- Email: [email protected]
Association between serum BDNF levels and maternal perinatal depression: A review
Journal of Affective Disorders xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research paper
Association between serum BDNF levels and maternal perinatal depression: A review Special Section on “Translational and Neuroscience Studies in Affective Disorders” Section Editor, Maria Nobile MD, PhD. G.M. Mandolinia,b, M. Lazzarettia, G. Delvecchiob, C. Bressia,b, J.C. Soaresc, P. Brambillaa,b, a b c
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Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Neurosciences and Mental Health, Milan, Italy University of Milan, Department of Pathophysiology and Transplantation, Milan, Italy Department of Psychiatry and Behavioural Neurosciences, University of Texas, Houston, TX, USA
ARTICLE INFO
ABSTRACT
Keywords: Serum brain-derived neurotrophic factor (BDNF) Biomarkers Perinatal depression Stress
Introduction: A large amount of studies demonstrated reduced serum Brain-Derived Neurotrophic Factor (BDNF) levels in stress-related and depressive disorders. However, it is still unclear if a similar deficit in BDNF concentrations might also characterize maternal perinatal depression. Methods: We performed a bibliographic search on PUBMED of all the studies investigating the association between maternal BDNF levels and perinatal depression. The inclusion criteria were met by thirteen studies. Results: Overall, the majority of the studies reported a significant reduction in serum BDNF levels among depressed mothers compared to healthy mothers either during pregnancy or in the postpartum period. Moreover, some studies also demonstrated that the BDNF reduction could be more evident in those depressed mothers with perinatal stressful life events and suicide risk. Limitations: BDNF were collected at different time points across the studies. Potential confounding factors, including the clinical characteristics of the samples employed by the original studies, might have influenced the results. Conclusions: So far, the evidences suggested the presence of decreased BDNF concentrations in perinatal depressive disorders. However, further studies are needed in order to confirm the role of BDNF in this disorder.
1. Introduction Perinatal depression is defined by the Diagnostic and Statistical Manual of Mental Disorder Fifth Edition (DSM-5) as a major depressive episode occurring during pregnancy or within four weeks after delivery (American Psychiatric Association, 2013). Perinatal depression represents a significant burden on women's health with an estimated prevalence of 11.9% (Woody et al., 2017). Additionally, it may also negatively impact children neurodevelopment, which may in turn increase the risk of onset of psychiatric disorders among offspring (Duan et al., 2019). Indeed, recent evidence demonstrated structural and functional alterations in the prefronto-amygdala connectivity in offspring who were exposed to perinatal depression, with significant reduction of both hippocampal maturation and cortical thickness (Duan et al., 2019). Notably, women psychopathology during pregnancy could be
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influenced by various factors such as previous anxiety or depressive episodes, transgenerational predisposition, lack of social and family support, history of abuse or violence and stressful live events (Duan et al., 2019). In this regard, a potential biological candidate of depressive disorders has been identified in the Brain-Derived Neurotrophic Factor (BDNF), a protein that is extensively expressed in the hippocampus, amygdala, hypothalamus, neocortex and cerebellum (Zhao et al., 2017). Peripheral BDNF is stored in platelets, it can cross the blood-barriers and it is considered to reflect BDNF concentrations in central nervous system (Serra-Millàs, 2016). Additionally, BDNF, acting by the receptor tropomyosin-related kinase receptor type B (TRKB), detains a major role in the regulation of neurogenesis, which has been associated with increased resilience towards stress events (Malhi and Mann, 2018). In the last decades, a large amount of studies has been conducted in order to better clarify the role of BDNF in depression (Molendijk et al.,
Corresponding author at: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy, via F. Sforza 35, 20122 Milan, Italy. E-mail address: [email protected] (P. Brambilla).
https://doi.org/10.1016/j.jad.2019.08.007 Received 15 May 2019; Received in revised form 1 August 2019; Accepted 5 August 2019 Available online 07 August 2019 0165-0327/ © 2019 Elsevier B.V. All rights reserved.
Please cite this article as: G.M. Mandolini, et al., Journal of Affective Disorders, https://doi.org/10.1016/j.jad.2019.08.007
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2014). Specifically, BDNF levels seemed to be reduced in stress-related disorders and in subjects with major depressive diseases (Duman and Li, 2012) and to be restored with antidepressant treatment (Malhi and Mann, 2018). Indeed, a reduction of neurotrophic factors, such as BDNF, has been associated with a decrease in excitatory neurotransmission and with a consequent neuronal atrophy and degeneration (Zhao et al., 2017). Moreover, BDNF Val66Met polymorphism, which reflects a decreased function of BDNF, was found to moderate the relation between depressive disorder and stressful life events (Zhao et al., 2017). However, despite these evidence, the role of BDNF Val66Met polymorphism in perinatal depression is still under debate. Indeed, while some studies observed no differences in BDNF genotype between depressed and non-depressed mothers (Figueira et al., 2010), some others found a significant association between this polymorphism and depressive symptoms at 6 weeks postpartum among mothers who delivered during autumn and winter (Comasco et al., 2011). Moreover, it is still unclear whether depressive episodes, occurring during the perinatal period, are characterized by significant BDNF plasma level reductions. Therefore, this review aims at summarizing the studies evaluating the association between serum BDNF levels and maternal perinatal depression, with the final goal of providing an overview of the evidence reported so far.
Notably, Yang et al. (2016) showed that BDNF concentrations were reduced in pregnant women with depression and post-traumatic stress disorder (PTSD) before 16th gestational week compared to pregnant women with isolated PTSD or neither condition. A similar result was detected by Yang et al. (2017) in a sample of 982 pregnant women who were assessed for serum BDNF concentrations and depressive symptoms before the 16th gestational week. Although the authors found no signification association between BDNF levels and severity of antepartum depression, they showed that women with moderate depressive symptoms before the 16th gestational week had decreased BDNF concentrations compared to women with mild or no antepartum depression. In a following study, 86 pregnant women were recruited in their early second trimester and depressive symptoms were assessed at 26th28th gestational week and at 36th gestational week (Pawluski et al., 2018). Blood sample were detected for serum BDNF analysis at 36 weeks’ gestation. The sample was divided in women treated with selective serotonin reuptake inhibitors (SSRI) and healthy controls who did not receive any treatment. The SSRI-group showed significant higher BDNF levels at 36th gestational week, while only in the healthy group lower BDNF concentrations were associated with augmented depressive symptoms. Furthermore, Christian et al. (2016) carried out a longitudinal study by recruiting 144 pregnant women who were assessed for serum BDNF levels and depressive symptoms at 1st, 2nd and 3rd trimester of pregnancy as well as at 4–11 weeks after delivery. The authors demonstrated significant changes in serum BDNF levels across time, with a progressive reduction during pregnancy and an increase after delivery. However, a significant inverse relationship between depressive symptoms and serum BDNF concentrations was detected only during the 3rd trimester and these symptoms were also preceded by lower BDNF levels at 2nd trimester. Remarkably, Lommatzsch et al. (2006) assessed serum BDNF levels among 40 pregnant and 40-non pregnant women. The results showed decreased BDNF concentrations in all pregnant women both before and after childbirth compared to non-pregnant women, with a non-significant trend of major decrease in case of maternal depression. Finally, Akbada et al. (2018) enrolled 136 pregnant women in their last trimester, including 25 subjects with major depressive disorder, 18 with anxiety disorders and 93 healthy controls. Surprisingly, although the authors observed that serum BDNF concentrations of women with major depressive disorders were lower compared to other subjects, the difference was not significant.
2. Methods We performed a bibliographic search in PubMed using “BDNF AND Perinatal Depression” and “BDNF AND Postpartum depression” and “BDNF AND Depression AND Pregnancy”. We selected published studies from January 2000 until April 2019. We excluded studies (a) exploring psychiatric disorders others than maternal perinatal depression and (b) not including the assessment of serum BDNF levels. The inclusion criteria were met by thirteen studies, whose methods and results are summarized in Table 1. Specifically, nine studies reported a significant correlation between serum BDNF levels and depressive symptoms during pregnancy (Christian et al., 2016; Dhiman et al., 2014; Fung et al., 2015; Gao et al., 2016; Gazal et al., 2012; Sonmez et al., 2019; Yang et al., 2017, 2016) or in pregnant depressed mothers with suicide risk (Pinheiro et al., 2012), one study found a not significant trend of lower BDNF levels in depressed mothers (Lommatzsch et al., 2006) and one study found higher BDNF levels in SSRI-treated depressed mothers and lower levels in non-SSRI treated healthy pregnant women (Pawluski et al., 2018). In contrast, two studies found no significant associations between serum BDNF levels and perinatal depression (Akbaba et al., 2018; Guintivano et al., 2018). Depressive symptoms were assessed mainly with the Edinburgh postnatal depression scale (EPDS) (Dhiman et al., 2014; Gao et al., 2016; Guintivano et al., 2018; Lommatzsch et al., 2006; Pawluski et al., 2018), the Edinburgh Postnatal Depression Inventory (EPDI) (Akbaba et al., 2018), the Beck Depression Inventory (BDI) (Gazal et al., 2012; Sonmez et al., 2019), the Patient Health Questionnaire-9 (PHQ-9) (Fung et al., 2015; Yang et al., 2017, 2016), the Hamilton Rating Scale for Depression (HAMD) (Pawluski et al., 2018), the Center for Epidemiologic Studies Depression Scale (CES-D) (Christian et al., 2016) and the Mini International Neuropsychiatric Interview (MINI) (Pinheiro et al., 2012).
3.2. Serum BDNF levels and postpartum depression As regard postpartum depression, six studies investigated serum BDNF levels in depressed women after birth. Specifically, Sonmez et al. (2019) found that cord blood BDNF level were significantly lower among infants of 23 pregnant women with perinatal depression compared to infants of 25 healthy pregnant women. However, no correlations between BDNF level and severity of depressive symptoms were detected. Moreover, Dhiman et al. (2014) explored BDNF levels among 103 women at 24–40 h post-delivery and at six weeks postpartum. In accordance with previous studies, the authors detected low serum BDNF levels in women with postpartum depression compared to healthy women. Similarly, in a following study, Gao et al. (2016) enrolled 340 women within 24–48 h after delivery and collected serum BDNF levels. After 3 months’ follow-up, 37 out of 340 women met the criteria for postpartum depression according to EPDS score and they had significant lower serum BDNF levels compared to women without postpartum depression. Additionally, the authors found a significant association between stressful life events and reduced BDNF levels in all subjects. In accordance with these results, in a casecontrol study, Gazal et al. (2012) compared BDNF concentrations among 36 mothers with postpartum depression and 36 healthy mothers. The authors found a significant association between lower BDNF levels and postpartum depression between 30 and 90 days after
3. Results 3.1. Serum BDNF levels and antepartum depression Overall, seven studies investigated serum BDNF levels in antepartum depression. Interestingly, a large cross-sectional study including 968 pregnant women (Fung et al., 2015) reported that lower maternal mean serum BDNF levels at the 16th gestational week were associated with augmented odds of antepartum depression, although no association between BDNF levels and depressive symptoms severity was found. 2
3
Cohort
Cohort
Yang et al. (2017)
Cohort
Yang et al. (2016)
Case control
Cross-sectional
Fung et al. (2015)
Guintivano et al. (2018)
Case control
Dhiman et al. (2014)
Longitudinal
Cross-sectional
Pinheiro et al. (2012)
Christian et al. (2016)
Case control
Gazal et al. (2012)
Longitudinal
Longitudinal
Lommatzsch et al. (2006)
Gao et al. (2016)
Study design
Article
982 Pr women
1517 Pr women (549 PPD, 968 HC)
139 Pr women
2899 Pr women (1591 With no PTSD or depression, 225 with isolated depression, 507 with isolated PTSD, 576 with comorbid PTSDdepression 944 BDNF 340 mothers (37 PPD, 303 no-PPD)
968 Pr women (688 depressed, 280 nondepressed)
103 mothers (58 PPD, 45 no-PPD)
190 mothers (29 PPAD, 161 no-PPAD)
72 mothers (36 PPD, 36 no-PPD)
80 women (40 Pr, 40 non-Pr)
Sample
Table 1 Summary of the studies described in the review.
Not specified
28 ± 6.2
17–45
24.8 ± 4.16
HAMD
EPDS Abuse and Trauma Inventory ESI PBQ PHQ-9
MINI
CES-D
EPDS
PCL-C PHQ-9
28.2 ± 6.2 28.0 ± 6.5
29.1 ± 2
PHQ-9
MINI, Life Events and Coping Scales EPDS
BDI
EPDS
Clinical evaluation
> 18
Not specified
> 18
18-46
21–40
Age (years old)
Before 16th gestational week
1st, 2nd, 3rd trimester, 4-11 weeks after delivery 6 weeks postpartum
3 months after delivery
Before 16th gestational week
24-48 hours after delivery and after 6 weeks Before 16th gestational week
45-90 days after delivery
30-90 days after delivery
30th,37th week of gestation, 1 and 8 weeks after delivery
Timing of clinical evaluation
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood Peripheral venous blood
Peripheral venous blood
BDNF sampling
Before 16th gestational week
1st, 2nd, 3rd trimester, 4-11 weeks after delivery 6 weeks postpartum
24-48 hours after delivery
Before 16th gestational week
24-48 hours after delivery and after 6 weeks Before 16th gestational week
45-90 days after delivery
30-90 days after delivery
30th,37th week of gestation, 1 and 8 weeks after delivery
Timing of blood sampling
S100B
None
Estradiol, Progesterone, Oxytocin, Allopregnanalone
Serum cortisol
None
None
None
None
None
SSRI
Not specified
Not specified
None
None
None
None
Not specified
None
None
(continued on next page)
Moderate antepartum depression was associated with lower serum BDNF levels compare with mild/no antepartum depression
Depressed pregnant women had lower BDNF serum level than non-depressed pregnant women Serum BDNF concentrations were lower among women with comorbid PTSDdepression as compared with women without either condition, even if with not statistical significance Serum BDNF levels after delivery were significantly lower in women with PPD compared to with women with no-PPD Depressive symptoms and serum BDNF levels were inversely associated only during the 3rd trimester No significant differences were detected between groups in BDNF levels
BDNF decreased in pregnant women. BDNF serum levels not significantly lower in depressed mother compared to mothers without depression Depressed mothers showed decreased BDNF serum levels compared to healthy mothers BDNF was lower in PPAD mothers with suicide risk compared to PPAD mothers without suicide risk Depressed mothers showed decreased BDNF serum level compared to healthy mothers
None
Serum levels of 17betaestradiol, progesterone, cortisol, dehydroepiandrosterone sulfate
None
Main results
Concomitant therapy
Other measurements
G.M. Mandolini, et al.
Journal of Affective Disorders xxx (xxxx) xxx–xxx
Cohort
Sonmez et al. (2019)
28.94 ± 5.98
27.76 ± 5.31
Age (years old)
BDI
EPDI
HAMA EPDS SCID-I
Clinical evaluation
During delivery/ cesarean section
Not specified
26th, 28th, 36th gestational week
Timing of clinical evaluation
Umbilical cord
Umbilical cord
Peripheral venous blood
BDNF sampling
During delivery/ cesarean section
During delivery/ cesarean section
36th gestational week
Timing of blood sampling
FGF2 TNF-alfa Neopterin None
NT-3
Other measurements
None
Not specified
Concomitant therapy
Cord blood BDNF levels in infants of depressed mothers were significantly lower compared to infants of healthy mothers
BDNF levels did not differ between the three groups
SSRI-treated group had higher BDNF serum level. Lower BDNF level were associated with increased depression only in non-SSRI treated group.
Main results
AD = Anxiety Disorder; BDI: Beck Depression Inventory; CES-D = Center for Epidemiologic Studies Depression Scale; EPDI = Edinburgh Postnatal Depression Inventory; EPDS = Edinburgh Postnatal Depression Scale; ESI = Everyday Stressors Index; HAMA = Hamilton Rating Scale for Anxiety; HAMD = Hamilton Rating Scale for Depression; MDD = Major Depressive Disorder; MINI = Mini International Neuropsychiatric Interview; non-Pr = Non Pregnant; no-PPD = Without Postpartum Depression; PBQ = Postpartum Bonding Questionnaire; PCL-C = The Posttraumatic Stress Disorder Checklist – Civilian Version; PHQ-9 = Patient Health Questionnaire-9; PPAD = Postpartum Affective Disorder; PPD = Postpartum Depression; Pr = Pregnant; S100 = S100 Calcium-Binding Protein B; SCID-I = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; SSRI = Selective serotonin Reuptake Inhibitors Reuptake.
50 (23 MDD, 25 HC)
136 (25 MDD, 18 AD, 93 HC)
Cohort
Akbaba et al. (2018)
Sample
86 Pr women (22-25 SSRI-treated, 33-38 nonSSRI-treated)
Study design
Pawluski et al. (2018)
Article
Table 1 (continued)
G.M. Mandolini, et al.
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delivery; moreover, the severity of depressive symptoms assessed through the BDI negatively correlated with BDNF levels. Additionally, Pinheiro et al. (2012) carried out a cross-sectional study on 190 women who were enrolled during their prenatal period and were assessed for the presence of postpartum affective disorder (PPAD) between 45 and 90 days after delivery. Remarkably, the authors found that, among women with PPAD (15.3% of the total sample including women with depression, mania/hypomania and mixed episodes), serum BDNF levels were significantly lower in those with suicide risk compared to women without it. However, no significant differences in BDNF levels were detected within the PPAD sample with suicide risk, regardless the presence of manic, depressive or mixed episodes. Lastly, reduced serum BDNF levels were detected in those mothers with three or more perinatal stressful live events. In contrast, one study conducted by Guintivano et al. (2018) showed no statistically significant differences in BDNF levels collected at 6 weeks port-partum between 549 women with postpartum depression and 968 healthy mothers.
regulation of perinatal neurotrophic factors, such as BDNF. 5. Limitations The present review should be considered in light of some limitations. First, BDNF levels were assessed at different time points during pregnancy and in the postpartum period, therefore not all the studies could be directly compared. Nevertheless, the evidence reported by the individual studies suggests that a reduction in BDNF levels among depressed pregnant women might characterized the whole perinatal period. Second, none of the studies investigated the presence of BDNF polymorphisms that are known to influence BDNF function (Zhao et al., 2017). Third, some other potential cofounding factors, which are known to have an influence on both BDNF levels and depressive symptoms, such as age, ethnicity, educational level, diet habits, severity of psychopathological symptoms, number of platelets, might have negatively contributed to the generalizability of the results (Hammen, 2018; Hing et al., 2018). Finally, BDNF, like all neurotrophins, is initially synthesized as a precursor (pro-BDNF), which is then processed into mature BDNF. However, although it is well known that these two forms of BDNF, pro-BDNF and mature BDNF, elicit opposite effects in neural functions (Hempstead, 2015) no studies discriminated between pro-BDNF and mature BDNF.
4. Discussion Overall, the majority of studies demonstrated reduced maternal BDNF levels in perinatal depression, either during pregnancy (Christian et al., 2016; Fung et al., 2015; Yang et al., 2017, 2016) or after delivery (Christian et al., 2016; Dhiman et al., 2014; Gao et al., 2016; Gazal et al., 2012; Sonmez et al., 2019), ultimately highlighting that maternal BDNF down-regulation seemed to characterize depressed mothers during both ante- and postpartum. Interestingly, these results are not surprising especially because it has been reported that the decrease in BDNF levels could be responsible for neuronal cell loss and atrophy in specific cerebral regions, such as hippocampus and prefrontal cortex, which have been found reduced in depressed subjects (Duman and Li, 2012). Additionally, recent animal models further supported the central role BDNF in depression by demonstrating that knock-out mice for BDNF had reduced neurogenesis in specific hippocampal regions and showed depressive and anhedonic-like behaviors (Taliaz et al., 2010). Furthermore, the link between BDNF and perinatal depression might be also explained by the interaction of BDNF with selective biological mechanisms. Specifically, Gao et al. (2016) underlined how BDNF interacts with the serotonin system to control neural development and plasticity and to induce significant hormonal changes within systems involved in depressive disorders. Moreover, lower BDNF concentrations might also represent a genetic vulnerability in subjects at risk for depression that may interact with other factors, such as stressful life events, in order to trigger depressive symptoms (Gao et al., 2016; Pinheiro et al., 2012; Sonmez et al., 2019). Also, BDNF might represent a valid mediator of antidepressant treatment efficacy, as shown by the increase in BDNF levels in SSRI-treated women with antepartum depression (Pawluski et al., 2018). In contrast, some studies also suggested that, based on the assumption that pregnancy is characterized by various physiological changes that include nervous, endocrine, immune and haematological systems (Datta et al., 2010), a decrease in BDNF levels may represent a clinical status that accompanies all women during perinatal period regardless of depressive symptoms (Lommatzsch et al., 2006). Moreover, it has been also proposed that a neurotrophic down-regulation during pregnancy might increase the risk for perinatal depression only in vulnerable women rather than being a biomarker of depression (Lommatzsch et al., 2006). However, this hypothesis could not be compared with other evidence since the study by Lommatzsch et al. (2006) was the only one where non-pregnant subjects were enrolled as a comparison group. Finally, from some of the abovementioned evidence it emerged that prenatal stress may represent a relevant factor to be considered (Pinheiro et al., 2012; Gao et al., 2016), further supporting its capacity to disrupt maternal endocrine, nervous and immune systems, with deleterious consequences for both mothers and their offspring (Cardwell, 2013), as well as its role in the
6. Conclusions In conclusion, the present review suggests that maternal serum BDNF levels could represent one of the potential biomarkers of perinatal depression in both ante- and postpartum period. Moreover, from the abovementioned results emerged that BDNF could be helpful not only for predicting depressive symptoms in women at risk, but also to monitor response to antidepressant treatment. However, the debate on the role of BDNF in perinatal depression is still open, since some authors did not consider lower BDNF levels a biological factor of depressive disorders, but rather a consequence of the depressive state (Bus and Molendijk, 2016). Therefore, longitudinal multi-centric investigations from the 1st gestational week until the postpartum period and studies with larger samples and a monthly assessment of depressive symptoms, pro-BDNF/BDNF levels and BDNF polymorphisms, are warranted. Role of funding source PB was partially supported by grants from the Italian Ministry of Health (RF-2016-02364582). CRediT authorship contribution statement G.M. Mandolini: Writing - original draft. M. Lazzaretti: Writing original draft. G. Delvecchio: Writing - review & editing. C. Bressi: Writing - review & editing. J.C. Soares: Writing - review & editing. P. Brambilla: Writing - review & editing. Declaration of Competing Interest None. Acknowledgement None. References Akbaba, N., Annagür, B.B., Annagür, A., Akbulut, H., Akyürek, F., Çelık, Ç, 2018. Neurotrophins and neuroinflammation in fetuses exposed to maternal depression and anxiety disorders during pregnancy: a comparative study on cord blood. Arch.
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G.M. Mandolini, et al. Women's Ment. Health. American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental Disorders, fifth ed. DSM-5, New York American Psychiatric Press Inc. Bus, B.A.A., Molendijk, M.L., 2016. [The neurotrophic hypothesis of depression]. Tijdschr. Psychiatr. Cardwell, M.S., 2013. Stress: pregnancy considerations. Obstet. Gynecol. Surv. Christian, L.M., Mitchell, A.M., Gillespie, S.L., Palettas, M., 2016. Serum brain-derived neurotrophic factor (BDNF) across pregnancy and postpartum: associations with race, depressive symptoms, and low birth weight. Psychoneuroendocrinology. Comasco, E., Sylvén, S.M., Papadopoulos, F.C., Oreland, L., Sundström-Poromaa, I., Skalkidou, A., 2011. Postpartum depressive symptoms and the BDNF Val66Met functional polymorphism: effect of season of delivery. Arch. Women's Ment. Health. Datta, S., Kodali, B.S., Segal, S., 2010. Maternal physiological changes during pregnancy, labor, and the postpartum period. Obstetric Anesthesia Handbook. Dhiman, P., Say, A., Rajendiren, S., Kattimani, S., Sagili, H., 2014. Association of foetal APGAR and maternal brain derived neurotropic factor levels in postpartum depression. Asian J. Psychiatry. Duan, C., Hare, M.M., Staring, M., Deligiannidis, K.M., 2019. Examining the relationship between perinatal depression and neurodevelopment in infants and children through structural and functional neuroimaging research. Int. Rev. Psychiatry. Duman, R.S., Li, N., 2012. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos. Trans. R. Soc. B. Figueira, P., Malloy-Diniz, L., Campos, S.B., Miranda, D.M., Romano-Silva, M.A., De Marco, L., Neves, F.S., Correa, H., 2010. An association study between the Val66Met polymorphism of the BDNF gene and postpartum depression. Arch. Women's Ment. Health. Fung, J., Gelaye, B., Zhong, Q.Y., Rondon, M.B., Sanchez, S.E., Barrios, Y.V., Hevner, K., Qiu, C., Williams, M.A., 2015. Association of decreased serum brain-derived neurotrophic factor (BDNF) concentrations in early pregnancy with antepartum depression. BMC Psychiatry. Gao, X., Wang, J., Yao, H., Cai, Y., Cheng, R., 2016. Serum BDNF concentration after delivery is associated with development of postpartum depression: a 3-month follow up study. J. Affect. Disord. Gazal, M., Motta, L.S., Wiener, C.D., Fernandes, J.C., Quevedo, L.Á., Jansen, K., Pinheiro, K.A.T., Giovenardi, M., Souza, D.O., Da Silva, R.A., Pinheiro, R.T., Portela, L.V., Oses, J.P., 2012. Brain-derived neurotrophic factor in post-partum depressive mothers. Neurochem. Res. Guintivano, J., Sullivan, P.F., Stuebe, A.M., Penders, T., Thorp, J., Rubinow, D.R., Meltzer-Brody, S., 2018. Adverse life events, psychiatric history, and biological predictors of postpartum depression in an ethnically diverse sample of postpartum women. Psychol. Med. Hammen, C., 2018. Risk factors for depression: an autobiographical review. Ann. Rev. Clin. Psychol.
Hempstead, B.L., 2015. Brain-derived neurotrophic factor: three ligands, many actions. Trans. Am. Clin. Climatol. Assoc. Hing, B., Sathyaputri, L., Potash, J.B., 2018. A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder. Am. J. Med. Genet. Part B. Lommatzsch, M., Hornych, K., Zingler, C., Schuff-Werner, P., Höppner, J., Virchow, J.C., 2006. Maternal serum concentrations of BDNF and depression in the perinatal period. Psychoneuroendocrinology. Malhi, G.S., Mann, J.J., 2018. Depression. Lancet. Molendijk, M.L., Spinhoven, P., Polak, M., Bus, B.A.A., Penninx, B.W.J.H., Elzinga, B.M., 2014. Serum BDNF concentrations as peripheral manifestations of depression: Evidence from a systematic review and meta-analyses on 179 associations (N=9484). Mol. Psychiatry. Pawluski, J.L., Brain, U., Hammond, G.L., Oberlander, T.F., 2018. Selective serotonin reuptake inhibitor effects on neural biomarkers of perinatal depression. Arch. Women's Ment. Health 1–5. Pinheiro, R.T., Pinheiro, K.A.T., Da Cunha Coelho, F.M., De Ávila Quevedo, L., Gazal, M., Da Silva, R.A., Giovenardi, M., Lucion, A.B., De Souza, D.O., Portela, L.V., Oses, J.P., 2012. Brain-derived neurotrophic factor levels in women with postpartum affective disorder and suicidality. Neurochem. Res. Serra-Millàs, M., 2016. Are the changes in the peripheral brain-derived neurotrophic factor levels due to platelet activation? World J. Psychiatry. Sonmez, E.O., Yilmaz, E., Uguz, F., Sahingoz, M., Sonmez, G., Gokmen, Z., Gezginc, K., Kucur, R., 2019. Effect of maternal depression on brain-derived neurotrophic factor levels in fetal cord blood. Klinik Psikofarmakoloji Bul. 17 (2), 308–313. Taliaz, D., Stall, N., Dar, D.E., Zangen, A., 2010. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol. Psychiatry. Woody, C.A., Ferrari, A.J., Siskind, D.J., Whiteford, H.A., Harris, M.G., 2017. A systematic review and meta-regression of the prevalence and incidence of perinatal depression. J. Affect. Disord. Yang, N., Gelaye, B., Zhong, Q., Rondon, M.B., Sanchez, S.E., Williams, M.A., 2016. Serum brain-derived neurotrophic factor (BDNF) concentrations in pregnant women with post-traumatic stress disorder and comorbid depression. Arch. Women's Ment. Health. Yang, N., Levey, E., Gelaye, B., Zhong, Q.Y., Rondon, M.B., Sanchez, S.E., Williams, M.A., 2017. Correlates of early pregnancy serum brain-derived neurotrophic factor in a Peruvian population. Arch. Women's Ment. Health. Zhao, M., Chen, L., Yang, J., Han, D., Fang, D., Qiu, X., Yang, X., Qiao, Z., Ma, J., Wang, L., Jiang, S., Song, X., Zhou, J., Zhang, J., Chen, M., Qi, D., Yang, Y., Pan, H., 2017. BDNF Val66Met polymorphism, life stress and depression: a meta-analysis of geneenvironment interaction. J. Affect. Disord.
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Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research paper
Association between serum BDNF levels and maternal perinatal depression: A review Special Section on “Translational and Neuroscience Studies in Affective Disorders” Section Editor, Maria Nobile MD, PhD. G.M. Mandolinia,b, M. Lazzarettia, G. Delvecchiob, C. Bressia,b, J.C. Soaresc, P. Brambillaa,b, a b c
⁎
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Neurosciences and Mental Health, Milan, Italy University of Milan, Department of Pathophysiology and Transplantation, Milan, Italy Department of Psychiatry and Behavioural Neurosciences, University of Texas, Houston, TX, USA
ARTICLE INFO
ABSTRACT
Keywords: Serum brain-derived neurotrophic factor (BDNF) Biomarkers Perinatal depression Stress
Introduction: A large amount of studies demonstrated reduced serum Brain-Derived Neurotrophic Factor (BDNF) levels in stress-related and depressive disorders. However, it is still unclear if a similar deficit in BDNF concentrations might also characterize maternal perinatal depression. Methods: We performed a bibliographic search on PUBMED of all the studies investigating the association between maternal BDNF levels and perinatal depression. The inclusion criteria were met by thirteen studies. Results: Overall, the majority of the studies reported a significant reduction in serum BDNF levels among depressed mothers compared to healthy mothers either during pregnancy or in the postpartum period. Moreover, some studies also demonstrated that the BDNF reduction could be more evident in those depressed mothers with perinatal stressful life events and suicide risk. Limitations: BDNF were collected at different time points across the studies. Potential confounding factors, including the clinical characteristics of the samples employed by the original studies, might have influenced the results. Conclusions: So far, the evidences suggested the presence of decreased BDNF concentrations in perinatal depressive disorders. However, further studies are needed in order to confirm the role of BDNF in this disorder.
1. Introduction Perinatal depression is defined by the Diagnostic and Statistical Manual of Mental Disorder Fifth Edition (DSM-5) as a major depressive episode occurring during pregnancy or within four weeks after delivery (American Psychiatric Association, 2013). Perinatal depression represents a significant burden on women's health with an estimated prevalence of 11.9% (Woody et al., 2017). Additionally, it may also negatively impact children neurodevelopment, which may in turn increase the risk of onset of psychiatric disorders among offspring (Duan et al., 2019). Indeed, recent evidence demonstrated structural and functional alterations in the prefronto-amygdala connectivity in offspring who were exposed to perinatal depression, with significant reduction of both hippocampal maturation and cortical thickness (Duan et al., 2019). Notably, women psychopathology during pregnancy could be
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influenced by various factors such as previous anxiety or depressive episodes, transgenerational predisposition, lack of social and family support, history of abuse or violence and stressful live events (Duan et al., 2019). In this regard, a potential biological candidate of depressive disorders has been identified in the Brain-Derived Neurotrophic Factor (BDNF), a protein that is extensively expressed in the hippocampus, amygdala, hypothalamus, neocortex and cerebellum (Zhao et al., 2017). Peripheral BDNF is stored in platelets, it can cross the blood-barriers and it is considered to reflect BDNF concentrations in central nervous system (Serra-Millàs, 2016). Additionally, BDNF, acting by the receptor tropomyosin-related kinase receptor type B (TRKB), detains a major role in the regulation of neurogenesis, which has been associated with increased resilience towards stress events (Malhi and Mann, 2018). In the last decades, a large amount of studies has been conducted in order to better clarify the role of BDNF in depression (Molendijk et al.,
Corresponding author at: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy, via F. Sforza 35, 20122 Milan, Italy. E-mail address: [email protected] (P. Brambilla).
https://doi.org/10.1016/j.jad.2019.08.007 Received 15 May 2019; Received in revised form 1 August 2019; Accepted 5 August 2019 Available online 07 August 2019 0165-0327/ © 2019 Elsevier B.V. All rights reserved.
Please cite this article as: G.M. Mandolini, et al., Journal of Affective Disorders, https://doi.org/10.1016/j.jad.2019.08.007
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2014). Specifically, BDNF levels seemed to be reduced in stress-related disorders and in subjects with major depressive diseases (Duman and Li, 2012) and to be restored with antidepressant treatment (Malhi and Mann, 2018). Indeed, a reduction of neurotrophic factors, such as BDNF, has been associated with a decrease in excitatory neurotransmission and with a consequent neuronal atrophy and degeneration (Zhao et al., 2017). Moreover, BDNF Val66Met polymorphism, which reflects a decreased function of BDNF, was found to moderate the relation between depressive disorder and stressful life events (Zhao et al., 2017). However, despite these evidence, the role of BDNF Val66Met polymorphism in perinatal depression is still under debate. Indeed, while some studies observed no differences in BDNF genotype between depressed and non-depressed mothers (Figueira et al., 2010), some others found a significant association between this polymorphism and depressive symptoms at 6 weeks postpartum among mothers who delivered during autumn and winter (Comasco et al., 2011). Moreover, it is still unclear whether depressive episodes, occurring during the perinatal period, are characterized by significant BDNF plasma level reductions. Therefore, this review aims at summarizing the studies evaluating the association between serum BDNF levels and maternal perinatal depression, with the final goal of providing an overview of the evidence reported so far.
Notably, Yang et al. (2016) showed that BDNF concentrations were reduced in pregnant women with depression and post-traumatic stress disorder (PTSD) before 16th gestational week compared to pregnant women with isolated PTSD or neither condition. A similar result was detected by Yang et al. (2017) in a sample of 982 pregnant women who were assessed for serum BDNF concentrations and depressive symptoms before the 16th gestational week. Although the authors found no signification association between BDNF levels and severity of antepartum depression, they showed that women with moderate depressive symptoms before the 16th gestational week had decreased BDNF concentrations compared to women with mild or no antepartum depression. In a following study, 86 pregnant women were recruited in their early second trimester and depressive symptoms were assessed at 26th28th gestational week and at 36th gestational week (Pawluski et al., 2018). Blood sample were detected for serum BDNF analysis at 36 weeks’ gestation. The sample was divided in women treated with selective serotonin reuptake inhibitors (SSRI) and healthy controls who did not receive any treatment. The SSRI-group showed significant higher BDNF levels at 36th gestational week, while only in the healthy group lower BDNF concentrations were associated with augmented depressive symptoms. Furthermore, Christian et al. (2016) carried out a longitudinal study by recruiting 144 pregnant women who were assessed for serum BDNF levels and depressive symptoms at 1st, 2nd and 3rd trimester of pregnancy as well as at 4–11 weeks after delivery. The authors demonstrated significant changes in serum BDNF levels across time, with a progressive reduction during pregnancy and an increase after delivery. However, a significant inverse relationship between depressive symptoms and serum BDNF concentrations was detected only during the 3rd trimester and these symptoms were also preceded by lower BDNF levels at 2nd trimester. Remarkably, Lommatzsch et al. (2006) assessed serum BDNF levels among 40 pregnant and 40-non pregnant women. The results showed decreased BDNF concentrations in all pregnant women both before and after childbirth compared to non-pregnant women, with a non-significant trend of major decrease in case of maternal depression. Finally, Akbada et al. (2018) enrolled 136 pregnant women in their last trimester, including 25 subjects with major depressive disorder, 18 with anxiety disorders and 93 healthy controls. Surprisingly, although the authors observed that serum BDNF concentrations of women with major depressive disorders were lower compared to other subjects, the difference was not significant.
2. Methods We performed a bibliographic search in PubMed using “BDNF AND Perinatal Depression” and “BDNF AND Postpartum depression” and “BDNF AND Depression AND Pregnancy”. We selected published studies from January 2000 until April 2019. We excluded studies (a) exploring psychiatric disorders others than maternal perinatal depression and (b) not including the assessment of serum BDNF levels. The inclusion criteria were met by thirteen studies, whose methods and results are summarized in Table 1. Specifically, nine studies reported a significant correlation between serum BDNF levels and depressive symptoms during pregnancy (Christian et al., 2016; Dhiman et al., 2014; Fung et al., 2015; Gao et al., 2016; Gazal et al., 2012; Sonmez et al., 2019; Yang et al., 2017, 2016) or in pregnant depressed mothers with suicide risk (Pinheiro et al., 2012), one study found a not significant trend of lower BDNF levels in depressed mothers (Lommatzsch et al., 2006) and one study found higher BDNF levels in SSRI-treated depressed mothers and lower levels in non-SSRI treated healthy pregnant women (Pawluski et al., 2018). In contrast, two studies found no significant associations between serum BDNF levels and perinatal depression (Akbaba et al., 2018; Guintivano et al., 2018). Depressive symptoms were assessed mainly with the Edinburgh postnatal depression scale (EPDS) (Dhiman et al., 2014; Gao et al., 2016; Guintivano et al., 2018; Lommatzsch et al., 2006; Pawluski et al., 2018), the Edinburgh Postnatal Depression Inventory (EPDI) (Akbaba et al., 2018), the Beck Depression Inventory (BDI) (Gazal et al., 2012; Sonmez et al., 2019), the Patient Health Questionnaire-9 (PHQ-9) (Fung et al., 2015; Yang et al., 2017, 2016), the Hamilton Rating Scale for Depression (HAMD) (Pawluski et al., 2018), the Center for Epidemiologic Studies Depression Scale (CES-D) (Christian et al., 2016) and the Mini International Neuropsychiatric Interview (MINI) (Pinheiro et al., 2012).
3.2. Serum BDNF levels and postpartum depression As regard postpartum depression, six studies investigated serum BDNF levels in depressed women after birth. Specifically, Sonmez et al. (2019) found that cord blood BDNF level were significantly lower among infants of 23 pregnant women with perinatal depression compared to infants of 25 healthy pregnant women. However, no correlations between BDNF level and severity of depressive symptoms were detected. Moreover, Dhiman et al. (2014) explored BDNF levels among 103 women at 24–40 h post-delivery and at six weeks postpartum. In accordance with previous studies, the authors detected low serum BDNF levels in women with postpartum depression compared to healthy women. Similarly, in a following study, Gao et al. (2016) enrolled 340 women within 24–48 h after delivery and collected serum BDNF levels. After 3 months’ follow-up, 37 out of 340 women met the criteria for postpartum depression according to EPDS score and they had significant lower serum BDNF levels compared to women without postpartum depression. Additionally, the authors found a significant association between stressful life events and reduced BDNF levels in all subjects. In accordance with these results, in a casecontrol study, Gazal et al. (2012) compared BDNF concentrations among 36 mothers with postpartum depression and 36 healthy mothers. The authors found a significant association between lower BDNF levels and postpartum depression between 30 and 90 days after
3. Results 3.1. Serum BDNF levels and antepartum depression Overall, seven studies investigated serum BDNF levels in antepartum depression. Interestingly, a large cross-sectional study including 968 pregnant women (Fung et al., 2015) reported that lower maternal mean serum BDNF levels at the 16th gestational week were associated with augmented odds of antepartum depression, although no association between BDNF levels and depressive symptoms severity was found. 2
3
Cohort
Cohort
Yang et al. (2017)
Cohort
Yang et al. (2016)
Case control
Cross-sectional
Fung et al. (2015)
Guintivano et al. (2018)
Case control
Dhiman et al. (2014)
Longitudinal
Cross-sectional
Pinheiro et al. (2012)
Christian et al. (2016)
Case control
Gazal et al. (2012)
Longitudinal
Longitudinal
Lommatzsch et al. (2006)
Gao et al. (2016)
Study design
Article
982 Pr women
1517 Pr women (549 PPD, 968 HC)
139 Pr women
2899 Pr women (1591 With no PTSD or depression, 225 with isolated depression, 507 with isolated PTSD, 576 with comorbid PTSDdepression 944 BDNF 340 mothers (37 PPD, 303 no-PPD)
968 Pr women (688 depressed, 280 nondepressed)
103 mothers (58 PPD, 45 no-PPD)
190 mothers (29 PPAD, 161 no-PPAD)
72 mothers (36 PPD, 36 no-PPD)
80 women (40 Pr, 40 non-Pr)
Sample
Table 1 Summary of the studies described in the review.
Not specified
28 ± 6.2
17–45
24.8 ± 4.16
HAMD
EPDS Abuse and Trauma Inventory ESI PBQ PHQ-9
MINI
CES-D
EPDS
PCL-C PHQ-9
28.2 ± 6.2 28.0 ± 6.5
29.1 ± 2
PHQ-9
MINI, Life Events and Coping Scales EPDS
BDI
EPDS
Clinical evaluation
> 18
Not specified
> 18
18-46
21–40
Age (years old)
Before 16th gestational week
1st, 2nd, 3rd trimester, 4-11 weeks after delivery 6 weeks postpartum
3 months after delivery
Before 16th gestational week
24-48 hours after delivery and after 6 weeks Before 16th gestational week
45-90 days after delivery
30-90 days after delivery
30th,37th week of gestation, 1 and 8 weeks after delivery
Timing of clinical evaluation
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood
Peripheral venous blood Peripheral venous blood
Peripheral venous blood
BDNF sampling
Before 16th gestational week
1st, 2nd, 3rd trimester, 4-11 weeks after delivery 6 weeks postpartum
24-48 hours after delivery
Before 16th gestational week
24-48 hours after delivery and after 6 weeks Before 16th gestational week
45-90 days after delivery
30-90 days after delivery
30th,37th week of gestation, 1 and 8 weeks after delivery
Timing of blood sampling
S100B
None
Estradiol, Progesterone, Oxytocin, Allopregnanalone
Serum cortisol
None
None
None
None
None
SSRI
Not specified
Not specified
None
None
None
None
Not specified
None
None
(continued on next page)
Moderate antepartum depression was associated with lower serum BDNF levels compare with mild/no antepartum depression
Depressed pregnant women had lower BDNF serum level than non-depressed pregnant women Serum BDNF concentrations were lower among women with comorbid PTSDdepression as compared with women without either condition, even if with not statistical significance Serum BDNF levels after delivery were significantly lower in women with PPD compared to with women with no-PPD Depressive symptoms and serum BDNF levels were inversely associated only during the 3rd trimester No significant differences were detected between groups in BDNF levels
BDNF decreased in pregnant women. BDNF serum levels not significantly lower in depressed mother compared to mothers without depression Depressed mothers showed decreased BDNF serum levels compared to healthy mothers BDNF was lower in PPAD mothers with suicide risk compared to PPAD mothers without suicide risk Depressed mothers showed decreased BDNF serum level compared to healthy mothers
None
Serum levels of 17betaestradiol, progesterone, cortisol, dehydroepiandrosterone sulfate
None
Main results
Concomitant therapy
Other measurements
G.M. Mandolini, et al.
Journal of Affective Disorders xxx (xxxx) xxx–xxx
Cohort
Sonmez et al. (2019)
28.94 ± 5.98
27.76 ± 5.31
Age (years old)
BDI
EPDI
HAMA EPDS SCID-I
Clinical evaluation
During delivery/ cesarean section
Not specified
26th, 28th, 36th gestational week
Timing of clinical evaluation
Umbilical cord
Umbilical cord
Peripheral venous blood
BDNF sampling
During delivery/ cesarean section
During delivery/ cesarean section
36th gestational week
Timing of blood sampling
FGF2 TNF-alfa Neopterin None
NT-3
Other measurements
None
Not specified
Concomitant therapy
Cord blood BDNF levels in infants of depressed mothers were significantly lower compared to infants of healthy mothers
BDNF levels did not differ between the three groups
SSRI-treated group had higher BDNF serum level. Lower BDNF level were associated with increased depression only in non-SSRI treated group.
Main results
AD = Anxiety Disorder; BDI: Beck Depression Inventory; CES-D = Center for Epidemiologic Studies Depression Scale; EPDI = Edinburgh Postnatal Depression Inventory; EPDS = Edinburgh Postnatal Depression Scale; ESI = Everyday Stressors Index; HAMA = Hamilton Rating Scale for Anxiety; HAMD = Hamilton Rating Scale for Depression; MDD = Major Depressive Disorder; MINI = Mini International Neuropsychiatric Interview; non-Pr = Non Pregnant; no-PPD = Without Postpartum Depression; PBQ = Postpartum Bonding Questionnaire; PCL-C = The Posttraumatic Stress Disorder Checklist – Civilian Version; PHQ-9 = Patient Health Questionnaire-9; PPAD = Postpartum Affective Disorder; PPD = Postpartum Depression; Pr = Pregnant; S100 = S100 Calcium-Binding Protein B; SCID-I = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; SSRI = Selective serotonin Reuptake Inhibitors Reuptake.
50 (23 MDD, 25 HC)
136 (25 MDD, 18 AD, 93 HC)
Cohort
Akbaba et al. (2018)
Sample
86 Pr women (22-25 SSRI-treated, 33-38 nonSSRI-treated)
Study design
Pawluski et al. (2018)
Article
Table 1 (continued)
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delivery; moreover, the severity of depressive symptoms assessed through the BDI negatively correlated with BDNF levels. Additionally, Pinheiro et al. (2012) carried out a cross-sectional study on 190 women who were enrolled during their prenatal period and were assessed for the presence of postpartum affective disorder (PPAD) between 45 and 90 days after delivery. Remarkably, the authors found that, among women with PPAD (15.3% of the total sample including women with depression, mania/hypomania and mixed episodes), serum BDNF levels were significantly lower in those with suicide risk compared to women without it. However, no significant differences in BDNF levels were detected within the PPAD sample with suicide risk, regardless the presence of manic, depressive or mixed episodes. Lastly, reduced serum BDNF levels were detected in those mothers with three or more perinatal stressful live events. In contrast, one study conducted by Guintivano et al. (2018) showed no statistically significant differences in BDNF levels collected at 6 weeks port-partum between 549 women with postpartum depression and 968 healthy mothers.
regulation of perinatal neurotrophic factors, such as BDNF. 5. Limitations The present review should be considered in light of some limitations. First, BDNF levels were assessed at different time points during pregnancy and in the postpartum period, therefore not all the studies could be directly compared. Nevertheless, the evidence reported by the individual studies suggests that a reduction in BDNF levels among depressed pregnant women might characterized the whole perinatal period. Second, none of the studies investigated the presence of BDNF polymorphisms that are known to influence BDNF function (Zhao et al., 2017). Third, some other potential cofounding factors, which are known to have an influence on both BDNF levels and depressive symptoms, such as age, ethnicity, educational level, diet habits, severity of psychopathological symptoms, number of platelets, might have negatively contributed to the generalizability of the results (Hammen, 2018; Hing et al., 2018). Finally, BDNF, like all neurotrophins, is initially synthesized as a precursor (pro-BDNF), which is then processed into mature BDNF. However, although it is well known that these two forms of BDNF, pro-BDNF and mature BDNF, elicit opposite effects in neural functions (Hempstead, 2015) no studies discriminated between pro-BDNF and mature BDNF.
4. Discussion Overall, the majority of studies demonstrated reduced maternal BDNF levels in perinatal depression, either during pregnancy (Christian et al., 2016; Fung et al., 2015; Yang et al., 2017, 2016) or after delivery (Christian et al., 2016; Dhiman et al., 2014; Gao et al., 2016; Gazal et al., 2012; Sonmez et al., 2019), ultimately highlighting that maternal BDNF down-regulation seemed to characterize depressed mothers during both ante- and postpartum. Interestingly, these results are not surprising especially because it has been reported that the decrease in BDNF levels could be responsible for neuronal cell loss and atrophy in specific cerebral regions, such as hippocampus and prefrontal cortex, which have been found reduced in depressed subjects (Duman and Li, 2012). Additionally, recent animal models further supported the central role BDNF in depression by demonstrating that knock-out mice for BDNF had reduced neurogenesis in specific hippocampal regions and showed depressive and anhedonic-like behaviors (Taliaz et al., 2010). Furthermore, the link between BDNF and perinatal depression might be also explained by the interaction of BDNF with selective biological mechanisms. Specifically, Gao et al. (2016) underlined how BDNF interacts with the serotonin system to control neural development and plasticity and to induce significant hormonal changes within systems involved in depressive disorders. Moreover, lower BDNF concentrations might also represent a genetic vulnerability in subjects at risk for depression that may interact with other factors, such as stressful life events, in order to trigger depressive symptoms (Gao et al., 2016; Pinheiro et al., 2012; Sonmez et al., 2019). Also, BDNF might represent a valid mediator of antidepressant treatment efficacy, as shown by the increase in BDNF levels in SSRI-treated women with antepartum depression (Pawluski et al., 2018). In contrast, some studies also suggested that, based on the assumption that pregnancy is characterized by various physiological changes that include nervous, endocrine, immune and haematological systems (Datta et al., 2010), a decrease in BDNF levels may represent a clinical status that accompanies all women during perinatal period regardless of depressive symptoms (Lommatzsch et al., 2006). Moreover, it has been also proposed that a neurotrophic down-regulation during pregnancy might increase the risk for perinatal depression only in vulnerable women rather than being a biomarker of depression (Lommatzsch et al., 2006). However, this hypothesis could not be compared with other evidence since the study by Lommatzsch et al. (2006) was the only one where non-pregnant subjects were enrolled as a comparison group. Finally, from some of the abovementioned evidence it emerged that prenatal stress may represent a relevant factor to be considered (Pinheiro et al., 2012; Gao et al., 2016), further supporting its capacity to disrupt maternal endocrine, nervous and immune systems, with deleterious consequences for both mothers and their offspring (Cardwell, 2013), as well as its role in the
6. Conclusions In conclusion, the present review suggests that maternal serum BDNF levels could represent one of the potential biomarkers of perinatal depression in both ante- and postpartum period. Moreover, from the abovementioned results emerged that BDNF could be helpful not only for predicting depressive symptoms in women at risk, but also to monitor response to antidepressant treatment. However, the debate on the role of BDNF in perinatal depression is still open, since some authors did not consider lower BDNF levels a biological factor of depressive disorders, but rather a consequence of the depressive state (Bus and Molendijk, 2016). Therefore, longitudinal multi-centric investigations from the 1st gestational week until the postpartum period and studies with larger samples and a monthly assessment of depressive symptoms, pro-BDNF/BDNF levels and BDNF polymorphisms, are warranted. Role of funding source PB was partially supported by grants from the Italian Ministry of Health (RF-2016-02364582). CRediT authorship contribution statement G.M. Mandolini: Writing - original draft. M. Lazzaretti: Writing original draft. G. Delvecchio: Writing - review & editing. C. Bressi: Writing - review & editing. J.C. Soares: Writing - review & editing. P. Brambilla: Writing - review & editing. Declaration of Competing Interest None. Acknowledgement None. References Akbaba, N., Annagür, B.B., Annagür, A., Akbulut, H., Akyürek, F., Çelık, Ç, 2018. Neurotrophins and neuroinflammation in fetuses exposed to maternal depression and anxiety disorders during pregnancy: a comparative study on cord blood. Arch.
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G.M. Mandolini, et al. Women's Ment. Health. American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental Disorders, fifth ed. DSM-5, New York American Psychiatric Press Inc. Bus, B.A.A., Molendijk, M.L., 2016. [The neurotrophic hypothesis of depression]. Tijdschr. Psychiatr. Cardwell, M.S., 2013. Stress: pregnancy considerations. Obstet. Gynecol. Surv. Christian, L.M., Mitchell, A.M., Gillespie, S.L., Palettas, M., 2016. Serum brain-derived neurotrophic factor (BDNF) across pregnancy and postpartum: associations with race, depressive symptoms, and low birth weight. Psychoneuroendocrinology. Comasco, E., Sylvén, S.M., Papadopoulos, F.C., Oreland, L., Sundström-Poromaa, I., Skalkidou, A., 2011. Postpartum depressive symptoms and the BDNF Val66Met functional polymorphism: effect of season of delivery. Arch. Women's Ment. Health. Datta, S., Kodali, B.S., Segal, S., 2010. Maternal physiological changes during pregnancy, labor, and the postpartum period. Obstetric Anesthesia Handbook. Dhiman, P., Say, A., Rajendiren, S., Kattimani, S., Sagili, H., 2014. Association of foetal APGAR and maternal brain derived neurotropic factor levels in postpartum depression. Asian J. Psychiatry. Duan, C., Hare, M.M., Staring, M., Deligiannidis, K.M., 2019. Examining the relationship between perinatal depression and neurodevelopment in infants and children through structural and functional neuroimaging research. Int. Rev. Psychiatry. Duman, R.S., Li, N., 2012. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos. Trans. R. Soc. B. Figueira, P., Malloy-Diniz, L., Campos, S.B., Miranda, D.M., Romano-Silva, M.A., De Marco, L., Neves, F.S., Correa, H., 2010. An association study between the Val66Met polymorphism of the BDNF gene and postpartum depression. Arch. Women's Ment. Health. Fung, J., Gelaye, B., Zhong, Q.Y., Rondon, M.B., Sanchez, S.E., Barrios, Y.V., Hevner, K., Qiu, C., Williams, M.A., 2015. Association of decreased serum brain-derived neurotrophic factor (BDNF) concentrations in early pregnancy with antepartum depression. BMC Psychiatry. Gao, X., Wang, J., Yao, H., Cai, Y., Cheng, R., 2016. Serum BDNF concentration after delivery is associated with development of postpartum depression: a 3-month follow up study. J. Affect. Disord. Gazal, M., Motta, L.S., Wiener, C.D., Fernandes, J.C., Quevedo, L.Á., Jansen, K., Pinheiro, K.A.T., Giovenardi, M., Souza, D.O., Da Silva, R.A., Pinheiro, R.T., Portela, L.V., Oses, J.P., 2012. Brain-derived neurotrophic factor in post-partum depressive mothers. Neurochem. Res. Guintivano, J., Sullivan, P.F., Stuebe, A.M., Penders, T., Thorp, J., Rubinow, D.R., Meltzer-Brody, S., 2018. Adverse life events, psychiatric history, and biological predictors of postpartum depression in an ethnically diverse sample of postpartum women. Psychol. Med. Hammen, C., 2018. Risk factors for depression: an autobiographical review. Ann. Rev. Clin. Psychol.
Hempstead, B.L., 2015. Brain-derived neurotrophic factor: three ligands, many actions. Trans. Am. Clin. Climatol. Assoc. Hing, B., Sathyaputri, L., Potash, J.B., 2018. A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder. Am. J. Med. Genet. Part B. Lommatzsch, M., Hornych, K., Zingler, C., Schuff-Werner, P., Höppner, J., Virchow, J.C., 2006. Maternal serum concentrations of BDNF and depression in the perinatal period. Psychoneuroendocrinology. Malhi, G.S., Mann, J.J., 2018. Depression. Lancet. Molendijk, M.L., Spinhoven, P., Polak, M., Bus, B.A.A., Penninx, B.W.J.H., Elzinga, B.M., 2014. Serum BDNF concentrations as peripheral manifestations of depression: Evidence from a systematic review and meta-analyses on 179 associations (N=9484). Mol. Psychiatry. Pawluski, J.L., Brain, U., Hammond, G.L., Oberlander, T.F., 2018. Selective serotonin reuptake inhibitor effects on neural biomarkers of perinatal depression. Arch. Women's Ment. Health 1–5. Pinheiro, R.T., Pinheiro, K.A.T., Da Cunha Coelho, F.M., De Ávila Quevedo, L., Gazal, M., Da Silva, R.A., Giovenardi, M., Lucion, A.B., De Souza, D.O., Portela, L.V., Oses, J.P., 2012. Brain-derived neurotrophic factor levels in women with postpartum affective disorder and suicidality. Neurochem. Res. Serra-Millàs, M., 2016. Are the changes in the peripheral brain-derived neurotrophic factor levels due to platelet activation? World J. Psychiatry. Sonmez, E.O., Yilmaz, E., Uguz, F., Sahingoz, M., Sonmez, G., Gokmen, Z., Gezginc, K., Kucur, R., 2019. Effect of maternal depression on brain-derived neurotrophic factor levels in fetal cord blood. Klinik Psikofarmakoloji Bul. 17 (2), 308–313. Taliaz, D., Stall, N., Dar, D.E., Zangen, A., 2010. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol. Psychiatry. Woody, C.A., Ferrari, A.J., Siskind, D.J., Whiteford, H.A., Harris, M.G., 2017. A systematic review and meta-regression of the prevalence and incidence of perinatal depression. J. Affect. Disord. Yang, N., Gelaye, B., Zhong, Q., Rondon, M.B., Sanchez, S.E., Williams, M.A., 2016. Serum brain-derived neurotrophic factor (BDNF) concentrations in pregnant women with post-traumatic stress disorder and comorbid depression. Arch. Women's Ment. Health. Yang, N., Levey, E., Gelaye, B., Zhong, Q.Y., Rondon, M.B., Sanchez, S.E., Williams, M.A., 2017. Correlates of early pregnancy serum brain-derived neurotrophic factor in a Peruvian population. Arch. Women's Ment. Health. Zhao, M., Chen, L., Yang, J., Han, D., Fang, D., Qiu, X., Yang, X., Qiao, Z., Ma, J., Wang, L., Jiang, S., Song, X., Zhou, J., Zhang, J., Chen, M., Qi, D., Yang, Y., Pan, H., 2017. BDNF Val66Met polymorphism, life stress and depression: a meta-analysis of geneenvironment interaction. J. Affect. Disord.
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