Antidepressants for Postnatal Depression

Antidepressants for Postnatal Depression Antidepressants are they a safe and effective choice for the treatment of postnatal depression? This review assessed the evidence concerning the effectiveness and safety of antidepressants in the management of postnatal depression. This would facilitate evidence-based clinical decisions in the treatment of patients. Data was sourced from several electronic Athens-based and free databases covering the psycho-biomedical and nursing literature. Studies found included randomised clinical trials, case- and cohort-controlled studies, questionnaire surveys, and qualitative/exploratory research. Previous reviews were also appraised. Outcomes from over 1200 mothers, mother-infant pairings, or infants, exposed to antidepressants were considered. Antidepressants appear to significantly alleviate depressive symptoms. Furthermore, the reported side effects are generally benign and clinically insignificant. However, methodological and analytic flaws negate conclusive inferences. Many studies fail to account for important covariates that may explain effects attributed to antidepressants. Furthermore, most studies fail to account for interactions between antidepressants and patient characteristics, which may reveal more severe adverse effects. Additionally, there is a paucity of literature on long-term effects. Finally, a lack of randomised clinical trials precludes inferences of causality. Given these constraints it is recommended that antidepressants are used as a last resort, and patients are closely monitored to identify unexpected side effects, or recovery induced by covariates rather than antidepressants. Chapter One Introduction, Rationale, AIMS Introduction According to Beckford-ball (2000) postnatal depression (PND) fails to attract public attention because it is associated with a positive event – childbirth – notwithstanding the evidence that a sizeable majority of women experience this phenomenon after delivering their baby (RCP , 2004). Nevertheless postnatal depression, if left untreated, can have adverse effects for mother-child relationship and infant development (Green, 1995). This brief reviews evidence concerning the safety and effectiveness of antidepressants for treating postnatal depression. It is argued that while antidepressants may alleviate depressive symptoms, with benign side effects, various methodological and analytic constraints in the literature negate conclusive inferences on the subject. Antidepressants According to the RCP antidepressants are drugs developed in the 1950s for treating symptoms of depression (RCP, 2006).They work by stimulating neurotransmitters in the brain. Three main types of antidepressants are specified: 1. Tricyclic’s (TCAs): amitriptyline, imipramine, nortriptyline. 2. Selective Serotonin Reuptake Inhibitors (SSRIs): sertraline, paroxetine, fluoxetine, citalopram, venlafaxine, moclobemide. 3. Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs): venlafaxine, reboxetine. 4. Monoamine Oxidase Inhibitors (MAOIs): tranylcypromine, moclobemide, phenelzine. The RCP posits that following three months of treatment 50% to 65%of people given an antidepressant show improvements in mood, compared with 25% to 30% of people administered a placebo. Thus, even after accounting for placebo effects, antidepressants still facilitate further recovery from depressive symptoms. TCAs are generally older than SSRIs and are considered to produce more side effects, especially if there is an overdose. However, all four classes of antidepressants are considered to have by-products, such as high blood pressure, anxiety, indigestion, dry mouth, heart tremor, and sleepiness. Most of the adverse effects are considered mild and expected to dissipate after few weeks. The RCP cites evidence of withdrawal symptoms in infants shortly after birth, especially with paroxetine (RCP, 2006). Babies can also receive a minute concentration of antidepressants via breastfeeding (Kohen,2005), albeit the risk of pathology is considered small due to the rapid development of kidneys and livers in infants. Overall, use of antidepressants during breastfeeding is not discouraged. Some pregnant women suffer a recurrence of depressive symptoms, and therefore may need to take antidepressants continually. The National Institute for Clinical Excellence (NICE, 2004) has published guidelines for the treatment of depression. However, there is no special emphasis on pregnancy-related depression. Antenatal and postnatal guidelines are due to be published by 2007 (Green, 2005). Postnatal Depression According to the RCP (2004) postnatal depression (PND) â€Å"is what happens when you become depressed after having a baby† (p.1). It is quite common, affecting circa 10% of newly delivered mothers, and can last for several months or longer if untreated. Symptoms include feeling depressed (unhappy, low, wretched, with symptoms becoming worse at particular times of the day), irritable(heightened sensitivity, especially to benign comments by others),tiredness, sleeplessness (late retirements, early rises), and lack of appetite and interest in sexual intercourse. Many women may feel they are unable to cope with the new situation, or even experience anxiety and detachment towards the infant. Various causes of PND have been identified including a previous history of depression, not having a supportive partner, having a sick infant or premature delivery, losing one’s own mother as a child, and stressful life events (e.g. bereavement, divorce, financial problems) within a short time scale. PND has also been associated with hormonal changes. PND appears to progress through several stages (Beckford-Ball, 2000; Green, 2005): 1. Postpartum ‘blues’; 2. Postnatal depression; 3. Puerperal psychosis. Postpartum ‘blues’ â€Å"is usually a transient phase occurring 3-5 days after the birth of the child, with few or no psychiatric symptoms. This stage is characterised by mood swings, tearfulness, fatigue, lack of concentration, confusion, anxiety and hostility† (p.126). This condition is easily treated using hormone replacement therapy. Postnatal depression is less frequent, and emerges as a deep and protracted ‘sadness’ which â€Å"is much more intense and persistent than postpartum blues and its symptoms rarely subside without help† (p.126).Many mothers may feel insecure, incompetent, irritable, guilty (about feeling sad following a happy event), weight changes, insomnia/hypersomnia, psychomotor retardation/agitation, tiredness, and loss of interest in activities. This condition often results in hospitalisation and treatment with antidepressants and cognitive-behavioural counselling. Puerperal psychosis is a severe mood disorder typified by delusions and hallucinations. This condition is considered a psychiatric emergency, necessitating admission to a psychiatric institution and treatment with antidepressants and other drugs. Rationale Despite clear guidelines regarding the use of antidepressants during pregnancy it is necessary to appraise existing literature on the topic, for several reasons: 1. Limited scope of existing reviews. 2. Identification of gaps and inconsistencies in the literature 3. Verification of current claims and guidelines, for example by the RCP, regarding the management of postnatal depression. Limited scope Previous literature reviews are considered in this brief (see Chapter 3). Most reviews are limited in scope mainly because they focus on studies using a particular research methodology(e.g. Booth et al, 2005), mother-child transmission through breastfeeding (e.g. Cohen, 2005), and effects on depressive symptoms(e.g. Hendricks, 2003; Bennett et al, 2004). Thus, there is a need for an all-inclusive review that offers a broader insight into current literature. Identification of gaps and inconsistencies Previous reviews on the topic have highlighted problems that need to be addressed in future research. However each review is different and new research findings continually emerge that may have implications for previous reviews. For example, past reviews have found little evidence of malformations resulting from SSRI use (e.g. Booth et al, 2005). However, new concerns are starting to emerge regarding various analytic and methodological constraints that negate conclusive inferences about the safety of SSRIs. Verification of current claims The RCP publishes an information guide for the use of antidepressants. Various claims are made regarding safety and efficacy of use during/after pregnancy, consistent with NICE(2004) standards. While most assertions are based on research evidence there is a need for on-going reviews that highlight recent findings and consider their implications for existing guidelines. Some of the key pronouncements and guidelines are as follows: 1. People who take antidepressants show a significant improvement over persons administered a placebo. 2. TCAs and SSRIs are equally effective but the latter (newer drug) is safer because it seems to have fewer side effects. 3. MAOIs can induce high blood pressure given certain (dietary) conditions 4. Babies whose mothers take antidepressants (especially paroxetine) may experience adverse effects. 5. It is best to carry on taking antidepressants while breastfeeding, since only minute amounts will be transferred to the baby. Livers and kidneys develop rapidly in babies only a few weeks old, helping to breakdown and filter antidepressants in the bloodstream. Aim The aim of the current review was to appraise evidence on the safety and effectiveness of antidepressants in the management of PND. Chapter Two Literature Review The evidence/data to be reviewed here is based on a comprehensive search of multiple databases including HIGHWIRE Press, ACADEMIC SEARCH PREMIER (access through EBSCO databases), Psych INFO, INTERNURSE, and the BRITISH MEDICAL JOURNAL database. The Internet was also searched with emphasis on peer-reviewed published journal articles. Key words included: ‘antidepressants’, ‘depression’, and ‘postnatal depression’. There were no problems of access: all the databases reviewed are available to the general public through university library resources and/or Athens protected resources. These particular databases were chosen because of their emphasis on psychological, biomedical, and practice-based literature, and easier access to full-text files. For example, Psych INFO contains more than1,500,000 references to journal articles, books, technical reports, and dissertations, published in numerous countries. As a form of psychopathology, PND is comprehensively addressed. INTERNURSE provides access specifically to the nursing literature and incorporates may key journals (e.g. British Journal of Nursing, Nurse Prescribing, Practice Nursing, and the International Journal of Palliative Nursing). HIGHWIRE Press is one of the two largest archives of free full-text science databases available, providing access to thousands of psych biomedical journal articles and books. ACADEMIC SEARCH PREMIER incorporates over4000 scholarly journals and 3100 peer review articles. These databases were preferred to others such as SCIENCE DIRECT, have a more general emphasis on scientific (rather than clinical, medical) literature, or not provide sufficient access to full-text articles. Only studies that satisfied the following criteria were eligible to be reviewed: 1. Empirical studies using either qualitative or quantitative methods. Thus, this included case studies, questionnaire surveys, retrospective/prospective designs, and randomised controlled trials(RCT). 2. Review articles and meta-analysis, including Cochrane reviews. 3. Focus on the effects of antidepressants on mother and/or child, and with or without breast-feeding. 4. Focus on postnatal depression, at any stage (i.e. postpartum ‘blues’, depression, and puerperal psychosis [Beckford-Ball, 2000]). 5. Focus on mothers perceptions of antidepressants as treatment for postnatal depression. The review also considered bits of literature published by the Department of Health (DOH), National Institute of Clinical Excellence(NICE), and the Royal College of Psychiatrists (RCP). The emphasis was on the role of SSRIs and TCAs albeit some literature on MAOIs and SNRIs was also considered. Individual studies are reviewed first, followed by review articles. Value of conducting a literature review The safety and effectiveness of antidepressants can easily be established by conducting an original empirical study. However, individual studies are severely constrained in scope and will ultimately provide a ‘snap-shot ‘or ‘localised’ insight on the subject. Moreover, scientific knowledge advances from the accumulation of evidence rather than the results of isolated studies, except in cases where there is a virtually no research on a topic, so that the findings of individual studies assume greater importance. Depression as a topic has been heavily researched. Numerous studies have been published on antidepressants and PND. The multiplicity of published literature reviews on antidepressants/PND attests to the abundance of empirical evidence on the topic. Thus, attempting to establish the safety and efficacy of antidepressants on the basis of a single study would still require an understanding of what has been done before and current knowledge on the topic. Otherwise the researcher is in danger of merely reinventing the wheel. Thus, proper scientific protocol dictates that the researcher first begins by reviewing the literature, in order to get a bird’s eye view of the available evidence, identify gaps in the literature, and highlight avenues for further research (Cool can, 1994). Effects of anti-depressants Appleby et al (1997) conducted a randomised control trial to assess the effects of fluoxetine and cognitive-behavioural counselling on postnatal depression. Another aim was to compare fluoxetine and placebo groups, and also drug combinations and counselling. Hitherto there had been a paucity of randomised clinical trials in this area. Appleby et al (1997) question the clinical benefits of using antidepressants, given that prognosis for PND is often good, despite concerns about over-sedation, and other considerations. The study aimed to establish the optimal treatment frond. The antidepressant of interest was the SSRI, fluoxetine. Participants were women identified at an urban health district(Manchester) as being depressed 6-8 weeks post childbirth. They completed the EPDS , and those with sufficiently high scores were interviewed using a revised clinical schedule, to identify cases of significant psychiatric depression. Women with a prior history of depression, substance abuse, severe illness that required hospitalisation, or breastfeeding, were excluded. Participants were randomly assigned to one of four experimental conditions: fluoxetine, placebo, one counselling session, and six counselling sessions. Mood assessments took place at 1, 4, and 12 weeks post-intervention, using the revised interview schedule, EPDS, and Hamilton depression scale. Data was analysed using analysis of variance for repeated measures (to account for the multiple outcome variables).Overall, 188 verified cases of PND were identified, from a sample of2978 women eligible to participate. Of these, 87 took part in the clinical trial. Results revealed significant improvements in all four treatment groups. Fluoxetine produced better improvement compared with the placebo: the percentage (geometric) differences in means scores based on the revised clinical interview schedule was 37.1% (at 4 weeks)and 40.7% (12 weeks). The effect of fluoxetine was not moderated by(i.e. did not interact with) counselling. Improvements in mood occurred within one week of participating in the clinical trial. The authors concluded â€Å"this study shows the effectiveness of both fluoxetine and cognitive-behavioural counselling in the treatment of women found by community based screening to be depressed 6-8 weeks after childbirth† (p.932). The use of a classic experimental design(RCT) permits causal inferences about the impact of an antidepressant. However, the analysis failed to control for potential confounding variables. While Appleby et al (1997) took steps to eliminate extraneous variance, through strict eligibility criteria, it would have been useful to incorporate detailed background information in the analysis (e.g. availability of social support, marital relationship, stressful life events, side-effect profile, history of drug compliance, patient preference [Green, 2005]) to demonstrate the statistical significance of these variables, and the unique contribution of SSRI treatment after controlling for covariates. Thus, analysis of covariance would have been a more appropriate test. Nolan et al (1997) assessed the effect of TCA and SSRI drugs on feta neurodevelopment. The study compared children of mothers who had been prescribed a tricyclic antidepressant during pregnancy, mothers who had taken fluoxetine during pregnancy, and mothers who had not taken antidepressants. Outcomes measures comprised global IQ and language development, assessed from 16 to 18 months postnatal, using age-specific Bailey Scales of Infant Development, McCarthy Scales of Children’s Abilities (measures IQ), and the Rendell Developmental Language Scales. Results revealed no significant group differences in any of the outcome variables, suggesting that in utero ingestion of either TCAs or fluoxetine does not impair cognitive, linguistic, or behavioural development in infants. Null man et al (2002) conducted follow-up prospective controlled study assessing the effects of TCA and fluoxetine use throughout pregnancy on child development. Three groups of mother-child pairs were recruited. The first two groups were drawn from the Mothers Program, a scheme that provides support to women suffering from major depression. All women recruited from this programme had received counselling under the scheme, with either TCA Rossi (fluoxetine) treatment, which had been maintained throughout the duration of the pregnancy. A comparison group was also recruited that comprised women with no history of psychopathology, depression (based on the Centre for Epidemiological Studies Depression Scale [CES-D]), exposure to chemical or radiation pollution, or severe health problems likely to affect fatal development. This group was randomly selected from among visitors to the author’s clinic. Women who had discontinued the use of antidepressants after conception or during the pregnancy were not eligible to participate. Women were also excluded from the comparison group based on the same criteria applied to the Mothers groups. Outcome data was collected using the CES-D, antenatal and postnatal assessments, neurobehavioral tests (Bailey Scales of Infant Development, McCarthy Scales of Children’s Abilities, age-appropriate Achenbach Child Behaviour Checklist), and follow-up testing of them other (Wechsler Adult Intelligence Scale, and other measures). A one-way analysis of variance was used to compare outcome measures across the three groups. Correlational and regression tests were used to assess the contribution of confounding variables. Results revealed no group differences in child’s global IQ, language development, or behaviour (see Figure 1). The authors concluded, â€Å"Exposure to tricyclic antidepressants or fluoxetine throughout the gestation period does not appear to adversely affect cognition, language development, or the temperament of preschool and early-school children. Although regression was used to account for the contribution of confounding factors, such as verbal comprehension and expressive language, the variance explained by these variables was not in fact partial led out before testing for group differences. This would have required a multivariate analysis of covariance in which adjustments for covariates are built into the analysis. More importantly, the observed similarity in outcomes across the three groups may reflect simple or complex interactions with other variables. This issue is discussed in greater detail in Chapter 3. Figure 1 Cognitive outcomes (mental and psychomotor development, and cognitive abilities) across antidepressant and control groups(Nolan et al, 2002). Differences are not significant. Wisner et al (2001) performed a double-blind randomised control trial to assess the effect of nortriptyline on the rate of reoccurrence of postpartum depression in non-depressed women who had previously had at least one depressive episode. Women were randomly exposed tonortriptyline or a placebo immediately after childbirth. Outcome data was collected over a 5-month period using the Hamilton Rating Scale for Depression, and Research Diagnostic Criteria for depression. No group differences emerged, suggesting that nortriptyline was no more effective than a placebo in treating PND. This study was followed up with another RCT (Wisner et al, 2004), this time evaluating the effect of sertraline on the rate of and time to reoccurrence of postpartum depression. They highlighted a paucity of clinical trials on the impact of antidepressants in women who have previously had a depressive episode, and hence may be prone to experience a reoccurrence. Participants were pregnant women with gestation periods of 9 months or less, and at least one episode of postpartum depression that fits that the DSM-IV definition of major depression. Women with other forms of psychopathology (e.g. psychosis, or bipolar disorder) were excluded. Participants were randomly assigned to a treatment (sertraline) or placebo group. The drug was administered immediately after birth, beginning with a 50mg/day dose, which was later dropped to 25mg/day to minimise side effects (e.g. headache). Data analysis using Fisher’s exact test showed a significant group difference in rate of reoccurrences, during a 17-week preventive treatment period. Reoccurrences occurred in 4/8 women assigned to the placebo group, and1/14 women in the treatment condition, translating into a 0.43difference in reoccurrence rates. All women had adhered to the treatment regime, thus minimising the confounded effect of on-compliance. There was also a significant group difference in time to reoccurrence, with first reoccurrence beginning much earlier for the placebo group (at 5 weeks, followed by more reoccurrences) compared with the treatment group (at 17 weeks, followed by more reoccurrences). However, the treatment group reported more side effects (e.g. Dizziness, drowsiness). This RCT clearly demonstrates the effectiveness of an SSRI in preventing the reoccurrence of postpartum depression, albeit the conclusiveness of these findings is constrained by the failure to control for key background variables, such as previous and recent history of psychopathology, and drug effect expectations. For example, lingering symptoms of a distant depressive episode may help precipitate a quicker reoccurrence. Figure 2 Rate of recurrence of postpartum depression in placebo and SSRI women (Wisner et al, 2004) Oberlander et al (2005) tested the effect of SSRI exposure on bio behavioural responses to acute procedural pain in new-born babies at2 months of age. Previous research has suggested altered behavioural and physiological reactions to a routine painful event in infants, after prenatal exposure to SSRI antidepressants. There is paucity of literature on the long-term effects of SSRIs on neuro behavioural variables, such as cognitive, language and motor development. Given that SSRIs work by inhibiting the reuptake of serotonin(5-hydroxytrypamine [5HT], a neurotransmitter that regulates cardiovascular function and pain signals in the developing brain), and given that SSRIs easily pass through the placenta, it is possible that regions of the brain associated with pain reactivity may be affected. Participants were recruited from a cohort of mothers and their infants during pregnancy, as part of a longitudinal study of prenatal medication use. Only Mothers/infants with no psychotropic or antidepressant use during pregnancy, whose pregnancy was 9 to 10 weeks, and no history of maternal mental illness, were eligible to be assigned to the control group. Three groups of infants were compared: (a) infants exposed to prenatal SSRI (fluoxetine); (b) infants exposed postnatal via breastfeeding(paroxetine, fluoxetine, sertraline); and (c) control infants. Behavioural (facial activity), physiological (variations in heart rate[HR], often used as a measure of pain reactivity in infants), and pharmacological (analysis of blood and breast milk samples) data was collected. Results showed impaired facial reactions in infants exposed to prenatal SSRI. Altered pain reactivity was observed in both prenatal and postnatal exposed infants, suggesting enduring neuro behavioural SSRI effects that extend beyond the new-born phase. Oberlander et all’s(2005) study was constrained by low power and generalizability (limited sample size), and lack of a non-medicated control group with depressive symptomatology. They were uncertain about the clinical implications of these findings, suggesting that use of SSRIs for treating maternal depression was appropriate pending further research on the sustained effects of SSRIs. Marcus et al (2005) screened prenatal depression in pregnant women attending an obstetrics clinic. The study aimed to assess the rates faint-depressant use and its association with depression, measured byte Centre for Epidemiological Studies Depression Scale (CES-D).Overall, 390 women who had used antidepressants within two years of conception were screened. Average age was 28.6 years, and most women were married and Caucasian (73%). Screening took place at around 24gestation weeks. Data was collected regarding the use of antidepressants during the past two years, and discontinued use following pregnancy, in addition to the CES-D data. The standard CES-Duct-off of 16 was used to establish the presence of depressive symptomatology. A t-Test was used to compare two groups: women who reported they stopped using anti-depressants and hence were not currently on medication (n=248); and women who continued to use antidepressants during pregnancy (n=68). The dependent/outcome variable was total CES-Scores. Chi-square was also used to assess use/non-use of antidepressant medication and CES-D groupings (i.e. Figure 3 CES-D data for women who did and those who did not use antidepressants during pregnancy (Marcus et al, 2005). Observed differences are not significant. The authors attributed the null results to poor treatment adherence, and inadequate prescribing/monitoring. Furthermore, they suggested that group differences might have been more pronounced if the study focused on unmediated women (i.e. those who had not used antidepressants at all, rather discontinued use). This study was unique because it assessed antidepressant use around the time of conception. However, the findings are compromised by several analytic constraints. Firstly, these of a t-Test is questionable. This test makes no provision for controlling for covariates (i.e. important background variables, such as patient preference, compliance history, side-effect profile, social support, quality of marital relationship, prior history depression)that may confound significant group differences, although this concerns less important given the null results. A more serious problem is the possibility that certain assumptions which underlie use of the t-Test were violated, notably homogeneity of variance. The huge disparity in group sizes (268 versus 68) hugely increases the possibility of significant differences in group variances, which in turn would obscure reliable differences in CES-Scores. The authors do not report Levine test results, which would have addressed the homogeneity issue. Perhaps a non-parametric test (e.g. Mann-Whitney) may have been more appropriate. Furthermore, it is not clear why the authors conducted a chi-square test! Collapsing the CES-Scores into a dichotomy reduces the quality of the data because it obscures subtle differences between scores. Overall, the chi-square analyses amounted to a less precise duplication of the t-Test results! Finally, this study was entirely based on women’s self-reports of medication use, with no familial, clinical, or other verification. Its therefore unclear to what extent the null results are attributable to self-report bias. Several review articles on antidepressants and postnatal depression have been published. These range from limited commentaries (e.g. Goldstein Sun dell, 1999; Yoshida et al, 1999; Misery Kostas’s, 2002; Hendricks, 2003; Bennett et al, 2004; Cohen, 2005;Marcus et al, 2005) to comprehensive and systematic appraisals. Goldstein and Sun dell (1999) reviewed literature on the safety of SSRIs during pregnancy. Their work was based on the premise that although antidepressants may be necessary during pregnancy it is essential identify and weigh the risks against the benefits in order to make an informed choice as to whether or not to use the drugs. Due to the paucity of randomised controlled trials on the topic, the review focused on evidence obtained from cohort/case-controlled studies, patient surveys, retrospective studies, and anecdotal reports. Electronic databases searched included Medline, EMBASE, Daren’t Drug File, and Psych INFO. Four cohort-controlled and 5 prospective studies were found which evaluated the impact of SSRI exposure. One study compared fluoxetine, TCA, and non-teratogen (e.g. antibiotics) exposed groups of non-depressed females. SSRI and TCA exposure produced no significant malformations, or differences in birth weight and infant prematurity. However, there was a greater tendency for fluoxetine- and tricyclic-exposed women to miscarry compared with controls. However, this effect was not significant and hence may simply have occurred by chance. Goldstein and Sun dell (1999) report another study which compared early exposed (prior to 25 weeks), late exposed (continuing after 24 weeks),and a non-teratogen control group. Again findings revealed no adverse effects in the treatment groups, albeit infants exposed to fluoxetine early showed a higher prevalence of minor anomalies that have little or no clinical importance. Furthermore late exposure to fluoxetine seemed to increase the rates of admission to special care nurseries and impaired fatal development. However, these findings were inconclusive due to prior group differences on previous psychotropic drug use, and failure to control for depression levels. Still other research suggests no effect of SSRIs (sertraline) on the prevalence of stillbirth, prematurity, mean birth weight and gestational age. Evidence suggests no statistically significant differences between SSRI exposed and control groups on IQ, language development, height, and head circumference. Of the prospective studies reviewed three assessed paroxetine, and fluoxetine, and two tested sertraline. All studies reported no significant increase in the rate of malformations and spontaneous abortion, although there was some evidence of lower birth weight given protracted use of antidepressants. Goldstein and Sun dell (1999) found one study, which showed that fluoxetine exposure during the first trimester did not increase the risk of malformations Antidepressants for Postnatal Depression Antidepressants for Postnatal Depression Antidepressants are they a safe and effective choice for the treatment of postnatal depression? This review assessed the evidence concerning the effectiveness and safety of antidepressants in the management of postnatal depression. This would facilitate evidence-based clinical decisions in the treatment of patients. Data was sourced from several electronic Athens-based and free databases covering the psycho-biomedical and nursing literature. Studies found included randomised clinical trials, case- and cohort-controlled studies, questionnaire surveys, and qualitative/exploratory research. Previous reviews were also appraised. Outcomes from over 1200 mothers, mother-infant pairings, or infants, exposed to antidepressants were considered. Antidepressants appear to significantly alleviate depressive symptoms. Furthermore, the reported side effects are generally benign and clinically insignificant. However, methodological and analytic flaws negate conclusive inferences. Many studies fail to account for important covariates that may explain effects attributed to antidepressants. Furthermore, most studies fail to account for interactions between antidepressants and patient characteristics, which may reveal more severe adverse effects. Additionally, there is a paucity of literature on long-term effects. Finally, a lack of randomised clinical trials precludes inferences of causality. Given these constraints it is recommended that antidepressants are used as a last resort, and patients are closely monitored to identify unexpected side effects, or recovery induced by covariates rather than antidepressants. Chapter One Introduction, Rationale, AIMS Introduction According to Beckford-ball (2000) postnatal depression (PND) fails to attract public attention because it is associated with a positive event – childbirth – notwithstanding the evidence that a sizeable majority of women experience this phenomenon after delivering their baby (RCP , 2004). Nevertheless postnatal depression, if left untreated, can have adverse effects for mother-child relationship and infant development (Green, 1995). This brief reviews evidence concerning the safety and effectiveness of antidepressants for treating postnatal depression. It is argued that while antidepressants may alleviate depressive symptoms, with benign side effects, various methodological and analytic constraints in the literature negate conclusive inferences on the subject. Antidepressants According to the RCP antidepressants are drugs developed in the 1950s for treating symptoms of depression (RCP, 2006).They work by stimulating neurotransmitters in the brain. Three main types of antidepressants are specified: 1. Tricyclic’s (TCAs): amitriptyline, imipramine, nortriptyline. 2. Selective Serotonin Reuptake Inhibitors (SSRIs): sertraline, paroxetine, fluoxetine, citalopram, venlafaxine, moclobemide. 3. Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs): venlafaxine, reboxetine. 4. Monoamine Oxidase Inhibitors (MAOIs): tranylcypromine, moclobemide, phenelzine. The RCP posits that following three months of treatment 50% to 65%of people given an antidepressant show improvements in mood, compared with 25% to 30% of people administered a placebo. Thus, even after accounting for placebo effects, antidepressants still facilitate further recovery from depressive symptoms. TCAs are generally older than SSRIs and are considered to produce more side effects, especially if there is an overdose. However, all four classes of antidepressants are considered to have by-products, such as high blood pressure, anxiety, indigestion, dry mouth, heart tremor, and sleepiness. Most of the adverse effects are considered mild and expected to dissipate after few weeks. The RCP cites evidence of withdrawal symptoms in infants shortly after birth, especially with paroxetine (RCP, 2006). Babies can also receive a minute concentration of antidepressants via breastfeeding (Kohen,2005), albeit the risk of pathology is considered small due to the rapid development of kidneys and livers in infants. Overall, use of antidepressants during breastfeeding is not discouraged. Some pregnant women suffer a recurrence of depressive symptoms, and therefore may need to take antidepressants continually. The National Institute for Clinical Excellence (NICE, 2004) has published guidelines for the treatment of depression. However, there is no special emphasis on pregnancy-related depression. Antenatal and postnatal guidelines are due to be published by 2007 (Green, 2005). Postnatal Depression According to the RCP (2004) postnatal depression (PND) â€Å"is what happens when you become depressed after having a baby† (p.1). It is quite common, affecting circa 10% of newly delivered mothers, and can last for several months or longer if untreated. Symptoms include feeling depressed (unhappy, low, wretched, with symptoms becoming worse at particular times of the day), irritable(heightened sensitivity, especially to benign comments by others),tiredness, sleeplessness (late retirements, early rises), and lack of appetite and interest in sexual intercourse. Many women may feel they are unable to cope with the new situation, or even experience anxiety and detachment towards the infant. Various causes of PND have been identified including a previous history of depression, not having a supportive partner, having a sick infant or premature delivery, losing one’s own mother as a child, and stressful life events (e.g. bereavement, divorce, financial problems) within a short time scale. PND has also been associated with hormonal changes. PND appears to progress through several stages (Beckford-Ball, 2000; Green, 2005): 1. Postpartum ‘blues’; 2. Postnatal depression; 3. Puerperal psychosis. Postpartum ‘blues’ â€Å"is usually a transient phase occurring 3-5 days after the birth of the child, with few or no psychiatric symptoms. This stage is characterised by mood swings, tearfulness, fatigue, lack of concentration, confusion, anxiety and hostility† (p.126). This condition is easily treated using hormone replacement therapy. Postnatal depression is less frequent, and emerges as a deep and protracted ‘sadness’ which â€Å"is much more intense and persistent than postpartum blues and its symptoms rarely subside without help† (p.126).Many mothers may feel insecure, incompetent, irritable, guilty (about feeling sad following a happy event), weight changes, insomnia/hypersomnia, psychomotor retardation/agitation, tiredness, and loss of interest in activities. This condition often results in hospitalisation and treatment with antidepressants and cognitive-behavioural counselling. Puerperal psychosis is a severe mood disorder typified by delusions and hallucinations. This condition is considered a psychiatric emergency, necessitating admission to a psychiatric institution and treatment with antidepressants and other drugs. Rationale Despite clear guidelines regarding the use of antidepressants during pregnancy it is necessary to appraise existing literature on the topic, for several reasons: 1. Limited scope of existing reviews. 2. Identification of gaps and inconsistencies in the literature 3. Verification of current claims and guidelines, for example by the RCP, regarding the management of postnatal depression. Limited scope Previous literature reviews are considered in this brief (see Chapter 3). Most reviews are limited in scope mainly because they focus on studies using a particular research methodology(e.g. Booth et al, 2005), mother-child transmission through breastfeeding (e.g. Cohen, 2005), and effects on depressive symptoms(e.g. Hendricks, 2003; Bennett et al, 2004). Thus, there is a need for an all-inclusive review that offers a broader insight into current literature. Identification of gaps and inconsistencies Previous reviews on the topic have highlighted problems that need to be addressed in future research. However each review is different and new research findings continually emerge that may have implications for previous reviews. For example, past reviews have found little evidence of malformations resulting from SSRI use (e.g. Booth et al, 2005). However, new concerns are starting to emerge regarding various analytic and methodological constraints that negate conclusive inferences about the safety of SSRIs. Verification of current claims The RCP publishes an information guide for the use of antidepressants. Various claims are made regarding safety and efficacy of use during/after pregnancy, consistent with NICE(2004) standards. While most assertions are based on research evidence there is a need for on-going reviews that highlight recent findings and consider their implications for existing guidelines. Some of the key pronouncements and guidelines are as follows: 1. People who take antidepressants show a significant improvement over persons administered a placebo. 2. TCAs and SSRIs are equally effective but the latter (newer drug) is safer because it seems to have fewer side effects. 3. MAOIs can induce high blood pressure given certain (dietary) conditions 4. Babies whose mothers take antidepressants (especially paroxetine) may experience adverse effects. 5. It is best to carry on taking antidepressants while breastfeeding, since only minute amounts will be transferred to the baby. Livers and kidneys develop rapidly in babies only a few weeks old, helping to breakdown and filter antidepressants in the bloodstream. Aim The aim of the current review was to appraise evidence on the safety and effectiveness of antidepressants in the management of PND. Chapter Two Literature Review The evidence/data to be reviewed here is based on a comprehensive search of multiple databases including HIGHWIRE Press, ACADEMIC SEARCH PREMIER (access through EBSCO databases), Psych INFO, INTERNURSE, and the BRITISH MEDICAL JOURNAL database. The Internet was also searched with emphasis on peer-reviewed published journal articles. Key words included: ‘antidepressants’, ‘depression’, and ‘postnatal depression’. There were no problems of access: all the databases reviewed are available to the general public through university library resources and/or Athens protected resources. These particular databases were chosen because of their emphasis on psychological, biomedical, and practice-based literature, and easier access to full-text files. For example, Psych INFO contains more than1,500,000 references to journal articles, books, technical reports, and dissertations, published in numerous countries. As a form of psychopathology, PND is comprehensively addressed. INTERNURSE provides access specifically to the nursing literature and incorporates may key journals (e.g. British Journal of Nursing, Nurse Prescribing, Practice Nursing, and the International Journal of Palliative Nursing). HIGHWIRE Press is one of the two largest archives of free full-text science databases available, providing access to thousands of psych biomedical journal articles and books. ACADEMIC SEARCH PREMIER incorporates over4000 scholarly journals and 3100 peer review articles. These databases were preferred to others such as SCIENCE DIRECT, have a more general emphasis on scientific (rather than clinical, medical) literature, or not provide sufficient access to full-text articles. Only studies that satisfied the following criteria were eligible to be reviewed: 1. Empirical studies using either qualitative or quantitative methods. Thus, this included case studies, questionnaire surveys, retrospective/prospective designs, and randomised controlled trials(RCT). 2. Review articles and meta-analysis, including Cochrane reviews. 3. Focus on the effects of antidepressants on mother and/or child, and with or without breast-feeding. 4. Focus on postnatal depression, at any stage (i.e. postpartum ‘blues’, depression, and puerperal psychosis [Beckford-Ball, 2000]). 5. Focus on mothers perceptions of antidepressants as treatment for postnatal depression. The review also considered bits of literature published by the Department of Health (DOH), National Institute of Clinical Excellence(NICE), and the Royal College of Psychiatrists (RCP). The emphasis was on the role of SSRIs and TCAs albeit some literature on MAOIs and SNRIs was also considered. Individual studies are reviewed first, followed by review articles. Value of conducting a literature review The safety and effectiveness of antidepressants can easily be established by conducting an original empirical study. However, individual studies are severely constrained in scope and will ultimately provide a ‘snap-shot ‘or ‘localised’ insight on the subject. Moreover, scientific knowledge advances from the accumulation of evidence rather than the results of isolated studies, except in cases where there is a virtually no research on a topic, so that the findings of individual studies assume greater importance. Depression as a topic has been heavily researched. Numerous studies have been published on antidepressants and PND. The multiplicity of published literature reviews on antidepressants/PND attests to the abundance of empirical evidence on the topic. Thus, attempting to establish the safety and efficacy of antidepressants on the basis of a single study would still require an understanding of what has been done before and current knowledge on the topic. Otherwise the researcher is in danger of merely reinventing the wheel. Thus, proper scientific protocol dictates that the researcher first begins by reviewing the literature, in order to get a bird’s eye view of the available evidence, identify gaps in the literature, and highlight avenues for further research (Cool can, 1994). Effects of anti-depressants Appleby et al (1997) conducted a randomised control trial to assess the effects of fluoxetine and cognitive-behavioural counselling on postnatal depression. Another aim was to compare fluoxetine and placebo groups, and also drug combinations and counselling. Hitherto there had been a paucity of randomised clinical trials in this area. Appleby et al (1997) question the clinical benefits of using antidepressants, given that prognosis for PND is often good, despite concerns about over-sedation, and other considerations. The study aimed to establish the optimal treatment frond. The antidepressant of interest was the SSRI, fluoxetine. Participants were women identified at an urban health district(Manchester) as being depressed 6-8 weeks post childbirth. They completed the EPDS , and those with sufficiently high scores were interviewed using a revised clinical schedule, to identify cases of significant psychiatric depression. Women with a prior history of depression, substance abuse, severe illness that required hospitalisation, or breastfeeding, were excluded. Participants were randomly assigned to one of four experimental conditions: fluoxetine, placebo, one counselling session, and six counselling sessions. Mood assessments took place at 1, 4, and 12 weeks post-intervention, using the revised interview schedule, EPDS, and Hamilton depression scale. Data was analysed using analysis of variance for repeated measures (to account for the multiple outcome variables).Overall, 188 verified cases of PND were identified, from a sample of2978 women eligible to participate. Of these, 87 took part in the clinical trial. Results revealed significant improvements in all four treatment groups. Fluoxetine produced better improvement compared with the placebo: the percentage (geometric) differences in means scores based on the revised clinical interview schedule was 37.1% (at 4 weeks)and 40.7% (12 weeks). The effect of fluoxetine was not moderated by(i.e. did not interact with) counselling. Improvements in mood occurred within one week of participating in the clinical trial. The authors concluded â€Å"this study shows the effectiveness of both fluoxetine and cognitive-behavioural counselling in the treatment of women found by community based screening to be depressed 6-8 weeks after childbirth† (p.932). The use of a classic experimental design(RCT) permits causal inferences about the impact of an antidepressant. However, the analysis failed to control for potential confounding variables. While Appleby et al (1997) took steps to eliminate extraneous variance, through strict eligibility criteria, it would have been useful to incorporate detailed background information in the analysis (e.g. availability of social support, marital relationship, stressful life events, side-effect profile, history of drug compliance, patient preference [Green, 2005]) to demonstrate the statistical significance of these variables, and the unique contribution of SSRI treatment after controlling for covariates. Thus, analysis of covariance would have been a more appropriate test. Nolan et al (1997) assessed the effect of TCA and SSRI drugs on feta neurodevelopment. The study compared children of mothers who had been prescribed a tricyclic antidepressant during pregnancy, mothers who had taken fluoxetine during pregnancy, and mothers who had not taken antidepressants. Outcomes measures comprised global IQ and language development, assessed from 16 to 18 months postnatal, using age-specific Bailey Scales of Infant Development, McCarthy Scales of Children’s Abilities (measures IQ), and the Rendell Developmental Language Scales. Results revealed no significant group differences in any of the outcome variables, suggesting that in utero ingestion of either TCAs or fluoxetine does not impair cognitive, linguistic, or behavioural development in infants. Null man et al (2002) conducted follow-up prospective controlled study assessing the effects of TCA and fluoxetine use throughout pregnancy on child development. Three groups of mother-child pairs were recruited. The first two groups were drawn from the Mothers Program, a scheme that provides support to women suffering from major depression. All women recruited from this programme had received counselling under the scheme, with either TCA Rossi (fluoxetine) treatment, which had been maintained throughout the duration of the pregnancy. A comparison group was also recruited that comprised women with no history of psychopathology, depression (based on the Centre for Epidemiological Studies Depression Scale [CES-D]), exposure to chemical or radiation pollution, or severe health problems likely to affect fatal development. This group was randomly selected from among visitors to the author’s clinic. Women who had discontinued the use of antidepressants after conception or during the pregnancy were not eligible to participate. Women were also excluded from the comparison group based on the same criteria applied to the Mothers groups. Outcome data was collected using the CES-D, antenatal and postnatal assessments, neurobehavioral tests (Bailey Scales of Infant Development, McCarthy Scales of Children’s Abilities, age-appropriate Achenbach Child Behaviour Checklist), and follow-up testing of them other (Wechsler Adult Intelligence Scale, and other measures). A one-way analysis of variance was used to compare outcome measures across the three groups. Correlational and regression tests were used to assess the contribution of confounding variables. Results revealed no group differences in child’s global IQ, language development, or behaviour (see Figure 1). The authors concluded, â€Å"Exposure to tricyclic antidepressants or fluoxetine throughout the gestation period does not appear to adversely affect cognition, language development, or the temperament of preschool and early-school children. Although regression was used to account for the contribution of confounding factors, such as verbal comprehension and expressive language, the variance explained by these variables was not in fact partial led out before testing for group differences. This would have required a multivariate analysis of covariance in which adjustments for covariates are built into the analysis. More importantly, the observed similarity in outcomes across the three groups may reflect simple or complex interactions with other variables. This issue is discussed in greater detail in Chapter 3. Figure 1 Cognitive outcomes (mental and psychomotor development, and cognitive abilities) across antidepressant and control groups(Nolan et al, 2002). Differences are not significant. Wisner et al (2001) performed a double-blind randomised control trial to assess the effect of nortriptyline on the rate of reoccurrence of postpartum depression in non-depressed women who had previously had at least one depressive episode. Women were randomly exposed tonortriptyline or a placebo immediately after childbirth. Outcome data was collected over a 5-month period using the Hamilton Rating Scale for Depression, and Research Diagnostic Criteria for depression. No group differences emerged, suggesting that nortriptyline was no more effective than a placebo in treating PND. This study was followed up with another RCT (Wisner et al, 2004), this time evaluating the effect of sertraline on the rate of and time to reoccurrence of postpartum depression. They highlighted a paucity of clinical trials on the impact of antidepressants in women who have previously had a depressive episode, and hence may be prone to experience a reoccurrence. Participants were pregnant women with gestation periods of 9 months or less, and at least one episode of postpartum depression that fits that the DSM-IV definition of major depression. Women with other forms of psychopathology (e.g. psychosis, or bipolar disorder) were excluded. Participants were randomly assigned to a treatment (sertraline) or placebo group. The drug was administered immediately after birth, beginning with a 50mg/day dose, which was later dropped to 25mg/day to minimise side effects (e.g. headache). Data analysis using Fisher’s exact test showed a significant group difference in rate of reoccurrences, during a 17-week preventive treatment period. Reoccurrences occurred in 4/8 women assigned to the placebo group, and1/14 women in the treatment condition, translating into a 0.43difference in reoccurrence rates. All women had adhered to the treatment regime, thus minimising the confounded effect of on-compliance. There was also a significant group difference in time to reoccurrence, with first reoccurrence beginning much earlier for the placebo group (at 5 weeks, followed by more reoccurrences) compared with the treatment group (at 17 weeks, followed by more reoccurrences). However, the treatment group reported more side effects (e.g. Dizziness, drowsiness). This RCT clearly demonstrates the effectiveness of an SSRI in preventing the reoccurrence of postpartum depression, albeit the conclusiveness of these findings is constrained by the failure to control for key background variables, such as previous and recent history of psychopathology, and drug effect expectations. For example, lingering symptoms of a distant depressive episode may help precipitate a quicker reoccurrence. Figure 2 Rate of recurrence of postpartum depression in placebo and SSRI women (Wisner et al, 2004) Oberlander et al (2005) tested the effect of SSRI exposure on bio behavioural responses to acute procedural pain in new-born babies at2 months of age. Previous research has suggested altered behavioural and physiological reactions to a routine painful event in infants, after prenatal exposure to SSRI antidepressants. There is paucity of literature on the long-term effects of SSRIs on neuro behavioural variables, such as cognitive, language and motor development. Given that SSRIs work by inhibiting the reuptake of serotonin(5-hydroxytrypamine [5HT], a neurotransmitter that regulates cardiovascular function and pain signals in the developing brain), and given that SSRIs easily pass through the placenta, it is possible that regions of the brain associated with pain reactivity may be affected. Participants were recruited from a cohort of mothers and their infants during pregnancy, as part of a longitudinal study of prenatal medication use. Only Mothers/infants with no psychotropic or antidepressant use during pregnancy, whose pregnancy was 9 to 10 weeks, and no history of maternal mental illness, were eligible to be assigned to the control group. Three groups of infants were compared: (a) infants exposed to prenatal SSRI (fluoxetine); (b) infants exposed postnatal via breastfeeding(paroxetine, fluoxetine, sertraline); and (c) control infants. Behavioural (facial activity), physiological (variations in heart rate[HR], often used as a measure of pain reactivity in infants), and pharmacological (analysis of blood and breast milk samples) data was collected. Results showed impaired facial reactions in infants exposed to prenatal SSRI. Altered pain reactivity was observed in both prenatal and postnatal exposed infants, suggesting enduring neuro behavioural SSRI effects that extend beyond the new-born phase. Oberlander et all’s(2005) study was constrained by low power and generalizability (limited sample size), and lack of a non-medicated control group with depressive symptomatology. They were uncertain about the clinical implications of these findings, suggesting that use of SSRIs for treating maternal depression was appropriate pending further research on the sustained effects of SSRIs. Marcus et al (2005) screened prenatal depression in pregnant women attending an obstetrics clinic. The study aimed to assess the rates faint-depressant use and its association with depression, measured byte Centre for Epidemiological Studies Depression Scale (CES-D).Overall, 390 women who had used antidepressants within two years of conception were screened. Average age was 28.6 years, and most women were married and Caucasian (73%). Screening took place at around 24gestation weeks. Data was collected regarding the use of antidepressants during the past two years, and discontinued use following pregnancy, in addition to the CES-D data. The standard CES-Duct-off of 16 was used to establish the presence of depressive symptomatology. A t-Test was used to compare two groups: women who reported they stopped using anti-depressants and hence were not currently on medication (n=248); and women who continued to use antidepressants during pregnancy (n=68). The dependent/outcome variable was total CES-Scores. Chi-square was also used to assess use/non-use of antidepressant medication and CES-D groupings (i.e. Figure 3 CES-D data for women who did and those who did not use antidepressants during pregnancy (Marcus et al, 2005). Observed differences are not significant. The authors attributed the null results to poor treatment adherence, and inadequate prescribing/monitoring. Furthermore, they suggested that group differences might have been more pronounced if the study focused on unmediated women (i.e. those who had not used antidepressants at all, rather discontinued use). This study was unique because it assessed antidepressant use around the time of conception. However, the findings are compromised by several analytic constraints. Firstly, these of a t-Test is questionable. This test makes no provision for controlling for covariates (i.e. important background variables, such as patient preference, compliance history, side-effect profile, social support, quality of marital relationship, prior history depression)that may confound significant group differences, although this concerns less important given the null results. A more serious problem is the possibility that certain assumptions which underlie use of the t-Test were violated, notably homogeneity of variance. The huge disparity in group sizes (268 versus 68) hugely increases the possibility of significant differences in group variances, which in turn would obscure reliable differences in CES-Scores. The authors do not report Levine test results, which would have addressed the homogeneity issue. Perhaps a non-parametric test (e.g. Mann-Whitney) may have been more appropriate. Furthermore, it is not clear why the authors conducted a chi-square test! Collapsing the CES-Scores into a dichotomy reduces the quality of the data because it obscures subtle differences between scores. Overall, the chi-square analyses amounted to a less precise duplication of the t-Test results! Finally, this study was entirely based on women’s self-reports of medication use, with no familial, clinical, or other verification. Its therefore unclear to what extent the null results are attributable to self-report bias. Several review articles on antidepressants and postnatal depression have been published. These range from limited commentaries (e.g. Goldstein Sun dell, 1999; Yoshida et al, 1999; Misery Kostas’s, 2002; Hendricks, 2003; Bennett et al, 2004; Cohen, 2005;Marcus et al, 2005) to comprehensive and systematic appraisals. Goldstein and Sun dell (1999) reviewed literature on the safety of SSRIs during pregnancy. Their work was based on the premise that although antidepressants may be necessary during pregnancy it is essential identify and weigh the risks against the benefits in order to make an informed choice as to whether or not to use the drugs. Due to the paucity of randomised controlled trials on the topic, the review focused on evidence obtained from cohort/case-controlled studies, patient surveys, retrospective studies, and anecdotal reports. Electronic databases searched included Medline, EMBASE, Daren’t Drug File, and Psych INFO. Four cohort-controlled and 5 prospective studies were found which evaluated the impact of SSRI exposure. One study compared fluoxetine, TCA, and non-teratogen (e.g. antibiotics) exposed groups of non-depressed females. SSRI and TCA exposure produced no significant malformations, or differences in birth weight and infant prematurity. However, there was a greater tendency for fluoxetine- and tricyclic-exposed women to miscarry compared with controls. However, this effect was not significant and hence may simply have occurred by chance. Goldstein and Sun dell (1999) report another study which compared early exposed (prior to 25 weeks), late exposed (continuing after 24 weeks),and a non-teratogen control group. Again findings revealed no adverse effects in the treatment groups, albeit infants exposed to fluoxetine early showed a higher prevalence of minor anomalies that have little or no clinical importance. Furthermore late exposure to fluoxetine seemed to increase the rates of admission to special care nurseries and impaired fatal development. However, these findings were inconclusive due to prior group differences on previous psychotropic drug use, and failure to control for depression levels. Still other research suggests no effect of SSRIs (sertraline) on the prevalence of stillbirth, prematurity, mean birth weight and gestational age. Evidence suggests no statistically significant differences between SSRI exposed and control groups on IQ, language development, height, and head circumference. Of the prospective studies reviewed three assessed paroxetine, and fluoxetine, and two tested sertraline. All studies reported no significant increase in the rate of malformations and spontaneous abortion, although there was some evidence of lower birth weight given protracted use of antidepressants. Goldstein and Sun dell (1999) found one study, which showed that fluoxetine exposure during the first trimester did not increase the risk of malformations