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Bipolar postpartum depression: An update and recommendations
Author’s Accepted Manuscript Bipolar postpartum depression: An update and recommendations Verinder Sharma, Minakshi Doobay, Christine Baczynski www.elsevier.com/locate/jad
PII: DOI: Reference:
S0165-0327(17)30360-9 http://dx.doi.org/10.1016/j.jad.2017.05.014 JAD8962
To appear in: Journal of Affective Disorders Received date: 16 February 2017 Revised date: 13 April 2017 Accepted date: 6 May 2017 Cite this article as: Verinder Sharma, Minakshi Doobay and Christine Baczynski, Bipolar postpartum depression: An update and recommendations, Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2017.05.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Bipolar postpartum depression: an update and recommendations Verinder Sharmaa1, Minakshi Doobayb, Christine Baczynskic a
Western University & Parkwood Institute - London, Ontario, Canada b
Western University - London, Ontario, Canada
c
Parkwood Institute - London, Ontario, Canada [email protected]
Abstract Background: Over the past few years there has been a surge of interest in the study of bipolar postpartum depression (PPD); however, questions remain about its prevalence, screening, clinical features, and treatment. Methods: Three electronic databases, MEDLINE/PubMed (1966–2016), PsycINFO (1806–2016), and the Cochrane Database of Systematic Reviews, were searched using a combination of the keywords bipolar, depression, postpartum, peripartum, prevalence, screening, diagnosis, treatment, drugs, and psychotherapy. The reference lists of articles identified were also searched. All relevant articles published in English were included. Results: Depending on the population studied, 21.4% to 54% of women with PPD have a diagnosis of bipolar disorder (BD). Characteristic clinical features include younger age at illness onset, first onset of depression after childbirth, onset immediately after delivery, atypical depressive symptoms, psychotic features, mixed features, and history of BD in first-degree family members. Treatment should be guided by symptom acuity, safety concerns, the patient’s response to past treatments, drug tolerability, and breastfeeding preference. In the absence of controlled treatment data, preference should be given to drugs normally indicated for bipolar depression including lithium, quetiapine and lamotrigine. Although antidepressants have been studied in combination with mood stabilizers in bipolar depression, these drugs should be avoided due to likelihood of elevated risk of induction of manic symptoms in the postpartum period. Conclusions: In the postpartum period, bipolar PPD is common, can be differentiated from unipolar PPD, and needs to be identified promptly in order to expedite appropriate treatment. Future studies on pharmacotherapy and psychotherapy should focus on the acute and preventative treatment of bipolar PPD. Keywords: bipolar; postpartum; depression; peripartum; prevalence; screening; diagnosis; treatment; drugs; psychotherapy
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Mail: Parkwood Institute Mental Health Care Building, 550 Wellington Road London, Ontario, Canada N6C 0A7
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1. Introduction Postpartum depression (PPD) is a common complication of childbearing that affects 21.9% of women during the first year postpartum (Kettunen et al., 2014; Postpartum Depression: Action Towards Causes and Treatment Consortium, 2015). Contrary to the popular notion, PPD is not a homogenous illness (Wisner et al., 2013). Various factors including different periods of onset of the depressive episode (e.g. during, prior to, or after pregnancy), varying symptom profiles, different levels of symptom severity, and duration may contribute to clinical heterogeneity. Depression can begin for the first time after birth, or it can be a recurrence in the context of major depressive disorder (MDD) or bipolar disorder (BD) (Azorin et al., 2012). Recent research studies have demonstrated that a sizeable proportion of women with PPD actually have BD; however, differentiating bipolar from unipolar PPD can be challenging for several reasons. First, there is a general lack of awareness among patients and physicians that PPD can be a manifestation of BD (Sharma et al., 2009). Second, women are usually screened for depression during and after pregnancy, but not for manic symptoms (Sharma and Penava, 2010). Third, hypomanic symptoms are common after delivery but require expert questioning to differentiate these from normal joy accompanying childbirth (Sharma et al., 2009). Thus, underdiagnosis or misdiagnosis of BD as MDD are not uncommon in the postpartum period. Failure to arrive at the proper diagnosis of bipolar PPD can be associated with serious consequences, including an increased risk of hospitalization, reduced ability of the mother to care for herself and her infant, and although rare, maternal suicide and infanticide (Munk-Olsen et al., 2006; Sharma et al., 2008). Of all the psychiatric disorders, BD is associated with the highest risk of psychiatric hospitalization in the postpartum period, with a 23-fold greater risk of psychiatric admission within the first 30 days after delivery compared to non-postpartum women with BD (Munk-Olsen et al., 2006). Women with BD are also at risk of adverse birth and neonatal outcomes including preterm birth, caesarean delivery, and babies that are severely small, or severely large for gestational age (Boden, 2012). Adverse pregnancy outcomes such as gestational hypertension (Lee and Lin, 2010) and antepartum hemorrhage (Jablensky et al., 2005) also occur more frequently in women with BD. Despite the voluminous literature on PPD, researchers have only recently started paying attention to challenges in the detection, diagnosis, and treatment of bipolar PPD. In this paper we conduct a literature review on the prevalence, clinical features, diagnosis, and treatment of bipolar PPD. Gaps current in the literature are identified and recommendations are made for treatment of bipolar PPD. Discussion of management of mania or postpartum psychosis is omitted since the focus of the paper is on bipolar depression only. 2. Methods Four electronic databases, MEDLINE/PubMed (1966–2016), PsycINFO (1806–2016), EMBASE (1980–2016), and the Cochrane Database of Systematic Reviews, were searched using a combination of the keywords bipolar, depression, postpartum, peripartum, prevalence, screening, diagnosis, treatment, drugs, and psychotherapy. The reference lists of articles identified were
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also searched. All relevant articles published in English were included.Since this is not a systematic review, caveats of non-systematic reviews such as the lack of exhaustive review of the literature, and formal data extraction should apply.
3. Epidemiology Two studies from the United States have assessed the prevalence of BD among women who screened positive (a score of 10 or higher) on the Edinburgh Postnatal Depression Scale (EPDS). A large study of ten thousand women who were screened at four to six weeks postpartum, found that 22.6% of women met the DSM-IV criteria for BD. Among women with a cut point of 13 or higher on the EPDS, a higher proportion (26.7%) was found to have BD (Wisner et al., 2013). In a study of women receiving prenatal care, 21.4% of participants with a positive EPDS had a positive screen on the Mood Disorder Questionnaire (MDQ; Merrill et al., 2015). A study from Poland found that at six to twelve weeks postpartum, 23.7% of women met the alternate scoring threshold (a score of >7 on the MDQ), and 4.6% of women met the traditional scoring cutoff (a score of >7, co-occurrence of symptoms, and accompaniment by moderate or serious functional criteria (Jaeschke et al., 2016). In a prospective study, women with MDD were screened using the Altman Self-Rated Mania scale at four time points –once during pregnancy (~26 weeks), and one week, one month, and three months postpartum. The authors found that 34.6% of women experienced mania/hypomania (defined by a score of ≥6 at more than one time point) during the postpartum period. The highest frequency of manic/hypomanic symptoms (26.4%) was at one week postpartum, and for the majority (54%) of women the onset was postpartum (Inglis et al., 2014) Hypomanic symptoms can begin for the first time or recur after childbirth. Sharma et al. (2014) reported that 6.5% of women with MDD had first onset of hypomania/mania during the first six months after childbirth. There were no cases of switching to BD-I, but in one participant the diagnosis changed from BD-II to BD-I during the three months after childbirth. BD is particularly common among women with treatment-resistant PPD. In one study, 54% of patients with a history of non-response to at least one antidepressant had BD. The breakdown of different types of BD was as follows: BD not otherwise specified (29%), BD-II (23%), and BD-I (2%; Sharma et al., 2008). A diagnosis of BD carries a high risk of recurrences of mood episodes in the postpartum period. In women with BD-I, approximately 20% of deliveries are followed by an episode of mania, or psychotic depression, and an additional 25% of deliveries are associated with an episode of nonpsychotic depression (Di Florio et al., 2013). Doyle et al. (2012) found that only 9.3% of women seen during pregnancy for management of BD had a postpartum episode of depression with or without psychosis, and an additional 9.3% had a mixed episode. Recurrence rate was much higher in a study by Freeman et al. (2002) that found a recurrence rate of 67% among women with BD. The postpartum recurrences were almost exclusively depressive episodes. The risk of recurrence following a subsequent pregnancy was 100% among women who had recurrence of a mood episode after first pregnancy. The risk of recurrence is exceptionally high in women with BD-II. In one study, 50% of women with BD-II reported PPD, compared to rates of 27.5% and 21.6% in women with BD-I and MDD respectively (Mandelli et al., 2016).
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In summary, manic symptoms are common after childbirth. Estimates of prevalence of bipolar PPD vary a great deal and depend on the population studied, thesetting, the definition of the postpartum period, the screening instruments used, and the definition of caseness. Also, studies have not paid attention to whether the depressive episode began in the postpartum period or it is continuation of depression from during or prior to pregnancy. 4. Clinical Features As part of the BRIDGE (bipolar disorders: improving diagnosis, guidance and education) study to detect hypo/mania in patients with a major depressive episode, Azorin et al. (2012) assessed rates of bipolarity in women experiencing their first episode of depression in the postpartum period. Compared to women with non-postpartum PPD, those with first onset of depression in the postpartum period were more likely to have higher rates of personal and family history of BD. Among women with a first depressive episode in the postpartum period, the rates of bipolarity varied from 15%-50% depending on the diagnostic criteria used. As shown in Table 1, it is possible to identify features of bipolarityin women with first onset of depression in the postpartum period (Azorin et al., 2012; Jaeschke et al., 2016; Sharma, 2006) Fisher et al. (2016) found agitation was the only symptom that separated unipolar and bipolar PPD. In a Polish study, women with bipolar PPD were significantly younger than those with unipolar PPD (Jaeschke et al., 2016). We were unable to find any studies on the comparison of symptoms of bipolar PPD and symptoms of bipolar depression occurring outside of the postpartum period. Given the ubiquitous presence of manic symptoms in the postpartum period, it is conceivable that mixed presentations may be more frequent in women with bipolar PPD. Significance of timing of illness onset as a distinguishing feature was explored in a large study that found that pre-pregnancy onset is more likely in women with bipolar depression (Wisner et al., 2013). A postpartum onset of psychiatric disorders such as non-affective psychosis or schizophrenia-like disorders also raises the possibility of underlying bipolarity. A study from Denmark found that approximately 14% of women with a first-time psychiatric contact during the first month after delivery converted to bipolar affective disorder within the first 15 years after their initial postpartum episode (Munk-Olsen et al., 2011). The majority of women with PPD in general have symptom onset during or prior to pregnancy; however, it is unclear whether this also holds true for women with bipolar PPD. There are no studies on the duration of untreated episodes of bipolar PPD. Although the data are limited, women with bipolar PPD appear to be at an extremely high risk of recurrence following subsequent deliveries (Freeman et al., 2002). Bipolar PPD is often accompanied by other psychiatric disorders including anxiety disorders or obsessive compulsive disorder (OCD). In one study, 27% of women had comorbid disorders with 84.8% being anxiety disorders (Wisner et al., 2013). However, it is not clear whether certain disorders are more likely to be associated with BD in the postpartum period compared to other periods in a woman’s life. A Polish study that analyzed the personality differences in women with unipolar and bipolar PPD found that women with the latter were more likely to exhibit traits of neuroticism on the NEOFive Factor Inventory. The authors concluded that neuroticism might be a marker of 'bipolar' PPD, as compared to the 'unipolar' form of the disorder (Dudek et al., 2014).
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Suicide is the second leading cause of death in postpartum women (Cantwell et al., 2011). A prospective study found that 16.97% of women with MDD or BD-II had thoughts of self-harm, and 6.16 % reported suicidal ideation during the first year postpartum. Interestingly, women with thoughts of self-harm or suicidal ideation also reported higher levels of depression and hypomanic symptoms (Dudek et al., 2014). Adverse effects of untreated PPD A diagnosis of PPD is a risk factor for impaired mother-infant bonding. Factors predictive of impaired boding include severity of PPD, self-reported suicidality, and delivery via Caesarean section. Support for severity of PPD as a risk factor comes from a study that compared parental bonding in patients with BD and general practice patients. Among the female patients there was an association between poor parental bonding and increased number of hospitalizations (Sockol et al., 2014). There are no studies on maternal infant bonding in women with bipolar PPD; however, it is likely that impaired maternal infant bonding may be more common in women with BD. Studies have also reported long-term negative effects of PPD on children's health and their social, emotional, cognitive and physical development (Field, 2010); however, there are no such studies in women with bipolar PPD. Risk factors for recurrences of bipolar PPD There is limited information on the risk factors for postpartum recurrence of mood episodes in women with BD. Risk factors include having symptoms prenatally, younger age, unplanned pregnancy, previous perinatal mood episodes, and a family history of BD (Doyle et al., 2012; Freeman et al., 2002). Women with BD-II appear to be at an exceptionally high risk for PPD. Having a postpartum occurrence of a mood episode after first delivery is a particularly potent risk factor for future postpartum recurrences. Occurrence of a mood episode after first delivery is a risk factor for future recurrences. In one study, every mother who had a postpartum mood episode after a first pregnancy had an episode following subsequent pregnancies, and most recurrences were depressive (Freeman et al., 2002). A recent review of clinical studies examining PPD found that for a large number of women, depression remains a long-term problem in spite of treatment; however, there are no studies on the course of BD, or the risk factors for persistence of bipolar PPD.
5. Management Screening There are several studies on screening for antenatal depression (Austin and Lumley, 2003), and routine screening for depression is now recommended both during and after pregnancy. The American College of Obstetricians and Gynecologists recommends screening all women for depression at least once during the perinatal period, but makes no such recommendation for BD screening (Committee on Obstetric Practice, 2015). In contrast, the Canadian Network for Mood and Anxiety Treatments and the International Society for Bipolar Disorders guidelines have recommended universal screening for BD during pregnancy (Yatham et al., 2013). Postpartum
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screening for BD may help to differentiate bipolar depression from unipolar depression and promotes the use of diagnosis-specific, evidence-based, and individualized psychotherapeutic and pharmacological treatment interventions. Of nearly a dozen screening tools for BD, the MDQ has been studied the most (Hirschfeld et al., 2000). There are only two studies of its psychometric properties in the perinatal population. Sharma and Xie (2011) validated the MDQ in 57 women with mood disorders assessed at an outpatient clinic. Frey et al. (2012) published the only study measuring sensitivity and specificity of the MDQ during pregnancy in a sample of 95 women referred for psychiatric consultation to a specialized clinic. The MDQ is a 15-item self-report inventory that assesses the lifetime prevalence of hypomanic or manic symptoms based on DSM-IV. It takes only five minutes to fill out. The psychometric properties of the MDQ vary with the population studied, and the sensitivity was improved by altering the traditional scoring method without decreasing the specificity. In the general population, the MDQ has a sensitivity of only 28% and a specificity of 97% (Hirschfeld et al., 2000). Among pregnant women, the traditional scoring yields sensitivity of 39% and specificity of 91% but a cut-off of seven or more endorsed symptoms without the supplementary questions (alternate scoring) yields a sensitivity of 89% and a specificity of 84% relative to DSM-IV (Frey et al., 2012). While the MDQ serves as an effective screening instrument, additional evaluation after a positive screen is required to confirm a diagnosis. Recent studies in perinatal populations have reported results using the alternate scoring method (Clark et al., 2015; Merrill et al., 2015) Using the cut off suggested by Frey et al. (2012), a recent study of 342 women reported a rate of 5% for BD during early pregnancy (Merrill et al., 2015). The authors recommend simultaneous screening for both depression and BD because approximately one third of patients with a positive MDQ screen had subthreshold scores on the EPDS. The lack of diagnostic confirmation using a structured instrument such as the Structured Clinical Interview for DSM (First et al., 2015) makes it difficult to interpret the results of this study. Although not studied in women with PPD, Hypomania Checklist-32 can be potentially useful for screening women. The prevalence of hypomania on day 3 postpartum was examined using two self-report mania scales: The Highs Scale and Altman Mania Rating Scale (AMRS). The scales show good correlation, however, 11% of women met the suggested threshold for caseness on the Highs Scale, and 44% on the AMRS (Inglis et al., 2014). The definition of what constitutes ‘a case’ of postnatal hypomania requires further validation against clinical interview and ability to predict variables of clinical importance. Studies have not addressed the issue of timing and frequency of screening for manic symptoms during and after pregnancy. Since women remain at risk for manic symptoms until 3 months postpartum (Jaeschke et al., 2016), it is prudent to continue screening women, especially those with subthreshold scores on the MDQ. There is accumulating evidence that a large number of women with postpartum mood episodes have symptom onset prior to childbirth. Approximately 60% of women with PPD have onset of symptoms before delivery (Wisner et al., 2013). In one study, the majority (54%) of women with
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postpartum manic/hypomanic symptoms had symptom onset during pregnancy (Inglis et al., 2014). Thus, antenatal detection is necessary for correct diagnosis and implementation of timely and appropriate strategies for acute and the prevention of bipolar PPD. In the absence of specific studies, it is unclear whether the Edinburgh Postnatal Depression Scale (EPDS) cut-offs are different for bipolar PPD. We are not aware if any other screening instrument for depression has been validated in bipolar PPD. Given the prevalent nature of psychiatric comorbidity, women should also be screened for common disorders such as anxiety disorders and OCD. Evaluation and differential diagnosis The DSM-5 allows the use of the peripartum specifier to denote depressive episodes only in women with BD-I, or BD-II even though other specified bipolar and related disorder may be the most common diagnostic subtype in the postpartum period. Correct identification of the bipolar diathesis of PPD is challenging, especially in women who have onset of the disorder with a depressive episode after childbirth. Given the potentially serious implications of underdiagnosing bipolar depression or misdiagnosing it as MDD, women presenting with a depressive episode in the postpartum period should be screened for BD. Psychiatric interview should include questions about personal or family history of BD and postpartum psychosis. Women with a history of BD should be inquired about type of the disorder, comorbid physical and psychiatric disorders (particularly anxiety disorders and OCD) , duration and frequency of mood episodes, previous peripartum episodes, and history of symptom exacerbation around the time of reproductive events, psychiatric hospitalizations, and breastfeeding status. Patients should also be asked about current symptoms, psychotic features, thoughts of suicide or homicide, and previous suicide attempts. A detailed treatment history including names and doses of psychotropic drugs tried, response to treatment, side effects, and treatment histories of first degree relatives with peripartum mood disorders should be obtained. Differential diagnosis includes MDD with mixed features, referred to as pre-BD in the DSM-5 (Çelik et al., 2016). The DSM-5 “mixed features” specifier requires the presence of at least three manic/hypomanic symptoms that do not overlap with symptoms of major depression. Currently, there are no studies to indicate a higher prevalence of mixed features in women with unipolar PPD; however, given the common occurrence of manic symptoms after childbirth, it is likely that mixed features may be more prevalent in women with unipolar PPD. Differentiating bipolar depression from MDD with mixed features can be challenging. Manic symptoms occur intraepisodically in MDD with mixed features rather than as discrete episodes in case of BD. Another important differential diagnosis is MDD with psychotic features, also referred to as depressive postpartum psychosis. Bipolar depression should be differentiated from maternity blues that are common but should not last more than two weeks. Bereavement following pregnancy loss or termination is another important differential diagnosis. Bipolar depression should also be distinguished from postpartum thyroiditis. Studies on the relationship of postpartum thyroiditis to PPD have yielded mixed results, with some (287) but not all (288) studies reporting a significant association. In patients with postpartum thyroiditis, transient thyrotoxicosis is followed by transient hypothyroidism and a return to the euthyroid state by the end of the initial postpartum year. According to the American Thyroid Association Taskforce on thyroid disease during pregnancy and postpartum, women with PPD should have thyroid stimulating hormone, free T4 and thyroid peroxidase antibodies checked (StagnaroGreen et al., 2011).
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6. Prognosis The course of BD is impacted by variables such as number of prior episodes, age at illness onset, first-episode polarity, predominant polarity (Volkert, et al., 2014), residual symptoms, and psychiatric comorbidity. Serretti et al. (2006) studied the impact of postpartum onset on the course of BD-I. Compared to the non-postpartum onset, the postpartum onset was associated with fewer recurrences of manic and mixed episodes; however, no differences emerged in the rates of depressive episodes. Currently there are no data to indicate that women with onset of bipolar depression during, or after pregnancy have different trajectories, or respond differently to treatment. Similarly, we don’t know whether depressive episodes with first onset after childbirth tend to recur only in the postpartum period. 7. Treatment Pharmacotherapy There is a paucity of studies on the pharmacotherapy of bipolar PPD. The extant literature is limited to two small studies of quetiapine. In contrast there are at least seven randomized, controlled trials of antidepressants in unipolar PPD (Thompson and Sharma, 2016). Women with BD are a high risk of recurrence in spite of higher utilization of psychotropic drugs in the postpartum period. In a prospective, observational study on the pharmacotherapy of bipolar II PPD, only 14% of participants were not on any psychotropic medication, approximately 35% received monotherapy, and over 50% were on combination therapy. While only 13.5% of participants were on 3 or more psychotropic drugs during pregnancy, 21.6% required 3 or more psychotropic drugs after childbirth. During the first year postpartum, 70% of women had a mood episode compared to a recurrence rate of 51 % in pregnancy (Sharma et al., 2013). Antidepressants: Antidepressants are commonly prescribed for women with PPD; however, there are no data on the extent of their use in women with bipolar PPD. Currently, there are no studies of antidepressants in the management of bipolar PPD. It is unclear whether antidepressants are associated with a greater risk of induction of mania when used in women with versus without PPD; however, given the potentially serious consequences of their use, these drugs should be avoided in the management of bipolar PPD (Sharma, 2006). Women with first onset of depression in the postpartum period, or those who have occurrence of depression during the early postpartum period may be at a particularly high risk for switching to BD following the use of antidepressants. Caution is also necessary when antidepressants are used in women with a history of BD in a first-degree relative. Mood stabilizers: Although lithium and lamotrigine are commonly prescribed for BD, there are no studies of their use in the acute treatment of bipolar PPD. A recent retrospective study of 18 women with BD-I, BD-II, or BD NOS, found quetiapine was effective in the management of bipolar PPD. At the end of 8 weeks of treatment, 83% of women were rated as “much” or “very much” improved. The median quetiapine dose was only 75 mg (range 12.5-500 mg; Sharma et al., 2015). Similar results were reported by Misri et al. (2015) who studied quetiapine XR in women with BD-II.
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Only 12 of 26 women who were enrolled in the 12-week open trial completed the study. The mean dose was 137.5 mg in this study. Psychotherapy Psychological treatments, such as interpersonal therapy, cognitive-behavioral therapy, and psychodynamic psychotherapy, as well as psychosocial interventions, such as nondirective counseling, have been studied in PPD. A Cochrane meta-analysis of ten randomized controlled trials of psychosocial and psychological treatments for PPD concluded that both psychosocial and psychological interventions are effective in PPD (Dennis and Hodnett, 2007) Surprisingly, there are no psychotherapeutic studies on the acute or preventative treatment of bipolar PPD. Psychoeducation, although effective in preventing recurrences of BD, has not been studied in the prevention of postpartum recurrences in women with BD. 8. Prophylactic Treatment Lithium is the most studied drug in the prevention of postpartum recurrences of mood or psychotic episodes. A recent meta-analysis of thirty-seven articles describing 5,700 deliveries in 4,023 patients found a postpartum relapse risk of 37% in women with BD (Wesseloo, et al., 2016). Continuation of treatment during pregnancy, particularly with lithium, was effective in the prevention of postpartum recurrences (Bergink et al., 2016); however, it is unclear whether lithium was also effective against recurrences of depression. A single-blind, nonrandomized clinical trial evaluated the effectiveness of valproate in the prevention of postpartum mood episodes in 26 women. Women received valproate plus symptom monitoring, or monitoring without valproate. Valproate was commenced during pregnancy and symptoms were assessed weekly for 20 weeks. There were no significant differences between groups in the proportions of women who developed hypomania/mania, depression, or mixed states. The time to recurrences of mood episodes also did not vary between groups (Wisner et al., 2004). Sharma et al. (2006) compared the relapse rates of 11 women receiving olanzapine, with or without an antidepressant or mood stabilizer, to 14 women receiving an antidepressant, a mood stabilizer or no medication. The study followed the women for four weeks after delivery. Women treated with olanzapine had a much lower relapse rate than women who did not receive olanzapine (18.2% vs. 57.1%). Used in combination with mood stabilizers, lamotrigine is effective in the prevention of bipolar mood episodes during pregnancy; however, there are no controlled data on its effectiveness in the prevention of postpartum recurrences. In a small case series, lamotrigine alone or in combination with quetiapine was effective in the prevention of BD-II PPD among patients who had shown a good response to the drug during the index pregnancy (Sharma and Sommerdyk, 2015). 9. Breastfeeding The WHO recommends exclusive breastfeeding up to 6 months of age, with continued breastfeeding along with appropriate complementary foods up to at least two years of age. While benefits of breastfeeding for the mother and her infant are well documented, decision to
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breastfeed also requires careful consideration of possible mood instability as a result of sleep disruption. Breastfeeding should be contraindicated in mothers with BD who may be at a particularly high risk of induction of mania or psychosis e.g. women with BD-I. Women who wish to breastfeed but are in need of pharmacotherapy should be informed about the risks and benefits of treatment for BD. Discussion should also take place about the safety of psychotropic drugs in breastfeeding infants. A recent systematic review concluded that mood stabilizers during breastfeeding can be used without any adverse events in most infants (Uguz and Sharma, 2016). Breastfeeding while taking lithium is recommended only if certain clinical characteristics are met: 1) stable maternal mood, 2) lithium monotherapy or a simple medication regimen, 3) adherence to infant monitoring recommendations, 4) a healthy infant and 5) a collaborative pediatrician. Laboratory monitoring should include assays of infant serum lithium and TSH, blood urea nitrogen, and creatinine levels starting in the immediate postpartum period up to 6 weeks of age (Viguera et al., 2007). Valproate and carbamazepine are generally considered compatible with breastfeeding. Short-term use of second generation antipsychotic drugs appears to be relatively safe in the exposed breastfed infants. Studies have shown low relative infant dose (RID) values for olanzapine, quetiapine and ziprasidone, moderate RID values for risperidone/paliperidone and aripiprazole and high RID values for amisulpride. With the exception of clozapine, adverse events were rarely reported in infants exposed to second generation antipsychotic drugs (Uguz, 2016). 10. Treatment Recommendations During pregnancy The peripartum period provides a remarkable opportunity for early identification and treatment of BD because most women neither have an accurate diagnosis of, nor treatment for BD until after they have children (Freeman et al., 2002). Antenatal screening is necessary to identify women with the disorder, as well as those at risk of developing BD (e.g. women with current depression who have a family history of BD) in the postpartum period. Due to the high risk of postpartum recurrence, women receiving anti bipolar pharmacotherapy should continue with the medication. A careful risk-benefit analysis is necessary if antidepressants are part of the drug regimen especially in women with BD-I. There are no data on the effectiveness of antidepressants in preventing postpartum recurrences of bipolar depression; however, abrupt discontinuation of antidepressants that are commonly associated with major withdrawal symptoms (e.g. paroxetine or venlafaxine) including insomnia, may increase risk of mania. As shown in Figure 1, PPD may be a continuation of an episode of major depression from pregnancy, or it may begin in pregnancy and reach the diagnostic threshold of a depressive episode after childbirth. Therefore, in case 1 the treatment focus should on the acute management of depression and its prevention after childbirth. In case 2, the treatment goal should be symptom monitoring in pregnancy, and prevention of depression after childbirth. Cases 3 and 4 represent clinical scenarios where treatments aimed at prophylaxis of depression are needed. Postpartum period Women with PPD should be screened for BD and treated based on the underlying psychiatric disorder. The role of antidepressants in the acute management of unipolar depression in certain
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sub populations of MDD with mixed features is unclear (Sharma, 2013). Table 2 lists disorders in which antidepressants should be used with caution, or avoided altogether in favor of mood stabilizers. If antidepressants are used because of patient preference or history of prior response to such a drug, patients should be observed for emergence of manic symptoms. Women with depression who decline the use of medication should be monitored closely for worsening of depressive symptoms, or emergence of manic symptoms. Since there are no controlled trials on the acute treatment of bipolar PPD, recommendations for first line monotherapy (e.g. lithium, quetiapine or lamotrigine) should be followed. Medications selected for acute treatment of bipolar depression should ideally be effective in the maintenance treatment as well. Patients who develop depression despite the use of a mood stabilizer should have the dose optimized, and if depression persists another first line drug for bipolar depression should be added before considering drugs recommended as combination therapies. Anxiety disorders and OCD are common in the postpartum period and their treatment can be challenging in the context of BD. In the absence of controlled treatment data, these disorders should be managed as much as possible with drugs commonly recommended for BD. There is some evidence for example that lamotrigine (Sharma and Sommerdyk, 2015) and valproate may have a role in the treatment of OCD. There are also reports of the effectiveness of lithium in women with bipolar PPD and comorbid trichotillomania (Sharma and Corpse, 2008). Psychoeducation should be an integral part of the overall treatment plan and should emphasize the importance of illness awareness, self-management, identification of early-warning signs, treatment adherence, and potential side effects of recommended drugs (Colom, 2014). Measures aimed at minimizing sleep disruption including help with nocturnal childcare should be encouraged. There is a strong association between infant sleep problems and PPD, thus addressing infant sleep could potentially attenuate maternal depressive symptoms (Hiscock and Wake, 2001). Once the patient’s condition is stable, issues such as parenting skills and mother– infant bonding should be addressed. 11. Suggestions for Future Research As mentioned, this article is not a formal systematic review. Caveats of non-systematic reviews such as lack of an exhaustive review of the literature and formal data extraction should be taken into consideration. Research on bipolar PPD is still in its infancy notwithstanding the significant strides over the past few years. A major impediment to research has to do with the nomenclature. The term PPD is generic and simply signifies occurrence of a depressive episode after childbirth. Precise labeling of different types of PPD is necessary for risk assessment and choosing disorder specific treatments. In order to facilitate early recognition and timely intervention, studies aimed at determination of timing of onset of depressive episodes are necessary. Based upon the literature reviewed, studies on the acute and maintenance treatment of bipolar PPD are urgently needed. Pharmacologic studies should explore the role of drugs such as lamotrigine, quetiapine and lithium. More importantly, rational treatments aimed at the putative causal factors (such as sleep loss) of bipolar PPD are needed. Hypomanic symptoms are common after childbirth and are a strong predictor of PPD (Glover et al., 1994). An important research question is whether prevention of
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hypomania after delivery is also effective in preventing PPD. There are no studies of psychotherapeutic interventions used alone or in combination with drugs. Researchers should focus on the duration and outcome of depressive periods since there are some women who have brief episodes that remit spontaneously without treatment. Also, risk factors contributing to chronicity, as well as predictors of response to various treatments need to be identified. The postpartum period should provide a remarkable opportunity to clarify the relationship of BD and comorbid psychiatric disorders.
Acknowledgements The authors thank Elizabeth Russell, Librarian at Parkwood Institute, London, Ontario, Canada for her assistance with the literature search.
References 1. Austin, M.P., Lumley, J., 2003. Antenatal screening for postnatal depression: a systematic review. Acta Psychiatry Scand. 107(1), 10-17. 2. Azorin, J.M., Angst, J., Gamma, A., Bowden, C.L., Perugi, G., Vieta, E., Young, A., 2012. Identifying features of bipolarity in patients with first-episode postpartum depression: findings from the international BRIDGE study. J Affect Disord. 136(3), 710-715. 3. Bergink, V., Rasgon, N., Wisner, K.L., 2016. Postpartum Psychosis: Madness, Mania, and Melancholia in Motherhood. Am J Psychiatry. 173(12), 1179-1188. 4. Boden, R., Lundgren, M., Brandt, L., Reutfors, J., Andersen, M., Kieler, H., 2012. Risks of adverse pregnancy and birth outcomes in women treated or not treated with mood stabilisers for bipolar disorder: population based cohort study. BMJ. 345, e 7085. 5. Cantwell, R., Clutton-Brock, T., Cooper, G., Dawson, A., Drife, J., Garrod, D., Harper, A., Hulbert, D., Lucas, S., McClure, J., Millward-Sadler, H., Neilson, J., Nelson-Piercy, C., Norman, J., O'Herlihy, C., Oates, M., Shakespeare, J., de Swiet, M., Williamson, C., Beale, V., Knight, M., Lennox C., Miller, A., Parmar, D., Rogers, J., Springett, A., 2011. Saving mothers’ lives; reviewing maternal deaths to make motherhood safer 2006–2008: the Eighth Report on Confidential Enquiries Into Maternal Deaths In the United Kingdom. BJOG. 118(suppl 1), 1–203. 6. Çelik, S.B., Bucaktepe, G.E., Uludağ, A., Bulut, İ.U., Erdem, Ö., Altınbaş, K., 2016. Screening mixed depression and bipolarity in the postpartum period at a primary health care center. Compr Psychiatry. 71, 57-62. 7. Clark, C.T., Sit, D.K., Driscoll, K, Eng, H.F., Confer, A.L., Luther, J.F., Wisniewski, S.R., Wisner, K.L., 2015. Does screening with the MDQ and EPDS improve identification of bipolar disorder in an obstetrical sample? Depress Anxiety. 32(7), 518526. 8. Colom, F., 2014. The evolution of psychoeducation for bipolar disorder: from lithium clinics to integrative psychoeducation. World Psychiatry. 13(1), 90-92.
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9. Committee on Obstetric Practice, 2015. The American College of Obstetricians and Gynecologists Committee Opinion no. 630. Screening for perinatal depression. Obstet Gynecol. 125, 1268-1271. 10. Dennis, C.L., Hodnett, E., 2007. Psychosocial and psychological interventions for treating postpartum depression. Cochrane Database Syst Rev., CD006116. 11. Di Florio, A., Forty, L., Gordon-Smith, K., Heron, J., Jones, L., Craddock, N., Jones, I., 2013. Perinatal episodes across the mood disorder spectrum. JAMA Psychiatry. 70(2), 168-175. 12. Doyle, K., Heron, J., Berrisford, G., Whitmore, J., Jones, L., Wainscott, G., Oyebode, F., 2012. The management of bipolar disorder in the perinatal period and risk factors for postpartum relapse. Eur Psychiatry. 27(8), 563-569. 13. Dudek, D., Jaeschke, R., Siwek, M., Mączka, G., Topór-Mądry, R., Rybakowski, J., 2014. Postpartum depression: identifying associations with bipolarity and personality traits. Preliminary results from a cross-sectional study in Poland. Psychiatry Res. 215(1), 69-74. 14. Field, T., 2010. Postpartum Depression Effects on Early Interactions, Parenting, and Safety Practices: A Review. Infant Behav Dev. 33(1), 1-9. 15. First, M.B., Williams, J.B.W., Karg, R.S., Spitzer, R.L., 2015. Structured Clinical Interview for DSM-5—Research Version (SCID-5 for DSM-5, Research Version; SCID5-RV). Arlington, VA, American Psychiatric Association. 16. Fisher, S.D., Wisner, K.L., Clark, C.T., Sit, D.K., Luther, J.F., Wisniewski, S., 2016. Factors associated with onset timing, symptoms, and severity of depression identified in the postpartum period. J Affect Disorder. 203, 111-120. 17. Freeman, M.P., Smith, K.W., Freeman, S.A., McElroy, S.L., Kmetz, G.E., Wright, R., Keck, P.E. Jr., 2002. The impact of reproductive events on the course of bipolar disorder in women. J Clin Psychiatry. 63, 284-287. 18. Frey, B.N., Simpson, W., Wright, L., Steiner, M., 2012. Sensitivity and specificity of the Mood Disorder Questionnaire as a screening tool for bipolar disorder during pregnancy and the postpartum period. J Clin Psychiatry. 73(11), 1456-1461. 19. Glover, V., Liddle, P., Taylor, A., Adams, D., Sandler, M., 1994. Mild hypomania (the highs) can be a feature of the first postpartum week. Association with later depression. Br J Psychiatry. 164(4), 517-521. 20. Hirschfeld, R.M., Williams, J.B., Spitzer, R.L., Calabrese, J.R., Flynn, L., Keck, P.E. Jr, Lewis, L., McElroy, S.L., Post, R.M., Rapport, D.J., Russell, J.M., Sachs, G.S., Zajecka, J., 2000. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 157(11), 1873-1875. 21. Hiscock, H., Wake, M., 2001. Infant sleep problems and postnatal depression: a community-based study. Pediatrics. 107(6), 1317-1322. 22. Inglis, A.J., Hippman, C.L., Carrion, P.B., Honer, W.G., Austin, J.C., 2014. Mania and depression in the perinatal period among women with a history of major depressive disorders. Arch Womens Ment Health. 17(2), 137-143. 23. Jablensky, A.V., Morgan, V., Zubrick, S.R., Bower, C., Yellachich, L.A., 2005. Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders. Am J Psychiatr. 162(1), 79–91.
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24. Jaeschke, R.R., Dudek, D., Topór-Madry, R., Drozdowicz, K., Datka, W., Siwek, M., Rybakowski, J., 2016. Postpartum depression: bipolar or unipolar? Analysis of 434 Polish postpartum women. Rev Bras Psiquiatr. doi:10.1590/1516-4446-2016-1983. 25. Kettunen, P., Koistinen, E., Hintikka, J., 2014. Is postpartum depression a homogenous disorder: time of onset, severity, symptoms and hopelessness in relation to the course of depression. BMC Pregnancy Childbirth. 14, 402. 26. Lee, H.C., Lin, H.C., 2010. Maternal bipolar disorder increased low birthweight and preterm births: A nationwide population-based study. J Affect Disord. 121(1–2), 100– 105. 27. Mandelli, L., Souery, D., Bartova, L., Kasper, S., Montgomery, S., Zohar, J., Mendlewicz, J., Serretti, A., 2016. Bipolar II disorder as a risk factor for postpartum depression. J Affect Disord. 204, 54-58. 28. Merrill, L., Mittal, L., Nicoloro, J., Caiozzo, C., Maciejewski, P.K., Miller, L.J., 2015. Screening for bipolar disorder during pregnancy. Arch Womens Ment Health. 18(4), 579583. 29. Misri, S., Abizadeh, J., Eng, A.B., Albert, G., Ryan, D., Swift, E., 2015. An Open-Label Study of Quetiapine Extended-Release in a Sample of Postpartum Women with Bipolar II Depressive Episode. Curr Psychopharmacol. 4(1), 17-26. 30. Munk-Olsen, T., Laursen, T.M., Meltzer-Brody, S., Mortensen, P.B., Jones, I., 2011. Psychiatric disorders with postpartum onset: possible early manifestation of bipolar affective disorders. Arch Gen Psychiatry. 69(4), 428-434. 31. Munk-Olsen, T., Laursen, T.M., Pedersen, C.B., Mors, O., Mortensen, P.B., 2006. New parents and mental disorders: a population-based register study. JAMA Psychiatry. 296(21), 2582-2589. 32. Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium, 2015. Heterogeniety of postpartum depression: a latent class analysis. Lancet Psychiatry. 2(1), 59-67. 33. Serretti, A., Olgiati, P., Colombo, C., 2006. Influence of postpartum onset on the course of mood disorders. BMC Psychiatry. 6, 4. 34. Sharma, V., 2006. A cautionary note on the use of antidepressants in postpartum depression. Bipolar Disord. 8(4), 411-414. 35. Sharma, V., 2013.Mixed depression in the postpartum period: diagnostic and treatment issues.. J Psychiatry Neurosci. 38(6), E30. 36. Sharma, V., Burk, V.K., Ritchie, H.L., 2009. Bipolar II postpartum depression: Detection, diagnosis and treatment. Am J Psychiatry. 166(11), 1217-1221. 37. Sharma, V., Corpse, C., 2008. Lithium treatment of trichotillomania with comorbid bipolar II disorder. Arch Womens Ment Health. 11(4), 305-306. 38. Sharma, V., Khan, M., Corpse, C., Sharma, P., 2008. Missed bipolarity and psychiatric comorbidity in women with postpartum depression. Bipolar Disord. 10(6), 742-747. 39. Sharma, V., Khan, M., Sommerdyk, C., 2015. Quetiapine in the Acute Treatment of Bipolar Postpartum Depression: A Chart Review. J Clin Psychopharmacol. 35(6), 733735. 40. Sharma, V., Penava, D., 2010. Screening for Bipolar Disorder during Pregnancy and the Postpartum Period. J Obstet Gyanaecol Can. 32(2), 278-281. 41. Sharma, V., Smith, A., Mazmanian, D., 2006. Olanzapine in the prevention of postpartum psychosis and mood episodes in bipolar disorder. 8(4), 400-404.
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42. Sharma, V., Sommerdyk, C., 2015. Obsessive-compulsive disorder in the postpartum period: diagnosis, differential diagnosis and management. Womens Health (Lond). 11(4), 543-552. 43. Sharma, V., Sommerdyk, C., Xie, B., Campbell, K., 2013. Pharmacotherapy of bipolar II disorder during and after pregnancy. Curr Drug Saf. 8(4), 246-252 44. Sharma, V., Xie, B., 2011. Screening for postpartum bipolar disorder: validation of The Mood Disorder Questionnaire. J Affect Disord. 131(1-3), 408-411. 45. Sharma, V., Xie, B., Campbell, M.K., Penava, D., Hampson, E., Mazmanian, D., Pope C.J., 2014. A prospective study of diagnostic conversion of major depressive disorder to bipolar disorder in pregnancy and postpartum. Bipolar Disord. 16(1), 16-21. 46. Sockol, L.E., Battle, C.L., Howard, M., Davis, T., 2014. Correlates of impaired motherinfant bonding in a partial hospital program for perinatal women. Arch Womens Ment Health. 17(5), 465-9. 47. Stagnaro-Green, A., Abalovich, M., Alexander, E., Azizi, F., Mestman, J., Negro, R., Nixon, A., Pearce, E.N., Soldin, O.P., Sullivan, S., Wiersinga, W., American Thyroid Association Taskforce on Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum, 2011. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 21(10), 1081-1125. 48. Thompson, M., Sharma, V., 2016. Therapeutics of postpartum depression. Expert Rev. Neurother. 9, 1-13. 49. Uguz F., 2016. Second-Generation Antipsychotics During the Lactation Period: A Comparative Systematic Review on Infant Safety. J Clin Psychopharmacol. 36(3), 244252. 50. Uguz, F., Sharma, V., 2016. Mood stabilizers during breastfeeding: a systematic review of the recent literature. Bipolar Disord. 18(4), 325-333. 51. Viguera, A. C., Newport, J., Ritchie, J., Stowe, Z., Whitfield, T., Mogielnicki, J., Baldessarini, R. J., Zurick, A., 2007. Lithium in Breast Milk and Nursing Infants: Clinical Implications. Am J Psychiatry. 164, 342-345. 52. Volkert, J., Zierhut, K.C., Schiele, M.A., Wenzel, M., Kopf, J., Kittel-Schneider, S., Reif, A., 2014. Predominant polarity in bipolar disorder and validation of the polarity index in a German sample. BMC Psychiatry. 14, 322. 53. Wesseloo, R., Kamperman, A.M., Munk-Olsen, T., Pop, V.J., Kushner, S.A., Bergink, V., 2016. Risk of Postpartum Relapse in Bipolar Disorder and Postpartum Psychosis: A Systematic Review and Meta-Analysis. Am J Psychiatry. 173(2), 117-127. 54. Wisner, K.L., Hanusa, B.H., Peindl, K.S., Perel, J.M., 2004. Prevent of postpartum episodes in women with bipolar disorder. Biol Psychiatry. 56(8), 592-596. 55. Wisner, K.L., Sit, D.K., McShea, M.C., Rizzo, D.M., Zoretich, R.A., Hughes, C.L., Eng, H.F., Luther, J.F., Wisniewski, S.R., Costantino, M.L., Confer, A.L., Moses-Kolko, E.L., Famy, C.S., Hanusa, B.H., 2013. Onset timing, thoughts of self-harm, and diagnoses in postpartum women with screen-positive depression findings. JAMA Psychiatry. 70(5), 490-498. 56. Yatham, L.N., Kennedy, S.H., Parikh, S.V., Schaffer, A., Beaulieu, S., Alda, M., O'Donovan, C., Macqueen, G., McIntyre, R.S., Sharma, V., Ravindran, A., Young, L.T., Milev, R., Bond, D.J., Frey, B.N., Goldstein, B.I., Lafer, B., Birmaher, B., Ha, K., Nolen, W.A., Berk, M., 2013. Canadian Network for Mood and Anxiety Treatments (CANMAT)
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and Internal Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management for patients with bipolar disorder: update 2013. Bipolar Disord. 15(1), 1-44.
Fig. 1. Classifications of Depression Contingent on the Timing of Onset of Symptoms During Pregnancy
Table 1. Features suggestive of bipolarity in women with PPD Illness onset
Younger age at illness onset First onset of depression during the postpartum period Depression onset immediately after delivery
Illness course & symptoms
High number of prior episodes Brief episodes of depression Depressive episodes with free intervals Seasonality of mood episodes Atypical features: hypersomnia, leaden paralysis or increased appetite Mixed depression Agitation Psychotic symptoms History of bipolar disorder in a first degree relative
Treatment response
Atypical antidepressant response: induction of mania, hypomania or mixed depressive episode; poor response; rapid response; loss of antidepressant response
(Azorin et al., 2012; Jaeschke et al., 2016; Sharma, 2006)
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Table 2. Types of PPD in which antidepressants should be avoided or used cautiously 1. 2. 3. 4. 5.
Major depressive disorder with mixed features Major depressive episode with first onset in the postpartum period Major depressive episode with onset in early postpartum period History of bipolar disorder in a first degree relative Atypical features: hypersomnia, leaden paralysis or increased appetite
(Azorin et al., 2012; Sharma, 2006; Sharma, 2013; Sharma et al., 2014)
Highlights 1. There has been a surge of interest in the study of bipolar postpartum depression. 2. Bipolar postpartum depression is common and can be distinguished from unipolar postpartum depression. 3. There is a paucity of literature on pharmacological and psychotherapeutic treatments.
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PII: DOI: Reference:
S0165-0327(17)30360-9 http://dx.doi.org/10.1016/j.jad.2017.05.014 JAD8962
To appear in: Journal of Affective Disorders Received date: 16 February 2017 Revised date: 13 April 2017 Accepted date: 6 May 2017 Cite this article as: Verinder Sharma, Minakshi Doobay and Christine Baczynski, Bipolar postpartum depression: An update and recommendations, Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2017.05.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Bipolar postpartum depression: an update and recommendations Verinder Sharmaa1, Minakshi Doobayb, Christine Baczynskic a
Western University & Parkwood Institute - London, Ontario, Canada b
Western University - London, Ontario, Canada
c
Parkwood Institute - London, Ontario, Canada [email protected]
Abstract Background: Over the past few years there has been a surge of interest in the study of bipolar postpartum depression (PPD); however, questions remain about its prevalence, screening, clinical features, and treatment. Methods: Three electronic databases, MEDLINE/PubMed (1966–2016), PsycINFO (1806–2016), and the Cochrane Database of Systematic Reviews, were searched using a combination of the keywords bipolar, depression, postpartum, peripartum, prevalence, screening, diagnosis, treatment, drugs, and psychotherapy. The reference lists of articles identified were also searched. All relevant articles published in English were included. Results: Depending on the population studied, 21.4% to 54% of women with PPD have a diagnosis of bipolar disorder (BD). Characteristic clinical features include younger age at illness onset, first onset of depression after childbirth, onset immediately after delivery, atypical depressive symptoms, psychotic features, mixed features, and history of BD in first-degree family members. Treatment should be guided by symptom acuity, safety concerns, the patient’s response to past treatments, drug tolerability, and breastfeeding preference. In the absence of controlled treatment data, preference should be given to drugs normally indicated for bipolar depression including lithium, quetiapine and lamotrigine. Although antidepressants have been studied in combination with mood stabilizers in bipolar depression, these drugs should be avoided due to likelihood of elevated risk of induction of manic symptoms in the postpartum period. Conclusions: In the postpartum period, bipolar PPD is common, can be differentiated from unipolar PPD, and needs to be identified promptly in order to expedite appropriate treatment. Future studies on pharmacotherapy and psychotherapy should focus on the acute and preventative treatment of bipolar PPD. Keywords: bipolar; postpartum; depression; peripartum; prevalence; screening; diagnosis; treatment; drugs; psychotherapy
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Mail: Parkwood Institute Mental Health Care Building, 550 Wellington Road London, Ontario, Canada N6C 0A7
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1. Introduction Postpartum depression (PPD) is a common complication of childbearing that affects 21.9% of women during the first year postpartum (Kettunen et al., 2014; Postpartum Depression: Action Towards Causes and Treatment Consortium, 2015). Contrary to the popular notion, PPD is not a homogenous illness (Wisner et al., 2013). Various factors including different periods of onset of the depressive episode (e.g. during, prior to, or after pregnancy), varying symptom profiles, different levels of symptom severity, and duration may contribute to clinical heterogeneity. Depression can begin for the first time after birth, or it can be a recurrence in the context of major depressive disorder (MDD) or bipolar disorder (BD) (Azorin et al., 2012). Recent research studies have demonstrated that a sizeable proportion of women with PPD actually have BD; however, differentiating bipolar from unipolar PPD can be challenging for several reasons. First, there is a general lack of awareness among patients and physicians that PPD can be a manifestation of BD (Sharma et al., 2009). Second, women are usually screened for depression during and after pregnancy, but not for manic symptoms (Sharma and Penava, 2010). Third, hypomanic symptoms are common after delivery but require expert questioning to differentiate these from normal joy accompanying childbirth (Sharma et al., 2009). Thus, underdiagnosis or misdiagnosis of BD as MDD are not uncommon in the postpartum period. Failure to arrive at the proper diagnosis of bipolar PPD can be associated with serious consequences, including an increased risk of hospitalization, reduced ability of the mother to care for herself and her infant, and although rare, maternal suicide and infanticide (Munk-Olsen et al., 2006; Sharma et al., 2008). Of all the psychiatric disorders, BD is associated with the highest risk of psychiatric hospitalization in the postpartum period, with a 23-fold greater risk of psychiatric admission within the first 30 days after delivery compared to non-postpartum women with BD (Munk-Olsen et al., 2006). Women with BD are also at risk of adverse birth and neonatal outcomes including preterm birth, caesarean delivery, and babies that are severely small, or severely large for gestational age (Boden, 2012). Adverse pregnancy outcomes such as gestational hypertension (Lee and Lin, 2010) and antepartum hemorrhage (Jablensky et al., 2005) also occur more frequently in women with BD. Despite the voluminous literature on PPD, researchers have only recently started paying attention to challenges in the detection, diagnosis, and treatment of bipolar PPD. In this paper we conduct a literature review on the prevalence, clinical features, diagnosis, and treatment of bipolar PPD. Gaps current in the literature are identified and recommendations are made for treatment of bipolar PPD. Discussion of management of mania or postpartum psychosis is omitted since the focus of the paper is on bipolar depression only. 2. Methods Four electronic databases, MEDLINE/PubMed (1966–2016), PsycINFO (1806–2016), EMBASE (1980–2016), and the Cochrane Database of Systematic Reviews, were searched using a combination of the keywords bipolar, depression, postpartum, peripartum, prevalence, screening, diagnosis, treatment, drugs, and psychotherapy. The reference lists of articles identified were
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also searched. All relevant articles published in English were included.Since this is not a systematic review, caveats of non-systematic reviews such as the lack of exhaustive review of the literature, and formal data extraction should apply.
3. Epidemiology Two studies from the United States have assessed the prevalence of BD among women who screened positive (a score of 10 or higher) on the Edinburgh Postnatal Depression Scale (EPDS). A large study of ten thousand women who were screened at four to six weeks postpartum, found that 22.6% of women met the DSM-IV criteria for BD. Among women with a cut point of 13 or higher on the EPDS, a higher proportion (26.7%) was found to have BD (Wisner et al., 2013). In a study of women receiving prenatal care, 21.4% of participants with a positive EPDS had a positive screen on the Mood Disorder Questionnaire (MDQ; Merrill et al., 2015). A study from Poland found that at six to twelve weeks postpartum, 23.7% of women met the alternate scoring threshold (a score of >7 on the MDQ), and 4.6% of women met the traditional scoring cutoff (a score of >7, co-occurrence of symptoms, and accompaniment by moderate or serious functional criteria (Jaeschke et al., 2016). In a prospective study, women with MDD were screened using the Altman Self-Rated Mania scale at four time points –once during pregnancy (~26 weeks), and one week, one month, and three months postpartum. The authors found that 34.6% of women experienced mania/hypomania (defined by a score of ≥6 at more than one time point) during the postpartum period. The highest frequency of manic/hypomanic symptoms (26.4%) was at one week postpartum, and for the majority (54%) of women the onset was postpartum (Inglis et al., 2014) Hypomanic symptoms can begin for the first time or recur after childbirth. Sharma et al. (2014) reported that 6.5% of women with MDD had first onset of hypomania/mania during the first six months after childbirth. There were no cases of switching to BD-I, but in one participant the diagnosis changed from BD-II to BD-I during the three months after childbirth. BD is particularly common among women with treatment-resistant PPD. In one study, 54% of patients with a history of non-response to at least one antidepressant had BD. The breakdown of different types of BD was as follows: BD not otherwise specified (29%), BD-II (23%), and BD-I (2%; Sharma et al., 2008). A diagnosis of BD carries a high risk of recurrences of mood episodes in the postpartum period. In women with BD-I, approximately 20% of deliveries are followed by an episode of mania, or psychotic depression, and an additional 25% of deliveries are associated with an episode of nonpsychotic depression (Di Florio et al., 2013). Doyle et al. (2012) found that only 9.3% of women seen during pregnancy for management of BD had a postpartum episode of depression with or without psychosis, and an additional 9.3% had a mixed episode. Recurrence rate was much higher in a study by Freeman et al. (2002) that found a recurrence rate of 67% among women with BD. The postpartum recurrences were almost exclusively depressive episodes. The risk of recurrence following a subsequent pregnancy was 100% among women who had recurrence of a mood episode after first pregnancy. The risk of recurrence is exceptionally high in women with BD-II. In one study, 50% of women with BD-II reported PPD, compared to rates of 27.5% and 21.6% in women with BD-I and MDD respectively (Mandelli et al., 2016).
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In summary, manic symptoms are common after childbirth. Estimates of prevalence of bipolar PPD vary a great deal and depend on the population studied, thesetting, the definition of the postpartum period, the screening instruments used, and the definition of caseness. Also, studies have not paid attention to whether the depressive episode began in the postpartum period or it is continuation of depression from during or prior to pregnancy. 4. Clinical Features As part of the BRIDGE (bipolar disorders: improving diagnosis, guidance and education) study to detect hypo/mania in patients with a major depressive episode, Azorin et al. (2012) assessed rates of bipolarity in women experiencing their first episode of depression in the postpartum period. Compared to women with non-postpartum PPD, those with first onset of depression in the postpartum period were more likely to have higher rates of personal and family history of BD. Among women with a first depressive episode in the postpartum period, the rates of bipolarity varied from 15%-50% depending on the diagnostic criteria used. As shown in Table 1, it is possible to identify features of bipolarityin women with first onset of depression in the postpartum period (Azorin et al., 2012; Jaeschke et al., 2016; Sharma, 2006) Fisher et al. (2016) found agitation was the only symptom that separated unipolar and bipolar PPD. In a Polish study, women with bipolar PPD were significantly younger than those with unipolar PPD (Jaeschke et al., 2016). We were unable to find any studies on the comparison of symptoms of bipolar PPD and symptoms of bipolar depression occurring outside of the postpartum period. Given the ubiquitous presence of manic symptoms in the postpartum period, it is conceivable that mixed presentations may be more frequent in women with bipolar PPD. Significance of timing of illness onset as a distinguishing feature was explored in a large study that found that pre-pregnancy onset is more likely in women with bipolar depression (Wisner et al., 2013). A postpartum onset of psychiatric disorders such as non-affective psychosis or schizophrenia-like disorders also raises the possibility of underlying bipolarity. A study from Denmark found that approximately 14% of women with a first-time psychiatric contact during the first month after delivery converted to bipolar affective disorder within the first 15 years after their initial postpartum episode (Munk-Olsen et al., 2011). The majority of women with PPD in general have symptom onset during or prior to pregnancy; however, it is unclear whether this also holds true for women with bipolar PPD. There are no studies on the duration of untreated episodes of bipolar PPD. Although the data are limited, women with bipolar PPD appear to be at an extremely high risk of recurrence following subsequent deliveries (Freeman et al., 2002). Bipolar PPD is often accompanied by other psychiatric disorders including anxiety disorders or obsessive compulsive disorder (OCD). In one study, 27% of women had comorbid disorders with 84.8% being anxiety disorders (Wisner et al., 2013). However, it is not clear whether certain disorders are more likely to be associated with BD in the postpartum period compared to other periods in a woman’s life. A Polish study that analyzed the personality differences in women with unipolar and bipolar PPD found that women with the latter were more likely to exhibit traits of neuroticism on the NEOFive Factor Inventory. The authors concluded that neuroticism might be a marker of 'bipolar' PPD, as compared to the 'unipolar' form of the disorder (Dudek et al., 2014).
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Suicide is the second leading cause of death in postpartum women (Cantwell et al., 2011). A prospective study found that 16.97% of women with MDD or BD-II had thoughts of self-harm, and 6.16 % reported suicidal ideation during the first year postpartum. Interestingly, women with thoughts of self-harm or suicidal ideation also reported higher levels of depression and hypomanic symptoms (Dudek et al., 2014). Adverse effects of untreated PPD A diagnosis of PPD is a risk factor for impaired mother-infant bonding. Factors predictive of impaired boding include severity of PPD, self-reported suicidality, and delivery via Caesarean section. Support for severity of PPD as a risk factor comes from a study that compared parental bonding in patients with BD and general practice patients. Among the female patients there was an association between poor parental bonding and increased number of hospitalizations (Sockol et al., 2014). There are no studies on maternal infant bonding in women with bipolar PPD; however, it is likely that impaired maternal infant bonding may be more common in women with BD. Studies have also reported long-term negative effects of PPD on children's health and their social, emotional, cognitive and physical development (Field, 2010); however, there are no such studies in women with bipolar PPD. Risk factors for recurrences of bipolar PPD There is limited information on the risk factors for postpartum recurrence of mood episodes in women with BD. Risk factors include having symptoms prenatally, younger age, unplanned pregnancy, previous perinatal mood episodes, and a family history of BD (Doyle et al., 2012; Freeman et al., 2002). Women with BD-II appear to be at an exceptionally high risk for PPD. Having a postpartum occurrence of a mood episode after first delivery is a particularly potent risk factor for future postpartum recurrences. Occurrence of a mood episode after first delivery is a risk factor for future recurrences. In one study, every mother who had a postpartum mood episode after a first pregnancy had an episode following subsequent pregnancies, and most recurrences were depressive (Freeman et al., 2002). A recent review of clinical studies examining PPD found that for a large number of women, depression remains a long-term problem in spite of treatment; however, there are no studies on the course of BD, or the risk factors for persistence of bipolar PPD.
5. Management Screening There are several studies on screening for antenatal depression (Austin and Lumley, 2003), and routine screening for depression is now recommended both during and after pregnancy. The American College of Obstetricians and Gynecologists recommends screening all women for depression at least once during the perinatal period, but makes no such recommendation for BD screening (Committee on Obstetric Practice, 2015). In contrast, the Canadian Network for Mood and Anxiety Treatments and the International Society for Bipolar Disorders guidelines have recommended universal screening for BD during pregnancy (Yatham et al., 2013). Postpartum
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screening for BD may help to differentiate bipolar depression from unipolar depression and promotes the use of diagnosis-specific, evidence-based, and individualized psychotherapeutic and pharmacological treatment interventions. Of nearly a dozen screening tools for BD, the MDQ has been studied the most (Hirschfeld et al., 2000). There are only two studies of its psychometric properties in the perinatal population. Sharma and Xie (2011) validated the MDQ in 57 women with mood disorders assessed at an outpatient clinic. Frey et al. (2012) published the only study measuring sensitivity and specificity of the MDQ during pregnancy in a sample of 95 women referred for psychiatric consultation to a specialized clinic. The MDQ is a 15-item self-report inventory that assesses the lifetime prevalence of hypomanic or manic symptoms based on DSM-IV. It takes only five minutes to fill out. The psychometric properties of the MDQ vary with the population studied, and the sensitivity was improved by altering the traditional scoring method without decreasing the specificity. In the general population, the MDQ has a sensitivity of only 28% and a specificity of 97% (Hirschfeld et al., 2000). Among pregnant women, the traditional scoring yields sensitivity of 39% and specificity of 91% but a cut-off of seven or more endorsed symptoms without the supplementary questions (alternate scoring) yields a sensitivity of 89% and a specificity of 84% relative to DSM-IV (Frey et al., 2012). While the MDQ serves as an effective screening instrument, additional evaluation after a positive screen is required to confirm a diagnosis. Recent studies in perinatal populations have reported results using the alternate scoring method (Clark et al., 2015; Merrill et al., 2015) Using the cut off suggested by Frey et al. (2012), a recent study of 342 women reported a rate of 5% for BD during early pregnancy (Merrill et al., 2015). The authors recommend simultaneous screening for both depression and BD because approximately one third of patients with a positive MDQ screen had subthreshold scores on the EPDS. The lack of diagnostic confirmation using a structured instrument such as the Structured Clinical Interview for DSM (First et al., 2015) makes it difficult to interpret the results of this study. Although not studied in women with PPD, Hypomania Checklist-32 can be potentially useful for screening women. The prevalence of hypomania on day 3 postpartum was examined using two self-report mania scales: The Highs Scale and Altman Mania Rating Scale (AMRS). The scales show good correlation, however, 11% of women met the suggested threshold for caseness on the Highs Scale, and 44% on the AMRS (Inglis et al., 2014). The definition of what constitutes ‘a case’ of postnatal hypomania requires further validation against clinical interview and ability to predict variables of clinical importance. Studies have not addressed the issue of timing and frequency of screening for manic symptoms during and after pregnancy. Since women remain at risk for manic symptoms until 3 months postpartum (Jaeschke et al., 2016), it is prudent to continue screening women, especially those with subthreshold scores on the MDQ. There is accumulating evidence that a large number of women with postpartum mood episodes have symptom onset prior to childbirth. Approximately 60% of women with PPD have onset of symptoms before delivery (Wisner et al., 2013). In one study, the majority (54%) of women with
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postpartum manic/hypomanic symptoms had symptom onset during pregnancy (Inglis et al., 2014). Thus, antenatal detection is necessary for correct diagnosis and implementation of timely and appropriate strategies for acute and the prevention of bipolar PPD. In the absence of specific studies, it is unclear whether the Edinburgh Postnatal Depression Scale (EPDS) cut-offs are different for bipolar PPD. We are not aware if any other screening instrument for depression has been validated in bipolar PPD. Given the prevalent nature of psychiatric comorbidity, women should also be screened for common disorders such as anxiety disorders and OCD. Evaluation and differential diagnosis The DSM-5 allows the use of the peripartum specifier to denote depressive episodes only in women with BD-I, or BD-II even though other specified bipolar and related disorder may be the most common diagnostic subtype in the postpartum period. Correct identification of the bipolar diathesis of PPD is challenging, especially in women who have onset of the disorder with a depressive episode after childbirth. Given the potentially serious implications of underdiagnosing bipolar depression or misdiagnosing it as MDD, women presenting with a depressive episode in the postpartum period should be screened for BD. Psychiatric interview should include questions about personal or family history of BD and postpartum psychosis. Women with a history of BD should be inquired about type of the disorder, comorbid physical and psychiatric disorders (particularly anxiety disorders and OCD) , duration and frequency of mood episodes, previous peripartum episodes, and history of symptom exacerbation around the time of reproductive events, psychiatric hospitalizations, and breastfeeding status. Patients should also be asked about current symptoms, psychotic features, thoughts of suicide or homicide, and previous suicide attempts. A detailed treatment history including names and doses of psychotropic drugs tried, response to treatment, side effects, and treatment histories of first degree relatives with peripartum mood disorders should be obtained. Differential diagnosis includes MDD with mixed features, referred to as pre-BD in the DSM-5 (Çelik et al., 2016). The DSM-5 “mixed features” specifier requires the presence of at least three manic/hypomanic symptoms that do not overlap with symptoms of major depression. Currently, there are no studies to indicate a higher prevalence of mixed features in women with unipolar PPD; however, given the common occurrence of manic symptoms after childbirth, it is likely that mixed features may be more prevalent in women with unipolar PPD. Differentiating bipolar depression from MDD with mixed features can be challenging. Manic symptoms occur intraepisodically in MDD with mixed features rather than as discrete episodes in case of BD. Another important differential diagnosis is MDD with psychotic features, also referred to as depressive postpartum psychosis. Bipolar depression should be differentiated from maternity blues that are common but should not last more than two weeks. Bereavement following pregnancy loss or termination is another important differential diagnosis. Bipolar depression should also be distinguished from postpartum thyroiditis. Studies on the relationship of postpartum thyroiditis to PPD have yielded mixed results, with some (287) but not all (288) studies reporting a significant association. In patients with postpartum thyroiditis, transient thyrotoxicosis is followed by transient hypothyroidism and a return to the euthyroid state by the end of the initial postpartum year. According to the American Thyroid Association Taskforce on thyroid disease during pregnancy and postpartum, women with PPD should have thyroid stimulating hormone, free T4 and thyroid peroxidase antibodies checked (StagnaroGreen et al., 2011).
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6. Prognosis The course of BD is impacted by variables such as number of prior episodes, age at illness onset, first-episode polarity, predominant polarity (Volkert, et al., 2014), residual symptoms, and psychiatric comorbidity. Serretti et al. (2006) studied the impact of postpartum onset on the course of BD-I. Compared to the non-postpartum onset, the postpartum onset was associated with fewer recurrences of manic and mixed episodes; however, no differences emerged in the rates of depressive episodes. Currently there are no data to indicate that women with onset of bipolar depression during, or after pregnancy have different trajectories, or respond differently to treatment. Similarly, we don’t know whether depressive episodes with first onset after childbirth tend to recur only in the postpartum period. 7. Treatment Pharmacotherapy There is a paucity of studies on the pharmacotherapy of bipolar PPD. The extant literature is limited to two small studies of quetiapine. In contrast there are at least seven randomized, controlled trials of antidepressants in unipolar PPD (Thompson and Sharma, 2016). Women with BD are a high risk of recurrence in spite of higher utilization of psychotropic drugs in the postpartum period. In a prospective, observational study on the pharmacotherapy of bipolar II PPD, only 14% of participants were not on any psychotropic medication, approximately 35% received monotherapy, and over 50% were on combination therapy. While only 13.5% of participants were on 3 or more psychotropic drugs during pregnancy, 21.6% required 3 or more psychotropic drugs after childbirth. During the first year postpartum, 70% of women had a mood episode compared to a recurrence rate of 51 % in pregnancy (Sharma et al., 2013). Antidepressants: Antidepressants are commonly prescribed for women with PPD; however, there are no data on the extent of their use in women with bipolar PPD. Currently, there are no studies of antidepressants in the management of bipolar PPD. It is unclear whether antidepressants are associated with a greater risk of induction of mania when used in women with versus without PPD; however, given the potentially serious consequences of their use, these drugs should be avoided in the management of bipolar PPD (Sharma, 2006). Women with first onset of depression in the postpartum period, or those who have occurrence of depression during the early postpartum period may be at a particularly high risk for switching to BD following the use of antidepressants. Caution is also necessary when antidepressants are used in women with a history of BD in a first-degree relative. Mood stabilizers: Although lithium and lamotrigine are commonly prescribed for BD, there are no studies of their use in the acute treatment of bipolar PPD. A recent retrospective study of 18 women with BD-I, BD-II, or BD NOS, found quetiapine was effective in the management of bipolar PPD. At the end of 8 weeks of treatment, 83% of women were rated as “much” or “very much” improved. The median quetiapine dose was only 75 mg (range 12.5-500 mg; Sharma et al., 2015). Similar results were reported by Misri et al. (2015) who studied quetiapine XR in women with BD-II.
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Only 12 of 26 women who were enrolled in the 12-week open trial completed the study. The mean dose was 137.5 mg in this study. Psychotherapy Psychological treatments, such as interpersonal therapy, cognitive-behavioral therapy, and psychodynamic psychotherapy, as well as psychosocial interventions, such as nondirective counseling, have been studied in PPD. A Cochrane meta-analysis of ten randomized controlled trials of psychosocial and psychological treatments for PPD concluded that both psychosocial and psychological interventions are effective in PPD (Dennis and Hodnett, 2007) Surprisingly, there are no psychotherapeutic studies on the acute or preventative treatment of bipolar PPD. Psychoeducation, although effective in preventing recurrences of BD, has not been studied in the prevention of postpartum recurrences in women with BD. 8. Prophylactic Treatment Lithium is the most studied drug in the prevention of postpartum recurrences of mood or psychotic episodes. A recent meta-analysis of thirty-seven articles describing 5,700 deliveries in 4,023 patients found a postpartum relapse risk of 37% in women with BD (Wesseloo, et al., 2016). Continuation of treatment during pregnancy, particularly with lithium, was effective in the prevention of postpartum recurrences (Bergink et al., 2016); however, it is unclear whether lithium was also effective against recurrences of depression. A single-blind, nonrandomized clinical trial evaluated the effectiveness of valproate in the prevention of postpartum mood episodes in 26 women. Women received valproate plus symptom monitoring, or monitoring without valproate. Valproate was commenced during pregnancy and symptoms were assessed weekly for 20 weeks. There were no significant differences between groups in the proportions of women who developed hypomania/mania, depression, or mixed states. The time to recurrences of mood episodes also did not vary between groups (Wisner et al., 2004). Sharma et al. (2006) compared the relapse rates of 11 women receiving olanzapine, with or without an antidepressant or mood stabilizer, to 14 women receiving an antidepressant, a mood stabilizer or no medication. The study followed the women for four weeks after delivery. Women treated with olanzapine had a much lower relapse rate than women who did not receive olanzapine (18.2% vs. 57.1%). Used in combination with mood stabilizers, lamotrigine is effective in the prevention of bipolar mood episodes during pregnancy; however, there are no controlled data on its effectiveness in the prevention of postpartum recurrences. In a small case series, lamotrigine alone or in combination with quetiapine was effective in the prevention of BD-II PPD among patients who had shown a good response to the drug during the index pregnancy (Sharma and Sommerdyk, 2015). 9. Breastfeeding The WHO recommends exclusive breastfeeding up to 6 months of age, with continued breastfeeding along with appropriate complementary foods up to at least two years of age. While benefits of breastfeeding for the mother and her infant are well documented, decision to
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breastfeed also requires careful consideration of possible mood instability as a result of sleep disruption. Breastfeeding should be contraindicated in mothers with BD who may be at a particularly high risk of induction of mania or psychosis e.g. women with BD-I. Women who wish to breastfeed but are in need of pharmacotherapy should be informed about the risks and benefits of treatment for BD. Discussion should also take place about the safety of psychotropic drugs in breastfeeding infants. A recent systematic review concluded that mood stabilizers during breastfeeding can be used without any adverse events in most infants (Uguz and Sharma, 2016). Breastfeeding while taking lithium is recommended only if certain clinical characteristics are met: 1) stable maternal mood, 2) lithium monotherapy or a simple medication regimen, 3) adherence to infant monitoring recommendations, 4) a healthy infant and 5) a collaborative pediatrician. Laboratory monitoring should include assays of infant serum lithium and TSH, blood urea nitrogen, and creatinine levels starting in the immediate postpartum period up to 6 weeks of age (Viguera et al., 2007). Valproate and carbamazepine are generally considered compatible with breastfeeding. Short-term use of second generation antipsychotic drugs appears to be relatively safe in the exposed breastfed infants. Studies have shown low relative infant dose (RID) values for olanzapine, quetiapine and ziprasidone, moderate RID values for risperidone/paliperidone and aripiprazole and high RID values for amisulpride. With the exception of clozapine, adverse events were rarely reported in infants exposed to second generation antipsychotic drugs (Uguz, 2016). 10. Treatment Recommendations During pregnancy The peripartum period provides a remarkable opportunity for early identification and treatment of BD because most women neither have an accurate diagnosis of, nor treatment for BD until after they have children (Freeman et al., 2002). Antenatal screening is necessary to identify women with the disorder, as well as those at risk of developing BD (e.g. women with current depression who have a family history of BD) in the postpartum period. Due to the high risk of postpartum recurrence, women receiving anti bipolar pharmacotherapy should continue with the medication. A careful risk-benefit analysis is necessary if antidepressants are part of the drug regimen especially in women with BD-I. There are no data on the effectiveness of antidepressants in preventing postpartum recurrences of bipolar depression; however, abrupt discontinuation of antidepressants that are commonly associated with major withdrawal symptoms (e.g. paroxetine or venlafaxine) including insomnia, may increase risk of mania. As shown in Figure 1, PPD may be a continuation of an episode of major depression from pregnancy, or it may begin in pregnancy and reach the diagnostic threshold of a depressive episode after childbirth. Therefore, in case 1 the treatment focus should on the acute management of depression and its prevention after childbirth. In case 2, the treatment goal should be symptom monitoring in pregnancy, and prevention of depression after childbirth. Cases 3 and 4 represent clinical scenarios where treatments aimed at prophylaxis of depression are needed. Postpartum period Women with PPD should be screened for BD and treated based on the underlying psychiatric disorder. The role of antidepressants in the acute management of unipolar depression in certain
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sub populations of MDD with mixed features is unclear (Sharma, 2013). Table 2 lists disorders in which antidepressants should be used with caution, or avoided altogether in favor of mood stabilizers. If antidepressants are used because of patient preference or history of prior response to such a drug, patients should be observed for emergence of manic symptoms. Women with depression who decline the use of medication should be monitored closely for worsening of depressive symptoms, or emergence of manic symptoms. Since there are no controlled trials on the acute treatment of bipolar PPD, recommendations for first line monotherapy (e.g. lithium, quetiapine or lamotrigine) should be followed. Medications selected for acute treatment of bipolar depression should ideally be effective in the maintenance treatment as well. Patients who develop depression despite the use of a mood stabilizer should have the dose optimized, and if depression persists another first line drug for bipolar depression should be added before considering drugs recommended as combination therapies. Anxiety disorders and OCD are common in the postpartum period and their treatment can be challenging in the context of BD. In the absence of controlled treatment data, these disorders should be managed as much as possible with drugs commonly recommended for BD. There is some evidence for example that lamotrigine (Sharma and Sommerdyk, 2015) and valproate may have a role in the treatment of OCD. There are also reports of the effectiveness of lithium in women with bipolar PPD and comorbid trichotillomania (Sharma and Corpse, 2008). Psychoeducation should be an integral part of the overall treatment plan and should emphasize the importance of illness awareness, self-management, identification of early-warning signs, treatment adherence, and potential side effects of recommended drugs (Colom, 2014). Measures aimed at minimizing sleep disruption including help with nocturnal childcare should be encouraged. There is a strong association between infant sleep problems and PPD, thus addressing infant sleep could potentially attenuate maternal depressive symptoms (Hiscock and Wake, 2001). Once the patient’s condition is stable, issues such as parenting skills and mother– infant bonding should be addressed. 11. Suggestions for Future Research As mentioned, this article is not a formal systematic review. Caveats of non-systematic reviews such as lack of an exhaustive review of the literature and formal data extraction should be taken into consideration. Research on bipolar PPD is still in its infancy notwithstanding the significant strides over the past few years. A major impediment to research has to do with the nomenclature. The term PPD is generic and simply signifies occurrence of a depressive episode after childbirth. Precise labeling of different types of PPD is necessary for risk assessment and choosing disorder specific treatments. In order to facilitate early recognition and timely intervention, studies aimed at determination of timing of onset of depressive episodes are necessary. Based upon the literature reviewed, studies on the acute and maintenance treatment of bipolar PPD are urgently needed. Pharmacologic studies should explore the role of drugs such as lamotrigine, quetiapine and lithium. More importantly, rational treatments aimed at the putative causal factors (such as sleep loss) of bipolar PPD are needed. Hypomanic symptoms are common after childbirth and are a strong predictor of PPD (Glover et al., 1994). An important research question is whether prevention of
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hypomania after delivery is also effective in preventing PPD. There are no studies of psychotherapeutic interventions used alone or in combination with drugs. Researchers should focus on the duration and outcome of depressive periods since there are some women who have brief episodes that remit spontaneously without treatment. Also, risk factors contributing to chronicity, as well as predictors of response to various treatments need to be identified. The postpartum period should provide a remarkable opportunity to clarify the relationship of BD and comorbid psychiatric disorders.
Acknowledgements The authors thank Elizabeth Russell, Librarian at Parkwood Institute, London, Ontario, Canada for her assistance with the literature search.
References 1. Austin, M.P., Lumley, J., 2003. Antenatal screening for postnatal depression: a systematic review. Acta Psychiatry Scand. 107(1), 10-17. 2. Azorin, J.M., Angst, J., Gamma, A., Bowden, C.L., Perugi, G., Vieta, E., Young, A., 2012. Identifying features of bipolarity in patients with first-episode postpartum depression: findings from the international BRIDGE study. J Affect Disord. 136(3), 710-715. 3. Bergink, V., Rasgon, N., Wisner, K.L., 2016. Postpartum Psychosis: Madness, Mania, and Melancholia in Motherhood. Am J Psychiatry. 173(12), 1179-1188. 4. Boden, R., Lundgren, M., Brandt, L., Reutfors, J., Andersen, M., Kieler, H., 2012. Risks of adverse pregnancy and birth outcomes in women treated or not treated with mood stabilisers for bipolar disorder: population based cohort study. BMJ. 345, e 7085. 5. Cantwell, R., Clutton-Brock, T., Cooper, G., Dawson, A., Drife, J., Garrod, D., Harper, A., Hulbert, D., Lucas, S., McClure, J., Millward-Sadler, H., Neilson, J., Nelson-Piercy, C., Norman, J., O'Herlihy, C., Oates, M., Shakespeare, J., de Swiet, M., Williamson, C., Beale, V., Knight, M., Lennox C., Miller, A., Parmar, D., Rogers, J., Springett, A., 2011. Saving mothers’ lives; reviewing maternal deaths to make motherhood safer 2006–2008: the Eighth Report on Confidential Enquiries Into Maternal Deaths In the United Kingdom. BJOG. 118(suppl 1), 1–203. 6. Çelik, S.B., Bucaktepe, G.E., Uludağ, A., Bulut, İ.U., Erdem, Ö., Altınbaş, K., 2016. Screening mixed depression and bipolarity in the postpartum period at a primary health care center. Compr Psychiatry. 71, 57-62. 7. Clark, C.T., Sit, D.K., Driscoll, K, Eng, H.F., Confer, A.L., Luther, J.F., Wisniewski, S.R., Wisner, K.L., 2015. Does screening with the MDQ and EPDS improve identification of bipolar disorder in an obstetrical sample? Depress Anxiety. 32(7), 518526. 8. Colom, F., 2014. The evolution of psychoeducation for bipolar disorder: from lithium clinics to integrative psychoeducation. World Psychiatry. 13(1), 90-92.
13
9. Committee on Obstetric Practice, 2015. The American College of Obstetricians and Gynecologists Committee Opinion no. 630. Screening for perinatal depression. Obstet Gynecol. 125, 1268-1271. 10. Dennis, C.L., Hodnett, E., 2007. Psychosocial and psychological interventions for treating postpartum depression. Cochrane Database Syst Rev., CD006116. 11. Di Florio, A., Forty, L., Gordon-Smith, K., Heron, J., Jones, L., Craddock, N., Jones, I., 2013. Perinatal episodes across the mood disorder spectrum. JAMA Psychiatry. 70(2), 168-175. 12. Doyle, K., Heron, J., Berrisford, G., Whitmore, J., Jones, L., Wainscott, G., Oyebode, F., 2012. The management of bipolar disorder in the perinatal period and risk factors for postpartum relapse. Eur Psychiatry. 27(8), 563-569. 13. Dudek, D., Jaeschke, R., Siwek, M., Mączka, G., Topór-Mądry, R., Rybakowski, J., 2014. Postpartum depression: identifying associations with bipolarity and personality traits. Preliminary results from a cross-sectional study in Poland. Psychiatry Res. 215(1), 69-74. 14. Field, T., 2010. Postpartum Depression Effects on Early Interactions, Parenting, and Safety Practices: A Review. Infant Behav Dev. 33(1), 1-9. 15. First, M.B., Williams, J.B.W., Karg, R.S., Spitzer, R.L., 2015. Structured Clinical Interview for DSM-5—Research Version (SCID-5 for DSM-5, Research Version; SCID5-RV). Arlington, VA, American Psychiatric Association. 16. Fisher, S.D., Wisner, K.L., Clark, C.T., Sit, D.K., Luther, J.F., Wisniewski, S., 2016. Factors associated with onset timing, symptoms, and severity of depression identified in the postpartum period. J Affect Disorder. 203, 111-120. 17. Freeman, M.P., Smith, K.W., Freeman, S.A., McElroy, S.L., Kmetz, G.E., Wright, R., Keck, P.E. Jr., 2002. The impact of reproductive events on the course of bipolar disorder in women. J Clin Psychiatry. 63, 284-287. 18. Frey, B.N., Simpson, W., Wright, L., Steiner, M., 2012. Sensitivity and specificity of the Mood Disorder Questionnaire as a screening tool for bipolar disorder during pregnancy and the postpartum period. J Clin Psychiatry. 73(11), 1456-1461. 19. Glover, V., Liddle, P., Taylor, A., Adams, D., Sandler, M., 1994. Mild hypomania (the highs) can be a feature of the first postpartum week. Association with later depression. Br J Psychiatry. 164(4), 517-521. 20. Hirschfeld, R.M., Williams, J.B., Spitzer, R.L., Calabrese, J.R., Flynn, L., Keck, P.E. Jr, Lewis, L., McElroy, S.L., Post, R.M., Rapport, D.J., Russell, J.M., Sachs, G.S., Zajecka, J., 2000. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 157(11), 1873-1875. 21. Hiscock, H., Wake, M., 2001. Infant sleep problems and postnatal depression: a community-based study. Pediatrics. 107(6), 1317-1322. 22. Inglis, A.J., Hippman, C.L., Carrion, P.B., Honer, W.G., Austin, J.C., 2014. Mania and depression in the perinatal period among women with a history of major depressive disorders. Arch Womens Ment Health. 17(2), 137-143. 23. Jablensky, A.V., Morgan, V., Zubrick, S.R., Bower, C., Yellachich, L.A., 2005. Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders. Am J Psychiatr. 162(1), 79–91.
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24. Jaeschke, R.R., Dudek, D., Topór-Madry, R., Drozdowicz, K., Datka, W., Siwek, M., Rybakowski, J., 2016. Postpartum depression: bipolar or unipolar? Analysis of 434 Polish postpartum women. Rev Bras Psiquiatr. doi:10.1590/1516-4446-2016-1983. 25. Kettunen, P., Koistinen, E., Hintikka, J., 2014. Is postpartum depression a homogenous disorder: time of onset, severity, symptoms and hopelessness in relation to the course of depression. BMC Pregnancy Childbirth. 14, 402. 26. Lee, H.C., Lin, H.C., 2010. Maternal bipolar disorder increased low birthweight and preterm births: A nationwide population-based study. J Affect Disord. 121(1–2), 100– 105. 27. Mandelli, L., Souery, D., Bartova, L., Kasper, S., Montgomery, S., Zohar, J., Mendlewicz, J., Serretti, A., 2016. Bipolar II disorder as a risk factor for postpartum depression. J Affect Disord. 204, 54-58. 28. Merrill, L., Mittal, L., Nicoloro, J., Caiozzo, C., Maciejewski, P.K., Miller, L.J., 2015. Screening for bipolar disorder during pregnancy. Arch Womens Ment Health. 18(4), 579583. 29. Misri, S., Abizadeh, J., Eng, A.B., Albert, G., Ryan, D., Swift, E., 2015. An Open-Label Study of Quetiapine Extended-Release in a Sample of Postpartum Women with Bipolar II Depressive Episode. Curr Psychopharmacol. 4(1), 17-26. 30. Munk-Olsen, T., Laursen, T.M., Meltzer-Brody, S., Mortensen, P.B., Jones, I., 2011. Psychiatric disorders with postpartum onset: possible early manifestation of bipolar affective disorders. Arch Gen Psychiatry. 69(4), 428-434. 31. Munk-Olsen, T., Laursen, T.M., Pedersen, C.B., Mors, O., Mortensen, P.B., 2006. New parents and mental disorders: a population-based register study. JAMA Psychiatry. 296(21), 2582-2589. 32. Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium, 2015. Heterogeniety of postpartum depression: a latent class analysis. Lancet Psychiatry. 2(1), 59-67. 33. Serretti, A., Olgiati, P., Colombo, C., 2006. Influence of postpartum onset on the course of mood disorders. BMC Psychiatry. 6, 4. 34. Sharma, V., 2006. A cautionary note on the use of antidepressants in postpartum depression. Bipolar Disord. 8(4), 411-414. 35. Sharma, V., 2013.Mixed depression in the postpartum period: diagnostic and treatment issues.. J Psychiatry Neurosci. 38(6), E30. 36. Sharma, V., Burk, V.K., Ritchie, H.L., 2009. Bipolar II postpartum depression: Detection, diagnosis and treatment. Am J Psychiatry. 166(11), 1217-1221. 37. Sharma, V., Corpse, C., 2008. Lithium treatment of trichotillomania with comorbid bipolar II disorder. Arch Womens Ment Health. 11(4), 305-306. 38. Sharma, V., Khan, M., Corpse, C., Sharma, P., 2008. Missed bipolarity and psychiatric comorbidity in women with postpartum depression. Bipolar Disord. 10(6), 742-747. 39. Sharma, V., Khan, M., Sommerdyk, C., 2015. Quetiapine in the Acute Treatment of Bipolar Postpartum Depression: A Chart Review. J Clin Psychopharmacol. 35(6), 733735. 40. Sharma, V., Penava, D., 2010. Screening for Bipolar Disorder during Pregnancy and the Postpartum Period. J Obstet Gyanaecol Can. 32(2), 278-281. 41. Sharma, V., Smith, A., Mazmanian, D., 2006. Olanzapine in the prevention of postpartum psychosis and mood episodes in bipolar disorder. 8(4), 400-404.
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42. Sharma, V., Sommerdyk, C., 2015. Obsessive-compulsive disorder in the postpartum period: diagnosis, differential diagnosis and management. Womens Health (Lond). 11(4), 543-552. 43. Sharma, V., Sommerdyk, C., Xie, B., Campbell, K., 2013. Pharmacotherapy of bipolar II disorder during and after pregnancy. Curr Drug Saf. 8(4), 246-252 44. Sharma, V., Xie, B., 2011. Screening for postpartum bipolar disorder: validation of The Mood Disorder Questionnaire. J Affect Disord. 131(1-3), 408-411. 45. Sharma, V., Xie, B., Campbell, M.K., Penava, D., Hampson, E., Mazmanian, D., Pope C.J., 2014. A prospective study of diagnostic conversion of major depressive disorder to bipolar disorder in pregnancy and postpartum. Bipolar Disord. 16(1), 16-21. 46. Sockol, L.E., Battle, C.L., Howard, M., Davis, T., 2014. Correlates of impaired motherinfant bonding in a partial hospital program for perinatal women. Arch Womens Ment Health. 17(5), 465-9. 47. Stagnaro-Green, A., Abalovich, M., Alexander, E., Azizi, F., Mestman, J., Negro, R., Nixon, A., Pearce, E.N., Soldin, O.P., Sullivan, S., Wiersinga, W., American Thyroid Association Taskforce on Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum, 2011. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 21(10), 1081-1125. 48. Thompson, M., Sharma, V., 2016. Therapeutics of postpartum depression. Expert Rev. Neurother. 9, 1-13. 49. Uguz F., 2016. Second-Generation Antipsychotics During the Lactation Period: A Comparative Systematic Review on Infant Safety. J Clin Psychopharmacol. 36(3), 244252. 50. Uguz, F., Sharma, V., 2016. Mood stabilizers during breastfeeding: a systematic review of the recent literature. Bipolar Disord. 18(4), 325-333. 51. Viguera, A. C., Newport, J., Ritchie, J., Stowe, Z., Whitfield, T., Mogielnicki, J., Baldessarini, R. J., Zurick, A., 2007. Lithium in Breast Milk and Nursing Infants: Clinical Implications. Am J Psychiatry. 164, 342-345. 52. Volkert, J., Zierhut, K.C., Schiele, M.A., Wenzel, M., Kopf, J., Kittel-Schneider, S., Reif, A., 2014. Predominant polarity in bipolar disorder and validation of the polarity index in a German sample. BMC Psychiatry. 14, 322. 53. Wesseloo, R., Kamperman, A.M., Munk-Olsen, T., Pop, V.J., Kushner, S.A., Bergink, V., 2016. Risk of Postpartum Relapse in Bipolar Disorder and Postpartum Psychosis: A Systematic Review and Meta-Analysis. Am J Psychiatry. 173(2), 117-127. 54. Wisner, K.L., Hanusa, B.H., Peindl, K.S., Perel, J.M., 2004. Prevent of postpartum episodes in women with bipolar disorder. Biol Psychiatry. 56(8), 592-596. 55. Wisner, K.L., Sit, D.K., McShea, M.C., Rizzo, D.M., Zoretich, R.A., Hughes, C.L., Eng, H.F., Luther, J.F., Wisniewski, S.R., Costantino, M.L., Confer, A.L., Moses-Kolko, E.L., Famy, C.S., Hanusa, B.H., 2013. Onset timing, thoughts of self-harm, and diagnoses in postpartum women with screen-positive depression findings. JAMA Psychiatry. 70(5), 490-498. 56. Yatham, L.N., Kennedy, S.H., Parikh, S.V., Schaffer, A., Beaulieu, S., Alda, M., O'Donovan, C., Macqueen, G., McIntyre, R.S., Sharma, V., Ravindran, A., Young, L.T., Milev, R., Bond, D.J., Frey, B.N., Goldstein, B.I., Lafer, B., Birmaher, B., Ha, K., Nolen, W.A., Berk, M., 2013. Canadian Network for Mood and Anxiety Treatments (CANMAT)
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and Internal Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management for patients with bipolar disorder: update 2013. Bipolar Disord. 15(1), 1-44.
Fig. 1. Classifications of Depression Contingent on the Timing of Onset of Symptoms During Pregnancy
Table 1. Features suggestive of bipolarity in women with PPD Illness onset
Younger age at illness onset First onset of depression during the postpartum period Depression onset immediately after delivery
Illness course & symptoms
High number of prior episodes Brief episodes of depression Depressive episodes with free intervals Seasonality of mood episodes Atypical features: hypersomnia, leaden paralysis or increased appetite Mixed depression Agitation Psychotic symptoms History of bipolar disorder in a first degree relative
Treatment response
Atypical antidepressant response: induction of mania, hypomania or mixed depressive episode; poor response; rapid response; loss of antidepressant response
(Azorin et al., 2012; Jaeschke et al., 2016; Sharma, 2006)
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Table 2. Types of PPD in which antidepressants should be avoided or used cautiously 1. 2. 3. 4. 5.
Major depressive disorder with mixed features Major depressive episode with first onset in the postpartum period Major depressive episode with onset in early postpartum period History of bipolar disorder in a first degree relative Atypical features: hypersomnia, leaden paralysis or increased appetite
(Azorin et al., 2012; Sharma, 2006; Sharma, 2013; Sharma et al., 2014)
Highlights 1. There has been a surge of interest in the study of bipolar postpartum depression. 2. Bipolar postpartum depression is common and can be distinguished from unipolar postpartum depression. 3. There is a paucity of literature on pharmacological and psychotherapeutic treatments.
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