Sem 4 Lectura 2 Inhibidores de Recaptación de Serotonina

16/8/2019 Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects - UpToDate
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Selective serotonin reuptake inhibitors: 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: Jul 2019. | This topic last updated: Jan 31, 2018.
INTRODUCTION
Selective serotonin reuptake inhibitors (SSRIs) are frequently used as first-line antidepressants because of their efficacy, tolerability, and general
safety in overdose. In addition, SSRIs potently treat anxiety, which is often part of depressive syndromes. The SSRIs include:
● Citalopram
● Escitalopram
● Fluoxetine
● Fluvoxamine
● Paroxetine
● Sertraline
The development of antidepressant medications has proceeded through different historical phases. Fluoxetine was synthesized in 1972, and in 1987
was the first SSRI approved by the United States Food and Drug Administration for treatment of major depression [1]. This was followed by sertraline
in 1991, paroxetine in 1993, citalopram in 1998, and escitalopram in 2002. Fluvoxamine was never approved for use as an antidepressant in the
United States, but was approved for treatment of obsessive-compulsive disorder in 1993.
Clinicians use SSRIs to treat many other psychiatric disorders besides depression, including panic disorder, obsessive-compulsive disorder,
generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, bulimia nervosa, binge eating disorder,
premenstrual dysphoric disorder (premenstrual syndrome), and somatoform disorders. See appropriate topic reviews.
The use of SSRIs for treating unipolar depression in adults is reviewed here. Sexual dysfunction associated with SSRIs, the serotonin syndrome, and
management of SSRI overdose are each discussed separately. In addition, initial treatment of depression in adults and managing treatment resistant
depression are discussed separately.
● (See "Sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs): Management".)
● (See "Serotonin syndrome (serotonin toxicity)".)
● (See "Selective serotonin reuptake inhibitor poisoning".)
● (See "Unipolar major depression in adults: Choosing initial treatment".)
● (See "Unipolar depression in adults: Choosing treatment for resistant depression".)
PHARMACOLOGY
Structure — The SSRIs vary considerably in their chemical structure. As examples, the structures of paroxetine and fluvoxamine are unrelated to
other SSRIs [1,2].
Citalopram and escitalopram — Citalopram consists of two stereoisomers that are mirror images of each other and thus not identical in that they
cannot be superimposed upon each other (similar to one’s hands) [3]. One of the stereoisomers, S-citalopram (escitalopram), more potently inhibits
reuptake of serotonin compared with the other stereoisomer.
Pharmacodynamics — SSRIs appear to treat depression by increasing serotonergic activity [4]. They are selective in that they have relatively little
affinity for other types of receptors.
Serotonin (5-hydroxytryptamine or 5-HT) is an indoleamine neurotransmitter released in the brain from neurons originating in the brainstem raphe
nuclei [4,5]. Serotonergic neurotransmission in the brain involves at least 14 different types of pre- and postsynaptic serotonin receptors. All SSRIs
potently decrease the action of the presynaptic serotonin reuptake pump, by 60 to 80 percent [4,6]. This increases the length of time that serotonin is
available in the synapse and increases postsynaptic serotonin receptor occupancy.
However, reuptake inhibition does not appear to be sufficient for the treatment of depression. Reuptake inhibition occurs soon after SSRIs are
started, and the full therapeutic effects of SSRIs may not appear for three to eight (or more) weeks after treatment has started. The full clinical
response may require additional “downstream” effects. As an example of one such effect, the initial increase in synaptic serotonin eventually leads to
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increased production of neuroprotective proteins such as brain-derived neurotrophic factor (BDNF) and Bc1-2 [7]. In addition, treatment with an SSRI
for weeks modifies the serotonergic receptors [4].
The relatively benign side effect profile of the SSRIs is due to their selectivity [4,8]. None of the SSRIs significantly affect alpha-adrenergic,
histaminic, or cholinergic receptors, with the exception of paroxetine, which weakly antagonizes the cholinergic receptor. Side effects that occur with
SSRI treatment are attributed to their effects upon serotonin receptors.
Pharmacokinetics — The absorption, distribution, metabolism, and elimination of the SSRIs are well described [6,9-11].
SSRIs are well absorbed in the gastrointestinal tract and reach peak plasma levels within one to eight hours [4,6]. Food generally does not affect
absorption. Following absorption, SSRIs bind to proteins and are widely distributed throughout the body, including the brain, because they are
lipophilic.
Metabolism and elimination occur largely in the liver [6]. Metabolism of each SSRI except fluvoxamine produces pharmacologically active metabolites
[2]. However, only fluoxetine yields a metabolite (norfluoxetine) that potently inhibits reuptake of serotonin and has antidepressant activity.
The elimination half-life for the SSRIs is approximately one day (ranging from about 20 to 30 hours), except for fluoxetine and fluvoxamine [4,9]. The
half-life for fluoxetine ranges from 1 to 3 days, and for its metabolite norfluoxetine, 4 to 16 days. Fluvoxamine has a half-life of approximately 15
hours.
Drug-drug interactions — Some SSRIs are moderate to potent inhibitors of hepatic cytochrome P450 drug metabolism and can cause drug-drug
interactions by altering blood levels of other medicines that depend on these enzymes for clearance or activation. Citalopram and escitalopram inhibit
liver enzymes less than other SSRIs and are thus the SSRIs of choice for situations in which drug-drug interactions are a concern [6,12]. Sertraline is
a reasonable alternative [8].
The specific cytochrome enzymes that each drug and their metabolites potently or moderately inhibit are as follows:
● Citalopram – none
● Escitalopram – none
● Fluoxetine – CYP2D6 (potent) and 2C19 (moderate)
● Fluvoxamine – CYP1A2 (potent) and 2C19 (moderate)
● Paroxetine – CYP2D6 (potent)
● Sertraline – none
All SSRIs weakly inhibit one or more cytochrome P450 drug metabolizing enzyme. However, weak inhibition of CYP450 metabolism rarely alters the
levels or activity of other medications to a degree that is clinically significant. Additional information about each drug and its inhibition of hepatic
enzymes can be found in the individual drug information topics in the section on Metabolism/Transport Effects.
Among the numerous potential drug-drug interactions that may occur with SSRIs is the interaction between tamoxifen and fluoxetine or paroxetine.
Tamoxifen is used to treat or prevent recurrence of breast cancer, and is a prodrug that is metabolized by cytochrome P450 2D6 to the active
metabolite. Although a review concluded that paroxetine and fluoxetine should not be prescribed to patients receiving tamoxifen [13], more recent
studies indicate that the clinical significance of the drug-drug interactions is not clear. (See "Mechanisms of action of selective estrogen receptor
modulators and down-regulators", section on 'Tamoxifen resistance in breast cancer'.).
Specific interactions of SSRIs with other medications may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate.
This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug
interactions.
PRESCRIBING SSRIs
Treating depression with SSRIs requires use of general pharmacotherapy principles as well as knowledge about the proper dose.
SSRIs are contraindicated in patients with hypersensitivity, as well as patients who received a monoamine oxidase inhibitor (MAOI) in the previous
two weeks, because SSRIs and MAOIs can interact to cause the serotonin syndrome. In addition, clinicians should exercise caution in prescribing
SSRIs with other serotonergic medications (eg, lithium or serotonin-norepinephrine reuptake inhibitors). The serotonin syndrome is discussed
separately (see "Serotonin syndrome (serotonin toxicity)").
The choice of a particular SSRI is based upon individual patient tolerance, cost, and clinician experience, because efficacy appears to be
comparable.
General principles
Guidelines to review with patients — Prior to prescribing SSRIs, side effects, time to response, drug interactions, and stopping the medication
should be discussed with patients. (See 'Side effects' below.)
Clinicians should review common side effects and the need to take the medication as prescribed rather than on an as needed basis. Patients should
also be informed that although some response may occur within the first two weeks of treatment, it may take several weeks to reach full clinical
effect.
Possible drug interactions should also be reviewed, including other drugs (eg, monoamine oxidase inhibitors) that increase serotonergic activity and
the possibility of the potentially fatal serotonin syndrome. (See 'Drug-drug interactions' above and "Serotonin syndrome (serotonin toxicity)".)
In addition, clinicians should discuss abrupt discontinuation of SSRIs, which may precipitate dysphoria, dizziness, gastrointestinal distress, fatigue,
chills, and myalgias. The discontinuation syndrome associated with suddenly stopping SSRIs is discussed separately. (See "Discontinuing
antidepressant medications in adults", section on 'SSRIs'.)
Medical tests and plasma levels — No specific medical tests are required before starting an SSRI [8].
SSRI serum concentrations are not routinely performed. Nevertheless, therapeutic drug monitoring may be indicated to assess adherence, determine
whether unresponsive patients are rapid metabolizers, monitor special populations (eg, children and adolescents; elderly, pregnant or breastfeeding
patients; and patients with hepatic disease), determine whether concomitant drugs are affecting SSRI serum concentrations, and to establish that it is
safe to begin another serotonergic drug (eg, a monoamine oxidase inhibitor) after discontinuing an SSRI, to avoid the serotonin syndrome [14]. (See
"Serotonin syndrome (serotonin toxicity)".)
Although measuring SSRI serum concentrations is not standard practice, several studies have attempted to correlate plasma levels and therapeutic
effects. Therapeutic reference ranges suggested by one practice guideline are as follows [14]:
● Citalopram – 50 to 110 ng/mL

● Escitalopram – 15 to 80 ng/mL
● Fluoxetine plus norfluoxetine – 120 to 500 ng/mL
● Fluvoxamine – 60 to 230 ng/mL
● Paroxetine – 30 to 120 ng/mL
● Sertraline – 10 to 150 ng/mL
Response time — Many depressed patients treated with an SSRI respond within one or two weeks, while other patients require several more
weeks of treatment [15-17]. Severity of illness and comorbid disease may affect how quickly depressed patients respond to treatment with SSRIs.
Time to response was evaluated in the following studies:
● A meta-analysis of 28 randomized trials (5872 patients with unipolar depression) found that SSRIs begin to have a small clinically beneficial
effect beyond the effect of placebo by the end of the first week of treatment [15]. Incremental improvement attributable to the SSRI continued at
a decreasing rate for the next five weeks. A second analysis of five studies (1365 patients) showed that response (≥ 50 percent reduction in
baseline depression rating scale score) by week one was 64 percent more likely in patients who received an SSRI compared with patients who
received placebo (relative risk 1.64, 95% CI 1.2-2.25).
● An open label study of 384 outpatients with major depression, treated with fluoxetine for eight weeks, evaluated time to sustained response,
defined as a 30 percent decrease in the baseline depression rating scale score that persisted and led to a 50 percent decrease by week eight
[16]. Patients were not severely ill in that none of the patients had previously failed an adequate antidepressant trial during the current episode.
Among the 182 patients who responded, 56 percent responded at week two, 25 percent at week four, and 9 percent at week six (the cumulative
probabilities of response were thus 56, 80, and 90 percent).
● Time to response was longer in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (2876 outpatients at 41 sites),
which treated patients who were more ill (more than 75 percent of the patients had recurrent or chronic depression, and most had multiple
comorbid medical and psychiatric illnesses) [17]. The average mean time to response (at least 50 percent reduction in baseline depression
rating scale score) to citalopram was six weeks. Among patients who eventually responded, 56 percent did so at or after eight weeks of
treatment. The average mean time to remission was seven weeks.
Pregnancy — It is not clearly established if SSRIs differ in their safety for use during pregnancy. Fluoxetine appears to be safe while paroxetine
may be associated with an increased risk of congenital heart defects [1,4].
Treatment of pregnant women with SSRIs and other antidepressants is discussed separately. (See "Severe antenatal unipolar major depression:
Treatment".)
Administration — The frequency and timing of each dose varies between SSRIs.
The entire dose of an SSRI is generally taken once a day because the elimination half-life averages about 24 hours [4]. Fluvoxamine is taken in two
divided doses when the total daily dose exceeds 100mg, because it has a shorter half-life.
Clinicians usually advise patients to take SSRIs in the morning to minimize insomnia, although there is no evidence that this side effect is related to
dose timing. Fluvoxamine is usually taken at bedtime at doses of 100 mg or less, and patients who experience drowsiness with other SSRIs can take
the drug at bedtime.
Sertraline is the only SSRI whose absorption is increased when taken with food. Although taking the other SSRIs on a full stomach will not improve
absorption, it may help prevent gastrointestinal distress.
Dose — We suggest starting with the lowest minimal effective dose in order to avoid side effects and slowly increasing the dose as needed.
Equipotent starting doses for the SSRIs are (table 1):
● Citalopram – 20 mg
● Escitalopram – 10 mg
● Fluoxetine – 20 mg
● Fluvoxamine – 50 to 100 mg
● Paroxetine – 20 mg
● Sertraline – 50 mg
Depressed patients with a comorbid anxiety disorder may tolerate the medication better by starting with half of the suggested dose. Dose
adjustments are made according to patient response, tolerability, and clinical urgency.
Finding the effective dose involves a process of trial and error. After starting an SSRI, response should be monitored over the next four weeks. If
there is an inadequate response but good tolerability after four weeks of treatment at the recommended minimum effective dose, the dose can be
slowly titrated upward. Further dose increases can generally be made at one to four week intervals as needed. Although genotype testing (eg,
CYP2D6 and CYP2C19 polymorphisms) is available to guide choosing a specific SSRI and dosing the drug [18], the tests are not standard practice
and we suggest not using them because of the preliminary nature of the data that underlie the tests.
Patients who recover from an episode of major depression should receive maintenance treatment with the full dose that successfully resolved the
episode, rather than a lower dose [19].
Citalopram — We suggest an initial dose of 20 mg in the morning. Older patients and those sensitive to side effects can be started at a dose of
10 mg.
The dose range is 20 to 40 mg once per day [4,8]. The dose can be titrated up in increments of 10 or 20 mg per day, every one or four weeks.
Clinicians should not prescribe citalopram at doses greater than 40 mg per day. The United States Food and Drug Administration issued a warning
that citalopram causes dose-dependent QT interval prolongation, which can lead to a life-threatening cardiac arrhythmia, torsade de pointes [20]. A
subsequent warning recommended a maximum dose of 20 mg per day in patients at risk for increased serum concentrations of citalopram, including
patients with [21]:
● Hepatic impairment
● Age >60 years
● CYP2C19 variants that slowly metabolize citalopram
● Concomitant medications that inhibit CYP2C19. Specific interactions of citalopram with other medications may be determined using the drug
interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the
individual drug information topics in the section on Drug interactions.
We typically review a baseline electrocardiogram (ECG) prior to prescribing citalopram doses greater than 40 mg per day, or 20 mg per day in
patients at risk for increased serum concentrations. In addition, we suggest an ECG when starting citalopram in any patient receiving concurrent
medications that can prolong the QTc interval and patients who are suffering palpitations or syncope. Additional information about the cardiac effects
of citalopram and other SSRIs is discussed elsewhere in this topic. (See 'Cardiac' below.)
The FDA does not make any recommendation about testing for CYP2C19 poor metabolizers, nor is it standard practice to test patients who are going
to receive citalopram.
A liquid concentrate formulation is available.
Escitalopram — We suggest an initial dose of 10 mg in the morning. Older patients and those sensitive to side effects can be started at a dose of
5 mg.
The standard dose range is 10 to 20 mg once per day [4,8]. The dose can be titrated up in increments of 5 or 10 mg per day, after one to four weeks.
Doses up to 30 mg per day have been used.
Escitalopram is a single isomer formulation of citalopram, and the United States Food and Drug Administration (FDA) has issued warnings that
citalopram causes dose-dependent QT interval prolongation that can lead to arrhythmias [20,21]. Although an analysis of a randomized trial by the
FDA found that escitalopram also caused dose-dependent QT interval prolongation, the finding was not deemed clinically significant, and no warning
was issued regarding escitalopram. Cardiac effects of escitalopram and other SSRIs and the structural relationship between escitalopram and
citalopram are discussed elsewhere in this topic. (See 'Cardiac' below and 'Citalopram and escitalopram' above.)
Fluoxetine — We suggest an initial dose of 20 mg in the morning. Older patients and those sensitive to side effects can be started at a dose of 10
mg.
The standard dose range is 20 to 40 mg once per day [4,8]. The dose can be titrated up in increments of 10 or 20 mg per day, every four weeks.
Doses up to 80 mg per day have been used.
Other formulations of fluoxetine are available, including a liquid concentrate. In addition, there is a 90 mg delayed release capsule taken once per
week. Patients must be stabilized on fluoxetine 20mg daily prior to switching to once-weekly dosing. The manufacturer recommends waiting seven
days after the last 20 mg daily dose of fluoxetine before beginning the once weekly regimen with the 90 mg delayed release formulation.
Fluoxetine should not be prescribed with tamoxifen. (See 'Drug-drug interactions' above.)
Fluvoxamine — We suggest an initial dose of 50 mg at bedtime. Older patients and those sensitive to side effects can be started at a dose of 25
mg.
The standard dose range is 50 to 200 mg per day [4,8]. The dose can be titrated up from the starting dose of 50 mg by increments of 25 or 50 mg per
day, every several days to two weeks. When the dose exceeds 100 mg per day, it should be given in two divided doses. The two doses may be
either equal, or a larger portion may be given at bedtime. The dose may be increased further by increments of 50 mg per day, every several days to
two weeks. Doses up to 300 mg per day have been used.
It is also available in an extended release formulation (100 and 150 mg) for once per day dosing at higher doses.
Paroxetine — We suggest an initial dose of 20 mg in the morning. Older patients and those sensitive to side effects can be started at a dose of
10 mg.
The standard dose range is 20 to 40 mg once per day [4,8]. The dose can be titrated up in increments of 10 or 20 mg per day, every one or four
weeks. Doses up to 50 mg per day have been used.
Other formulations of paroxetine are available, including a liquid concentrate. In addition, there is an enteric coated, controlled-release formulation. It
may cause less nausea than the immediate release formulation for patients who are experiencing this adverse effect; otherwise, there is no
compelling reason to change from one formulation to the other. The controlled-release formulation is less bioavailable, thus, a 12.5 mg dose of the
controlled release formulation is equivalent to 10 mg of regular release paroxetine. The recommended starting dose of the controlled-release
formulation is 25 mg/day; the maximum dose is 75 mg/day.
Paroxetine should not be prescribed with tamoxifen. (See 'Drug-drug interactions' above.)
Sertraline — We suggest an initial dose of 50 mg in the morning. Older patients and those sensitive to side effects can be started at a dose of 25
mg.
The standard dose range is 50 to 150 or 200 mg once per day [4,8]. The dose can be titrated up in increments of 25 or 50 mg per day, every one to
four weeks. Doses up to 300 mg per day have been used.
Sertraline reaches its peak plasma concentration sooner when taken with food [22].
SIDE EFFECTS
Overview — The SSRIs tend to have similar side effect profiles [4]. However, certain SSRIs may be more likely to cause specific side effects (table
2) [23]. Thus, some patients who cannot tolerate one SSRI may do well with another [8].
The SSRIs are often first-line treatment for depression because they are better tolerated than tricyclics or monoamine oxidase inhibitors [4,8,23,24].
In three-arm randomized trials, discontinuation because of an adverse event was typically lowest for placebo, intermediate for the SSRI, and highest
for the tricyclic (5 to 10 versus 10 to 20 versus 30 to 35 percent) [4].
Nevertheless, SSRIs often cause adverse side effects. A telephone survey of 401 patients treated with an SSRI for major depression found that 55
percent suffered at least one bothersome side effect during the first three months of treatment [24]. The incidence of each bothersome side effect
was:
● Sexual dysfunction – 17 percent

● Drowsiness – 17 percent
● Weight gain – 12 percent
● Insomnia – 11 percent
● Anxiety – 11 percent
● Dizziness – 11 percent
● Headache – 10 percent
● Dry mouth – 7 percent
● Blurred vision – 6 percent
● Nausea – 6 percent
● Rash or itching – 6 percent
● Tremor – 5 percent
● Constipation – 5 percent
● Stomach upset – 3 percent
Some patients on SSRIs describe asthenia, a type of daytime sedation associated with malaise, diminished mental energy, or emotional blunting
[23]. Other side effects include diaphoresis, diarrhea, hyperprolactinemia, and syndrome of inappropriate antidiuretic hormone (SIADH) and
hyponatremia [8].
Observational studies suggest that SSRIs may be associated with movement disorders, including akathisia, dyskinesia, dystonia, parkinsonism,
tremor, and tardive dyskinesia; bruxism has also been reported [25-27].
While any SSRI can cause side effects, there are a few general trends in side effect frequency [23,28]. Nausea and sedation may be more likely to
occur with paroxetine and fluvoxamine, diarrhea with sertraline, and activation may be more likely to occur with fluoxetine and sertraline.
For many patients, side effects persist even after three months of treatment [24]. Reducing the dose may help alleviate the problem if the dose was
previously titrated up. Dividing the dose during the day may also help.
Suicide risk — There is no clear evidence that treating depressed patients with SSRIs, or antidepressants in general, increases or decreases risk of
suicidality (suicidal ideation, preparatory act, attempt, or death) [29,30]. However, there may be an age-specific effect of antidepressants upon
suicidality. Antidepressants in general may raise the risk of suicidality in patients age 18 to 24 years, have no effect upon patients age 25 to 30 years,
and may lower the risk in patients 31 years and older. It is also important to note that untreated depression may lead to suicidality.
Suicidal ideation and behavior in adults and the potential effect of SSRIs on suicidal ideation and behavior in adults and children are discussed
separately. (See "Suicidal ideation and behavior in adults" and "Effect of antidepressants on suicide risk in adults" and "Effect of antidepressants on
suicide risk in children and adolescents".)
Cardiac — SSRIs can prolong the QT interval (corrected for heart rate). In a meta-analysis of 10 trials (n = 2599 patients) that compared SSRIs with
placebo, SSRIs were associated with an increase in the corrected QT interval of 6 milliseconds, and prolongation was dose dependent [31]. The
SSRI with the highest value for QTc prolongation was citalopram.
Citalopram — Citalopram causes dose-dependent QT interval prolongation, which can lead to a life-threatening cardiac arrhythmia, torsade de
pointes (a form of polymorphic ventricular tachycardia) [20,21]. An analysis by the United States Food and Drug Administration (FDA) of a
randomized trial (n = 119) found that the maximum mean prolongation in the individually corrected QT intervals was longer for citalopram 60 mg per
day (18.5 milliseconds, 90% CI 16.0-21.0) compared to 20 mg per day (8.5 milliseconds, 90% CI 6.2-10.8). Retrospective studies have also found an
association between increasing doses of citalopram and corrected QT interval prolongation [32,33].
In addition, a randomized trial compared citalopram (target dose 30 mg per day) with placebo in patients with Alzheimer disease and agitation (n =
48; mean age approximately 78 years) [34]. Increases in corrected QT interval were greater with citalopram and an increase >30 milliseconds
occurred in more patients who received citalopram than placebo (7 versus 1 patient).
Thus, clinicians should not prescribe citalopram at doses greater than 40 mg per day. Patients at risk for increased serum concentrations of
citalopram (eg, age >60 years) should receive no more than 20 mg per day. Furthermore, citalopram should be avoided in patients with congenital
long QT syndrome, persistent corrected QT measurements >500 milliseconds, bradycardia, hypokalemia, hypomagnesemia, recent myocardial
infarction, or uncompensated heart failure, as well as patients taking other drugs that prolong the QT interval. Additional information about dosing
citalopram and risk for increased serum concentrations is discussed elsewhere in this topic. (See 'Citalopram' above.)
Some authorities disagree with our dose recommendations, based upon a review that found no cases of citalopram induced sudden cardiac death
among patients who were taking up to 60 mg per day of citalopram and were free of identified risk factors for QT prolongation and torsade de pointes
[35]. In addition, a retrospective study of national registry data found that among depressed patients prescribed citalopram (n >610,000), the risk of
ventricular arrhythmia was less with daily doses >40 mg compared with doses ≤20 mg (hazard ratio 0.7, 95% CI 0.6-0.8), and the risk of cardiac
mortality was comparable for the two dose regimens [36]. However, problems that undermine the validity of the study include confounding and
selection bias (eg, prescribing clinicians may have prescribed lower doses to patients at greater risk of arrhythmia) [37-39].
Other SSRIs — Escitalopram, the single isomer formulation of citalopram, may also prolong the corrected QT interval [33]. In a randomized trial
(n = 113), the FDA found that the maximum mean prolongation in the individually corrected QT intervals was longer for escitalopram 30 mg per day
(10.7 milliseconds, 90% CI 8.7-12.7) compared to 10 mg per day (4.5 milliseconds, 90% CI 2.5-6.4); however, the FDA concluded that the finding
was not clinically significant and did not justify a warning. (See 'Escitalopram' above.)
Other SSRIs have been associated with QT prolongation, but appear to be unlikely to cause serious arrhythmia when used in usual recommended
doses and in patients without other risk factors. Risk factors for a serious arrhythmia due to drug-induced QTc prolongation include baseline QT
prolongation, underlying heart disease (particularly heart failure, myocardial infarction, and left ventricular hypertrophy), bradycardia, electrolyte
derangements (especially hypokalemia and hypomagnesemia), concurrent use of more than one drug that can prolong the QT interval, female
gender, and advanced age (eg, >60 years). SSRI drug interactions that may place a patient at elevated risk due to QTc prolongation can be
determined with the Lexi-Interact program included with UpToDate.
The acquired long QT syndrome and torsade de pointes are discussed separately. (See "Acquired long QT syndrome: Definitions, causes, and
pathophysiology".)
An internet resource with updated lists of specific drugs that prolong the QT interval is available at the University of Arizona Center for Education and
Research on Therapeutics website (www.crediblemeds.org/).
Overdose — A single-substance SSRI overdose rarely causes death or serious sequelae [40-42]. Overdoses of up to 30 times the usual daily dose
typically produce minor or no symptoms, while larger ingestions may cause drowsiness, tremor, and gastrointestinal distress. In addition, overdoses
may lead to the serotonin syndrome. Nearly all fatalities from SSRI overdoses involve extremely large doses or co-ingestion of other substances [43].
The toxicity and management of SSRI overdoses and the serotonin syndrome are discussed separately. (See "Selective serotonin reuptake inhibitor
poisoning" and "Serotonin syndrome (serotonin toxicity)".)
Serotonin syndrome — Serotonin syndrome is a potentially lethal condition caused by overstimulation of central and peripheral serotonin receptors.
It typically results from an interaction between multiple medications that increase serotonergic neurotransmission (table 3). However, the syndrome
can occur after initiating or increasing a single serotonergic drug. Clinical features include anxiety, agitation, delirium, diaphoresis, tachycardia,
hypertension, hyperthermia, gastrointestinal distress, tremor, muscle rigidity, myoclonus, and hyperreflexia. It is not known whether SSRIs differ in
their likelihood to cause this syndrome.
The clinical features, diagnosis, treatment, and prevention of serotonin syndrome are discussed separately. (See "Serotonin syndrome (serotonin
toxicity)".)
Sexual dysfunction and infertility — SSRIs can cause sexual dysfunction. The incidence, assessment, and management of SSRI induced sexual
dysfunction is discussed separately. (See "Sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs): Management".)
In addition, SSRIs may interfere with male fertility. A study evaluated DNA integrity, which correlates with fertility and pregnancy outcomes, in semen
samples from healthy male volunteers [44]. Abnormal levels of DNA fragmentation were significantly more frequent after four weeks of daily
paroxetine, compared with baseline (50 versus 10 percent).
Weight change — The effect of SSRIs upon weight depends upon the specific medication prescribed and the length of treatment. Short-term
treatment for two to three months with SSRIs usually causes little or no weight change [45-51]. However, short-term therapy is not clinically
appropriate for most patients.
Treatment with SSRIs for longer periods of time may result in weight gain. However, in some cases it is not clear if this is a true medication side
effect or the result of recovery from depression and the reversal of undesired weight loss. The evidence suggests that fluoxetine may be the least
problematic SSRI with regard to undesired weight gain and that paroxetine may the most problematic. Studies lasting between 6 and 30 months
have reported the following weight effects:
● Fluoxetine leads to small weight changes ranging from a loss of 0.2 percent of body weight at baseline [52] to a gain of 0.9 percent [45]. A
randomized trial showed a mean weight gain of 3.0 kg (6.6 lb) for fluoxetine, compared to 3.2 kg (7.0 lb) for placebo [46].
● Citalopram leads to weight changes ranging from none [53] to a gain of 2.5 percent of baseline body weight [45].
● Fluvoxamine leads to weight gain of 2.6 percent of baseline body weight [45].
● Paroxetine leads to weight gain in 6 percent of patients [54], ranging from 1.6 to 3.6 percent of baseline body weight [45,52].
● Sertraline leads to weight gain ranging from 1.0 to 1.6 percent of baseline body weight [45,52]. A randomized trial showed a mean weight gain of
1.5 kg (3.3 lb) for sertraline, compared to 1.8 kg (4.0 lb) for placebo [55].
Most studies have evaluated patients suffering from major depressive disorder. It is not clear whether weight change caused by SSRIs differs
according to different demographic profiles such as age or sex.
A review found that weight gain during treatment with SSRIs may be due to remission of major depression, improved appetite, increased
carbohydrate craving, and changes in serotonin 2C receptor activity [56]. In addition, weight gain during SSRI treatment is significantly related to
poor appetite at the beginning of treatment [46]. Additionally, there may be a genetic component involving polymorphisms in the catechol-O-
methyltransferase gene [57].
Weight gain due to long-term treatment with SSRIs may lead to diabetes mellitus. A nested case-control study of patients with depression found that
use of moderate to high daily doses of SSRIs for periods greater than 24 months was associated with a significant two-fold increased risk of
developing diabetes mellitus, compared to not using antidepressants (incidence rate ratio: 2.06, 95% CI 1.20-3.52) [58]. Analysis of individual
antidepressants found an increased risk estimate for paroxetine (incidence rate ratio: 1.33, 95% CI 1.02-1.73), suggesting the possibility that the
increased risk for SSRIs might have been primarily due to paroxetine.
Bleeding — High quality studies (randomized trials) indicate that SSRIs do not cause bleeding [59,60]. Although many observational studies have
found an association between SSRIs and an increased risk of abnormal bleeding [61-63], the low quality of this evidence leads us to suggest that
clinicians should generally not change their practice with regard to using SSRIs [64]. Associations between SSRIs and bleeding that are found in
observational studies may be confounded by many factors, such as intracranial small vessel disease, diabetes mellitus, smoking, and alcohol abuse.
In addition, depressed patients who received SSRIs may have been compared with healthy controls; thus, observed associations between SSRI
exposure and bleeding may be confounded by exposure to depression (confounding by indication).
Bleeding complications of SSRIs identified in observational studies include upper gastrointestinal bleeding, stroke, postpartum hemorrhage, and
intraoperative bleeding, as well as more minor problems such as easy bruising, petechiae and purpura, epistaxis, and hematomas [65-68]. The
association between SSRI exposure and abnormal bleeding across multiple studies appears to be more consistent with upper gastrointestinal
bleeding than stroke. In addition, the risk of bleeding in observational studies was amplified in patients who were taking other medications that can
cause bleeding, such as nonsteroidal antiinflammatory drugs (NSAIDS; eg, aspirin, ibuprofen, or naproxen), other antiplatelet agents (eg,
clopidogrel), or anticoagulants (eg, warfarin) [63,69-72]. Among the different SSRIs, there is little indication that any specific SSRI is more strongly
associated with bleeding.
The biological plausibility of the association between SSRIs and increased bleeding is supported by the finding that SSRIs can inhibit serotonin
uptake into platelets and decrease intraplatelet serotonin concentrations, which may affect platelet aggregation [73-75]. In addition, SSRIs may
increase gastric acid secretion [75].
However, bleeding has been observed in association with other antidepressants, which lends weight to the idea that depression, rather than SSRIs,
is associated with bleeding. As an example, a retrospective study of a nationwide health insurance database compared the risk of intracranial
hemorrhage in patients exposed to antidepressants plus NSAIDS with patients exposed to antidepressants alone (total n >4,000,000), and used
propensity scoring to match the two groups with regard to observed potential confounders (eg, age, comorbidity, and exposure to other medications)
[72]. The risk of bleeding was higher with antidepressants plus NSAIDS compared with antidepressants alone (hazard ratio 1.6). In addition, the risk
of bleeding was comparable for patients who received SSRIs, tricyclics, or serotonin-norepinephrine reuptake inhibitors.
The association between exposure to SSRIs and postpartum hemorrhage is discussed separately. (See "Antenatal use of antidepressants and risk of
teratogenicity and adverse pregnancy outcomes: Selective serotonin reuptake inhibitors (SSRIs)", section on 'Postpartum hemorrhage'.)
Upper gastrointestinal bleeding — Multiple meta-analyses of observational studies suggest that SSRIs are associated with an elevated risk of
upper gastrointestinal bleeding [76-78]; however, the absolute risk is low [75]. As an example, one meta-analysis compared the risk of upper
gastrointestinal bleeding in SSRI users with the risk in non-SSRI users, pooling data from 22 observational studies (n >1,000,000 individuals,
including more than 56,000 cases of bleeding) [79]. Exposure to SSRIs was associated with an increased risk of bleeding (odds ratio 1.6, 95% CI
1.4-1.8). The risk was even greater in the subgroup of patients who took SSRIs plus NSAIDS (odds ratio 3.7, 95% CI 3.0-4.7). By contrast, a
separate subgroup analysis found that the risk of bleeding was comparable for patients who took SSRIs plus NSAIDS plus acid suppressing drugs
and for patients who were not exposed to SSRIs. Based upon these findings, some clinicians use non-SSRI antidepressants in patients at high risk
for bleeding (eg, prior history of upper gastrointestinal bleeding), or prescribe a proton pump inhibitor when SSRIs are used in conjunction with
NSAIDS; however, this is not standard practice.
Stroke — Although several observational studies suggest that SSRIs are associated with new onset stroke, many randomized trials indicate that
SSRIs are beneficial for patients who have suffered a stroke:
● A meta-analysis of 16 observational studies (n >500,000) found that the risk of intracranial hemorrhage was elevated in patients who received
SSRIs compared to controls who did not (RR 1.72, 95% CI 1.16-2.55); heterogeneity across studies was small to moderate [70]. However, the
clinical significance of these findings is not clear; SSRI use was associated with a trend toward a protective effect against subarachnoid
hemorrhage (RR 0.62, 95% CI 0.38-1.01). In addition, the absolute risk of any stroke in patients using SSRIs was thought to be very low [70,80];
based upon the meta-analysis, it was estimated that SSRIs may lead to one additional intracerebral hemorrhage for every 10,000 patients
treated for one year.
● A meta-analysis of 52 randomized trials compared SSRIs with control conditions in stroke survivors (n >4000), and found that disability and
neurologic deficit were each substantially less in patients who received SSRIs [59,60]. (See "Initial assessment and management of acute
stroke", section on 'SSRIs'.)
Mortality after stroke — Most evidence suggests that SSRIs do not increase the risk of death in patients with strokes:
● Among patients who use SSRIs and subsequently suffer a stroke, it is not clear whether SSRIs are associated with increased mortality due to
contradictory results across observational studies:
• A prospective, five year study of patients who suffered a stroke included patients who were taking an SSRI at the time of the stroke (n = 55)
and patients who were not (n = 1082) [81]. Mortality in the two groups was comparable. However, depression three months after the stroke
was associated with an increased risk of death (hazard ratio 1.4, 95% CI 1.1-1.7).
• A national registry study identified patients who had suffered hemorrhagic strokes and used SSRIs in the 90 days before the stroke (n =
626), and patients with strokes who had not used SSRIs (n = 626) [82]. Propensity scoring was used to match the two groups with regard to
observed potential confounders (eg, age, sex, history of general medical illnesses, and exposure to other medications). Prestroke SSRI use
was associated with an elevated risk of death in the 30 days after the stroke (odds ratio 1.6, 95% CI 1.2-2.2).
● Based upon randomized trials, the risk of death is not increased in patients who suffer a stroke and are subsequently treated with SSRIs. As an
example, a meta-analysis of 46 trials compared SSRIs with control conditions in patients who suffered strokes (n >3000) [59,60]. Mortality was
comparable in the two groups.
Bone fractures — Many observational studies have found an association between SSRI use and bone fractures, which is discussed separately.
(See "Drugs that affect bone metabolism", section on 'Antidepressants'.)
Issues in breast cancer — Although concerns have been raised that paroxetine or fluoxetine may interact with tamoxifen and interfere with
tamoxifen treatment of breast cancer, the clinical significance of the drug-drug interactions is not clear. Nevertheless, we prefer to avoid using
CPY2D6 inhibitors with tamoxifen if alternative strategies are available. (See 'Drug-drug interactions' above and "Mechanisms of action of selective
estrogen receptor modulators and down-regulators", section on 'Tamoxifen resistance in breast cancer'.)
Cataracts — Although two retrospective studies have found an association between exposure to SSRIs and development of cataracts [83,84], the
low quality of this evidence, as well as the small effect (eg, relative risk 1.15), leads us to suggest that clinicians should generally not change their
practice with regard to using SSRIs.
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 drug prices (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 http://www.nimh.nih.gov/health/publications/mental-health-medications/what-
medications-are-used-to-treat-depression.shtml. Material explaining the symptoms, causes, and treatment for depression is also available in a
booklet entitled "Depression" that is available online at the website http://www.nimh.nih.gov/health/publications/depression/index.shtml. 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 (http://www.dbsalliance.org 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 (http://www.nami.org 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
● Selective serotonin reuptake inhibitors (SSRIs) are frequently used as first-line antidepressants because of their efficacy, tolerability, and general
safety in overdose. The six commonly available SSRIs are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. (See
'Introduction' above.)
● SSRIs inhibit the serotonin reuptake pump and increase postsynaptic serotonin receptor occupancy. This initial action may cause subsequent
changes involved in treating depression. SSRIs are selective in that they have relatively little affinity for other types of receptors. (See
'Pharmacodynamics' above.)
● The SSRIs may inhibit hepatic cytochrome P450 enzymes that metabolize other medications and cause drug-drug interactions. Citalopram and
escitalopram inhibit liver enzymes less than other SSRIs and are thus the SSRIs of choice for situations in which drug-drug interactions are a
concern. (See 'Drug-drug interactions' above.)
● SSRIs should generally be started at their minimal effective dose (table 1). A process of trial and error is used to find the effective dose. Dose
adjustments are made according to patient response, tolerability, and clinical urgency. Clinicians should not prescribe citalopram at doses that
exceed 40 mg per day because of dose-dependent QT interval prolongation. In addition, the dose should not exceed 20 mg per day in patients
with risk factors for increased serum concentrations of citalopram, including hepatic impairment, age >60 years, CYP2C19 variants that slowly
metabolize citalopram, and concomitant medications that inhibit CYP2C19. (See 'Dose' above and 'Cardiac' above.)
● Common SSRI side effects (table 2) include sexual dysfunction, drowsiness, weight gain, insomnia, anxiety, dizziness, headache, and dry
mouth. In addition, observational studies suggest SSRIs may increase the risk of diabetes, abnormal bleeding, and bone loss. (See 'Side effects'
above.)
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Topic 14675 Version 53.0
GRAPHICS
Unipolar depression in adults: Antidepressant doses*
Usual total starting dose per

Usual total dose per day Extreme daily dose range
Drug day
(mg) (mg) ¶
(mg) ¶
Selective serotonin reuptake inhibitors
Citalopram 20 20 to 40 Δ 10 to 40 Δ
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 to 120 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 available in United 25 25 to 50 25 to 50

States)
Bupropion 200 300 (maximum single dose 150 mg) 100 to 450
Bupropion SR 12 hour 150 300 (maximum single dose 200 mg) 150 to 400
Bupropion XL 24 hour 150 300 150 to 450 (United States)

150 to 300 (Europe)
Bupropion hydrobromide 24 hour 174 348 174 to 522
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 25 150 to 300 25 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 150
Protriptyline 10 15 to 60 5 to 60
Trimipramine 25 150 to 300 25 to 300
Monamine oxidase inhibitors †
Isocarboxazid 10 10 to 40 10 to 60
Phenelzine 15 15 to 90 7.5 to 90
Selegiline transdermal 6 mg/24 hour patch 6 to 12 mg/24 hour patch 6 to 12 mg/24 hour 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 end doses may be useful for initiating or maintaining elderly, 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.
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 up to 120 mg per day have been used, there is no evidence that doses >60 mg per day provide any additional benefit in treatment of depression.
¥ Agomelatine may be hepatotoxic and is contraindicated with any degree of liver impairment. Transaminase monitoring is required according to the product information.
‡ 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 © 1978-2018 Lexicomp, Inc. All Rights Reserved.
Graphic 53818 Version 27.0
Side effects of antidepressant medications
Orthostatic QTc Gastrointestinal Weight Sexua

Drug Anticholinergic Drowsiness Insomnia/agitation
hypotension prolongation* toxicity gain dysfunct
Selective serotonin reuptake inhibitors (SSRIs) ¶
Citalopram 0 0 1+ 1+ 1+ Δ 1+ (all SSRIs: see ¶) 1+ 3+
Escitalopram 0 0 1+ 1+ 1+ 1+ 1+ 3+
Fluoxetine 0 0 2+ 1+ 1+ 1+ 1+ 3+
Fluvoxamine 0 1+ 1+ 1+ 0 to 1+ 1+ 1+ 3+
Paroxetine 1+ 1+ 1+ 2+ 0 to 1+ 1+ 2+ 4+
Sertraline 0 0 2+ 1+ 0 to 1+ 2+ ◊ 1+ 3+
Atypical agents
Agomelatine § 0 1+ 1+ 0 0 1+ 0 0 to 1+
(not available in
United States)
Bupropion 0 0 2+ (immediate release) 0 1+ 1+ 0 0

1+ (sustained release)
Mirtazapine 1+ 4+ 0 0 1+ 0 4+ 1+
Serotonin-norepinephrine reuptake inhibitors (SNRIs) ¶,◊◊
Desvenlafaxine ¥ 0 0 1+ 0 0 2+ unknown 1+
Duloxetine 0 0 1+ 0 0 2+ ¶ 0-1+ 1+
Levomilnacipran ¥ 0‡ 0 0-1+ 0-1+ 0 2+ ¶ 0 1+
Milnacipran ¥ 0 1+ 0 0 0 2+ ¶ 0 1+
Venlafaxine ¥ 0 1+ 1+ 0 1+ 2+ 0-1+ 3+
Serotonin modulators
Nefazodone ¶¶ 1+ 2+ 0 1+ 0 2+ 0 0
Trazodone 0 4+ 0 1+ (hypnotic 1+ (hypnotic dose) 1+ (hypnotic dose) 0 (hypnotic 1+ †

dose) 2+ (antidepressant 3+ (antidepressant dose)
3+ dose) dose) 1+
(antidepressant (antidepressant
dose) dose)
Vilazodone 0 0 2+ 0 0 4+** 0 2+
Vortioxetine 0 0 0 0 0 3+ 0 1+
Tricyclic and tetracyclic antidepressants (TCAs) ΔΔ
Amitriptyline 4+ 4+ 0 3+ 3+ 1+ (all TCAs see ΔΔ) 4+ 3 to 4+
Amoxapine 2+ 2+ 2+ 2+ 2+ 0 2+ ND
Clomipramine 4+ 4+ 1+ 2+ 2+ 1+ 4+ 4+
Desipramine 1+ 2+ 1+ 2+ 3+ 0 1+ ND
Doxepin 3+ 3+ 0 2+ 3+ 0 4+ 3+
Imipramine 3+ 3+ 1+ 4+ 3+ 1+ 4+ 3+
Maprotiline 2+ 3+ 0 2+ 3+ 0 2+ ND
Nortriptyline 2+ 2+ 0 1+ 3+ 0 1+ ND
Protriptyline 2+ 1+ 1+ 2+ 3+ 1+ 1+ 3 to 4+
Trimipramine 4+ 4+ 1+ 3+ 1+ 0 4+ ND
Monoamine oxidase inhibitors
Isocarboxazid 1+ 1+ 2+ 2+ 0 1+ 1+ 4+
Phenelzine 1+ 2+ 1+ 3+ 0 1+ 2+ 4+
Selegiline 1+ 0 1+ 1+ 0 0 0 0
Tranylcypromine 1+ 1+ 2+ 2+ 0 1+ 1+ 4+
Scale: 0 = none; 1+ = slight; 2+ = low; 3+ = moderate; 4+ = high; ND = inadequate data.
* Risk of QTc prolongation or torsades de pointes is also elevated with advanced age, female sex, heart disease, congenital long QT syndrome, hypokalemia or hypomagnesemia, elevated
serum drug concentrations (eg, drug overdose, interacting drugs, organ failure) and combination of drugs with QTc prolonging effects. Refer to topic on acquired long QT syndrome.
¶ All SSRIs and SNRIs are associated with transient nausea and gastrointestinal discomfort upon initiation or dose increase.
Δ Based upon reports of dose related QTc prolongation and arrhythmia, the maximum recommended dose of citalopram is 20 mg for patients at increased risk of elevated citalopram serum
concentrations.
◊ Sertraline is associated with higher rates of diarrhea.
§ Agomelatine may be hepatotoxic and is contraindicated with any degree of liver impairment. Transaminase monitoring is required.
¥ May cause persistent dose-related increases in blood pressure (primarily diastolic) and heart rate. Monitor blood pressure regularly.
‡ Levomilnacipran has dose dependent effects on urinary hesitancy.
† Trazodone is associated rarely with priapism, which is considered a medical emergency. Refer to UpToDate topic on Serotonin modulators.
** Vilazodone is associated with higher rates of nausea, vomiting, and diarrhea.
¶¶ Caution: can cause liver failure. Not available in Europe, Canada, and several other countries.
ΔΔ Gastrointestinal forms of anticholinergic side effects include: dry mouth, constipation, epigastric distress, decreased esophagogastric tone. Refer to "Anticholinergic" data for frequency
rankings.
◊◊ None of the SNRIs have anticholinergic activity. However, SNRIs can produce anticholinergic-like effects (which appear to be mediated by noradrenergic effects on the autonomic
nervous system) such as dry mouth and constipation, and should be used with caution in narrow angle glaucoma. In addition, levomilnacipran is associated with urinary hesitancy.
Data from:
1. Nelson JC. Tricyclic and tetracyclic drugs. In: The American Psychiatric Publishing Textbook of Psychopharmacology, 4th ed, Schatzberg AF, Nemeroff CB (Ed), American Psychiatric
Publishing, Washington, DC 2009. p.263.
2. 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.
3. 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.
4. Howland RH. A benefit-risk assessment of agomelatine in the treatment of major depression. Drug Saf 2011; 34:709.
5. Lexicomp Online. Copyright © 1978-2019 Lexicomp, Inc. All Rights Reserved.
6. 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.
Examples of drugs that can precipitate serotonin syndrome
Mechanism Drugs involved
Increases serotonin formation Tryptophan
Increases release of serotonin Amphetamines (including dextroamphetamine, methamphetamine)
Cocaine
MDMA (Ecstasy)
Amphetamine derivatives (including fenfluramine, dexfenfluramine, phentermine)
Levodopa, carbidopa-levodopa (indirectly causes release serotonin)
Impairs reuptake from the synaptic cleft Cocaine

into the presynaptic neuron
MDMA (Ecstasy)
Meperidine
Tramadol
Pentazocine
Selective serotonin reuptake inhibitors (SSRIs; including citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline)
Serotonin-norepinephrine reuptake inhibitors (SNRIs; including desvenlafaxine, duloxetine, milnacipran, and venlafaxine)
Dopamine-norepinephrine reuptake inhibitors (including bupropion)
Serotonin modulators (including nefazodone, trazodone, and vilazodone)
Tricyclic antidepressants (TCAs; including amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline,
nortriptyline, protriptyline, trimipramine)
St. John's wort (Hypericum perforatum)
5-HT3 receptor antagonists (including dolasetron, granisetron, ondansetron, palonosetron)
Metoclopramide
Valproate
Carbamazepine
Sibutramine
Dextromethorphan
Cyclobenzaprine
Inhibits serotonin metabolism (ie, Monoamine oxidase inhibitors (MAOIs; including phenelzine, tranylcypromine, isocarboxazid, moclobemide, safinamide, selegiline,
inhibits monoamine oxidase activity) rasagiline, linezolid, tedizolid, methylene blue, procarbazine, Syrian rue [Peganum harmala, harmine])
Direct serotonin agonist Buspirone
Triptans (including sumatriptan, rizatriptan, others)
Ergot derivatives (including ergotamine, methylergonovine)
Fentanyl
Lysergic acid diethylamide (LSD)
Increases sensitivity of postsynaptic Lithium

receptor
Data courtesy of authors with additional data from: Boyer EW, Shannon M. The serotonin syndrome. NEJM 2005; 352:1112.
Contributor Disclosures
Michael Hirsch, MD Nothing to disclose Robert J Birnbaum, MD, PhD Grant/Research/Clinical Trial Support: Avanir, Eli Lilly (PI Education Innovation Research).
Consultant/Advisory Boards: Consultant, Knowledge Factor, Inc. (Education IT Platform). Peter P Roy-Byrne, MD Employment: Mass Medical Society (journal
Watch); Wiley Lliss (Depression and Anxiety) [Editor in Chief]. Stock Options: Valant Medical Solutions [behavioral health (EMR)]. David Solomon, MD Nothing 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.
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16/8/2019 Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects - UpToDate

Official reprint from UpToDate®

Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects

● Citalopram – 50 to 110 ng/mL

Time to response was evaluated in the following studies:

● Age >60 years

● CYP2C19 variants that slowly metabolize citalopram

A liquid concentrate formulation is available.

A liquid concentrate formulation is available.

A liquid concentrate formulation is available.

● Sexual dysfunction – 17 percent

INFORMATION FOR PATIENTS

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 14675 Version 53.0

Unipolar depression in adults: Antidepressant doses*

Usual total starting dose per

Selective serotonin reuptake inhibitors

Fluvoxamine 50 50 to 200 25 to 300

Fluvoxamine CR 100 100 to 200 100 to 300

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 to 120 30 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

Agomelatine § (not available in United 25 25 to 50 25 to 50

Bupropion XL 24 hour 150 300 150 to 450 (United States)

Bupropion hydrobromide 24 hour 174 348 174 to 522

Nefazodone ‡ 200 300 to 600 50 to 600

Trazodone 100 200 to 400 100 to 600

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 25 150 to 300 25 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 150

Trimipramine 25 150 to 300 25 to 300

Monamine oxidase inhibitors †

Graphic 53818 Version 27.0

Side effects of antidepressant medications

Orthostatic QTc Gastrointestinal Weight Sexua

Selective serotonin reuptake inhibitors (SSRIs) ¶

Citalopram 0 0 1+ 1+ 1+ Δ 1+ (all SSRIs: see ¶) 1+ 3+

Bupropion 0 0 2+ (immediate release) 0 1+ 1+ 0 0

Serotonin-norepinephrine reuptake inhibitors (SNRIs) ¶,◊◊

Levomilnacipran ¥ 0‡ 0 0-1+ 0-1+ 0 2+ ¶ 0 1+

Trazodone 0 4+ 0 1+ (hypnotic 1+ (hypnotic dose) 1+ (hypnotic dose) 0 (hypnotic 1+ †

Tricyclic and tetracyclic antidepressants (TCAs) ΔΔ

Amitriptyline 4+ 4+ 0 3+ 3+ 1+ (all TCAs see ΔΔ) 4+ 3 to 4+

Monoamine oxidase inhibitors

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

Graphic 62488 Version 18.0

Examples of drugs that can precipitate serotonin syndrome

Mechanism Drugs involved

Increases serotonin formation Tryptophan

Increases release of serotonin Amphetamines (including dextroamphetamine, methamphetamine)

Amphetamine derivatives (including fenfluramine, dexfenfluramine, phentermine)

Levodopa, carbidopa-levodopa (indirectly causes release serotonin)

Impairs reuptake from the synaptic cleft Cocaine