#36364: Postpartum Depression

Serotonin is a neurotransmitter known to be involved in mood and anxiety disorders. It is one of the major classes of chemical messengers known as monoamines and is associated with the induction of emotional calmness and the perception and regulation of pain, restful sleep, sexual behavior, and appetite control. A person's general level of well-being depends largely on his or her levels of serotonin [19].

Serotonin imbalance is thought to be one of the causes of depression, and it may be a source of PPD. Inadequate amounts of serotonin may lead to sleep disturbance, agitation, worry, lethargy, and hopelessness, all of which are symptoms of depression [39,40]. Multiple studies have linked low-expressing serotonin transporter (5-HTT) genotypes and PPD, and this is an interesting area of research for future treatment options [41].

Serotonin levels in the brain are regulated by reabsorption into the nerve cell, breakdown within the synapse, availability of storage, timing of release, number of receptors, and the amount of tryptophan in the daily diet. Changes occurring in any of these areas can alter the serotonin pathway and/or availability and lead to anxiety or depression. Serotonin is formed from tryptophan, a basic protein building block stored in nerve cells. Adequate levels of tryptophan are essential to ensure the availability of serotonin. Alternatively, a depressive state can be induced by a depletion of tryptophan [13].

As noted, there are numerous estrogen and progesterone receptors in the same area of the brain where serotonin acts. Research has indicated that reproductive hormone levels seem to influence the availability of tryptophan [42]. The serotonin pathway is heavily influenced by hormonal fluctuations occurring normally during the menstrual cycle and during other major reproductive events, including the postpartum period. The integrity of this serotonin pathway may be jeopardized after childbirth due to the precipitous drop in estrogen and progesterone [13].

Women have a greater lifetime risk than men for depression, with two times the incidence of depressive episodes or recurrent depression [43,44]. Because higher risk is correlated with gender, it is highly likely that reproductive hormones in women play a role in mood instability [43,44].

Stabilization of brain chemistry is necessary in order for all systems to function normally. Any disturbances in any one area of the prefrontal-limbic complex affects all other areas. A woman's reproductive cycle and the resultant shifts in hormone levels within the brain can produce a disruption. If a woman's brain chemistry has been altered by previous stressful life events, hormonal shifts can be the catalyst that destabilizes the system and disrupts the capacity to stabilize mood. The impact of normal hormonal fluctuations caused either by the menstrual cycle or reproduction on an already destabilized brain chemistry may induce depression [13].

Estrogen

Estrogen and progesterone can induce changes in all of the neurochemical pathways involved in mood disturbances. This may be a vital aspect of mental health for women, but it remains largely unstudied [13,44,45]. Estrogen and progesterone influence serotonin levels as well as the function of the other neurotransmitters [42].

Estrogen receptors are present in many areas of the brain; however, they are found significantly clustered in the limbic area. Estrogen appears to help maintain the orderly firing rates of serotonin, dopamine, acetylcholine, and norepinephrine from nerve cells, which are involved with promoting positive moods, memory, thinking, perception, motivation, appetite, sex drive, anxiety, and stress responses. Estrogen can affect the action of these chemicals by altering the number of receptors on the nerve cells, slowing the breakdown of neurotransmitters, and enhancing sensitivity. Estrogen also enhances glutamate activity; glutamate is another neurotransmitter that encourages mood stability [13].

Sichel and Driscoll believe that estrogen may act within the brain as a natural antidepressant and mood stabilizer [13]. When estrogen levels drop, as they do after childbirth, this effect would presumably be reversed. Fluctuations of estrogen levels at any point during a woman's reproductive cycle can disrupt the delicate balance of neurotransmitters and affect a woman's mood stability. Thus, under normal circumstances, estrogen could be regarded as protecting women against depression [46].

Mood changes, however, do not occur in all women during their menstrual cycle or during the postpartum period [48]. Therefore, it seems that some women have a natural resilience to withstand the impact of hormonal changes. In a study to explore possible early biomarkers of PPD, researchers found that serum estradiol and estriol levels were similar among patients with and without PPD, indicating that a difference in sensitivity of the pathway, at the receptor level or the targets themselves, may be responsible for onset of PPD [49]. In fact, the women in the study who developed PPD were found to be more likely to have an estrogen-sensitive gene expression pattern, indicating that genetic testing of at-risk women may be useful in guiding treatment decisions in the future. Other researchers have proposed that a subgroup of women who constitute a "hormone-sensitive" PPD phenotype may be particularly sensitive to the effects of perinatal changes in hormone levels. Study of this subgroup independent of other PPD phenotypes may identify the underlying pathophysiology and help in the development of novel treatment targets [50].

Progesterone

Progesterone is produced during the second phase of the menstrual cycle and functions to dismantle the nerve connections established by estrogen, decreasing the number of available estrogen receptors [13]. Like estrogen, progesterone is also available in large quantities during pregnancy and drops significantly after childbirth.

Estrogen, progesterone, and endorphins work in concert to influence the brain's chemical pathways. The hypothalamus is responsible for controlling reproductive hormones (i.e., follicle-stimulating hormone [FSH], luteinizing hormone [LH], estrogen, and progesterone), mood, weight, and the circadian day/night rhythm. When an event changes the production or availability of any one of these, there can be an upset of the delicate balance of all the components. During the abrupt decline in estrogen and progesterone, for example, following labor and delivery, there may be a subsequent instability of mood, sleep, and weight (gain or loss) [10].

Conversely, as soon as conception occurs, levels of estrogen and progesterone begin to rise. When the placenta takes over the production of estrogen and progesterone from the ovaries, the level of progesterone rises to 50 times higher than the normal peak of progesterone during the menstrual cycle, and the level of estrogen rises to 130 times higher than the normal peak [10,19]. The amount of hormones produced by the adrenals also increases during pregnancy; therefore, twice as many corticosteroids are produced. During pregnancy all of these hormones are controlled by the hypothalamus, the placenta, and the fetal adrenals [10].

As noted, after childbirth and delivery of the placenta, there is a precipitous drop in the levels of estrogen and progesterone. A small amount of estrogen is present, but progesterone is almost completely absent. As a result of these falling levels, available serotonin also decreases. There is an approximate six-week period postpartum during which estrogen and progesterone production is absent; this persists until a new menstrual cycle begins. It is during this critical period, between birth and six weeks postpartum, that a new mother is considered to be the most susceptible to emotional disturbance [10].

Studies conducted by Dalton and colleagues in the United Kingdom indicated a correlation between symptoms in women who were feeling postpartum blues and a drop in blood levels of progesterone [10]. Levels of progesterone were measured over a five-day period. As progesterone levels decreased, women in the study reported increased feelings of sadness [10].

Another study administered high doses of estradiol and progesterone to women, then withdrew it abruptly. Researchers found that 62% of women in the study with a history of PPD had an onset of mood disorder. Interestingly, none of the women without a history of PPD demonstrated symptoms of a mood disorder [30].

Traumatic events provoke a stress response and the release of cortisol, along with other stress hormones. While necessary for survival, this protective stress hormone can exhaust or overwhelm an individual if its level remains too high. When the stress response continues unabated, the nerve cells can continue to maintain the response after the precipitating event has ended, causing emotional distress [13].

In pregnant patients, placental hormones stimulate the production of cortisol, the level of which remains high until the placenta is delivered. There is conflicting evidence regarding the role of cortisol levels in PPD [52,53,54]. Discrepancies in the studies of cortisol and PPD may result from the lack of control for variables that influence cortisol levels, such as stressful life events. However, it is possible that the sustained high levels, and subsequent drop, of cortisol may have an effect on mood stability in the postpartum period. Some have suggested that women for whom cortisol levels remain higher after delivery of the placenta may have a greater risk of developing PPD [52].

The role of the thyroid gland is to produce thyroid hormones, including levothyroxine (T4) and L-triiodothyronine (T3). These hormones influence the body's metabolism as well as the function of many organs. T3 is the more biologically active hormone, and it is thought to be the hormone that functions at the cellular level. When the thyroid is underactive, nonfunctioning, or has been surgically removed, hypothyroidism, or insufficient production of thyroid hormone, will develop. Thyroid hormones affect the body's metabolism in multiple areas, including the regulation of vitamins, proteins, carbohydrates, electrolytes, water, and the immune system. They can also alter the actions of other hormones and drugs.

According to the American Thyroid Association, studies evaluating the relationship of postpartum thyroiditis to postpartum depression have been inconsistent. However, they recommend that all patients with depression, including postpartum depression, should be screened for thyroid dysfunction.

(https://www.liebertpub.com/doi/10.1089/thy.2016.0457 Last Accessed: March 23, 2023)

Level of Evidence: Strong recommendation, low-quality evidence

Approximately 5% to 7% of postpartum women have abnormal thyroid levels [55,56]. Thyroid dysfunction is associated with depressed mood, and in one study, having a thyroid-stimulating hormone (TSH) level greater than 4.0 mU/L at delivery was associated with increased risk for depressive symptoms at six months postpartum [42,57,58,59]. Thyroid dysfunction has not been consistently identified in PPD; however, there may be a subgroup for whom it does play a role.

If thyroid levels remain abnormal, it can alter the effectiveness of the treatment for depression [13]. Therefore, laboratory tests of thyroid function, particularly in women with signs or symptoms of thyroid dysfunction, should be included in the evaluation for PPD. Screening for thyroid dysfunction in the postpartum period may help identify women at risk for PPD; however, consensus guidelines do not advocate screening of all women [42,60,61].

Healthcare professionals in contact with a mother who is experiencing postpartum blues should listen to her without judgment and explain that what she is experiencing is not uncommon, she is not to blame, and the symptoms should soon resolve, allowing her to return to her normal state. Women are treated by one set of healthcare professionals during prenatal visits and an entirely new set after childbirth. This can produce its own set of problems. The attitude of nurses and other healthcare professionals towards mothers who are experiencing postpartum blues can help or hinder the mothers' recovery [10].

The postpartum period is a challenging time for any mother but may be particularly difficult for first-time mothers who may feel insecure and apprehensive about their new maternal responsibilities. Attending to the demands of a new infant who requires total care while also recovering from fatigue and sleeplessness can be overwhelming. In some countries, home visits are key in providing emotional support and practical advice to new mothers as a matter of routine. For example, in the United Kingdom, it is common for nurses to make home visits to provide support and advice to new mothers. In the United States, however, this is less common, with minimal support often available for mothers during this unique and stressful time. In most instances, a mother is discharged from the hospital to her home situation and is left to navigate the postpartum period and care for herself and her new baby on her own [2].

An estimated 10% to 25% of women experiencing the transient state of postpartum blues will subsequently become seriously depressed [2,3,78]. The development of a more serious depression involves psychologic and psychosocial factors that are not prevalent in the development of the postpartum blues. An early warning sign for more serious depression is feeling overwhelmed combined with suicidal ideation; this should not be ignored. Feeling overwhelmed is normal after childbirth, but feeling suicidal is not. Being overwhelmed and/or distressed for longer than two weeks should be a warning signal that the patient requires an evaluation for depression.

The emotional symptoms of PPD may include [2,3,5,10,13,82]:

The physical manifestations of PPD are diverse and include [2,3,5,13,82]:

When PPD affects cognitive abilities, it may present as [2,3,10,82]:

Finally, the behavioral symptoms of PPD are [2,3,10,82]:

Symptoms may vary among women and over time in any one woman. Not every woman will have all of these symptoms. There are some general ways these symptoms might be expressed, giving the clinician clues to look for in women who might be predisposed to PPD.

Due to the shame experienced by some women with PPD and the subsequent secrecy with which they may hide their symptoms, it may not be obvious to a clinician how this illness impacts mothers and their children, spouses, and families. Women with PPD who ask for help often find that their problems are minimized or trivialized. It is crucial to understand how much women suffer from this disorder and acknowledge that their symptoms are not trivial. A description of the most common symptoms of PPD may therefore be helpful in diagnosing and managing the disorder.

Some women may feel sad most of the time; others have days in which their moods seem more normal and they feel good. However, the good moods do not last more than one or two days, after which the sadness falls upon them again.

Women who are depressed suffer from lethargy, fatigue, and apathy. Family and friends may find it difficult to accept that activities that once brought the individual pleasure no longer interest her. It may be too difficult for women with PPD to generate sufficient energy to even engage in certain activities.

Irritability is one of the main mood changes most women experience with PPD. This type of irritability is characterized by emotional swings from anger to distress. Frequently, attacks of irritability end with uncontrollable sobbing. Mothers find that this irritability is out of their control, which adds to the distress [3,10]. If the irritability continues, it can make dealing with the tasks of caring for an infant very difficult and can damage other relationships. Irritability may be expressed either verbally or through physical violence. Mothers may describe themselves as intolerant, impatient, jittery, short-tempered, spiteful, or quarrelsome. Irritability varies in its intensity among women with PPD and may develop in the weeks to months after childbirth.

Another of the most common symptoms of PPD is tearfulness and uncontrollable sobbing, with or without discernible external stimuli. These symptoms are also common among women who experience the postpartum blues; however, if these symptoms continue beyond two weeks after birth, they should be considered as part of the onset of PPD.

All new mothers experience a change in sleep patterns. Due to the baby's presence and the need for feedings during the night, most new mothers suffer from some degree of sleep deprivation. There is a different quality to sleep problems in women with PPD. These women have difficulty getting to sleep, have disturbed sleep, and/or wake early and are unable to go back to sleep. Insomnia is a common complaint. Even when they do sleep, it is never enough; the sleep is not refreshing. Five hours of solid sleep is often recommended; however, women with PPD are rarely able to sleep for that length of time. It is usual for new mothers to have their sleep interrupted by a crying baby, but women with PPD report that they cannot go to sleep even when the baby is settled and goes to sleep. They may lie awake worrying. Although rare, some women with PPD report sleeping too much [2,82].

Most mothers realize that they have new responsibilities and demands with the arrival of a child. Some new mothers feel overwhelmed by the constant demands of caring for infants, fulfilling the role of mother and wife/partner, and maintaining other relationships. They may also feel pressure to run the household smoothly, especially if caring for additional children. Bothered by fatigue and lack of sleep, it is difficult not to feel overwhelmed at times. However, mothers experiencing PPD can feel overwhelmed by the smallest tasks, such as changing diapers. A strong feeling of helplessness and a lack of confidence in her ability to cope undermines any self-confidence she may have enjoyed prior to her depression.

For some women with PPD, there is a loss of hope in life. Women may wish they were dead and have thoughts of suicide. Although thoughts of harming oneself are prevalent among women suffering from PPD, these drastic thoughts often are not that they actually want to die, but that they want the situation to change and feel hopeless about being able to change it. In some instances, thoughts of suicide may become too strong to resist, and some women with PPD do die by suicide. Any thoughts of suicide should be taken seriously and warrant immediate intervention [2,69].

An inability to cope with everyday functions may lead to a negative self-concept and negative self-talk. The negative perception of self can be so convincing that an individual believes she is incompetent as a woman, wife, and mother. Such feelings are difficult to eliminate for women who are depressed [69].

One of the most prominent features that a woman with PPD experiences is that somehow she is not worthy of having a child; she may feel that because of the depressive symptoms, she is a bad mother. These thoughts may cause an individual to detach herself, in an effort to hide perceived inadequacies from others. Women who believe that they are "bad mothers" also have significant feelings of guilt. There is an accompanying loss of self-confidence in other areas of life that is difficult to shake. These women may have excessive guilt about any minor wrongs committed in the past [2,69].

The loss of concentration associated with PPD may cause women to forget things that ordinarily come easily, such as turning off the stove or putting things away. Everyday tasks may become so difficult that they seem monumental. In order to cover up the confusion, women may avoid certain activities. Women who were previously leaders or extroverts or who enjoyed a high level of confidence prior to childbirth may be distressed by a loss of confidence. Loss of confidence is often accompanied by a desire to withdraw from one's surroundings, become detached, and avoid socializing or making contact with other people [10,69].

Anxiety is a common symptom that accompanies depression. Symptoms of anxiety may be felt emotionally, cognitively, and/or physically. Anxiety permeates everything a woman with PPD experiences, bringing with it a feeling of dread that does not resolve with any amount of reassurance. Anxiety can be incapacitating, affecting the ability to think, concentrate, or make sound decisions [34,69].

Any thoughts of harming the baby should be taken seriously, and immediate help should be given. Unfortunately, suicide and homicide can be consequences of PPD. Although a mother may not wish to harm her baby, these thoughts may have an alarming obsessive quality that could eventually override her ability to make rational judgments to control her behavior [2,69].

In the United Kingdom, it was lawyers, not medical professionals, who first appreciated that a mother who killed her baby was temporarily mentally disturbed. The crime of infanticide was introduced into law in England and Wales in 1922, and later amended in the Infanticide Act of 1938 [87,88]. This law states that a mother who kills her own child can be charged with a lesser offence of infanticide, not murder. Murder, if proved, must be punished by a prison sentence. This only covers the killing of an infant younger than 12 months of age and does not extend to other individuals [10].

Given the rigidity with which the legal system in the United States views mental illness, infanticide becomes legally challenging. By the time a case of infanticide reaches trial, the mother's mental status has usually improved and is no longer psychotic. An aggressive prosecutor can make it appear as though the psychosis was fabricated to cover up the crime. In many cases, there are inadequate records to support the mother's claim that she did not know what she was doing and that she killed her child, "in a fit of insanity, which has since passed" [8].

The public understandably finds infanticide repugnant and incomprehensible. Without proper instruction from the judge at trial and without a specific law to guide jurisprudence in cases of infanticide, it is difficult for a jury to acquit a mother when an infant has been killed. However, given the media focus on cases of infanticide, some guilty verdicts have been overturned in the Court of Appeals. There may be a tendency toward leniency developing in the United States; however, mothers in the United States who commit infanticide may face the death penalty [89]. In a case study of 24 infanticide cases in the United States in which postpartum psychosis was the defense, 33% of defendants were found not guilty by reason of insanity, 17% were given probation, and 42% were incarcerated, with 8% sentenced to life in prison [87]. The laws in the United States that govern insanity pleas and infanticide remain inconsistent, differing from state to state [88,89,90]. The lack of formal DSM-5-TR diagnostic criteria for postpartum psychiatric disorders contributes to disparate treatment under the law [89,91]. Judges, without precedents to follow, generally attempt to give broad latitude to infanticide defendants [8].

Broad latitude shown to infanticide defendants by the justice system is a step in the right direction, but it does not fully address the realities of postpartum psychosis. Sichel and Driscoll have stipulated that, "there is a difference between a person who kills with malice and one who kills under the influence of postpartum psychosis" [13]. There are women who do harm their children with malice; however, the criminal justice system, when properly supplied with accurate information regarding postpartum psychosis, should conceivably be able to enact laws that protect women who kill their infants while under the influence of postpartum psychosis [13,89].

Infanticidal fears, or women who think about or are frightened about harming their baby and manage to resist, have not been studied carefully. There are few statistics on the frequency of these fears in women with PPD or postpartum psychosis. Mothers may not readily confess to such fears if they are aware that they may be incarcerated or that their children may be removed from their care [10].

Dalton studied PPD and, in her research, saw an unusual number of women charged with infanticide or who, under the influence of postpartum psychosis, have very nearly killed their children. She noted three varieties of infanticide: those occurring shortly after birth while the mother is acutely psychotic; those occurring with the return of menstruation; and those occurring during "domestic feuds." According to Dalton, many of these incidents "do not appear in the press or in law reports and remain hidden from the public" [10].

The benefits of bonding are well known. Most hospitals have incorporated a ritual of mother-infant bonding that occurs shortly after delivery, whereby the infant is placed in the mother's arms. It is often referred to as the moment of "falling in love," when the mother looks into the eyes of the infant and the infant looks back. Whether born of myth or scientific reasoning, bonding is considered an important element in initiating the mother-infant attachment. The ritual is important, but not essential. If, for some reason, this initial bonding is missed, as in the case of a caesarean section, it is obtainable the moment the mother sees her baby for the first time [108].

Bonding, in actuality, is a process of closeness, comfort, and familiarity that develops over time [19]. When the process of bonding with an infant is disrupted, it can have long-term consequences for the future relationship between mother and child. The delay in developing attachment may be unusually prolonged and delayed with a clinically depressed mother. This attachment difficulty may take different forms. The mother may not be nurturing to the infant, or she may have limited interaction with the infant. In some cases, the depressed mother may reject her baby emotionally and refuse to have anything to do with the infant. The mother may have an adverse sentiment towards the baby and handle the baby with irritability. Depressed mothers may also be outwardly angry or resentful toward the infant. Some mothers are so consumed with fears of harming their child that they avoid even touching him or her. All of these emotions and attitudes toward the child affect the process of attachment [2,109].

Klier and Muzik describe the role of perinatal psychiatry in maternal-infant bonding issues [110]. They classify the disorders of mother-infant bonding into three groups [110]:

A study of approximately 100 subjects found that mother-infant bonding disorders were present in 29% of those diagnosed with PPD [111].

Bonding difficulties should be assessed immediately to determine if intervention is necessary. Women may be reluctant to admit these problems, but they also may be grateful to receive help from someone who understands their distress [110].

Researchers of infant behavior have come to acknowledge that the establishment of social relationships is a primary process of development. When a child successfully accomplishes communication with others, normal development occurs. A child who does not engage the world successfully will not develop normally, regardless of the source of the failure. Success or failure depends upon three critical processes [112]:

These processes make up what is called "mutual regulation," which is the capacity of both the mother (or other caregiver) and infant to express their intentions, appreciate the intentions of the other, and allow each other to achieve their goals [112].

The literature on maternal-child interactions supports the concept of caretaker behavior as an external regulator of the infant's states. Maternal body warmth modulates infants' physiologic systems [108,112]. The quality of a caretaker's efforts affects the function, structure, and neurochemical architecture of the infant brain. Both mother and infant appreciate and adjust their behavior in relation to their partner's behavior and the state of the interaction. This system of meaning is established long before the child can engage in words, and the effects have lifetime consequences [112].

Both mother and infant develop the skill to sense when the interaction fulfills the infant's needs or when the mother's intervention met her intention. Adjustments are made as they develop sensitivity to each other's responses. This is how the mother-child relationship develops and sets the course for the development of future relationships for the infant. The development of an effective sense of self and a reliable relationship with caregivers is crucial for the establishment of stable and secure relationships in the future [112,113].

Studies have shown that when the mother is depressed, a break in the mutual regulatory system occurs [114]. Depressed mothers disrupt the interaction in two distinct ways: intrusiveness and withdrawal. It has been reported that intrusive mothers with PPD engaged in rough handling, spoke in an angry tone of voice, and interfered with their infants' activities. Withdrawn mothers, by contrast, were disengaged, unresponsive, and affectively flat and did little to support their infants' activities.

Both disruptions have a deleterious effect on the infant's development [112]. The infants of intrusive mothers eventually adopt an angry and protective style of coping, which is used defensively in anticipation of the mother's behavior. Infants of withdrawn mothers attempt to regulate their own emotional states. They may fail at social connectedness due to the mother's lack of response. Eventually, the infant will attempt to regulate their affective states, resulting in passivity and withdrawal [115]. Infants of either intrusive or withdrawn mothers develop a negative affective core characterized by anger and sadness, a representation of the mother as unresponsive and untrustworthy, and a representation of themselves as ineffective and helpless. This does not lead to successful normal development unless some intervention changes the mother's interaction style [112,115,116].

New mothers should consume two to three portions daily of protein-rich foods, such as fish, cheese, eggs, nuts, or meat. Four to five portions of fruit and vegetables should also be part of the diet [10]. Dalton and Horton recommend that starchy foods every three hours be added to the regular diet for a woman with PPD [10]. This may allow women with PPD to maintain sufficiently high blood sugar levels required to effectively utilize available progesterone. A carbohydrate-rich food should be eaten within one hour of waking and one hour before bedtime. Foods high in carbohydrates include flour, rice, potatoes, oats, and corn. Starchy foods added to a healthy diet of fruits, vegetables, and protein are not necessarily fattening; this may be stressed to new mothers.

Tryptophan is a vital amino acid that must be consumed, as the body does not produce it. Tryptophan can be obtained through plant or animal proteins, such as peanuts, brown rice, soybeans, fish, turkey, and beef. In the brain, tryptophan is converted into serotonin, which facilitates a calming effect [19]. Ensuring that sufficient quantities of iron, folic acid, and vitamin A are being obtained is also an important aspect of the postpartum diet [1].

Research has indicated that omega fatty acids may have a protective effect against PPD. In a Norwegian study of omega-3 fatty acid levels (generally from seafood consumption) in women throughout and after pregnancy, a low omega-3 index in late pregnancy was associated with higher depression score three months postpartum [148]. A 2012 meta-analysis supported this finding, noting that poor omega-3 intake is common among women of childbearing age [41].

Sleep is necessary to restore a woman's mood and brain chemistry following pregnancy, labor, and delivery. The brain requires a minimum of five hours of uninterrupted sleep per day to restore itself to normal functioning [13].

If possible, a spouse or other caregiving partner can alternate nights getting up to take care of the baby, allowing the mother to sleep at least five hours at a time. Knowing in advance that arrangements for nighttime feedings and attention to the baby can be made, mothers may ask for help without feelings of guilt or inadequacy [5]. Because women with PPD often complain of insomnia, a safe sedative may be prescribed to allow patients to obtain enough sleep.

As women with PPD may be overstressed and overly focused on perceived inadequacies, only those things that are of high priority, such as taking care of herself and the baby, should be attempted. Ideally, she should obtain assistance with household chores, such as cooking, cleaning, and shopping, at least for the first few weeks to allow more time for her to rest. Extended family can be useful if they are available and willing to help [5]. Family members or friends should also be allowed to help with childcare and other activities of daily living. This will free the mother's time for therapy sessions, support groups, and unpressured time with the baby [5].

Exercise is important to a sense of well-being, as it enhances production of endorphins in the brain. Exercise can also help to promote a sense of calm, relaxation, and better sleep. For women with PPD, exercises should be gentle, not strenuous, and may include walking, swimming, physical therapy, and massage [149,150].

Although it may be difficult to do, a woman should be encouraged to discuss her feelings with her partner/husband, close family members, and intimate friends. Hiding feelings due to shame and embarrassment contributes to isolation and loneliness. Therefore, although it may be difficult, it will ultimately help a depressed woman to have companionship. Isolation can lead to a sense of detachment from others, which may make depressive symptoms worsen. The depressed woman should avoid spending all of her time alone. Whenever possible, she should be encouraged to get dressed and leave the house.

It is also important for a woman with PPD to spend time alone with her partner/husband when the baby is quiet or asleep. These times together can be productive for both parents and allow them to be together without the usual stress of caring for a new baby [5].

A reduction in hormones after delivery is thought to be a major factor in the etiology of PPD in predisposed women. Therefore, the use of hormonal treatment as prophylaxis or a treatment component seems plausible. Since 1970, several studies were carried out investigating the efficacy of either estrogen or progesterone in the management of PPD. There are several problem areas in these studies, both in regards to methodologic issues and in the use of different hormones in the studies [153]. More structured research is necessary in order to ascertain efficacy.

Estrogen

The value of estrogen in the treatment of PPD is supported by studies conducted between 1970 and 2002. However, methodologic shortcomings make the studies unreliable. The use of estrogen in the postpartum period, particularly the use of synthetic estrogen, may have significant side effects [153]. In addition, more recent evidence indicates the impact of reproductive hormones may be mediated by differences in sensitivity to estrogen among postpartum women [49].

Measurements of hormonal levels proved to be one methodologic flaw. Levels of hormones measured from plasma sampling determine the total amounts of progesterone and estrogen rather than the free fraction, which is unbound to plasma proteins and freely permeates into the central nervous system. It is this biologically active fraction that modulates the synthesis of proteins, neurotransmitters, and receptors in the central nervous system. Thus, serum levels of hormones may render inaccurate results [153]. Dalton and Horton stipulate that the only accurate method of measuring free estrogen and progesterone levels is via saliva testing [10].

In 1996, Gregoire et al. conducted a double-blind, placebo-controlled study of estrogen skin patches in the treatment of PPD [154]. The women who participated in the study had either severe or chronic depressive symptoms that began 3 months postpartum and persisted up to 18 months. The women were assessed monthly using the EPDS. Although the study concluded that estrogen was better than placebo in relieving both dysphoric mood and biologic symptoms of depression, many of the women who received estrogen took antidepressants simultaneously [154]. The use of estrogen combined with antidepressants requires further consideration.

According to the Scottish Intercollegiate Guidelines Network, the use of estrogen therapy in the routine management of patients with postpartum depression is not recommended.

(https://www.sign.ac.uk/assets/sign127_update.pdf Last Accessed: March 23, 2023)

Level of Evidence: B (High-quality systematic reviews of case control or cohort studies, directly applicable to the target population, and demonstrating overall consistency of results)

Other studies have been conducted evaluating estrogen as a treatment for PPD; however, many of these studies were also complicated by the co-administration of antidepressants, which leads to inconclusive evidence of the benefits of estrogen alone to treat PPD. Whether estrogen is of value in the treatment of PPD is yet to be determined [153,155,156].

There are concerns regarding the risks associated with the use of synthetic estrogens in the postpartum period, including the increased risk for the development of deep vein thrombosis, cardiovascular complications, endometrial hyperplasia, problems with breastfeeding, and increased depression. The safest dosage and route of administration should be clarified before it can be recommended [153]. There are no reported studies on the use of natural estrogen in the treatment of PPD [155].

Estrogen may be taken orally, vaginally, transdermally, or through a device inserted into the uterus. Natural estrogens are available through the use of skin patches, transdermal creams, or vaginal creams [13]. Natural transdermal estrogen creams, such as bio-identical 17-beta estradiol and vaginal creams, are available only from compounding pharmacies.

Progesterone

It has been suggested that only naturally occurring progesterone has mood-elevating properties [10]. Thus, studies using synthetic progestogens as prophylaxis or treatment for PPD are not comparable to studies using natural progesterone.

Critics of Dalton's use of progesterone both as prophylaxis and treatment for PPD cite methodologic problems and the fact that the dosages are not standardized. Other criticisms include the fact that patients who participated in the studies were volunteers and there was not an adequately constructed control group against which to test the treatments [153]. Although criticisms of Dalton's progesterone treatments persist, no further studies have been conducted on the use of natural progesterone for the treatment of PPD [155].

One problem with the use of progesterone is that it cannot be given successfully by mouth or as a skin patch but must be administered by injection or vaginal or rectal suppository. According to Dalton and Horton, 400-mg suppositories administered twice daily are the minimum effective dose [10]. However, empirical data has not found progesterone to be effective in the treatment of PPD and it may intensify depressive symptoms in some patients [157].

As with estrogen, the largest concentration of progesterone receptors is in the limbic area of the brain, which is considered to be the center of emotion. The amount of progesterone present in the blood is not as important in regard to PPD treatment as the amount of progesterone that reaches the nuclei and is then metabolized [10].

Progesterone receptors will not transport molecules of progesterone in the presence of adrenalin, because during times of stress the receptors transport corticosteroids rather than progesterone into the nuclei. If there is low blood sugar, the progesterone receptors transport glucocorticoids back into the cells in preference to progesterone. This helps to explain why oral progesterone is not effective. Oral progesterone must pass through the liver, which contains many progesterone receptors that metabolize the progesterone before it reaches the brain. Also, progesterone does not pass easily through the skin into the blood stream and is therefore not suitable for administration by cream or patch. There are no routine laboratory tests to determine the number or function of progesterone receptors [10].

Progesterone therapy may be given with any other medications, including antidepressants. It is considered safe for women who are breastfeeding. Progesterone should be halted for a 14-day period every month beginning with menstruation. As noted, the minimum effective dose for management of depressive symptoms is 400 mg suppositories twice daily or, alternatively, one 50 mg injection daily. These doses can be titrated upward to a maximum of six 400 mg suppositories daily or one 100 mg injection daily. Blood sugar should be monitored and kept stable [10].

Given the controversy over treatment of PPD with estrogen or progesterone, consensus has not been reached on the use of hormonal treatments for PPD. This area of inquiry deserves further study.

SSRIs affect the action of the neurotransmitter serotonin. When serotonin is released in the synapse between neurons, it is reabsorbed by the brain cells, through the process of reuptake. Depression is assumed to be connected with decreased availability of serotonin and other neurotransmitters; therefore, interference with the reuptake of serotonin allows more to be available to boost communication in the brain. SSRIs inhibit only the reuptake of serotonin. Because SSRIs affect only one neurotransmitter, they presumably have fewer uncomfortable side effects than the more traditional antidepressants [158,159]. The more acceptable side effect profile of SSRIs makes them the drugs of choice for many depressive disorders [159,160].

Some of the most commonly used SSRIs are fluoxetine, paroxetine, sertraline, fluvoxamine, escitalopram, and citalopram [159,161]. Of these drugs, fluoxetine, paroxetine, and sertraline are prescribed most often [159,162]. Fluvoxamine, which is approved to treat obsessive-compulsive disorder, is sometimes used off-label to treat depression [161].

Benefits

The major benefit of SSRIs is their effectiveness in reducing symptoms of depression more quickly than the tricyclic antidepressants. These medications are also less likely than other antidepressants to have adverse interactions with other medications. However, some do exist [161].

SSRIs are especially useful if given in the early stages of depression, when symptoms are mild-to-moderate and are particularly effective in patients with obsessive-compulsive symptoms (particularly fluvoxamine) [161]. However, they are also effective for severe depressive disorders. Administration of an SSRI should result in elevated mood, lessened depressive symptoms, and an increase in self-confidence. Women should also experience less fatigue and a renewed ability to care for themselves and their babies. As depression improves, medication may be gradually decreased and eventually discontinued altogether [158,160].

Treatment with antidepressants as early as possible in the course of the illness may shorten and lessen the symptoms of PPD, affecting change within several weeks rather than months. Antidepressant treatment also reduces parenting stress. Improvement in the mother-infant interaction then has the benefit of reducing the negative impact of PPD on child development [127,133]. It should be noted that the effects of the SSRIs may not be seen for many days or weeks after instituting treatment.

Possible Adverse Reactions

The side effects of SSRIs are generally considered to be milder than traditional antidepressants, although there are still several side effects. They may initially increase anxiety or panic symptoms, and so should be avoided in patients whose depression includes these features. Those sensitive to SSRIs may have more severe reactions. Side effects may include [162,163]:

Side effects that do occur usually subside after two weeks, when the body adjusts to the medications [161,162]. Adverse drug interactions have been noted with [162,163]:

These substances should be avoided while taking an SSRI for depression [162].

There are also certain medical conditions that warrant caution when considering the use of SSRIs, including [162,163]:

Patients should be cautioned not to abruptly stop taking SSRIs, as withdrawal symptoms may occur [162,166].

Risks

The U.S. Food and Drug Administration (FDA) has alerted healthcare professionals and the public regarding a potentially life-threatening condition called serotonin syndrome. Serotonin syndrome, or serotonin toxicity, results from an excess of serotonergic activity in the central nervous system. It is seen only rarely in postpartum women, usually when multiple antidepressants, such as TCAs, MAOIs, St. John's wort, or opioids are combined. Serotonin syndrome is a medical emergency that requires immediate treatment. Symptoms and signs of this syndrome include [167,168]:

A risk of violent behavior has been associated with the use of SSRIs in a small number of people. In adverse drug event monitoring in the United Kingdom, violent events were reported in 56 of 13,741 (0.41%) patients taking paroxetine and 60 of 12,692 (0.47%) patients taking fluoxetine [169]. At the time of the study, researchers concluded that instances of serious violence among individuals using antidepressants were likely to be very rare [169]. However, Swedish researchers examined data from more than 850,000 individuals and found that SSRI use was linked to a 43% increased risk for violent crime among people 15 to 24 years of age. There was no significant association among older individuals [170].

An increased risk of suicidal thinking and behavior has been observed in young adults 18 to 24 years of age who are taking antidepressants, generally during the first one to two months of treatment. In 2004, the FDA issued a black-box warning about the increased risk of suicidality for all antidepressants. The warning has been updated and states that, "antidepressants increased the risk [compared to placebo] of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder and other psychiatric disorders. Anyone considering the use of [any antidepressant] in a child or adolescent must balance this risk with the clinical need" [171; 172]. The warning statements also emphasize that depression and certain other psychiatric disorders are themselves the most important causes of suicide [172].

Patients of all ages, including adolescent mothers with PPD, should be monitored carefully for clinical worsening, unusual changes in behavior, or suicidal risk both if treated with antidepressants or if no pharmacologic treatment is offered. Families and caregivers should be advised of the need for close observation and communication with the prescriber [172]. Fluoxetine is approved for use in children and adolescents for the treatment of major depressive disorder. Fluoxetine, sertraline, and fluvoxamine are approved for use in children and adolescents for the treatment of obsessive-compulsive disorder [163]. The remaining antidepressants are not FDA-approved for use in children [163,172,173]. The issue of treatment of depression in the pediatric population is hotly debated and requires additional research [174,175].

The FDA has recommended that healthcare providers consider the following points when treating patients with antidepressants [172]:

Patients taking antidepressants should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (i.e., psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, as changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [171,172].

Women who are planning to breastfeed should be made aware that antidepressant medications are secreted in breast milk, and breastfeeding while taking antidepressants exposes infants to potential effects of these drugs. However, the concentration of antidepressants in breast milk represents relatively low doses. In general, if lower-risk interventions are not effective, pharmacotherapy should be considered. As with any medication use, the benefits should be carefully weighed against the risks to the patient and infant. The same risk assessment should apply to continuing breastfeeding in those with severe depressive symptoms. For those taking antidepressants, toxic symptoms appearing in an infant should be reported immediately [133].

The AAP recommends exclusive breastfeeding for six months, with continuation for one additional year as mutually desired by the mother and child. If breastfeeding is helping a mother bond with her infant (rather than contributing to symptoms), it should be incorporated into PPD treatment. Alternatively, if breastfeeding is contributing to a woman's distress, she should not feel guilty for choosing to seek alternative forms of feeding.

Studies have shown that SSRIs peak in the breast milk seven to nine hours after maternal dosing. The highest concentrations are found in the hindmilk [163,176,232]. The best time to nurse is one hour before taking the SSRIs. If a mother must breastfeed during the peak concentration, she may nurse for a brief period and discard the hindmilk, which will help to reduce the amount of medication the baby receives [177].

A few studies of breastfeeding children have found low infant serum levels of sertraline [178,179]. Another study indicated the relative safety of nortriptyline, paroxetine, and sertraline [180]. Although sertraline may appear to be the safest SSRI for breastfeeding mothers, the long-term neurobehavioral development of exposed infants has not been investigated [163,176]. A review of evidence about the safety of each SSRI during pregnancy found evidence suggesting a teratogenic potential of the whole SSRI class. The teratogenic effects are mainly in the heart region, often described as septal defects [181].

The Scottish Intercollegiate Guidelines Network recommends avoiding doxepin for treatment of depression in women who are breastfeeding. If initiating selective serotonin reuptake inhibitor treatment in breastfeeding women, then fluoxetine, citalopram, and escitalopram should be avoided, if possible.

(https://www.sign.ac.uk/assets/sign127_update.pdf Last Accessed: March 23, 2023)

Level of Evidence: D (Non-analytic studies or expert opinion)

Fluoxetine produces the highest proportion of infant levels (22%), elevated more than 10% above the average maternal level, and fluoxetine has a longer half-life than either sertraline or paroxetine [166]. Two case reports of nursing infants whose mothers were taking fluoxetine related instances of increased irritability, colic, increased crying, decreased sleep, increased vomiting, and watery stools [176]. The long-term neurobehavioral development of infants exposed to fluoxetine has not been investigated. It is a drug "of concern" and should be used with caution in nursing mothers [163].

In the past, the AAP has maintained a list of drugs for which the effect on nursing infants is unknown but may be of concern [182]. However, in 2010 the AAP retired this guideline [183]. The AAP now states that only a small proportion of medications are contraindicated in breastfeeding mothers or are associated with adverse effects on their infants [184]. Prescribers are advised to follow labelled warnings and consult online tools, such as LactMed (https://www.ncbi.nlm.nih.gov/books/NBK501922), for up-to-date information on medication use during breastfeeding [165,184,185].

SNRIs act by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepinephrine and therefore an increase in neurotransmission [186,187]. Most SNRIs, including venlafaxine, desvenlafaxine, levomilnacipran, and duloxetine, are several-fold more selective for serotonin over norepinephrine.

Benefits

SNRIs are a newer class of antidepressants, with use in the United States beginning in the 2000s. As such, there is not a large body of evidence comparing SNRIs to other available antidepressants. Venlafaxine is especially beneficial in treating anxiety in depressed patients. At lower doses (75 mg/day), venlafaxine acts much like an SSRI; SSRI-like side effects such as gastrointestinal upset often improve at higher doses (150–300 mg/day) [187]. However, discontinuation syndrome has been reported to be markedly worse for venlafaxine when compared to other SNRIs. The SNRIs also have an important role as second-line agents in patients who have not responded to SSRIs

Adverse Reactions

Safety, tolerability, and side effect profiles of SNRIs are similar to SSRIs, with the exception that the SNRIs have been associated (rarely) with sustained elevated blood pressure. SNRIs can be used as first-line agents, particularly in patients with significant fatigue or pain syndromes associated with the episode of depression [186,187]. Typical side effects include [163]:

The manufacturer of venlafaxine specifically does not recommend breastfeeding during therapy [163].

TCAs act by increasing levels of both serotonin and norepinephrine in the brain. In this way, TCAs differ from SSRIs in that they affect two neurotransmitters rather than just serotonin, and they have a different side effect profile. As with SSRIs, there is no way of knowing which antidepressant will be most beneficial to each individual woman [159].

The most common TCAs are clomipramine, amitriptyline, nortriptyline, desipramine, trimipramine, and imipramine. Treatment with TCAs should be at the lowest possible therapeutic dose to minimize possible side effects. To be most effective, antidepressant treatment should be combined with counseling or psychotherapy in most instances [162].

Benefits

The main benefit of TCAs is their long history of effectiveness in treating depression. TCAs were first utilized in the late 1950s and have amassed a record of treatment success [162]. Therefore, TCAs remain a viable option. Women for whom PPD is a recurrent depression may have a prior history of success with one of the TCAs, which makes the choice easier [160].

Some benefits of TCA use are the same as those described for SSRIs, including the reduction of symptoms and the potential positive effects of the mother's rapid recovery. Relief from symptoms can help a mother function despite continuing depressive symptoms and difficulty coping with problems. The degree of response, from a slight relief of symptoms to complete relief, depends on a variety of factors related to the individual woman and the severity of the depression being treated [159]. A potential benefit of nortriptyline for breastfeeding women is that it usually produces undetectable infant levels [180]. There are no food restrictions with any of the TCAs, with the exception of caffeine and alcohol.

Adverse Reactions

TCAs tend to have more adverse side effects than SSRIs. Although side effects associated with TCAs vary with the individual and the specific antidepressant taken, in some cases, the side effects may make the drug unusable for some women. Some typical side effects are [163,189]:

These side effects usually resolve within two weeks and can be reduced by lowering the dosage or switching to another TCA. If the adverse effects are unbearable or if they do not resolve, use of the medication is discontinued. When discontinuing an antidepressant, doses should be gradually tapered to avoid withdrawal symptoms [159].

Risks

There are a variety of factors that contraindicate the use of TCAs. TCAs should not be prescribed to anyone with a history of heart disease, as they may cause cardiovascular problems. There have also been cases of TCAs triggering manic episodes in patients with a personal or family history of bipolar disorder [190,191]. It is also important not to prescribe TCAs with any of the following medications or other items, as there are risks of dangerous interactions [189]:

Heart arrhythmias have been reported in adolescents taking desipramine; therefore, extreme caution is advised about the use of desipramine with adolescent mothers [159,189]. The drug is not FDA approved for use in pediatric patients [163]. Due to the possibility of serious cardiac complications, TCAs can be lethal if misused at high doses [163]. Because suicidality is a risk in PPD, the danger of overdosing should be considered in prescribing TCAs [162].

As approximately 50% of all new mothers choose to breastfeed, treatment with antidepressants should be of concern [133]. As mentioned, while essentially all antidepressant medications transfer to breast milk, different medications are excreted at different levels. The treatment goal should be to minimize the amount of antidepressant the baby receives while maximizing the mother's emotional health. For healthy, full-term babies, the known benefits of breast milk could outweigh the potential hazards of most antidepressant medications [177]. The TCA doxepin should be avoided due to a case report of infant respiratory distress. Data on citalopram, fluvoxamine, bupropion, and venlafaxine are more limited, and their use cannot be recommended during breastfeeding. One study evaluating the potential consequences of TCA exposure through breast milk followed exposed children through preschool age and found that exposed children were developmentally similar to non-exposed children [186].

There are a small number of people for whom MAOIs are the best treatment [159]. Monoamine oxidase, an enzyme found in the brain, destroys neurotransmitters such as serotonin and norepinephrine. MAOIs act by inhibiting the activity of monoamine oxidase, blocking the breakdown of the neurotransmitters and making more serotonin and norepinephrine available to the neurons [162,193]. The traditional MAOIs are phenelzine, tranylcypromine, selegiline, and isocarboxazid [162,193].

Benefits

MAOIs work more quickly than TCAs and provide relief from symptoms shortly after beginning treatment. MAOIs are generally prescribed for people who do not initially respond to TCAs or SSRIs and for cases of atypical depression. Due to their stimulating effect, MAOIs may be preferable in the treatment of chronic low-level depression [159,163].

Adverse Reactions

The side effects of the common MAOIs are generally minimal. When adverse effects do occur, they include dizziness, rapid heartbeat, loss of sexual interest, and food interactions [162,163]. MAOIs can react with certain foods, alcohol, and some medications to produce a severe reaction. Reactions, which may not appear until several hours following ingestion of the medication, may include a severe rise in blood pressure, headache, nausea, vomiting, rapid heartbeat, confusion, seizures, stroke, psychotic symptoms, or coma [162].

Foods that contain a high level of tyramine can interact with MAOIs [163]. These foods mostly consist of aged cheeses; smoked, dried, or fermented meat; fish; air-dried sausages; soy products; red wine; beer and ale; fava beans; ripe figs; Brewer's yeast or yeast extracts; pickled or salted herring; beef or chicken liver; overripe bananas or avocados; sauerkraut; soups made from beef bouillon or Asian soup stocks, such as miso soup; white wine; gin; vodka; sour cream; yogurt; saccharine; and chocolate. Any of these foods can cause problems if ingested in large amounts [162].

Drug interactions are similar to those described for TCAs and may occur with [162,163]:

MAOIs should also never be combined with SSRIs due to the risk of serotonin syndrome [159,163]. Serotonin syndrome, or serotonin toxicity, results from an excess of serotogenic activity in the central nervous system. The symptoms include tachycardia, diaphoresis, hypertension, hyperthermia, clonus, and disseminated intravascular coagulation. It is seen only rarely in postpartum women, usually when multiple antidepressants, such as SSRIs, SNRIs, TCAs, MAOIs, and St. John's wort, are combined [159,163].

In 2019, the FDA approved the first drug specifically for the treatment of PPD [226]. Chemically, brexanolone is identical to endogenous allopregnanolone, a hormone that decreases after childbirth. It modulates GABA-A receptors, which become dysregulated in the postpartum period [163]. It is administered as a continuous IV infusion over a total of 60 hours (2.5 days) [226].

At the time of its approval, available only through a restricted program called the Zulresso Risk Evaluation and Mitigation Strategy (REMS) program that requires the drug be administered by a healthcare provider in a certified healthcare facility. Patients must be enrolled in the program prior to administration of the drug [226].

Benefits

Studies indicate that infusion of brexanolone results in a significant and clinically meaningful reduction in HAM-D total score in women with severe PPD, compared with placebo [227]. The drug appears to have a rapid onset of action and durable treatment response, adding a novel option for women with severe or refractory disease [227,228].

Adverse Reactions

Side effects to brexanolone can occur after the infusion has concluded and the patient has been discharged home. Moderate effects include sedation, dizziness, faintness, xerostomia (dry mouth), and skin flushing. More serious and/or potentially life-threatening effects include loss of consciousness, severe sedation, anaphylaxis, and suicidal thoughts (particularly in those younger than 25 years of age) [236].

Risks

Brexanolone includes a black-box warning regarding the risk of serious harm due to the sudden loss of consciousness and for potential risk to children. During treatment, patients are monitored every two hours for loss of consciousness. If loss of consciousness occurs, treatment is immediately discontinued until the patient regains consciousness and symptoms resolve. Patients are also monitored for hypoxia via continuous pulse oximetry with alarm throughout treatment. If hypoxia develops, treatment is immediately terminated [225]. While receiving the infusion, patients must be accompanied during interactions with their child(ren). Patients should be counseled on the risks and instructed that they must be monitored for these effects at a healthcare facility for the entire 60 hours of infusion. Patients should not drive, operate machinery, or do other dangerous activities until feelings of sleepiness from the treatment have completely dissipated [226].

In February 2023, the FDA accepted the filing of a New Drug Application for Zuranolone, which is being evaluated as a potential 14-day, rapid-acting, once-daily, oral medication to treat major depressive disorder and, specifically, PPD. Zuranolone is an oral neuroactive steroid (NAS) GABA-A receptor positive allosteric modulator (PAM). The GABA system is the major inhibitory signaling pathway of the brain and central nervous system and contributes to regulating brain function [32]. In August 2023, the FDA approved this agents for adults with postpartum (or perinatal) depression [242]. The daily recommended dose is 50 mg taken once per day in the evening with a high-fat meal.

The continual introduction of novel drugs specifically designed to help in the treatment of PPD and the maternal mental health is crucial to the amelioration of this preventable and/or manageable condition.

Often, individual therapy and antidepressant medications are combined in a treatment regimen. However, some women with PPD will respond well to psychotherapy alone [63]. The decision of whether to use a medication is based on a complex combination of factors that include the severity of symptoms, the individual's preferences, the response to other treatments or changes in support, and the risk of side effects. In many cases, support and education alone are not effective treatments for PPD, and medication must be added. The presence of certain symptoms, such as loss of concentration, severe insomnia, confusion, extreme indecisiveness, and severe feelings of guilt, indicate that psychotherapy alone will not be a sufficient treatment option. It is important to remember that in severe cases of PPD, medications may contribute to a quicker, fuller, and longer-lasting recovery [63,196].

Success has been reported with the use of interpersonal psychotherapy [66,196]. However, it is unclear whether individual psychotherapy is effective prophylaxis to prevent recurrence of PPD in the five years after the initial onset of depression. Individual psychodynamic psychotherapy and cognitive behavioral therapy have also been effective in the treatment of PPD [196,197,198]. All women with PPD should be offered psychosocial treatment, and this is of particular urgency for women with severe symptoms or psychosis. Some women, however, may refuse treatment.

As is well known, group therapy is an established form of professional treatment involving several individuals with similar issues meeting together at a specified time. The group is usually led by a singular therapist but may include more than one group leader. Group therapy sessions may be limited to a specific number of meetings or may be ongoing. Meetings may be structured, with a set agenda or format for each group, or nondirective, with no specific topic except those issues that the participants decide to discuss. To obtain the best results, group therapy should be combined with individual psychotherapy rather than undertaken as a singular therapeutic regimen, especially for those depressed mothers who require individualized care.

The advantages of group therapy are that it is cost effective, reduces isolation, and offers support and empathy from others with similar problems. The disadvantages are that there is no one-on-one interaction between the therapist and each individual, and the group is not specifically tailored to meet each individual's particular needs [34]. Additionally, some mothers' childcare responsibilities may interfere with their ability to attend and participate in group therapy sessions [199]. A feasibility study on the effects of telecare therapy (i.e., a combination of cognitive-behavioral therapy, relaxation techniques, and problem-solving strategies) indicated that this may be an effective treatment option for women with PPD who are unable to attend group therapy sessions or support groups [200].

Social groups and self-help groups specifically established for women with PPD may be very helpful. These groups are not intended to provide therapeutic outcomes, but are created to provide support, empathetic listening, understanding, and information, all of which are important for depressed mothers. Women who wrote about their experiences with PPD specified that these groups gave them valuable practical guidance on day-to-day issues [11,99].

Self-help groups for PPD are usually led by a woman who has personal experience with PPD. This woman shares her knowledge and experience as guidance for other women, helping them deal with PPD. Resources for treatment of PPD and practical advice are usually part of such groups. They are also beneficial experiences for those women who feel alone and isolated [63].

According to one study, social support groups did not positively affect depressive symptoms per se, but did have a positive effect on the mother-infant interaction [66]. Another small study found that depression scores following participation in a weekly peer support group were similar to a community sample [31]. Support groups and self-help groups are no substitute for formal treatment. Like group therapy, they are best used as an adjunct to traditional therapy and medical intervention.

Overall, both psychosocial (e.g., peer support, nondirective counseling) and psychologic (e.g., cognitive behavioral therapy, interpersonal psychotherapy) interventions have been found to be effective in reducing symptoms of PPD and, more recently, to be effective in preventing PPD [201]. These interventions significantly reduce the number of women who develop PPD. However, the long-term benefits are unknown and larger trials are needed to determine the specific benefits of each type of intervention [201,202].

Mothers suffering from severe mental illness in the postpartum period will inevitably require psychiatric hospitalization as part of their treatment. Unless the mother and infant are admitted together to a specialty unit, there may be little or no contact between them for several days or weeks. Separation of the mother and infant may have negative consequences [203]. However, the consequences (e.g., delayed bonding, cessation of breastfeeding) are secondary to the patient's and child's safety.

The physical separation of mother and infant protects the infant from the potential risks of interaction with a severely ill mother. However, separating mother and infant may have adverse effects on their subsequent relationship and the infant's socioemotional development. Although there are concerns about admitting infants with their mothers to psychiatric hospitals, there is no evidence of major disadvantages, and the advantages afforded to the mother and infant seem to be great [203].

Other concerns about the effects of separation include stunting of parenting skills and lack of infant attachment. These concerns have led mental health units in some countries to develop ways to provide psychiatric care for mentally ill mothers without separating them from their children [204].

Studies have shown that mothers separated from their infants during hospitalization have a longer duration of illness and experience greater difficulty bonding with their infants than mothers jointly admitted to a mother-baby unit. Most of the mothers admitted to a mother-baby unit showed a positive clinical outcome and were discharged home to care for their infant without further supervision. Mothers in a supportive social relationship had the best chance for a positive outcome [205].

Mother-baby units have been difficult to maintain in the United States. Although they offer significant advantages to mothers and families, data to support cost effectiveness are not available, which is a barrier to implementation [206]. As an example, the Women and Infant's Hospital, associated with Brown Medical School in Rhode Island, has operated since 1999. Services are provided in a mother-baby day hospital. The hospital admits both pregnant patients with psychiatric problems and postpartum psychiatric patients for therapy [20].

Most interventions to prevent PPD focus on just the mother rather than on the mother-infant dyad. One study examined the effectiveness of practical resources for effective postpartum parenting, a new PPD prevention protocol that aims to treat women at risk for PPD by promoting maternally mediated behavioral changes in their infants, while also including mother-focused skills [218]. Fifty-four women were included in this randomized control trial. Results indicate that this novel, brief intervention was well tolerated and effective in reducing maternal symptoms of anxiety and depression, particularly at six weeks postpartum [218].

Another study tested perinatal dyadic psychotherapy (PDP), a dual-focused mother-infant intervention designed to prevent or decrease maternal PPD and improve aspects of the mother-infant relationship that are related to the child's development [219]. Forty-two first-time mothers with depressive symptoms (recruited from hospital postpartum units) and their 6-week-old infants were enrolled and randomized to receive either the PDP intervention or usual care plus depression monitoring by telephone. The PDP intervention consisted of eight home-based, nurse-delivered mother-infant sessions consisting of supportive, relationship-based, mother-infant psychotherapy and a developmentally based infant-oriented component focused on promoting positive mother-infant interactions. Measures of maternal depression, anxiety, self-esteem, parenting stress, and mother-infant interaction were collected at baseline, post-intervention, and three-month follow-up. Depression and anxiety symptoms and diagnoses decreased significantly, and maternal self-esteem increased significantly across the study time frame, with no differences between the two groups. There also were no significant differences between the groups on parenting stress or mother-infant interaction. No participants developed onset of PPD during the study. The authors concluded that although this novel intervention holds potential for treating depression in the context of the mother-infant relationship, usual care plus depression monitoring showed equal benefit [219]. Further research is needed.

A novel maternal-infant dyadic group therapy intervention was the focus of an open-label pilot study that targeted mothers with mood or anxiety disorders and their infants 6 to 12 months of age [220]. Three 12-week groups were conducted using evidence-based maternal and mother-infant dyadic strategies to enhance mood, insight, parenting, and mentalizing capacity. Outcome measures included recruitment and retention rates, reasons for nonparticipation, and missed sessions. Enhanced insight, parenting capacity, affect regulation, and positive interaction with the infant were supported with self-report surveys and interviews [220].