Version July 2025
Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. Vortioxetine is not approved for use in pediatric patients.
Major depressive disorder (unipolar) (alternative agent): Oral: Initial: 5 to 10 mg once daily; may increase daily dose based on response and tolerability in increments of 5 to 10 mg at ≥1-week intervals up to target dose of 20 mg once daily (usual maximum dose: 20 mg/day) (Ref).
Maximum dose in known CYP2D6 poor metabolizers: 10 mg/day.
Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for ≥4 weeks, it is recommended that patients receiving 15 or 20 mg/day be tapered to 10 mg/day for 1 week before full discontinuation (Ref). For brief treatment (eg, 2 to 3 weeks), may taper over 1 to 2 weeks; <2 weeks of treatment generally does not warrant tapering (Ref). Patients with a prior history of antidepressant withdrawal symptoms or on a high dose may require a slower taper (eg, over 4 weeks) (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).
Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks, depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches but is contraindicated when switching to or from a monoamine oxidase inhibitor (MAOI). A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between a selective serotonin reuptake inhibitor and vortioxetine), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, pharmacodynamics), and the degree of symptom control desired (Ref).
Switching to or from an MAOI:
Allow 14 days to elapse between discontinuing an MAOI and initiation of vortioxetine.
Allow 21 days to elapse between discontinuing vortioxetine and initiation of an MAOI. Due to prolonged washout in patients who are obese (BMI ≥35 kg/m2), consider allowing 32 days to elapse between discontinuing vortioxetine and initiating an MAOI (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: Oral: No dosage adjustment necessary for any degree of kidney impairment (Ref).
Hemodialysis, intermittent (thrice weekly): Oral: Unlikely to be significantly dialyzed (highly protein bound, large volume of distribution): No supplemental dose or dosage adjustment necessary (Ref).
Peritoneal dialysis: Oral: Unlikely to be significantly dialyzed (highly protein bound, large volume of distribution): No dosage adjustment necessary (Ref).
CRRT: Oral: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Oral: No dosage adjustment necessary (Ref).
No dosage adjustment necessary.
Refer to situation-specific dosing for obesity-related information (may not be available for all indications).
Major depressive disorder:
US labeling: Refer to adult dosing.
Canadian labeling: Oral: Initial: 5 mg once daily; may increase to 10 mg once daily as tolerated. Use caution with doses >10 mg daily (maximum: 20 mg/day).
Antidepressants (when used as monotherapy) may precipitate a mixed/manic episode in patients with bipolar disorder. A mixed/manic mood switch has been reported in a patient receiving vortioxetine who was also receiving maintenance medications for bipolar disorder (Ref). Treatment-emergent mania or hypomania has also been reported rarely in patients with unipolar major depressive disorder (MDD) receiving vortioxetine, as many cases of bipolar disorder present in episodes of MDD (Ref).
Mechanism: Non–dose-related; idiosyncratic. Unclear to what extent mood switches represent an uncovering of unrecognized bipolar disorder or a more direct pharmacologic effect independent of diagnosis (Ref).
Onset: Intermediate; among the limited case reports involving vortioxetine, the time until onset of mania/hypomania following initiation or a dose increase varied from 7 to 14 days (Ref).
Risk factors:
Antidepressants in general:
• Family history of bipolar disorder (Ref)
• Depressive episode with psychotic symptoms (Ref)
• Younger age at onset of depression (Ref)
• Antidepressant resistance (Ref)
• Female sex (Ref)
Serotonergic antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), may increase the risk of bleeding, particularly if used concomitantly with antiplatelets and/or anticoagulants. Vortioxetine, a multimodal antidepressant with serotonergic activity, may also increase the risk of bleeding, although data are limited. For SSRIs, multiple observational studies have found an association with SSRI use and a variety of bleeding complications, although prospective studies have not determined if the cause of the increased risk of bleeding is due to SSRI use alone (Ref).
Mechanism: SSRIs are believed to affect bleeding via inhibition of serotonin-mediated platelet activation (inhibition of the reuptake of serotonin into platelets leading to depletion of platelet serotonin thereby resulting in subsequent platelet dysfunction). Vortioxetine’s mechanism has not been fully elucidated but is believed to be multimodal with inhibition of serotonin (5-HT) reuptake and via direct modulation of various serotonin receptors as a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B partial agonist, and a 5HT1A agonist (Ref). Vortioxetine is hypothesized to have high serotonin transporter binding affinity (Ref).
Onset: Varied; based on data evaluating SSRIs, it has been suggested that the onset of risk is likely delayed for several weeks until SSRI-induced platelet serotonin depletion becomes clinically significant (Ref), although the onset of bleeding may be more unpredictable if patients are taking concomitant antiplatelets, anticoagulants, or nonsteroidal anti-inflammatory drugs (NSAIDs).
Risk factors:
• Concomitant use of antiplatelets and/or anticoagulants (based on SSRI-derived literature) (Ref)
• Concomitant use of NSAIDs (based on SSRI-derived literature) (Ref)
• Preexisting platelet dysfunction or coagulation disorders (eg, von Willebrand factor) (based primarily on SSRI-derived literature) (Ref)
Limited data from observational studies involving mostly older adults (≥50 years of age) suggest antidepressant use may be associated with an increased risk of bone fractures. The antidepressants evaluated in the literature predominantly involve the selective serotonin reuptake inhibitors (SSRIs) and the tricyclic antidepressants (TCAs), followed to a lesser extent by the serotonin norepinephrine reuptake inhibitors (SNRIs) (Ref). To date, data are too limited to determine whether an association with fractures and vortioxetine, a multimodal antidepressant with serotonergic activity, exists although a rare case of stress fracture has been observed with use (Ref).
Mechanism: Time-related; based on mostly SSRI-derived literature, the mechanism has not been fully elucidated, although postulated to be through a direct effect by serotonergic agents on bone metabolism via interaction with 5-HT and osteoblast, osteocyte, and/or osteoclast activity (Ref). SSRIs may also contribute to fall risk, contributing to the incidence of fractures (Ref). Of note, data are too limited to determine whether an association exists with vortioxetine and fractures.
Onset: Delayed; using data on mostly SSRI-derived literature, risk appears to increase after initiation and may continue to increase with long-term use. A meta-analysis found risk of fracture increased from 2.9% over 1 year to 5.4% over 2 years; within 5 years, risk increased to 13.4% (Ref). Of note, data are too limited to determine whether an association exists with vortioxetine and fractures.
Risk factors:
• Long-term use (potential risk factor) (SSRI-derived literature) (Ref). Of note, data are too limited to determine whether an association exists with vortioxetine and fractures.
Antidepressants (selective serotonin reuptake inhibitors [SSRIs] most commonly) are associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH) and/or hyponatremia (including severe cases), predominantly in older adults (Ref). Hyponatremia has been reported rarely with vortioxetine (Ref).
Mechanism: Antidepressants may cause SIADH via release of antidiuretic hormone (ADH) (Ref) or may cause nephrogenic SIADH by increasing the sensitivity of the kidney to ADH (Ref).
Onset: Intermediate; based on data involving SSRIs, hyponatremia usually develops within the first few weeks of treatment (Ref).
Risk factors:
Based on data involving SSRIs, risk factors include:
• Older age (Ref)
• Females (Ref)
• Concomitant use of diuretics (Ref)
• Low body weight (Ref)
• Lower baseline serum sodium concentration (Ref)
• Volume depletion (Ref)
• History of hyponatremia (potential risk factors) (Ref)
• Symptoms of psychosis (potential risk factors) (Ref)
Antidepressants (selective serotonin reuptake inhibitors [SSRIs] and serotonin norepinephrine reuptake inhibitors [SNRIs] most commonly implicated) are associated with acute angle-closure glaucoma (AACG) in case reports. AACG may cause symptoms including eye pain, changes in vision, swelling, and redness, which can rapidly lead to permanent blindness if not treated (Ref). Data are too limited to determine if vortioxetine, a multimodal antidepressant with serotonergic activity, is associated with an increased risk for AACG.
Mechanism: Unclear; hypothesized that serotonergic antidepressants like SSRIs may increase the intraocular pressure via serotonergic effects on ciliary body muscle activation and pupil dilation (Ref).
Risk factors:
Based on SSRI- and SNRI-derived literature:
• Females (Ref)
• ≥50 years of age (slight increase) (Ref)
• Hyperopia (slight increase) (Ref)
• Personal or family history of AACG (Ref)
• Inuit or Asian descent (Ref)
Serotonin syndrome has been reported with serotonergic agents, including rarely with vortioxetine, and typically occurs with coadministration of multiple serotonergic drugs. There is also a case report of serotonin syndrome occurring in a patient receiving vortioxetine at therapeutic doses and without any concomitant serotonergic agents (Ref). The diagnosis of serotonin syndrome is made based on the Hunter Serotonin Toxicity Criteria (Ref) and may result in a spectrum of symptoms, such as anxiety, agitation, confusion, delirium, hyperreflexia, muscle rigidity, myoclonus, tachycardia, tachypnea, and tremor. Severe cases may cause hyperthermia, significant autonomic instability (ie, rapid and severe changes in blood pressure and pulse), coma, and seizures (Ref).
Mechanism: Dose-related; overstimulation of serotonin receptors by serotonergic agents (Ref).
Onset: Rapid; in most serotonin-syndrome cases (74%) (predominantly involving selective serotonin reuptake inhibitors, tricyclic antidepressants, and/or monoamine oxidase inhibitors [MAOIs]), onset occurred within 24 hours of treatment initiation, overdose, or change in dose (Ref).
Risk factors:
• Concomitant use of drugs that increase serotonin synthesis, block serotonin reuptake, and/or impair serotonin metabolism (eg, MAOIs). Of note, concomitant use of some serotonergic agents, such as MAOIs, are contraindicated.
• Obesity (potential risk factor due to the prolongation of half-life observed in individuals with obesity compared to individuals without obesity) (Ref)
Antidepressants, primarily the selective serotonin reuptake inhibitors (SSRIs), are commonly associated with male sexual disorder and female sexual disorder. Vortioxetine, a multimodal antidepressant with serotonergic activity, is typically associated with either low rates of treatment-emergent sexual dysfunction or incidences comparable to placebo in the few clinical trials available. In addition, limited data suggest that vortioxetine may have some beneficial effects on sexual functioning in depressed patients who switched from an antidepressant with high rates of dysfunction to vortioxetine. However, treatment-emergent sexual dysfunction is typically underreported and clinical benefit on sexual functioning is difficult to ascertain in clinical trials (Ref).
Mechanism: The mechanism attributed to vortioxetine’s role (if any) in sexual dysfunction is unknown; however, using literature involving SSRIs, it has been postulated that increases in serotonin may affect other hormones and neurotransmitters involved in sexual function. Vortioxetine is a multimodal antidepressant with serotonergic activity through direct modulation of 5-HT receptors and inhibition of serotonin reuptake (Ref).
Risk factors:
• Depression (sexual dysfunction is commonly associated with depression; antidepressant-induced sexual dysfunction may be difficult to differentiate in treated patients) (Ref)
Antidepressants are associated with an increased risk of suicidal ideation and suicidal tendencies in pediatric and young adult patients (18 to 24 years) in short-term studies. In adults >24 years of age, short-term studies did not show an increased risk of suicidal thinking and behavior, and in older adults ≥65 years of age, a decreased risk was observed. Although data have yielded inconsistent results regarding the association of antidepressants and risk of suicide, particularly among adults, collective evidence shows a trend of an elevated risk of suicidality in younger age groups (Ref). Of note, the risk of a suicide attempt is inherent in major depression and may persist until remission occurs.
Mechanism: Not established; one of several postulated mechanisms is antidepressants may energize suicidal patients to act on impulses; another suggests that antidepressants may produce a worsening of depressive symptoms, leading to the emergence of suicidal thoughts and actions (Ref).
Onset: Varied; increased risk observed in short-term studies (ie, <4 months) in pediatric and young adults; it is unknown whether this risk extends to longer-term use (ie, >4 months).
Risk factors:
• Children and adolescents (Ref)
• Depression (risk of suicide is associated with major depression and may persist until remission occurs)
Withdrawal syndrome, consisting of both somatic symptoms (eg, dizziness, chills, light-headedness, vertigo, shock-like sensations, paresthesia, fatigue, headache, nausea, tremor, diarrhea, visual disturbances) and psychological symptoms (eg, anxiety, agitation, confusion, insomnia, irritability, mania), have been reported with serotonergic antidepressants, primarily following abrupt discontinuation. Withdrawal symptoms may also occur following gradual tapering. In general, antidepressant discontinuation symptoms usually last a few weeks, but occasionally may persist for months or possibly even years (ie, persistent postwithdrawal disorder) (Ref). Data from clinical trials and observational data with vortioxetine specifically suggest that discontinuation symptoms may occur, particularly with abrupt withdrawal, but the incidence is low and/or similar to placebo, possibly due to its relatively long half-life (~66 hours in adults) (Ref).
Mechanism: Withdrawal; due to reduced availability of serotonin in the CNS with decreasing levels of the serotonergic agent. Other neurotransmission systems, including increased glutamine and dopamine, may also be affected, as well as the hypothalamic-pituitary-adrenal axis (Ref).
Onset: Rapid; in literature derived from selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors discontinuation, symptom onset usually occurs within a few days after discontinuation (Ref). In a small number of patients (n=8) from the retrospective chart review of vortioxetine experiencing discontinuation symptoms (primarily those who discontinued therapy without medical consultation), onset was 3 days following therapy withdrawal and symptoms lasted for a median of 7 days (Ref).
Risk factors:
• Abrupt discontinuation (rather than dose taper) or tapering the antidepressant too quickly (Ref).
• Drugs with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)
• Higher doses (Ref)
• Longer duration of treatment (eg, ≥4 weeks) (Ref)
• Prior history of antidepressant withdrawal symptoms (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Gastrointestinal: Nausea (21% to 32%)
Genitourinary: Female sexual disorder (≤2%; Arizona Sexual Experiences Scale: 22% to 34%) (table 1), male sexual disorder (3% to 5%; Arizona Sexual Experiences Scale: 16% to 29%) (table 2)
|
Drug (Vortioxetine) |
Placebo |
Dose |
Number of Patients (Vortioxetine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
2% |
<1% |
20 mg/day |
455 |
1,621 |
N/A |
|
1% |
<1% |
10 mg/day |
699 |
1,621 |
N/A |
|
<1% |
<1% |
15 mg/day |
449 |
1,621 |
N/A |
|
<1% |
<1% |
5 mg/day |
1,013 |
1,621 |
N/A |
|
34% |
20% |
20 mg/day |
67 |
135 |
Arizona Sexual Experiences Scale |
|
33% |
20% |
15 mg/day |
57 |
135 |
Arizona Sexual Experiences Scale |
|
23% |
20% |
10 mg/day |
94 |
135 |
Arizona Sexual Experiences Scale |
|
22% |
20% |
5 mg/day |
65 |
135 |
Arizona Sexual Experiences Scale |
|
Drug (Vortioxetine) |
Placebo |
Dose |
Number of Patients (Vortioxetine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
5% |
2% |
20 mg/day |
455 |
1,621 |
N/A |
|
4% |
2% |
15 mg/day |
449 |
1,621 |
N/A |
|
4% |
2% |
10 mg/day |
699 |
1,621 |
N/A |
|
3% |
2% |
5 mg/day |
1,013 |
1,621 |
N/A |
|
29% |
14% |
20 mg/day |
59 |
162 |
Arizona Sexual Experiences Scale |
|
20% |
14% |
10 mg/day |
86 |
162 |
Arizona Sexual Experiences Scale |
|
19% |
14% |
15 mg/day |
67 |
162 |
Arizona Sexual Experiences Scale |
|
16% |
14% |
5 mg/day |
67 |
162 |
Arizona Sexual Experiences Scale |
1% to 10%:
Dermatologic: Pruritus (2% to 3%)
Gastrointestinal: Constipation (5% to 6%), diarrhea (7% to 10%), flatulence (2% to 3%), vomiting (3% to 6%), xerostomia (7% to 8%)
Nervous system: Abnormal dreams (2% to 3%), dizziness (8% to 9%)
<1%:
Endocrine & metabolic: Hyponatremia
Nervous system: Hypomania, mania
Frequency not defined:
Cardiovascular: Flushing
Gastrointestinal: Dysgeusia, dyspepsia
Nervous system: Suicidal ideation, suicidal tendencies, vertigo
Ophthalmic: Mydriasis
Postmarketing:
Dermatologic: Hyperhidrosis, skin rash, urticaria
Endocrine & metabolic: Amenorrhea (Ref), hyperprolactinemia, weight gain
Gastrointestinal: Acute pancreatitis
Hypersensitivity: Hypersensitivity reaction (including anaphylaxis)
Nervous system: Aggressive behavior, agitation, anosmia (including hyposmia), headache, hostility, irritability, outbursts of anger, restless leg syndrome (Ref), seizure, serotonin syndrome (Ref), withdrawal syndrome (Ref)
Neuromuscular & skeletal: Stress fracture (Ref)
Respiratory: Eosinophilic pneumonitis (Ref)
Hypersensitivity (eg, angioedema) to vortioxetine or any component of the formulation; use of monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders (concurrently or within 21 days of discontinuing vortioxetine or within 14 days of discontinuing the MAOI); initiation of vortioxetine in a patient receiving IV methylene blue.
Note: Although vortioxetine is contraindicated per the manufacturer labeling when used in combination with linezolid, new evidence suggests that the combination is unlikely to cause serotonin syndrome (0.06% to 3% risk), and therefore these agents can be administered concomitantly when necessary. Monitor patients on this combination; average duration of serotonin toxicity is ~4 days; however, risks may be greater with longer durations of concurrent therapy. Educate patients on the signs and symptoms of serotonin syndrome (Bai 2022; Butterfield 2012; Karkow 2017; Kufel 2023; Narita 2007; Taylor 2006a).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Major psychiatric warnings:
• Suicidal thinking/behavior: Consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years of age. Instruct the patient's family or caregiver to closely observe the patient and communicate condition with health care provider, particularly during the first few months of therapy or during periods of dose adjustments. A medication guide concerning the use of antidepressants should be dispensed with each prescription.
-The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
-Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression occurs.
Concerns related to adverse effects:
• Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, NSAIDs, warfarin or other anticoagulants. Risk of postpartum bleeding may be increased with SSRI use, particularly in the month prior to delivery. Bleeding related to antidepressant use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).
• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.
• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic antidepressants (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, TCAs, fentanyl, lithium, meperidine, methadone, tramadol, buspirone, amphetamines, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, monoamine oxidase inhibitors [MAOIs] intended to treat psychiatric disorders and other MAOIs, including IV methylene blue). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.
• SIADH and hyponatremia: Serotonergic drugs have been associated with the development of SIADH; hyponatremia has been reported (including severe cases with serum sodium <110 mmol/L). Age (the elderly), volume depletion and/or concurrent use of diuretics likely increases risk. Discontinue treatment in patients with symptomatic hyponatremia.
Disease-related concerns:
• Bariatric surgery: Presurgical assessment of the indication for use, symptoms, and goals of therapy should be documented to enable postsurgical assessment. A case report describes a loss of efficacy due to a significant decrease in vortioxetine concentrations after bariatric surgery (Vandenberghe 2021). Monitor for continued efficacy after bariatric surgery; if symptoms worsen consider switching to alternate medication.
• Mania/hypomania: Screen patients for history or family history of bipolar disorder, mania, or hypomania prior to initiating therapy; may precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer should also be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants (CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with depressive symptoms should be screened for bipolar disorder. Vortioxetine is not FDA approved for the treatment of bipolar depression.
• Seizure disorders: Use with caution in patients with seizure disorders, a prior history of seizure disorder, or conditions predisposing to seizures; seizures (rare) have been reported in patients without a prior history of seizures.
Other warnings/precautions:
• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Trintellix: 5 mg, 10 mg, 20 mg
No
Tablets (Trintellix Oral)
5 mg (per each): $20.57
10 mg (per each): $20.57
20 mg (per each): $20.57
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Trintellix: 5 mg, 10 mg, 20 mg
Administer without regard to meals.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Trintellix: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/204447s026lbl.pdf#page=33
Major depressive disorder: Treatment of major depressive disorder (MDD).
Vortioxetine may be confused with duloxetine, fluoxetine, paroxetine
Brintellix may be confused with Brilinta
Beers Criteria: Selective Serotonin Reuptake Inhibitors (SSRIs) are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2023]).
Substrate of CYP2A6 (Minor), CYP2B6 (Minor), CYP2C19 (Minor), CYP2C8 (Minor), CYP2C9 (Minor), CYP2D6 (Major), CYP3A4 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Abciximab: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Abrocitinib: Agents with Antiplatelet Effects may increase antiplatelet effects of Abrocitinib. Risk X: Avoid
Acalabrutinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Agents with Blood Glucose Lowering Effects: Selective Serotonin Reuptake Inhibitor may increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Ajmaline: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Alcohol (Ethyl): May increase adverse/toxic effects of Selective Serotonin Reuptake Inhibitor. Specifically, the risk of psychomotor impairment may be enhanced. Management: Patients receiving selective serotonin reuptake inhibitors should be advised to avoid alcohol. Monitor for increased psychomotor impairment in patients who consume alcohol during treatment with selective serotonin reuptake inhibitors. Risk D: Consider Therapy Modification
Almotriptan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Alosetron: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Amphetamines: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor
Anagrelide: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Anticoagulants (Miscellaneous Agents): Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Anticoagulants (Miscellaneous Agents). Risk C: Monitor
Antiemetics (5HT3 Antagonists): May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Antiplatelet Agents (P2Y12 Inhibitors): Agents with Antiplatelet Effects may increase antiplatelet effects of Antiplatelet Agents (P2Y12 Inhibitors). Risk C: Monitor
Antipsychotic Agents: Serotonergic Agents (High Risk) may increase adverse/toxic effects of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Artemether and Lumefantrine: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Aspirin: Selective Serotonin Reuptake Inhibitor may increase antiplatelet effects of Aspirin. Risk C: Monitor
Brexanolone: Selective Serotonin Reuptake Inhibitor may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Bromopride: May increase adverse/toxic effects of Selective Serotonin Reuptake Inhibitor. Risk X: Avoid
BuPROPion: May increase adverse/toxic effects of Vortioxetine. BuPROPion may increase serum concentration of Vortioxetine. Management: The vortioxetine dose should be reduced by 50% when used together with bupropion. Following cessation of bupropion, the vortioxetine dose should be returned to the normal level. Risk D: Consider Therapy Modification
BusPIRone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Caplacizumab: Agents with Antiplatelet Effects may increase adverse/toxic effects of Caplacizumab. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Citalopram: May increase serotonergic effects of Selective Serotonin Reuptake Inhibitor. This could result in serotonin syndrome. Citalopram may increase antiplatelet effects of Selective Serotonin Reuptake Inhibitor. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor
Collagenase (Systemic): Agents with Antiplatelet Effects may increase adverse/toxic effects of Collagenase (Systemic). Specifically, the risk of injection site bruising and or bleeding may be increased. Risk C: Monitor
Cyclobenzaprine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
CYP2D6 Inhibitors (Moderate): May increase serum concentration of Vortioxetine. Risk C: Monitor
CYP2D6 Inhibitors (Strong): May increase serum concentration of Vortioxetine. Management: The vortioxetine dose should be reduced by 50% when used together with a strong CYP2D6 inhibitor. Following cessation of the strong CYP2D6 inhibitor, the vortioxetine dose should be returned to the normal level. Risk D: Consider Therapy Modification
CYP3A4 Inducers (Moderate): May decrease serum concentration of Vortioxetine. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of Vortioxetine. Management: Consider increasing the vortioxetine dose to no more than 3 times the original dose when used with a strong drug metabolism inducer for more than 14 days. The vortioxetine dose should be returned to normal within 14 days of stopping the strong inducer. Risk D: Consider Therapy Modification
Cyproheptadine: May decrease therapeutic effects of Selective Serotonin Reuptake Inhibitor. Risk C: Monitor
Dapoxetine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid
Dasatinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Deoxycholic Acid: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Desmopressin: Hyponatremia-Associated Agents may increase hyponatremic effects of Desmopressin. Risk C: Monitor
Dexmethylphenidate-Methylphenidate: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Dextromethorphan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Direct Oral Anticoagulants (DOACs): Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Direct Oral Anticoagulants (DOACs). Risk C: Monitor
DULoxetine: Selective Serotonin Reuptake Inhibitor may increase serotonergic effects of DULoxetine. This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitor may increase antiplatelet effects of DULoxetine. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor
Eletriptan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Epinephrine (Racemic): Selective Serotonin Reuptake Inhibitor may increase adverse/toxic effects of Epinephrine (Racemic). Risk X: Avoid
Ergot Derivatives: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Fenfluramine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Fondaparinux: Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Fondaparinux. Risk C: Monitor
Gepirone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Gilteritinib: May decrease therapeutic effects of Selective Serotonin Reuptake Inhibitor. Management: Avoid use of this combination if possible. If the combination cannot be avoided, monitor closely for evidence of reduced response to the selective serotonin reuptake inhibitor. Risk D: Consider Therapy Modification
Glycoprotein IIb/IIIa Inhibitors: Agents with Antiplatelet Effects may increase antiplatelet effects of Glycoprotein IIb/IIIa Inhibitors. Risk C: Monitor
Heparin: Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Heparin. Risk C: Monitor
Heparins (Low Molecular Weight): Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Heparins (Low Molecular Weight). Risk C: Monitor
Herbal Products with Anticoagulant/Antiplatelet Effects: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Ibritumomab Tiuxetan: Agents with Antiplatelet Effects may increase antiplatelet effects of Ibritumomab Tiuxetan. Risk C: Monitor
Ibrutinib: Agents with Antiplatelet Effects may increase adverse/toxic effects of Ibrutinib. Specifically, the risk of bleeding and hemorrhage may be increased. Risk C: Monitor
Inotersen: Agents with Antiplatelet Effects may increase adverse/toxic effects of Inotersen. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Ioflupane I 123: Coadministration of Selective Serotonin Reuptake Inhibitor and Ioflupane I 123 may alter diagnostic results. Risk C: Monitor
Lasmiditan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Levomethadone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Limaprost: May increase adverse/toxic effects of Agents with Antiplatelet Effects. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Linezolid: May increase serotonergic effects of Selective Serotonin Reuptake Inhibitor. This could result in serotonin syndrome. Risk X: Avoid
Mavorixafor: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk X: Avoid
Metaxalone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Methadone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Methylene Blue: Selective Serotonin Reuptake Inhibitor may increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid
Metoclopramide: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Miscellaneous Antiplatelets: Agents with Antiplatelet Effects may increase antiplatelet effects of Miscellaneous Antiplatelets. Risk C: Monitor
Mivacurium: Selective Serotonin Reuptake Inhibitor may increase serum concentration of Mivacurium. Risk C: Monitor
Monoamine Oxidase Inhibitors (Antidepressant): Selective Serotonin Reuptake Inhibitor may increase serotonergic effects of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome. Risk X: Avoid
Nefazodone: May increase serotonergic effects of Selective Serotonin Reuptake Inhibitor. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Selective Serotonin Reuptake Inhibitor may increase antiplatelet effects of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may decrease therapeutic effects of Selective Serotonin Reuptake Inhibitor. Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents (Nonselective): Selective Serotonin Reuptake Inhibitor may increase antiplatelet effects of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Nonsteroidal Anti-Inflammatory Agents (Nonselective) may decrease therapeutic effects of Selective Serotonin Reuptake Inhibitor. Management: Consider alternatives to NSAIDs. Monitor for evidence of bleeding and diminished antidepressant effects. It is unclear whether COX-2-selective NSAIDs reduce risk. Risk D: Consider Therapy Modification
Nonsteroidal Anti-Inflammatory Agents (Topical): May increase antiplatelet effects of Selective Serotonin Reuptake Inhibitor. Risk C: Monitor
Obinutuzumab: Agents with Antiplatelet Effects may increase adverse/toxic effects of Obinutuzumab. Specifically, the risk of bleeding may be increased. Management: Consider avoiding coadministration of obinutuzumab and agents with antiplatelet effects, especially during the first cycle of obinutuzumab therapy. Risk D: Consider Therapy Modification
Ondansetron: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Opioid Agonists (metabolized by CYP3A4 and CYP2D6): May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Opioid Agonists (metabolized by CYP3A4): May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Opioid Agonists: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Opipramol: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Oxitriptan: Serotonergic Agents (High Risk) may increase serotonergic effects of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
OxyCODONE: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Peginterferon Alfa-2b: May decrease serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Pentosan Polysulfate Sodium: Agents with Antiplatelet Effects may increase adverse/toxic effects of Pentosan Polysulfate Sodium. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor
Pirtobrutinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Psilocybin: Antidepressants may decrease therapeutic effects of Psilocybin. Risk C: Monitor
Ramosetron: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Rasagiline: Selective Serotonin Reuptake Inhibitor may increase serotonergic effects of Rasagiline. This could result in serotonin syndrome. Risk X: Avoid
Safinamide: May increase serotonergic effects of Selective Serotonin Reuptake Inhibitor. This could result in serotonin syndrome. Risk X: Avoid
Selective Serotonin Reuptake Inhibitor: Vortioxetine may increase serotonergic effects of Selective Serotonin Reuptake Inhibitor. This could result in serotonin syndrome. Vortioxetine may increase antiplatelet effects of Selective Serotonin Reuptake Inhibitor. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor
Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): May increase serotonergic effects of Vortioxetine. This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase antiplatelet effects of Vortioxetine. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase serum concentration of Vortioxetine. Management: Consider alternatives to this drug combination. If combined, reduce the vortioxetine dose by half and monitor for signs and symptoms of bleeding and serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, autonomic instability). Risk D: Consider Therapy Modification
Selegiline: Selective Serotonin Reuptake Inhibitor may increase serotonergic effects of Selegiline. This could result in serotonin syndrome. Risk X: Avoid
Selumetinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Serotonergic Agents (High Risk, Miscellaneous): May increase serotonergic effects of Selective Serotonin Reuptake Inhibitor. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Serotonergic Non-Opioid CNS Depressants: Selective Serotonin Reuptake Inhibitor may increase serotonergic effects of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Serotonergic Opioids (High Risk): May increase serotonergic effects of Selective Serotonin Reuptake Inhibitor. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor
Serotonin 5-HT1D Receptor Agonists (Triptans): May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Serotonin/Norepinephrine Reuptake Inhibitor: Selective Serotonin Reuptake Inhibitor may increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitor may increase antiplatelet effects of Serotonin/Norepinephrine Reuptake Inhibitor. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor
St John's Wort: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Syrian Rue: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Thiazide and Thiazide-Like Diuretics: Selective Serotonin Reuptake Inhibitor may increase hyponatremic effects of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor
Thrombolytic Agents: Agents with Antiplatelet Effects may increase adverse/toxic effects of Thrombolytic Agents. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Thyroid Products: Selective Serotonin Reuptake Inhibitor may decrease therapeutic effects of Thyroid Products. Thyroid product dose requirements may be increased. Risk C: Monitor
Tilidine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
TraMADol: May increase adverse/toxic effects of Selective Serotonin Reuptake Inhibitor. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and seizures when these agents are combined. Risk C: Monitor
Tricyclic Antidepressants: May increase serotonergic effects of Vortioxetine. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor
Vasopressin: Drugs Suspected of Causing SIADH may increase therapeutic effects of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor
Venlafaxine: Selective Serotonin Reuptake Inhibitor may increase antiplatelet effects of Venlafaxine. Selective Serotonin Reuptake Inhibitor may increase serotonergic effects of Venlafaxine. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor
Vitamin E (Systemic): May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Vitamin K Antagonists: Antidepressants with Antiplatelet Effects may increase anticoagulant effects of Vitamin K Antagonists. Risk C: Monitor
Volanesorsen: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Zanubrutinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Ziprasidone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Evaluate pregnancy status prior to initiating treatment in patients who could become pregnant. Treatment should not be withheld, but pharmacologic management may vary based on reproductive status, severity of illness, and history of antidepressant response (ACOG 2023; WFSBP [Dodd 2018]). When treating depression, vortioxetine is not a first-line medication for use prior to conception in patients who are treatment naive or who do not have a history of effective treatment. Patients effectively treated may continue their current medication when planning a pregnancy unless contraindications exist (BAP [McAllister-Williams 2017]). Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]).
Amenorrhea without hyperprolactinemia has been reported following use of vortioxetine (Işik 2022). Serotonergic antidepressants are associated with an increased risk of sexual dysfunction. Depression is also associated with menstrual changes and sexual dysfunction (Padda 2021).
Data specific to vortioxetine use in pregnancy are limited (Shweiki 2021).
Vortioxetine has a multimodal mechanism of action. It shares some properties of selective serotonin reuptake inhibitors (SSRIs); additionally, it modulates other serotoninergic activity. Adverse effects in the newborn following SSRI exposure in the third trimester include neonatal adaptation syndrome and persistent pulmonary hypertension of the newborn. Neonatal adaptation syndrome can occur shortly after birth and typically resolves within 2 weeks. Mechanisms of neonatal adaptation syndrome are not well understood but may be due to either SSRI toxicity or withdrawal. Reducing the dose or discontinuing the SSRI prior to delivery to reduce the risk of neonatal adaptation syndrome is not recommended (ACOG 2023). Symptoms can include apnea, constant crying, cyanosis, feeding difficulty, hyperreflexia, hypo- or hypertonia, hypoglycemia, irritability, jitteriness, respiratory distress, seizures, temperature instability, tremor, and vomiting. Prolonged hospitalization, respiratory support, or tube feedings may be required.
Persistent pulmonary hypertension of the newborn is a rare complication of SSRI use during pregnancy with symptoms of respiratory distress within the first hours of life and an increased risk of neonatal mortality (ACOG 2023). Monitoring of infants exposed to SSRIs late in pregnancy is recommended (Masarwa 2019; Ng 2019). Data related to the long-term effects of in utero SSRI exposure on infant neurodevelopment and behavior are limited (CANMAT [MacQueen 2016]; Lebin 2022).
SSRIs may increase the risk of bleeding. Exposure late in pregnancy is associated with less than a 2-fold increase in postpartum hemorrhage. The clinical significance of this is uncertain (BAP [McAllister-Williams 2017]; Lebin 2022).
Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes. Untreated or undertreated depression is associated with preterm birth, low birth weight, preeclampsia, postpartum depression, and impaired infant attachment (associated with long-term developmental effects). Discontinuing effective medications during pregnancy increases the risk of symptom relapse. Management should be made as part of a shared decision-making process (ACOG 2023).
Patients effectively treated for depression prepregnancy may use the same medication during pregnancy unless contraindications exist (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]). Treatment should not be withheld or discontinued based only on pregnancy status. Vortioxetine is not a first-line medication for pregnant patients who are treatment naive or who do not have a history of effective treatment with another medication (ACOG 2023).
When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Monthly monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023).
Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Pregnant patients ≤45 years of age with a history of psychiatric illness are encouraged to enroll in the National Pregnancy Registry for Antidepressants (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants).
Vortioxetine is present in breast milk.
Reports which summarize data related to the presence of vortioxetine in breast milk are available:
• A case series reports data from 3 lactating women 1 to 6 months post partum. Breast milk was sampled prior to and at intervals for 24 hours after the dose. All patients were at steady state and exclusively breastfeeding their infants:
- Following a dose of vortioxetine 10 mg/day (n = 2), the maximum breast milk concentration was 13.89 ng/mL and occurred 7 hours after the dose. Based on this information, authors of the study calculated the relative infant dose (RID) of vortioxetine to be 1.1%, providing an estimated daily infant dose via breast milk of 0.0017 mg/kg/day, based on the weight-adjusted maternal dose.
- Following a dose of vortioxetine 20 mg/day (n = 1), the maximum breast milk concentration was 52.32 ng/mL and occurred 5 hours after the dose. Based on this information, the authors of the study calculated the RID of vortioxetine to be 1.7%, providing an estimated daily infant dose via breast milk of 0.0052 mg/kg/day (Marshall 2021).
• Data is also available from a study evaluating a method for determining the presence of vortioxetine and other medications in breast milk. Breast milk was sampled over 24 hours following the last dose of vortioxetine to one patient. Using a mean milk concentration of 6 ng/mL, authors of the study calculated the estimated daily infant dose of vortioxetine via breast milk to be 0.9 mcg/kg/day, providing a RID of 1.2% compared to a weight-adjusted maternal dose of 76.1 mcg/kg/day. The highest breast milk concentration reported was 8.2 ng/mL. Vortioxetine is highly protein bound, which contributes to low passage into breast milk (Monfort 2021).
• In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000); however, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Anderson 2021).
Vortioxetine has a multimodal mechanism of action. Vortioxetine shares some properties of selective serotonin reuptake inhibitors (SSRIs); additionally, it modulates other serotoninergic activity. Infants exposed to an SSRI via breast milk should be monitored for irritability and changes in sleep, feeding patterns, and behavior, as well as growth and development (ABM [Sriraman 2015]; BAP [McAllister-Williams 2017]; Weissman 2004).
Maternal use of serotonin reuptake inhibitors during pregnancy may cause delayed lactogenesis (Marshall 2010); however, the underlying maternal illness and various other factors may also influence this outcome. Patients who wish to breastfeed during treatment with a serotonin reuptake inhibitor may need additional assistance to initiate and maintain breastfeeding (Anderson 2021).
According to the manufacturer, the decision to breastfeed during vortioxetine therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Patients effectively treated for depression during pregnancy may continue their medication postpartum unless contraindications to breastfeeding exist. The presence and concentration of the drug in breast milk, efficacy of maternal treatment, and infant age should be considered when initiating a medication for the first time postpartum. When first initiating an antidepressant in a patient who is treatment naïve and breastfeeding, an agent other than vortioxetine may be preferred (ABM [Sriraman 2015]; BAP [McAllister-Williams 2017]). Treatment should not be withheld or discontinued based only on breastfeeding status (ACOG 2023).
Mental status for depression, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks; akathisia; signs/symptoms of hyponatremia.
Inhibits reuptake of serotonin (5-HT); also has agonist activity at the 5-HT1A receptor and antagonist activity at the 5-HT3 receptor. Additionally, vortioxetine is a weak antagonist at 5-HT7 and 5-HT1D receptors, as well as a partial agonist at 5-HT1B receptors (Bang-Andersen 2011; Kelliny 2015).
Onset of action: Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009; Taylor 2006b).
Distribution: Vd: 2,600 L.
Protein binding: 98%.
Metabolism: Hepatic primarily through oxidation via CYP450 isoenzymes, primarily CYP2D6, and subsequent glucuronic acid conjugation to an inactive carboxylic acid metabolite.
Bioavailability: 75%.
Half-life elimination: ~66 hours.
Time to peak: 7 to 11 hours.
Excretion: Urine (59%); feces (26%).
Obesity: In a study comparing the pharmacokinetic profile of vortioxetine in obese patients (BMI ≥35 kg/m2 vs those with a BMI between 18.5 and 25 kg/m2), the mean elimination half-life was prolonged by 48% in obese patients (3.26 ± 1.22 days vs 2.21 ± 0.54 days) (Greenblat 2018).
