AND

There is some evidence of epigenetic changes in AND. In a series of studies that began with animal research and extended into women, the Payne and Kaminsky group identified altered DNA methylation at two loci at the heterochromatin protein 1, binding protein 3 (HP1BP3 – associated with oestrogen signalling) and tetratricopeptide repeat domain 9B (TTC9B – associated with synaptic plasticity) as predictors of AND.^{Reference Osborne, Clive, Kimmel, Gispen, Guintivano and Brown5,Reference Payne, Osborne, Cox, Kelly, Meilman and Jones6} Their study included blood samples from four prospectively collected cohorts, with DNA methylation data available from the first, second and/or third trimesters, depending on the cohort. Research has also linked epigenetic modifications in the nuclear receptor subfamily 3 group C member 1 (NR3C1 – associated with glucocorticoid signalling) gene to AND, with a positive correlation between increased methylation at CpG 4 and antenatal depressive symptoms.^{Reference Castro, Gardini, Iliadis, Ehlert, Kallak and Skalkidou7} Another study found that DNA methylation changes in T-lymphocyte genes, particularly within a CD3 gene CpG cluster, were associated with AND.^{Reference Robakis, Lee, Werner, Liu, Miller and Wylie8}

In addition, placental DNA methylation analysis identified 16 CpGs associated with AND, including two CpGs linked to the expression of ADAM23 (a disintegrin and metalloproteinase domain-containing protein 23) and CTDP1 (CTD phosphatase subunit 1) – genes implicated in neurodevelopment and neuropsychiatric disorders.^{Reference Tesfaye, Chatterjee, Zeng, Joseph and Tekola-Ayele9} These findings suggest that prenatal depression may induce epigenetic changes in the placenta, potentially influencing fetal brain development.

PPD

A growing body of evidence suggests that DNA methylation variations can serve as predictive biomarkers of PPD. The Payne and Kaminsky biomarkers at TTC9B and HPIBP3, mentioned above under AND, were first studied for PPD. The group found that DNA methylation at two loci on these genes remains stable throughout pregnancy and significantly predicts PPD (area under the curve (AUC) 0.87).^{Reference Guintivano, Arad, Gould, Payne and Kaminsky10} These initial studies were carried out in women who were euthymic in pregnancy and went on to develop PPD. Subsequent studies in independent cohorts provided further validation of the predictive value of these markers, and identified that the two genes in question were involved in oestrogen signalling (HP1BP3) and synaptic plasticity (TTC9B).^{Reference Osborne, Clive, Kimmel, Gispen, Guintivano and Brown5,Reference Payne, Osborne, Cox, Kelly, Meilman and Jones6}

Several studies have also examined epigenetic changes in the oxytocin receptor (OXTR, associated with oxytocin receptor) gene. Bell et al^{Reference Bell, Carter, Steer, Golding, Davis and Steffen11} revealed an association between higher methylation levels at CpG site (−934) and increased PPD risk in women who were euthymic in pregnancy, particularly in those carrying the rs53576 GG genotype. Kimmel et al^{Reference Kimmel, Clive, Gispen, Guintivano, Brown and Cox12} identified a significant association between PPD and an intronic region of OXTR located proximal to an oestrogen receptor binding region; CpGs in the region interacted with adverse life events to mediate the risk for PPD. Notably, adverse life events was associated with significantly increased DNA methylation in women who did not develop PPD.^{Reference Kimmel, Clive, Gispen, Guintivano, Brown and Cox12} This finding was replicated in an independent cohort; moreover, DNA methylation in the region was negatively correlated with oestradiol (E2) ratios, and the interaction between E2 and OXTR methylation was positively associated with the ratio of allopregnanolone (ALLO) to progesterone (PROG). Interestingly, OXTR DNA methylation patterns have also been identified as potential epigenetic biomarkers of childhood adversity, with associations observed between PPD and mother–child bonding.^{Reference Robakis, Zhang, Rasgon, Li, Wang and Roth13} Furthermore, lower OXTR methylation was associated with increased sensitivity to postnatal depressive symptoms in Latina mothers.^{Reference Rodriguez, Smith, Harris, Nephew, Santos and Murgatroyd14}

Other studies identified additional epigenetic markers of PPD. One study identified positive correlation of NR3C1 methylation at CpG 2 with postpartum depressive symptoms.^{Reference Castro, Gardini, Iliadis, Ehlert, Kallak and Skalkidou7} Another study investigated inflammatory markers of PPD and identified that lower TNF-α expression in late pregnancy was associated with PPD in patients who had high methylation at the FOXP3 (forkhead box P3) Treg-cell-specific demethylated region (TSDR). This suggests that discrimination-induced stress may enhance hypothalamic-pituitary-adrenal (HPA) activity, leading to immune suppression and altered inflammatory gene regulation.^{Reference Sluiter, Incollingo Rodriguez, Nephew, Cali, Murgatroyd and Santos15}

PND

One study found that persistent depressive symptoms occurring during the perinatal period (either prenatally, postpartum or both) were associated with higher OXTR methylation within exon 3 and lower methylation in the intergenic region (IGR) between the oxytocin (OXT) and vasopressin (AVP) genes.^{Reference King, Robins, Chen, Yerko, Zhou and Nagy16}

Perinatal anxiety

Two of the studies covered in the PPD section also investigated epigenetic changes in perinatal anxiety.^{Reference Robakis, Lee, Werner, Liu, Miller and Wylie8,Reference Sluiter, Incollingo Rodriguez, Nephew, Cali, Murgatroyd and Santos15} One study observed that DNA methylation changes in T-lymphocyte genes, particularly within a CD3 gene CpG cluster, were associated with antenatal anxiety.^{Reference Robakis, Lee, Werner, Liu, Miller and Wylie8} The other study identified lower TNF-α expression in late pregnancy was associated with postpartum anxiety symptoms in those with elevated methylation at the FOXP3 TSDR.^{Reference Sluiter, Incollingo Rodriguez, Nephew, Cali, Murgatroyd and Santos15}

pOCD

The Payne and Kaminsky group examined the epigenetic markers they identified for PPD in pOCD. They found that increased methylation at one of these same markers, TTC9B, along with increased methylation at the membrane-spanning 4A gene family (MS4A7), predicted OCD symptom exacerbation during pregnancy with moderate accuracy. Incorporating a methylome-wide approach, they further identified a DNA methylation proxy of the ratio of monocytes to non-monocytes, which improved the accuracy of the prediction model (AUC 0.75, 95% CI: 0.59–0.91). While promising, the small sample size (N = 24) and balanced case–control distribution may overestimate predictive performance. Further validation in larger, diverse cohorts is needed to confirm clinical applicability and explore whether these epigenetic changes are causally linked to pOCD.^{Reference Kaminsky, Osborne, Guglielmi, Jones, Grenier and Clark17}

PMDD

A study using a comparative whole-genome RNA-seq analysis between the mouse ventral hippocampus and lymphoblastoid cell lines from women with and without PMDD identified shared epigenetic biomarkers across species and cell types, including epigenetic modifiers of the ESC/E(Z) complex (ESC/E(Z):Extra Sex Combs/Enhancer of Zeste), a key regulator in the response to ovarian steroids.^{Reference Marrocco, Einhorn, Petty, Li, Dubey and Hoffman18}

AND

A study of 96 third-trimester pregnant women found that those with elevated depression scores (Montgomery–Åsberg Depression Rating Scale – self-rating version; MADRS-S ≥ 13) had significantly lower ALLO levels and a negative correlation with concurrent self-reported depression scores,^{Reference Hellgren, Åkerud, Skalkidou, Bäckström and Sundström-Poromaa26} while another study of 14 women linked lower PROG and combined ALLO and pregnanolone levels in the second trimester to increased negative emotional reactions to stress.^{Reference Crowley, O’Buckley, Schiller, Stuebe, Morrow and Girdler27}

Our group found no significant association between concurrent depressive symptoms and PROG and ALLO levels during pregnancy in women with a prior mood disorder (n = 60).^{Reference Osborne, Gispen, Sanyal, Yenokyan, Meilman and Payne28} Similarly, in another study (n = 111) we found no significant relationship between ALLO levels and depression during pregnancy.^{Reference Standeven, Osborne, Betz, Yenokyan, Voegtline and Hantsoo29} Another study in 284 pregnant women found no relationship between ALLO and concurrent mood symptoms during pregnancy,^{Reference Hellgren, Comasco, Skalkidou and Sundström-Poromaa30} but did find that those who were homozygous for the minor allele in a polymorphism on the AKR1C2 gene (the gene for a key enzyme in the PROG metabolic pathway) had lower levels of ALLO and a steeper rise in depressive symptoms across pregnancy.

PPD

While at least one older study found no significant differences in postpartum ALLO levels between women with and without PPD at 9 weeks or 6 months postpartum,^{Reference Epperson, Gueorguieva, Czarkowski, Stiklus, Sellers and Krystal31} our group identified both cross-sectional and predictive relationships between NASs and postpartum depressive symptoms. We reported that higher ALLO levels at week 6 postpartum were associated with worse mood symptoms^{Reference Standeven, Osborne, Betz, Yenokyan, Voegtline and Hantsoo29} and found that lower ALLO levels in euthymic women during the second trimester predicted postpartum-onset PPD, with each additional ng/mL decreasing the odds of developing PPD by 63%.^{Reference Osborne, Gispen, Sanyal, Yenokyan, Meilman and Payne28} Similarly, a subsequent study found that participants with a one-unit increase in PROG as well as in the isoallopregnanolone/pregnanolone ratio at the third trimester (T3) had higher odds of developing PPD, while those with a one-unit increase in the log pregnanolone/PROG ratio had lower odds.^{Reference Osborne, Etyemez, Pinna, Alemani, Standeven and Wang32} Conversely, another found no differences in either pregnancy or postpartum levels of pregnanolone, ALLO, pregneolone or their ratios to PROG between those with and without PPD.^{Reference Deligiannidis, Sikoglu, Shaffer, Frederick, Svenson and Kopoyan33} Recent clinical trials with synthetic ALLO also support a role for GABAergic NASs in PPD.^{Reference Meltzer-Brody, Colquhoun, Riesenberg, Epperson, Deligiannidis and Rubinow34} These findings suggest that it may not be the absolute levels of NASs that matter, but rather the dynamics of their withdrawal postpartum and changes in GABA-A receptor sensitivity, which may contribute to psychiatric symptoms. This underscores the importance of precise timing in evaluating potential biomarkers.

PND

Another study of 75 women found that those at risk for depression during pregnancy or the postpartum (The Edinburgh Postnatal Depression Scale (EPDS) >10 or a history of PND or MDD) had elevated levels of 5-alpha-dihydroprogesterone (5α-DHP) and 5-beta-dihydroprogesterone (5β-DHP) (the intermediary molecules between PROG and, respectively, ALLO and pregnanolone) and ALLO compared to healthy controls,^{Reference Deligiannidis, Kroll-Desrosiers, Tan, Dubuke and Shaffer35} while the same group showed that at-risk women also had higher PROG and pregnanolone levels, with pregnanolone positively associated with Hamilton Rating Scale for Depression (HAMD-17) and Hamilton Anxiety Rating Scale (HAM-A) scores, and lower GABA levels negatively associated with these scores.^{Reference Deligiannidis, Kroll-Desrosiers, Tan, Dubuke and Shaffer35}

In light of this inconclusive evidence in AND, PPD and PND, some researchers have also explored ratios of NASs to their precursors in the PROG metabolic pathway. The Deligiannidis group^{Reference Deligiannidis, Kroll-Desrosiers, Tan, Dubuke and Shaffer35} found significant differences in the ratio of ALLO to 5α-DHP among participants with PND, those at risk and healthy controls, and in the ratio of pregnanolone to 5β-DHP between healthy controls and at-risk women, although no differences were noted between healthy controls and those with PND. In addition, another study reported a correlation between increased ratios of ALLO to PROG and pregnanolone to PROG with concurrent depressive symptoms during the first and second trimesters compared to healthy controls in a diverse population.^{Reference Wenzel, Pinna, Eisenlohr-Moul, Bernabe, Tallon and Nagelli36}

A recent meta-analysis of 13 studies (2509 women, including 849 with peripartum depressive symptoms (PDSs), encompassing several of the studies listed above) examined the relationship between ALLO blood concentrations and PDSs. Overall, no significant differences in ALLO levels were observed between women with and without PDSs at any time point during the second or third trimesters or postpartum (p > 0.05). However, subgroup analyses revealed higher ALLO levels in women with PDSs at gestational weeks 21–24 and 25–28. Methodological factors, including sample type and analytical techniques, influenced the results. These findings underscore the challenges posed by heterogeneous time points, cohorts and methods in understanding the role of NASs like ALLO in PDSs.^{Reference Schoretsanitis, Osborne, Sundström-Poromaa, Wenzel, Payne and Barbui37}

Perinatal anxiety

Our group found a correlation between low ALLO levels in the second trimester and subsequent postpartum anxiety,^{Reference Osborne, Betz, Yenokyan, Standeven and Payne38} while higher ALLO levels were associated with increased concurrent anxiety symptoms at 6 weeks postpartum.^{Reference Standeven, Osborne, Betz, Yenokyan, Voegtline and Hantsoo29} Our recent study broadened this scope to explore the entire PROG metabolic pathway in women with and without clinically significant anxiety, excluding those with comorbid depression. We found a significant moderating effect of anxiety group on the relationship between PROG and ALLO. In particular, when compared to healthy controls, women with anxiety exhibited a more pronounced shift from the third trimester to postpartum week 6 in metabolism towards the end-points of the PROG metabolic pathway.^{Reference Etyemez, Miller, Voegtline, Özdemir, Standeven and Santovito39} We also found that women with at least one minor allele at AKR1C2 rs1937863 (the gene for a key enzyme in the PROG metabolic pathway) had higher concentrations of 5α-DHP and a lower ratio of ALLO:5α-DHP at T3.

The variability in these results may stem from differences in study designs, including how anxiety is defined and timed, the presence of comorbid psychiatric disorders and the methods used for quantifying NASs.

PMDD

There is a substantial body of literature on fluctuations in NASs throughout the menstrual cycle and their role in the symptoms of PMDD. The primary NASs whose fluctuations have been studied during the menstrual cycle and are relevant to PMDD include PROG, its metabolite ALLO and E2. Ovarian steroid hormone levels may not differ between women with PMDD versus without;^{Reference Nguyen, Reuter, Gaikwad, Rotroff, Kucera and Motsinger-Reif40} rather, symptom onset in PMDD may be connected with an abnormal response caused by altered sensitivity of central nervous system receptors to normal hormonal fluctuations.^{Reference Dubey, Hoffman, Schuebel, Yuan, Martinez and Nieman41} Researchers have proposed the Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC) framework, suggesting that ALLO mediates hormonal effects on mood. This model links atypical responses to E2 and PROG fluctuations with distinct affective changes, offering a transdiagnostic approach to hormone sensitivity in psychiatric disorders.^{Reference Peters, Schmalenberger, Eng, Stumper, Martel and Eisenlohr-Moul42} Some evidence shows that PMDD symptoms start with the increase in PROG and E2 levels during the luteal phase, worsen in the luteal phase as hormone levels decline and improve with the start of menstruation.^{Reference Cunningham, Yonkers, O’Brien and Eriksson43} A recent study did report, however, that PROG had a distinct pattern in PMDD, featuring an early leftward shift that begins in the periovulatory phase followed by a rapid decrease during the mid to late luteal phase.^{Reference Hamidovic, Mumford, Schisterman, Davis and Soumare44} Other studies lend support to a difference in hormone levels. Elevated ALLO levels and ALLO/PROG ratios in women with PMDD compared to those without PMDD have also been observed, with a curious inverse relationship between ALLO levels and symptom severity.^{Reference Girdler, Straneva, Light, Pedersen and Morrow45} Another study found that isoallopregnanolone potentially alleviates negative mood symptoms by antagonising ALLO’s effects on the GABA-A receptor.^{Reference Bixo, Johansson, Timby, Michalski and Bäckström46} Brain activity in emotion-processing regions during the late luteal phase has been shown to correlate with the isoallopregnanolone/ALLO ratio in PMDD, while the opposite was observed in controls.^{Reference Stiernman, Dubol, Comasco, Sundström-Poromaa, Boraxbekk and Johansson47}

Furthermore, PMDD patients show altered sensitivity to ALLO across the menstrual cycle, with changes in saccadic eye velocity (SEV).^{Reference Timby, Bäckström, Nyberg, Stenlund, Wihlbäck and Bixo48} This study aimed to examine how PMDD patients respond to intravenous ALLO across the menstrual cycle, using SEV as a measure of GABA-A receptor activity. PMDD patients exhibited a decreased SEV response in the follicular phase compared to the luteal phase, while controls showed the opposite pattern. These findings suggest that PMDD patients have altered sensitivity to ALLO, which is influenced by the menstrual cycle.^{Reference Timby, Bäckström, Nyberg, Stenlund, Wihlbäck and Bixo48}

There is also evidence of disrupted ALLO–GABA-A receptor interactions, contributing to PMDD symptoms and increased stress sensitivity, particularly because of dysregulation of the HPA axis during the luteal phase.^{Reference Hantsoo and Epperson49} A randomised study showed that blocking 5-alpha reductase (which converts PROG to ALLO) reduced PMDD symptoms, supporting the idea that NAS regulation is involved in PMDD.^{Reference Martinez, Rubinow, Nieman, Koziol, Morrow and Schiller50}

PMDD also involves disrupted autonomic nervous system regulation, with lower heart rate variability (HRV) and altered stress responses.^{Reference Hamidovic, Davis, Soumare, Naveed, Ghani and Semiz51} Baseline ALLO levels significantly predicted peak high frequency of the heart rate (HF-HRV) changes in the PMDD group, suggesting its role in modulating stress responses in PMDD.^{Reference Hamidovic, Davis, Soumare, Naveed, Ghani and Semiz51} Another study investigated the relationship between neuroactive PROG metabolites, such as ALLO, and HPA axis function in women with PMDD. While there were no differences in diurnal cortisol secretion or dexamethasone suppression between PMDD patients and healthy controls, higher ALLO levels in PMDD patients were associated with blunted nocturnal cortisol levels compared to controls with lower ALLO. This suggests that diurnal cortisol secretion in PMDD may be influenced by luteal phase ALLO levels, potentially explaining inconsistencies in previous studies of HPA axis function in PMDD.^{Reference Segebladh, Bannbers, Moby, Nyberg, Bixo and Bäckström52}

The studies on PMDD inevitably point toward the contribution of fluctuations of the levels of such hormones, including PROG and its metabolite ALLO, to causation and exacerbation of PMDD. The key findings point towards the altered responsiveness of the central nervous system toward such fluctuations of the hormones, and not toward abnormalities of the levels of the hormones, and this may be contributing to the severity of the symptoms, more significantly in the luteal phase. Also, impaired interaction of ALLO with the GABA-A receptor, increased sensitivity to stress and dysfunction of the autonomic nervous system, more significantly in the luteal phase, are contributing factors to PMDD’s pathogenesis, and targets of treatment could be modulation of NAS action and the HPA axis.

Perimenopausal depression

As women transition to menopause, ovarian function gradually declines, particularly marked by decreased E2 and PROG levels. This weakens these hormones’ negative feedback on the pituitary gland, leading to increased follicle-stimulating hormone (FSH) and luteinising hormone.^{Reference Randolph, Zheng, Sowers, Crandall, Crawford and Gold53} E2 fluctuations are linked to significant changes in FSH, resulting in more menstrual cycles without follicular development and reduced PROG levels.^{Reference Joffe, de Wit, Coborn, Crawford, Freeman and Wiley54} Changes in PROG and its metabolites during the perimenopausal period are believed to contribute to mood fluctuations, with studies linking NAS variability to depression, anxiety and irritability.^{Reference Gordon, Girdler, Meltzer-Brody, Stika, Thurston and Clark55,Reference Schweizer-Schubert, Gordon, Eisenlohr-Moul, Meltzer-Brody, Schmalenberger and Slopien56} and mixed evidence on whether differences in absolute levels are important.^{Reference Joffe, de Wit, Coborn, Crawford, Freeman and Wiley54,Reference Han, Xia, Zheng, Zhong, Zhao and Wang57,Reference Süss, Willi, Grub and Ehlert58} There is also considerable evidence concerning changes in E2 at the menopausal transition, with studies indicating correlation between higher depressive symptoms or mood fluctuations and increased E2 variability^{Reference Joffe, de Wit, Coborn, Crawford, Freeman and Wiley54,Reference Willi, Süss, Grub and Ehlert59} or a sudden drop in E2 levels.^{Reference Gordon and Sander60,Reference Schmidt, Ben Dor, Martinez, Guerrieri, Harsh and Thompson61}

AND

Biancardi et al^{Reference Bianciardi, Barone, Lo Serro, De Stefano, Giacchetti and Aceti68} found higher levels of IL-6 and TNF-α in depressed women with a history of trauma during the second trimester compared to depressed women without a trauma history, suggesting that trauma prior to the pregnancy may worsen immune dsyregulation and be related to depressive symptoms during pregnancy. In contrast, another study illustrated the opposite correlation between increased levels of TNF-α and depressive symptoms in the third trimester, indicating dynamic immune changes during pregnancy and in patients with AND.^{Reference Buglione-Corbett, Deligiannidis, Leung, Zhang, Lee and Rosal69} In addition, Leff Gelman et al^{Reference Leff Gelman, Mancilla-Herrera, Flores-Ramos, Saravia Takashima, Cruz Coronel and Cruz Fuentes70} reported positive correlations between depressive symptoms and cytokines such as interleukin 2 (IL-2), IL-6, TNF-α, Th2-related mediators interleukin 13 (IL-13), interleukin 10 (IL-10) and interleukin 9 (IL-9) and the T-helper 17 (Th17)-associated cytokine interleukin 17A (IL-17A) during the third trimester. Furthermore, a study by Miller et al^{Reference Miller, Sakowicz, Roy, Yang, Sullivan and Grobman71} reported that higher levels of pro-inflammatory cytokines such as IL-1β, interleukin 23 (IL-23) and interleukin 33 (IL-33) in cerebrospinal fluid (CSF) were correlated with an increased risk for AND, suggesting that these inflammatory markers in the brain may play a more significant role in AND than peripheral inflammation alone. Interestingly, this study found little correlation between levels in CSF and those in the periphery. Most other studies have focused on the periphery alone, and it is unknown how correlations found in the periphery – even when associated with illness – may be correlated with action in the central nervous system.

Besides cytokine studies, several studies have shown that the KYN pathway is also influenced by inflammatory activity in AND. They found that prenatal Trp levels and the KYN/Trp ratio moderate the association between IL-6 levels and AND. Moreover, levels of IL-6, QUIN, TNF and KYN in the second trimester showed strong individual accuracy in predicting depression risk and severity in the third trimester, making them potential biomarkers for AND.^{Reference Nazzari, Molteni, Valtorta, Comai and Frigerio72} In addition, a longitudinal study by Sha et al found that elevated levels of inflammatory cytokines (IL-6 and TNFα) and alterations in markers of Trp metabolism (QUIN and KYN) during pregnancy can accurately predict depressive symptoms during pregnancy.^{Reference Sha, Madaj, Keaton, Escobar Galvis, Smart and Krzyzanowski73} Another recent study by the same group reported that low expression of critical KYN pathway enzymes such as quinolinate phosphoribosyltransferase (QPRT) and 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD) in placenta samples was associated with increased levels of plasma cytokines and a dysregulated KYN metabolite pattern, which were linked to depressive symptoms, suggesting the role of inflammation and KYN pathway enzymes as possible therapeutic targets in peripartum depression.^{Reference Sha, Escobar Galvis, Madaj, Keaton, Smart and Edgerly74} In addition, some of the studies have shown that elevated C-reactive protein (CRP) levels, alongside lower Trp levels, were correlated with AND.^{Reference Lahti-Pulkkinen, Girchenko, Robinson, Lehto, Toffol and Heinonen75,Reference Saadat, Zhang, Hyer, Padmanabhan, Woo and Engeland76} In contrast, women with depressive symptoms in the second trimester showed lower CRP levels.^{Reference Blackmore, Moynihan, Rubinow, Pressman, Gilchrist and O’Connor77}

PPD

Recent research has identified key immunological biomarkers associated with PPD, particularly focusing on cytokines, the KYN pathway and extracellular vesicles.^{Reference Modzelewski, Oracz, Iłendo, Sokół and Waszkiewicz78,Reference Zhu, Jin and Tang79} As reviewed by Osborne and Monk,^{Reference Osborne and Monk67} numerous studies have found elevated pro-inflammatory markers such as IL-6 and TNF-α associated with increased risk of PPD, while a few studies have reported decreased cytokine levels linked with PPD symptoms, suggesting that cytokine–cortisol interactions may vary among individuals with PPD.^{Reference Corwin, Pajer, Paul, Lowe, Weber and McCarthy80} In addition, one study reported that prenatal Trp levels and the KYN/Trp ratio moderated the association between IL-6 levels and PPD.^{Reference Nazzari, Molteni, Valtorta, Comai and Frigerio72} Two studies have shown that low levels of anti-inflammatory cytokines, particularly IL-10, increase susceptibility to PPD. This highlights the protective role of anti-inflammatory states against mood disturbances.^{Reference Bränn, Papadopoulos, Fransson, White, Edvinsson and Hellgren81,Reference Ono, Yu, Obara, Ishikuro, Murakami and Kikuya82} Some researchers have attempted to consolidate such findings by developing composite inflammation scores; these have been able to predict the onset of PPD, but less effectively than a clinical history of prior depression.^{Reference Bränn, Papadopoulos, Fransson, White, Edvinsson and Hellgren81} The same research team conducted metabolic profiling studies, revealing variations in immune-related metabolic pathways associated with PPD. They identified distinct metabolic profiles connected to postpartum depressive symptoms, indicating that disruptions in lipid metabolism and immune-related metabolites may play a key role in the development of PPD.^{Reference Bränn, Malavaki, Fransson, Ioannidi, Henriksson and Papadopoulos83} Furthermore, another study by Min et al^{Reference Min, Li and Ying84} found a positive correlation between elevated Th17 cells and related cytokine IL-17A with both PPD and anxiety, which further supports the role of Th17-mediated inflammation in these conditions. Our own group has explored the connection between cellular immune dysfunction and PPD. We found that defects in regulatory T-cells are linked to immune dysregulation and contribute to PPD,^{Reference Osborne, Gilden, Kamperman, Hoogendijk, Spicer and Drexhage85} and that altered mRNA communication in extracellular vesicles during pregnancy, tied to reduced autophagy, is also associated with subsequent PPD, suggesting that molecular signalling pathways involving immune cells may further contribute to the disorder.^{Reference Osborne, Payne, Sherer and Sabunciyan86}

Research on the KYN pathway has also provided insights into underlying pathways of PPD. Sha et al^{Reference Sha, Achtyes, Nagalla, Keaton, Smart and Leach87} have shown that hormonal changes, especially higher E2 levels, were linked to a pro-inflammatory profile and neurotoxic KYN metabolites, while PROG was associated with an anti-inflammatory profile, shedding light on the hormonal and immune interactions influencing PPD. In addition, another study has explored the role of the KYN pathway and kynurenic aminotransferase (KAT) alleles in PPD following caesarean section in Chinese women; their findings indicate that postpartum depressive symptoms (PDSs) are associated with decreased KAT activity and an increased QUIN/KYNA ratio, although no significant relationship was found between KAT alleles and PDSs.^{Reference Quan, Wang, Duan, Ma, Yu and Yang88}

In summary, the current literature emphasises the complex role of cytokine profiles, immune cell activity, metabolic pathways and molecular signalling in the etiology and progression of PPD. These findings suggest that immune-related biomarkers are likely to be the key to the identification of women at risk of PPD and may provide new targets for treatment. However, methodological variations and small sample sizes are notable across these studies, with effect sizes differing depending on the demographic characteristics and immune markers measured.

PND

In our own study, we examined the role of pro-inflammatory cytokines in depression across the perinatal period and found increased levels of IL-6 and macrophage inflammatory protein-1 α, chemokine (C-C motif) ligand 3 (MIP-1α/CCL3) beginning in the third trimester and continuing through the early postpartum in more depressed women. This study also found that women with higher pro-inflammatory cytokine values were more likely to be Hispanic, but less likely to be African American or overweight/obese compared to women with lower pro-inflammatory cytokine values, suggesting differential patterns in cytokine levels by race, ethnicity and overweight/obesity status.^{Reference Osborne, Yenokyan, Fei, Kraus, Moran and Monk89}

Small sample sizes, heterogeneity of mood assessment tools and cytokine detection techniques in these studies affect generalisability and consistency across findings. These findings highlight how inflammatory changes during pregnancy may contribute to PND, with immune dysregulation potentially persisting into the postpartum period. Understanding the trajectory of these immune alterations is of key importance to the discovery of biological mechanisms influencing mood disturbance during the perinatal phase.

Perinatal anxiety

Several studies have reported positive associations between high levels of pro-inflammatory cytokines such as IL-6, C-X-C motif chemokine ligand 8 (IL-8/CXCL-8) and TNF-α and/or a composite pro-inflammatory score with higher anxiety symptoms during pregnancy and postpartum.^{Reference Osborne, Yenokyan, Fei, Kraus, Moran and Monk89,Reference Mancuso, Ross, Accortt, Coussons-Read, Okun and Irwin90} Notably, Sherer et al^{Reference Sherer, Voegtline, Park, Miller, Shuffrey and Klein91} found a negative correlation, where lower levels of pro-inflammatory cytokines were associated with higher anxiety. This finding is particularly relevant as it examines anxiety independently of depression, suggesting that there may be distinct immune mechanisms underlying perinatal anxiety versus comorbid anxiety and depression. In addition, population differences may be important to these differential findings.^{Reference Furtado, Van Lieshout, Van Ameringen, Green and Frey92} Furthermore, some studies have found that a pro-inflammatory profile is accompanied by elevated levels of anti-inflammatory cytokines (IL-13, IL-10), possibly as a compensatory response,^{Reference Karlsson, Nousiainen, Scheinin, Maksimow, Salmi and Lehto93} whereas other studies have linked increased levels of inflammation with increased cortisol concentrations in participants with higher levels of anxiety and depressive symptoms.^{Reference Weis, Yuan, Walker, Gibbons and Chan94} Notably worthy of mention is that only a few studies have been conducted in populations with anxiety alone, without comorbid depression – so findings may be partially explained by that discrepancy.

In addition, studies exploring chemokine profiles in perinatal anxiety have revealed elevated levels of pro-inflammatory chemokines, such as IL-8/CXCL-8, monocyte chemoattractant protein 1 chemokine (C-C motif) ligand 2 (MCP-1)/CCL2 and macrophage inflammatory protein 1 beta chemokine (C-C motif) ligand 4 (MIP-1β)/CCL4, as well as an increase in composite pro-inflammatory chemokine score in women with moderate to severe anxiety, suggesting that chemokine profiles may play a crucial role in immune dysregulation and mood disturbances,^{Reference Camacho-Arroyo, Flores-Ramos, Mancilla-Herrera, Cruz, Hernández-Ruiz and Diaz95} although some studies have not found differences.^{Reference Sherer, Voegtline, Park, Miller, Shuffrey and Klein91} We conducted a study in perinatal anxiety without comorbid depression in Pakistan and showed a distinct pattern of cytokine and chemokine profiles associated with perinatal anxiety, differing from those found in other populations, indicating that population-level factors may influence immune responses.^{Reference Etyemez, Mehta, Tutino, Zaidi, Atif and Rahman96} Specifically, elevated chemokine activity across pregnancy in highly anxious women was observed. Our group has also developed a composite factor score by performing principal component analysis (PCA) and clustering innate immune markers as well as chemokine markers with anxiety symptoms in a longitudinal framework, enabling us to assess immune patterns across multiple time points in this population.^{Reference Etyemez, Mehta, Tutino, Zaidi, Atif and Rahman96} Few studies in perinatal anxiety have moved beyond cytokines and chemokines to consider dysregulation in immune cells; one such study found that increases in the cytotoxic to helper T-cell ratio and altered balance between Th17 and Treg cells were associated with perinatal anxiety symptoms.^{Reference Sherer, Voegtline, Park, Miller, Shuffrey and Klein91}

PPP

Research suggests that immune dysregulation, particularly alterations in cytokine levels and Trp metabolism, plays a vital role in the development of PPP.^{Reference Bergink, Gibney and Drexhage97} Bergink et al^{Reference Bergink, Burgerhout, Weigelt, Pop, de Wit and Drexhage98} found distinct immune changes in first-onset PPP, including elevated MCP-1/CCL2 and reduced anti-inflammatory glucocorticoid receptor alpha (GR-α) compared to healthy postpartum and non-postpartum controls. In addition, higher IL-1β levels were observed in healthy postpartum women, indicating immune shifts specific to the postpartum period that may contribute to PPP’s pathophysiology. Furthermore, they reported significantly elevated T-cells (both T-effector and T-regulatory cells) in healthy women postpartum, whereas patients with PPP lacked this elevation. Instead, they had increased monocyte levels and upregulated immune-related monocyte genes compared to both postpartum and non-postpartum controls. Their findings suggest a balanced interplay between pro-inflammatory and anti-inflammatory responses, indicating that the immune system adapts during the postpartum period to maintain equilibrium and prevent excessive inflammation.^{Reference Bergink, Burgerhout, Weigelt, Pop, de Wit and Drexhage98} Similarly, Sathyanarayanan et al^{Reference Sathyanarayanan, Thippeswamy, Mani, Venkataswamy, Kumar and Philip99} also showed elevated IL-6 and uniquely elevated IL-8/CXCL-8 in the PPP group, suggesting a specific role of IL-8/CXCL-8 in PPP development. In addition, studies on Trp metabolism found imbalances in neurotoxic and neuroprotective metabolites, with increases in 3-hydroxykynurenine (3HK) and decreases in KYNA, suggesting immune activation as a potential etiology for neuropsychiatric symptoms in PPP.^{Reference Veen, Myint, Burgerhout, Schwarz, Schütze and Kushner100}

PMDD

Recent evidence suggests that the inflammatory response, which may be triggered by hormonal fluctuations, could contribute to the mood disturbances, fatigue and physical symptoms commonly seen in PMDD and PMS.^{Reference Tiranini and Nappi101} Barone et al^{Reference Barone, Ho, Osborne, Eisenlohr-Moul, Morrow and Payne102} presented elevated levels of the pro-inflammatory markers IL-8/CXCL-8 and TNF-α during the luteal phase in a PMDD group compared to controls. Also, they found positive association between premenstrual symptom severity with higher levels of IL-8/CXCL-8, highlighting the potential role of inflammation in the manifestation of PMDD symptoms. Despite all these results, evidence in this area is still limited, and further studies are needed to better understand the underlying immunological mechanisms of PMDD.

Perimenopausal depression

Perimenopausal depression is a significant psychiatric illness that arises in the context of the menopausal transition, characterised by mood fluctuations, anxiety and cognitive symptoms. Growing evidence suggests that hormonal disturbances, neuroinflammation and oxidative stress contribute to its development.^{Reference Liang, Kow, Yusof, Tham, Ho and Lee103} One of the earliest immunological changes observed in perimenopausal depression is an increase in pro-inflammatory cytokines. As reviewed by Liang et al,^{Reference Liang, Kow, Yusof, Tham, Ho and Lee103} there have been many studies reporting elevated levels of interleukin-8 (IL-8), TNF-α, IL-1β and IL-6 in women experiencing perimenopausal depression. These cytokines are important mediators of neuroinflammation, synaptic dysfunction and neuronal apoptosis, all contributing to mood disorders.^{Reference Liang, Kow, Yusof, Tham, Ho and Lee103} In addition, Matthews et al^{Reference Matthews, Schott, Bromberger, Cyranowski, Everson-Rose and Sowers104} also suggested that perimenopausal women with higher depressive symptoms exhibit increased fibrinogen and plasminogen activator inhibitor type 1 (PAI-1), both of which are markers of systemic inflammation and hypercoagulability. These findings highlight an increased cardiovascular risk associated with perimenopausal depression, further linking immune dysregulation to broader health concerns. Furthermore, decreased E2 levels favour a pro-inflammatory state, which in turn enhances IDO activity, leading to a shunt of Trp metabolism through the KYN pathway. This yields an overproduction of QUIN, a neurotoxic metabolite, that hyperstimulates NMDA receptors, resulting in glutamatergic excitotoxicity, oxidative stress and neurodegeneration. Concurrently, the levels of KYNA, a neuroprotective metabolite, are reduced, further destabilising the neuroprotection versus neurotoxicity balance, potentially leading to mood disturbances, cognitive impairment and increased vulnerability to depression during perimenopausal transition.^{Reference Liang, Kow, Yusof, Tham, Ho and Lee103} Due to this strong link among immune dysregulation, KYN metabolism and neuroinflammation, targeting these pathways could provide novel therapeutic opportunities for the prevention and treatment of perimenopausal depression.

AND, PND and PPD

Imaging studies in pregnant women are limited, with most data focusing on PPD. Recent research suggests that pregnancy induces significant, lasting changes in brain structure, function and neural plasticity, which are generally considered adaptive to the reproductive transition.^{Reference Pritschet, Taylor, Cossio, Faskowitz, Santander and Handwerker105}

There are no studies focusing exclusively on the antenatal period. For PPD, recent structural neuroimaging studies report abnormal changes in grey matter volume, cortical thickness, white matter integrity and network connectivity. A comparison of 29 women with PPD and 23 healthy postpartum women found a correlation between EPDS scores and cortical and subcortical differences in PPD, with greater cortical thickness in frontal and visual areas.^{Reference Yang, Jiang, Ma, Xiao, Liu and Ren106} Conversely, decreased cortical thickness in women with PPD in the right inferior parietal lobule was reported in another study comparing 21 PPD women to 18 controls.^{Reference Li, Chu, Che, Dong, Shi and Ma107} Additionally, increased grey matter volume in the left dorsolateral prefrontal cortex (DLPFCL) and the right anterior insula and increased surface area in several regions, including the DLPFC and insula, was found in women with postpartum depressive symptoms versus healthy controls.^{Reference Li, Chu, Che, Dong, Shi and Ma107,Reference Chen, Li, Zhang, Liu, Wang and Xu108} Recent studies have shifted focus from individual brain regions to examining the combined regions of the default mode network (DMN) and reward network. A few studies have used diffusion tensor imaging (DTI) techniques in PPD and have reported altered white matter integrity of the cortical thalamic circuits in PPD women compared to healthy controls.^{Reference Long, Zhou, Zhang, Li, Wang and Meng109,Reference Silver, Moore, Villamarin, Jaitly, Hall and Rothschild110}

While imaging is largely confined to postpartum, there are some studies that conduct imaging postpartum but consider depressive symptoms during both pregnancy and postpartum. One recent study found that the severity of both AND and PPD symptoms, along with antepartum ALLO concentrations, predicted volume changes in brain regions within the DMN and reward network involved in emotion regulation and cognition among postpartum women.^{Reference Hare, Barber, Shaffer and Deligiannidis111}

While research on structural neuroimaging is limited, functional magnetic resonance imaging (fMRI) has extensively identified brain regions linked to PPD symptoms. There are no studies confined to the antenatal period. Deligiannidis et al^{Reference Deligiannidis, Sikoglu, Shaffer, Frederick, Svenson and Kopoyan33,Reference Deligiannidis, Fales, Kroll-Desrosiers, Shaffer, Villamarin and Tan112} found altered functional connectivity within areas of the DMN and in corticocortical and corticolimbic regions in PPD compared to healthy controls. In addition, they noted a relationship between postpartum ALLO concentrations and resting-state functional connectivity (RSFC) in the DMN for PPD.^{Reference Deligiannidis, Fales, Kroll-Desrosiers, Shaffer, Villamarin and Tan112} The DMN, which is involved in self-referential thinking and emotional processing, is particularly significant in PPD as disruptions in this network may contribute to the negative self-appraisal and rumination often observed in the disorder. Other fMRI studies observed reduced amygdala response to negative stimuli and decreased striatal activation after reward in PPD.^{Reference Moses-Kolko, Perlman, Wisner, James, Saul and Phillips113,Reference Moses-Kolko, Fraser, Wisner, James, Saul and Fiez114} The reward network is also critical in PPD, as altered responses to reward may be associated with the anhedonia often seen in depression. Additional studies noted alterations within the DMN, limbic system (LIN) and interhemispheric connectivity.^{Reference Zhang, Li, Liu, Hou and Zhang115} By contrast, Schnakenberg et al^{Reference Schnakenberg, Hahn, Stickel, Stickeler, Habel and Eickhoff116} did not find any structural or functional changes in PPD.

Structural and functional imaging can identify brain regions associated with symptoms, while magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) imaging can examine differences of biochemical systems at the molecular level in the brain. An initial MRS study of PPD found no significant differences in occipital cortex GABA levels compared with healthy controls.^{Reference Epperson, Gueorguieva, Czarkowski, Stiklus, Sellers and Krystal31} Another study reported higher glutamate concentrations in the medial prefrontal cortex (MPFC).^{Reference McEwen, Burgess, Hanstock, Seres, Khalili and Newman117} Conversely, lower combined glutamate plus glutamine and combined N-acetylaspartate (NAA) plus N-acetylaspartylglutamate were reported in the left DLPFC, with no differences in the anterior cingulate gyrus (ACG), in PPD versus healthy controls.^{Reference Rosa, Soares, Figueiredo, Cavalli, Barbieri and Schaufelberger118} In addition, blunted HPA axis responses were found to be linked with low levels of glutamate and glutamine in the ACG in PPD.^{Reference de Rezende, Rosa, Garcia-Leal, de Figueiredo, Cavalli and Bettiol119} A combined fMRI and MRS study noted a link between cortical GABA concentration and RSFC in the DMPFC in postpartum women, with no GABA differences, in PPD and healthy controls.^{Reference Deligiannidis, Fales, Kroll-Desrosiers, Shaffer, Villamarin and Tan112} PET studies in PPD revealed elevated brain monoamine oxidase-A (MAO-A) binding in the ACC and prefrontal cortex,^{Reference Sacher, Wilson, Houle, Rusjan, Hassan and Bloomfield120,Reference Sacher, Rekkas, Wilson, Houle, Romano and Hamidi121} and decreased postsynaptic serotonin 1 A receptor binding in regions of the ACC, the mesiotemporal and the lateral orbitofrontal cortices,^{Reference Moses-Kolko, Wisner, Price, Berga, Drevets and Hanusa122} while no differences were found in dopaminergic D2/3 receptor binding in the striatum.^{Reference Moses-Kolko, Price, Wisner, Hanusa, Meltzer and Berga123}

Perinatal anxiety

Very few papers have examined imaging features in women with perinatal anxiety without mood symptoms. Those that exist are confined to the postpartum period. Two studies reported that greater neural responses to negative infant cues were correlated with higher postpartum anxiety symptoms.^{Reference Finnegan, Kane, Heller and Laurent124,Reference Malak, Crowley, Mayes and Rutherford125} Increased maternal anxiety was associated with stronger connections between caregiving behaviours and amygdala and right posterior superior temporal sulcus connectivity.^{Reference Guo, Moses-Kolko, Phillips, Swain and Hipwell126} In addition, several studies have explored perinatal anxiety in relation to PPD. Women with PPD with anxiety showed changes in the subgenual anterior cingulate cortex (sgACC) and dynamic functional connectivity (dFC) between the sgACC and superior temporal sulcus compared to women with PPD and without anxiety.^{Reference Cheng, Wang, Roberts, Zhou, Wang and Deng127} Functional connectivity density linked both anxiety and depression to common and specific circuit disruptions.^{Reference Cheng, Zhou, Kwok, Li, Wang and Zhao128} PPD with anxiety disrupted the lateral prefrontal-striatal circuit, while PPD without anxiety affected the occipito-parieto-frontal circuit.^{Reference Cheng, Zhou, Kwok, Li, Wang and Zhao128} Irregularities in the DMN distinguished PPD from PPD with anxiety.^{Reference Chen, Yang, Li, Chen, Chen and Shao129}

pOCD

One study that compared postpartum women with OCD to those without (as well as to a comparison group of mothers past the postpartum period) found that, compared to healthy postpartum women, those with OCD had heightened stress responses (both self-report and endocrine) in response to psychosocial stress, and that this response was associated with a distinct pattern of activation in the orbitofrontal and temporal cortices.^{Reference Lord, Steiner, Soares, Carew and Hall130}

PPP

Research on neuroimaging in PPP is limited, but some evidence of structural and functional differences has been noted. One study found decreased volume in the parahippocampal gyrus, anterior cingulate cortex (ACC), postcentral gyrus and superior temporal gyrus (STG) in postpartum women with recent psychotic episodes compared to at-risk women without such episodes.^{Reference Fusté, Pauls, Worker, Reinders, Simmons and Williams131} Two other studies reported increased connectivity between the DLPFC and other areas along with functional differences in working memory and emotional recognition in women at risk of PPP.^{Reference Kowalczyk, Pauls, Fusté, Williams, Hazelgrove and Vecchio132} In addition, one study found that, while connectivity in areas related to executive functioning increased overall, it decreased during emotional tasks.^{Reference Sambataro, Cattarinussi, Lawrence, Biaggi, Fusté and Hazelgrove133}

PMDD

A major recent advancement in the structural neuroimaging literature on PMDD comes from the Comasco lab, which conducted studies based on an unprecedentedly large sample. The findings highlight the value of large-scale, phase-specific imaging studies to better characterise the neurobiological basis of PMDD. These studies investigated structural changes in grey matter in women with PMDD during the luteal phase. One study found higher depressive symptoms in PMDD correlated with lower bilateral amygdala volume.^{Reference Dubol, Wikström, Lanzenberger, Epperson, Sundström-Poromaa and Comasco134} Another study reported that PMDD is associated with greater white matter volume in the right uncinate fasciculus and increased fractional anisotropy in several brain regions compared to controls.^{Reference Gu, Dubol, Stiernman, Wikström, Hahn and Lanzenberger135} The same group also investigated structural differences in PMDD in both mid-follicular and late luteal phases and found that women with PMDD consistently showed thinner cortices and reduced gyrification compared to controls, regardless of menstrual cycle phase – suggesting trait-like brain differences.^{Reference Dubol, Stiernman, Sundström-Poromaa, Bixo and Comasco136} In addition, menstrual cycle-related changes in cortical architecture were observed across all participants.^{Reference Dubol, Stiernman, Sundström-Poromaa, Bixo and Comasco136} While Dubol et al^{Reference Dubol, Stiernman, Wikström, Lanzenberger, Epperson and Sundström-Poromaa137} reported reduced volume in the cerebellum, right amygdala and ventral putamen, earlier studies noted increased volume in posterior cerebellar volume and in the left hippocampal gyrus^{Reference Berman, London, Morgan and Rapkin138} and decreased parahippocampal gyrus in PMDD compared to healthy controls.^{Reference Jeong, Ham, Yeo, Jung and Joe139}

fMRI studies reveal significant changes in brain reactivity to emotional stimuli during the luteal phase in PMDD. These include increased amygdala response decreased prefrontal cortex activity to negative and social stimuli^{Reference Protopopescu, Tuescher, Pan, Epstein, Root and Chang140,Reference Petersen, Ghahremani, Rapkin, Berman, Liang and London141} and reduced ACC activity to social and emotion regulation tasks.^{Reference Gingnell, Ahlstedt, Bannbers, Wikström, Sundström-Poromaa and Fredrikson142,Reference Comasco, Hahn, Ganger, Gingnell, Bannbers and Oreland143} In addition, increased insula activation occurs during emotional tasks and social tasks,^{Reference Gingnell, Ahlstedt, Bannbers, Wikström, Sundström-Poromaa and Fredrikson142,Reference Bannbers, Gingnell, Engman, Morell, Comasco and Kask144} alongside hyperconnectivity in the basal ganglia and thalamus.^{Reference Dan, Reuveni, Canetti, Weinstock, Segman and Goelman145}

PET and MRS imaging studies have examined biochemical changes in PMDD. Increased glucose metabolism in the cerebellum and abnormal activation during working memory tasks in the DLPFC were observed from the follicular to the late luteal phase in PMDD compared to healthy controls.^{Reference Baller, Wei, Kohn, Rubinow, Alarcón and Schmidt146,Reference Rapkin, Berman, Mandelkern, Silverman, Morgan and London147} Alterations in the serotonergic system included a smaller increase in serotonin 1A receptor (5-HT_1A) binding in dorsal raphe nuclei from the follicular to the late luteal phase in PMDD,^{Reference Jovanovic, Cerin, Karlsson, Lundberg, Halldin and Nordström148} altered levels of serotonin precursor 5-hydroxytryptophan (5-HTP) in prefrontal regions and the striatum correlated with symptom severity in PMDD.^{Reference Eriksson, Wall, Marteinsdottir, Agren, Hartvig and Blomqvist149} Recently, increased availability of serotonin transporter in the midbrain during the luteal phase was described.^{Reference Sacher, Zsido, Barth, Zientek, Rullmann and Luthardt150} MRS studies found higher GABA levels in the occipital cortex from the follicular to the mid- and late luteal phases^{Reference Epperson, Haga, Mason, Sellers, Gueorguieva and Zhang151} and lower GABA levels in the ACC/MPFC and left basal ganglia.^{Reference Liu, Wang, Gao, Gao, Zhao and Qiao152} However, some studies reported no differences in glutamate or other metabolite levels in the MPFC and cingulate gyrus between PMDD and healthy controls.^{Reference Batra, Seres-Mailo, Hanstock, Seres, Khudabux and Bellavance153,Reference Rasgon, Thomas, Guze, Fairbanks, Yue and Curran154}

Perimenopausal depression

To date, brain imaging research has not focused on perimenopausal depression. (While there are reports of brain changes in response to the hormone shifts that are characteristic of perimenopause – with possible implications that could be important for future studies on depression – those studies are outside the scope of this paper. Similarly, there are imaging studies of cognitive changes in perimenopause as well.^{Reference Metcalf, Duffy, Page and Novick155}) Wang et al^{Reference Wang, Tao, Zhong, Liu, Han and Zhang156} is the only study to have used DTI to investigate this subgroup and found alterations in white matter microstructure in the insula and subcortical areas that correlated with depressive symptoms in perimenopausal women.