Version August 2024
INTRODUCTION — Although delivering a baby is typically a happy event, some postpartum females become depressed. Patients may manifest postpartum blues consisting of mild mood lability symptoms that are self-limited, or more severe syndromes such as unipolar major depression (major depressive disorder) that require treatment. Postpartum major depression can be life-threatening, and is a toxic exposure for the infant that can result in short- and long-term negative consequences for the infant and family [1-4].
This topic reviews choosing a specific treatment for severe postpartum unipolar major depression. Other topics discuss treatment of mild to moderate episodes of postpartum unipolar major depression, the clinical features and diagnosis of postpartum major depression, safety of infant exposure to psychotropic drugs through breastfeeding, the postpartum blues, and the diagnosis and treatment of antepartum unipolar major depression and postpartum bipolar mood episodes.
●(See "Mild to moderate postpartum unipolar major depression: Treatment".)
●(See "Postpartum unipolar major depression: Epidemiology, clinical features, assessment, and diagnosis".)
●(See "Safety of infant exposure to antidepressants and benzodiazepines through breastfeeding".)
●(See "Postpartum blues".)
●(See "Mild to moderate episodes of antenatal unipolar major depression: Choosing treatment".)
●(See "Severe antenatal unipolar major depression: Choosing treatment".)
●(See "Bipolar disorder in postpartum women: Epidemiology, clinical features, assessment, and diagnosis".)
●(See "Bipolar disorder in postpartum women: Treatment".)
DEFINITIONS
Postpartum period and disorders
●Postpartum period – We define the postpartum period as the first 12 months after birth. Definitions of the puerperium range from the first 1 to 12 months following a live birth. (See "Postpartum unipolar major depression: Epidemiology, clinical features, assessment, and diagnosis", section on 'Definition of postpartum period'.)
●Postpartum blues – During the puerperium, mild, transient depressive symptoms such as dysphoria, insomnia, emotional lability, and decreased concentration occur in many women. (See "Postpartum blues".)
●Postpartum unipolar major depression – The diagnostic criteria for postpartum unipolar major depression (postpartum major depressive disorder) are the same as those used to diagnose nonpuerperal major depression (table 1). (See "Postpartum unipolar major depression: Epidemiology, clinical features, assessment, and diagnosis", section on 'Diagnosis' and "Unipolar depression in adults: Clinical features".)
Severity of illness — Factors involved in choosing a treatment for postpartum unipolar major depression include the severity of illness:
●Mild to moderate – Mild to moderate episodes of major depression are generally characterized by five or six depressive symptoms, including depressed mood and/or anhedonia (table 1); symptoms occur nearly every day for at least two weeks. Alternatively, a study of patients with postpartum unipolar major depression (n >4000) empirically defined relatively mild episodes as an average score of 11 on the self-report, 10-item Edinburgh Postnatal Depression Scale (figure 1A-B), and moderate episodes as an average score of 15 [5]. In addition, mild to moderate depression is indicated by a score <20 points on the self-report Patient Health Questionnaire – Nine Item (PHQ-9) (table 2). The Edinburgh Postnatal Depression Scale and PHQ-9 are discussed separately. (See "Postpartum unipolar major depression: General principles of treatment", section on 'Monitoring symptoms' and "Using scales to monitor symptoms and treat depression (measurement based care)", section on 'Patient Health Questionnaire - Nine Item'.)
Patients with mild to moderate illness generally do not manifest suicidal behavior or obvious impairment of functioning and are less likely to develop complications such as psychotic and catatonic features. Mild to moderate major depression can typically be managed in outpatient or partial (day) hospital settings.
●Severe – Severe major depression is generally characterized by seven to nine depressive symptoms, including depressed mood and/or anhedonia (table 1); symptoms occur nearly every day for at least two weeks. Alternatively, a study of patients with postpartum unipolar major depression (n >4000) empirically defined relatively severe episodes as an average score of 20 on the Edinburgh Postnatal Depression Scale (figure 1A-B) [5]. In addition, severe depression is indicated by a score ≥20 points on the self-report PHQ-9 (table 2).
Severely ill patients often endorse suicidal ideation and/or behavior, and often manifest poor judgement that places the patient and others (including the infant and older children) at risk for near-term harm. Also, patients typically demonstrate obvious or grossly impaired functioning. Examples include patients who are bed bound, manifest poor hygiene, are not drinking and eating, and/or not interacting with the baby or other family members.
In addition, severely ill patients are more likely to develop complications such as psychotic and catatonic features and have a history of severe or recurrent episodes. Patients with severe major depression should be referred to a psychiatrist for management and often require hospitalization [6,7]. Treating major depression with psychotic features or catatonia is discussed separately. (See "Unipolar major depression with psychotic features: Acute treatment" and "Catatonia: Treatment and prognosis".)
Symptoms of depressed mood or anhedonia must be present for a diagnosis of major depression. However, difficulties may arise in determining the number of other depressive symptoms present during the puerperium because changes in appetite, energy, and sleep may be due to either depression or normal postnatal-related changes. If these somatic symptoms are present, they should be evaluated in the context of normal expectations for the postpartum period. As an example, postpartum patients frequently lack energy due to sleep deprivation and caring for an infant. However, lack of energy to the point that patients need to make a significant effort to initiate or maintain usual daily activities can be a mild to moderate depressive symptom, and anergia to the point that patients cannot get out of bed for hours is probably a symptom of severe depression. Persistent uncertainty as to whether an episode of major depression is mild to moderate or severe can be resolved by referral to a psychiatrist (preferably one specializing in perinatal disorders).
GENERAL PRINCIPLES — The general principles and issues that are involved in treating postpartum unipolar major depression (major depressive disorder) include:
●Setting (eg, outpatient or inpatient)
●History of prior treatment
●Educating patients and families
●Adherence to treatment
●Monitoring symptoms
●Prescribing antidepressants
●Managing nonresponse
●Making referrals
These general principles are discussed in detail separately. (See "Postpartum unipolar major depression: General principles of treatment".)
CHOOSING TREATMENT
Overview — For patients with severe, postpartum unipolar major depression (major depressive disorder), acute treatment depends upon the patient’s clinical history and treatment preferences, as well as the availability of specific treatments. The major treatments include the antidepressant zuranolone, which is classified as a neuroactive steroid; standard antidepressants such as selective serotonin reuptake inhibitors (SSRIs); and electroconvulsive therapy (ECT) [8-11]. In addition, psychotherapy is nearly always indicated as an adjuvant to pharmacotherapy, unless symptoms render the patient incapable of participating. An overview of choosing treatment is presented in the algorithm (algorithm 1).
Maintenance treatment is often indicated for patients who respond to acute treatment of unipolar major depression, especially patients with an increased risk of recurrence. (See 'Maintenance treatment and monitoring' below.)
Breastfeeding, antidepressants, and safety — Many females with severe postpartum depression are likely to breastfeed their infants. One review estimated that among all patients who deliver, breastfeeding is initiated by approximately 80 percent [12].
The primary treatments for patients with severe postpartum depression are antidepressant medications [13]. Patients who are breastfeeding need to understand and weigh various risks when deciding whether to use an antidepressant [3,10,14-17]:
●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
•Cognitive impairment and psychopathology in the children
(See "Postpartum depression: Adverse consequences in mothers and their children".)
●Although some patients who are breastfeeding may express concerns about using antidepressants and infant exposure, they can be reassured that relatively low amounts are excreted into breast milk and that antidepressants are generally regarded as safe [18]. Uncommon side effects that may occur include sedation and difficulties with feeding and sleeping. (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.
In addition, antidepressant treatment has been associated with treatment-emergent suicidal ideation and behavior in young people up to the age of 24 years [19]. (See "Effect of antidepressants on suicide risk in adults".)
However, the small risk of suicidality in young adults associated with antidepressants needs to be balanced against the clear risk of suicidality associated with depressive syndromes [20]; patients should be informed that self-harm is an underrecognized cause of maternal death [21].
The discussion of these risks should emphasize that the benefits and harms of treatment are uncertain [14].
Patients treated with antidepressants during pregnancy — Antenatal unipolar major depression may remit with an antidepressant that is discontinued prior to delivery. For those patients who subsequently develop postpartum unipolar major depression, we suggest resuming the same antidepressant, even if the patient is breastfeeding and there are better lactation safety data for other medications; using a different antidepressant increases the number of drug exposures [3,22-25]. In addition, exposure to antidepressants that has already occurred in utero is substantially greater than exposure through breast milk. Resuming the same antidepressant is consistent with practice guidelines from the American College of Obstetricians and Gynecologists [26].
The safety of using antidepressants during breastfeeding is discussed separately. (See "Safety of infant exposure to antidepressants and benzodiazepines through breastfeeding".)
However, patients with severe postpartum unipolar major depression may not respond to the same antidepressant that successfully treated the antenatal depressive episode. For these patients, we suggest further pharmacotherapy trials. (See 'Initial treatment' below.)
Patients treated with pharmacotherapy prior to the pregnancy — Patients who present with severe, postpartum unipolar major depression may have a history of depression that occurred prior to the pregnancy and was successfully treated with pharmacotherapy. For these patients, we suggest resuming the same regimen; this includes breastfeeding patients, provided the regimen is compatible with breastfeeding [3,14,23,26-28]. Medication regimens that are compatible with breastfeeding include those that consist of an antidepressant plus add-on treatment with a second-generation antipsychotic, lithium, or triiodothyronine. The safety of using psychotropic medications during breastfeeding is discussed separately. (See "Safety of infant exposure to antidepressants and benzodiazepines through breastfeeding" and "Breastfeeding infants: Safety of exposure to antipsychotics, lithium, stimulants, and medications for substance use disorders".)
Patients with severe postpartum unipolar major depression may not respond to the same pharmacotherapy regimen that successfully treated the prior depressive episode, or that regimen may not be compatible with breastfeeding. For these patients, we suggest further pharmacotherapy trials. (See 'Initial treatment' below.)
Patients not previously treated for depression — Patients with no prior history of treatment for either perinatal (antenatal or postnatal) or nonperinatal depression may present with severe, postpartum unipolar major depression. For these patients, acute treatment proceeds according to the sequence described in the three subsections immediately below. Patients receive initial treatment, and if they do not respond, progress to next step treatment, and if necessary, third-line treatment:
●Initial treatment
•First line
•Reasonable alternative
●Next-step treatment
●Third-line treatment
However, no head-to-head trials have compared the different options for postpartum depression, and it is reasonable to use any of them as initial treatment for postpartum depression, based upon availability, affordability, and patient preference.
Patients who respond to treatment may require maintenance treatment with an antidepressant. (See 'Maintenance treatment and monitoring' below.)
Initial treatment — For patients who present with severe, postpartum unipolar major depression and no prior history of treatment for depression, we suggest initial treatment with an antidepressant medication [12,22,25]. Multiple randomized trials indicate that antidepressants are efficacious for postpartum depression [29]. In addition, for patients who are breastfeeding, 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 [10,18,22,28]. Antidepressants are more available than structured, evidence-based psychotherapy, and using antidepressants is consistent with multiple practice guidelines, including the United Kingdom National Institute for Health and Care Excellence and the Canadian Network for Mood and Anxiety Treatments [6,7,14,15,27,30-32].
First line — In choosing an antidepressant for initial treatment of severe postpartum major depression in patients who have not been treated with antidepressants in the past, we suggest zuranolone, which is classified as a neuroactive steroid. Zuranolone is easy to administer, provides a relatively rapid response, and is usually well tolerated. Treatment with zuranolone is consistent with practice guidelines from the American College of Obstetricians and Gynecologists [33].
A reasonable alternative to zuranolone is the antidepressant brexanolone, which is also a rapid-acting neuroactive steroid. However, it is administered as a 60-hour infusion at a health care facility, whereas zuranolone is taken orally and can thus be administered at home. Detailed information about brexanolone, including its administration, efficacy, adverse effects, and use in breastfeeding patients is discussed elsewhere in this topic. (See 'Reasonable alternative' below.)
For patients who receive zuranolone but do not respond, we recommend against prescribing brexanolone as next step-treatment. The two drugs are similar as neurosteroid therapeutics, and we think it is unlikely that one will be effective if the other is not [34]. Next-step treatment for severe postpartum depression that is unresponsive to zuranolone is discussed below. (See 'Next-step treatment' below.)
Zuranolone is a synthetic preparation of the neuroactive steroid allopregnanolone, the primary metabolite of progesterone; the mechanism of action for zuranolone may involve modulation of gamma-aminobutyric acid type A (GABA-A) [35,36]. In 2023, zuranolone became the first oral antidepressant approved by the US Food and Drug Administration (FDA) specifically for treating postpartum depression [37,38].
●Administration – Zuranolone is administered orally at a dose of 50 mg each evening for 14 days, either as monotherapy or combined with another antidepressant [39]. The drug is taken with fat-containing food (eg, 400 to 1000 calories consisting of 25 to 50 percent fat) to facilitate absorption. If moderate to severe somnolence occurs, the dose is decreased to 40 mg each evening for the remainder of the 14-day period.
If the patient has either severe hepatic impairment (Child-Pugh Class C), or moderate to severe kidney impairment (estimated glomerular filtration rate <60 mL/min per 1.73 m2), the starting dose of zuranolone is 30 mg/day [33,39]. In addition, 30 mg/day is the starting dose for patients taking concomitant medications that strongly inhibit CYP3A4 (eg, erythromycin, diltiazem, and verapamil), and thus increase zuranolone concentrations.
Additional information about administering zuranolone is available through the prescribing information approved by the FDA [39].
●Efficacy – Evidence demonstrating the benefit of zuranolone for postpartum depression includes two randomized trials conducted by the same group of investigators using similar methods [39]. The trials compared zuranolone with placebo in outpatients with postpartum unipolar major depression who were not breastfeeding (n = 150 and 196) [36,40]. One trial prescribed zuranolone 30 mg/day and the other 50 mg/day; study drugs were taken for 14 days each evening, and concomitant antidepressants were prescribed to a minority of patients (19 or 15 percent). The primary findings included the following:
•In both trials, response (reduction of baseline symptoms ≥50 percent) and/or remission occurred in more patients treated with zuranolone than placebo, starting at day 3 and continuing at day 15, as well as one month after the end of study treatments. As an example, in the larger trial (n = 196), remission at day 45 was two times more likely in patients who received zuranolone 50 mg/day than placebo (44 versus 29 percent; odds ratio 2.1, 95% CI 1.1-3.9) [36].
•Improvement of anxiety and global maternal functioning were greater with zuranolone in both trials [36,40].
One of the strengths of the trials was the diverse ethnic and racial composition of the study patients. In the larger trial (n = 196), Hispanic patients constituted 38 percent of the sample and Black patients 22 percent, thus increasing the generalizability of the results [36].
The randomized trials may have underestimated the benefit of zuranolone due to the frequent clinic visits and assessments (eg, eight times in 45 days) of study patients [36]. The frequent visits provided the placebo group the benefit of social contact with study personnel who were interested in the patients’ symptoms and provided an opportunity to discuss them, a benefit typically not available with usual care.
Indirect evidence of the efficacy of zuranolone for postpartum depression includes randomized trials conducted in the general population of patients with unipolar major depression. (See "Unipolar depression in adults: Investigational and nonstandard treatment", section on 'Zuranolone'.)
Based upon clinical experience, patients with complex, longstanding illnesses (eg, comorbid substance use disorders or personality disorders) may not respond as well as those with new-onset postpartum depression.
●Adverse effects – Zuranolone is usually well tolerated. In the two randomized trials described above in the bullet point “Efficacy,” discontinuation of treatment due to adverse effects was comparable for zuranolone 30 mg/day and placebo (1 and 0 percent of patients), as well as zuranolone 50 mg/day and placebo (4 and 2 percent of patients) [36,40].
The most common adverse effect of zuranolone is somnolence/sedation. The larger trial (n = 196) found that somnolence occurred five times more often with zuranolone 50 mg/day than placebo (27 versus 5 percent) [36].
Somnolence caused by zuranolone can impair driving performance. A randomized trial in healthy adults (n = 67) found that nine hours after taking zuranolone 50 mg or placebo at nighttime, computer-based driving simulation was worse in those who received zuranolone [39]. Thus, the FDA prescribing information carries a boxed warning that patients should avoid driving or other potentially hazardous activities for at least 12 hours after taking zuranolone.
In addition, zuranolone may increase the risk of respiratory infections. The larger trial (n = 196) found that onset of coronavirus 2019 (COVID-19) in the group that received zuranolone 50 mg/day or placebo occurred in 5 and 0 percent of patients [36]. The smaller trial (n = 150) found that upper respiratory infections with zuranolone 30 mg/day or placebo occurred in 8 and 1 percent of patients [40].
In one trial (n = 196), diarrhea occurred three times more often with zuranolone 50 mg/day than placebo (6 and 2 percent of patients) [36].
Zuranolone is a federally controlled substance due to the potential for abuse and physical dependence. A study in healthy individuals found that the abuse potential of zuranolone was comparable to that of alprazolam and greater than placebo [39].
●Breastfeeding – Zuranolone is compatible with breastfeeding and does not appear to present a significant risk of adverse effects to infants who are breastfeeding [39,41]. Although the effects of zuranolone on breastfed infants are largely unknown, the level of zuranolone in breast milk appears to be low. In a lactation study of 14 healthy lactating females who received zuranolone 30 mg/day for five days, the maximum relative infant dose was <0.4 percent compared with the maternal dose [39,41]. Four to six days after the last dose, concentrations of zuranolone in breastmilk could not be quantified.
It is not clear if zuranolone decreases breastmilk production. In the study of 14 healthy lactating females who received zuranolone 30 mg/day, the volume of breastmilk collected at day 5 was 8 percent less than volume at baseline [39,41]. However, this modest reduction may be due to the study methods, because during the study, the subjects stopped breastfeeding and pumped their milk.
For patients who are breastfeeding but prefer to avoid infant exposure to zuranolone, they can pump their breast milk and discard it (“pump and dump”) during the 14-day course of treatment, and temporarily bottle-feed their newborn. Patients can resume breastfeeding one week after the last dose. This approach is consistent with the procedures followed in the two pivotal trials that were conducted [36,40].
Patients who respond to zuranolone may require maintenance treatment with an antidepressant. (See 'Maintenance treatment and monitoring' below.)
If zuranolone is not available, affordable, or effective, or is declined, patients should be offered next-step treatment. (See 'Next-step treatment' below.)
Reasonable alternative — If zuranolone is not available, affordable, or is declined as initial treatment of severe postpartum depression, intravenous brexanolone is a reasonable alternative. Using brexanolone for postpartum depression is consistent with practice guidelines from the American College of Obstetricians and Gynecologists [26].
In addition, brexanolone may be preferred over zuranolone as initial treatment of severe postpartum depression that requires psychiatric hospitalization, due to symptoms such as unrelenting suicidal ideation or grossly impaired functioning. As described below in this section, the relatively short duration of treatment with brexanolone (60 hours), compared with zuranolone (14 days), may dictate using brexanolone rather than zuranolone in hospitalized patients. Nevertheless, some patients treated with zuranolone improve within three days [36,40].
However, for patients who receive zuranolone but do not respond, we recommend against using brexanolone as next step-treatment. Our view is that the two drugs are similar as neurosteroid therapeutics, and we think it is unlikely that one will be effective if the other is not [34]. Likewise, for patients who receive brexanolone as initial treatment but do not respond, we recommend not prescribing zuranolone as next step-treatment.
Brexanolone is a neuroactive steroid that is a synthetic preparation of the progesterone metabolite allopregnanolone [9,10,42]. The mechanism of action for brexanolone may involve modulation of gamma-aminobutyric acid type A (GABA-A). In 2019, intravenous brexanolone was the first antidepressant approved by the FDA specifically for treating postpartum depression [8,43,44].
●Administration – In the United States, brexanolone is dispensed only to certified health care facilities and patients who enroll in a Risk Evaluation and Mitigation Strategy program [18,43-45]. The program requires on-site clinicians to monitor patients for excessive sedation and sudden loss of consciousness during the intravenous infusion, and also requires 24-hour, continuous pulse oximetry to monitor for hypoxia.
Brexanolone is administered continuously as a single intravenous infusion for 60 hours in an inpatient facility [44]. The dosing schedule is as follows:
•0 to 4 hours – 30 mcg/kg/hour
•4 to 24 hours – 60 mcg/kg/hour
•24 to 52 hours – 90 mcg/kg/hour (however, 60 mcg/kg/hour is a reasonable alternative for patients who cannot tolerate the higher dose)
•52 to 56 hours – 60 mcg/kg/hour
•56 to 60 hours – 30 mcg/kg/hour
Infusions should be immediately terminated in patients who develop excessive sedation or sudden loss of consciousness [44]. After the drug is stopped, clinicians can expect the adverse effect to remit within 15 to 60 minutes. Following resolution of the sedation/loss of consciousness, brexanolone can be resumed at the same or a lower dose.
In addition, clinicians should immediately stop the infusion if pulse oximetry indicates that the patient is hypoxic [44]. After hypoxia resolves, the infusion should not be resumed.
Additional information about administering brexanolone is available through the prescribing information approved by the FDA [44].
●Efficacy – Randomized trials, in which a minority of patients received concomitant antidepressants, demonstrate that infusion of brexanolone for 60 hours can provide a rapid, beneficial response for moderate to severe postpartum unipolar major depression. Separate pooled analyses of the same three trials compared brexanolone with placebo in a total of 209 patients [46,47]. Study drugs were administered as a single, continuous intravenous infusion in a medically monitored setting for 60 hours, during which brexanolone was titrated up to either 60 or 90 mcg/kg/hour. The primary findings included the following:
•Remission at 60 hours occurred in two times more patients with brexanolone than placebo (50 versus 26 percent). In addition, remission 30 days after the trial remained greater with brexanolone than placebo (32 versus 16 percent).
•Response (reduction of baseline symptoms ≥50 percent) was superior with brexanolone than placebo, and the median time to onset of response was faster with active drug (24 versus 36 hours).
•Improvement of anxiety and insomnia was greater with brexanolone.
●Adverse effects – Brexanolone is usually well-tolerated. In a pooled analysis of three randomized trials that compared brexanolone with placebo (total n = 209 patients), discontinuation of treatment due to an adverse effect was similar (2 and 1 percent) [47]. In addition, results from two randomized trials (total n = 140 patients) showed that interruption of or dose reduction due to an adverse effect of brexanolone or placebo occurred in 7 and 3 percent [44].
The incidence of the following adverse effects in patients treated with brexanolone was at least 5 percent and at least two times greater than the rate with placebo [44]:
•Dry mouth
•Flushing/hot flash
•Loss of consciousness
•Sedation/somnolence
Sedation/somnolence may occur more frequently in patients treated with brexanolone plus antidepressants, compared with patients who receive brexanolone monotherapy [44,48].
The FDA prescribing information carries a boxed warning that during brexanolone infusions, clinicians must monitor patients for excessive sedation or loss of consciousness [44]. In addition, patients who interact with their children during the infusion with brexanolone must be accompanied, due to the risk of sedation/somnolence and loss of consciousness.
●Breastfeeding – For patients who are breastfeeding, we recommend that they temporarily cease nursing during treatment with brexanolone and wait until four days have elapsed before they resume breastfeeding; these were the procedures followed in the two largest randomized trials that were conducted [49]. Our concern is that patients are at risk of sedation secondary to the drug. However, it is reasonable to continue breastfeeding during the brexanolone infusion based upon patient preferences; in this case, a second caregiver should be present [50].
Low-quality evidence suggests that brexanolone is excreted into breast milk for only a brief time [45]. In one small study, the drug was administered intravenously to 12 healthy females for 60 hours according to the recommended dosing schedule, with a maximum dose of 90 mcg/kg/hour [44]. Thirty-six hours after the infusion was completed, the concentration of brexanolone in breast milk was low. In addition, the drug has low bioavailability, and it is thus expected that infant exposure is low.
Patients who respond to brexanolone may require maintenance treatment with an antidepressant. (See 'Maintenance treatment and monitoring' below.)
Next-step treatment — Zuranolone or brexanolone may not be effective in patients with severe postpartum major depression, or the drugs may not be available or affordable, or they may be declined. For these patients, we suggest SSRIs (eg, sertraline) because of their efficacy, tolerability, and availability for postpartum depression [10,12,22,25,28,51,52].
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 [53]. Each specific SSRI can be used because the safety record for the class appears to be benign. In addition, treatment with SSRIs is consistent with practice guidelines from the American College of Obstetricians and Gynecologists [26]. Nevertheless, reasonable alternatives to SSRIs include serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine, and nortriptyline [26].
For patients who receive zuranolone but do not respond, we recommend not using brexanolone as next step-treatment. Our view is that the two drugs are similar as neurosteroid therapeutics, and we think it is unlikely that one will be effective if the other is not [34]. Likewise, for patients who receive brexanolone but do not respond, we recommend against prescribing zuranolone as next step-treatment.
Treatment with standard antidepressants such as SSRIs or SNRIs, including administration, potential side effects, monitoring, and duration of an adequate trial, is discussed separately. (See "Major depressive disorder in adults: Initial treatment with antidepressants" and "Postpartum unipolar major depression: General principles of treatment".)
Indirect evidence supporting the use of standard antidepressants for severe, postpartum unipolar major depression includes numerous randomized trials that demonstrated multiple antidepressants (eg, SSRIs, SNRIs, and mirtazapine) can help the general population of patients with major depression, including severe episodes. (See "Major depressive disorder in adults: Approach to initial management", section on 'Efficacy of antidepressants'.)
Direct evidence supporting the efficacy of SSRIs for severe, postpartum unipolar major depression includes the following randomized trials [29]:
●A meta-analysis of four trials compared fluoxetine, paroxetine, or sertraline with placebo in 251 females with postpartum unipolar depression, some of whom were breastfeeding [54]. Improvement at 5- to 12-week follow-up was greater with active treatment than placebo, and the clinical effect was small to moderate. In each of the trials, the incidence of adverse effects was generally comparable for the SSRI and placebo, and other analyses found that discontinuation of treatment due to any reason with SSRIs and placebo was similar. However, the patients generally had mild to moderate depression, sample sizes were small, and attrition was high.
●A four-week trial, not included in the meta-analysis, compared antidepressants (primarily SSRIs) with usual care (nondirective counseling) in patients with postpartum unipolar major depression (n = 254) [55]. More than 40 percent of the patients were breastfeeding their infants. Improvement (Edinburgh Postnatal Depression Scale (figure 1A-B) score <13) occurred in twice as many patients who received antidepressants than usual care (45 versus 20 percent).
It is not clear whether specific antidepressants differ in their efficacy for postpartum depression, because few head-to-head randomized trials have been conducted. One trial (n = 109 patients, including 29 who breastfed) compared sertraline (50 to 200 mg/day) with nortriptyline (25 to 150 mg/day) for 16 weeks and found that improvement was comparable [56,57].
Patients with severe postpartum unipolar major depression often do not respond to initial treatment with an antidepressant [58]. As an example, a pooled analysis of three randomized trials found that among postpartum patients (n = 72) who were treated with SSRIs, response occurred in only 54 percent [59,60].
For patients who show little or no response (eg, improvement <25 percent) to treatment with an SSRI, we suggest switching antidepressants rather than augmentation with a second drug [22,25]. Options include switching to an SNRI (eg, desvenlafaxine, duloxetine, or venlafaxine), the atypical antidepressant mirtazapine, or the tricyclic nortriptyline [10,52]. The specific choice depends upon prior treatment history, side effects, and patient preference. Choosing next-step treatment and the process of switching antidepressants are discussed separately in the context of the general treatment of resistant depression. (See "Unipolar depression in adults: Choosing treatment for resistant depression", section on 'Next step treatment' and "Switching antidepressant medications in adults".)
For lactating patients who are switching to another antidepressant, some drugs (eg, bupropion and doxepin) are typically avoided due to concerns about their safety in breastfeeding infants [22,25,31]. (See "Safety of infant exposure to antidepressants and benzodiazepines through breastfeeding", section on 'Antidepressants'.)
For patients with a partial response (eg, reduction of baseline symptoms by 25 to 49 percent) to an SSRI, including patients who are breastfeeding, we add a second drug, rather than switch antidepressants [25,28]. Among the options available for add-on pharmacotherapy, we prefer second-generation antipsychotics, such as aripiprazole, risperidone, or olanzapine, which appear to be safe in breastfeeding patients. Alternatives include lithium and triiodothyronine. A small retrospective study found that among postpartum patients treated with antidepressants (n = 26), medication combinations were required for 60 percent [61]. The safety of these add-on psychotropic drugs in breastfeeding infants is discussed separately. (See "Breastfeeding infants: Safety of exposure to antipsychotics, lithium, stimulants, and medications for substance use disorders".)
Third-line treatment — Zuranolone or brexanolone may not be available, affordable, or efficacious for patients with severe postpartum depression, or may be declined, and SSRIs may not be efficacious or may be declined. For these patients, we suggest ECT. The treatment is particularly useful when rapidly effective treatment is imperative; specific indications include psychotic depression, plans and intent to kill oneself or one’s infant, and fluid and food refusal leading to dehydration and malnutrition [22,25,31,62].
There are few studies in breastfeeding mothers who were exposed to ECT anesthetic drugs, such as glycopyrrolate, methohexital, propofol, and succinylcholine [27]. Nevertheless, the risk of these drugs passing into breast milk appears low; after each ECT treatment, breastfeeding can be resumed when the patient recovers from anesthesia. Using ECT in patients who are breastfeeding is consistent with multiple practice guidelines, including those from the United Kingdom National Institute for Health and Care Excellence and the Canadian Network for Mood and Anxiety Treatments [14,15,27,31].
Indirect evidence supporting the use of ECT for severe postpartum major depression includes randomized trials that excluded lactating patients [22]. (See "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)", section on 'Acute ECT'.)
In addition, retrospective studies suggest that ECT is beneficial for postpartum major depression, and is safe option in the context of breastfeeding because there appear to be few if any adverse effects upon lactation [27,58], as well as few adverse effects for either the mother or infant [63]:
●One review of retrospective studies (total n = 87 postpartum patients) concluded that ECT was effective and well tolerated [64].
●A subsequent national registry study identified patients with postpartum depression who were treated with ECT (n = 99), and found that response occurred in 81 percent [65].
Further information about response to ECT in the general population of patients with unipolar major depression, including those with suicidality, is discussed separately. (See "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)".)
In addition, general information about ECT is discussed separately. (See "Overview of electroconvulsive therapy (ECT) for adults" and "Medical evaluation for electroconvulsive therapy" and "Technique for performing electroconvulsive therapy (ECT) in adults".)
Patients who respond to ECT may require maintenance treatment with an antidepressant. (See 'Maintenance treatment and monitoring' below.)
For patients with severe unipolar major depression who begin treatment with ECT but do not respond, we suggest zuranolone as next step treatment. (See 'First line' above.)
Patients unresponsive zuranolone, SSRIs, and ECT should receive further pharmacotherapy trials. (See "Unipolar depression in adults: Choosing treatment for resistant depression".)
Managing specific symptoms
Anxiety or insomnia — For breastfeeding patients with postpartum major depression that includes significant anxiety or insomnia, monotherapy with an antidepressant medication is usually preferred over the combination of an antidepressant and a benzodiazepine [14]. In particular, the neuroactive steroids zuranolone and brexanolone have demonstrated efficacy for anxiety and insomnia in randomized trials that compared each antidepressant with placebo [46]. (See 'First line' above and 'Reasonable alternative' above.)
Nevertheless, for patients with severe anxiety or insomnia who select treatment with a standard antidepressant such as an SSRI, we often prescribe an adjunctive benzodiazepine at initiation of treatment [22,25]. In addition, add-on benzodiazepines can help with intractable anxiety or insomnia that does not respond to a standard antidepressant. However, we avoid prescribing benzodiazepines to patients receiving zuranolone or brexanolone, each of which frequently causes sedation and somnolence. (See 'First line' above and 'Reasonable alternative' above.)
Caution in using benzodiazepines is warranted in patients with a history of substance-related and addictive disorders [66]. In addition, benzodiazepines may result in falls and cognitive impairment.
Benzodiazepines that are added at the beginning of pharmacotherapy are prescribed at standard doses. The benzodiazepine is intended to be used for a relatively short period (eg, two weeks), and then gradually discontinued once the antidepressant begins to take effect [66,67]. However, longer use of benzodiazepines may be necessary to achieve remission of anxiety and/or insomnia. The efficacy and use of adjunctive benzodiazepines for the general treatment of anxious depression are discussed separately. (See "Unipolar depression in adults: Treatment with anxiolytics", section on 'Benzodiazepines'.)
Clonazepam and lorazepam are generally preferred for anxious depression; benzodiazepines with shorter half-lives (eg, alprazolam) can also be helpful, but long-term use (eg, four weeks) may result in maternal rebound anxiety upon discontinuation of the drug. Lorazepam is often preferred over clonazepam because lorazepam has a shorter half-life [66].
The safety of infant exposure to benzodiazepines through breast milk is discussed separately. (See "Safety of infant exposure to antidepressants and benzodiazepines through breastfeeding", section on 'Benzodiazepines'.)
Agitation — Severe unipolar major depression may include episodes of agitation, which is defined as nonproductive, excess motor activity in conjunction with inner tension [68,69]. The initial assessment of agitation in patients with a known diagnosis of unipolar major depression should focus upon determining whether the agitation is due to causes beyond depression, such as a general medical disorder, or intoxication or withdrawal from substances such as alcohol, cocaine, or methamphetamines [70]. In addition, clinicians should assess patient safety, including risk for suicide, and develop a treatment plan.
Hospitalized postnatal patients with severe major depression who are acutely agitated often require oral, inhaled, or intramuscular medications to manage threatening or aggressive behavior, and may also require seclusion from other patients and physical restraints [27]. Patients placed in seclusion should be constantly observed by clinical staff. In addition, the patient should be kept hydrated and vital signs should be regularly monitored.
The goal of pharmacologic tranquilization is to rapidly eliminate the need for seclusion and restraints, and to prevent or reduce self-harm and harm to others. We suggest a second-generation antipsychotic, such as aripiprazole or olanzapine; however, first-generation antipsychotics such as haloperidol are reasonable alternatives. Doses are shown in a table (table 4). Another alternative for managing acute behavioral disturbances is a benzodiazepine such as lorazepam, using a dose of 0.5 to 2 mg.
Intramuscular medications are typically administered in the gluteal muscle or lateral thigh. Oral rapidly dissolving formulations and short-acting intramuscular formulations generally have a calming effect within minutes.
Suicidal ideation and behavior — Suicide is a leading cause of death in postnatal women. Treatment specific for suicidality is discussed separately.
Psychotic depression — Treatment of unipolar psychotic major depression in breastfeeding patients is similar to treatment of nonpostpartum patients. Psychotic depression is generally treated with an antidepressant plus an antipsychotic; however, ECT is a reasonable first-line option given its relatively rapid onset of action [14,22,25,31,71]. The choice between pharmacotherapy and ECT depends upon several factors that are discussed separately, as is the administration of treatment and evidence of efficacy. (See "Unipolar major depression with psychotic features: Acute treatment", section on 'First line'.)
The safety of infant exposure to antipsychotics through breast milk is also discussed separately. (See "Breastfeeding infants: Safety of exposure to antipsychotics, lithium, stimulants, and medications for substance use disorders", section on 'Antipsychotics'.)
Information about ECT for patients with postpartum unipolar major depression is discussed above. (See 'Third-line treatment' above.)
ADJUNCTIVE TREATMENTS
Psychotherapy — Patients receiving pharmacotherapy for severe postpartum unipolar major depression typically receive psychotherapy as an adjuvant if they are not too ill to participate in therapy [10]. Most patients prefer combination therapy; a study of women with perinatal unipolar major depression (n = 100, including 73 postpartum patients) found that pharmacotherapy plus psychotherapy was preferred by 55 percent, whereas medication monotherapy was preferred by only 8 percent [72].
Indirect evidence supporting the use of add-on psychotherapy includes numerous, relatively large, randomized trials that excluded breastfeeding patients; these trials found that combination therapy is more efficacious than pharmacotherapy alone. Although several randomized trials in patients with postnatal depression have failed to show that combination therapy is superior to monotherapy, each study was small and underpowered, and many of the patients had mild to moderate episodes of major depression, rather than severe depression [73-76]. The efficacy of antidepressants plus psychotherapy for treating the general population of patients with severe unipolar major depression is discussed separately. (See "Major depressive disorder in adults: Approach to initial management".)
In addition, multiple randomized trials in patients with mild to moderate postpartum major depression have found that psychotherapy alone is beneficial. (See "Mild to moderate postpartum unipolar major depression: Treatment", section on 'Evidence of efficacy'.)
Exercise — Based upon limited evidence, we suggest adjunctive aerobic exercise for patients with severe postpartum depression, provided they have sufficient energy, interest, and motivation to engage in this activity. A small meta-analysis of five randomized trials compared aerobic exercise at moderate intensity for at least 2.5 hours/week with usual care in patients with perinatal depressive symptoms (n = 242) [77]. Improvement was greater in those who participated in exercise, and the clinical benefit was small to moderate.
MAINTENANCE TREATMENT AND MONITORING — For patients who recover from an episode of postpartum unipolar major depression, maintenance treatment with a standard antidepressant, such as a selective serotonin reuptake inhibitor, may be indicated to prevent recurrence. The decision depends upon the patient’s clinical history:
●First lifetime depressive episode – If the episode of postpartum depression from which the patient recovered is the first lifetime episode of depression, we do not administer maintenance treatment. Rather, we monitor the patient for symptoms of depression, beginning one week after recovery, then every two weeks for the following month, then monthly for the next six months, and then every three months until the patient has achieved one year of remission.
If the patient begins to decompensate, and was treated for the postpartum episode with a standard antidepressant, we resume that drug. If the patient recovered with zuranolone, brexanolone, or electroconvulsive therapy (ECT), we start a standard antidepressant. (See "Major depressive disorder in adults: Initial treatment with antidepressants".)
●Prior episodes of antenatal or postpartum depression – If the patient has only had episodes of antenatal or postpartum depression, we manage her in the same manner described immediately above.
●Depressive episodes aside from the perinatal period – If the patient has had depressive episodes that occurred at times other than antenatal or postpartum periods, and was treated with zuranolone or ECT for the current episode, we administer maintenance treatment with a standard antidepressant that was previously beneficial in the past. If the current episode resolved with a standard antidepressant, we continue treatment with that drug.
The safety of infant exposure to other psychotropic drugs through breastfeeding is discussed separately. (See "Safety of infant exposure to antidepressants and benzodiazepines through breastfeeding" and "Breastfeeding infants: Safety of exposure to antipsychotics, lithium, stimulants, and medications for substance use disorders".)
The self-report Edinburgh Postnatal Depression Scale (figure 1A-B) can help clinicians monitor symptoms in patients with postpartum depression. A reasonable alternative is the Patient Health Questionnaire – Nine Item (PHQ-9) (table 2). (See "Postpartum unipolar major depression: General principles of treatment", section on 'Monitoring symptoms'.)
Detailed information about continuation and maintenance treatment, including indications, selecting a treatment, and efficacy, is discussed separately in the context of the general population of patients with unipolar depression. (See "Unipolar depression in adults: Continuation and maintenance treatment".)
INVESTIGATIONAL TREATMENTS — Investigational treatments for severe postpartum depression include the neuroactive steroid ganaxolone, which acts at gamma-aminobutyric acid receptors and is being tested as an oral and intravenous drug [34,48,78]. In addition, a small randomized trial in 14 patients with postpartum depression found that improvement on some outcomes was greater with active repetitive transcranial magnetic stimulation than sham treatment [79].
TREATMENTS WITH LITTLE OR NO EVIDENCE OF BENEFIT — The hormones progestin and estrogen are generally not used for treating postpartum depression due to the lack or paucity of supporting evidence [3,28]. 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 [80]. 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.
SAFETY OF INFANT EXPOSURE TO PSYCHOTROPIC DRUGS THROUGH BREASTFEEDING — The safety of infant exposure to psychotropic medications through breastfeeding is discussed separately. (See "Safety of infant exposure to antidepressants and benzodiazepines through breastfeeding" and "Breastfeeding infants: Safety of exposure to antipsychotics, lithium, stimulants, and medications for substance use disorders".)
ANTENATAL UNIPOLAR MAJOR DEPRESSION — Treatment of severe unipolar depression during pregnancy is discussed separately. (See "Severe antenatal unipolar major depression: Choosing treatment".)
POSTPARTUM BIPOLAR MAJOR DEPRESSION — Treatment of postpartum patients with bipolar major depression is discussed separately. (See "Bipolar disorder in postpartum women: Treatment", section on 'Bipolar major depression'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Depressive disorders" and "Society guideline links: Postpartum care".)
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)" and "Patient education: Depression during and after pregnancy (The Basics)")
●Beyond the Basics topics (see "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)")
In addition, several government, academic, and lay group resources offer support and education to women with postpartum mood disorders and their family members, including the:
●Centers for Disease Control and Prevention Division of Reproductive Health – This agency of the United States federal government provides information and is involved in other activities related to reproductive, maternal, and infant health.
●Postpartum Support International – The organization holds local, state, national, and international meetings; the telephone number is 1-800-944-4773.
●National Women's Health Information Center – This group provides educational information.
●National Maternal Mental Health Hotline – This organization provides real-time support and information; the telephone number is 1-833-852-6262.
●MGH Center for Women's Health – Information about multiple aspects of women’s health is available, including postpartum depression.
●National Alliance on Mental Illness – This national organization consists of local and state chapters of patients and families who provide advocacy, education, support, and public awareness of mental illness, including postpartum depression.
SUMMARY AND RECOMMENDATIONS
●Definitions – The diagnostic criteria for postpartum unipolar major depression are the same as those used to diagnose nonpuerperal major depression (table 1). At least one of the symptoms is either depressed mood or loss of interest or pleasure.
Severe unipolar major depression is generally characterized by seven to nine depressive symptoms. Severely ill patients often endorse suicidal ideation and behavior, typically demonstrate obvious impairment of functioning, and often manifest poor judgement that places the patient and others at risk for near-term harm. (See 'Definitions' above.)
●General principles of treatment – The general principles and issues involved in treating postpartum unipolar major depression include setting, educating patients and families, adherence, monitoring symptoms, and making referrals. (See "Postpartum unipolar major depression: General principles of treatment".)
●Overview – An overview of choosing acute treatment is presented in the algorithm (algorithm 1). (See 'Overview' above.)
●Breastfeeding, antidepressants, and safety – Many females with severe postpartum depression are likely to breastfeed their infants. Patients who are breastfeeding need to understand and weigh various risks when deciding whether to use an antidepressant. Whereas untreated depression poses risks to the mother and infant, antidepressants are generally regarded as safe. (See 'Breastfeeding, antidepressants, and safety' above.)
●Patients treated with antidepressants during pregnancy – Antenatal unipolar major depression may remit with an antidepressant that is discontinued prior to delivery. For those patients who subsequently develop postpartum unipolar major depression, we suggest resuming the same antidepressant, even if the patient is breastfeeding and there are better lactation safety data for other medications (Grade 2C). Using a different antidepressant increases the number of medication exposures. (See 'Patients treated with antidepressants during pregnancy' above.)
●Patients treated with antidepressants prior to the pregnancy – Patients who present with severe, postpartum unipolar major depression may have been successfully treated with pharmacotherapy for a depressive episode that occurred prior to the pregnancy. For these patients, we suggest resuming the same regimen for these patients, provided it is compatible with breastfeeding (Grade 2C). (See 'Patients treated with pharmacotherapy prior to the pregnancy' above.)
●Patients not previously treated for depression – Patients with no prior history of treatment for either perinatal (antenatal or postnatal) or nonperinatal depression may present with severe, postpartum unipolar major depression.
•Initial treatment – For these patients, we suggest initial treatment with the neuroactive steroid zuranolone, rather than other antidepressants (Grade 2C). Zuranolone is easy to administer, response is relatively rapid, and the drug is usually well tolerated. (See 'Initial treatment' above.)
If the zuranolone is not available, affordable, or is declined, a reasonable alternative is brexanolone. (See 'Reasonable alternative' above.)
•Next-step treatment – Zuranolone or brexanolone may not be effective in patients with severe postpartum major depression, or the drugs may not be available or affordable, or they may be declined. For these patients, we suggest selective serotonin reuptake inhibitors (SSRIs; eg, sertraline), rather than other antidepressants (Grade 2C).
In patients who do not respond to zuranolone, we do not prescribe brexanolone as next step-treatment. The two drugs are similar as neuroactive steroids and it is unlikely that one will be effective if the other is not. Likewise, in patients who receive brexanolone but do not respond, we do not prescribe zuranolone as next step-treatment. (See 'Next-step treatment' above.)
•Third-line treatment – Zuranolone or brexanolone may not be efficacious for patients with severe postpartum depression, or may be declined, and SSRIs may not be efficacious or may be declined. For these patients, we suggest electroconvulsive therapy rather than other treatments (Grade 2C). (See 'Third-line treatment' above.)
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