SSRIs
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.
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 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.
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.
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.
SSRIs often cause adverse side effects, although overall they are better tolerated than tricyclics or monoamine
oxidase inhibitors [4,8,24,25]. 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 [25]. 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 [24]. 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 [26-28].
While any SSRI can cause side effects, there are a few general trends in side effect frequency [24,29]. 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 [25]. Reducing the dose may help
alleviate the problem if the dose was previously titrated up. Dividing the dose during the day may also help.
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.)
MILD TO MODERATE POSTPARTUM MAJOR DEPRESSION
Initial treatment — For mild to moderate postpartum unipolar major depression, we suggest psychotherapy as
initial treatment [8-10]. This approach is consistent with multiple practice guidelines, and is especially useful for
lactating patients who do not want to expose their infants to antidepressants [6,7,11-14]. However,
antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake
inhibitors, bupropion, and mirtazapine) are a reasonable alternative if psychotherapy is not available, not
successful, or is declined, or if the patient has previously responded to antidepressants. In addition, combination
treatment with pharmacotherapy plus psychotherapy is useful for some patients.
For patients with mild to moderate unipolar major depression who are breastfeeding and choose treatment with
an antidepressant, there is a general consensus that the benefits of antidepressants outweigh the potential risks
to the infant. The risks are regarded as low; as an example, most SSRIs pass into breast milk at a dose that is less
than 10 percent of the maternal level and are generally considered compatible with breastfeeding of healthy, fullterm infants [15].
When using psychotherapy to treat postpartum major depression, we typically choose either cognitive-behavioral
therapy or interpersonal psychotherapy, based upon their demonstrated efficacy in multiple randomized trials in
the general population of patients with major depression, as well as patients with postpartum depression [14].
However, reasonable alternatives include behavioral activation, nondirective counseling, and psychodynamic
psychotherapy. Few head-to-head psychotherapy trials have been conducted in patients with postpartum
depression.
Summary —
● An episode of unipolar major depression is a period lasting at least two weeks, with five or more of the
following symptoms: depressed mood, loss of interest or pleasure in most or all activities, insomnia or
hypersomnia, change in appetite or weight, psychomotor retardation or agitation, low energy, poor
concentration, guilt or thoughts of worthlessness, and recurrent thoughts about death or suicide (table 1).
Mild to moderate episodes of unipolar major depression are generally characterized by five or six depressive
symptoms. Patients with mild to moderate illness generally do not manifest suicidal behavior or substantial
impairment of functioning, are less likely to develop complications such as psychotic features, and can
typically be managed in outpatient or partial hospital settings.
Severe unipolar major depression is characterized by seven to nine depressive symptoms. Severely ill
patients often report suicidal ideation and behavior, typically demonstrate obvious impairment of
functioning, and often manifest poor judgement that places the patient and others at risk for imminent
harm. Patients with severe major depression should be referred to a psychiatrist for management and often
require hospitalization. (See 'Definitions' above.)
● The general principles and issues involved in treating postpartum unipolar major depression include
setting, history of prior treatment, educating patients and families, adherence, monitoring symptoms,
prescribing antidepressants, managing nonresponse, and making referrals. (See "Postpartum unipolar
major depression: General principles of treatment".)
● For mild to moderate postpartum unipolar major depression, we suggest psychotherapy as initial
treatment rather than other treatments (Grade 2B). However, antidepressants (eg, selective serotonin
reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, bupropion, and mirtazapine) are a
reasonable alternative if psychotherapy is not available, not successful, or is declined, or if the patient has
previously responded to antidepressants. In addition, combination treatment with pharmacotherapy plus
psychotherapy is useful for some patients.
When using psychotherapy, we typically choose either cognitive-behavioral therapy (CBT) or interpersonal
psychotherapy. Reasonable alternatives include behavioral activation, nondirective counseling, and
psychodynamic psychotherapy. (See 'Initial treatment' above.)
● Patients with postpartum major depression of mild to moderate severity may not respond to initial
treatment with either CBT or interpersonal psychotherapy. For these treatment resistant patients who
achieve a partial response (eg, reduction of baseline symptoms 25 to 49 percent), we suggest increasing the
total number of sessions and the frequency of treatment (Grade 2C). For patients who are treated with
either CBT or interpersonal psychotherapy and achieve only a minimal response (eg, improvement <25
percent), we suggest switching to the other psychotherapy (Grade 2C). (See 'Treatment resistant
patients' above.)
● Next step treatment for postnatal major depression of mild to moderate severity that does not respond to
sequential courses of CBT and interpersonal psychotherapy is generally an antidepressant. (See 'Treatment
refractory patients' above.)
● Other options for patients with mild to moderate postpartum depression who do not respond to initial and
subsequent therapies include the following adjunctive interventions: exercise, social/peer support,
parenting education, and couples/family therapy. (See 'Other options' above.)
SEVERE POSTPARTUM MAJOR DEPRESSION
Initial treatment — For patients with severe, postpartum unipolar major depression who are breastfeeding, we
suggest antidepressant medications [9-11]. Multiple randomized trials indicate that antidepressants are
efficacious for postpartum depression (see 'Choosing an antidepressant' below). In addition, the potential risks of
most antidepressants to the infant are typically regarded as low, and there is a general consensus that the
benefits of antidepressants outweigh the risks [8,10,12]. Antidepressants are more available than structured,
evidence-based psychotherapy, and using antidepressants is consistent with multiple practice guidelines,
including the National Institute for Health and Care Excellence and the Canadian Network for Mood and Anxiety
Treatments [6,7,13-18]. The potential risks of antidepressants to breastfeeding infants are discussed separately.
(See "Safety of infant exposure to antidepressants and benzodiazepines through breastfeeding".)
Using psychotherapy alone is a reasonable alternative to antidepressants for severe postpartum depression in
patients with a prior history of poor response to multiple antidepressants, or if patients decline pharmacotherapy
after weighing the risks (see 'Discussing the risks' below) [13]. Psychotherapy alone is appropriate provided that
the depressive syndrome does not include suicidal ideation or obvious impairment of function.
Discussing the risks — Postpartum patients with severe major depression who are breastfeeding need to
understand and weigh various risks when deciding whether to use an antidepressant [3,8,13,15,24,25]:
● Untreated depression poses risks to the mother and infant, such as nonadherence with postnatal care,
poor self-care, neglect of the infant (and other children), disrupted maternal-infant bonding, family
dysfunction, child abuse, and suicidal behavior. Also, complications of depression may ensue, including
psychotic features, catatonia, and comorbid substance use disorders. (See "Postpartum unipolar major
depression: Epidemiology, clinical features, assessment, and diagnosis", section on 'Adverse
consequences'.)
In addition, postnatal depression is associated with:
•Abnormal child development (see "Postpartum depression: Risks of abnormal child development")
•Cognitive impairment and psychopathology in the children (see "Postpartum depression: Risks of
cognitive impairment and psychopathology in the children")
● Maternal use of antidepressants poses risks to breastfeeding infants. (See "Safety of infant exposure to
antidepressants and benzodiazepines through breastfeeding".)
● Antidepressants carry the risk of maternal side effects (table 3). As an example, antidepressant-induced
sedation can interfere with the mother’s ability to care for her baby.
Choosing an antidepressant — The choice of antidepressant for severe postpartum unipolar major depression in
patients who are breastfeeding depends primarily upon the prior treatment history and potential adverse effects
for the mother and nursing infant. There is no compelling evidence that among commonly used antidepressants,
specific drugs differ in their safety [17].
For patients with severe major depression who are breastfeeding and have not been treated with antidepressants
in the past, we suggest initial treatment with SSRIs because of their efficacy and tolerability for postpartum
depression [9-12,18,28]. SSRIs have been used and more widely studied in breastfeeding patients than other
antidepressant classes; as an example, a retrospective study of women (n = 459) who were treated for postpartum
depression with antidepressants found that SSRIs were used in 90 percent [29]. Nevertheless, reasonable
alternatives to SSRIs include serotonin-norepinephrine reuptake inhibitors, mirtazapine, and nortriptyline.
Among SSRIs, we generally choose paroxetine or sertraline for initial treatment because adverse effects in infants
appear to be low, and studies suggest that paroxetine and sertraline are usually undetectable in the sera of infants
who are exposed through breast milk [8,10,11,17,30]. However, citalopram is a reasonable alternative [10,16].
Escitalopram, fluoxetine, and fluvoxamine are used less often for initial treatment of postpartum depression in
patients who are breastfeeding. Escitalopram and fluvoxamine have been studied in fewer nursing infants than
other SSRIs [9,15,18].
Evidence supporting the efficacy of SSRIs for severe, postpartum unipolar major depression includes randomized
trials [31]:
● A meta-analysis of three trials lasting six or eight weeks compared paroxetine (10 to 40 mg/day)
or sertraline (50 to 200 mg/day) with placebo in 146 patients with postpartum unipolar major depression,
some of whom were breastfeeding [32,33]. Remission occurred in more patients who were treated with
SSRIs than placebo (relative risk 1.8, 95% CI 1.1-3.0), and in each of the studies, the incidence of adverse
effects was comparable for active drug and placebo. However, the patients generally had mild to moderate
depression, sample sizes were small, and attrition was high [3].
● A four-week trial compared antidepressants (primarily SSRIs) with usual care in 254 patients with
postpartum unipolar major depression (n = 254) [34]. More than 40 percent of the patients were
breastfeeding their infants. Improvement (Edinburgh Postnatal Depression Scale (figure 1A-B) score <13)
occurred in more patients who received antidepressants than usual care (45 versus 20 percent).
In addition, randomized trials in the general population of patients with severe major depression support using
SSRIs for severe postpartum depression. (See "Unipolar major depression in adults: Choosing initial treatment",
section on 'Choosing an antidepressant'.)
Few head-to-head randomized trials have compared different antidepressants for treating postpartum
depression. A 16-week trial (n = 109 patients, including 29 who breastfed) compared sertraline (50 to 200 mg/day)
with nortriptyline (25 to 150 mg/day) and found that improvement was comparable [35,36].
Treatments with little or no benefit — The hormones progestin and estrogen are generally not used for treating
postpartum depression due to the lack of supporting evidence [3,12]. A systematic review found that in one
randomized trial (n = 168 patients), the benefits of progestin (single norethisterone 200 mg injection) and placebo
were comparable [53]. In addition, the review identified one small randomized trial (n = 61) that compared
estrogen (transdermal 17 beta-estrogen 200 mg/day plus cyclical dydrogesterone) with placebo; improvement
was greater with estrogen than placebo.
Summary —
● An episode of unipolar major depression is a period lasting at least two weeks, with five or more of the
following symptoms: depressed mood, loss of interest or pleasure in most or all activities, insomnia or
hypersomnia, change in appetite or weight, psychomotor retardation or agitation, low energy, poor
concentration, guilt or thoughts of worthlessness, and recurrent thoughts about death or suicide (table 1).
Severe unipolar major depression is characterized by seven to nine depressive symptoms. Severely ill
patients often report suicidal ideation and behavior, typically demonstrate obvious impairment of
functioning, and often manifest poor judgement that places the patient and others at risk for imminent
harm. Patients with severe major depression should be referred to a psychiatrist for management and often
require hospitalization. (See 'Definitions' above.)
● The general principles and issues involved in treating postpartum unipolar major depression include
setting (eg, outpatient or inpatient), history of prior treatment, educating patients and families, adherence,
monitoring symptoms, prescribing antidepressants, managing nonresponse, and making referrals.
(See "Postpartum unipolar major depression: General principles of treatment".)
● For patients with severe, postpartum unipolar major depression who are breastfeeding, we suggest
antidepressant medications rather than other treatments (Grade 2B). There is a general consensus that the
benefits of antidepressants outweigh the potential risks to the infant. Patients receiving pharmacotherapy
typically receive psychotherapy as an adjuvant.
However, psychotherapy alone is a reasonable alternative in patients with a prior history of poor response to
multiple antidepressants, or if patients decline pharmacotherapy after weighing the risks. Using
psychotherapy alone is appropriate provided that the depressive syndrome does not include suicidal
ideation or obvious impairment of function. (See 'Initial treatment' above and 'Discussing the risks' above.)
● For postpartum patients treated with antidepressants during pregnancy, it is preferable to use the same
medication while breastfeeding, even if there are better lactation safety data for other drugs, because
switching increases the risk of relapse and number of drug exposures. The evidence regarding the use of
antidepressants during breastfeeding does not clearly demonstrate that one drug is safer than another. In
addition, exposure to antidepressants that has already occurred in utero is substantially greater than
exposure through breast milk. (See 'Choosing an antidepressant' above.)
● For patients who have not been treated with antidepressants in the past, we suggest selective serotonin
reuptake inhibitors (SSRIs) as initial treatment, rather than other antidepressants (Grade 2B). We typically
select paroxetine or sertraline. However, reasonable alternatives to SSRIs include serotonin-norepinephrine
reuptake inhibitors, mirtazapine, and nortriptyline. (See 'Choosing an antidepressant' above.)
● Patients with severe postpartum unipolar major depression who are breastfeeding often do not respond to
initial treatment with an antidepressant. For patients showing a minimal response (eg, improvement <25
percent), we suggest switching to a different antidepressant (Grade 2C). For patients showing a partial
response (eg, reduction of baseline symptoms by 25 to 49 percent), we suggest augmentation with a drug
that is compatible with breastfeeding, such as a second-generation antipsychotic, lithium, and
triiodothyronine (Grade 2C). (See 'Treatment resistant patients' above.)
● Postpartum patients with unipolar major depression who are breastfeeding may not respond to multiple
(eg, four) sequential medication trials; for these refractory patients, we suggest electroconvulsive therapy
(ECT) (Grade 2B). An option for patients who do not respond to or who decline ECT is
intravenous brexanolone. (See 'Treatment refractory patients' above.)
● Treatment options for acute behavioral disturbances in patients with postpartum major depression who
are breastfeeding include an antipsychotic or a benzodiazepine. (See 'Agitation' above.)
● In postpartum patients who are not breastfeeding, initial and next step treatment of severe unipolar major
depression is similar to treatment in the general population of patients with severe depression.
(See "Unipolar major depression in adults: Choosing initial treatment", section on 'Severe major
depression' and "Unipolar depression in adults: Choosing treatment for resistant depression".)
SAFETY OF INFANT EXPOSURE TO ANTIDEPRESSANTS AND BENZODIAZEPINES THROUGH
BREASTFEEDING
Risks — Patients with postpartum mental disorders who require pharmacotherapy should generally not be
discouraged from breastfeeding because the benefits of breastfeeding typically appear to outweigh the small risk
posed by psychotropic medications [8,11,12]. However, formula feeding is a reasonable alternative for women
who choose not to breastfeed or who suffer from increased mood or anxiety symptoms due to difficulties with
breastfeeding [6].
All psychotropic medications are transferred to breast milk in varying amounts and are thus passed on to the
nursing infant [3,6]. Milk is a fatty substance, and psychotropic medications are lipophilic. However, the amount
of medication secreted into breast milk is highly variable across different patients [15,16].
Infant exposure to medications through breast milk can generally be decreased by choosing medications with
shorter half-lives and greater protein binding [2,23].
Medication administration — For lactating women who commence pharmacotherapy, the medication should be
started at the lowest effective dose and titrated slowly because infant exposure through breast milk may be doserelated [24].
Efforts to reduce infant exposure by taking medication immediately after nursing or by discarding breast milk
obtained at the time of peak drug concentration are not recommended [3,5,11]. There is little evidence to support
either timing drug administration or discarding breast milk, which are both impractical and can potentially make
breastfeeding more difficult.
For breastfeeding infants who are exposed to antidepressants, routine assessment of serum concentrations is not
recommended [3,6,11]. However, a serum assay can be helpful if the infant appears to be suffering an adverse
event [3,11]. In addition, infant serum samples that reveal minimal drug levels can reassure breastfeeding mothers
who are taking antidepressants but are anxious about infant exposure.
Composite data — Prescribing antidepressants to lactating women involves possible risks to infants because all
antidepressants are secreted into breast milk [11,26]. However, reviews have concluded that the risk to infants
from most antidepressants is relatively low [3] because the frequency of adverse events in babies who are
exposed to antidepressants is low [25,27]. As an example:
● In a study of a nationwide database that included reports of adverse reactions to drugs transmitted
through breast milk (n = 174 breastfed children), the list of drugs that were most frequently implicated did
not include any antidepressants [28].
● A prospective study included 280 lactating mothers treated with psychotropic drugs (more than 80
percent received antidepressants) and 152 lactating mothers treated with antibiotics compatible with
breastfeeding [26]. The frequency of adverse reactions in the two groups of breastfeeding infants was
similar. In addition, growth and gross motor development were in the normal range in both groups of
children.
Infant exposure to selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors
(SNRIs), and atypical antidepressants through lactation is generally low or negligible [11]. Among these
antidepressants, infant serum concentrations appear to be lower with paroxetine and sertraline and higher
with citalopram, fluoxetine, and venlafaxine plus desvenlafaxine [8,11,29]. However, these data do not indicate
that women who have given birth while taking citalopram, fluoxetine, or venlafaxine and have responded well
should be switched to a different antidepressant if they decide to breastfeed.
Selective serotonin reuptake inhibitors — SSRIs are probably the most widely prescribed antidepressants in
lactating women [30], and several studies have concluded that women treated with SSRIs should not be
discouraged from breastfeeding [1,7,12]. The literature on using SSRIs is generally reassuring regarding shortterm adverse effects [11,12,31,32]. As an example:
● A study of breastfeeding infants (n = 20) exposed to SSRIs (citalopram, fluoxetine, paroxetine,
and sertraline) and infants (n = 68) whose mothers were not treated with medications found that adverse
events (eg, irritability, loud crying, feeding problems, and decreased sleep) were comparable [1].
● A six-month prospective study of 75 lactating mothers treated for major depression with SSRIs
(citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) found that infant weight gain was
comparable to published national norms [33]. However, infant weight gain was less among mothers who
suffered depressive relapses lasting at least two months, compared with infants of mothers who did not
relapse or who suffered relapses lasting less than two months.
● Multiple reviews concluded that serum concentrations of SSRIs in breastfed infants are often undetectable
and that signs of drug toxicity are rare [12,30].
Among SSRIs, paroxetine and sertraline may be preferable in lactating women who are starting an
antidepressant, because the amount of paroxetine or sertraline that is secreted into breast milk may be less,
compared with other SSRIs [1,8,29,30]. A review of 34 studies that examined SSRI use in breastfeeding motherinfant pairs found that paroxetine and sertraline usually produced undetectable infant serum levels,
whereas fluoxetine appeared more likely to accumulate in nursing infants [9]. In addition, the review (arbitrarily)
defined elevated infant serum drug concentrations as those that exceeded 10 percent of maternal concentrations
and found that the proportion of infants with elevated serum levels of specific drugs was as follows:
●Citalopram (n = 12 infants) – 17 percent
●Fluoxetine (n = 36 infants) – 22 percent
●Fluvoxamine (n = 4) – 0 percent
●Paroxetine (n = 47 infants) – 2 percent
●Sertraline (n = 60 infants) – 7 percent
However, these data do not indicate that women who have given birth while taking citalopram or fluoxetine and
have responded well to citalopram or fluoxetine should be switched to a different SSRI if they decide to
breastfeed.
Fluvoxamine has been studied in fewer nursing infants, compared with citalopram, fluoxetine, paroxetine,
and sertraline [36].
Summary —
● Patients with postpartum mental disorders who require pharmacotherapy should generally not be
discouraged from breastfeeding. Untreated maternal depression is associated with risks to the child, and
low-quality studies suggest that the benefits of breastfeeding typically outweigh the small risk posed by
psychotropic medications that are used to treat postpartum mental disorders in lactating mothers.
(See 'General principles' above and 'Composite data' above.)
● All psychotropic medications are transferred to breast milk in varying amounts and thus are passed onto
the nursing infant. The drug should be started at the lowest effective dose and titrated slowly. Additional
caution about exposure through breastfeeding is warranted for premature, low-birthweight, or sick infants.
(See 'General principles' above.)
● Patients who are successfully treated with psychotropic drugs during pregnancy should generally not
change medications for the purpose of breastfeeding. In addition, lactating patients who initiate
pharmacotherapy should be treated with medications that were efficacious in the past. Exposure can
generally be decreased by choosing medications with shorter half-lives and greater protein binding.
Polypharmacy should be avoided if possible. (See 'Choosing a drug' above.)
● Infants exposed to medications via breast milk should be assessed by pediatricians at baseline and
subsequently monitored periodically for adverse events. If adverse events in infants are suspected, mothers
should immediately suspend breastfeeding. (See 'Monitoring' above.)
● Selective serotonin reuptake inhibitors (SSRIs;
eg, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) appear to be compatible
with breastfeeding because adverse events in exposed infants are typically minimal. Postpartum, lactating
patients who start treatment with an antidepressant are often prescribed paroxetine or sertraline because
of their safety record. In addition, the amount of paroxetine and sertraline that is secreted into breast milk is
generally low or undetectable, and may be less compared with other SSRIs. (See 'Selective serotonin
reuptake inhibitors' above.)
● The serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine and desvenlafaxine appear to be
safe to use in breastfeeding women, based upon observational studies of exposed infants and the lack of
adverse events. However, infant exposure may be greater with venlafaxine and desvenlafaxine than it is for
some other antidepressants. (See 'Serotonin-norepinephrine reuptake inhibitors' above.)
● Most atypical antidepressants have been studied in fewer nursing infants than SSRIs and SNRIs;
however, mirtazapine may be compatible with breastfeeding. (See 'Atypical' above.)
● There are few data regarding the safety of serotonin modulators in breastfeeding patients. (See 'Serotonin
modulators' above.)
● Several tricyclic antidepressants are compatible with breastfeeding. For women who start a tricyclic
during lactation, nortriptyline is usually favored due to its safety record; by contrast, doxepin is generally
avoided. (See 'Tricyclics' above.)
● Benzodiazepines that have short half-lives and no active metabolites (eg, lorazepam) are generally
preferred in the context of breastfeeding. Potential adverse effects of benzodiazepines include withdrawal
and sedation in infants. Diazepam appears to be incompatible with breastfeeding.
(See 'Benzodiazepines' above.)