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Vortioxetine: Drug information

Vortioxetine: Drug information
(For additional information see "Vortioxetine: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Suicidal thoughts and behaviors:

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.

Brand Names: US
  • Trintellix
Brand Names: Canada
  • Trintellix
Pharmacologic Category
  • Antidepressant, Selective Serotonin Reuptake Inhibitor;
  • Serotonin 5-HT1A Receptor Agonist;
  • Serotonin 5-HT3 Receptor Antagonist
Dosing: Adult
Major depressive disorder

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) (Alvarez 2012; Citrome 2014; manufacturer's labeling).

Maximum dose in known CYP2D6 poor metabolizers: 10 mg/day.

Discontinuation of therapy: The half-life of vortioxetine is significantly greater than 24 hours, decreasing the risk of withdrawal symptoms. Although few withdrawal symptoms due to abrupt discontinuation of vortioxetine have been described, it is recommended that patients receiving 15 or 20 mg/day be tapered to 10 mg/day for 1 week before full discontinuation (Hirsch 2021a; manufacturer's labeling). Patients with a prior history of antidepressant withdrawal symptoms or on a high dose may require a slower taper (eg, over 4 weeks) (Hirsch 2021a). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Shelton 2001). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (WFSBP [Bauer 2015]). Evidence supporting ideal taper rates is limited (Shelton 2001; WFSBP [Bauer 2015]).

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 (Hirsch 2021b; Ogle 2013; WFSBP [Bauer 2013]).

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 (Greenblat 2018).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

No dosage adjustment necessary.

Dosing: Hepatic Impairment: Adult

No dosage adjustment necessary.

Dosing: Older Adult

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).

Dosing: Obesity: Adult

Refer to situation-specific dosing for obesity-related information (may not be available for all indications).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Trintellix: 5 mg, 10 mg, 20 mg

Generic Equivalent Available: US

No

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Trintellix: 5 mg, 10 mg, 20 mg

Medication Guide and/or Vaccine Information Statement (VIS)

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/2021/204447s024lbl.pdf#page=33

Administration: Adult

Administer without regard to meals.

Use: Labeled Indications

Major depressive disorder: Treatment of major depressive disorder (MDD).

Medication Safety Issues
Sound-alike/look-alike issues:

Vortioxetine may be confused with duloxetine, fluoxetine, paroxetine

Brintellix may be confused with Brilinta

Older Adult: High-Risk Medication:

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 because of their association with falls and fractures and should be avoided in patients 65 years and older with a history of falls or fractures. In addition, the SSRIs should be avoided 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 2019]).

Adverse Reactions (Significant): Considerations
Activation of mania or hypomania

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)

Bleeding risk

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)

Fragility fractures

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.

Hyponatremia

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)

Ocular effects

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

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)

Sexual dysfunction

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)

Suicidal thinking/behavior

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

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 (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 gradual dosage reduction) of an antidepressant treatment that has lasted for >3 weeks, particularly a drug with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref). Of note, vortioxetine has a long half-life (~66 hours in adults) (Ref)

• Prior history of antidepressant withdrawal symptoms (Ref)

• High dose (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Gastrointestinal: Nausea (21% to 32%)

Nervous system: 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)

Vortioxetine: Adverse Reaction: Female Sexual Disorder

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

Vortioxetine: Adverse Reaction: Male Sexual Disorder

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: Hyperprolactinemia, stress fracture (Ref), weight gain

Gastrointestinal: Acute pancreatitis

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Nervous system: Aggressive behavior, agitation, headache, hostility, irritability, outbursts of anger, seizure, serotonin syndrome (Ref), withdrawal syndrome (Ref)

Contraindications

Hypersensitivity (eg, angioedema) to vortioxetine or any component of the formulation; use of MAO inhibitors intended to treat psychiatric disorders (concurrently or within 21 days of discontinuing vortioxetine or within 14 days of discontinuing the MAO inhibitor); initiation of vortioxetine in a patient receiving linezolid or intravenous methylene blue.

Warnings/Precautions

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. 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, tramadol, buspirone, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous 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:

• 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 may be effective for acute treatment of bipolar major depressive episodes, but should 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).

Metabolism/Transport Effects

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

Drug Interactions

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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Abrocitinib: Agents with Antiplatelet Properties may enhance the antiplatelet effect of Abrocitinib. Management: Do not use antiplatelet drugs with abrocitinib during the first 3 months of abrocitinib therapy. The abrocitinib prescribing information lists this combination as contraindicated. This does not apply to low dose aspirin (81 mg/day or less). Risk X: Avoid combination

Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Risk C: Monitor therapy

Agents with Blood Glucose Lowering Effects: Selective Serotonin Reuptake Inhibitors may enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. 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 enhance the serotonergic effect 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 therapy

Alosetron: May enhance the serotonergic effect 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 therapy

Amphetamines: May enhance the serotonergic effect 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 therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect 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 therapy

Antipsychotic Agents: Serotonergic Agents (High Risk) may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Risk C: Monitor therapy

Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Aspirin: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Bemiparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Brexanolone: Selective Serotonin Reuptake Inhibitors may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Risk X: Avoid combination

BuPROPion: May enhance the adverse/toxic effect of Vortioxetine. BuPROPion may increase the 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 enhance the serotonergic effect 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 therapy

Caplacizumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Caplacizumab. Specifically, the risk of bleeding may be increased. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Citalopram: May enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors. Citalopram may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. 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 therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and or bleeding may be increased. Risk C: Monitor therapy

Cyclobenzaprine: May enhance the serotonergic effect 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 therapy

CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Vortioxetine. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the 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 the serum concentration of Vortioxetine. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the 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 diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Risk C: Monitor therapy

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk C: Monitor therapy

Dapoxetine: May enhance the serotonergic effect 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 combination

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect 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 therapy

Dextromethorphan: May enhance the serotonergic effect 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 therapy

DULoxetine: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of DULoxetine. Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of DULoxetine. 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 therapy

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Risk C: Monitor therapy

Eletriptan: May enhance the serotonergic effect 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 therapy

Enoxaparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Ergot Derivatives: May enhance the serotonergic effect 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 therapy

Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Gilteritinib: May diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. 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

Heparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Risk D: Consider therapy modification

Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Risk C: Monitor therapy

Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Icosapent Ethyl: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Ioflupane I 123: Selective Serotonin Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Risk C: Monitor therapy

Lasmiditan: May enhance the serotonergic effect 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 therapy

Levomethadone: May enhance the serotonergic effect 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 therapy

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Linezolid: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination

Lipid Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect 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 therapy

Metaxalone: May enhance the serotonergic effect 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 therapy

Methadone: May enhance the serotonergic effect 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 therapy

Methylene Blue: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination

Metoclopramide: May enhance the serotonergic effect 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 therapy

MetyroSINE: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Risk C: Monitor therapy

Mivacurium: Selective Serotonin Reuptake Inhibitors may increase the serum concentration of Mivacurium. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors (Antidepressant): Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome. Risk X: Avoid combination

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Nefazodone: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. 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 therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (Nonselective): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. 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 enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors. Risk C: Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Ondansetron: May enhance the serotonergic effect 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 therapy

Opioid Agonists: May enhance the serotonergic effect 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 therapy

Opioid Agonists (metabolized by CYP3A4 and CYP2D6): May enhance the serotonergic effect 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 therapy

Opioid Agonists (metabolized by CYP3A4): May enhance the serotonergic effect 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 therapy

Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect 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 therapy

Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Ramosetron: May enhance the serotonergic effect 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 therapy

Rasagiline: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Rasagiline. This could result in serotonin syndrome. Risk X: Avoid combination

Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk C: Monitor therapy

Safinamide: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Use the lowest effective dose of SSRIs in patients treated with safinamide and monitor for signs and symptoms of serotonin syndrome/serotonin toxicity. Risk D: Consider therapy modification

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: Vortioxetine may enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors. Vortioxetine may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. 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 therapy

Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): May enhance the antiplatelet effect of Vortioxetine. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may enhance the serotonergic effect of Vortioxetine. This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the 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 Inhibitors may enhance the serotonergic effect of Selegiline. This could result in serotonin syndrome. Risk X: Avoid combination

Selumetinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Serotonergic Agents (High Risk, Miscellaneous): May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. 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 therapy

Serotonergic Non-Opioid CNS Depressants: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect 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 therapy

Serotonergic Opioids (High Risk): May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. 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 therapy

Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect 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 therapy

Serotonin/Norepinephrine Reuptake Inhibitors: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Serotonin/Norepinephrine Reuptake Inhibitors. Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. 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 therapy

St John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the 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 therapy

Syrian Rue: May enhance the serotonergic effect 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 therapy

Thiazide and Thiazide-Like Diuretics: Selective Serotonin Reuptake Inhibitors may enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy

Thyroid Products: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Thyroid Products. Thyroid product dose requirements may be increased. Risk C: Monitor therapy

TraMADol: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. 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 therapy

Tricyclic Antidepressants: May enhance the serotonergic effect 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 therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Risk X: Avoid combination

Vasopressin: Drugs Suspected of Causing SIADH may enhance the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor therapy

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Selective Serotonin Reuptake Inhibitors may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Zanubrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Reproductive Considerations

Vortioxetine is approved for the treatment of unipolar major depressive disorder. If treatment for major depressive disorder is initiated for the first time in patients planning to become pregnant, vortioxetine is not a preferred antidepressant (Larsen 2015).

Vortioxetine may be associated with male and female treatment-emergent sexual dysfunction. Sexual dysfunction has been reported in males and females following vortioxetine use.

Pregnancy Considerations

Information specific to vortioxetine use in pregnancy is limited (Shweiki 2021).

Vortioxetine shares some properties of selective serotonin reuptake inhibitors (SSRIs); additionally, it modulates other serotoninergic activity. As a class, SSRIs have been evaluated extensively in pregnant patients. Studies focusing on newborn outcomes following first trimester exposure often have inconsistent results due to differences in study design and confounders such as maternal disease and social factors (Anderson 2020; Biffi 2020; Fitton 2020; Reefhuis 2015; Womersley 2017).

Adverse effects in the newborn following SSRI exposure late in the third trimester 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. Symptoms may be due to the toxicity of the SSRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with SSRI treatment. Persistent pulmonary hypertension of the newborn has been reported with SSRI exposure; although the absolute risk is small, monitoring of infants exposed to SSRIs late in pregnancy is recommended (Masarwa 2019; Ng 2019). The long-term effects of in utero SSRI exposure on infant neurodevelopment and behavior are not known (CANMAT [MacQueen 2016]).

If treatment for major depressive disorder is initiated for the first time during pregnancy, vortioxetine is not one of the preferred antidepressants (CANMAT [MacQueen 2016]; Larsen 2015; WFSBP [Bauer 2013]). Untreated or inadequately treated psychiatric illness may lead to poor adherence with prenatal care and adverse pregnancy outcomes. Therapy with antidepressants during pregnancy should be individualized; treatment with antidepressant medication is recommended for pregnant patients with severe major depressive disorder (ACOG 2008; CANMAT [MacQueen 2016]). Patients treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued (68%) as compared to pregnant patients who continue taking antidepressant medications (26%) (Cohen 2006).

Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Patients exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants. Pregnant patients 18 to 45 years of age or their health care providers may contact the registry to enroll; enrollment should be done as early in pregnancy as possible (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/).

Breastfeeding Considerations

Vortioxetine is present in breast milk.

Information related to the presence of vortioxetine in breast milk is available from 3 lactating women 1 to 6 months postpartum. 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).

- In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).

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]; Sachs 2013; Weissman 2004; WFSBP [Bauer 2013]).

Maternal use of an SSRI during pregnancy may cause delayed lactogenesis (Marshall 2010); however, the underlying maternal illness may also influence this outcome (Grzeskowiak 2018). Untreated severe or chronic depression in the postpartum period also has negative effects on the mother and the infant (Slomian 2019).

Psychotherapy or other nonmedication therapies are recommended for the initial treatment of mild depression in breastfeeding patients; however, antidepressant medication is recommended when psychotherapy is not an option or when symptoms are moderate to severe. If a specific SSRI was used effectively during pregnancy, it can be continued while breastfeeding if no contraindications exist (ABM [Sriraman 2015]). 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. When first initiating an antidepressant in a patient who is breastfeeding, agents other than vortioxetine are preferred (ABM [Sriraman 2015]; CANMAT [MacQueen 2016]; Larsen 2015).

Monitoring Parameters

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 serotonin syndrome and/or hyponatremia.

Mechanism of Action

Inhibits reuptake of serotonin (5-HT); also has agonist activity at the 5-HT1A receptor and antagonist activity at the 5-HT3 receptor.

Pharmacokinetics

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 2006).

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%).

Pharmacokinetics: Additional Considerations

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).

Pricing: US

Tablets (Trintellix Oral)

5 mg (per each): $17.77

10 mg (per each): $17.77

20 mg (per each): $17.77

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Brintellix (AR, AT, AU, BB, BE, BR, CH, CR, CZ, DK, DO, EE, EG, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, IE, IL, IS, KR, KW, LB, LT, LV, MX, MY, NI, NL, NO, PA, PH, PL, PT, RO, SE, SG, SI, SK, SV, TR, TW);
  • Vortiocyrl (EG)


For country code abbreviations (show table)
  1. 2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi: 10.1111/jgs.15767. [PubMed 30693946]
  2. Alvarez E, Perez V, Dragheim M, Loft H, Artigas F. A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder. Int J Neuropsychopharmacol. 2012;15(5):589‐600. doi:10.1017/S1461145711001027 [PubMed 21767441]
  3. American College of Obstetricians and Gynecologists (ACOG). ACOG Committee on Practice Bulletins - Obstetrics. ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists Number 92, April 2008 (Replaces Practice Bulletin Number 87, November 2007). Use of Psychiatric Medications During Pregnancy and Lactation. Obstet Gynecol. 2008;111(4):1001-1020. [PubMed 18378767]
  4. American Psychiatric Association (APA). Treatment recommendations for patients with major depressive disorder. 3rd ed. May 2010. Available at http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf
  5. Anderson KN, Lind JN, Simeone RM, et al. Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects. JAMA Psychiatry. 2020;77(12):1246-1255. doi:10.1001/jamapsychiatry.2020.2453 [PubMed 32777011]
  6. Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52. doi:10.1002/cpt.377 [PubMed 27060684]
  7. Andrade C, Sandarsh S, Chethan KB, Nagesh KS. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry. 2010;71(12):1565-1575. doi:10.4088/JCP.09r05786blu [PubMed 21190637]
  8. Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109(6):811-819. doi:10.1038/ajg.2014.82 [PubMed 24777151]
  9. Aydın EP, Dalkıran M, Özer OA, Karamustafalıoğlu KO. Hypomanic switch during vortioxetine treatment: a case report. Psychiatry and Clinical Psychopharmacology. 2019;29(1):114-116. doi:10.1080/24750573.2018.1435602
  10. Baldessarini RJ, Faedda GL, Offidani E, et al. Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: a review. J Affect Disord. 2013;148(1):129-135. doi:10.1016/j.jad.2012.10.033 [PubMed 23219059]
  11. Baldwin DS, Chrones L, Florea I, et al. The safety and tolerability of vortioxetine: analysis of data from randomized placebo-controlled trials and open-label extension studies. J Psychopharmacol. 2016;30(3):242-252. doi:10.1177/0269881116628440 [PubMed 26864543]
  12. Bartlett D. Drug-induced serotonin syndrome. Crit Care Nurse. 2017;37(1):49-54. doi:10.4037/ccn2017169. [PubMed 28148614]
  13. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller HJ; World Federation of Societies of Biological Psychiatry Task Force on Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14(5):334-385. doi:10.3109/15622975.2013.804195 [PubMed 23879318]
  14. Bauer M, Severus E, Köhler S, Whybrow PC, Angst J, Möller HJ; WFSBP Task Force on Treatment Guidelines for Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders. Part 2: maintenance treatment of major depressive disorder-update 2015. World J Biol Psychiatry. 2015;16(2):76-95. doi:10.3109/15622975.2014.1001786 [PubMed 25677972]
  15. Biffi A, Cantarutti A, Rea F, Locatelli A, Zanini R, Corrao G. Use of antidepressants during pregnancy and neonatal outcomes: an umbrella review of meta-analyses of observational studies. J Psychiatr Res. 2020;124:99-108. doi:10.1016/j.jpsychires.2020.02.023 [PubMed 32135392]
  16. Bixby AL, VandenBerg A, Bostwick JR. Clinical management of bleeding risk with antidepressants. Ann Pharmacother. 2019;53(2):186-194. doi:10.1177/1060028018794005 [PubMed 30081645]
  17. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120. doi:10.1056/NEJMra041867. Erratum in: N Engl J Med. 2007;356(23):2437. Erratum in: N Engl J Med. 2009;361(17):1714. [PubMed 15784664]
  18. Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA. The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psychother Psychosom. 2016;85(5):270-288. doi:10.1159/000447034 [PubMed 27508501]
  19. Chen G, Zhang W, Serenko M. Lack of effect of multiple doses of vortioxetine on the pharmacokinetics and pharmacodynamics of aspirin and warfarin. J Clin Pharmacol. 2015;55(6):671-679. doi:10.1002/jcph.456 [PubMed 25641606]
  20. Chen VC, Ng MH, Chiu WC, et al. Effects of selective serotonin reuptake inhibitors on glaucoma: a nationwide population-based study. PLoS One. 2017;12(3):e0173005. doi:10.1371/journal.pone.0173005 [PubMed 28257449]
  21. Citrome L. Vortioxetine for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2014;68(1):60‐82. doi:10.1111/ijcp.12350 [PubMed 24165478]
  22. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507. doi:10.1001/jama.295.5.499 [PubMed 16449615]
  23. Coskuner ER, Culha MG, Ozkan B, Kaleagasi EO. Post-SSRI sexual dysfunction: preclinical to clinical. Is it fact or fiction?. Sex Med Rev. 2018;6(2):217-223. doi:10.1016/j.sxmr.2017.11.004 [PubMed 29463440]
  24. Costagliola C, Parmeggiani F, Semeraro F, Sebastiani A. Selective serotonin reuptake inhibitors: a review of its effects on intraocular pressure. Curr Neuropharmacol. 2008;6(4):293-310. doi:10.2174/157015908787386104 [PubMed 19587851]
  25. Coupland CA, Dhiman P, Barton G, et al. A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database. Health Technol Assess. 2011;15(28):1-202. doi:10.3310/hta15280 [PubMed 21810375]
  26. Coupland C, Hill T, Morriss R, Arthur A, Moore M, Hippisley-Cox J. Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database. BMJ. 2015;350:h517. doi: 10.1136/bmj.h517 [PubMed 25693810]
  27. Dalton SO, Johansen C, Mellemkjaer L, Nørgård B, Sørensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med. 2003;163(1):59-64. doi:10.1001/archinte.163.1.59 [PubMed 12523917]
  28. de Abajo FJ, García-Rodríguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry. 2008;65(7):795-803. doi:10.1001/archpsyc.65.7.795 [PubMed 18606952]
  29. D'Agostino A, English CD, Rey JA. Vortioxetine (brintellix): a new serotonergic antidepressant. P T. 2015;40(1):36-40. [PubMed 25628505]
  30. D'Andrea G, De Ronchi D, Giaccotto L, Albert U. Vortioxetine treatment-emergent mania in the elderly: a case report. Australas Psychiatry. 2019;27(4):413. doi:10.1177/1039856219839471 [PubMed 31328985]
  31. de Boer MK, Schoevers RA. Methodological differences as an explanation for the divergent results of studies on sexual dysfunction related to the use of vortioxetine. J Psychopharmacol. 2017;31(3):389-390. doi:10.1177/0269881116681520 [PubMed 28245753]
  32. De Picker L, Van Den Eede F, Dumont G, Moorkens G, Sabbe BG. Antidepressants and the risk of hyponatremia: a class-by-class review of literature. Psychosomatics. 2014;55(6):536-547. doi: 10.1016/j.psym.2014.01.010 [PubMed 25262043]
  33. Douros A, Ades M, Renoux C. Risk of intracranial hemorrhage associated with the use of antidepressants inhibiting serotonin reuptake: a systematic review. CNS Drugs. 2018;32(4):321-334. doi:10.1007/s40263-018-0507-7 [PubMed 29536379]
  34. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635-642. doi:10.1093/qjmed/hcg109 [PubMed 12925718]
  35. Ezra DG, Storoni M, Whitefield LA. Simultaneous bilateral acute angle closure glaucoma following venlafaxine treatment. Eye (Lond). 2006;20(1):128-129. doi:10.1038/sj.eye.6701815 [PubMed 15746956]
  36. Fava GA, Benasi G, Lucente M, Offidani E, Cosci F, Guidi J. Withdrawal symptoms after serotonin-noradrenaline reuptake inhibitor discontinuation: systematic review. Psychother Psychosom. 2018;87(4):195-203. doi:10.1159/000491524 [PubMed 30016772]
  37. Fava GA, Gatti A, Belaise C, Guidi J, Offidani E. Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: a systematic review. Psychother Psychosom. 2015;84(2):72-81. doi:10.1159/000370338 [PubMed 25721705]
  38. Fava M. Prospective studies of adverse events related to antidepressant discontinuation. J Clin Psychiatry. 2006;67(suppl 4):14-21. [PubMed 16683858]
  39. Findling RL, Robb AS, DelBello M, et al. Pharmacokinetics and safety of vortioxetine in pediatric patients. J Child Adolesc Psychopharmacol. 2017;27(6):526-534. doi:10.1089/cap.2016.0155 [PubMed 28333546]
  40. Fitton CA, Steiner MFC, Aucott L, et al. In utero exposure to antidepressant medication and neonatal and child outcomes: a systematic review. Acta Psychiatr Scand. 2020;141(1):21-33. doi:10.1111/acps.13120 [PubMed 31648376]
  41. Friedman RA, Leon AC. Expanding the black box - depression, antidepressants, and the risk of suicide. N Engl J Med. 2007;356(23):2343-2346. doi:10.1056/NEJMp078015 [PubMed 17485726]
  42. Gabriel M, Sharma V. Antidepressant discontinuation syndrome. CMAJ. 2017;189(21):E747. doi:10.1503/cmaj.160991 [PubMed 28554948]
  43. Gandhi S, Shariff SZ, Al-Jaishi A, et al. Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults. Am J Kidney Dis. 2017;69(1):87-96. doi:10.1053/j.ajkd.2016.08.020 [PubMed 27773479]
  44. Gill N, Bayes A, Parker G. A review of antidepressant-associated hypomania in those diagnosed with unipolar depression-risk factors, conceptual models, and management. Curr Psychiatry Rep. 2020;22(4):20. doi:10.1007/s11920-020-01143-6 [PubMed 32215771]
  45. Greenblatt DJ, Harmatz JS, Chow CR. Vortioxetine disposition in obesity: potential implications for patient safety. J Clin Psychopharmacol. 2018;38(3):172-179. doi:10.1097/JCP.0000000000000861 [PubMed 29596146]
  46. Gregorian RS, Golden KA, Bahce A, Goodman C, Kwong WJ, Khan ZM. Antidepressant-induced sexual dysfunction. Ann Pharmacother. 2002;36(10):1577-1589. doi:10.1345/aph.1A195 [PubMed 12243609]
  47. Grunze H, Vieta E, Goodwin GM, et al; Members of the WFSBP Task Force on Bipolar Affective Disorders working on this topic. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: Acute and long-term treatment of mixed states in bipolar disorder. World J Biol Psychiatry. 2018;19(1):2-58. doi: 10.1080/15622975.2017.1384850. [PubMed 29098925]
  48. Grzeskowiak LE, Leggett C, Costi L, Roberts CT, Amir LH. Impact of serotonin reuptake inhibitor use on breast milk supply in mothers of preterm infants: a retrospective cohort study. Br J Clin Pharmacol. 2018;84(6):1373-1379. doi:10.1111/bcp.13575 [PubMed 29522259]
  49. Haddad PM. Antidepressant discontinuation syndromes. Drug Saf. 2001;24(3):183-197. [PubMed 11347722]
  50. Halperin D, Reber G. Influence of antidepressants on hemostasis. Dialogues Clin Neurosci. 2007;9(1):47-59. doi:10.31887/DCNS.2007.9.1/dhalperin [PubMed 17506225]
  51. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63(3):332-339. doi:10.1001/archpsyc.63.3.332 [PubMed 16520440]
  52. Hetrick SE, McKenzie JE, Cox GR, Simmons MB, Merry SN. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2012;11:CD004851. doi:10.1002/14651858.CD004851.pub3 [PubMed 23152227]
  53. Hirsch M, Birnbaum RJ. Discontinuing antidepressant medications in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 29, 2021a.
  54. Hirsch M, Birnbaum RJ. Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed March 9, 2021b.
  55. Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126. doi:10.1056/NEJM200007133430208 [PubMed 10891521]
  56. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother. 2006;40(9):1618-1622. doi:10.1345/aph.1G293 [PubMed 16896026]
  57. Jacobsen PL, Harper L, Chrones L, Chan S, Mahableshwarkar AR. Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-label, flexible-dose, 52-week extension study. Int Clin Psychopharmacol. 2015a;30(5):255-264. doi:10.1097/YIC.0000000000000081 [PubMed 26020712]
  58. Jacobsen PL, Mahableshwarkar AR, Chen Y, Chrones L, Clayton AH. Effect of vortioxetine vs. escitalopram on sexual functioning in adults with well-treated major depressive disorder experiencing SSRI-induced sexual dysfunction. J Sex Med. 2015b;12(10):2036-2048. doi:10.1111/jsm [PubMed 26331383]
  59. Jacobsen PL, Mahableshwarkar AR, Palo WA, Chen Y, Dragheim M, Clayton AH. Treatment-emergent sexual dysfunction in randomized trials of vortioxetine for major depressive disorder or generalized anxiety disorder: a pooled analysis. CNS Spectr. 2016;21(5):367-378. doi:10.1017/S1092852915000553 [PubMed 26575433]
  60. Jacobsen PL, Nomikos GG, Zhong W, Cutler AJ, Affinito J, Clayton A. Clinical implications of directly switching antidepressants in well-treated depressed patients with treatment-emergent sexual dysfunction: a comparison between vortioxetine and escitalopram. CNS Spectr. 2020;25(1):50-63. doi:10.1017/S1092852919000750 [PubMed 31010445]
  61. Jacobsen P, Zhong W, Nomikos G, Clayton A. Paroxetine, but not vortioxetine, impairs sexual functioning compared with placebo in healthy adults: a randomized, controlled trial. J Sex Med. 2019;16(10):1638-1649. doi:10.1016/j.jsxm.2019.06.018 [PubMed 31405765]
  62. Jha MK, Rush AJ, Trivedi MH. When discontinuing SSRI antidepressants is a challenge: management tips. Am J Psychiatry. 2018;175(12):1176-1184. doi:10.1176/appi.ajp.2018.18060692 [PubMed 30501420]
  63. Jing E, Straw-Wilson K. Sexual dysfunction in selective serotonin reuptake inhibitors (SSRIs) and potential solutions: a narrative literature review. Ment Health Clin. 2016;6(4):191-196. doi: 10.9740/mhc.2016.07.191 [PubMed 29955469]
  64. Katona C, Hansen T, Olsen CK. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol. 2012;27(4):215-223.
  65. Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry. 2003;160(4):790-792. doi:10.1176/appi.ajp.160.4.790 [PubMed 12668373]
  66. Khanassov V, Hu J, Reeves D, van Marwijk H. Selective serotonin reuptake inhibitor and selective serotonin and norepinephrine reuptake inhibitor use and risk of fractures in adults: a systematic review and meta-analysis. Int J Geriatr Psychiatry. 2018;33(12):1688-1708. doi:10.1002/gps.4974 [PubMed 30247774]
  67. Kirkham J, Seitz D. Evidence of ocular side effects of SSRIs and new warnings. Evid Based Ment Health. 2017;20(1):27. doi:10.1136/eb-2016-102528 [PubMed 27993931]
  68. Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction. CMAJ. 2011;183(16):1835-1843. doi:10.1503/cmaj.100912 [PubMed 21948719]
  69. Larsen ER, Damkier P, Pedersen LH, et al. Use of psychotropic drugs during pregnancy and breast-feeding. Acta Psychiatr Scand Suppl. 2015;(445):1-28. [PubMed 26344706]
  70. Leon AC. The revised warning for antidepressants and suicidality: unveiling the black box of statistical analyses. Am J Psychiatry. 2007;164(12):1786-1789. doi:10.1176/appi.ajp.2007.07050775 [PubMed 18056231]
  71. Leth-Møller KB, Hansen AH, Torstensson M, et al. Antidepressants and the risk of hyponatremia: a Danish register-based population study. BMJ Open. 2016;6(5):e011200. doi:10.1136/bmjopen-2016-011200 [PubMed 27194321]
  72. MacQueen GM, Frey BN, Ismail Z, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: Section 6. Special populations: youth, women, and the elderly. Can J Psychiatry. 2016;61(9):588-603. doi:10.1177/0706743716659276 [PubMed 27486149]
  73. Mahableshwarkar AR, Affinito J, Reines EH, Xu J, Nomikos G, Jacobsen PL. Suicidal ideation and behavior in adults with major depressive disorder treated with vortioxetine: post hoc pooled analyses of randomized, placebo-controlled, short-term and open-label, long-term extension trials. CNS Spectr. 2020;25(3):352-362. doi:10.1017/S109285291900097X [PubMed 31199210]
  74. Mahableshwarkar AR, Jacobsen PL, Chen Y, Serenko M, Trivedi MH. A randomized, double-blind, duloxetine-referenced study comparing efficacy and tolerability of 2 fixed doses of vortioxetine in the acute treatment of adults with MDD. Psychopharmacology (Berl). 2015;232(12):2061-2070. doi:10.1007/s00213-014-3839-0 [PubMed 25575488]
  75. Mannesse CK, Jansen PA, Van Marum RJ, et al. Characteristics, prevalence, risk factors, and underlying mechanism of hyponatremia in elderly patients treated with antidepressants: a cross-sectional study. Maturitas. 2013;76(4):357-363. doi:10.1016/j.maturitas.2013.08.010 [PubMed 24094459]
  76. Marshall AM, Nommsen-Rivers LA, Hernandez LL, et al. Serotonin transport and metabolism in the mammary gland modulates secretory activation and involution. J Clin Endocrinol Metab. 2010;95(2):837-846. [PubMed 19965920]
  77. Marshall K, Datta P, Rewers-Felkins K, Krutsch K, Baker T, Hale TW. Transfer of the serotonin modulator vortioxetine into human milk: a case series. Breastfeed Med. Published online April 16, 2021. doi:10.1089/bfm.2021.0074 [PubMed 33861632]
  78. Martin A, Young C, Leckman JF, Mukonoweshuro C, Rosenheck R, Leslie D. Age effects on antidepressant-induced manic conversion. Arch Pediatr Adolesc Med. 2004;158(8):773-780. doi:10.1001/archpedi.158.8.773 [PubMed 15289250]
  79. Masarwa R, Bar-Oz B, Gorelik E, Reif S, Perlman A, Matok I. Prenatal exposure to selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors and risk for persistent pulmonary hypertension of the newborn: a systematic review, meta-analysis, and network meta-analysis. Am J Obstet Gynecol. 2019;220(1):57.e1-57.e13. doi:10.1016/j.ajog.2018.08.030 [PubMed 30170040]
  80. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine (Baltimore). 2000;79(4):201-209. doi:10.1097/00005792-200007000-00001 [PubMed 10941349]
  81. Maud C. Vortioxetine in bipolar depression induces a mixed/manic switch. Australas Psychiatry. 2016;24(2):206-207. doi:10.1177/1039856215614986 [PubMed 26994277]
  82. Mazza MG, Rossetti A, Botti ER, Clerici M. Vortioxetine overdose in a suicidal attempt: a case report. Medicine (Baltimore). 2018;97(25):e10788. doi:10.1097/MD.0000000000010788 [PubMed 29923970]
  83. McIntyre RS. The role of new antidepressants in clinical practice in Canada: a brief review of vortioxetine, levomilnacipran ER, and vilazodone. Neuropsychiatr Dis Treat. 2017;13:2913-2919. doi:10.2147/NDT.S150589 [PubMed 29238196]
  84. Moura C, Bernatsky S, Abrahamowicz M, et al. Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS). Osteoporos Int. 2014;25(5):1473-1481. doi:10.1007/s00198-014-2649-x [PubMed 24566587]
  85. Nelson JC, Devanand DP. A systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia. J Am Geriatr Soc. 2011;59(4):577-585. [PubMed 21453380]
  86. Ng QX, Venkatanarayanan N, Ho CYX, Sim WS, Lim DY, Yeo WS. Selective serotonin reuptake inhibitors and persistent pulmonary hypertension of the newborn: an update meta-analysis. J Womens Health (Larchmt). 2019;28(3):331-338. doi:10.1089/jwh.2018.7319 [PubMed 30407100]
  87. Ogle NR, Akkerman SR. Guidance for the discontinuation or switching of antidepressant therapies in adults. J Pharm Pract. 2013;26(4):389-396. doi:10.1177/0897190012467210 [PubMed 23459282]
  88. Ong CY, Vasanwala FF. Diaphoresis: a presentation of serotonin syndrome from vortioxetine. Prim Care Companion CNS Disord. 2018;20(3):17l02191. doi:10.4088/PCC.17l02191 [PubMed 29917334]
  89. Papakostas GI, Perlis RH, Scalia MJ, Petersen TJ, Fava M. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol. 2006;26(1):56-60. doi:10.1097/01.jcp.0000195042.62724.76 [PubMed 16415707]
  90. Patel R, Reiss P, Shetty H, et al. Do antidepressants increase the risk of mania and bipolar disorder in people with depression? A retrospective electronic case register cohort study. BMJ Open. 2015;5(12):e008341. doi:10.1136/bmjopen-2015-008341 [PubMed 26667012]
  91. Pelayo-Terán JM, Martínez-Pérez MM, Zapico-Merayo Y. Safety in the use of antidepressants: vortioxetine-induce hyponatremia in a case report. Rev Psiquiatr Salud Ment. 2017;10(4):219-220. doi:10.1016/j.rpsm.2017.07.001 [PubMed 28844296]
  92. Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry. 2005;66(2):148-158. doi:10.4088/jcp.v66n0201 [PubMed 15704999]
  93. Rabenda V, Nicolet D, Beaudart C, Bruyère O, Reginster JY. Relationship between use of antidepressants and risk of fractures: a meta-analysis. Osteoporos Int. 2013;24(1):121-137. doi: 10.1007/s00198-012-2015-9. [PubMed 22638709]
  94. Rauma PH, Pasco JA, Berk M, et al. The association between major depressive disorder, use of antidepressants and bone mineral density (BMD) in men. J Musculoskelet Neuronal Interact. 2015;15(2):177-185. [PubMed 26032210]
  95. Reefhuis J, Devine O, Friedman JM, Louik C, Honein MA; National Birth Defects Prevention Study. Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous reports. BMJ. 2015;351:h3190. doi:10.1136/bmj.h3190 [PubMed 26156519]
  96. Reeves RR, Ladner ME. Antidepressant-induced suicidality: an update. CNS Neurosci Ther. 2010;16(4):227-234. doi:10.1111/j.1755-5949.2010.00160.x [PubMed 20553304]
  97. Richards JB, Papaioannou A, Adachi JD, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167(2):188-194. doi:10.1001/archinte.167.2.188 [PubMed 17242321]
  98. Rizzoli R, Cooper C, Reginster JY, et al. Antidepressant medications and osteoporosis. Bone. 2012;51(3):606-613. doi: 10.1016/j.bone.2012.05.018. [PubMed 22659406]
  99. Sachs HC, Committee On Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013;132(3):e796-e809. [PubMed 23979084]
  100. Shelton RC. Steps following attainment of remission: discontinuation of antidepressant therapy. Prim Care Companion J Clin Psychiatry. 2001;3(4):168-174. [PubMed 15014601]
  101. Shweiki S, Diav-Citrin O. Pregnancy outcome after first trimester exposure to vortioxetine: a case series. Birth Defects Res. Published online January 19, 2021. doi:10.1002/bdr2.1864 [PubMed 33463081]
  102. Siwek M, Chrobak AA, Gorostowicz A, Krupa AJ, Dudek D. Withdrawal symptoms following discontinuation of vortioxetine-retrospective chart review. Pharmaceuticals (Basel). 2021;14(5):451. doi:10.3390/ph14050451 [PubMed 34064611]
  103. Slomian J, Honvo G, Emonts P, Reginster JY, Bruyère O. Consequences of maternal postpartum depression: a systematic review of maternal and infant outcomes. Womens Health (Lond). 2019;15:1745506519844044. doi:10.1177/1745506519844044 [PubMed 31035856]
  104. Sobieraj DM, Baker WL, Martinez BK, et al. Adverse effects of pharmacologic treatments of major depression in older adults [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2019. Report No.: 19-EHC011-EF. [PubMed 30964616]
  105. Sobreira G, Oliveira J, Brissos S. Vortioxetine-induced manic mood switch in patient with previously unknown bipolar disorder. Braz J Psychiatry. 2017;39(1):86. doi:10.1590/1516-4446-2016-2113 [PubMed 28273272]
  106. Sriraman NK, Melvin K, Meltzer-Brody S. ABM clinical protocol #18: use of antidepressants in breastfeeding mothers. Breastfeed Med. 2015;10(6):290-299. [PubMed 26204124]
  107. Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord. 1998;51(3):215-235. doi:10.1016/s0165-0327(98)00221-3 [PubMed 10333979]
  108. Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: a review. Expert Opin Drug Saf. 2008;7(5):587-596. doi:10.1517/14740338.7.5.587 [PubMed 18759711]
  109. Szegedi A, Jansen WT, van Willigenburg AP, van der Meulen E, Stassen HH, Thase ME. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry. 2009;70(3):344-353. doi:10.4088/jcp.07m03780 [PubMed 19254516]
  110. Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry. 2006;63(11):1217-23. doi:10.1001/archpsyc.63.11.1217 [PubMed 17088502]
  111. Tondo L, Vázquez G, Baldessarini RJ. Mania associated with antidepressant treatment: comprehensive meta-analytic review. Acta Psychiatr Scand. 2010;121(6):404-414. doi:10.1111/j.1600-0447.2009.01514.x [PubMed 19958306]
  112. Trintellix (vortioxetine) [prescribing information]. Lexington, MA: Takeda Pharmaceuticals America Inc; September 2021.
  113. Trintellix (vortioxetine) [product monograph]. St-Laurent, Quebec, Canada: Lundbeck Canada Inc; February 2021.
  114. Uljon S, Kataria Y, Flood JG. Vortioxetine use may cause false positive immunoassay results for urine methadone. Clin Chim Acta. 2019;499:1-3. doi:10.1016/j.cca.2019.08.026 [PubMed 31469980]
  115. Wadhwa R, Kumar M, Talegaonkar S, Vohora D. Serotonin reuptake inhibitors and bone health: a review of clinical studies and plausible mechanisms. Osteoporos Sarcopenia. 2017;3(2):75-81. doi:10.1016/j.afos.2017.05.002 [PubMed 30775508]
  116. Wang CY, Fu SH, Wang CL, Chen PJ, Wu FL, Hsiao FY. Serotonergic antidepressant use and the risk of fracture: a population-based nested case-control study. Osteoporos Int. 2016;27(1):57-63. doi:10.1007/s00198-015-3213-z [PubMed 26126579]
  117. Warden SJ, Fuchs RK. Do selective serotonin reuptake inhibitors (SSRIs) cause fractures? Curr Osteoporos Rep. 2016;14(5):211-218. doi:10.1007/s11914-016-0322-3 [PubMed 27495351]
  118. Warner, CH, Bobo W, Warner C, et al. Antidepressant discontinuation syndrome. Am Fam Physician. 2006;74:449-456. [PubMed 16913164]
  119. Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry. 2004;161(6):1066-1078. doi:10.1176/appi.ajp.161.6.1066 [PubMed 15169695]
  120. Wiciński M, Kaluzny BJ, Liberski S, Marczak D, Seredyka-Burduk M, Pawlak-Osińska K. Association between serotonin-norepinephrine reuptake inhibitors and acute angle closure: what is known? Surv Ophthalmol. 2019;64(2):185-194. doi:10.1016/j.survophthal.2018.09.006 [PubMed 30278181]
  121. Williams AJ, Lai Z, Knight S, Kamali M, Assari S, McInnis MG. Risk factors associated with antidepressant exposure and history of antidepressant-induced mania in bipolar disorder. J Clin Psychiatry. 2018;79(3):17m11765. doi:10.4088/JCP.17m11765 [PubMed 29873955]
  122. Womersley K, Ripullone K, Agius M. What are the risks associated with different selective serotonin re-uptake inhibitors (SSRIs) to treat depression and anxiety in pregnancy? An evaluation of current evidence. Psychiatr Danub. 2017;29(suppl 3):629-644. [PubMed 28953843]
  123. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170. doi: 10.1111/bdi.12609. [PubMed 29536616]
  124. Yonkers KA, Wisner KL, Stewart DE, et al. The Management of Depression During Pregnancy: A Report From the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol. 2009;114(3):703-713. [PubMed 19701065]
  125. Zhang J, Mathis MV, Sellers JW, et al. The US Food and Drug Administration's perspective on the new antidepressant vortioxetine. J Clin Psychiatry. 2015;76(1):8-14. doi:10.4088/JCP.14r09164 [PubMed 25562777]
  126. Zhou N, Zhao JX, Zhu YN, Zhang P, Zuo Y. Acute angle-closure glaucoma caused by venlafaxine. Chin Med J (Engl). 2018;131(12):1502-1503. doi:10.4103/0366-6999.233952 [PubMed 29893371]
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