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Prenatal and Childhood Immuno-Metabolic Risk Factors for Adult Depression and Psychosis

Kappelmann, Nils PhD; Perry, Benjamin I. MRCPsych; Khandaker, Golam M. PhD

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Harvard Review of Psychiatry: 1/2 2022 - Volume 30 - Issue 1 - p 8-23
doi: 10.1097/HRP.0000000000000322
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Abstract

Convincing evidence points to a developmental facet to the origin of unipolar major depression and nonaffective psychosis. About half of all cases of psychiatric disorders develop by the early 20s and three-quarters by the mid-20s,1 which suggests that biopsychosocial factors operating from the fetal period through early adulthood are likely to represent crucial risk and protective factors for adult psychopathology. The influence of early-life factors is consistent with the developmental-programming hypothesis proposed by David Barker,2 which posits that exposure to risk factors during critical developmental windows may “program” certain physiologic systems to increase the risk of chronic diseases in adulthood. Although Barker’s work primarily focused on cardiometabolic disease, the concept of developmental programming is pertinent to psychiatric disorders, which are often comorbid with cardiometabolic illnesses.3–6

In the late 1980s, Daniel Weinberger,7 Robin Murray,8 and others proposed the neurodevelopmental hypothesis for schizophrenia, which is now supported by population-based longitudinal studies providing evidence for neurobiological alterations, including delayed acquisition of developmental milestones (e.g., language) and premorbid intelligence quotient (IQ) deficit in childhood—which could be both risk factors for, and early manifestations of, an emerging illness process.9–12 Population-based studies also suggest that impaired neurodevelopment in future cases of schizophrenia may arise from unique environmental factors such as childhood infection, rather than from shared genetic or shared environmental factors.13–17 For depression, evidence highlights the importance of early-life adversity at different developmental stages. This support includes population-based evidence that prenatal stress increases the risk for depression in adulthood18 and findings that childhood trauma can dysregulate the hypothalamus-pituitary-adrenal axis, leading to excess activity following psychosocial stress in adults.19

Accumulating evidence from population-based cohort studies and from genetic and clinical research now points to a role of early-life infection, inflammation, and metabolic dysfunction in the etiology of depression and psychosis in adulthood.20–23 This evidence represents a fundamental shift in our current thinking about the origin of major mental disorders in two ways. First, a potential role of the immune system provides an alternative mechanistic explanation, which could be relevant for at least some cases of these disorders and is distinct from currently dominant monoamine-centric pathophysiologic explanations for depression and schizophrenia. Second, this evidence highlights strong interactions between the body, brain, and mind, dispelling the Cartesian dichotomy between these systems. Despite the growing body of evidence implicating immuno-metabolic alterations in depression and psychosis, several key questions still remain. For instance, it is unclear whether immuno-metabolic alterations are a cause or consequence of illness. As a related point, it is unclear if cross-sectional and longitudinal associations of immuno-metabolic alterations with depression and psychosis reflect potentially causal effects or can be explained by residual confounding. Finally, it is unclear whether there is a distinct developmental window during which exposure to immuno-metabolic dysfunction is most harmful.

In this nonsystematic review, we synthesize key epidemiological evidence from studies of prenatal and childhood infection, inflammation, and metabolic alterations—which we collectively refer to as immuno-metabolic risk factors—and the risk of depression and psychosis in adulthood. We particularly focus on two issues: causality of association and sensitive period for exposure. Regarding causality, we focus on evidence from large-scale, population-representative longitudinal studies and genetic Mendelian randomization studies that can address the problems of reverse causality and residual confounding. Regarding the sensitive period, we discuss longitudinal evidence covering key developmental epochs, including prenatal life, childhood, and adolescence. Studies and evidence discussed have been selected based on the reviewers’ knowledge of this field of research and the snowballing of reference lists of selected studies, particularly prioritizing evidence quality based on key methodologic aspects such as study design, sample size, and population representativeness. Evidence is integrated in a proposed working model in Figure 1. We use the terms depression and psychosis throughout this review to refer to unipolar depression and nonaffective psychoses, respectively, unless otherwise specified. For context, we also discuss studies of childhood/adolescent depressive and psychotic symptoms where relevant.

Figure 1
Figure 1:
Schematic overview displaying proposed associations between early-life immuno-metabolic risk factors and adult depression and psychosis. The color coding describes non-immuno-metabolic risk factors in gray, immunological risk factors in orange, and metabolic risk factors in green. Psychiatric outcome phenotypes are color coded in purple. Of note, maternal and childhood infections are color coded as immunological risk factors in orange as infections directly trigger an immune response. These infections can have non-immunological pathomechanisms, however, including via direct effects of the pathogen as described in the section “Potential Mechanisms Linking Immuno-Metabolic Alterations to Depression and Psychosis.” Time is shown on the x-axis.

EPIDEMIOLOGIC EVIDENCE FOR PRENATAL AND CHILDHOOD INFECTION, INFLAMMATION, AND METABOLIC ALTERATIONS IN DEPRESSION AND PSYCHOSIS

Relevance of Immuno-Metabolic Risk Factors During Critical Periods of Development

Given that the human brain continues to mature until early adulthood,24 insults during important neurodevelopmental periods could detrimentally affect the growth and maturation of the nervous system, which may ultimately lead to long-term psychiatric risk. For example, evidence from rodent work suggests that maternal infections during early and late gestation can impair adult sensorimotor gating and working-memory function, respectively.25 In addition, findings from human population-based cohort studies shows that early childhood infections and childhood adiposity are particularly associated with lower intelligence in late adolescence/early adulthood.17,26 Taken together, this work highlights that early-life immuno-metabolic risk factors can impair healthy brain development and that these risk factors may contribute to adult psychosocial disturbances, including development of overt psychiatric disorders such as depression and psychosis.

Prenatal and Childhood Infections

Studies on maternal infections have primarily investigated these risk factors regarding their associations with later psychosis rather than depression. For example, initial evidence in psychosis implicating early-life infection comes from ecological studies suggesting increased risk of schizophrenia among individuals who were in utero during influenza epidemics.27–30 Ecological studies are prone to misclassification bias, however, since it is unlikely all pregnant mothers classified as “exposed” have an infection.31–34 This limitation was subsequently overcome by prospective birth cohort and retrospective-record linkage studies that used laboratory tests or hospital records to confirm exposure to infection at the individual level.35–39 Systematic reviews of these longitudinal studies indicate that prenatal maternal infection with herpes simplex virus type 2, Toxoplasma gondii, or influenza, as well as respiratory and genitourinary infections, are associated with the risk of schizophrenia and related psychosis in offspring in adulthood.40–42 Although the evidence was restricted in statistical power, the increased risk from infections seemed to be more pronounced for early stages of gestation and could have direct effects on neurodevelopment and cognitive functioning in childhood.36,39,41,43 In general, it is also important to note that not all studies found evidence for an association (notably, for influenza),44,45 and hospital-linkage studies are likely to miss less severe infections and psychiatric outcomes. Furthermore, parental infection before or after pregnancy has also been associated with the risk of psychosis, suggesting that shared familial confounding may at least partly explain this association.46,47

Childhood infections have been studied extensively in relation to the risk for both depression and psychosis in adulthood, with a majority of studies using large-scale record-linkage data from Nordic countries. Danish population-based studies have reported associations of childhood infections with a number of mental disorders subsequently in adulthood, including psychotic disorders, depression, eating disorders, obsessive-compulsive disorder, personality and behavior disorders, intellectual disability, autistic spectrum disorder, attention-deficit/hyperactivity disorder, oppositional defiant and conduct disorder, and tic disorders.48–52 These studies also provided evidence for a dose-response relationship, with a greater number of infections being associated with greater risk for later depression and schizophrenia.48,50–52 Results further indicated that the risk for these disorders was increased in exposed individuals who suffered from comorbid autoimmune diseases.51,52 Similar results for adult psychosis have been reported from Finland and Sweden, which suggested that infections with mumps, cytomegalovirus (CMV), the enterovirus Coxsackie B5 (CBV-5), and adenovirus 7 (which can invade the brain parenchyma) and particularly infections in the first year of life were associated with schizophrenia and other nonaffective psychotic disorders in early adulthood.17,53,54 A meta-analysis of population-based studies has reported similar results for schizophrenia and found that viral infections such as mumps, CBV-5, varicella zoster, and CMV during childhood increased the later risk for psychosis.55

While register-based studies are helpful to disentangle effects of severe infections, cohort studies with direct measurement of antibodies to certain infections allow ascertaining the risk posed by less severe infections. For example, the Avon Longitudinal Study of Parents and Children (ALSPAC) followed a population-based birth cohort of over 14,000 mothers (with expected date of delivery between April 1991 and December 1992), their partners, and offspring, who are now in their late 20s.56 Results from the ALSPAC cohort suggested that childhood exposure to Epstein-Barr virus was associated with depressive symptoms and psychotic experiences in later life.57

Taken together, these findings indicate that there could be a sensitive period during early childhood when exposure to certain infections is harmful and can increase the risk for adult depression and psychosis.

Inflammation and Immune Alterations

Meta-analyses of case-control studies confirm that levels of inflammatory markers, including acute-phase proteins (e.g., C-reactive protein [CRP]) and cytokines (e.g., interleukin 6 [IL-6] and tumor necrosis factor alpha [TNFα]) are elevated in the blood and CSF of patients with depression and psychosis versus healthy controls.20,21,58–63 In depression, inflammation could be relevant for a subset of patients such as those with atypical/neurovegetative symptoms, including increased appetite/weight, fatigue, psychomotor slowing, leaden paralysis, and hypersomnia.20,64–66 Compared to depression, fewer studies have investigated associations of inflammatory markers with individual symptoms of psychosis. Nevertheless, these studies are compatible with a uniformly elevated profile of systemic inflammation or with specific associations with symptoms such as anhedonia and auditory hallucinations.60,67

Cross-sectional and case-control studies are, by definition, unable to examine whether inflammation is likely to be a cause or consequence of the mental disorder, and they can be biased by residual confounding factors. Therefore, recent studies have employed longitudinal designs using serum inflammatory data or genetic predisposition to greater inflammation in large, general population cohorts. In adults, these studies have suggested that higher serum CRP, IL-6, and TNFα, indexed using serum assays or polygenic risk scores, are associated with certain subsequent symptoms, including depressive symptoms such as changes in appetite, hypersomnia, and fatigue and negative symptoms of schizophrenia.68–73

In contrast to the more established literature base in adults, however, fewer studies are available in children and adolescents. To our knowledge, the largest cohort investigations of inflammatory markers have been conducted as part of the ALSPAC study. Across multiple follow-up time points, children from the ALSPAC cohort provided blood samples, which were assayed for concentrations of CRP and IL-6 at age 9 years. Multiple studies have assessed associations between these markers and later psychiatric symptoms using data from over 2000 children and controlling for important sociodemographic and lifestyle covariates such as age, sex, body mass index (BMI), ethnicity, father’s occupation, past psychological and behavioral problems, and maternal postpartum depression. Throughout this work, IL-6 at age 9 years showed associations with persistent depressive symptoms between 10 and 19 years,74 risk for depression and psychosis at ages 18 and 24 years,75,76 and hypomanic symptoms at age 22 years.77 Among depressive symptoms, IL-6 at age 9 years was also specifically associated with depressive symptoms of diurnal variation in mood, concentration difficulties, fatigue, and sleeping problems,78 and the evidence suggested a dose-response relationship, with higher IL-6 conferring greater risk for subsequent depressive and psychotic symptoms.75 In contrast to IL-6, CRP levels at age 9 years were not associated with depression and psychosis subsequently at ages 18 or 24 years.75,76 Other studies from the ALSPAC cohort, however, have reported cross-sectional and longitudinal associations of CRP levels at age 16 years with generalized anxiety disorder at age 16 years79 and auditory hallucinations and anhedonia at age 17 years.67 This raises the possibility that adolescent rather than childhood CRP may be more relevant for adult psychopathology or that CRP constitutes an illness state marker rather than a risk factor—hypotheses that need to be tested in future. Finally, in-depth proteomics analyses in ALSPAC data have suggested an alteration of complement pathway proteins in individuals with psychosis in early adulthood versus matched healthy controls.80–82

Other cohorts have reported similar results for CRP, IL-6, and other immune markers with psychosis and depression. For psychosis, cohort studies have reported associations between acute-phase protein levels as early as the neonatal period, but also later for CRP levels at age 16 years and erythrocyte sedimentation rate at age 18 years, with subsequent psychosis.83–85 For depression, results suggested that higher IL-6 levels could increase risk for depressive symptoms subsequently in a subgroup of individuals, with one study observing an association in adolescent girls who suffered childhood maltreatment86 and another study observing an association in girls at 10- to 30-month follow-up.87 In another cohort, evidence from time-lagged analyses suggested that within-person increases in TNFα over time increased depressive symptoms subsequently.88 Modeling inflammatory changes in a within-person design has the benefit that it controls for between-subject confounding variables. Results for CRP from these and one additional study did not suggest any association with later depression, which again aligns with findings from ALSPAC.86,87,89

Given that longitudinal associations are still at risk of residual confounding, evidence from quasi-experimental and experimental studies, and not just from person-centered designs, is needed to discount the risk of residual confounding and to fully ascertain causality of inflammatory markers on depression and psychosis. First, Mendelian randomization has recently been used as an alternative to address the issue of confounding; this approach takes advantage of Mendel’s law of inheritance and uses genetic variants as unbiased proxies for inflammatory indices.90 In depression, Mendelian randomization studies confirm a potential causal effect of IL-6 activity for depression and specifically for symptoms of fatigue, sleeping problems, and suicidality.91–97 In schizophrenia and psychosis, evidence from such studies pointed toward a more complex immunological dysregulation with potential protective effects of higher CRP and risk-increasing effects of soluble IL-6 receptor levels.96–98 Second, studies have suggested, for instance, that individuals receiving their annual flu vaccine and experiencing greater mood disturbance had greater increases in IL-6 previously.99 Third, up to 50% of patients receiving pro-inflammatory treatment for cancer and hepatitis C develop depression subsequently.100–103 Fourth, studies have also experimentally upregulated innate immune activity with endotoxin stimulation, which has consistently induced depression-like experiences in participants.104,105

Metabolic Alterations

Cardiometabolic disorders are more prevalent in schizophrenia and depression than in the general population106 and are the leading cause for a shortened life expectancy in both mental disorders.107 However, since depression and schizophrenia are both associated with a higher prevalence of smoking,108 physical inactivity and sedentariness,109 a poor diet,110,111 and prescription of metabolically active psychotropic medications,112 the excess physical comorbidity has traditionally been considered a consequence of the mental disorder. Indeed, for psychosis, early meta-analyses found no evidence for a higher prevalence of type 2 diabetes mellitus or metabolic syndrome in young adults with first-episode psychosis than in matched controls.113 These early meta-analyses failed to consider, however, that the absence of relatively mature cardiometabolic phenotypes such as type 2 diabetes and metabolic syndrome does not necessarily equate to the absence of cardiometabolic dysfunction. Indeed, more recent meta-analyses have consistently shown that subtle forms of disrupted glucose-insulin homeostasis, such as insulin resistance, impaired glucose tolerance, and dyslipidemia, are detectable in first-episode psychosis and even in unaffected first-degree relatives of patients with schizophrenia.114–118 Findings from these meta-analyses therefore called into question the traditional understanding of the direction of association of metabolic dysfunction with mental disorders; participants included in the studies were mostly psychotropic naive and relatively young, and consequently less affected by commonly attributed lifestyle and clinical factors. Nevertheless, because all the included studies in the meta-analyses either were cross-sectional or featured existing cases of psychosis, further elucidation on the direction of association could not be ascertained.

At present, a relative dearth of longitudinal research examines the metabolic associations of depression and psychosis. Findings from existing studies, however, can be broadly separated into studies examining adiposity, disrupted glucose-insulin homeostasis, or dyslipidemia.

The majority of the evidence for longitudinal associations of metabolic alterations with depression and psychosis can be found in studies examining adiposity. Regarding depression, a meta-analysis in 2010 did not identify evidence for longitudinal associations of BMI, measured in childhood and adolescence, with depression.119 More recently, however, a study using data from the Northern Finland Birth Cohort 1986 found evidence for an association between adolescent BMI and risk of depression in adulthood, particularly in females.120 Similarly, recent research from the ALSPAC cohort found evidence that a trend of BMI increase around the age of puberty onset was specifically associated with depression outcomes at age 24 years and that this association appeared stronger in females.121 The association remained after detailed confounding adjustment, including childhood emotional and behavioral problems, which helps to rule out reverse causality. In addition, evidence from Mendelian randomization studies suggests that BMI likely has a causal role in depression,122 with a likely specificity in the risk-increasing effect of higher BMI for symptoms of atypical depression and, specifically, increased appetite.92,123,124 Evidence from meta-analyses of longitudinal studies also supports a bidirectional association of BMI and depression,125 further suggesting that the mechanisms of association between BMI and depression are likely to be complex and multifaceted. Nevertheless, the importance of potential sex differences in immuno-metabolic processes is beginning to be recognized and warrants further investigation in the future.126

Regarding psychosis, the character of longitudinal associations with adiposity appears distinct from the character of associations found with depression. For example, findings from several large cohort, whole-population, and genetic correlation studies have suggested that lower BMI in childhood and adolescence is associated with a higher risk for developing schizophrenia in adulthood.127–131 Conversely, a study conducted in ALSPAC investigated BMI developmental trajectories from ages 1 to 24 years with the risk of psychosis at age 24 years and did not observe an association of BMI trajectories with adult psychosis.121 It is possible that the ALSPAC study has been underpowered to detect a subtle subgroup of individuals with persistently low BMI. Genetic studies of low BMI and psychosis are also limited, as current genome-wide association studies (GWAS) and Mendelian randomization studies have typically focused on obesity rather than low BMI and on BMI in adults rather than throughout development.5,121,122 Overall, evidence therefore indicates that BMI increases from around the age of puberty onset may be associated with an increased risk of depression in adulthood but that, conversely, a lower BMI in childhood and adolescence may be associated with increased risk of psychosis in adulthood.

Regarding disrupted glucose-insulin homeostasis, depression and psychosis also appear to be different. Early studies from the ALSPAC cohort on the topic found no evidence for an association of a single point measurement of fasting insulin at age 9 years with either depression or psychosis at age 18 years.132,133 A more recent study from the same cohort, however—which included repeat measurements of cardiometabolic indices to better capture dynamic temporal changes—found that a trend of persistently high fasting-insulin levels through childhood and adolescence was strongly associated with increased risk of psychosis at age 24 years in a dose-dependent fashion, though with no evidence for an association with depression.121 These findings indicate that disrupted glucose-insulin homeostasis may predate the onset of psychosis and may be specific to it. Longitudinal research also suggests that insulin resistance at baseline in first-episode psychosis may be a risk factor for weight gain during the first year after onset.134 In depression, the association with disrupted glucose-insulin homeostasis may be reversed. For example, two longitudinal studies have found associations of childhood depressive symptoms with the later development of insulin resistance in adolescence and adulthood, independent of BMI.135,136

Regarding dyslipidaemia, longitudinal studies have indicated that baseline levels of triglycerides at the first episode of psychosis may be associated with worse psychiatric outcomes at both one year137 and two years.138 Lipid alterations have also been detected in cases of psychosis at-risk mental states and may be useful as predictors of transition to psychosis.139,140 One longitudinal study found an association between childhood alterations in lipid profiles with psychotic symptoms at age 18 years.141 In addition, longitudinal studies have found that associations of cholesterol levels between birth and adolescence are associated with the later development of depressive symptoms.142–144

FACTORS CONTRIBUTING TO CHILDHOOD IMMUNO-METABOLIC ALTERATIONS IN DEPRESSION AND PSYCHOSIS

Genetic Predisposition

Several lines of evidence suggest that genetic factors could partly influence immuno-metabolic alterations. First, GWAS of psychiatric phenotypes have suggested that some of the prominent loci are in immune-relevant regions. The most notable example has been a GWAS on schizophrenia that implicated the major histocompatibility complex region and enrichment of immune-related pathways in the disorder.145 Follow-up work suggested that this association was arising from variation of genes coding the complement component 4.146 In addition, analyses of schizophrenia GWAS data have shown an enrichment of genetic risk for cardiovascular risk factors in common schizophrenia risk variants.147 Results have also suggested that distinct subgroups of schizophrenia patients could have unique metabolic risk loci and that leveraging pleiotropy with cardiovascular risk factors can aid in the discovery of schizophrenia risk variants.147,148

Second, genetic predisposition to immuno-metabolic diseases has been associated with depression and psychosis. For instance, recent work from ALSPAC has found that genetic predisposition to type 2 diabetes was associated with an increased risk of psychosis at age 18 years, and vice versa; genetic predisposition to schizophrenia was associated with an increased risk of insulin resistance at age 18 years.4 The study also found that the genotype-phenotype associations were mediated by inflammatory markers measured in childhood. These results indicate the potential for common underlying genetic mechanisms for comorbid psychosis and disrupted glucose-insulin homeostasis, which may involve genetic influences on inflammatory pathways. Other observational studies have found similar results. For example, the prevalence of insulin resistance149 and impaired glucose tolerance150 is higher in unaffected relatives of patients with schizophrenia than in matched controls, suggesting that genetic influences in glucose-insulin signaling may co-occur with genetic influences for psychosis, independent of disease expression and treatment effects. In addition, a prospective GWAS from a relatively small sample has shown that, compared to controls, people with comorbid schizophrenia and type 2 diabetes have a higher genetic predisposition for both disorders.151

Third, genetic correlation analyses highlight the pronounced co-heritability between psychiatric disorders and immuno-metabolic phenotypes. For example, the largest GWAS of CRP has suggested positive genetic correlations of CRP with schizophrenia and depressive symptoms.152 Genetic studies have also identified the potential for common variants that simultaneously increase the risk for both schizophrenia and cardiometabolic disorders, of which several are related to inflammation or the immune system.153 Regarding depression, evidence from polygenic risk score and genetic correlation analyses further supports a role of CRP, lipids, and BMI in major depressive disorder with atypical features and regarding symptoms such as changes in appetite specifically.70,92 In sum, these studies suggest that genetic predisposition to immuno-metabolic dysregulation could be an important contributor to the risk-increasing associations seen in epidemiological work.

Early-Life Adversity

Early-life adversity such as childhood abuse/maltreatment, which constitutes one of the most consistent trans-diagnostic risk factors for psychiatric disorders,154–156 is also associated with the development of adult cardiovascular disease.157 Consistent with Barker’s hypothesis, evidence from multiple population-based studies suggests that early-life adversity contributes to immuno-metabolic dysfunction.

Meta-analytic evidence indicates that childhood maltreatment could increase adult levels of CRP, IL-6, and TNFα.158 Similarly, childhood maltreatment has been meta-analytically associated with obesity.159 More-focused investigations report that patients suffering from first-episode psychosis and reporting childhood maltreatment can be characterized by a unique profile of increased CRP and BMI, which was not observed in patients without a history of childhood maltreatment or in healthy controls.160 With regard to depression, Slavich and Irwin161 have formulated the potential mediating role of inflammation between childhood maltreatment and later depression under what they call the social signal transduction theory of depression. This theory suggests that the stress associated with childhood maltreatment may manifest as systemic low-grade inflammation. Similar processes may occur regarding metabolic dysfunctions, but future research needs to disentangle these processes, particularly regarding developmental timing and direction of effect. Therefore, whether immuno-metabolic dysfunction mediates the link between early-life adversity and risks for depression and psychosis in adulthood is an important hypothesis that requires testing.

POTENTIAL MECHANISMS LINKING IMMUNO-METABOLIC ALTERATIONS TO DEPRESSION AND PSYCHOSIS

Several plausible mechanisms could potentially underlie associations of maternal and childhood immuno-metabolic risk factors with adult depression and psychosis. Regarding maternal infections, pathogens or antibodies following infection could exert direct and potentially pathogen-specific effects on the brain, but pathomechanisms could also be less pathogen-specific, including processes such as placental insufficiency, maternal or fetal nutritional deprivation, and activation of stress-response systems.162 These mechanisms have been explored in several animal studies, in which pregnant mice were infected with pathogens such as influenza virus, injected with immune-activating agents mimicking bacterial or viral infection, or directly injected with cytokines such as IL-6.163 Findings from these studies have shown relatively consistent abnormalities in the offspring, including sensorimotor-gating and cognitive-functioning deficits, decreased exploratory behavior, and decreased social interaction.162–164 Mechanistically, pro-inflammatory activity may at least partly mediate some of these effects. It is also noteworthy that some of the cognitive and behavioral deficits emerged only post-puberty,162,163 which aligns with peak age-of-onset prevalence for depression and psychosis in late adolescence and early adulthood.1 Regarding childhood infections, similar mechanisms to those in maternal infection have been proposed, including direct pathogen effects in the central nervous system (CNS) or corollary inflammatory mechanisms. Animal studies have tested these mechanisms, for instance, by demonstrating neurovirulence of mumps and CMV in periventricular regions, with the potential to disrupt learning and plasticity processes or with delayed neuronal effects through latent reactivation of dormant pathogens.53,165,166

Innate immune activation resulting from maternal or childhood infection, genetic predisposition, environmental adversity, or other environmental stressors could affect several plasticity-related neurodevelopmental processes and thereby contribute to the pathophysiology of adult depression and psychosis. Although the blood-brain barrier partially shields the CNS from immune cell infiltration, there are several communication pathways between these systems. First, cytokines can signal afferent nerves such as the vagus nerve, can enter the CNS in circumventricular zones via volume diffusion or active blood-brain barrier transport, and are produced locally within the CNS by periventricular macrophages.167 Second, prolonged inflammatory activity can lead to chemokine-dependent CNS infiltration of circulating myeloid and lymphoid cells.168 Third, the recently characterized glymphatic pathway is responsible for waste clearance, with the consequence that a dysfunction in this system could result in protein waste accumulation and inflammation.169 Centrally, cytokine receptors are also present on multiple cell types, including neurons, astrocytes, and microglia, and cytokine signaling on these cells can affect monoaminergic and glutamatergic neurotransmission.170 Cytokines can also signal major histocompatibility complex class I proteins on neurons to downregulate synaptic plasticity; experimental animal studies have specifically implicated IL-1β, IL-6, and TNFα in long-term potentiation, long-term depression, and synaptic scaling.171,172 Finally, cytokines can activate microglia—the resident macrophages of the brain that have neurodevelopmentally relevant roles in synaptic pruning and neurogenesis—which are disrupted following cytokine signaling.171,173

Multiple metabolic mechanisms, acting via immunological mechanisms or independent from them, could also potentially explain risk-increasing effects of metabolic factors for adult depression and psychosis. Cytokines are produced locally in white adipose tissue by infiltrating macrophages; additionally, lipids, ceramides, and reactive oxygen species can initiate NOD-like receptor 3 (NLPR3) inflammasome formation by activating pattern recognition receptors in subcutaneous or visceral adipose tissue.174,175 In turn, these NLPR3 inflammasomes can have further metabolic and inflammatory cascades via IL-1β and IL-18 release, insulin signaling disruption, and glucocorticoid receptor cleavage.175,176 Independent from inflammation, metabolic dysregulation (e.g., via adiposity) could also lead to resistance to the anorexigenic molecule leptin, which is the body’s main satiety signal.176 Leptin resistance can change CNS signaling between hypothalamus and reward circuits that regulate wanting and liking aspects of food and can alter autonomic and executive-control network processes.177 This can disinhibit eating behaviour, leading to further aggravation of metabolic risk factors.

Taken together, these proposed mechanisms can be integrated well with epidemiological evidence of maternal and childhood immuno-metabolic risk factors and adult depression and psychosis. One Swedish population-based study has suggested that the risk-increasing effect of childhood infections on adult nonaffective psychoses may be mediated and moderated by lower IQ in adolescence/early-adulthoood.17 Results also showed that risk-increasing effects were likely due to unique environmental factors, rather than shared environmental or genetic factors, suggesting a direct effect of the infection independent from any genetic predisposition existing in the family.17 This aligns with evidence showing that infections and genetic predisposition to schizophrenia have independent effects on schizophrenia.178 A study using ALSPAC data investigated whether the effect of infection on neurodevelopment might be mediated through systemic low-grade inflammation as indexed using CRP levels. While CRP was associated with lower IQ, there was no independent association of childhood infections with CRP levels after controlling for BMI, maternal occupation, and atopic disorders.179 This challenges the mediation hypothesis via CRP and could point, instead, to other inflammatory or noninflammatory mechanisms—for example, a potential metabolic role in mediating the effect of childhood infection on later depression and psychosis. Prenatal infection is also associated with lasting changes to the immune function of offspring; multiple studies show that childhood infections increase the risk for cardiometabolic illnesses in adulthood, which suggests that immuno-metabolic alterations following infections could be plausible risk mediators.180–183 Future studies are required to test associations of early-life infections with subsequent immuno-metabolic alterations, depression and psychosis risk, and whether childhood/adolescent immuno-metabolic alterations mediate the relationship between early-life infection and adult psychiatric risk.

EARLY-LIFE IMMUNO-METABOLIC ALTERATIONS AS POTENTIAL PREVENTION AND TREATMENT TARGETS FOR DEPRESSION AND PSYCHOSIS

Evidence for potential causal associations between childhood immuno-metabolic factors and adult depression and psychosis suggests that early-life infection, inflammation, and metabolic alterations could be important targets for treatment and prevention of these disorders.

First, immuno-metabolic risk factors could provide intervention targets in adults. In depression, initial randomized, controlled trials (RCTs) did not suggest that anti-inflammatory drugs were effective overall.64,184–186 Some evidence from post hoc analyses, however, indicated that these drugs could be effective for a subgroup of patients with inflammation or inflammation-related risk factors.64,184,185 This aligns with RCTs suggesting antidepressant effects of anti-inflammatory drugs in patients with chronic inflammatory illnesses and with an emerging evidence base suggesting the presence of a subgroup of patients with immuno-metabolic dysregulation.65,94,187–191 In schizophrenia and psychosis, evidence is also restricted; a few, relatively small RCTs have tested anti-inflammatory drugs, including the tetracyclic minocycline, the statin simvastatin, nonsteroidal anti-inflammatory drugs such as aspirin or celecoxib, and the anti-IL-6R monoclonal antibody tocilizumab, as adjuncts to standard antipsychotic medication.192–201 As summarized in a recent meta-analysis, these RCTs reported promising results for some drugs, particularly regarding negative symptoms of schizophrenia that are usually difficult to treat.192–197 There were also notable negative findings, however, warranting replication in larger RCTs that should selectively recruit patients with early psychosis and high baseline levels of inflammation.198–202

Overall, the evidence from RCTs of anti-inflammatory treatments for depression and psychosis makes apparent that these treatments are unlikely to provide a uniform treatment strategy for all patients. This is not a surprise, as immuno-metabolic alterations are not universally present in all cases of depression or psychosis. The key issues for future RCTs to consider are choice of patients, treatment target, and intervention. Regarding patient selection, evidence from RCTs of infliximab and minocycline as treatments for depression show that patients with evidence of inflammation may be more likely to be suitable candidates for immunotherapy.64,185 Further understanding of clinical and biochemical characteristics of depressed/psychosis patients with evidence of inflammation is required to refine patient selection in future RCTs. Emerging evidence indicates that inflammation-related depression is associated with neurovegetative/somatic symptoms,65,94 poor response to current treatment,203 and metabolic dysregulation.92,176,204 Regarding treatment target, while IL-6 and CRP have been studied extensively, a system-level, biomarker-based approach is needed to understand which immune pathways are causal and therefore represent the most promising therapeutic targets. Regarding choice of intervention, identification of specific causal targets may aid selection of specific monoclonal antibodies and also, depending upon the target population, nonspecific broad spectrum pharmacological (e.g., nonsteroidal anti-inflammatory drugs) and nonpharmacological (e.g., diet, exercise) interventions.

Second, targeting immuno-metabolic risk factors in childhood could be key for preventing instances of depression and psychosis as well as comorbid cardiometabolic diseases in adulthood. To this end, prevention of maternal or childhood infection needs to be a key public health objective facilitated by the development of vaccines, protective behaviors, early recognition of infections through regular screenings, and immediate treatment. At the same time, systemic inflammation and metabolic alterations throughout childhood and adolescence could be targeted with lifestyle and nutritional interventions. Studies in adults have suggested that the Mediterranean diet, characterized by a focus on fruits, vegetables, legumes, and grains, could have a favorable anti-inflammatory profile compared to current Western diets in North America and Europe.205 The evidence also suggests that omega-3 polyunsaturated fatty acids, particularly those rich in eicosapentaenoic acid, could be beneficial for patients with depression and psychosis.206–209 Similarly, greater cardiorespiratory fitness is associated with less depression and anxiety, and physical activity can mitigate the increased genetic predisposition to incident depression.210–212 Mechanistically, physical activity has been shown to reduce lipid and fasting-glucose concentrations in adults at high risk for type 2 diabetes,213 which parallels the findings in obese adolescents that showed improved lipid profiles, lower levels of insulin resistance, and lower blood pressure after physical activity, with more subtle benefits for non-obese adolescents.214 As demonstrated by initial studies in psychosis,215–218 lifestyle interventions could be particularly promising earlier in life, when lifestyle behaviors may be more amenable to change, or psychiatric illnesses less consolidated. Therefore, research needs to test large-scale physical activity and nutritional programs for children and adolescents, particularly those at increased risk of cardio-metabolic dysfunctions.

FUTURE OUTLOOK

Key outstanding questions regarding the role of childhood immuno-metabolic factors and later psychosis and depression in adulthood include whether findings on these risk factors extend to other populations, whether these risk factors are causal, whether potentially critical developmental windows can be identified, and what mechanistic pathways mediate their risk.

First, evidence from population-based studies in children and adolescents is so far mostly restricted to a small number of population-based samples. Large-scale population cohorts from Nordic countries have contributed evidence regarding infections, and smaller cohort studies such as ALSPAC have contributed a large proportion of the evidence for immuno-metabolic risk factors in childhood and adolescence.41,55 Give that these smaller cohort studies are at larger risk of selection bias from selective recruitment and attrition, future studies should aim to be more representative. In the future, studies are also needed from low- and middle-income countries as much of the existing evidence comes from affluent European and North American populations.219,220 As different samples and study designs each have their own limitations and biases, it would be helpful to apply evidence triangulation approaches whenever possible.221,222 The advent of genetic approaches such as Mendelian randomization studies is a promising example of such an approach; although it relies on its own set of assumptions, it can mimic a clinical trial for research questions when actual clinical trials are not possible.90,223

Second, future work will benefit from more fine-grained exposure and outcome phenotyping and testing of specific mechanistic pathways. Ideally, these data should include detailed GWAS summary data for specific immuno-metabolic risk factors and psychiatric phenotypes, including age at exposure and age at onset. Regarding age at exposure, for instance, it has been shown that the risk-increasing effects of adiposity in early life on adult cardiovascular disease and type 2 diabetes are mediated by adiposity in adulthood, which is clinically relevant as it suggests that adiposity constitutes a modifiable risk factor throughout life.224 Moreover, given that immuno-metabolic risk factors could differ across age of onset or recurrence and also for types of depression and psychosis, future studies should disentangle psychiatric outcome phenotypes into early onset, late onset, postpartum, and specific symptom-based groups, among others.65,225,226 Finally, only a few studies have formally tested mechanistic pathways, critical developmental windows, and whether risk factors represent shared familial or unique environmental factors. For instance, Perry and colleagues5 have shown that inflammation is a shared risk factor for schizophrenia and insulin resistance, and Børglum and colleagues227 have tested genome-wide interaction of genetic variants with CMV infection in relation to schizophrenia risk. Future studies need to apply similar approaches to evaluate mechanisms connecting maternal and childhood infection, genetic predisposition, and immuno-metabolic risk factors in childhood and adolescence with adulthood depression and psychosis.

CONCLUSIONS

Taken together, evidence from longitudinal cohort and genetic studies indicates that immuno-metabolic risk factors are implicated in the development of depression and psychosis in adulthood and could mediate some of the risk conferred from genetic predispositions and early-life adversity. First, studies indicate that maternal and childhood infections increase the risk primarily for later psychosis in adulthood. Second, studies show that inflammatory markers in childhood and adolescence could increase the risk for both depression and psychosis in adulthood. Findings also highlight, however, that these associations are likely complex, as exemplified by associations with specific inflammatory markers at the exposure level and with specific symptom-based subgroups at the outcome/disorder level. Third, studies on metabolic alterations suggest that higher BMI and adiposity increase the risk for later depression, whereas lower BMI increases the risk for later psychosis—which suggests that BMI could be a potential disorder-specific risk factor. Disrupted glucose-insulin homeostasis also seems to be disorder specific; studies primarily highlight risk-increasing associations with later psychosis, whereas depression could lead to glucose-insulin dysregulation subsequently. Some evidence suggests, too, that dyslipidemia could be associated with both disorders. Future research needs to confirm the mechanistic pathways proposed in this review (see Figure 1); to triangulate evidence for causality for these risk factors using novel approaches such as Mendelian randomization and using more fine-grained exposure and outcome phenotyping; to determine potential critical developmental windows; and to test generalizability of findings across different populations and ethnicities. In turn, the emerging understanding of immuno-metabolic risk factors could help improve treatment of adult psychosis and depression—for instance, by using anti-inflammatory drugs for a subgroup of patients. It could also inform preventive lifestyle interventions targeting immuno-metabolic risk factors in childhood and adolescence. Such interventions could ultimately help improve the debilitating rates of morbidity and mortality associated with these disorders in adulthood.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

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Keywords:

childhood; depression; infection; inflammation; metabolic dysregulation; prenatal; psychosis

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