily dose, larger doses may be given at bedtime because of sedation
  • For maintenance therapy, the total daily dose may be given as a single dose at bedtime
  • May take up to 30 days for full therapeutic effect to develop
  • May take without regard to food
Depression (children ≥ 12 years old)
  • Starting: 50 mg/day in divided doses
  • Maintenance: 50 - 100 mg/day
  • Max: 150 mg/day
  • When dividing the daily dose, larger doses may be given at bedtime because of sedation
  • For maintenance therapy, the total daily dose may be given as a single dose at bedtime
  • May take up to 30 days for full therapeutic effect to develop
  • May take without regard to food
Migraine prevention (off-label)
Diabetic neuropathy (off-label)
Kidney disease
  • Manufacturer does not make a recommendation
Liver disease
  • Exposure is increased. Use caution.

Efficacy

Migraine prevention

Generic / Price

- YES/$

Mechanism of action

  • Tricyclic antidepressant
  • Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity. This interference with the reuptake of norepinephrine and/or serotonin is believed by some to underlie the antidepressant activity of amitriptyline.

FDA-approved indication

  • Depression in adults and children ≥ 12 years old

Side effects

NOTE: The incidence of amitriptyline side effects is not well-defined. Clomipramine, another TCA, has more detailed information, which can be reviewed here - clomipramine side effects.
  • Dry mouth (very common)
  • 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 - exposure is increased. Use caution.
  • Kidney disease - manufacturer does not make a recommendation

Clomipramine (Anafranil™)

Dosage forms

Capsule
  • 25 mg
  • 50 mg
  • 75 mg

Dosing

Obsessive-compulsive disorder (adults)
  • Start with 25 mg daily and gradually increase, as tolerated, to approximately 100 mg during the first 2 weeks. During initial titration, Anafranil should be given in divided doses with meals to reduce gastrointestinal side effects. Thereafter, the dosage may be increased gradually over the next several weeks, up to a maximum of 250 mg daily. After titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.
Obsessive-compulsive disorder (children ≥ 10 years old)
  • Start with 25 mg daily and gradually increase (also given in divided doses with meals to reduce gastrointestinal side effects) during the first 2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller. Thereafter, the dosage may be increased gradually over the next several weeks up to a daily maximum of 3 mg/kg or 200 mg, whichever is smaller. After titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.
Kidney disease
  • Has not been studied. Use caution.
Liver disease
  • Has not been studied. Use caution.

Generic / Price

- YES/$

Mechanism of action

  • Tricyclic antidepressant
  • Clomipramine is presumed to influence obsessive and compulsive behaviors through its effects on serotonergic neuronal transmission. The actual neurochemical mechanism is unknown, but clomipramine's capacity to inhibit the reuptake of serotonin (5-HT) is thought to be important.

FDA-approved indications

  • Obsessive-compulsive disorder (OCD) in adults and children ≥ 10 years old

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 - has not been studied. Use caution.
  • Kidney disease - has not been studied. Use caution.

Desipramine (Norpramin®)

Dosage forms

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

Dosing

Depression (adults)
  • 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
Depression (elderly and adolescents)
  • Starting: 25 mg/day
  • Maintenance: 25 - 100 mg/day
  • Max: 150 mg/day
  • May be given once daily or in divided doses
  • May take without regard to food
Kidney disease
  • Exposure is increased. Use caution.
Liver disease
  • Has not been studied. Use caution.

Generic / Price

- YES/$

Mechanism of action

  • Tricyclic antidepressant
  • While the precise mechanism of action of the tricyclic antidepressants is unknown, a leading theory suggests that they restore normal levels of neurotransmitters by blocking the re-uptake of these substances from the synapse in the central nervous system. Evidence indicates that the secondary amine tricyclic antidepressants, including desipramine, may have greater activity in blocking the re-uptake of norepinephrine. Tertiary amine tricyclic antidepressants, such as amitriptyline, may have greater effect on serotonin re-uptake.

FDA-approved indications

  • Depression

Side effects

NOTE: The incidence of desipramine side effects is not well-defined. Clomipramine, another TCA, has more detailed information, which can be reviewed here - clomipramine side effects.
  • Dry mouth (very common)
  • 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 - has not been studied. Use caution
  • Kidney disease - exposure is increased. Use caution.

Imipramine | Tofranil® | Tofranil-PM®

Dosage forms

Tablet (Tofranil®)
  • 10 mg
  • 25 mg
  • 50 mg
  • Tofranil is imipramine hydrochloride
Capsule (Tofranil-PM®)
  • 75 mg
  • 100 mg
  • 125 mg
  • 150 mg
  • Tofranil-PM is imipramine pamoate

Dosing - Tofranil

Depression (adults)
  • Starting: 75 mg/day
  • Maintenance: 50 - 150 mg/day
  • Max: 200 mg/day
  • May be given once daily or in divided doses
  • Antidepressant effect may not be seen for 1 - 3 weeks
  • May take without regard to food
Depression (adolescent and geriatric patients)
  • Starting: 30 - 40 mg/day
  • Max: 100 mg/day
  • May be given once daily or in divided doses
  • Antidepressant effect may not be seen for 1 - 3 weeks
  • May take without regard to food
Enuresis (≥ 6 years old)
  • Starting: 25 mg one hour before bedtime. May increase dose after 1 week.
  • 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/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
Kidney disease
  • Use caution
Liver disease
  • Use caution

Dosing - Tofranil-PM

Depression (adults)
  • Starting: 75 mg/day
  • Maintenance: 75 - 150 mg/day
  • Max: 200 mg/day
  • Doses higher than 75 mg/day may be given once daily or in divided doses. Doses may be given at bedtime.
  • Antidepressant effect may not be seen for 1 - 3 weeks
  • May take without regard to food
Depression (adolescent and geriatric patients)
  • Starting: 25 - 50 mg/day
  • Maintenance: 25 - 100 mg/day
  • Max: 100 mg/day
  • Total daily dose may be given once daily, preferably at bedtime
  • Tofranil tablets must be used for doses under 75 mg
  • Antidepressant effect may not be seen for 1 - 3 weeks
  • May take without regard to food
Kidney disease
  • Use caution
Liver disease
  • Use caution

Generic / Price

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

Mechanism of action

  • Tricyclic antidepressant
  • The mechanism of action of imipramine is not definitely known. However, it does not act primarily by stimulation of the central nervous system. The clinical effect is hypothesized as being due to potentiation of adrenergic synapses by blocking uptake of norepinephrine at nerve endings. The mode of action of the drug in controlling childhood enuresis is thought to be apart from its antidepressant effect.

FDA-approved indications

Tofranil®
  • Depression
  • Childhood enuresis (≥ 6 years old)
Tofranil PM®
  • Depression

Side effects

NOTE: The incidence of imipramine side effects is not well-defined. Clomipramine, another TCA, has more detailed information, which can be reviewed here - clomipramine side effects.
  • Dry mouth (very common)
  • 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. 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 (adults)
  • Dosing: 75 - 100 mg/day given in one dose or 3 - 4 divided doses. Start with lower doses and titrate as needed.
  • Max: 150 mg/day
  • May take without regard to food
Depression (adolescent and elderly)
  • Dosing: 30 - 50 mg/day given in one dose or divided doses
  • May take without regard to food
Herpes zoster neuralgia (off-label)
  • Starting: 25 mg at bedtime
  • Max: 150 mg/day
  • Increase dose by 25 mg/day every 2 - 3 days as tolerated
  • May take without regard to food
  • Dosing recommendation from the Infectious Disease Society of America
Kidney disease
  • Manufacturer makes no recommendation
Liver disease
  • Manufacturer makes no recommendation

Lab monitoring

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

Generic / Price

- YES/$

Mechanism of action

  • Tricyclic antidepressant
  • Inhibits norepinephrine and serotonin reuptake by neurons

FDA-approved indications

- Depression

Side effects

NOTE: The incidence of nortriptyline side effects is not well-defined. Clomipramine, another TCA, has more detailed information, which can be reviewed here - clomipramine side effects.
  • Dry mouth (very common)
  • 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 - manufacturer makes no recommendation
  • Kidney disease - manufacturer makes no recommendation


Trazodone (Desyrel®)

Dosage forms

Tablet
  • 50 mg
  • 100 mg
  • 150 mg
  • 300 mg

Dosing

Depression (adults)
  • Starting: 150 mg/day given in divided doses
  • Maintenance: 150 - 400 mg/day given in divided doses
  • Max: 400 mg/day
  • Increase dose by 50 mg/day every 3 - 4 days
  • Trazodone tablets are scored and can be broken in half
  • When taken after a meal or light snack, absorption is increased
Insomnia in adults (off-label)
  • Starting: 50 mg at bedtime
  • Maintenance: 50 - 150 mg at bedtime
  • Trazodone tablets are scored and can be broken in half
  • When taken after a meal or light snack, absorption is increased
Kidney disease
  • Has not been studied. Use caution.
Liver disease
  • Has not been studied. Use caution.

Generic / Price

  • Trazodone - YES/$

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 in adults

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.
  • Strong CYP3A4 inducers and inhibitors - trazodone is a CYP3A4 sensitive substrate. Consider reducing the dose when given with strong CYP3A4 inhibitors and increasing the dose when combined with strong CYP3A4 inducers.
  • 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.
  • 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 - has not been studied. Use caution.
  • Kidney disease - has not been studied. Use caution.

Vilazodone (Viibryd®)

Dosage forms

Tablet
  • 10 mg
  • 20 mg
  • 40 mg
Starter kit (40 mg dose)
  • 10 mg X 7
  • 20 mg X 7
  • 40 mg X 16
Starter kit (20 mg dose)
  • 10 mg X 7
  • 20 mg X 23

Dosing

Depression
  • Starting: 10 mg once daily for 7 days, then 20 mg once daily
  • Maintenance: 20 - 40 mg once daily
  • Max: 40 mg once daily
  • Increase dose as needed at a minimum interval of 7 days
  • Take with food. Food increases absorption.
When taken with CYP3A4 modulators
  • CYP3A4 strong inhibitors: dose should not exceed 20 mg once daily
  • CYP3A4 strong inducers: consider increasing the dosage by 2-fold, up to a maximum of 80 mg once daily, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days. If CYP3A4 inducers are discontinued, gradually reduce the dosage to its original level over 1 to 2 weeks.
  • See CYP3A4 for more
Discontinuation
  • Vilazodone should be tapered from the 40 mg once daily dose to 20 mg once daily for 4 days, followed by 10 mg once daily for 3 days. Patients taking 20 mg once daily should be tapered to 10 mg once daily for 7 days.
Kidney disease
  • No dose adjustment necessary
Liver disease
  • No dose adjustment necessary

Generic / Price

- YES/$$

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 in adults

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.
  • Strong CYP3A4 inducers and inhibitors - may affect levels of vilazodone. See Dosing above for 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 - no dose adjustment necessary
  • Kidney disease - no dose adjustment necessary


Mirtazapine | Remeron® | Remeron Soltab®

Dosage forms

Tablet (Remeron®)
  • 7.5 mg
  • 15 mg
  • 30 mg
  • 45 mg
Orally disintegrating tablet (Remeron Soltab®)
  • 15 mg
  • 30 mg
  • 45 mg

Dosing

Depression (adults)
  • Starting: 15 mg once daily at bedtime
  • Maintenance: 15 - 45 mg once daily at bedtime
  • Max: 45 mg once daily at bedtime
  • Increase dose at intervals of no less than 1 - 2 weeks
  • Soltabs are placed on the tongue where they dissolve and are swallowed. They should not be broken.
  • May take without regard to food
Kidney disease
  • CrCl < 60 ml/min: exposure is increased. Consider dose reductions. In studies, clearance was reduced by approximately 30% in patients with a GFR of 11 - 39 ml/min and 50% in patients with a GFR < 10 ml/min.
Liver disease
  • Child-Pugh B or C: exposure is increased. Consider dose reductions.

Efficacy

Agitated behavior in dementia

Generic / Price

- YES/$ (tablet and ODT)

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 in adults

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 were 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
  • Strong CYP3A4 inhibitors and inducers - mirtazapine is a CYP3A4 sensitive substrate. Consider reducing the dose when given with strong CYP3A4 inhibitors and increasing the dose when combined with strong CYP3A4 inducers.
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome
  • Cimetidine - cimetidine, a CYP1A2, CYP2D6, and CYP3A inhibitor, increases mirtazapine exposure by up to 50%. Consider reducing the mirtazapine dose when combining.
  • Benzodiazepines and alcohol - mirtazapine may potentiate the cognitive impairment and sedation caused by alcohol and benzodiazepines, and their combined use should be avoided
  • Drugs that prolong the QT interval - mirtazapine may potentiate the effects of QT-prolonging drugs. Use caution when combining.
  • Warfarin - mirtazapine may increase the effects of warfarin. Monitor INR values closely when combining.
  • Alpha blockers - mirtazapine may increase the risk of orthostatic hypotension when given with alpha blockers

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.
  • Weight gain - mirtazapine can stimulate appetite and cause weight gain in some patients. In studies, weight gain of ≥ 7% of baseline body weight occurred in 7.5% of mirtazapine-treated patients and 0% of placebo-treated patients.
  • Cholesterol increase - in studies, cholesterol increases ≥ 20% above the ULN occurred in 15% of mirtazapine-treated patients and 7% of placebo-treated patients, and triglyceride increases to ≥ 500 mg/dl were seen in 6% and 3%, respectively.
  • Hepatotoxicity - in studies, ALT elevations ≥ 3 X ULN occurred in 2% of mirtazapine-treated patients and 0.3% of placebo-treated patients. In some cases, ALT levels returned to normal despite continued mirtazapine use. Use caution in susceptible patients.
  • Somnolence - in studies, over half of patients treated with mirtazapine reported somnolence. Mirtazapine should be taken at bedtime, and patients should use caution before engaging in activities that require mental alertness (e.g. driving), especially during initiation.
  • Orthostatic hypotension - in early pharmacology trials, mirtazapine was associated with significant orthostatic hypotension in some patients. In trials involving depressed patients, orthostatic hypotension was infrequent. Use caution in susceptible patients (e.g. dehydration, heart disease, concomitant antihypertensives).
  • Low white blood cells - in premarketing trials, 3 out of 2796 mirtazapine-treated patients developed agranulocytosis. Onset occurred within 60 days, and white counts returned to normal after mirtazapine was stopped. If patients develop signs of an infection (e.g. fever, sore throat, stomatitis) and a low white count, mirtazapine should be stopped.
  • 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.
  • Prolonged QT syndrome - mirtazapine has been shown to prolong the QT interval; however, the effect does not appear to be clinically meaningful at recommended doses. Postmarketing cases of QT prolongation and Torsades de Pointes have been reported in patients receiving mirtazapine; most occurred with overdoses or when mirtazapine was given with other QT-prolonging drugs.
  • 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).
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) - postmarketing reports of DRESS have been reported in patients receiving mirtazapine. Symptoms of DRESS include cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Mirtazapine should be discontinued immediately if DRESS is suspected.
  • Phenylketonuria (SolTab) - Remeron SolTabs contain phenylalanine in the following amounts: 15 mg - 2.6 mg, 30 mg - 5.2 mg, 45 mg - 7.8 mg.
  • Liver disease
    • Child-Pugh B or C: exposure is increased. Consider dose reductions.
  • Kidney disease
    • CrCl < 60 ml/min: exposure is increased. Consider dose reductions. In studies, clearance was reduced by approximately 30% in patients with a GFR of 11 - 39 ml/min and 50% in patients with a GFR < 10 ml/min.

Vortioxetine (Trintellix®)

Dosage forms

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

Dosing

Depression
  • Starting: 10 mg once daily
  • Maintenance: 5 - 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
  • See CYP2D6 for more
CYP2D6 poor metabolizers
  • Maximum dose is 10 mg once daily
When taken with strong CYP inducers
  • Consider increasing the dose when taken with a strong CYP inducer (e.g. rifampin, carbamazepine, phenytoin) for more than 14 days.The maximum dose should not exceed three times the original dose. When stopping the inducer, taper vortioxetine back the original dose over 14 days.
Discontinuation
  • If taking 15 - 20 mg once daily, reduce dose to 10 mg for 1 week before discontinuing
Kidney disease
  • No dose adjustment necessary
Liver disease
  • No dose adjustment necessary

Generic / Price

- NO/$$$$

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 in adults

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

  • 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.
  • 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 its exposure. Reduced the vortioxetine dose by half when taken with a CYP2D6 strong inhibitor. After stopping the CYP2D6 inhibitor, increase vortioxetine back to the original dose.
  • CYP strong inducers - consider increasing the vortioxetine dose when taken with a strong CYP inducer (e.g. rifampin, carbamazepine, phenytoin) for more than 14 days. The maximum dose should not exceed three times the original dose. When stopping the inducer, taper vortioxetine back the original dose over 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.
  • Serotonergic drugs - combining drugs with serotonergic activity may increase risk the risk of serotonin syndrome

Lab interactions

  • Methadone assays - false-positive urine enzyme immunoassays for methadone have been reported in patients receiving vortioxetine. If a false-positive result is suspected, gas chromatography/mass spectrometry testing can be used to distinguish between vortioxetine and methadone.

Contraindications / Precautions

  • CYP2D6 poor metabolizers - vortioxetine exposure is increased in CYP2D6 poor metabolizers, and the maximum dose should not exceed 10 mg/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 - no dose adjustment necessary
  • 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
  • No therapy interruption
  • Does not require tapering
  • In the studies listed below, this method was well-tolerated
Disadvantages
  • The direct switch method increases the risk of a drug interaction between the first and second antidepressant. 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) pose the greatest risk (see antidepressant half-lives above).
  • Since it takes about 5 half-lives for the new drug to reach steady state, withdrawal symptoms from the first drug may occur, particularly if it has a short half-life.
Conservative switch
Method
  • Current antidepressant is tapered and stopped. Second antidepressant is started after the taper ends or after a washout period with no drug.
Advantages
  • 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 during the taper at a low dose. Second antidepressant is then titrated to full dose.
Advantages
  • Patient does not have a period without treatment
  • May limit withdrawal symptoms from the first antidepressant
Disadvantages
  • 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

Pharmacogenomic testing
Pharmacogenomic-guided Treatment vs Usual Care in Patients with MDD, JAMA (2022) [PubMed abstract]
  • Design: Randomized controlled trial (N=1944 | length = 24 weeks) in adults with MDD who were initiating or switching treatment with a single antidepressant
  • Treatment: Pharmacogenomic-guided treatment vs Usual Care. Providers in the pharmacogenomic group were given results of gene testing relevant to antidepressants (e.g. CYP and UGT alleles). Only investigators who were measuring depression outcomes were blinded.
  • Primary outcome: Co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire–9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5).
  • Results:
    • Primary outcome (remission at 24 weeks): Pharmacogenomic-guided - 17.2%, Usual care - 16% (p=0.45)
    • Primary outcome (drug-gene interaction): The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group.
  • Findings: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission.

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 randomized 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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