Antidepressants for Postnatal Depression
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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.
Introduction, Rationale, AIMS
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.
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).
According to the RCP (2004) postnatal depression (PND) “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’ “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 “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.
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.
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.
The aim of the current review was to appraise evidence on the safety and effectiveness of antidepressants in the management of PND.
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 “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, “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. <16 versus. ≥16scores). Chi-square revealed no reliable differences in depression scores between women taking and those not taking antidepressants during pregnancy. The t-Test also revealed no group differences in actuals-D scores. Thus, antidepressant use seemed to have no bearing on depression levels.
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. Rates of spontaneous abortion and prematurity were no greater than historical patterns. One study assessed the effects of third trimester exposure to depressants, and up till delivery, indicating that fluoxetine intake during the third trimester produces no significant adverse effects.
Goldstein and Sun dell (1999)emphasise the importance of acknowledging the limitations of case/cohort control studies, surveys, retrospective designs, and other uncontrolled correlational methods, compared with randomised clinical trials. It is important that findings from less rigorous designs are interpreted with caution. Overall, this review summarises outcomes from1000+ pregnancies exposed to fluoxetine, and 300 pregnancies exposed toothier SSRIs. All report little or no increased risk from using antidepressants.
Yoshida et al (1999) appraised existing case reports and studies on breastfeeding in relation to antidepressants, specifically TCAs and SSRIs. The review revealed that the preponderance of studies were single case studies - there was a lack of randomised controlled trials or prospective controlled studies. Comparison of findings across different studies has hampered by methodological differences or absence of essential information. Most of the literature focused on TCAs, but these studies in total only tested a limited (n=66) number of mother-infant pairs.
By contrast there was less evidence concerning the impact of SSRIs. Yoshida et al (1999) surmised that the benefits of taking TCAs probably outweigh the risks provided recommended TCAs are being taking, and at the right dosage. Furthermore, the infant must be healthy. It is suggested that an accumulation of case control studies will ultimately provide a platform for launching clinical trials designed to identify severe toxic and long-term health outcomes of antidepressant use during breastfeeding.
Simpson and Noble (2000) reviewed the literature on the effects of thesis fluoxetine on depression in women, noting the paucity of literature in this area. Studies confirmed that fluoxetine is secreted into breast milk and that breast-fed infants ingest from 3% to 10.8% of their mothers fluoxetine intake. However, traces of the drug can accumulate in infants to a significant degree. Evidence from randomised controlled trials suggests that fluoxetine has no adverse surgical, medical or cosmetic effects on the foetus.
The rate of malformations is no greater for pregnancies exposed to fluoxetine compared with on-exposed pregnancies. Simpson and Noble (2000) also considered evidence from the manufacturer, who retained accumulated records of over 3000 fluoxetine-exposed pregnancies since the drug became available on the open market. Only a minority (3.5%) of pregnancies with verified exposure during the first trimester developed major abnormalities.
Only 0.2% developed minor problems, compared with 2.3% and 14% for controls. However, at least one study (prospective, cohort) found higher incidence of minor abnormalities in first-trimester fluoxetine-exposed pregnancies, compared to control pregnancies. Crucially, this group difference remained significant even after controlling for other psychotherapeutic drugs (benzodiazepine) also consumed by mothers taking fluoxetine.
Furthermore, the probability of premature birth, admission to special care nurseries, and poor neonatal development was higher during the third trimester compared with early-exposed (first or second trimester) or control pregnancies (see Figure 4). Furthermore, late-exposed infants had significantly lower birth weight and length compared with early exposed or control infants(see Figure 5).
Figure 4 Adverse effects of fluoxetine as a function of trimester of exposure (Simpson & Noble, 2000)
Figure 5 Effects of fluoxetine on weight as a function of trimester of exposure (Simpson & Noble, 2000)
Other research found no adverse effects for fluoxetine compared with CA-exposed or control pregnancies. Studies on breastfeeding were also considered. Simpson and Noble (2000) noted that fluoxetine is not recommended for breastfeeding mothers, albeit the drug may be useful in this arena. A mixture of case reports and retrospective studies painted confusing picture.
On the one hand fluoxetine has been found to produce no significant malformations in breast-fed infants. On the other hand there have been exceptions. One 3-week old infant appeared to develop vomiting and watery stools; another experienced ‘seizure-like’ fits, while a third became irritable. Fluoxetine has also been implicated in impaired growth rate for breast-fed infants. However, one study monitored the development of several breast-fed infants for over a year and found no abnormalities upon neurological assessment.
It was noted that the long half-life of fluoxetine means that traces of the drug ingested during the third trimester may persist in breast milk and be passed on to an infant, even if the mother did not take fluoxetine during breastfeeding. Nevertheless, fluoxetine is considered to play an important role in postnatal depression. Simpson and Noble(2000) note that antidepressants can be recommended when depressive symptoms become severe and start to retard the mother’s well-being.
Moreover, use of antidepressants, including SSRIs, is often inevitable due to the significant number of unexpected pregnancies and high prevalence of depression in the general population . Overall, Simpson and Noble (2000) conclude that the existing evidence reveals no “significant association between the use of fluoxetine during the first trimester and major malformations in the foetus… Information on third trimester exposure is very limited, making it impossible to draw definitive conclusions” (p.321).
Simpson and Noble (2000) also reviewed the literature on postpartum depression. No other antidepressant other than fluoxetine appeared to have been tested using randomised controlled (double-blind) trials. Findings suggest symptom improvement in treatment compared with placebo subjects. However, methodological and analytic constraints negate any conclusive inferences.
TCAs are more commonly prescribed in this setting, although there is a paucity of conclusive evidence concerning the clinical viability of TCAs over SSRIs. Data on the impact of fluoxetine specifically is limited and Simpson and Noble (2000)declined to draw any firm conclusions. Overall, they surmised that use of fluoxetine by pregnant women requires thorough cost-benefit appraisals, albeit taking the drug during the first trimester appears to entail less risk.
Hoff brand et al (2002) report a Cochrane review (also cited by the Royal College of Psychiatrists [RCN, 2004]), on the safety and efficacy of antidepressant treatment for PND. The review was based on a search of clinical trials registered by the Cochrane Depression, Anxiety, and Neurosis Group, and the Cochrane Pregnancy and Childbirth Group, another databases.
Only randomised trials in which women reporting depressive symptoms within the first 6 months after childbirth were randomly assigned to receive an antidepressant alone, or in combination with other interventions, or receive a placebo, were eligible to be included. Only one trial (Appleby et al, 1997) was eligible to be reviewed. This study (already reviewed elsewhere in this chapter)showed that fluoxetine was more effective than a placebo and as effective as cognitive-behavioural therapy. Overall, this review highlighted the need for more trials incorporating a longer follow-up period.
Misery and Kostas’s (2002) considered the literature on the various risks and benefits to mother and child of using antidepressants to treat postnatal depression. It is recognised that many newly delivered mothers who require antidepressants may also intend to breastfeed. SSRIs and TCAs are identified as the most commonly used antidepressants, with very scant literature available regarding the use of MAOIs. The literature search was conducted using MEDLINE, and dating back 20 years.
Figure 6 shows the number of infants assessed and adverse events reported by existing studies of SSRIs. Nor fluoxetine, the active component of fluoxetine, may accumulate in the serum of breastfeeding infants due to its long half-life. Studies have reported various adverse effects including colic, crying, lower body weight, fussiness, and seizures. However, they reported no abnormal effects although most studies indicate low concentrations of the drug in breast milk and infant serum. Low concentration levels may be too weak to stimulate malformations.
The evidence for sertraline, paroxetine, fluvoxamine, and citalopram is mixed. Like fluoxetine, these SSRIs were generally detected in low concentrations, with generally no adverse effects. Fluvoxamine has been found to be an effective remedy for postnatal depression. Overall, the evidence base for SSRIs other than fluoxetine was too scant to warrant firm conclusions about their impact on postnatal depression.
Figure 6 Number of infants and adverse events reported for various SSRIs (Misery & Kostas’s, 2002)
Figure 7 Number of infants and adverse events reported for various TCAs (Misery & Kostas’s, 2002)
Research findings on TCAs are summarised in Figure 7. Like SSRIs, Tasted to be found in low concentrations in breast milk and serum. Doxepin has been shown to produce abnormalities (respiratory depression, muscle hypotonic, jaundice, vomiting, poor sucking, and drowsiness). However other TCAs – amitriptyline, clomipramine, desipramine, imipramine and nortriptyline - do not appear to produce any adverse health outcomes. The negative effects of doxepin are attributed to the long half-life of its active metabolite, so use of this TCA is generally not recommended. Literature on other depressants was also considered.
Hendricks (2003) comments on literature concerning the effectiveness of antidepressants and psychotherapeutic interventions. She argues that postnatal depression is often overlooked in paediatric clinics. Her review highlights the paucity of randomised controlled trials on the impact of antidepressants on depressive symptomatology. One study was found in this regard (see Appleby et al, 1997). This investigation showed that an antidepressant – fluoxetine – was no more effective than cognitive behaviour therapies.
Other studies suggest that sertraline, paroxetine, venlafaxine, and nortriptyline generally have no adverse health outcomes, although some reports suggest fluoxetine can induce sleeplessness and irritability. Furthermore, there is a paucity of literature on the long-term effects of antidepressants. By contrast, psychotherapeutic treatments have been found to be both highly acceptable and effective.
Nevertheless Hendricks (2003) concluded that antidepressants can be helpful and need not necessitate suspension of breastfeeding. Overall the review is rather limited in scope (only 12studies are cited) and hence the reliability of her deductions may be questionable. However, the conclusions seem to concur with more comprehensive literature reviews discussed here.
Bennett et al (2004) reviewed evidence on the use of antidepressants for treatment of post-natal depression. The review focused on clinical outcomes for untreated postnatal depression. Data from twenty-nine studies was considered, including cohort studies of fluoxetine, venlafaxine, fluvoxamine, sertraline, paroxetine, trazodone/nefazodone, SSRIs in general and tricyclic antidepressants (TCAs), which generally indicate no adverse clinical effects on fatal development.
Longitudinal studies reported no adverse effects of antidepressants on intellectual, language, or behavioural development in children exposed to TCAs or fluoxetine while in the uterus. By contrast, there was a paucity of randomised controlled trials (RCTs) focusing on pregnant women, due to concerns about possible adverse health outcomes. Thus, most clinical trials have used male participants. Consequently, little is known about the causal relationship between use of antidepressants and postnatal depression.
Bennett et al (2004) note that, in the absence of conclusive evidence, health warnings against the use of antidepressants during pregnancy may have little practical value since many pregnant women use psychotropic drugs for several days or weeks after conception before realising they are pregnant. Several studies suggest that antidepressants may in fact produce negative health outcomes.
Infants exposed to antidepressants such as fluoxetine and paroxetine during the third trimester have been found to develop neonatal withdrawal symptoms (e.g. excessive crying, difficulty eating), and other complications (e.g. jaundice), not to mention impaired psychomotor development, pain response, premature delivery, miscarriages, and other clinical maladies, and a higher probability of admission to special care nurseries. It is not entirely clear whether these effects were caused by antidepressants or other confounding ‘third’ variables, such as the impact of other antenatal drugs. There is a lack of research controlling for such extraneous variables. However, until such evidence accumulates, caution is necessary in prescribing antidepressants during pregnancy.
The picture is further obscured by non-recognition of depressive symptoms (by both clinicians and patients), under-prescribing, patient on-compliance with drug regimes, and other factors. Furthermore, there is a lack of evidence on correct dose requirements during pregnancy –various antenatal physiological changes (e.g. decrease in gastrointestinal activity) may require specific dose alterations.
SSRI dose requirements have been found to vary across the three trimesters. The lack of clinical guidelines about antidepressants dose specifications during pregnancy increases the probability of under- Andover-prescribing, with significant implications for foetus development. Overall Bennett et all’s (2004) review highlights the uncertainty regarding the use of antidepressants. More importantly it documents evidence suggesting that antidepressants can have adverse maternal and fatal health outcomes.
A more recent review by Booth et al (2005) focused on the findings of randomised controlled trials on the effectiveness of interventions, including antidepressants, in the treatment of postnatal depression. The paper is based on a comprehensive review of multiple electronic databases, including Psych INFO, CINAHL, EMBASE, and Medline, in addition to searches of various electronic journals (e.g. British Journal of Psychiatry, the Journal of Affective Disorders). The literature dated back to the mid-1960s.
Over 100 articles were found of which 25 were randomised controlled trials, and 21 actually reviewed. Aide range of interventions have been evaluated including psychological interventions, interpersonal therapy, postnatal stress debriefing, reconfiguring midwifery and other service provision, home based care, hormonal prevention and use of antidepressants. Unsurprisingly only erect was found that tested the effect of antidepressants (Wisner et al,2005; this study is reviewed in detail elsewhere in this chapter).
Noting the limited efficacy of other interventions, none of which demonstrated long-term success, Booth et al (2005) argued that there Isa need for an ‘integrated approach’, in which antidepressants and other interventions are combined. The main constraint of Booth et all’s (2001)review is its scope. The focus on RCTs meant that reliable data from prospective and cohort studies was not considered. Such designs are especially relevant for testing the effect of antidepressants given the ethical constraints associated with conducting clinical trials.
Cohen (2005) also reviewed the antidepressant literature in relation to breast feeding, surmising from the outset that the concentrations in breast milk are minute, and that research on TCAs and SSRIs reveal “nonclinical indication for women treated with either [TCAs or SSRIs] to stop breast-feeding, provided that the infant is healthy and its progress is monitored” (p.372). However, several methodological and analytic criticisms of the literature are highlighted, notably the preponderance of case studies and small series, and lack of power in statistical analysis.
Evidence for individual TCAs and SSRIs are considered separately. Studies of TCAs in general show that these drugs do not accumulate in breastfed infants, although the short-term design of studies means that little is known about long-term effects. Thus, Cohen (2005) advises a full risk-benefit evaluation before prescribing TCAs to breastfeeding mothers.
Studies have found little or no traces of amitriptyline, nortriptyline, or doxepin in infant’s breastfed by mothers taking these drugs. Levels of Clomipramine have been found tube high immediately after delivery but decline to its lowest detectable concentration after 5 weeks. Furthermore, studies have generally reported few if any side effects from using TCAs, although the longer acting metabolite of doxepin may induce respiratory depression and sleepiness. Cohen (2005) recommends amitriptyline and imipramine facts are to be prescribed.
Regarding SSRIs, fluoxetine and its metabolite (nor fluoxetine) have been found in extremely small concentrations (<10% clinical threshold) with no adverse health effects on infant development. However, this data may be confounded by sample heterogeneity and dosage, both of which may obscure significant treatment effects. Some single case studies of women on higher fluoxetine doses have reported adverse outcomes such as somnolence, fever, hypotonic, and weight loss.
Nevertheless, the general consensus is that these side effects are clinically benign. Cohen (2005) recommends careful monitoring of mothers and infants on fluoxetine regimes. Paroxetine, citalopram, and venlafaxine, have all been found in very low concentrations (<10%threshold) and produce no adverse health effects, although studies suggest that citalopram can cause restlessness, irritability, and somnolence.
No studies of mirtazapine, nefazodone, or bupropion were found. There is a paucity of research on the effects of MAOIs in infants, albeit no cases of adverse health outcomes have been reported. In view of this lack of empirical data and the availability of newer antidepressants, it is recommended that use of MAOIs be discontinued.
Cohen (2005) concludes by highlighting the importance of conducting risk-benefit evaluations prior to recommending antidepressants to breastfeeding mothers. These appraisals should be based on details of the psychopathology (e.g. severity, frequency), availability of social support (e.g. friends, family), the patients’ prior attendance record and compliance with treatment regimes, and other factors. The following conclusions are reached:
1. There is a clear treatment protocol for use of antidepressants with breast-feeding women;
2. TCAs and SSRIs are generally safe to use while breastfeeding;
3. Use of MAOIs should be discontinued.
A number of studies have considered women’s perceptions of antidepressants. Negative attitudes towards this form of treatment may have implications for adherence to drug regimes, and even seeking treatment for postnatal depression in the first place.
Booth et al (2004) considered women’s experiences of taking antidepressants for post-natal depression. Research suggests that depressed pregnant women are sometimes prescribed no medication or medication dosages that are too low to be therapeutic. Participants were thirty-five women clinically diagnosed with depression who had been prescribed antidepressants. They were involved in a wider study on the cost-effectiveness on service provision for post-natal depression.
A health visitor recruited women who had a 6-week to 1-year-old baby and scored over the Edinburgh Postnatal Depression Scale (EPDS)threshold of 12. A Standardised Psychiatric Interview (SPI) was conducted to verify the presence of clinical depression and generate diagnosis consistent with Research Diagnostic Criteria. A psychiatrist independently verified the diagnosis. A questionnaire assessing women’s experiences of using antidepressants was administered during each interview, incorporating both Liker style and open-ended questions.
Overall, 60 women fulfilled the eligibility criteria and 35 of these were prescribed antidepressants, of which 31 took their medication. Of these, most (25) had been prescribed tricyclic antidepressants (TCAs),while 5 were prescribed SSRIs, and 1 was on flupenthixol alone. Thematic analysis was used to identify common subjects in the data.
Various themes emerged including ‘helpfulness of treatment’, ‘alternatives to medication’, ‘self-regulatory behaviours’, ‘information for health professionals’, and ‘suggestions for improvement’. These themes were further grouped into four categories: ‘women’s views on antidepressants’, ‘self-regulation of antidepressants’, ‘discontinuation of antidepressants’, and ‘communication and concordance’.
Overall, the majority of women found antidepressants helpful. Nevertheless, data from some women indicated possible low compliance rates, highlighting the need for more reliable information on medication adherence. Low compliance can have significant clinical consequences if undetected.
One concern with this study is the lack of information regarding the reliability and validity of the findings. While the Kappa test was used to establish good inter-observer reliability this in itself does not demonstrate the authenticity of the emerging themes. Methods such as triangulation (i.e. using a different method [e.g. quantitative analysis] to verify observations), participant feedback, Andre-checking of negative cases (i.e. observations which don’t fit the emerging themes) could have been used to verify the themes (Coolican,1994). In the absence of such corroboration the current findings at best can be considered inconclusive.
Charbroil et al (2004) assessed the acceptability of antidepressants amongst 405 delivered mothers admitted in maternity clinics over affixed period. Using obstetric clinics as the setting for this study allowed the implementation of health promotion initiatives. Three treatments were compared: antidepressants, and psychotherapy via consultations and home visits.
The study assessed women’s views concerning the presence of anti-depressants in maternal breast milk and infant serum, which can adversely affect fatal development. It was expected that mothers would view antidepressants less favourably when presented with information that traces of these drugs may be present in breast milk. Furthermore, mother’s views on antidepressants and postpartum blues were also assessed.
During the 3 days post-delivery mothers received information on the incidence and prevalence of postnatal depression, the impact on mother-child bonding, infant development, available treatments, and their efficacy. Participants then completed a questionnaire assessing their intention to breastfeed and acceptance of the three therapies, and also the EPDS. Analysis of variance and the t-Test were used to assess treatment acceptability pre- and post-information, and also across treatments.
Results showed that mothers who were breastfeeding viewed antidepressants less favourably at post-information compared with mothers not breastfeeding. No group differences emerged for the other therapies. Furthermore, participants with an EPDS score ≥10 or <10did not differ in their acceptance of antidepressants (or the other treatments) pre- or post-information.
In essence postpartum depression did not appear to affect attitudes towards antidepressant drugs. However, t-Test results showed that antidepressants tended to be less acceptable than the other treatments, irrespective of breastfeeding status. Furthermore, endorsement of antidepressants (and other treatments) was significantly lower post-information.
Figure 8 Acceptance of treatments at pre- and post-information(Charbroil et al, 2004). Acceptance measured on visual analogue scale(0-10, from unacceptable to very acceptable)
Charbroil et al (2004) suggested that low acceptance of antidepressants may decrease patient adherence to prescriptions, especially amongst breastfeeding mothers. However caution is advised in interpreting the findings. The computation of multiple t-Tests increased the probability of a type I error (obtaining a significant result by chance). Moreover, the use of a less stringent significance level (p<.10, rather than<.05) inspires less confidence in the findings - it increases the probability that the results occurred by chance.
The authors do not indicate whether assumptions underlying use of the t-Test/analysis of variance were satisfied. More importantly, the study failed to control for covariates, meaning that group differences may be confounded by relevant background variables, such as past experience (use of antidepressants, pregnancy) and knowledge of postnatal depression prior to the study.
Overall Synthesis, Critical Analysis of The Literature
Overall, existing literature suggests that antidepressants can be effective in treating PND, and generally have few if any side effects. However, conclusive inferences are negated by various analytic and methodological constraints. These include:
1. Failure to account for covariates
2. Failure to account for moderator effects (which might reveal conditions under which significant treatment-control group differences may emerge)
3. Lack of randomised clinical trials
4. Low statistical power and liberal significance levels
5. Lack of research on MAOIs and other antidepressants (e.g. mirtazapine, nefazodone, bupropion) (Cohen, 2005).
Most studies reviewed here, including randomised controlled trials, failed to adequately control for key background variables that may confound observed effects of antidepressants on mood and other outcome variables. Green (2005) identified several important background variables including previous history of depression and other psychopathology (e.g. anxiety) during pregnancy, level of social support (e.g. from friends, family), state of marital relationship, stressful life events (e.g. financial and employment troubles) during pregnancy.
Other factors include previous treatment history and response, side-effect profile, history of compliance with drug regimes, and patient preference for particular treatments. Any differences between antidepressant and placebo or control groups reported in the literature may be confounded by these variables – or covariates. Most prospective controlled and randomised clinical trials reviewed here made attempts to control for background variables, for example by using strict eligibility criteria (Wisner et al, 2004).
Randomisation itself is a form of control, distributing extraneous influences evenly across experimental groups. However the majority of studies are in the form of cohort- or case-controlled designs in which self-selected groups (e.g. Breastfeeding mothers, and/or mothers who used antidepressants) are compared.
Covariates can be controlled during data analysis. Some studies employ simple analysis of variance, which is inappropriate because it fails to account for covariates. A more appropriate test would be an analysis of covariance, which controls for extraneous variables (Field, 2000).
Other studies have employed regression procedures (e.g. multiple or logistic regression) but failed to use a hierarchical procedure, whereby the influence of background variables is first partial led out at an earlier step in the analysis before assessing the unique contribution of antidepressant versus placebo/control group membership(Field, 2000). Failure to account for covariates renders the findings inconclusive, because there is a possibility for example that reported effects of antidepressants are attributable to unknown prenatal conditions (e.g. better regime compliance rates in a fluoxetine compared with a placebo group).
Inconsistencies in the literature may reflect third-variable moderate effects. A moderator variable specifies the conditions under which one variable (e.g. antidepressants) will have an effect on another (e.g. Postnatal depression, health outcomes, cognitive development) (Baron& Kenny, 1986) (see Figure 9). This is especially relevant for studies reporting no adverse effects for antidepressants (Goldstein& Sun dell, 1999).
It is possible that SSRIs or TCAs do produce significant health outcomes but only under certain conditions. For example Booth et al (2004) found evidence for low compliance rates among women prescribed antidepressants. Low compliance may result in negligible if any differences between treatment and control or placebo groups. In this case compliance rate functions as a moderator, determining the conditions under which antidepressants will affect health outcomes.
Similarly Charbroil et al (2004) found evidence of low acceptance of antidepressants, which in turn may obscure health outcomes: antidepressants may produce significant improvements in mood only in a sample of women who approve of this treatment (and hence maybe more likely to adhere to prescriptions), denoting an interaction between antidepressants and acceptance levels (with the latter operating as the ‘moderator’).
Figure 9 Effects of antidepressants on outcome measures may be moderated by (i.e. interact with) other variables (Baron & Kenny,1986)
Randomised Controlled Trials
This review has revealed a distinct lack of randomised controlled trials, consistent with the other reviews (e.g. Yoshida et al, 1999;Hoffbrand et al, 2002; Misery & Kostas’s, 2002; Cohen, 2005). This negates causal inferences about the link between antidepressants and mood or adverse effects.
Prospective studies may imply causality, based on the sequence of events (e.g. antidepressants were taken before the onset of infant malformations, therefore the latter could not have caused the former) but they do not actually demonstrate causality, which would require manipulation under controlled (randomised)conditions. However, randomised controlled trials may be difficult to implement due to ethical concerns. Ultimately, any assumptions of causality need to be made with caution, subject to verification.
MAOIs and other antidepressants
There is a paucity of recent literature on the effectiveness of MAOIs, especially in terms of long-term outcomes. Most studies have focused outcast and SSRIs. The RCP (2004) does not encourage the use of MAOIs duet concerns about its cardiovascular. Thus, the state of current literature seems to reflect a shift away from these antidepressants.
Limits of Review
This review is limited by its lack of systematic and mathematical methodology. In other words, it’s failure to achieve the standards of ammeter-analysis. This critique can also be levelled at previous reviews of this literature, most of which report conclusions based on the overall and subjective appraisals of the writer(s) (e.g. Goldstein and Sun dell, 1999; Misery & Kostas’s, 2002; Marcus et al, 2005).
The use of a subjective (i.e. non-mathematical) approach has several disadvantages. Firstly, estimates of the overall magnitude of group differences (e.g. fluoxetine versus control groups) across studies are entirely subjective and hence imprecise. Thus, based on the current review, it would appear that in general use of SSRIs helps to alleviate depressive symptomato
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