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Serotonin modulators: Pharmacology, administration,

and side effects
Authors: Michael Hirsch, MD, Robert J Birnbaum, MD, PhD
Section Editor: Peter P Roy-Byrne, MD
Deputy Editor: David Solomon, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Dec 2022. | This topic last updated: Aug 09, 2022.

INTRODUCTION

Advances in understanding brain neurophysiology have led to the development of serotonin

modulators, including [1]:

● Nefazodone
● Trazodone
● Vilazodone
● Vortioxetine

The serotonin modulators are distinct from other classes of antidepressants that include
selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, atypical
antidepressants, tricyclics, and monoamine oxidase inhibitors. Serotonin modulators act as
antagonists and agonists at postsynaptic serotonin receptors and inhibit reuptake of
postsynaptic serotonin to varying degrees; effects upon norepinephrine reuptake are minimal.

The pharmacology, administration, and side effects of serotonin modulators are reviewed here.
Choosing a regimen for the initial treatment of depression and treatment of resistant
depression is discussed separately, as are other antidepressant drug classes:

● (See "Unipolar major depression in adults: Choosing initial treatment".)

● (See "Unipolar depression in adults: Choosing treatment for resistant depression".)
● (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side
effects".)
 ● (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and
side effects".)
● (See "Atypical antidepressants: Pharmacology, administration, and side effects".)
● (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects".)
● (See "Monoamine oxidase inhibitors (MAOIs): Pharmacology, administration, safety, and
side effects".)

GENERAL PRINCIPLES

Drug interactions and metabolism — Coadministration of serotonin modulators with another

drug can decrease or increase the metabolism of the serotonin modulator, which may
necessitate either adjusting the dose of the serotonin modulator or using a different
antidepressant. Thus, prior to initiating or altering therapy with serotonin modulators, clinicians
should check interactions with other medications using the Lexicomp drug interactions tool
(Lexi-Interact Online) included in UpToDate. The drug interaction tool provides specific dose
recommendations for prescribing serotonin modulators concomitantly with drugs that affect
the serotonin modulator’s metabolism.

Serotonin modulators are metabolized by hepatic cytochrome P450 3A4 (CYP3A4) or 2D6
(CYP2D6) enzymes. Administering a serotonin modulator in conjunction with another drug that
inhibits these enzymes can increase serum concentrations of the serotonin modulator, resulting
in drug accumulation and toxicity. Prescribing a serotonin modulator concurrently with
medications that induce the enzymes can decrease serum concentrations of the serotonin
modulator and lead to therapeutic failure. The hepatic metabolism of the serotonin modulators
includes the following:

● Trazodone and vilazodone – Trazodone and vilazodone undergo extensive hepatic

metabolism by CYP3A4 [2,3]. Strong CYP3A4 inhibitors and inducers are listed in the table
( table 1).

● Vortioxetine – Vortioxetine undergoes extensive metabolism by CYP2D6 and is also

metabolized by other CYP enzymes [4]. Drug-drug interactions can occur when
vortioxetine is coadministered with medications that inhibit CYP2D6 metabolism, or
medications that induce other CYP metabolic pathways. CYP2D6 inhibitors are listed in the
table ( table 2).

● Nefazodone – Although nefazodone seems to undergo extensive metabolism by CYP3A4

based upon in vitro data, this has not been well studied [5,6]. Strong CYP3A4 inhibitors and
 inducers are listed in the table ( table 1).

Nefazodone is itself a strong inhibitor of CYP3A4 and can elevate levels of comedications
that are dependent upon CYP3A4 for clearance.

Serotonin modulators can also interact with other medications that elevate serotonin in the
central nervous system, potentially resulting in the serotonin syndrome. These drug-drug
interactions (eg, with monoamine oxidase inhibitors) can be severe and are described in more
detail separately. (See "Serotonin syndrome (serotonin toxicity)".)

Guidelines to review with patients — Prior to prescribing serotonin modulators, clinicians

should discuss:

● Drug interactions
● Side effects
● Time to response
● Stopping the medication

Common and serious side effects ( table 3) and the need to take the medication as prescribed
rather than on an as needed basis should be reviewed. Patients should also be informed that
although some response often occurs within the first two weeks of treatment, it may take many
weeks (eg, 8 to 14) for a full response (severity of illness and comorbid disease may affect how
quickly depressed patients respond to treatment) [7].

Medical tests and plasma levels — No specific medical tests are required before starting
serotonin modulators, and drug serum concentrations are not routinely monitored because
they have not been shown to correlate with clinical response. However, levels can assess
adherence and whether unresponsive patients are rapid metabolizers. Levels can also establish
that it is safe to begin another serotonergic drug (eg, a monoamine oxidase inhibitor) after
discontinuing a serotonin modulator, in order to avoid the serotonin syndrome ( table 4). (See
"Serotonin syndrome (serotonin toxicity)".)

Dosing — We suggest starting with a low dose in order to avoid side effects and slowly
increasing the dose. Starting doses and target dose ranges of each serotonin modulator are
listed in the table ( table 5). Depressed patients with high levels of anxiety may tolerate the
medication better by starting with half of the suggested dose. Doses are adjusted according to
patient response, tolerability, and clinical urgency.

Finding the effective dose of an antidepressant involves trial and error. After starting the drug
and titrating up to the minimum effective dose, response should be monitored over the
following two to four weeks. For patients who tolerate the antidepressant but do not respond,
we continue titrating up the dose slowly (to avoid side effects) every two to four weeks. For
unresponsive patients who do not tolerate the drug, we suggest switching to a different
antidepressant. (See "Switching antidepressant medications in adults" and "Unipolar major
depression in adults: Choosing initial treatment" and "Unipolar depression in adults: Choosing
treatment for resistant depression", section on 'Switching to a different treatment'.)

Patients who recover from an episode of major depression should generally receive
maintenance treatment with the full dose that successfully resolved the episode, rather than a
lower dose. (See "Unipolar depression in adults: Continuation and maintenance treatment",
section on 'Dose'.)

Separate sections below discuss specific dose recommendations for each serotonin modulator.

Pregnancy — Treatment of pregnant women with antidepressants is discussed separately. (See

"Severe antenatal unipolar major depression: Choosing treatment".)

Serotonin syndrome — Serotonin modulators increase serotonergic neurotransmission and

can cause the serotonin syndrome. (See "Serotonin syndrome (serotonin toxicity)".)

Suicide — The potential effect of antidepressants on suicidal ideation and behavior in adults is

discussed separately. (See "Effect of antidepressants on suicide risk in adults".)

NEFAZODONE

Nefazodone is used to treat major depression and premenstrual syndrome. The drug is
contraindicated in patients with elevated serum transaminases, active liver disease, or liver
injury due to previous nefazodone treatment.

Pharmacology — Nefazodone is a phenylpiperazine whose structure resembles that of

trazodone [1,8]. Nefazodone antagonizes and down regulates postsynaptic serotonin 5-HT2A
receptors, and weakly inhibits presynaptic serotonin and norepinephrine reuptake; these
actions increase activity at the serotonin 5-HT1A receptors [1,9,10]. The drug has little to no
affinity for alpha-adrenergic receptors, cholinergic, dopamine D2, and histamine H1 receptors.
The pharmacokinetic parameters of nefazodone are displayed in the table ( table 6).

Administration, dose, and discontinuation — The usual starting dose of nefazodone for

major depression is 100 mg twice daily ( table 5) [9]. For patients who do not respond after
two to four weeks, the dose is increased to 150 to 200 mg twice daily. The dose is increased
further by increments of 100 to 200 mg per day every two to four weeks until the desired clinical
response is achieved; the maximum dose is 300 mg twice daily. In clinically urgent situations,
dose increases can occur once a week as tolerated. The effectiveness and tolerability of once
daily and twice daily dosing may be comparable [11].

Based upon in vitro data, nefazodone seems to undergo extensive metabolism by cytochrome
P450 3A4 (CYP3A4) enzymes. However, this has not been well studied and the manufacturer
does not provide dose adjustment recommendations for use with CYP3A4 inhibitors or inducers
[5,6]. Nevertheless, if nefazodone is co-prescribed with a strong inhibitor of CYP3A4, decreasing
the dose of nefazodone may be warranted; if nefazodone is given concomitantly with a strong
inducer, the dose of nefazodone may need to be increased. Strong CYP3A4 inhibitors and
inducers are listed in the table ( table 1).

Although abrupt discontinuation of nefazodone does not cause a withdrawal syndrome, we

taper the drug over one week before stopping it, which is consistent with the preferred method
of discontinuing any psychotropic medication. In two randomized trials, patients with major
depression (n = 259 and 131) who received nefazodone for 16 weeks were randomly assigned to
either continue the drug or abruptly stop it and start placebo (as part of relapse prevention
studies); the incidence of discontinuation symptoms was comparable for the two groups [12,13].
Additional information about discontinuing antidepressants is discussed separately. (See
"Discontinuing antidepressant medications in adults".)

Side effects — Nefazodone can injure the liver; the estimated incidence of hepatotoxicity based
upon a national registry in Spain is 29 cases per 100,000 patients per year [14]. Adverse hepatic
reactions can occur with doses as low as 100 mg per day and generally occur within six months
of starting the drug [15]. These reactions include acute liver failure; the estimated incidence is 1
case per 200,000 to 300,000 patient years, which is three to four times greater than expected
[16]. A 2010 study of the World Health Organization Programme for International Drug
Monitoring database found 94 cases of acute liver failure attributed to nefazodone, including
patients who received a liver transplant or died [17]. Thus, nefazodone is not commonly used in
United States; generic versions are available, but the brand-name version is no longer
manufactured. In addition, the drug has been withdrawn from the market in several countries.
Patients receiving the drug should be monitored for signs and symptoms of liver failure
(nausea, abdominal pain, jaundice, impaired synthetic function, coagulopathy, and delirium).
Although periodic liver function tests (eg, every two to six months) may possibly be useful, there
is no evidence that testing prevents hepatic injury [12].

Nefazodone can cause several other side effects ( table 3). A pooled analysis of randomized
trials (n = 2185 patients, most with unipolar major depression) found that the incidence of
discontinuing nefazodone because of side effects was 12 percent and for placebo was 7 percent
[18]. Adverse effects that occurred more frequently with nefazodone included:

● Nausea – 21 percent of patients who received nefazodone

● Somnolence – 19 percent
● Dry mouth – 19 percent
● Dizziness – 12 percent
● Constipation – 11 percent
● Weakness – 11 percent
● Blurred vision – 6 percent

Each of these adverse effects, except dry mouth and weakness, appear to be dose related and
less likely to occur at doses ≤300 mg per day [9].

Reduced systolic blood pressure (≤90 mmHg and ≥20 mmHg reduction from baseline) occurred
in more patients who received nefazodone than placebo (5 versus 3 percent), but the incidence
of syncope was comparable (0.02 and 0.03 percent) [18]. In addition, asymptomatic sinus
bradycardia was detected by electrocardiogram in more patients who received nefazodone than
placebo (1.3 versus 0.4 percent).

Sexual dysfunction with nefazodone and placebo appear to be comparable, based upon a meta-
analysis [19] as well as a pooled analysis of randomized trials (n = 2185 patients) [18]. In
addition, weight gain during treatment lasting between 3 to 13 months is comparable for
nefazodone and placebo [18].

Compared with selective serotonin reuptake inhibitors, nefazodone is less activating and causes
less gastrointestinal distress (eg, nausea, diarrhea, and anorexia), sexual dysfunction, and
weight gain during long-term treatment (eg, 16 to 46 weeks), but causes more dry mouth,
dizziness, constipation, visual disturbances, and confusion [9,20].

Overdose — Nefazodone appears to have a wide therapeutic index [1,18]:

● A study (primarily retrospective) examined 1338 cases of nefazodone poisoning collected

from 67 poison control centers in the United States; exposures involving concomitant
drugs were excluded [21]. No deaths occurred; the most common clinical effects were
drowsiness (17 percent), nausea (10 percent), dizziness (9 percent), and vomiting (8
percent); the most common, potentially serious clinical effects were hypotension (2
percent) and bradycardia (1 percent). Clinical effects generally began within 1 to 4 hours of
ingestion and resolved within 8 to 24 hours. None of the patients required intubation,
 mechanical ventilation, or vasopressors. Suicide attempt was suspected in 35 percent,
including one patient who ingested 13,500 mg.

● In a two year retrospective study of 12 patients who deliberately or accidentally overdosed

on nefazodone (mean dose 4594 mg, maximum 12,500 mg), none of the patients suffered
seizures, prolonged corrected QT ≥450 milliseconds, or arrhythmias, and none required
airway management or ventilatory support [22].

TRAZODONE

Trazodone is used to treat major depression as well as functional dyspepsia. In addition, it is

often used as a hypnotic to treat insomnia in the context of depression, as well as insomnia
associated with antidepressants (eg, bupropion or fluoxetine) [23]. However, the efficacy of
trazodone for insomnia in the absence of depression appears to be short-lived. (See
"Pharmacotherapy for insomnia in adults", section on 'Trazodone'.)

Pharmacology — Trazodone is a triazolopyridine whose structure resembles that of

nefazodone [8]. Trazodone acts upon postsynaptic serotonin 5-HT2A and 5-HT2C receptors and
weakly inhibits presynaptic serotonin reuptake. The effects appear to be dose dependent such
that at low doses the drug acts as a serotonin antagonist and at high doses as a serotonin
agonist [8,24]. Effects on norepinephrine and dopamine reuptake are minimal. In addition, the
drug blocks postsynaptic alpha-adrenergic receptors (which may account for the side effects of
orthostatic hypotension and priapism) and histamine H1 receptors (which may explain its
sedative effect) [8,24,25]. The drug does not affect cholinergic receptors.

The pharmacokinetic parameters of trazodone are displayed in the table ( table 6).

Administration, dose, and discontinuation — Trazodone immediate release is typically dosed

as follows for major depression ( table 5). The drug is started at 50 mg twice daily, which is
then increased by increments of 50 mg per day every three to seven days to a dose of 75 to 150
mg twice daily. The dose is subsequently increased by 50 to 100 mg per day every two to four
weeks until the desired clinical response is achieved, to a maximum dose of 600 mg per day.
Doses >400 mg per day warrant cautious use and additional monitoring, particularly in the
elderly and other patients at risk for cardiovascular toxicity. The drug’s sedative effects may be
better tolerated if patients are given a smaller daytime dose and larger bedtime dose (eg, 100
mg in the morning and 200 mg at bedtime); some patients receive the entire dose at bedtime.
An extended release preparation is available in a few countries, but no longer in the United
States.
Patients with insomnia associated with antidepressants (eg, selective serotonin reuptake
inhibitors) may benefit from immediate release trazodone 50 to 100 mg at bedtime [23]. When
adjunctive trazodone is prescribed as a hypnotic for insomnia associated with depression, doses
typically range from 50 to 300 mg at bedtime [26]. Although doses up to 600 mg at bedtime
have been studied for insomnia in the context of depression, we rarely use more than 200 mg.

Trazodone undergoes extensive hepatic metabolism by hepatic cytochrome P450 3A4 (CYP3A4)
enzymes [3]. If trazodone is co-prescribed with a strong inhibitor of CYP3A4, decreasing the
dose of trazodone may be warranted. If trazodone is given concomitantly with a strong inducer,
the dose of trazodone may need to be increased. Strong CYP3A4 inhibitors and inducers are
listed in the table ( table 1).

We suggest tapering the drug over two to four weeks prior to discontinuation. Rapid or abrupt
discontinuation of trazodone may be followed by withdrawal symptoms, including
gastrointestinal distress, anxiety, and sleep disturbances [27]. Additional information about
discontinuing antidepressants is discussed separately. (See "Discontinuing antidepressant
medications in adults".)

Side effects — Trazodone can cause several side effects ( table 3) [26,27]. A randomized trial
that compared trazodone immediate release with placebo in 153 patients with major
depression found that discontinuation of treatment due to side effects was greater in patients
who received trazodone than placebo (23 versus 4 percent); trazodone caused a higher
incidence of [28]:

● Sedation – 61 percent of patients who received trazodone

● Dizziness – 36 percent
● Dry mouth – 27 percent
● Nausea – 19 percent

Orthostatic hypotension and headache are also common with trazodone [29].

Rare but serious side effects of trazodone include:

● Priapism – Penile priapism secondary to trazodone is an emergency that should be

evaluated immediately by a urologist (rare cases of clitoral priapism have also been
reported) [30]. Trazodone induced priapism is estimated to occur 1 in 1000 to 1 in 10,000
patients, and has been reported at doses ranging from 50 to 400 mg per day. Although
most cases occur within the first month of treatment, priapism may occur up to 18 months
after onset of treatment. A prolonged erection during treatment may be a risk factor for
 subsequent priapism. Additional information about priapism is discussed separately. (See
"Priapism".)

● Cardiac arrhythmias – A review identified case reports of atrial and ventricular arrhythmias
in patients treated with trazodone [27]. Thus, the drug should be used with caution in
patients with cardiac disease.

Trazodone appears to be weight neutral during treatment lasting 4 to 12 weeks, based upon a
meta-analysis of three heterogeneous randomized trials (n = 155 patients treated with
trazodone for with major depression) [31].

Overdose — Overdose with trazodone alone is typically not lethal; a study of 35 cases with
doses up to 6400 mg and a second study of 22 cases with doses up to 3500 mg both found that
no deaths occurred [32,33]. However, at least one fatal case of suicide with trazodone alone has
been reported, in which the patient developed torsades de pointes, complete atrioventricular
block, and multiple organ failure [34]; the serum concentration was 25 mcg/mL (steady state
concentrations with recommended doses are approximately 1 to 3 mcg/mL [32]). Although most
patients recover uneventfully, overdose can cause arrhythmias, respiratory arrest, coma, and
priapism [32,33].

In addition, overdoses with trazodone plus alcohol and/or other drugs are often lethal. A study
of 49 patients found that 9 (18 percent) died [32].

VILAZODONE

Vilazodone is used to treat major depression.

Pharmacology — Vilazodone is an indolalkylamine that inhibits presynaptic reuptake of

serotonin and also acts as a partial agonist at postsynaptic serotonin 5-HT1A receptors [35].
Inhibition of norepinephrine and dopamine reuptake is minimal. The pharmacokinetic
parameters of vilazodone are displayed in the table ( table 6).

Administration, dose, and discontinuation — The usual starting dose of vilazodone for major
depression is 10 mg per day at bedtime, for one week ( table 5). The dose is then increased to
20 mg per day for week 2 [36]. This two-week titration schedule is intended to reduce
gastrointestinal toxicity. The target dose is 20 to 40 mg per day. The drug should be taken with
food to increase bioavailability. Dose adjustments are not required for patients with severe renal
impairment [35]; use of the drug in patients with severe hepatic impairment has not been
studied [37].
Concurrent use of vilazodone with other medications that inhibit or induce hepatic cytochrome
P450 3A4 (CYP3A4) metabolism can alter vilazodone serum concentrations, which may
necessitate adjusting the dose of vilazodone. Strong CYP3A4 inhibitors and inducers are listed in
the table ( table 1). Recommendations for specific vilazodone dose adjustments are as follows
[2]:

● Vilazodone given with strong CYP3A4 inhibitors – Vilazodone dose should not exceed 20
mg once daily. If the CYP3A4 inhibitor is discontinued, readjust vilazodone to original dose.

● Vilazodone given with strong CYP3A4 inducers – Based upon clinical response, clinicians
may need to increase the vilazodone dose two-fold when coadministered with CYP3A4
inducer for more than 14 days. Maximum daily dose of vilazodone is 80 mg. If the CYP3A4
inducer is discontinued, reduce vilazodone dose to the original dose over 7 to 14 days.

Specific interactions of serotonin modulators with other medications can be determined using
the Lexicomp drug interactions tool (Lexi-Interact Online) included in UpToDate.

Although withdrawal symptoms due to abrupt discontinuation of vilazodone have not been
described, we taper drug doses of 20 to 40 mg per day for one to two weeks prior to
discontinuation [35]; tapering is the preferred method of discontinuing any psychotropic
medication. Additional information about discontinuing antidepressants is discussed separately.
(See "Discontinuing antidepressant medications in adults".)

Side effects — Vilazodone can cause several side effects ( table 3). A pooled analysis
examined adverse effects in two randomized trials that compared vilazodone 40 mg per day
with placebo for eight weeks in 891 patients with unipolar major depression; the following
adverse effects occurred more often in patients who received vilazodone than placebo, and the
incidence with vilazodone was as follows [38]:

● Diarrhea – 28 percent
● Nausea – 23 percent
● Sexual dysfunction
• 16 percent of males
• 5 percent of females
● Dizziness – 8 percent
● Insomnia – 6 percent
● Vomiting – 5 percent

Although discontinuation of treatment due to side effects was greater in patients who received
vilazodone than placebo (7 versus 3 percent) [38], the clinical effect was small. A pooled analysis
of two randomized trials lasting eight weeks (n = 891) compared vilazodone (40 mg/day) to
placebo with regard to discontinuation of treatment due to adverse effects [39]. The analysis
found that the number needed to harm was 27; this means that on average, a clinician would
need to treat 27 patients with vilazodone and 27 patients with placebo before observing one
more patient stopping vilazodone than placebo because of an adverse event.

Patients treated with vilazodone have reported the potentially life threatening serotonin
syndrome. In premarketing studies of patients with unipolar major depression, symptoms of
the syndrome were found in 0.1 percent [40]. The clinical features and management of the
serotonin syndrome are discussed separately. (See "Serotonin syndrome (serotonin toxicity)".)

Concerns have been raised about the possibility that maternal use of vilazodone during
pregnancy may cause persistent pulmonary hypertension of the newborn. (See "Antenatal
exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine
reuptake inhibitors (SNRIs): Neonatal outcomes", section on 'Persistent pulmonary
hypertension of the newborn'.)

Based upon placebo controlled trials, vilazodone appears to have little or no effect upon [37,38]:

● Vital signs
● Electrocardiogram parameters (including cardiac repolarization [corrected QT interval])
● Laboratory tests (including liver function tests)
● Body weight

Overdose — The clinical features, toxicology, and management of overdoses with vilazodone

are discussed separately. (See "Acute poisoning from atypical (non-SSRI) antidepressants,
including serotonin-norepinephrine reuptake inhibitors (SNRIs)".)

VORTIOXETINE

Vortioxetine is used to treat major depression [41-43]. In addition, improvement of cognitive

dysfunction in patients with unipolar major depression may be greater with vortioxetine than
other antidepressants (eg, duloxetine), and this benefit may be independent of resolving the
depressive syndrome [44,45].

Pharmacology — Vortioxetine is a bis-aryl-sulphanyl amine that inhibits presynaptic reuptake

of serotonin, which is considered the primary mechanism of action underlying the drug’s
antidepressant effect [46]. In addition, vortioxetine interacts with several serotonin receptor
subtypes; the medication is a potent antagonist at serotonin 5-HT3 receptors, a weaker
antagonist at 5-HT7 and 5-HT1D receptors, a partial agonist at 5-HT1B receptors, and a full
agonist at 5-HT1A receptors [47-49]. The downstream pharmacodynamic effects include
increased levels of serotonin, acetylcholine, dopamine, and norepinephrine in specific areas of
the brain [50]. Although the clinical significance of the drug’s effects upon the serotonin
receptor subtypes is unknown [46,48], these effects may perhaps mediate the drug’s
therapeutic benefits and its side effect profile [45,48].

The pharmacokinetic parameters of vortioxetine are displayed in the table ( table 6) [46,51].

Administration, dose, and discontinuation — We suggest starting vortioxetine at a dose of 10

mg once daily ( table 5) [46]. For patients who tolerate the drug in week 1, the dose is
increased to the target dose of 20 mg per day. However, a reasonable alternative is to initiate
treatment with a dose of 5 mg/day for week 1 and then titrate up to 10 mg/day for week 2,
followed by either 20 mg/day for week 3 or 15 mg/day for week 3 and 20 mg/day for week 4. In
addition, it is reasonable to evaluate the effectiveness of each dose for two to four weeks before
titrating up. (Multiple randomized trials found that vortioxetine 5, 10, 15, and 20 mg/day were
each superior to placebo [42,52]).

Dose adjustments are not required for older patients (eg, age ≥65 years) and for patients with
renal impairment or mild to moderate hepatic impairment; use of the drug in patients with
severe hepatic impairment has not been studied [46,48].

Vortioxetine undergoes extensive metabolism by hepatic cytochrome P450 2D6 (CYP2D6)

enzymes and is also metabolized by other CYP enzymes [4]. For patients who slowly metabolize
CYP2D6 substrates, the maximum recommended dose is 10 mg/day. In addition, dose
adjustments may be necessary if vortioxetine is coadministered with medications that inhibit
CYP2D6 metabolism ( table 2), or medications that induce other CYP metabolic pathways (eg,
carbamazepine and phenytoin). Thus, prior to initiating or altering therapy with vortioxetine,
clinicians should check drug-drug interactions with other medications using the Lexicomp drug
interactions tool (Lexi-Interact Online) included in UpToDate. The drug interaction tool provides
specific dose recommendations for administering vortioxetine concomitantly with strong
CYP2D6 inhibitors or with inducers of other CYP enzymes.

Although abrupt discontinuation of vortioxetine does not cause a withdrawal syndrome, we

taper drug doses of 15 or 20 mg/day to 10 mg/day for one week before stopping it [46,51];
tapering is the preferred method of discontinuing any psychotropic medication. Evidence
regarding the lack of discontinuation symptoms includes the following:

● Three randomized trials lasting eight weeks compared vortioxetine (10, 15, or 20 mg/day)
with placebo in patients with acute unipolar major depression (n >1300), and then abruptly
 stopped the study drugs [53]. During the subsequent two weeks, the level of withdrawal
symptoms was comparable for the two groups, which was probably due to the relatively
long half-life of vortioxetine ( table 6).

● A maintenance treatment study (n = 396 remitted patients) compared vortioxetine (5 or 10

mg/day) with placebo for up to 64 weeks and then abruptly stopped the study drugs [54].
During the subsequent two weeks, the level of withdrawal symptoms was comparable for
the two groups.

Additional information about discontinuing antidepressants is discussed separately. (See

"Discontinuing antidepressant medications in adults".)

Side effects — Although vortioxetine can cause several side effects, especially nausea
( table 3), the drug is generally well tolerated [48,53]. As an example, a pooled analysis of 11
short-term (six or eight weeks) randomized trials compared vortioxetine (5 to 20 mg/day) with
placebo in patients with unipolar major depression (n >4800) [39]. The analysis found that the
number needed to harm, defined as discontinuing treatment due to side effects, was 43. This
means that on average, a clinician would need to treat 43 patients with vortioxetine and 43
patients with placebo before observing one more patient stopping vortioxetine than placebo
because of an adverse event. Nevertheless, randomized trials have demonstrated that the
overall difference between vortioxetine and placebo, with regard to stopping treatment due to
adverse effects, is statistically significant [41,55].

Based upon a pooled analysis of 11 short-term randomized trials that compared vortioxetine
with placebo in depressed patients (n >4800), the absolute rate of discontinuing treatment due
to adverse effects was as follows [53]:

● Placebo – 4 percent of patients

● Vortioxetine 5 mg/day – 5 percent
● Vortioxetine 10 mg/day – 5 percent
● Vortioxetine 15 mg/day – 8 percent
● Vortioxetine 20 mg/day – 7 percent

Comparable figures are found in longer studies. A maintenance trial included 396 patients who
initially remitted with open-label vortioxetine and were then randomly assigned to vortioxetine
(5 or 10 mg/day) or placebo for treatment lasting up to 64 weeks [54]. Discontinuation of
treatment due to adverse events occurred in 8 and 3 percent of patients.

The side effect that most often causes patients to stop vortioxetine is nausea [53], and the most
frequent side effect of vortioxetine is nausea [48]. A pooled analysis of 11 short-term
randomized trials (n >4800 depressed patients) compared vortioxetine with placebo and found
that the incidence of nausea was as follows [53]:

● Placebo – 8 percent of patients

● Vortioxetine 5 mg/day – 21 percent
● Vortioxetine 10 mg/day – 23 percent
● Vortioxetine 15 mg/day – 31 percent
● Vortioxetine 20 mg/day – 28 percent

Onset of nausea was most frequent in week 1 [46], and the median duration of nausea was 9 to
16 days, depending upon the dose [53]. Among patients taking 10 to 20 mg/day at the end of
the short-term trials, nausea was present in 10 percent [46].

In addition, a study treated acutely depressed patients with open-label vortioxetine for 12
weeks and then randomly assigned remitted patients (n = 396) to vortioxetine (5 or 10 mg/day)
or placebo for maintenance treatment lasting up to 64 weeks; the incidence of nausea was
greater with vortioxetine than placebo (9 versus 3 percent of patients) [54].

Other side effects that occur more often with vortioxetine than placebo include vomiting and
constipation [56]. However, the incidence of vomiting and constipation is relatively low,
compared with the incidence of nausea. As an example, a pooled analysis of 11 short-term
randomized trials (n >4800 depressed patients) found that the frequency of vomiting in patients
treated with vortioxetine (5 to 20 mg/day) ranged from 3 to 6 percent, depending upon the
dose; the rate with placebo was 1 percent [53]. Similarly, the frequency of constipation in
patients treated with vortioxetine ranged from 3 to 6 percent, and the rate with placebo was 3
percent.

In multiple short-term randomized trials of acutely depressed patients, vortioxetine and placebo
were comparable with regard to changes in electrocardiogram parameters, laboratory values
(eg, complete blood counts, electrolytes, and liver function tests), and vital signs [53]. Similar
results were found in one randomized trial that compared vortioxetine (5 or 10 mg/day) with
placebo as maintenance treatment in patients (n = 396) [54]. In addition, patients who initially
completed five short-term randomized trials (total n = 2587) were treated with vortioxetine in
open-label extension studies; no clinically significant changes in electrocardiogram parameters,
laboratory values, or vital signs were observed [57-61].

Other studies suggest that side effects are less problematic with vortioxetine than other
antidepressants, such as agomelatine, duloxetine, and venlafaxine [62,63]. As an example, a
meta-analysis of five randomized trials (n >2000 depressed patients) lasting eight weeks
compared vortioxetine (2.5 to 20 mg/day) with duloxetine (60 mg/day) and found that adverse
effects were less likely to occur with vortioxetine than duloxetine (relative risk 0.88, 95% CI 0.82-
0.94), including nausea (relative risk 0.70, 95% CI 0.56-0.87) [64].

Overdose — Information about overdoses with vortioxetine is limited to clinical trials in which

subjects accidentally or intentionally consumed doses up to 75 mg. Ingestion of vortioxetine at
a dose of 40 to 75 mg was associated with an increased incidence of nausea, abdominal
discomfort, diarrhea, pruritus, flushing, and somnolence [51].

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.”
The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on “patient info” and the keyword(s) of interest.)

● Basics topics (see "Patient education: Coping with high drug prices (The Basics)")

● Beyond the Basics topics (see "Patient education: Depression treatment options for adults
(Beyond the Basics)" and "Patient education: Depression in adults (Beyond the Basics)" and
"Patient education: Coping with high prescription drug prices in the United States (Beyond
the Basics)")

The National Institute of Mental Health also has educational material on the use of
antidepressants, including SSRIs, entitled, "What medications are used to treat depression?"
that is available online at the website. Material explaining the symptoms, causes, and
treatment for depression is also available in a booklet entitled "Depression" that is available
online at the website. Both publications can also be obtained through a toll-free number,
866-615-6464. The web site also provides references, summaries of study results in language
intended for the lay public, and information about clinical trials currently recruiting patients.
The Depression and Bipolar Support Alliance (available at the website or 800-826-3632) is a
national organization whose mission is to educate members about depression and how to cope
with it. Other functions include increasing public awareness of the illness and advocating for
more research and services. The organization is administered and maintained by patients and
family members, and has local chapters.

The National Alliance on Mental Illness (available at the website or 800-950-6264) is a

similarly structured organization devoted to providing education, support, and advocacy for
patients with any mental illness. Depression is one of their priorities.

SUMMARY

● Specific drugs – Serotonin modulators include nefazodone, trazodone, vilazodone, and

vortioxetine. (See 'Introduction' above.)

● Pharmacokinetics – The pharmacokinetic parameters of serotonin modulators are

presented in the table ( table 6). Nefazodone may inhibit the hepatic enzyme CYP3A4.
(See 'Drug interactions and metabolism' above.)

● What to discuss with patients – Prior to prescribing serotonin modulators, clinicians

should discuss drug interactions, side effects ( table 3), time to response, and stopping
the medication.

● Medical tests and plasma levels – No specific medical tests are required before starting
serotonin modulators, and drug plasma levels are not routinely performed. (See 'General
principles' above.)

● Dosing – We suggest starting with a low dose in order to avoid side effects ( table 3) and
slowly increasing the dose. Starting doses and target dose ranges of each serotonin
modulator are listed in the table ( table 5). (See 'Dosing' above.)

● Adverse effects

• Serotonin syndrome – Serotonin modulators can cause the serotonin syndrome. (See
"Serotonin syndrome (serotonin toxicity)".)

• Nefazodone – Nefazodone can injure the liver and is contraindicated in patients with
elevated serum transaminases, active liver disease, or liver injury due to previous
nefazodone treatment. Other adverse effects include nausea, somnolence, dry mouth,
dizziness, constipation, weakness, and blurred vision. (See 'Nefazodone' above.)
 • Trazodone – Common adverse effects of trazodone include somnolence, dry mouth,
dizziness, fatigue, constipation, vision blurred, sexual dysfunction, orthostatic
hypotension, and headache. Rare but serious side effects include priapism and cardiac
arrhythmias. (See 'Trazodone' above.)

• Vilazodone – Adverse effects of vilazodone include diarrhea, nausea, sexual

dysfunction, dizziness, insomnia, and vomiting. (See 'Vilazodone' above.)

• Vortioxetine – The primary adverse effect of vortioxetine is nausea. Other potential

side effects include vomiting and constipation. (See 'Vortioxetine' above.)

Use of UpToDate is subject to the Terms of Use.

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30. Thompson JW Jr, Ware MR, Blashfield RK. Psychotropic medication and priapism: a
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31. Serretti A, Mandelli L. Antidepressants and body weight: a comprehensive review and meta-
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32. Gamble DE, Peterson LG. Trazodone overdose: four years of experience from voluntary
reports. J Clin Psychiatry 1986; 47:544.
33. Henry JA, Ali CJ, Caldwell R, Flanagan RJ. Acute trazodone poisoning: clinical signs and
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34. de Meester A, Carbutti G, Gabriel L, Jacques JM. Fatal overdose with trazodone: case report
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35. McCormack PL. Vilazodone: a review in major depressive disorder in adults. Drugs 2015;
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36. Rickels K, Athanasiou M, Robinson DS, et al. Evidence for efficacy and tolerability of
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37. Frampton JE. Vilazodone: in major depressive disorder. CNS Drugs 2011; 25:615.
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66:356.
39. Citrome L. Vortioxetine for major depressive disorder: An indirect comparison with
duloxetine, escitalopram, levomilnacipran, sertraline, venlafaxine, and vilazodone, using
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pril, 2014. US National Library of Medicine. (Available online at www.dailymed.nlm.nih.gov.
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41. Pae CU, Wang SM, Han C, et al. Vortioxetine: a meta-analysis of 12 short-term, randomized,
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Neurosci 2015; 40:174.
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placebo-controlled trials of vortioxetine for the treatment of major depressive disorder in
adults. Eur Neuropsychopharmacol 2016; 26:979.

43. Baldwin DS, Florea I, Jacobsen PL, et al. A meta-analysis of the efficacy of vortioxetine in
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44. McIntyre RS, Harrison J, Loft H, et al. The Effects of Vortioxetine on Cognitive Function in
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Trials. Int J Neuropsychopharmacol 2016.
45. Thase ME. US Food and Drug Administration's review of the novel antidepressant
vortioxetine. J Clin Psychiatry 2015; 76:e120.

46. 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; 76:8.
47. Bang-Andersen B, Ruhland T, Jørgensen M, et al. Discovery of 1-[2-(2,4-
dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for
the treatment of major depressive disorder. J Med Chem 2011; 54:3206.

48. Kelliny M, Croarkin PE, Moore KM, Bobo WV. Profile of vortioxetine in the treatment of
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49. Mørk A, Pehrson A, Brennum LT, et al. Pharmacological effects of Lu AA21004: a novel
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50. Sanchez C, Asin KE, Artigas F. Vortioxetine, a novel antidepressant with multimodal activity:
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51. Trintellix (vortioxetine), package insert. Deerfield, IL; Lundbeck; 2016 https://us.trintellix.co
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treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2014;
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54. Boulenger JP, Loft H, Florea I. A randomized clinical study of Lu AA21004 in the prevention
of relapse in patients with major depressive disorder. J Psychopharmacol 2012; 26:1408.

55. Meeker AS, Herink MC, Haxby DG, Hartung DM. The safety and efficacy of vortioxetine for
acute treatment of major depressive disorder: a systematic review and meta-analysis. Syst
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56. Li G, Wang X, Ma D. The efficacy and safety of 10 mg vortioxetine in the treatment of major
depressive disorder: a meta-analysis of randomized controlled trials. Neuropsychiatr Dis
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57. Baldwin DS, Hansen T, Florea I. Vortioxetine (Lu AA21004) in the long-term open-label
treatment of major depressive disorder. Curr Med Res Opin 2012; 28:1717.
58. Alam MY, Jacobsen PL, Chen Y, et al. Safety, tolerability, and efficacy of vortioxetine (Lu
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59. Jacobsen PL, Harper L, Chrones L, et al. Safety and tolerability of vortioxetine (15 and 20 
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60. Filippov G, Christens P. Vortioxetine (Lu AA21004 15 and 20 mg/day: open-label long-term
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(Suppl. 2):S325.
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63. Alvarez E, Perez V, Dragheim M, et al. A double-blind, randomized, placebo-controlled,

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Topic 86265 Version 21.0
GRAPHICS

Cytochrome P450 3A (including 3A4) inhibitors and inducers

Strong inhibitors Moderate Strong inducers Moderate inducers

inhibitors

Atazanavir Amiodarone* Apalutamide Bexarotene

Ceritinib Aprepitant Carbamazepine Bosentan
Clarithromycin Berotralstat Enzalutamide Cenobamate
Cobicistat and Cimetidine* Fosphenytoin Dabrafenib
cobicistat- Conivaptan Lumacaftor Dexamethasone¶
containing Crizotinib Lumacaftor- Dipyrone
coformulations ivacaftor
Cyclosporine* Efavirenz
Darunavir Mitotane
Diltiazem Elagolix, estradiol,
Idelalisib Phenobarbital and norethindrone
Duvelisib
Indinavir Phenytoin therapy packΔ
Dronedarone
Itraconazole Primidone Eslicarbazepine
Erythromycin
Ketoconazole Rifampin Etravirine
Fedratinib
Levoketoconazole (rifampicin) Lorlatinib
Fluconazole
Lonafarnib Mitapivat
Fosamprenavir
Lopinavir Modafinil
Fosaprepitant*
Mifepristone Nafcillin
Fosnetupitant-
Nefazodone palonosetron Pexidartinib
Nelfinavir Grapefruit juice Rifabutin
Nirmatrelvir- Imatinib Rifapentine
ritonavir Sotorasib
Isavuconazole
Ombitasvir- (isavuconazonium St. John's wort
paritaprevir- sulfate)
ritonavir
Lefamulin
Ombitasvir-
Letermovir
paritaprevir-
Netupitant
ritonavir plus
dasabuvir Nilotinib

Posaconazole Ribociclib

Ritonavir and Schisandra

ritonavir-containing Verapamil
coformulations
Saquinavir
Telithromycin
Tucatinib
Voriconazole
 For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can
alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver
enzymes, including CYP3A4, for elimination or activation.
These classifications are based upon US Food and Drug Administration (FDA) guidance.[1,2]
Other sources may use a different classification system resulting in some agents being classified
differently.
Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose,
method, and timing of administration.
Weak inhibitors and inducers are not listed in this table with exception of a few examples.
Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg,
target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index).
Accordingly, specific interactions should be checked using a drug interaction program such as the
Lexicomp drug interactions program included within UpToDate.
Refer to UpToDate topics on specific agents and indications for further details.

* Classified as a weak inhibitor of CYP3A4 according to FDA system.[1]

¶ Classified as a weak inducer of CYP3A4 according to FDA system.[1]

Δ The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4
induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer.
Norethindrone and estradiol are not CYP3A4 inducers.

Data from: Lexicomp Online (Lexi-Interact). Copyright © 1978-2022 Lexicomp, Inc. All Rights Reserved.

References:
1. Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance
for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions.
2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and
Inducers. Available at: FDA.gov website.

Graphic 76992 Version 87.0

Cytochrome P450 2D6 (CYP2D6) inhibitors

Strong inhibitors Moderate inhibitors

Bupropion Abiraterone

Dacomitinib Cinacalcet

Fluoxetine Darifenacin

Paroxetine Darunavir

Quinidine Duloxetine

Tipranavir Givosiran

Lorcaserin

Mirabegron

Perhexiline*

Rolapitant

Terbinafine (systemic)

Thioridazine

This table lists strong and moderate CYP450 2D6 inhibitors; there are no known clinically relevant
inducers of CYP2D6.
Inhibitors of CYP2D6 metabolism listed above can alter serum concentrations of other drugs that
are dependent on CYP2D6 liver enzymes for activation or elimination:
Codeine, tamoxifen, and tramadol are examples of drugs that require transformation by
CYP2D6 to their active metabolite(s). The presence of CYP2D6 inhibitors can decrease efficacy
of these drugs.
Amitriptyline, clozapine, desipramine, flecainide, haloperidol, nortriptyline, risperidone, and
valbenazine are examples of drugs that are eliminated by CYP2D6 metabolism. The presence
of CYP2D6 inhibitors can increase levels of these drugs.
The specific effect of CYP2D6 inhibition on CYP2D6 substrate blood levels varies widely among
individual patients because of variability in CYP2D6 function (ie, genetic polymorphism). Poor,
intermediate, extensive, and ultrarapid CYP2D6 function types have been well characterized.
These classifications are based upon US Food and Drug Administration (FDA) guidance.[1,2]
Other sources may use a different classification system resulting in some agents being classified
differently.
For additional information on CYP2D6 drug metabolism, refer to the UpToDate topic review of
pharmacogenomics, section on CYP2D6 variants, and clinical topic reviews of the use of these
agents and their drug interactions.
Specific drug interactions and management suggestions may be determined by using the
Lexicomp drug interactions program included with UpToDate. Refer to UpToDate topics on
specific agents and indications for further details.
CYP2D6: cytochrome P450 2D6.

* Not available in United States.

Data from: Lexicomp Online (Lexi-Interact). Copyright © 1978-2022 Lexicomp, Inc. All Rights Reserved.

References:
1. US Food and Drug Administration. Clinical drug interaction studies — Cytochrome P450 enzyme- and transporter-
mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-
transporter-mediated-drug-interactions (Accessed on June 5, 2020).
2. US Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and
Inducers. Available at: FDA.gov website.

Graphic 116164 Version 19.0

Side effects of antidepressant medications[1-7]

Orthostatic
Drug Anticholinergic Drowsiness Insomnia/agitation
hypotension

Selective serotonin reuptake inhibitors¶

Citalopram 0 0 1+ 1+

Escitalopram 0 0 1+ 1+

Fluoxetine 0 0 2+ 1+

Fluvoxamine 0 1+ 1+ 1+

Paroxetine 1+ 1+ 1+ 2+

Sertraline 0 0 2+ 1+

Atypical agents

Agomelatine§ 0 1+ 1+ 0
(not available in
United States)

Bupropion 0 0 2+ (immediate release) 0

1+ (sustained release)

Mirtazapine 1+ 4+ 0 0

Serotonin-norepinephrine reuptake inhibitors¶,¥

Desvenlafaxine‡ 0 0 1+ 0

Duloxetine 0 0 1+ 0

Levomilnacipran‡ 0† 0 0 to 1+ 0 to 1+

Milnacipran‡ 0 1+ 0 0

Venlafaxine‡ 0 1+ 1+ 0

Serotonin modulators

Nefazodone** 1+ 2+ 0 1+

Trazodone 0 4+ 0 1+ (hypnotic
dose)

3+
(antidepressant
dose)

Vilazodone 0 0 2+ 0

Vortioxetine 0 0 0 0
 Tricyclic and tetracyclic antidepressants

Amitriptyline 4+ 4+ 0 3+

Amoxapine 2+ 2+ 2+ 2+

Clomipramine 4+ 4+ 1+ 2+

Desipramine 1+ 2+ 1+ 2+

Doxepin 3+ 3+ 0 2+

Imipramine 3+ 3+ 1+ 4+

Maprotiline 2+ 3+ 0 2+

Nortriptyline 2+ 2+ 0 1+

Protriptyline 2+ 1+ 1+ 2+

Trimipramine 4+ 4+ 1+ 3+

Monoamine oxidase inhibitors

Isocarboxazid 1+ 1+ 2+ 2+

Phenelzine 1+ 2+ 1+ 3+

Selegiline 1+ 0 1+ 1+

Tranylcypromine 1+ 1+ 2+ 2+

Scale: 0 = none; 1+ = slight; 2+ = low; 3+ = moderate; 4+ = high; ND = inadequate data.

SSRI: selective serotonin reuptake inhibitors; SNRI: serotonin-norepinephrine reuptake inhibitor.

* Relative mean QTc prolongation at therapeutic doses; arrhythmogenic potential can be

significantly increased in overdose (eg, for cyclic antidepressants, bupropion, citalopram, duloxetine,
venlafaxine, and some others). QTc prolongation classifications are based upon US Food and Drug
Administration guidance.[6] The use of other classification criteria may lead to some agents being
classified differently by other sources. Refer to UpToDate topics on acquired long QT syndrome and
acute antidepressant poisonings.

¶ All SSRIs and SNRIs can cause transient nausea and gastrointestinal discomfort when starting
therapy or increasing dose.

Δ Based upon reports of dose-related QTc prolongation and arrhythmia, the maximum
recommended dose of citalopram is 40 mg/day in most patients; for patients at increased risk of
elevated serum concentrations (eg, age >60 years, significant hepatic impairment, receiving
interacting medications), the maximum daily dose is 20 mg.

◊ Sertraline is associated with higher rates of diarrhea.

§ Agomelatine may be hepatotoxic and is contraindicated in any degree of liver impairment.

Transaminase monitoring is required.

¥ SNRIs do not have significant anticholinergic effects. However, SNRIs can produce anticholinergic-
like effects (which appear to be mediated by noradrenergic stimulation) such as dry mouth and
constipation, and they should be used with caution in narrow angle glaucoma. Levomilnacipran is
associated with urinary hesitancy.

‡ May cause persistent dose-related increases in blood pressure (primarily diastolic) and heart rate.
Monitor blood pressure regularly.

† Levomilnacipran can cause dose-dependent urinary hesitancy.

** Caution: can cause liver failure; transaminase monitoring is required. Withdrawn from market due
to hepatotoxicity in many countries.

¶¶ Trazodone is associated rarely with priapism, which is considered a medical emergency. Refer to
UpToDate topic on serotonin modulators.

ΔΔ Gastrointestinal effects include nausea, vomiting, and diarrhea.

◊◊ Gastrointestinal forms of anticholinergic side effects include: dry mouth, constipation, epigastric
distress, decreased esophagogastric tone. Refer to "Anticholinergic" data column for frequency
rankings.

References:
1. Wenzel-Seifert K, Wittmann M, Haen E: QTc prolongation by psychotropic drugs and the risk of torsade de pointes.
Dtsch Arztebl Int 2011; 108:687.
2. Reichenpfader U, Gartlehner G, Morgan LC, et al. Sexual dysfunction associated with second generation
antidepressants in patients with major depressive disorder: Results from a systematic review with network meta-
analysis. Drug Saf 2014; 37:19.
3. Howland RH. A benefit-risk assessment of agomelatine in the treatment of major depression. Drug Saf 2011; 34:709.
4. Lexicomp Online. Copyright © 1978-2022 Lexicomp, Inc. All Rights Reserved.
5. 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; 30:242.
6. Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs –
Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017. Available at:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073161.pdf.
7. The American Psychiatric Association Publishing Textbook of Psychopharmacology, 5th ed, Schatzberg AF, Nemeroff
CB (Eds), American Psychiatric Association Publishing 2017.

Graphic 62488 Version 24.0

Examples of agents that can precipitate serotonin syndrome

Mechanism Agent involved

Increases serotonin Tryptophan, oxitriptan*

formation

Increases release of Amphetamines (including dextroamphetamine, methamphetamine)

serotonin
MDMA (ecstasy)

Amphetamine derivatives (including fenfluramine, dexfenfluramine,

phentermine)

Cocaine

Mirtazapine

Impairs serotonin reuptake Cocaine

from the synaptic cleft into
MDMA (ecstasy)
the presynaptic neuron
Meperidine

Tramadol

Pentazocine

Dextromethorphan

Selective serotonin reuptake inhibitors (SSRIs; citalopram,

escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline)

Serotonin-norepinephrine reuptake inhibitors (SNRIs; desvenlafaxine,

duloxetine, levomilnacipran, milnacipran, and venlafaxine)

Sibutramine

Bupropion¶

Serotonin modulators (nefazodone, trazodone, vilazodone, and

vortioxetine)

Cyclic antidepressants (amitriptyline, amoxapine, clomipramine,

desipramine, doxepin, imipramine, maprotiline, nortriptyline,
protriptyline, trimipramine)

St. John's wort (Hypericum perforatum)

5-HT3 receptor antagonists (dolasetron, granisetron, ondansetron,

palonosetron)

Cyclobenzaprine

Methylphenidate, dexmethylphenidate

Inhibits serotonin MAO inhibitors, nonselective (isocarboxazid, linezolid, phenelzine,

metabolism by inhibition of Syrian rue [Peganum harmala, harmine], and tranylcypromine)
 MAO MAO-A inhibitorsΔ (methylene blue, moclobemide)

MAO-B inhibitorsΔ (rasagiline, safinamide, and selegiline)

Direct serotonin receptor Buspirone

agonist
Triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan,
sumatriptan, zolmitriptan)

Ergot derivatives (including dihydroergotamine, ergotamine,

methylergonovine)

Fentanyl

Lysergic acid diethylamide (LSD)

Lasmiditan

Lorcaserin◊

Metaxalone

Increases sensitivity of Lithium

postsynaptic serotonin
receptor

Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic

activity in the CNS. Serotonin syndrome can occur with therapeutic medication use, overdose, or as
the result of additive or synergistic effects due to drug interaction(s). For additional information on
clinical use and precautions related to serotonergic effects, refer to UpToDate topic reviews including
the serotonin syndrome topic and Lexicomp drug monographs and drug interactions tool included
within UpToDate.

MAO: monoamine oxidase; CNS: central nervous system; OTC: over-the-counter.

* Within the United States, tryptophan (L-tryptophan) and oxitriptan are available as OTC
supplements. In other areas, these agents may be available OTC or by prescription.

¶ Bupropion inhibits neuronal uptake of dopamine and norepinephrine without known effects on
serotonin; however, there have been case reports of serotonin syndrome when co-administered with
other serotonergic drugs (eg, SSRIs); in some cases this may have been due to bupropion's inhibition
of SSRI metabolism by CYP2D6.

Δ MAO selectivity is lost at higher doses and with drug interactions that increase serum drug
concentrations. Inhibition of MAO-A is more likely to result in increased levels of serotonin within the
CNS (ie, increased risk of serotonin syndrome) relative to MAO-B inhibition.

◊ Withdrawn from United States market.

Data from:
1. Boyer EW, Shannon M. The serotonin syndrome. NEJM 2005; 352:1112.
2. Finberg JPM, Rabey JM. Inhibitors of MAO-A and MAO-B in psychiatry and neurology. Front Pharmacol 2016; 7:340.
3. Lexicomp Online. Copyright © 1978-2022 Lexicomp, Inc. All Rights Reserved.
Graphic 64604 Version 21.0
Unipolar depression in adults: Antidepressant doses*

Usual total
Usual total dose Extreme daily dose
starting dose per
Drug per day
range

day

(mg) (mg)¶
(mg)¶

Selective serotonin reuptake inhibitors

Citalopram 20 20 to 40Δ 10 to 40Δ

Escitalopram 10 10 to 20 5 to 30

Fluoxetine 20 20 to 60 10 to 80

Fluvoxamine 50 50 to 200 25 to 300

Fluvoxamine CR 100 100 to 200 100 to 300

Paroxetine 20 20 to 40 10 to 50

Paroxetine CR 25 25 to 50 12.5 to 62.5

Sertraline 50 50 to 200 25 to 300

Serotonin-norepinephrine reuptake inhibitors

Desvenlafaxine 25 to 50 50 to 100 50 to 400◊

Duloxetine 30 to 60 60 30 to 120§

Levomilnacipran 20 40 to 80 20 to 120

Milnacipran 12.5 100 to 200 50 to 300

Venlafaxine 37.5 to 75 75 to 375 75 to 375

Venlafaxine XR 37.5 to 75 75 to 225 75 to 375

Atypical agents

Agomelatine¥ (not 25 25 to 50 25 to 50
available in United
States)

Bupropion 200 300 (maximum single 100 to 450

dose 150 mg)

Bupropion SR 12 150 300 (maximum single 150 to 400

hour dose 200 mg)

Bupropion XL 24 150 300 150 to 450 (United

hour States)

150 to 300 (Europe)

Bupropion 174 348 174 to 522

 hydrobromide 24
hour

Mirtazapine 15 15 to 45 7.5 to 60

Serotonin modulators

Nefazodone‡ 200 300 to 600 50 to 600

Trazodone 100 200 to 400 100 to 600

Vilazodone 10 40 10 to 40

Vortioxetine 10 20 5 to 20

Tricyclics and tetracyclics†

Amitriptyline 25 150 to 300 10 to 300

Amoxapine 25 200 to 300 25 to 400

Clomipramine 25 100 to 250 25 to 300

Desipramine 25 150 to 300 25 to 300

Doxepin 25 100 to 300 10 to 300

Imipramine 25 150 to 300 10 to 300

Maprotiline 25 100 to 225 25 to 225

Nortriptyline 25 50 to 150 10 to 200

Protriptyline 10 15 to 60 5 to 60

Trimipramine 25 150 to 300 25 to 300

Monoamine oxidase inhibitors†

Isocarboxazid 10 10 to 40 10 to 60

Phenelzine 15 15 to 90 7.5 to 90

Selegiline 6 mg/24 hour patch 6 to 12 mg/24 hour 6 to 12 mg/24 hour

transdermal patch patch

Tranylcypromine 10 30 to 60 10 to 60

* Total daily oral doses shown in table may need to be given as two or three equally divided doses
per day, depending on specific antidepressant and other factors. For additional detail, refer to
individual Lexicomp drug monographs included with UpToDate.

¶ Lower doses may be useful for initiating or maintaining patients who are older or medically
compromised (eg, renal or hepatic illness), or drug-sensitive patients, as well as patients with a low
body mass index. High doses may be used for medications that are well tolerated but ineffective at
lower doses. In patients with panic disorder, UpToDate contributors initiate treatment at one-half or
less of the usual starting dose shown and titrate more gradually; refer to clinical topic on
management of panic disorder.
Δ Maximum recommended dose of citalopram is 20 mg for patients >60 years of age, with significant
hepatic insufficiency, or taking interacting medications that can increase citalopram levels. For more
information refer to the UpToDate topic on unipolar depression in adults and selective serotonin
reuptake inhibitors.

◊ Although desvenlafaxine doses up to 400 mg per day have been studied, there is no evidence that
doses >50 mg per day provide any additional benefit.

§ Although duloxetine doses >60 mg/day did not confer additional benefit in clinical trials, individual
patients may benefit from dose escalation up to a maximum of 120 mg/day.

¥ Agomelatine may be hepatotoxic and is contraindicated with any degree of liver impairment.
Transaminase monitoring is required.

‡ Caution: can cause liver failure. Not available in Europe, Canada, and several other countries.

† Conservative starting doses shown in table are lower than starting doses shown in some other
references. For additional information, refer to UpToDate topics on unipolar depression in adults
and cyclic antidepressants and monoamine oxidase inhibitors for treatment of adults with
depression.

Data from:
1. The American Psychiatric Publishing Textbook of Psychopharmacology, 4th edition. Schatzberg AF, Nemeroff CB (eds);
American Psychiatric Publishing, Inc. Washington, D.C. (2009).
2. Labbate LA, Fava M, Rosenbaum JF, Arana GW. Drugs for the treatment of depression. In: Handbook of Psychiatric
Drug Therapy, 6th ed, Lippincott Williams and Wilkins, Philadelphia 2010. p.54.
3. Gartlehner G, Thaler K, Hill S, Hansen RA. How should primary care doctors select which antidepressants to
administer? Curr Psychiatry Rep 2012; 14:360.
4. Lexicomp Online. Copyright © 1978-2022 Lexicomp, Inc. All Rights Reserved.

Graphic 53818 Version 35.0

Serotonin modulator antidepressants: Pharmacokinetics

Major effects
Time to peak on
Metabolism and
Elimi
Bioavailability plasma metabolism
Drug pharmacokinetic ha
(%) concentration of co-
interactions* (ho
(hours) administered
drugs

Trazodone 65 (taken without 1 (unfed) Hepatic via CYP3A4 None 5 to 9

food)
2 (fed) If taken with a
Up to 100 (taken strong CYP3A4
with food) inhibitor, a dose
reduction of
trazodone may be
warranted

If taken with a
strong CYP3A4
inducer for more
than 7 to 14 days, a
dose increase of
trazodone may be
considered

Monitor clinical
effect and
tolerability; a list of
CYP3A4 inhibitors
and inducers is
provided as a
separate table in
UpToDate

Vilazodone 72 (taken with 4 to 5 Hepatic via CYP3A4 None 25

food)
If taken with a
Decreased if strong inhibitor of
taken on empty CYP3A4, label
stomach recommends specific
dose reduction of
vilazodone

If taken with a
strong inducer of
CYP3A4 for >14 days,
label suggests
 considering a
vilazodone dose
increase

For specific
recommendations
refer to clinical topic
and drug
interactions
program; a list of
CYP3A4 inhibitors
and inducers is
provided as a
separate table in
UpToDate

Vortioxetine 75 (not affected 7 to 11 Hepatic via CYP2D6 None 66

by food) and other CYP
enzymes (eg
CYP3A4)

If taken with a
strong inhibitor of
CYP2D6, label
recommends specific
dose reduction of
vortioxetine

If taken with a
strong CYP inducer
for >14 days, label
suggests
considering a
vortioxetine dose
increase¶

For specific
recommendations
refer to drug
interactions
program; a list of
CYP2D6 inhibitors is
provided as a
separate table in
UpToDate

NefazodoneΔ 20 (may be 0.5 to 2 (delayed Hepatic via CYP3A4 Nefazodone is a 2 to 5

decreased if by food) strong inhibitor
Dose adjustment of 2 to 33
taken with food) of CYP3A4; it
nefazodone may be metab
can significantly
 warranted if taken elevate levels of
with either a strong co-administered
CYP3A4 inhibitor or medications
inducer. The safety that are
of such dependent on
combinations has CYP3A4
not been established metabolism for
and avoidance of clearance
coadministration
should be
considered, if
appropriate;
approach should be
individualized.

A list of strong
CYP3A4 inhibitors
and inducers is
provided as a
separate table in
UpToDate

CYP: cytochrome P450; Pgp: P-glycoprotein efflux transporter.

* The metabolism and clearance of serotonin modulators may be altered by co-administration of

medications that inhibit or induce CYP450 hepatic drug metabolism. Prior to initiating treatment
with a serotonin modulator or adjusting comedications, drug interactions should be analyzed using
the drug interactions program included within UpToDate. Serotonin modulators are not dependent
upon kidney function for a significant amount of clearance of unchanged (ie, active) drug.

¶ Although there are no drugs that are known to be specific inducers of CYP2D6, drugs that induce
other CYP enzymes that are coadministered for 14 days or more can reduce vortioxetine levels; refer
to the drug interactions program to determine specific interactions and management suggestions.

Δ Nefazodone is not a first- or second-line choice. Rare reports of fatal hepatotoxicity have led to
market withdrawal in many countries. Avoid use in setting of liver disease and/or elevated
transaminases.

Lexicomp Online. Copyright © 1978-2022 Lexicomp, Inc. All Rights Reserved with additional data from:

1. Spina E, Trifirò G, Caraci F. Clinically significant drug interactions with newer antidepressants. CNS Drugs 2012; 26:39.
2. Frampton JE. Vilazodone: in major depressive disorder. CNS Drugs 2011; 25:615.
3. 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; 76:8.

Graphic 88062 Version 12.0

Contributor Disclosures
Michael Hirsch, MD No relevant financial relationship(s) with ineligible companies to disclose. Robert J
Birnbaum, MD, PhD Grant/Research/Clinical Trial Support: Eli Lilly[JAK-STAT Immunology].
All of the
relevant financial relationships listed have been mitigated. Peter P Roy-Byrne, MD Employment: Mass
Medical Society [Psychiatry].
All of the relevant financial relationships listed have been mitigated. David
Solomon, MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy