Do Defective Immune System-Mediated Myelination Processes Increase Postpartum Psychosis Risk?

Postpartum psychosis (PP) is a rare, severe psychiatric disorder affecting some women shortly after childbirth. While the risk factors for PP are relatively well understood, our knowledge of the underlying pathophysiology is extremely poor; however, there is some evidence that immune system dysregulation may play a role. A recent study has shown that regulatory T cells (Tregs) may promote remyelination via the CCN family of proteins. Here, we argue, on the basis of emerging immunological, animal model, and neuroimaging findings, that PP risk may be elevated due to abnormalities in the Treg–CCN–(re)myelination axis and that risk and protective/treatment factors for the disorder may influence this axis. Postpartum (or puerperal) psychosis (PP) is a rare, severe psychiatric disorder that affects women shortly after childbirth; risk is particularly high in individuals with a history of bipolar disorder or PP, but the underlying pathophysiology remains poorly understood. Emerging evidence suggests that immune system (dys)function plays an important role in disorder onset. On the basis of new findings from clinical and animal model studies, we hypothesise that the abundance and/or activity of regulatory T cells, and the efficacy of consequent (re)myelination processes in the brain mediated by CCN proteins, is perturbed in PP; this pathway may be modulated by risk and protective/treatment factors for the disorder, and identifying abnormalities within it could signpost novel predictive biomarkers and therapeutic targets. Postpartum (or puerperal) psychosis (PP) is a rare, severe psychiatric disorder that affects women shortly after childbirth; risk is particularly high in individuals with a history of bipolar disorder or PP, but the underlying pathophysiology remains poorly understood. Emerging evidence suggests that immune system (dys)function plays an important role in disorder onset. On the basis of new findings from clinical and animal model studies, we hypothesise that the abundance and/or activity of regulatory T cells, and the efficacy of consequent (re)myelination processes in the brain mediated by CCN proteins, is perturbed in PP; this pathway may be modulated by risk and protective/treatment factors for the disorder, and identifying abnormalities within it could signpost novel predictive biomarkers and therapeutic targets. Postpartum psychosis (PP) is a severe psychiatric disorder affecting approximately one or two of every 1000 women shortly after childbirth (most often within 6 weeks); the main symptoms include hallucinations, delusions, cognitive disorganisation, and mood abnormalities [1Bergink V. et al.Postpartum psychosis: madness, mania, and melancholia in motherhood.Am. J. Psychiatry. 2016; 173: 1179-1188Crossref PubMed Scopus (69) Google Scholar]. PP risk is highly predictable, with a risk recently reported to be ∼35% for women with a history of either bipolar affective disorder or previous PP [2Wesseloo R. et al.Risk of postpartum relapse in bipolar disorder and postpartum psychosis: a systematic review and meta-analysis.Am. J. Psychiatry. 2016; 173: 117-127Crossref PubMed Scopus (155) Google Scholar]. Although PP occurs concomitantly with the biological sequelae of childbirth, its neurobiological basis remains poorly understood. The most intensively studied biological changes in PP have been those that occur in maternal reproductive hormones shortly after childbirth; however, no differences in absolute levels of oestrogen or progesterone have been identified in women who develop an episode of PP [3Kumar R. et al.Neuroendocrine and psychosocial mechanisms in post-partum psychosis.Prog. Neuropsychopharmacol. Biol. Psychiatry. 1993; 17: 571-579Crossref Scopus (14) Google Scholar, 4Wisner K.L. Stowe Z.N. Psychobiology of postpartum mood disorders.Semin. Reprod. Endocrinol. 1997; 15: 77-89Crossref PubMed Scopus (84) Google Scholar]. A genetic liability to PP has also been suggested: a linkage study in women with bipolar affective PP implicated chromosomal regions 16p13 and 8q24 (regions previously associated with bipolar disorder vulnerability) [5Jones I. et al.Bipolar affective puerperal psychosis: genome-wide significant evidence for linkage to chromosome 16.Am. J. Psychiatry. 2007; 164: 1099-1104Crossref PubMed Scopus (57) Google Scholar], while genetic association studies have provided suggestive, albeit inconclusive, evidence of risk variants within candidate genes involved in serotonergic, hormone-dependent, or stress-response pathways [6Jones I. et al.Bipolar disorder, affective psychosis, and schizophrenia in pregnancy and the post-partum period.Lancet. 2014; 384: 1789-1799Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 7Kumar H.B. et al.Serotonergic candidate genes and puerperal psychosis: an association study.Psychiatr. Genet. 2007; 17: 253-260Crossref PubMed Scopus (22) Google Scholar, 8Thippeswamy H. et al.Estrogen pathway related genes and their association with risk of postpartum psychosis: a case control study.Asian J. Psychiatry. 2017; 26: 82-85Crossref PubMed Scopus (5) Google Scholar]. Key obstacles in identifying biological risk and protective factors for PP include low disorder prevalence, high between-patient symptom heterogeneity, lack of accessibility to patient brain tissue, and a historical lack of amenable model systems [9Davies W. Understanding the pathophysiology of postpartum psychosis: challenges and new approaches.World J. Psychiatry. 2017; 7: 77-88Crossref Scopus (12) Google Scholar]. However, understanding the pathophysiology of PP is crucial for identifying both novel therapeutic targets (for more efficacious drugs with fewer adverse effects) and predictive biomarkers (for identification of the most ‘at risk’ women before, or during, pregnancy, thereby facilitating earlier, more individualised clinical interventions). Recent evidence has highlighted a potentially important role for the immune system in the onset of PP: women with the disorder have higher rates of autoimmune thyroid dysfunction and pre-eclampsia (considered a disease of immunological maternal-fetal incompatibility) [1Bergink V. et al.Postpartum psychosis: madness, mania, and melancholia in motherhood.Am. J. Psychiatry. 2016; 173: 1179-1188Crossref PubMed Scopus (69) Google Scholar, 10Bergink V. et al.Pre-eclampsia and first-onset postpartum psychiatric episodes: a Danish population-based cohort study.Psychol. Med. 2015; 45: 3481-3489Crossref PubMed Scopus (43) Google Scholar], and some cases of PP involve an autoimmune response against the N-methyl-d-aspartic acid receptor [11Bergink V. et al.Autoimmune encephalitis in postpartum psychosis.Am. J. Psychiatry. 2015; 172: 901-908Crossref PubMed Scopus (53) Google Scholar]. The link between PP pathophysiology and the immune system may not be surprising, given that immune system dysregulation, characterised by elevated levels of serum proinflammatory cytokines such as interleukin (IL)-6, IL-1, and tumour necrosis factor-α, and alterations in the expression of associated genes now features prominently in pathophysiological models of depression (including in the postpartum period) [12Boufidou F. et al.CSF and plasma cytokines at delivery and postpartum mood disturbances.J. Affect. Disord. 2009; 115: 287-292Crossref PubMed Scopus (60) Google Scholar, 13Kohler C.A. et al.Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies.Acta Psychiatr. Scand. 2017; 135: 373-387Crossref PubMed Scopus (423) Google Scholar], bipolar affective disorder [14Drexhage R.C. et al.Inflammatory gene expression in monocytes of patients with schizophrenia: overlap and difference with bipolar disorder. A study in naturalistically treated patients.Int. J. Neuropsychopharmacol. 2010; 13: 1369-1381Crossref PubMed Scopus (112) Google Scholar], and psychosis [15Bergink V. et al.Autoimmunity, inflammation, and psychosis: a search for peripheral markers.Biol. Psychiatry. 2014; 75: 324-331Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 16Miller B.J. et al.Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects.Biol. Psychiatry. 2011; 70: 663-671Abstract Full Text Full Text PDF PubMed Scopus (1046) Google Scholar]. PP occurs at a time of naturally heightened immune responsiveness. In pregnancy, a predominant anti-inflammatory T helper (Th)2-type immunity (whereby Th2 cell activity, including cytokine expression, is that from has been for maternal to the from maternal immunity and et and the role of the immune system at the 2011; PubMed Scopus Google Scholar]. 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