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1. Introduction

Pharmacotherapy of postpartum depression: current practice and future directions

2. Methods

Oleg V Tcheremissine† & Lori M Lieving

3. Current best practice

of Psychiatry and Behavioural Science, University of Texas Health Science Center, 1300 Moursund Street, Houston, TX 77030-3497, USA

†Department

4. Conclusions 5. Expert opinion

Postpartum depression has well-documented consequences for the mother, child, family and society as a whole. Despite an increasing awareness of postpartum depression, it often remains unrecognised by clinicians and poorly understood by researchers. The current trend is undoubtedly a result of the complex nature of depressive disorders accentuated by difficulties with the current classification schemas. Systematic prospective data on the onset of depression during pregnancy and the postpartum period, as well as on the risk of relapse during these periods in women with previous histories of mood and anxiety disorders, are limited. This article reviews clinically relevant outcomes and current trends in the pharmacotherapy of postpartum depression from selected clinical trials. Critical issues of the neurobiology and phenomenology of postpartum depression are raised, and future directions of the pharmacological treatments of postpartum depression are examined. Keywords: clinical trials, pharmacotherapy, postpartum depression Expert Opin. Pharmacother. (2005) 6(12):1999-2005

1.

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Introduction

The World Health Organization reported that depression is the leading cause of disability, as measured by years lived with disability for adults 18 – 45 years of age, and the fourth overall leading contributor to the burden of disease, as measured by disability adjusted life years (DALY) in 2000. The report predicted that major depressive disorders (MDDs) would be the second greatest overall cause of DALYs in adults by 2020, behind ischaemic heart disease only [1]. Over 340 million people are affected by major depression, with females comprising approximately two-thirds of that number. For most women, the childbearing years represent a time of greater vulnerability for mood and anxiety disorders in comparison with men of the same age groups across all cultures [2], with a threefold increase in the onset of depression in the first 5 weeks postpartum compared with matched controls [3]. Postpartum psychiatric disorders are a heterogeneous group of mood- and anxiety-related symptoms and syndromes that occur after childbirth. Postpartum psychiatric disorders lead to direct negative consequences to mother and/or infant health, the establishment of secure mother–infant attachment, and the optimal cognitive, emotional and behavioural development of the offspring [4]. The American Psychiatric Association Diagnostic and Statistical Manual of Mental Health Disorders-IV (DSM-IV) applies the term ‘postpartum’ to describe symptoms of MDD, bipolar disorders I and II, or brief psychotic disorder beginning within 4 weeks of childbirth [5]. From the clinical viewpoint, postpartum depressive disorders can be further divided into following categories: i) postpartum blues; ii) postpartum depression (PPD) (non-psychotic); and iii) puerperal psychosis. Although these nosological categories vary in severity of clinical symptoms, it is not

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Pharmacotherapy of postpartum depression: current practice and future directions

clear whether they actually represent three distinct disorders or if they exist along a continuum, as there may be significant overlap between clinical symptoms of these three diagnostic subtypes. The complete description of the postpartum psychiatric disorders is beyond the scope of this review. In this paper, the authors will mainly focus on PPD without psychotic features. The true prevalence of PPD is difficult to estimate. Longitudinal and epidemiological studies have demonstrated varying prevalence rates, ranging from 3 to > 25% of women in the first year postpartum; for example, Chaudron estimates that PPD affects ≤ 10 – 20% of new mothers [6]. The recent findings of Dennis [7] that almost 30% of new mothers exhibit depressive symptomatology 1 week after delivery clearly implies that many women experience some form of psychological distress. Data from a meta-analysis of 59 studies indicated the overall prevalence of major PPD to be 13% in the first few weeks postpartum [3]. Perhaps one of the potential sources for this discrepancy lies in the fact that the precise time frame for defining PPD varies across numerous studies and classifications. The DSM-IV applies the term ‘postpartum’ to specifically describe symptoms of mood disorders and/or psychosis beginning within 4 weeks of childbirth, whereas the International Classification of Diseases (ICD-10) extends this period up to 6 weeks [8]. However, most studies of PPD have continued to use wider time frames based on epidemiological data that found that women continue to express vulnerability to depressive episodes for at least the first 6 months after childbirth, or even up to 1 year according to some studies [6,9]. 2. Methods

PUBMED and PsycInfo were searched from 1985 to 2005, using the search terms antenatal, postnatal, postpartum, pregnancy and depression, restricting papers to English. All papers coded as controlled trials, clinical trials or randomised controlled trials were reviewed in terms of therapeutic outcomes. The individual studies were too clinically heterogeneous and methodologically variable to justify a quantitative metaanalysis. Therefore, the authors chose to examine these studies based on the empirically derived inclusion criteria: • Study design: randomised controlled trials and quasirandomised trials involving alternate allocation or assignment by time period • Participants: pregnant women or women in the first year after birth • Types of interventions: pharmacological agents, including hormones • Exclusion criteria: trials that were neither randomised nor quasi-randomised. The selection of the studies for inclusion in this paper involved two steps. First, the authors independently reviewed the abstracts of all studies identified by the literature search and excluded those for which it was agreed that the eligibility 2000

criteria were not met. Next, the remaining articles were reviewed in detail and the authors made a final decision about inclusion or exclusion by consensus. 3.

Current best practice

From the serendipitous discoveries in the 1950s that iproniazid and imipramine were effective in the treatment of depression, antidepressants not only dramatically improved treatment, but also had a profound impact on the way depression was viewed [10-12]. Thus, the modern era of depression research began, which has been mainly focused on monoamines, different receptor families and neurotransmitter transporters. Consequently, new advances led to the development of numerous second-generation antidepressants (e.g., serotonin-selective re-uptake inhibitors [SSRIs] and noradrenaline-selective re-uptake inhibitors [NSRIs]). Since their emergence almost two decades ago, newer antidepressants have been shown to be comparable in effectiveness to the first generation of antidepressants, but with superior subjective tolerability and a more favourable side effect profile. These properties have led to increased medication adherence and have changed the prescription patterns of both psychiatrists and non-psychiatrists alike. Although the treatment advancements associated with the newer antidepressants have expanded the medication availability to pregnant and nursing women, there is a relative paucity of formal effectiveness and safety data. Results from the numerous clinical studies of the pharmacological management of PPD have been promising [13-15], despite the fact that most of these studies did not control for a number of differences in the original design that might have influenced their outcomes, such as placebo groups, comorbid conditions and the number of patients enrolled in studies. Previously, pregnancy has been described as a time of emotional well-being for women, providing natural protection against psychiatric disorders, including depression, due to numerous hormonal changes [16]. Today, the results of many studies do not support these observations. In fact, according to some experts, screening and treatment for depression should begin prior to and during pregnancy because as many as 50% of women with PPD report symptoms of depression before parturition [17]. The risk of PPD is higher in women with a history of prior depression (25% risk), a history of a prior PPD (50 – 60% risk) or depressive symptomatology during pregnancy (96 – 98% risk) [18,19]. Women with a history of PPD are at particularly high risk in subsequent pregnancies. Therefore, it is essential to monitor this patient population and implement preventative strategies carefully. The theoretical framework of the strategy of administering an antidepressant to asymptomatic women after birth to prevent the recurrence of postpartum-onset major depression was tested by Wisner and colleagues [20]. In total, 22 non-depressed pregnant women with at least one past episode of PPD were recruited into a 17-week trial of

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sertraline or placebo immediately after birth. The duration of 17 weeks was selected to cover the risk period defined in epidemiological studies [21]. Of the 14 participants who took sertraline, only one patient (7%) suffered a recurrent episode of PPD. Of the eight subjects from the placebo arm, four women (50%) suffered from depression following childbirth. The results of this clinical trial indicated that sertraline demonstrated statistically significant preventative efficacy. Importantly, when sertraline was tapered, two women became depressed within a 6-week period. As a result, the authors concluded that a minimum period of 29 weeks was needed for the treatment, which is consistent with treatment guidelines for a single episode of depression [22]. Another open study of 26 women with depressive symptoms that developed within 6 months of delivery found that sertraline reduced baseline scores on the 21-item Hamilton Rating Scale for Depression by > 50%. In addition, women with symptoms onset within 4 weeks postpartum improved more rapidly and required lower doses of medication than women with an onset of depression after 4 weeks postpartum [14]. The effectiveness of the SSRI fluoxetine has been examined in one randomised controlled trial, double-blind in relation to drug treatment because all patients received cognitive-behavioural counselling [23]. The authors identified 188 confirmed cases of PPD, of whom 87 agreed to enter the 12-week treatment trial with four treatment cells: fluoxetine or placebo plus one or six sessions of counselling. Highly significant improvement was seen in all four groups. However, the improvement in patients that received fluoxetine was significantly greater than in those that received placebo. The improvement after six sessions of counselling was significantly greater than after a single session. These differences were noted after 1 week of participation and improvement in all groups was complete after 4 weeks. There was no added benefit in combining fluoxetine and multiple counselling sessions. Recently, Misri and colleagues [24] reported that another SSRI, paroxetine, was effective in reducing depressive and anxious symptoms based on the results of 12-week trial of paroxetine alone and paroxetine in combination with cognitive behavioural therapy (CBT). In total, 35 women with a DSM-IV diagnosis of PPD and anxious features participated in the trial. Patients were randomly assigned to one of two treatment groups: paroxetine-only monotherapy (n = 16) or paroxetine plus 12 sessions of CBT (n = 19). Progress in treatment was monitored by a blinded rater, using the Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, Yale-Brown Obsessive Compulsive Scale, Clinical Global Impressions Scale and Edinburgh Postnatal Depression scale (EPDS). The initial dose of paroxetine in this study was 10 mg. Based on a flexible-dose regimen, the daily dose was titrated uniformly across the two groups up to a maximum of 50 mg. Patients in the paroxetine plus CBT group followed the same protocol as outlined for the pharmacological treatment only. In addition, they received a 1-h individual CBT session every week for 12 weeks. Both treatments

resulted in statistically significant improvements in maternal depressive and anxious symptoms. In this sample, the results also indicated that no additional benefits were noted from the combination of two treatment modalities. However, this study did not attempt to examine the effectiveness of CBT in the treatment of PPD. Rather, the purpose of this study was to evaluate whether the combination of antidepressant and psychological intervention was as effective as medication management alone. The finding that the combination therapy was not superior to antidepressant alone is consistent with those of Appleby and colleagues previously discussed [23]. SSRIs have become the first-line of antidepressants for depression during pregnancy and postpartum mainly based on the effectiveness and safety data from the treatment of nonpostpartum depression. According to some experts, this strategy adds an additional concern suggesting that prenatal exposure to SSRIs could lead to neonatal withdrawal symptoms [25]. Clinical features of this condition include nonspecific symptoms such as irritability, excessive crying, shivering, increased muscle tonus, feeding difficulties, jitteriness and, in severe cases, even seizures. Using the data-mining method routinely used to screen the World Health Organization database of adverse drug reactions, Sanz and colleagues [25] examined the association between SSRIs and neonatal withdrawal syndrome. The database contains information from 72 countries and holds > 3 million records. The presence of a withdrawal reaction to SSRIs is now widely recognised and the number of cases of neonatal withdrawal syndrome associated with the drugs, characterised by convulsions, irritability, abnormal crying and tremor, have been reported. The investigators found that by November 2003, a total of 93 cases of neonatal withdrawal syndrome, including 13 instances of seizures, had been documented, suggesting a possible causal relationship. Of these 93 cases, 64 were associated with paroxetine, 14 with fluoxetine, 9 with sertraline and 7 with citalopram. Although the doses of paroxetine were reported in only 13 cases and were in the range of 10 – 50 mg/day, investigators concluded that paroxetine should not be used in pregnancy; if used, it should be prescribed at the lowest effective dose. Whether or not these data are sufficient enough to draw definite conclusions with respect to therapeutic value of paroxetine or others SSRIs in the treatment of depression during pregnancy continues to be a point of debate. A number of other studies have investigated the possible effects of in utero exposure to SSRIs [26-29]. No differences in intelligence quotient, language, motor skills or seizure disorders were found [26-28]. In one study, children exposed to SSRIs during pregnancy had lower Apgar scores, as compared with nonexposed children [29]. However, the relevance of this finding is unknown. What is more certain is that the outcomes of these studies are in line with the notion that: i) the therapeutic value of a given drug must be assessed against adverse effects on the fetus before and after birth; and ii) the severity of maternal depressive symptoms is an important factor in the risk–benefit decision-making process [30]. In other words, the decision

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to continue or initiate antidepressant treatment during pregnancy or lactation must be balanced with maternal well-being and fetal/infant safety. Another concern is the exposure to antidepressants that an infant may experience through breast milk. Most antidepressants pass into breast milk [31]. Although antidepressant concentrations in breast milk are relatively low, the significance of such exposure is unknown. No controlled trials have ever examined the outcomes on the infant following antidepressant therapy in nursing women. The current literature is mostly limited to case studies [32-36]. Commonly reported adverse events included uneasy sleep, crying, emesis, diarrhoea and hyperactivity; therefore, breastfeeding while taking antidepressants may present additional safety concerns [37]. Although the use of antidepressants in the treatment of PPD is common and documented, another hypothesis with respect to the aetiology of PPD that has been put forward in recent years is related to the role of gonadal hormones (i.e., oestrogen and progesterone) in the development of mood symptoms in the immediate postpartum period. Although researchers have failed to consistently demonstrate a causal relationship between gonadal hormone levels and a quality of mood in postpartum period [38,39], it is generally recognised that gonadal hormones are responsible for modulating the synthesis of proteins, neurotransmitters and receptors in the CNS. Therefore, it is not surprising that therapeutic effectiveness of gonadal hormones in the treatment and prevention of PPD has been examined by a number of investigators; for example, Dalton [40,41] suggested that progesterone could be used in the prophylaxis of PPD, but it is not effective as a treatment. In contrast, based on the results from a double-blind randomised clinical trial, Lawrie et al. [42] suggested that progesterone was not only ineffective as a treatment, but perhaps even caused depressive symptoms. In terms of oestrogen therapy, the results from one double-blind placebo-controlled trial showed the beneficial effects of the oestrogens in high doses. In this study, Gregoire and colleagues [43] used transdermal oestrogen patches delivering oestradiol 200 µg/day or placebo patches identical in appearance. The two groups (active n = 34, placebo n = 27) were compared on a range of measures, which were obtained before treatment. Severity of depressive symptoms was measured by the EPDS and by clinical psychiatric interview (schedule for affective disorders and schizophrenia [SADS]) prior to the randomisation into the treatment groups. After 1 month of treatment, 50% of patients in the active group rated themselves below the EPDS threshold for major depressive disorder (< 14), in comparison with 74% of patients in the placebo group. Patients receiving placebo also improved over time, but, on average, their scores did not fall below the screening thresholds for major depression for ≥ 4 months. Based on these results, the authors postulated that oestrogen was better than placebo in relieving symptoms of PPD. However, the results of this study were limited by the use of 2002

psychotropic medications, which were not a part of the exclusion criteria. The concurrent use of different antidepressants in a number of patients (16 out of 34 in the active group and 10 out of 27 in the placebo group) could have added further factors, the importance of which in the overall therapeutic response is difficult to estimate. In addition, the authors had originally hoped to recruit 100 women for the study, but recruitment had to be stopped at 64 patients due to time constraints as a consequence of the strict exclusion and inclusion criteria, which, subsequently, presented an issue of selection bias. Although oestrogen and/or progesterone therapy might provide some additional antidepressant effects in the treatment of mood disorders, including PPD, the harsh reality of the placebo-controlled, doubleblind studies, is far less encouraging. The therapeutic effectiveness of gonadal hormones in the prevention or the treatment of PPD has not been unequivocally proven by wellcontrolled double-blind studies. In addition, there are a number of serious safety concerns regarding the use of gonadal hormones during the postpartum period, including deep vein thrombosis, fluid retention and endometrial hyperplasia. Importantly, gonadal hormones are secreted in the breast milk and, therefore, might present an additional health risk for nursing infants. 4.

Conclusions

Given the relative scarcity of well-designed and well-controlled studies evaluating the treatment outcomes in PDD, new information derived from prospective studies will provide welcome relief from years of decision-making based on case reports and uncontrolled data. The results from the reviewed studies have demonstrated the clinical and methodological feasibility of conducting pharmacological research in PPD, highlighted by the relative paucity of reliable and replicable data, and indicated by the great need to improve current therapeutic outcomes. However, there are real problems in designing clinical trials for PPD related to the number of methodological and diagnostical difficulties. In this paper, the authors would like to not only present an overview of the current trends in pharmacological management of PPD, but also outline strategies for further development of pharmacology of PPD. First, categorical classifications (i.e., DSM-IV and ICD-10) assume that clear boundaries separate one disorder from another and nondisorder. To distinguish disorders from nondisorders, categorical systems rely on ‘symptoms thresholds’ to determine the presence or absence of disorder (e.g., five or more symptoms out of a list of nine indicate the presence of MDD whereas four or fewer indicate its absence). In fact, most of the disorders of depressive spectrum occur on a continuum without any clear demarcations between disorder and normality. The current diagnostic classifications undoubtedly contribute to the difficulties in the general understanding of the phenomenology of PPD by viewing this phenomenon as a cluster of depressive symptoms, which is indistinguishable from MDD, but occurs during a

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postpartum period. Therefore, this approach does not necessarily describe a homogenous disorder, but rather describes common final pathways of different pathophysiological processes [44]. Second, although most investigators believe the symptoms of PPD are no different from those of MDD [45,46], the limited data available on the phenomenology of depression in postpartum period suggest that some features may differentiate it from typical MDD; for example, women with histories of depression with onset during pregnancy and postpartum were found to be an average of 5 – 10 years younger at illness onset than women without these episodes [47-49]. In addition, it has been previously noted that women with PPD seem to be more likely to present with anxious features than non-postpartum women [24,49,50]. Although the DSM-IV does not formally apply the term ‘postpartum’ to other psychiatric conditions, including a wide range of anxiety disorders (e.g., panic disorders, phobias and obsessivecompulsive disorders), disorders of this spectrum can have an onset or exacerbation in the postpartum period. Presence of anxious features in patients with unipolar depression has been previously associated with poorer treatment outcome [51,52]. In part, the increased level of anxiety might be associated with increased level of responsibilities, changes in sleep, appetite, libido and fatigue that are normal childbirth sequelae. For that reason, it would be interesting to assess whether anxiety as a baseline trait is a predictor or a contributing factor for the development of PPD. Most importantly, no pharmacological studies, at least to the authors’ knowledge, have compared the treatment responses and the treatment outcomes between postpartum and non-postpartum populations of women. Thus, the relationship between MDD and PPD is a subject of future investigations. Furthermore, a growing body of evidence indicates that for a significant percentage of women, PPD continues beyond the early postpartum period, becoming prolonged or chronic, whereas, for others, depressive symptoms resolve spontaneously. How and why depressive symptoms resolve for one group of women, but not for another, is still poorly understood. Third, the randomised controlled clinical trial methodology has unambiguously demonstrated its value and has come to be seen as the optimal standard for evaluating all treatments. This model has been the standard for assessing the effectiveness of different types of pharmacological agents, including antidepressants, for > 30 years. However, the use of placebo has come under criticism in recent years. Although the risk of using placebo is not supported by an objective evaluation of data [53,54], according to some experts in bioethics of research the use of a placebo in depressed patients can result in a delay in instituting active treatment and, subsequently, cause clinically relevant problems [55]. At the same time, many authors, including the authors of this review, believe that the high placebo response rates often confound the treatment outcomes of MDD. Between 30 and 50% of depressed patients in clinical trials have substantial reduction in symptoms during treatment with placebo [56,57]. Once a larger base of well-controlled clinical trials has been established, the effectiveness of different pharmacological agents (e.g., SSRIs,

hormonal therapy) in treating symptoms of PPD can be evaluated and compared more thoroughly. Finally, few specific animal models have been able to provide biological insights related to PPD, including abnormalities in neurotransmission, neuropathological changes in specific areas in the cortex and changes of selective behavioural traits. It seems almost unavoidable to use animal experiments to improve our understanding of neurochemical systems implicated in depression, even though such data should not be used uncritically in making assumptions concerning human disorders. The biology and behaviour of animals can help scientists to gain specific knowledge, given the important number of parallels that can be discerned between animal and human behaviours. Therefore, in the past, this inability to develop satisfactory animal models is a factor that has prevented further development of research into the neurobiology of PPD and future drug development in this field. Once appropriate homologous animal models of PPD are identified, the progress of this line of research should dramatically hasten. 5. Expert

opinion

PPD is a significant public health problem affecting approximately one in seven women after childbirth. Apart from the direct adverse consequences of depression on womens health, there are a number of additional concerns about the negative impact of maternal depression on overall child development. Today, there is growing body of evidence that PPD is a highly treatable condition. The current review is focused on psychopharmacology, but this is only part of a comprehensive treatment approach. In addition to the large number of pharmacological agents available today for the treatment of PPD, other therapeutic modalities such as psychotherapy, administered alone or an adjunct to drug therapy, have been found to be effective. Psychotherapeutic modalities found to be effective in the treatment of PPD include CBT, interpersonal therapy, psychodynamic therapy, supportive therapy and psychoeducation [58]. Importantly, it has been highlighted in this review that there are numerous aetiological pathways by which women develop PPD. Therefore, it is highly unlikely that a single therapeutic modality will be proven to be effective for the majority of patients. The treatment goals are more likely to be achieved by applying a biopsychosocial approach to the treatment of PPD, which is derived from the notion that biological, psychological and psychosocial factors contribute to the development of psychiatric diseases, including PPD. Consequently, the success of therapeutic interventions will depend on the ability to identify and diagnose individuals at risk effectively, as well as to develop an integrative treatment approach.

Disclaimer The opinions expressed in this article do not represent the formal position of the University of Texas School of Medicine.

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Affiliation

Oleg V Tcheremissine† & Lori M Lieving †Author for correspondence Department of Psychiatry and Behavioural Science, University of Texas Health Science Center, 1300 Moursund Street, Houston, TX 77030-3497, USA Tel: +1 713 500 2869; Fax: +1 713 500 2618; E-mail: [email protected]

2005