Dr. Kim is director of the Hennepin Women’s Mental Health Program at Hennepin County Medical Center in Minneapolis, Minnesota, and clinical assistant professor of psychiatry at the University of Minnesota Medical School in Minneapolis. Dr. Kolpe is staff psychiatrist at the Hennepin Women’s Mental Health Program and clinical assistant professor of psychiatry at the University of Minnesota Medical School.
Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Helen Kim, MD, Hennepin Women’s Mental Health Program, S110 Clinic, Hennepin County Medical Center, 900 S 8th St, Minneapolis, MN 55404; Tel: 612-347-6851; Fax: 612-373-1859; E-mail: email@example.com.
What should a clinician consider in selecting a psychotropic medication for pregnant and lactating women with psychiatric symptoms? While postpartum depression is increasingly recognized as a public health priority, vulnerability to depression and anxiety begin in pregnancy. Clinicians are often called upon to counsel pregnant and postpartum patients about the risks and benefits of psychotropic medication. Patients generally overestimate the risks of psychotropic drugs and underestimate the impact of untreated psychiatric illness on themselves and their families. This article reviews recent studies and treatment considerations in selecting psychotropic medications for perinatal women with mood and anxiety symptoms.
The perinatal period can be a high-risk time for worsening mood and anxiety symptoms. While postpartum depression has been identified as a major public health concern,1 vulnerability to depression clearly begins before delivery and continues into the postpartum.2-6 A systematic review of perinatal depression found that the point of prevalence of major depressive disorder (MDD) and minor depression during pregnancy ranged from 6.5% to 12.9%, while another study of >3,000 pregnant patients found that 20% had significant depressive symptoms.7 Many factors have been implicated in worsening mood and anxiety symptoms during pregnancy, including psychosocial risk factors as well as physiologic changes associated with the perinatal period.8-11 Disrupting a maintenance antidepressant may also lead to worsening symptoms in pregnancy as demonstrated in a recent study by Cohen and colleagues,12 in which 68% of women with a history of recurrent MDD relapsed with depression after discontinuing antidepressants compared to 26% who maintained treatment.
With the high prevalence of MDD among women of reproductive age, clinicians are often called upon to help patients weigh the benefits and risks of psychotropic medications during pregnancy and lactation. Recent studies have highlighted both the potential risks of antidepressants in pregnancy as well as the effects of untreated psychiatric symptoms during and after pregnancy. Several studies from the renowned Motherisk Program in Toronto have examined the tendency of pregnant patients to underestimate this risk of untreated depression and anxiety13,14 and overestimate the risk of medication. For example, though the baseline rate of malformations in the general population is approximately 3% to 4%, women exposed to known nonteratogens assigned themselves a risk of 24% for major malformation before hearing about relevant medical studies, and then 14.5% thereafter.15 This misperception of risk can lead patients and physicians to avoid or terminate otherwise wanted pregnancies or avoid needed pharmacotherapy. Clinicians can help put the risks of medication into context by reminding patients that pregnancy itself carries many risks including spontaneous abortion and congenital defects. Many studies have documented the fact that untreated psychiatric illness can compound these risks by contributing to poor self care, decreased prenatal compliance, increased nicotine and substance misuse,16,17 poor obstetrical outcomes,18,19 and increased risk of postpartum depression.20 Given the potential risks of medication during pregnancy, patients often feel like they must not put their own need for symptom relief ahead of the well-being of the pregnancy. Clinicians can help patients realize that these two priorities are inextricably tied since emotional distress also impacts the pregnancy.
Routine formalized screening for major Axis I diagnoses both prenatally and postnatally can assist clinicians in identifying patients with psychiatric symptoms.21,22 Risk factors for depression and anxiety during and after pregnancy are also readily identifiable and include prior history of depression, young age, poverty, stressful life events, and limited social support.23,24 After screening for these risk factors, evaluating current symptoms, and ruling out possible medical conditions (eg, anemia or thyroid dysfunction) that may be contributing to mood, anxiety, and neurovegetative symptoms, clinicians must then direct patients toward the most appropriate course of treatment. This process involves careful review of the risks of untreated illness versus the risks and benefits of available treatment including medication, therapy, and supportive interventions. As Stowe and colleagues25 eloquently articulated, perinatal patients must be guided toward minimizing not only exposure to medication but exposure to illness as well. This article reviews recent studies and focuses on treatment considerations in selecting psychotropic medications for perinatal women with mood and anxiety symptoms.
Pharmacologic Considerations in Pregnancy
Medications taken during pregnancy are considered teratogenic if they increase the risk of congenital malformations above the baseline risk of 3% to 4%. Most studies of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are reassuring and show no increased risk of major congenital malformations.26,27 However, while previous studies have shown no association between paroxetine and congenital malformations,28-30 the manufacturer of paroxetine issued a warning in 2005 that two studies found a possible association between first-trimester paroxetine exposure and increased risk for cardiac defects, particularly atrial and ventral septal in nature.31 Subsequently, the Food and Drug Administration issued a similar warning that first-trimester paroxetine use was associated with an increased risk of major malformations (4% versus 3%), particularly cardiac defects (2% versus 1%), and changed the pregnancy labeling from category C to D, which indicates that controlled or observational studies in pregnant women have demonstrated a risk to the fetus. In addition, the American College of Obstetricians and Gynecologists has recommended avoiding paroxetine use in pregnant women unless the benefits outweigh the risks of discontinuing the medication.32
While there have been fewer reported cases of prenatal exposures to non-SSRIs, the limited data available have not shown an increased risk of congenital malformations with venlafaxine,33 mirtazapine,34 nefazodone, or trazodone.35 In an admirable attempt to prospectively assess reproductive risk, the drug manufacturer of bupropion established a postmarketing epidemiologic surveillance registry in 1997. This registry reported a preliminary finding of a possible association between bupropion exposure and increased risk of birth defects involving the heart and great vessels. In the most recent report from this registry spanning September 1997 through August 2006, 1,443 prospectively registered pregnancies involved exposure to bupropion.36 Among this group, 483 were lost to follow up and 134 pregnancies were pending. Among the remaining 833 prospectively reported pregnancy outcomes, the Bupropion Pregnancy Registry Advisory Committee found no evidence of increased risk of birth defects; however, they warned that the relatively small sample size and large percentage of patients lost to follow up make it impossible to draw definitive conclusions about the possible teratogenic risk of bupropion. These findings are consistent with other studies including a prospective study of 136 women exposed to bupropion in the first trimester of pregnancy that found no increased risk of major malformations,37 and a claims-based, retrospective cohort study using the United Healthcare database which found no consistent pattern of birth defects associated with prenatal exposure to bupropion.38 To register pregnancies in women on bupropion, clinicians can call the GlaxoSmithKline Pregnancy Registry at 800-336-2176.
Perinatal Effects Following Late-Pregnancy Antidepressant Exposure
In utero exposure to antidepressants has been associated with transient symptoms of possible medication withdrawal or toxicity in neonates. These symptoms have been described with many SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) and include irritability, tremulousness, insomnia, poor feeding, temperature dysregulation, increased or decreased muscle tone, and/or respiratory distress.39,40 Using a formal screening tool, one study found that 30% of newborns exposed to SSRIs in late pregnancy developed neonatal abstinence symptoms.41 Although these neonatal syndromes are generally transient and not life threatening, in 2004 antidepressant manufacturers and the FDA decided to modify their drug labeling to include a recommendation to consider tapering antidepressants in the last part of pregnancy. For women with recurrent depression or anxiety conditions, this strategy may not be prudent since it would withdraw treatment just as patients are transitioning to the postpartum, a time of increased risk for affective instability.
Another recent study highlighted another concerning finding regarding antidepressant use in pregnancy. In 2006, Chambers and colleagues42 published a study that found a possible association between SSRI exposure after 20 weeks’ gestation and persistent pulmonary hypertension of the newborn (PPHN), a serious and rare condition with a baseline rate of 1–2 out of 1,000 live births and mortality rate of 10% to 20%. Although this study was retrospective in design and involved only a small number of affected infants, its findings are concerning and highlight the uncertainty that patients and providers must assume in choosing to use antidepressants or any psychotropic medications during pregnancy.
Long-Term Neurobehavioral Effects
It remains to be seen whether in utero antidepressant exposure is associated with any long-term neurologic or behavioral effects. In a cohort of children 4–5 years of age exposed in utero to SSRIs, levels of internalizing and externalizing behavior did not differ significantly between children who were (N=22) or were not (N=14) exposed prenatally to SSRIs.43,44 In another study, Nulman and colleagues45 compared a cohort of mother-child pairs exposed throughout gestation to TCAs (N=46) or fluoxetine (N=40) to a nondepressed comparison group (N=36). Children between 15 and 71 months of age were assessed and compared in terms of intelligence quotient (IQ), language, behavior, and temperament, with adjustment for severity of maternal depression, maternal IQ, socioeconomic status, maternal smoking, and alcohol history. Children exposed in utero to TCAs or fluoxetine were found to have no difference in temperament, language, or cognitive development compared to nonexposed children. In fact, it was exposure to maternal depression and not medication itself that was associated with less language and cognitive achievement.
Lithium use during pregnancy has been associated with perinatal toxicity, including case reports of lethargy, hypotonia, cyanosis, respiratory distress, and diabetes insipidus.46 In addition, lithium use during the first trimester has been associated with an increased risk of a serious congenital heart defect known as Ebstein’s anomaly and occurs in approximately 1 out of 1,000 live births. For women with moderate-to-severe bipolar disorder with recurrent episodes of mania or depression, the relatively small risk of these adverse pregnancy outcomes may be far overshadowed by the much greater risk of relapse. Maintenance lithium treatment for these patients during pregnancy may be the most prudent treatment option. For women with less severe bipolar disorder who have had significant periods of stability, slowly tapering off lithium and reintroducing it after the first trimester or just after delivery may help lower medication exposure while also minimizing risk of relapse during the postpartum, a time of known high risk in women with bipolar disorder.47
Lamotrigine is another highly effective mood stabilizer, particularly for bipolar depression. As with bupropion, the manufacturer of lamotrigine took a very proactive step in 1992 and established a pregnancy registry to assess the reproductive safety risk of lamotrigine. In January 2007, the Lamotrigine Pregnancy Registry reported its most recent update spanning the time period from September 1992 through September 2006 during which there were 1,539 prospectively registered pregnancies involving lamotrigine exposure.48 Among this group 908 outcomes involved first-trimester lamotrigine exposure with 26 (2.9%) major birth defects. This is similar to the baseline frequency of malformations reported in cohorts of women using antiepileptic monotherapy. Of note, in the 133 pregnancy outcomes involving polytherapy with lamotrigine and valproate, plus or minus another anticonvulsant, there was an alarming 11.3% rate of major congenital defects. Overall, the findings for lamotrigine monotherapy have been reassuring and consistent with other reports.49 However, the North American Antiepileptic Drug Pregnancy Registry recently found that infants who are exposed to lamotrigine as monotherapy during pregnancy have a much higher risk of oral cleft defects.50 In this study, 564 children exposed to lamotrigine monotherapy had a prevalence rate of major malformations of 2.7%; however, five infants had oral cleft lip/palate, yielding a prevalence rate of 9 out of 1,000 births compared to a baseline prevalence of 0.5–2.0 per 1,000 in unexposed infants. A larger sample size is needed to confirm this finding. Even if future prospective studies also find this association between first-trimester lamotrigine use and oral cleft lip and palate, the overall risk appears to be low and may be overshadowed by the high risk of recurrent illness in women with moderate-to-severe forms of bipolar disorder. Clinicians can help expand the available database of lamotrigine exposures by registering all pregnant patients on lamotrigine with the Lamotrigine Pregnancy Registry by calling 800-336-2176, or having patients enroll themselves in the North American AED Pregnancy Registry by calling 888-233-2334.
Valproic acid and carbamazepine have well-established risks of neural tube defects of 1.0% to 5.0% and 0.5% to 1.0%, respectively.51,52 In utero valproate exposure has also been associated with a higher frequency of major anomalies53,54 as well as neurodevelopmental delay in exposed children.55,56 Neonatal complications associated with valproate include irritability, jitteriness, and feeding problems.57 Liver toxicity has also been described following valproate and carbamazepine use during pregnancy.58,59 Less is known about the reproductive safety of newer anticonvulsants such as gabapentin, oxcarbazepine, and topiramate. While these newer anticonvulsants would not be the first choice in pregnancy, they may be indicated for pregnant women with refractory bipolar illness and a history of good response to these medications. Providers should encourage pregnant women who elect to continue any mood stabilizer to take high-dose folate (4 mg/day) for the theoretical benefit of reducing risk of neural tube defects. In addition, pregnant women should undergo a second trimester Level II ultrasound to screen for major congenital anomalies.
Untreated psychosis can be harmful in pregnancy, as demonstrated by one study that found a two-fold increase in adverse pregnancy outcomes (eg, stillbirth, preterm delivery, low birth weight) in women diagnosed with schizophrenia during pregnancy.60 Psychotic symptoms can also lead to disorganized behavior, increased paranoia, avoidance of prenatal care, increased drug and alcohol use, and other high-risk behaviors. First-generation antipsychotics with high and midpotency (eg, haloperidol, perphenazine) are generally considered to be the antipsychotics of choice during pregnancy since they have not consistently demonstrated teratogenic risk.57 Low-potency phenothiazines (eg, chlorpromazine) have shown increased risk of congenital malformations and should be avoided.61 Case reports of neonatal toxicity following in utero exposure to typical antipsychotics have been described and include motor restlessness, tremor, feeding difficulties, increased muscle tone, and abnormal motor movements.62,63
Studies of the reproductive safety of atypical antipsychotics have been limited to small case reports and case series. Olanzapine was not associated with major malformations in a manufacturer-sponsored study of 23 prospectively ascertained pregnancies.64 McKenna and colleagues65 reported on 151 pregnancy outcomes following exposure to olanzapine (N=60), risperidone (N=49), quetiapine (N=36), and clozapine (N=6). Among this total group there were 110 (approximately 73%) live births, 22 (approximately 15%) spontaneous abortions, 15 (approximately 10%) therapeutic abortions, four (approximately 3%) stillbirths, and one (approximately 1%) infant with major malformations. There was no statistically significant difference in pregnancy outcomes between this group and a comparison group of pregnant women except for a higher rate of low birth weight in exposed babies (approximately 10% versus 2%). Given the small sample sizes and the notable differences between the exposed and comparison group (eg, differences in socioeconomic background and rates of elective abortion), no definitive conclusions can be drawn about the reproductive safety of atypical antipsychotics in general. However, one theoretical concern with these medications is their propensity to cause significant weight gain that in pregnancy can lead to or exacerbate pre-existing hypertension and diabetes. This must be considered along with the potentially hazardous consequences of discontinuing an antipsychotic that is effectively treating a pregnant woman with a history of psychotic symptoms.
Based on the available evidence, experts have supported the use of typical antipsychotics for acute treatment of mania or psychosis during pregnancy.57 Others have suggested that the risk with high-potency typical antipsychotics may be less than the risks associated with available mood stabilizers,61 and that they offer a reasonable treatment alternative for women with bipolar disorder with recurrent symptoms during pregnancy.57
Benzodiazepine use during pregnancy has been associated with case reports of perinatal toxicity, including temperature dysregulation, apnea, depressed APGAR scores, hypotonia, and poor feeding. In addition, early studies revealed an elevated risk of oral cleft palate defects compared to the baseline risk in the general population.66 However, more recent studies have shown that the overall risk of cleft lip and palate with benzodiazepine use in pregnancy is likely quite low.67,68 In considering the risks and benefits of benzodiazepines, clinicians should also consider the risks of untreated insomnia and anxiety in pregnancy, which may lead to physiologic effects as well as diminished self care, worsening mood, and impaired functioning. Given the consequences of untreated psychiatric symptoms and the limited and controversial risks associated with benzodiazepine use, some women with overwhelming anxiety symptoms or sleep disturbance may find that the benefits outweigh any theoretical risks.
Pharmacologic Considerations in the Postpartum
Women can experience a range of emotional and psychological symptoms following delivery. Heightened emotional sensitivity, anxiety, and sleep disturbance can affect 80% of women after delivery in the form of the postpartum blues, a normal and self-limited syndrome that usually begins 2–3 days postpartum and resolves in 7–14 days. Approximately 10% to 20% of all postpartum women experience a more serious condition called postpartum depression (PPD). The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision,69 classifies PPD as MDD that occurs within 4 weeks postpartum; however, many new mothers develop symptoms more than 2–3 months after delivery. Postpartum anxiety syndromes are also extremely common and can include panic attacks, intense anxiety about not getting enough sleep, obsessive worry about the baby’s health or safety, and intrusive thoughts or mental images of hurting the baby.70 New mothers with intrusive thoughts are often ashamed of these ego-dystonic images and may develop behaviors to diffuse some of their anxiety and fear, such as avoiding sharp objects or compulsively checking their infants’ breathing. Postpartum patients can be reassured that though intrusive thoughts are common, violently acting them out is very uncommon. Postpartum psychosis is a serious and rare condition that occurs in 1–2 of every 1,000 postpartum women. Postpartum psychosis can begin acutely within the first 48–72 hours after delivery and may include delirium, agitation, irritability, and mood lability. Psychosis can also occur in new mothers with a history of a chronic psychotic disorder or as part of a major depressive or manic episode. Psychotic symptoms in any postpartum woman require immediate intervention in order to protect both mother and infant from harm.
Evaluation of Postpartum Women with Psychiatric Risk Factors or Symptoms
Evaluation of postpartum psychiatric symptoms includes assessment for medical conditions such as anemia or thyroid disorders that can contribute to low mood, anxiety, fatigue, and sleep disturbance. Systematic screening for psychosocial risk factors as well as current symptoms facilitates prevention, detection, and treatment of postpartum psychiatric syndromes. The Edinburgh Postnatal Depression Scale (EPDS) is a widely recommended, cost-effective means of screening for PPD.71 The EPDS is a 10-item self-rating scale that has been validated in Spanish and English and asks about depressive symptoms in the preceding week, including crying spells, decreased interest and pleasure, increased guilt, anxiety, sleeping problems, and thoughts of self harm.72 To improve prevention interventions, clinicians can also screen for risk factors both during and after pregnancy. These risk factors include a personal history of mood or anxiety disorder, psychiatric symptoms during pregnancy, limited social support, interpersonal conflicts, and negative life events during and after pregnancy.73-75 In addition, a history of extreme premenstrual irritability may be a possible marker for increased vulnerability during times of hormone fluctuation, such as the dramatic hormone shifts after delivery.76
Despite the high prevalence of postpartum psychiatric illness, there are only a limited number of medication treatment studies. In small open studies, venlafaxine (N=15),77 bupropion (N=8),78 fluvoxamine (N=6),79 and sertraline (N=26),80 have shown efficacy in treating PPD. Paroxetine alone (N=16) or in combination with 12 sessions of cognitive-behavioral therapy (CBT; N=19) improved mood and anxiety symptoms in a group of women with PPD and anxiety symptoms.81 In small randomized trials, sertraline has shown benefit in both preventing82 and treating83 PPD. In another controlled study of 61 women with PPD, fluoxetine was significantly more effective than placebo in treating PPD.84 Combining fluoxetine with six sessions of CBT did not produce additional improvement. Of note, 101 out of 188 eligible patients refused to enter the trial, mainly because of ambivalence about being randomized to take an antidepressant. Furthermore, the trial excluded nursing mothers as well as women with a history of severe or chronic depression. All these factors limit the generalizability of the findings and underscore the difficulty in carrying out randomized trials in this population. Clearly, more studies are needed with larger sample sizes and longer follow-up periods to compare different antidepressants and other psychosocial interventions.85
The choice of an antidepressant is largely guided by a patient’s depressive symptoms and past history of medication response. If a patient plans to breastfeed, clinicians must facilitate a careful risk-benefit discussion about taking psychotropic medication during lactation (see below). In addition, patients must consider the risks of untreated maternal depression which can lead to impaired mother-infant attachment.86-88 and higher risk of cognitive and behavioral problems.89,90 Women at increased risk for postpartum depression should consider initiating prophylactic antidepressants either in late pregnancy or early postpartum. Alternatively, women may elect a wait-and-see approach; however, patients, their loved ones, and psychiatrists should be vigilant for early signs of recurrence in order to institute prompt treatment.
To temper the tremendous changes in estrogen and progesterone following birth, some studies have looked at hormone therapy. In one study, women with PPD who received transdermal estrogen had significantly lower mean EPDS scores at 4 weeks of treatment compared to placebo.91 However, in another study a single dose of synthetic progestogen administered within 48 hours after delivery was significantly more likely than placebo to be associated with increased depressive symptoms at 6 weeks postpartum.92 Given the limited data available, no specific recommendations can be made regarding the use of hormone therapy for PPD.93,94
All psychotropic medications are secreted into breast milk. Mothers on psychotropic medications require a thorough discussion of the risks and benefits of breastfeeding while taking medication to treat psychiatric symptoms.
A recent analysis of the available studies of antidepressants during lactation revealed that sertraline, paroxetine, and nortriptyline are the least likely to lead to accumulation in the infant.95 Other studies of TCAs and SSRIs have been reassuring and show no consistent association between any particular antidepressant and problems in nursing newborns. There have been isolated case reports of elevated infant levels and toxicity with breastfeeding mothers taking doxepin or fluoxetine.96 Little is known about the safety of other antidepressants during lactation, such as venlafaxine, bupropion, or mirtazapine.
For women with bipolar disorder, the choice to nurse while on a mood stabilizer is even less clear cut than with antidepressants. Lithium can quickly accumulate in the nursing infant and lead to levels exceeding 50% of the maternal level. Given this risk of lithium toxicity in the nursing infant, breastfeeding while on lithium is generally not recommended,97,98 however, a recent case series of 10 mother-infant pairs noted low infant lithium levels in nursing infants.99 The authors of this article encourage reassessment of general recommendations against lithium during breastfeeding and suggest that nursing on lithium may be appropriate for mothers with bipolar disorder who have healthy infants and who can reliably work with a pediatrician to monitor the infant and obtain infant lithium level, thyroid-stimulating hormone, blood urea nitrogen, and creatinine in the immediate postpartum, at 4–6 weeks postpartum, and then every 8–12 weeks thereafter.
Although not absolutely contraindicated in nursing mothers, valproate has been associated with infant anemia and thrombocytopenia, and carbamazepine has been associated with transient hepatic dysfunction.97 Mothers should be informed of signs of hepatic dysfunction or anemia, such as sedation or poor feeding. Among the few available reports, breastfed infants of mothers on lamotrigine have been shown to have serum levels that are approximately 30% of the mothers’ level.100,101 Though no adverse effects were noted in these infants, the severe life-threatening rash associated with lamotrigine in children and adults may also be a concern for infants exposed to lamotrigine through breastmilk.97
In general, clinicians should advise nursing women on psychotropic medications to monitor infants for behavioral changes, such as excessive sedation, jitteriness, or inconsolable crying. Infants who develop these symptoms should be evaluated by their pediatricians for possible drug toxicity. In the meantime, mothers can consider temporarily pumping and storing/discarding their breastmilk and using formula to see if their infants’ symptoms resolve. In infants who are preterm or have any medical problems, mothers on psychotropic medication could also consider pumping and storing/discarding breastmilk and introducing nursing later when the infant is healthy and can presumably metabolize medication more efficiently.
Although a detailed discussion is beyond the scope of this article, it is important to note that nonpharmacologic interventions such as education, support services, and psychotherapy can be invaluable alternatives or adjuncts to medication for women with perinatal psychiatric symptoms. Establishing a therapeutic alliance; exploring feelings about the pregnancy and motherhood; and taking inventory of strengths, supports, and stressors can help target interventions. Studies have demonstrated that depressed pregnant and postpartum women can also benefit greatly from interpersonal psychotherapy, a time-limited therapy focused on certain areas of particular relevance to pregnant women such as role transitions and interpersonal disputes.102-105 Supportive therapy and CBT have also been shown anecdotally to help with perinatal depression and anxiety as well as referrals to mothers’ groups, childcare resources, and financial assistance agencies. Clinicians can also refer women to Postpartum Support International, an organization with many local chapters that offers support and resources for women with postpartum psychiatric illness.
The perinatal period can be a high-risk time for significant psychiatric symptoms. In treating pregnant and postpartum patients, clinicians must adopt an individualized treatment approach that incorporates an up-to-date discussion of the risks and benefits of medication and psychosocial interventions as well as the impact of untreated psychiatric symptoms on mothers and families. Several recent studies have highlighted the fact that reproductive psychiatry is a dynamic field with treatment recommendations that continue to evolve and currently can only serve as general guides rather than absolute mandates. Ultimately, clinicians must help patients reflect on these guidelines in the context of their own experience of illness as well as their own perception of the risks and benefits of different treatment options. PP
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