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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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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.


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


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.


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.


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.


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.


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.


1. Kessler RC, Amminger GP, Aguilar-Gaxiola S, Alonso J, Lee S, Üstün TB. Age of onset of mental disorders: a review of recent literature. Curr Opin Psychiatry 2007;20:359–64.
2. Barker DJ. The fetal and infant origins of adult disease. BMJ 1990;301:1111.
3. Abel KM, Wicks S, Susser ES, et al. Birth weight, schizophrenia, and adult mental disorder. Arch Gen Psychiatry 2010;67:923–30.
4. Perry BI, Jones HJ, Richardson TG, et al. Common mechanisms for type 2 diabetes and psychosis: findings from a prospective birth cohort. Schizophr Res 2020;223:227–35.
5. Perry BI, Burgess S, Jones HJ, et al. The potential shared role of inflammation in insulin resistance and schizophrenia: a bidirectional two-sample mendelian randomization study. PLOS Med 2021;18:e1003455.
6. Perry BI, Oltean BP, Jones PB, Khandaker GM. Cardiometabolic risk in young adults with depression and evidence of inflammation: a birth cohort study. Psychoneuroendocrinology 2020;116:104682.
7. Weinberger DR. The pathogenesis of schizophrenia; a neurodevelopmental theory. In: Nasrallah HA, Weinberger DR, eds. The neurology of schizophrenia. Amsterdam: Elsevier, 1986:397–406.
8. Murray RM, Lewis SW. Is schizophrenia a neurodevelopmental disorder?Br Med J (Clin Res Ed) 1987;295:681–2.
9. Insel TR. Rethinking schizophrenia. Nature 2010;468:187–93.
10. Courchesne E, Pierce K, Schumann CM, et al. Mapping early brain development in autism. Neuron 2007;56:399–413.
11. Jones P, Rodgers B, Murray RM, Marmot M. Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet 1994;344:1398–402.
12. Cannon TD, Bearden CE, Hollister JM, Rosso IM, Sanchez LE, Hadley T. Childhood cognitive functioning in schizophrenia patients and their unaffected siblings: a prospective cohort study. Schizophr Bull 2000;26:379–93.
13. Kendler KS, Ohlsson H, Keefe RSE, Sundquist K, Sundquist J. The joint impact of cognitive performance in adolescence and familial cognitive aptitude on risk for major psychiatric disorders: a delineation of four potential pathways to illness. Mol Psychiatry 2018;23:1076–83.
14. Kendler KS, Ohlsson H, Mezuk B, Sundquist JO, Sundquist K. Observed cognitive performance and deviation from familial cognitive aptitude at age 16 years and ages 18 to 20 years and risk for schizophrenia and bipolar illness in a Swedish national sample. JAMA Psychiatry 2016;73:465–71.
15. Kendler KS, Ohlsson H, Sundquist J, Sundquist K. IQ and schizophrenia in a Swedish national sample: their causal relationship and the interaction of IQ with genetic risk. Am J Psychiatry 2015;172:259–65.
16. Kendler KS, Ohlsson H, Mezuk B, Sundquist K, Sundquist J. A Swedish national prospective and co-relative study of school achievement at age 16, and risk for schizophrenia, other nonaffective psychosis, and bipolar illness. Schizophr Bull 2016;42:77–86.
17. Khandaker GM, Dalman C, Kappelmann N, et al. Association of childhood infection with IQ and adult nonaffective psychosis in Swedish men: a population-based longitudinal cohort and co-relative study. JAMA Psychiatry 2018;75:356–62.
18. Entringer S, Buss C, Wadhwa PD. Prenatal stress, development, health and disease risk: a psychobiological perspective—2015 Curt Richter Award Paper. Psychoneuroendocrinology 2015;62:366–75.
19. Stetler C, Miller GE. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med 2011;73:114–26.
20. Osimo EF, Baxter LJ, Lewis G, Jones PB, Khandaker GM. Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychol Med 2019;49:1958–70.
21. Köhler CA, Freitas TH, Maes M, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand 2017;135:373–87.
22. Orlovska-Waast S, Köhler-Forsberg O, Brix SW, et al. Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry 2019;24:869–87.
23. Yuan N, Chen Y, Xia Y, Dai J, Liu C. Inflammation-related biomarkers in major psychiatric disorders: a cross-disorder assessment of reproducibility and specificity in 43 meta-analyses. Transl Psychiatry 2019;9:233.
24. Tamnes CK, Østby Y, Fjell AM, Westlye LT, Due-Tønnessen P, Walhovd KB. Brain maturation in adolescence and young adulthood: regional age-related changes in cortical thickness and white matter volume and microstructure. Cereb Cortex 2010;20:534–48.
25. Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J. Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun 2008;22:469–86.
26. Lawlor DA, Najman JM, Batty GD, O’Callaghan MJ, Williams GM, Bor W. Early life predictors of childhood intelligence: findings from the Mater-University study of pregnancy and its outcomes. Paediatr Perinat Epidemiol 2006;20:148–62.
27. Mednick SA, Machon RA, Huttunen MO, Bonett D. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 1988;45:189–92.
28. Barr CE, Mednick SA, Munk-Jorgensen P. Exposure to influenza epidemics during gestation and adult schizophrenia: a 40-year study. Arch Gen Psychiatry 1990;47:869–74.
29. Sham PC, O’Callaghan E, Takei N, Murray GK, Hare EH, Murray RM. Schizophrenia following prenatal exposure to influenza epidemics between 1939 and 1960. Br J Psychiatry 1992;160:461–6.
30. O’Callaghan E, Gibson T, Colohan HA, et al. Season of birth in schizophrenia. Br J Psychiatry 1991;158:764–9.
31. Selten J-PCJ, Slaets JPJ. Evidence against maternal influenza as a risk factor for schizophrenia. Br J Psychiatry 1994;164:674–6.
32. Susser E, Lumey LH, Lin SP, Ph D, Brown AS. No relation between risk of schizophrenia and prenatal exposure to influenza in Holland. Am J Psychiatry 1994;151:922–4.
33. Erlenmeyer-Kimling L, Folnegovic Z, Hrabak-Zerjavic V, Borcic B, Folnegovic-Smalc V, Susser ES. Schizophrenia and prenatal exposure to the 1957 A2 influenza epidemic in Croatia. Am J Psychiatry 1994;151:1496–8.
34. Morgan V, Castle D, Page A, et al. Influenza epidemics and incidence of schizophrenia, affective disorders and mental retardation in Western Australia: no evidence of a major effect. Schizophr Res 1997;26:25–39.
35. Buka SL. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry 2001;58:1032–7.
36. Brown AS, Begg MD, Gravenstein S, et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 2004;61:774–80.
37. Brown AS, Schaefer CA, Wyatt RJ, et al. Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study. Schizophr Bull 2000;26:287–95.
38. Mortensen PB, Nørgaard-Pedersen B, Waltoft BL, et al. Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth. Biol Psychiatry 2007;61:688–93.
39. Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry 2006;163:927–9.
40. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 2010;167:261–80.
41. Khandaker GM, Zimbron J, Lewis G, Jones PB. Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol Med 2013;43:239–57.
42. Zhou Y, Zhang W, Chen F, Hu S, Jiang H. Maternal infection exposure and the risk of psychosis in the offspring: a systematic review and meta-analysis. J Psychiatr Res 2021;135:28–36.
43. Sørensen HJ, Mortensen EL, Reinisch JM, Mednick SA. Association between prenatal exposure to bacterial infection and risk of schizophrenia. Schizophr Bull 2009;35:631–7.
44. Selten J-P, Frissen A, Lensvelt-Mulders G, Morgan VA. Schizophrenia and 1957 pandemic of influenza: meta-analysis. Schizophr Bull 2010;36:219–28.
45. Selten J-P, Termorshuizen F. The serological evidence for maternal influenza as risk factor for psychosis in offspring is insufficient: critical review and meta-analysis. Schizophr Res 2017;183:2–9.
46. Nielsen PR, Laursen TM, Mortensen PB. Association between parental hospital-treated infection and the risk of schizophrenia in adolescence and early adulthood. Schizophr Bull 2013;39:230–7.
47. Lydholm CN, Köhler-Forsberg O, Nordentoft M, et al. Parental infections before, during, and after pregnancy as risk factors for mental disorders in childhood and adolescence: a nationwide Danish study. Biol Psychiatry 2019;85:317–25.
48. Köhler-Forsberg O, Petersen L, Gasse C, et al. A nationwide study in Denmark of the association between treated infections and the subsequent risk of treated mental disorders in children and adolescents. JAMA Psychiatry 2019;76:271–9.
49. Breithaupt L, Köhler-Forsberg O, Larsen JT, et al. Association of exposure to infections in childhood with risk of eating disorders in adolescent girls. JAMA Psychiatry 2019;76:800–9.
50. Köhler O, Petersen L, Mors O, et al. Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study. Acta Psychiatr Scand 2017;135:97–105.
51. Benros ME, Waltoft BL, Nordentoft M, et al. Autoimmune diseases and severe infections as risk factors for mood disorders. JAMA Psychiatry 2013;70:812–20.
52. Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry 2011;168:1303–10.
53. Dalman C, Allebeck P, Gunnell D, et al. Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry 2008;165:59–65.
54. Koponen H, Rantakallio P, Veijola J, Jones P, Jokelainen J, Isohanni M. Childhood central nervous system infections and risk for schizophrenia. Eur Arch Psychiatry Clin Neurosci 2004;254:9–13.
55. Khandaker GM, Zimbron J, Dalman C, Lewis G, Jones PB. Childhood infection and adult schizophrenia: a meta-analysis of population-based studies. Schizophr Res 2012;139:161–8.
56. Golding J, Pembrey M, Jones R; Alspac Study Team. ALSPAC—the Avon Longitudinal Study of Parents and Children. I. Study methodology. Paediatr Perinat Epidemiol 2001;15:74–87.
57. Chaplin AB, Jones PB, Khandaker GM. Association between common early-childhood infection and subsequent depressive symptoms and psychotic experiences in adolescence: a population-based longitudinal birth cohort study. Psychol Med 2020 [online ahead of print].
58. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010;67:446–57.
59. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun 2015;49:206–15.
60. Pillinger T, Osimo EF, Brugger S, Mondelli V, McCutcheon RA, Howes OD. A meta-analysis of immune parameters, variability, and assessment of modal distribution in psychosis and test of the immune subgroup hypothesis. Schizophr Bull 2019;45:1120–33.
61. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2011;70:663–71.
62. Upthegrove R, Manzanares-Teson N, Barnes NM. Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophr Res 2014;155:101–8.
63. Pillinger T, D’Ambrosio E, McCutcheon R, Howes OD. Is psychosis a multisystem disorder? A meta-review of central nervous system, immune, cardiometabolic, and endocrine alterations in first-episode psychosis and perspective on potential models. Mol Psychiatry 2019;24:776–94.
64. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 2013;70:31–41.
65. Milaneschi Y, Lamers F, Berk M, Penninx BWJH. Depression heterogeneity and its biological underpinnings: toward immunometabolic depression. Biol Psychiatry 2020;88:369–80.
66. Lamers F, Milaneschi Y, Vinkers CH, Schoevers RA, Giltay EJ, Penninx BWJH. Depression profilers and immuno-metabolic dysregulation: longitudinal results from the NESDA study. Brain Behav Immun 2020;88:174–83.
67. Khandaker GM, Stochl J, Zammit S, Lewis G, Dantzer R, Jones PB. Association between circulating levels of C-reactive protein and positive and negative symptoms of psychosis in adolescents in a general population birth cohort. J Psychiatr Res 2021;143:534–42.
68. Mac Giollabhui N, Ng TH, Ellman LM, Alloy LB. The longitudinal associations of inflammatory biomarkers and depression revisited: systematic review, meta-analysis, and meta-regression. Mol Psychiatry 2021;26:3302–14.
69. Badini I, Coleman JR, Hagenaars SP, et al. Depression with atypical neurovegetative symptoms shares genetic predisposition with immuno-metabolic traits and alcohol consumption. Psychol Med 2020 [online ahead of print].
70. Milaneschi Y, Lamers F, Peyrot WJ, et al. Genetic association of major depression with atypical features and obesity-related immunometabolic dysregulations. JAMA Psychiatry 2017;74:1214–25.
71. Kappelmann N, Czamara D, Rost N, et al. Polygenic risk for immuno-metabolic markers and specific depressive symptoms: a multi-sample network analysis study. Brain Behav Immun 2021;95:256–68.
72. Krynicki CR, Dazzan P, Pariante CM, et al. Deconstructing depression and negative symptoms of schizophrenia; differential and longitudinal immune correlates, and response to minocycline treatment. Brain Behav Immun 2021;91:498–504.
73. Feng T, McEvoy JP, Miller BJ. Longitudinal study of inflammatory markers and psychopathology in schizophrenia. Schizophr Res 2020;224:58–66.
74. Khandaker GM, Stochl J, Zammit S, Goodyer I, Lewis G, Jones PB. Childhood inflammatory markers and intelligence as predictors of subsequent persistent depressive symptoms: a longitudinal cohort study. Psychol Med 2018;48:1514–22.
75. Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry 2014;71:1121–8.
76. Perry BI, Zammit S, Jones PB, Khandaker GM. Childhood inflammatory markers and risks for psychosis and depression at age 24: examination of temporality and specificity of association in a population-based prospective birth cohort. Schizophr Res 2021;230:69–76.
77. Hayes JF, Khandaker GM, Anderson J, et al. Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study. Psychol Med 2017;47:23–33.
78. Chu AL, Stochl J, Lewis G, Zammit S, Jones PB, Khandaker GM. Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort. Brain Behav Immun 2019;76:74–81.
79. Khandaker GM, Zammit S, Lewis G, Jones PB. Association between serum C-reactive protein and DSM-IV generalized anxiety disorder in adolescence: findings from the ALSPAC cohort. Neurobiol Stress 2016;4:55–61.
80. Mongan D, Föcking M, Healy C, et al. Development of proteomic prediction models for transition to psychotic disorder in the clinical high-risk state and psychotic experiences in adolescence. JAMA Psychiatry 2020;46(supp 1):S238–9.
81. English JA, Lopez LM, O’Gorman A, et al. Blood-based protein changes in childhood are associated with increased risk for later psychotic disorder: evidence from a nested case-control study of the ALSPAC longitudinal birth cohort. Schizophr Bull 2018;44:297–306.
82. Föcking M, Sabherwal S, Cates HM, et al. Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress. Mol Psychiatry 2021;26:524–33.
83. Gardner RM, Dalman C, Wicks S, Lee BK, Karlsson H. Neonatal levels of acute phase proteins and later risk of non-affective psychosis. Transl Psychiatry 2013;3:e228.
84. Metcalf SA, Jones PB, Nordstrom T, et al. Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: A prospective birth cohort study. Brain Behav Immun 2017;59:253–9.
85. Kappelmann N, Khandaker GM, Dal H, et al. Systemic inflammation and intelligence in early adulthood and subsequent risk of schizophrenia and other non-affective psychoses: a longitudinal cohort and co-relative study. Psychol Med 2019;49:295–302.
86. Miller GE, Cole SW. Clustering of depression and inflammation in adolescents previously exposed to childhood adversity. Biol Psychiatry 2012;72:34–40.
87. Moriarity DP, Mac Giollabhui N, Ellman LM, et al. Inflammatory proteins predict change in depressive symptoms in male and female adolescents. Clin Psychol Sci 2019;7:754–67.
88. Moriarity DP, Kautz MM, Mac Giollabhui N, et al. Bidirectional associations between inflammatory biomarkers and depressive symptoms in adolescents: potential causal relationships. Clin Psychol Sci 2020;8:690–703.
89. Copeland WE, Shanahan L, Worthman C, Angold A, Costello EJ. Cumulative depression episodes predict later c-reactive protein levels: a prospective analysis. Biol Psychiatry 2012;71:15–21.
90. Lawlor DA, Harbord RM, Sterne JAC, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008;27:1133–63.
91. Khandaker GM, Zuber V, Rees JMB, et al. Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort. Mol Psychiatry 2020;25:1477–86.
92. Kappelmann N, Arloth J, Georgakis MK, et al. Dissecting the association between inflammation, metabolic dysregulation, and specific depressive symptoms: a genetic correlation and 2-sample mendelian randomization study. JAMA Psychiatry 2021;78:161–70.
93. Kelly K, Smith JA, Mezuk B. Depression and interleukin-6 signaling: a Mendelian randomization study. Brain Behav Immun 2021;95:106–14.
94. Milaneschi Y, Kappelmann N, Ye Z, et al. Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts. Mol Psychiatry 2021 [online ahead of print}.
95. Ye Z, Kappelmann N, Moser S, et al. Role of inflammation in depression and anxiety: tests for disorder specificity, linearity and potential causality of association in the UK Biobank. EClinicalMedicine 2021;100992.
96. Khandaker GM, Zammit S, Burgess S, Lewis G, Jones PB. Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort. Brain Behav Immun 2018;69:264–72.
97. Perry BI, Upthegrove R, Kappelmann N, Jones PB, Burgess S, Khandaker GM. Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: a bi-directional two-sample mendelian randomization study. Brain Behav Immun 2021;97:176–85.
98. Hartwig FP, Borges MC, Horta BL, Bowden J, Davey Smith G. Inflammatory biomarkers and risk of schizophrenia. JAMA Psychiatry 2017;74:1226–33.
99. Kuhlman KR, Robles TF, Dooley LN, Boyle CC, Haydon MD, Bower JE. Within-subject associations between inflammation and features of depression: using the flu vaccine as a mild inflammatory stimulus. Brain Behav Immun 2018;69:540–7.
100. Capuron L, Ravaud A, Dantzer R. Timing and specificity of the cognitive changes induced by interleukin-2 and interferon-α treatments in cancer patients. Psychosom Med 2001;63:376–86.
101. Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the prevention of depression induced by interferon alfa. N Engl J Med 2012;5701:961–6.
102. Raison CL, Miller AH. Depression in cancer: new developments regarding diagnosis and treatment. Biol Psychiatry 2003;54:283–94.
103. Udina M, Castellvi P, Moreno-Espana J, et al. Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry 2012;73:1128–38.
104. Schedlowski M, Engler H, Grigoleit JS. Endotoxin-induced experimental systemic inflammation in humans: a model to disentangle immune-to-brain communication. Brain Behav Immun 2014;35:1–8.
105. Eisenberger NI, Inagaki TK, Mashal NM, Irwin MR. Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain Behav Immun 2010;24:558–63.
106. Firth J, Siddiqi N, Koyanagi A, et al. The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness. Lancet Psychiatry 2019;6:675–712.
107. Plana-Ripoll O, Pedersen CB, Agerbo E, et al. A comprehensive analysis of mortality-related health metrics associated with mental disorders: a nationwide, register-based cohort study. Lancet 2019;394:1827–35.
108. Lawrence D, Mitrou F, Zubrick SR. Smoking and mental illness: results from population surveys in Australia and the United States. BMC Public Health 2009;9:285.
109. Vancampfort D, Firth J, Schuch FB, et al. Sedentary behavior and physical activity levels in people with schizophrenia, bipolar disorder and major depressive disorder: a global systematic review and meta-analysis. World Psychiatry 2017;16:308–15.
110. Khalid S, Williams CM, Reynolds SA. Is there an association between diet and depression in children and adolescents?A systematic review. Br J Nutr 2016;116:2097–108.
111. Dipasquale S, Pariante CM, Dazzan P, Aguglia E, McGuire P, Mondelli V. The dietary pattern of patients with schizophrenia: a systematic review. J Psychiatr Res 2013;47:197–207.
112. Mazereel V, Detraux J, Vancampfort D, van Winkel R, De Hert M. Impact of psychotropic medication effects on obesity and the metabolic syndrome in people with serious mental illness. Front Endocrinol (Lausanne) 2020;11:573479.
113. Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders—a systematic review and meta-analysis. Schizophr Bull 2013;39:306–18.
114. Perry BI, McIntosh G, Weich S, Singh S, Rees K. The association between first-episode psychosis and abnormal glycaemic control: systematic review and meta-analysis. Lancet Psychiatry 2016;3:1049–58.
115. Pillinger T, Beck K, Gobjila C, Donocik JG, Jauhar S, Howes OD. Impaired glucose homeostasis in first-episode schizophrenia. JAMA Psychiatry 2017;74:261–9.
116. Greenhalgh AM, Gonzalez-Blanco L, Garcia-Rizo C, et al. Meta-analysis of glucose tolerance, insulin, and insulin resistance in antipsychotic-naïve patients with nonaffective psychosis. Schizophr Res 2017;179:57–63.
117. Misiak B, Stańczykiewicz B, Łaczmański Ł, Frydecka D. Lipid profile disturbances in antipsychotic-naive patients with first-episode non-affective psychosis: a systematic review and meta-analysis. Schizophr Res 2017;190:18–27.
118. Misiak B, Wiśniewski M, Lis M, Samochowiec J, Stańczykiewicz B. Glucose homeostasis in unaffected first-degree relatives of schizophrenia patients: a systematic review and meta-analysis. Schizophr Res 2020;223:2–8.
119. Luppino FS, de Wit LM, Bouvy PF, et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry 2010;67:220–9.
120. Herva A, Laitinen J, Miettunen J, et al. Obesity and depression: results from the longitudinal Northern Finland 1966 Birth Cohort Study. Int J Obes 2006;30:520–7.
121. Perry BI, Stochl J, Upthegrove R, et al. Longitudinal trends in childhood insulin levels and body mass index and associations with risks of psychosis and depression in young adults. JAMA Psychiatry 2021;78:416–25.
122. Hartwig FP, Bowden J, Loret de Mola C, Tovo-Rodrigues L, Davey Smith G, Horta BL. Body mass index and psychiatric disorders: a Mendelian randomization study. Sci Rep 2016;6:32730.
123. Milaneschi Y, Lamers F, Penninx BWJH. Dissecting depression biological and clinical heterogeneity—the importance of symptom assessment resolution. JAMA Psychiatry 2021;78:341.
124. Pistis G, Milaneschi Y, Vandeleur CL, et al. Obesity and atypical depression symptoms: findings from Mendelian randomization in two European cohorts. Transl Psychiatry 2021;11:96.
125. Mannan M, Mamun A, Doi S, Clavarino A. Prospective associations between depression and obesity for adolescent males and females—a systematic review and meta-analysis of longitudinal studies. PLoS One 2016;11:e0157240.
126. Goldstein JM, Hale T, Foster SL, Tobet SA, Handa RJ. Sex differences in major depression and comorbidity of cardiometabolic disorders: impact of prenatal stress and immune exposures. Neuropsychopharmacology 2019;44:59–70.
127. Sormunen E, Saarinen MM, Salokangas RKR, et al. Body mass index trajectories in childhood and adolescence—risk for non-affective psychosis. Schizophr Res 2019;206:313–7.
128. Zammit S, Rasmussen F, Farahmand B, et al. Height and body mass index in young adulthood and risk of schizophrenia: a longitudinal study of 1 347 520 Swedish men. Acta Psychiatr Scand 2007;116:378–85.
129. Weiser M, Knobler H, Lubin G, et al. Body mass index and future schizophrenia in israeli male adolescents. J Clin Psychiatry 2004;65:1546–9.
130. Sorensen HJ, Mortensen EL, Reinisch JM, Mednick SA. Height, weight and body mass index in early adulthood and risk of schizophrenia. Acta Psychiatr Scand 2006;114:49–54.
131. Bahrami S, Steen NE, Shadrin A, et al. Shared genetic loci between body mass index and major psychiatric disorders: a genome-wide association study. JAMA Psychiatry 2020;77:503–12.
132. Perry BI, Khandaker GM, Marwaha S, et al. Insulin resistance and obesity, and their association with depression in relatively young people: findings from a large UK birth cohort. Psychol Med 2020;50:556–65.
133. Perry BI, Upthegrove R, Thompson A, et al. Dysglycaemia, inflammation and psychosis: findings from the UK ALSPAC birth cohort. Schizophr Bull 2019;45:330–8.
134. Keinänen J, Mantere O, Kieseppä T, et al. Early insulin resistance predicts weight gain and waist circumference increase in first-episode psychosis—a one year follow-up study. Schizophr Res 2015;169:458–63.
135. Shomaker LB, Tanofsky-Kraff M, Stern EA, et al. Longitudinal study of depressive symptoms and progression of insulin resistance in youth at risk for adult obesity. Diabetes Care 2011;34:2458–63.
136. Pulkki-Råback L, Elovainio M, Kivimäki M, et al. Depressive symptoms and the metabolic syndrome in childhood and adulthood: a prospective cohort study. Health Psychol 2009;28:108–16.
137. Nettis MA, Pergola G, Kolliakou A, et al. Metabolic-inflammatory status as predictor of clinical outcome at 1-year follow-up in patients with first episode psychosis. Psychoneuroendocrinology 2019;99:145–53.
138. Osimo EF, Perry BI, Cardinal RN, et al. Inflammatory and cardiometabolic markers at presentation with first episode psychosis and long-term clinical outcomes: a longitudinal study using electronic health records. Brain Behav Immun 2021;91:117–27.
139. Dickens AM, Sen P, Kempton MJ, et al. Dysregulated lipid metabolism precedes onset of psychosis. Biol Psychiatry 2021;89:288–97.
140. Lamichhane S, Dickens AM, Sen P, et al. Association between circulating lipids and future weight gain in individuals with an at-risk mental state and in first-episode psychosis. Schizophr Bull 2021;47:160–9.
141. Madrid-Gambin F, Föcking M, Sabherwal S, et al. Integrated lipidomics and proteomics point to early blood-based changes in childhood preceding later development of psychotic experiences: evidence from the avon longitudinal study of parents and children. Biol Psychiatry 2019;86:25–34.
142. Mesirow MSC, Roberts S, Cecil CAM, et al. Serum cholesterol, MTHFR methylation, and symptoms of depression in children. Dev Psychol 2019;55:2575–86.
143. Manczak EM, Gotlib IH. Lipid profiles at birth predict teacher-rated child emotional and social development 5 years later. Psychol Sci 2019;30:1780–9.
144. Park JH, Jung SJ, Jung Y, Ahn SV, Lee E, Kim HC. Association between the change of total cholesterol during adolescence and depressive symptoms in early adulthood. Eur Child Adolesc Psychiatry 2021;30:261–9.
145. Ripke S, Neale BM, Corvin A, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511:421–7.
146. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature 2016;530:177–83.
147. Andreassen OA, Djurovic S, Thompson WK, et al. Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. Am J Hum Genet 2013;92:197–209.
148. Strawbridge RJ, Johnston KJA, Bailey MES, et al. The overlap of genetic susceptibility to schizophrenia and cardiometabolic disease can be used to identify metabolically different groups of individuals. Sci Rep 2021;11:632.
149. Chouinard V-A, Henderson DC, Dalla Man C, et al. Impaired insulin signaling in unaffected siblings and patients with first-episode psychosis. Mol Psychiatry 2019;24:1513–22.
150. Ferentinos P, Dikeos D. Genetic correlates of medical comorbidity associated with schizophrenia and treatment with antipsychotics. Curr Opin Psychiatry 2012;25:381–90.
151. Hackinger S, Prins B, Mamakou V, et al. Evidence for genetic contribution to the increased risk of type 2 diabetes in schizophrenia. Transl Psychiatry 2018;8:252.
152. Ligthart S, Vaez A, Võsa U, et al. Genome analyses of >200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders. Am J Hum Genet 2018;103:691–706.
153. So H-C, Chau K-L, Ao F-K, Mo C-H, Sham P-C. Exploring shared genetic bases and causal relationships of schizophrenia and bipolar disorder with 28 cardiovascular and metabolic traits. Psychol Med 2019;49:1286–98.
154. Hoppen TH, Chalder T. Childhood adversity as a transdiagnostic risk factor for affective disorders in adulthood: a systematic review focusing on biopsychosocial moderating and mediating variables. Clin Psychol Rev 2018;65:81–151.
155. Scott KM, McLaughlin KA, Smith DAR, Ellis PM. Childhood maltreatment and DSM-IV adult mental disorders: comparison of prospective and retrospective findings. Br J Psychiatry 2012;200:469–75.
156. Varese F, Smeets F, Drukker M, et al. Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull 2012;38:661–71.
157. Kershaw KN, Brenes GA, Charles LE, et al. Associations of stressful life events and social strain with incident cardiovascular disease in the women’s health initiative. J Am Heart Assoc 2014;3:e000687.
158. Baumeister D, Akhtar R, Ciufolini S, Pariante CM, Mondelli V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry 2016;21:642–9.
159. Danese A, Tan M. Childhood maltreatment and obesity: systematic review and meta-analysis. Mol Psychiatry 2014;19:544–54.
160. Hepgul N, Pariante CM, Dipasquale S, et al. Childhood maltreatment is associated with increased body mass index and increased C-reactive protein levels in first-episode psychosis patients. Psychol Med 2012;42:1893–901.
161. Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull 2014;140:774–815.
162. Meyer U, Feldon J. Epidemiology-driven neurodevelopmental animal models of schizophrenia. Prog Neurobiol 2010;90:285–326.
163. Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci 2003;23:297–302.
164. Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 2007;27:10695–702.
165. Kristensson K, Löve A, Norrby E. Experimental mumps virus infections in the developing nervous system. In: Johnson RT, Lyon G, eds. Virus infections and the developing nervous system. Dordrecht: Kluwer, 1988:143–50.
166. Tsutsui Y, Kosugi I, Kawasaki H. Neuropathogenesis in cytomegalovirus infection: indication of the mechanisms using mouse models. Rev Med Virol 2005;15:327–45.
167. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008;9:46–56.
168. Thomson CA, McColl A, Graham GJ, Cavanagh J. Sustained exposure to systemic endotoxin triggers chemokine induction in the brain followed by a rapid influx of leukocytes. J Neuroinflammation 2020;17:94.
169. Verheggen ICM, Van Boxtel MPJ, Verhey FRJ, Jansen JFA, Backes WH. Interaction between blood-brain barrier and glymphatic system in solute clearance. Neurosci Biobehav Rev 2018;90:26–33.
170. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016;16:22–34.
171. Jiang NM, Cowan M, Moonah SN, Petri WA. The impact of systemic inflammation on neurodevelopment. Trends Mol Med 2018;24:794–804.
172. McAfoose J, Baune BT. Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev 2009;33:355–66.
173. Paolicelli RC, Bolasco G, Pagani F, et al. Synaptic pruning by microglia is necessary for normal brain development. Science 2011;333:1456–8.
174. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 2012;18:363–74.
175. Sharma BR, Kanneganti T. NLRP3 inflammasome in cancer and metabolic diseases. Nat Immunol 2021;22:550–9.
176. Milaneschi Y, Simmons WK, van Rossum EFC, Penninx BWJH. Depression and obesity: evidence of shared biological mechanisms. Mol Psychiatry 2019;24:18–33.
177. Cui H, López M, Rahmouni K. The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat Rev Endocrinol 2017;13:338–51.
178. Benros ME, Trabjerg BB, Meier S, et al. Influence of polygenic risk scores on the association between infections and schizophrenia. Biol Psychiatry 2016;80:609–16.
179. MacKinnon N, Zammit S, Lewis G, Jones PB, Khandaker GM. Association between childhood infection, serum inflammatory markers and intelligence: findings from a population-based prospective birth cohort study. Epidemiol Infect 2017;146:256–64.
180. Hamer M, Batty GD. Markers of early life infection in relation to adult diabetes: prospective evidence from a national birth cohort study over four decades. Diabetes Care 2020;43:e61–2.
181. Pussinen PJ, Paju S, Koponen J, et al. Association of childhood oral infections with cardiovascular risk factors and subclinical atherosclerosis in adulthood. JAMA Netw Open 2019;2:e192523.
182. Burgner DP, Cooper MN, Moore HC, et al. Childhood hospitalisation with infection and cardiovascular disease in early-mid adulthood: a longitudinal population-based study. PLoS One 2015;10:e0125342.
183. Pedersen JM, Mortensen EL, Meincke RH, et al. Maternal infections during pregnancy and offspring midlife inflammation. Matern Health Neonatol Perinatol 2019;5:4.
184. McIntyre RS, Subramaniapillai M, Lee Y, et al. Efficacy of adjunctive infliximab vs placebo in the treatment of adults with bipolar I/II depression: a randomized clinical trial. JAMA Psychiatry 2019;76:783–90.
185. Nettis MA, Lombardo G, Hastings C, et al. Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial. Neuropsychopharmacology 2021;46:939–48.
186. Husain MI, Chaudhry IB, Khoso AB, et al. Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial. Lancet Psychiatry 2020;7:515–27.
187. Köhler-Forsberg O, Nicolaisen Lydholm C, Hjorthøj C, Nordentoft M, Mors O, Benros ME. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand 2019;139:404–19.
188. Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry 2018;23:335–43.
189. Wittenberg GM, Stylianou A, Zhang Y, et al. Effects of immunomodulatory drugs on depressive symptoms: a mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders. Mol Psychiatry 2020;25:1275–85.
190. Jokela M, Virtanen M, Batty G, Kivimäki M. Inflammation and specific symptoms of depression. JAMA Psychiatry 2016;73:87–8.
191. Lynall M-E, Turner L, Bhatti J, et al. Peripheral blood cell–stratified subgroups of inflamed depression. Biol Psychiatry 2020;88:185–96.
192. Laan W, Grobbee DE, Selten J-P, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders. J Clin Psychiatry 2010;71:520–7.
193. Müller N, Riedel M, Scheppach C, et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry 2002;159:1029–34.
194. Akhondzadeh S, Tabatabaee M, Amini H, Ahmadiabhari S, Abbasi S, Behnam B. Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res 2007;90:179–85.
195. Müller N, Krause D, Dehning S, et al. Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment. Schizophr Res 2010;121:118–24.
196. Chaudhry IB, Hallak J, Husain N, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol 2012;26:1185–93.
197. Levkovitz Y, Mendlovich S, Riwkes S, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry 2010;71:138–49.
198. Rapaport MH, Delrahim KK, Bresee CJ, Maddux RE, Ahmadpour O, Dolnak D. Celecoxib augmentation of continuously Ill patients with schizophrenia. Biol Psychiatry 2005;57:1594–6.
199. Deakin B, Suckling J, Barnes TRE, et al. The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial. Lancet Psychiatry 2018;5:885–94.
200. Girgis RR, Ciarleglio A, Choo T, et al. A randomized, double-blind, placebo-controlled clinical trial of tocilizumab, an interleukin-6 receptor antibody, for residual symptoms in schizophrenia. Neuropsychopharmacology 2018;43:1317–23.
201. Sommer IE, Gangadin SS, de Witte LD, et al. Simvastatin augmentation for patients with early-phase schizophrenia-spectrum disorders: a double-blind, randomized placebo-controlled trial. Schizophr Bull 2021;47:1108–15.
202. Çakici N, van Beveren NJM, Judge-Hundal G, Koola MM, Sommer IEC. An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis. Psychol Med 2019;49:2307–19.
203. Liu JJ, Wei Y Bin, Strawbridge R, et al. Peripheral cytokine levels and response to antidepressant treatment in depression: a systematic review and meta-analysis. Mol Psychiatry 2020;25:339–50.
204. McLaughlin AP, Nikkheslat N, Hastings C, et al. The influence of comorbid depression and overweight status on peripheral inflammation and cortisol levels. Psychol Med 2021 [online ahead of print].
205. Galland L. Diet and inflammation. Nutr Clin Pract 2010;25:634–40.
206. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry 2011;72:1577–84.
207. Fusar-Poli P, Berger G. Eicosapentaenoic acid interventions in schizophrenia: meta-analysis of randomized, placebo-controlled studies. J Clin Psychopharmacol 2012;32:179–85.
208. Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-chain ω-3 fatty acids for indicated prevention of psychotic disorders. Arch Gen Psychiatry 2010;67:146–54.
209. Grosso G, Galvano F, Marventano S, et al. Omega-3 fatty acids and depression: scientific evidence and biological mechanisms. Oxid Med Cell Longev 2014;2014:313570 (Figure 1).
210. Kandola AA, Osborn DPJ, Stubbs B, Choi KW, Hayes JF. Individual and combined associations between cardiorespiratory fitness and grip strength with common mental disorders: a prospective cohort study in the UK Biobank. BMC Med 2020;18:303.
211. Choi KW, Zheutlin AB, Karlson RA, et al. Physical activity offsets genetic risk for incident depression assessed via electronic health records in a biobank cohort study. Depress Anxiety 2020;37:106–14.
212. Kandola A, Lewis G, Osborn DPJ, Stubbs B, Hayes JF. Depressive symptoms and objectively measured physical activity and sedentary behaviour throughout adolescence: a prospective cohort study. Lancet Psychiatry 2020;7:262–71.
213. Kujala UM, Jokelainen J, Oksa H, et al. Increase in physical activity and cardiometabolic risk profile change during lifestyle intervention in primary healthcare: 1-year follow-up study among individuals at high risk for type 2 diabetes. BMJ Open 2011;1:e000292.
214. Gutin B, Owens S. The influence of physical activity on cardiometabolic biomarkers in youths: a review. Pediatr Exerc Sci 2011;23:169–85.
215. Speyer H, Christian Brix Nørgaard H, Birk M, et al. The CHANGE trial: no superiority of lifestyle coaching plus care coordination plus treatment as usual compared to treatment as usual alone in reducing risk of cardiovascular disease in adults with schizophrenia spectrum disorders and abdominal obesity. World Psychiatry 2016;15:155–65.
216. Teasdale SB, Curtis J, Ward PB, et al. The effectiveness of the Keeping the Body in Mind Xtend pilot lifestyle program on dietary intake in first-episode psychosis: two-year outcomes. Obes Res Clin Pract 2019;13:214–6.
217. Curtis J, Watkins A, Rosenbaum S, et al. Evaluating an individualized lifestyle and life skills intervention to prevent antipsychotic-induced weight gain in first-episode psychosis. Early Interv Psychiatry 2016;10:267–76.
218. Fisher E, Wood SJ, Upthegrove R, Aldred S. Designing a feasible exercise intervention in first-episode psychosis: exercise quality, engagement and effect. Psychiatry Res 2020;286:112840.
219. Munafò MR, Tilling K, Taylor AE, Evans DM, Smith GD. Collider scope: when selection bias can substantially influence observed associations. Int J Epidemiol 2018;47:226–35.
220. Henrich J, Heine SJ, Norenzayan A. Most people are not WEIRD. Nature 2010;466:29.
221. Lawlor DA, Tilling K, Davey Smith G. Triangulation in aetiological epidemiology. Int J Epidemiol 2016;45:1866–86.
222. Ohlsson H, Kendler KS. Applying causal inference methods in psychiatric epidemiology. JAMA Psychiatry 2020;77:637–44.
223. Hingorani A, Humphries S. Nature’s randomised trials. Lancet 2005;366:1906–8.
224. Richardson TG, Sanderson E, Elsworth B, Tilling K, Davey Smith G. Use of genetic variation to separate the effects of early and later life adiposity on disease risk: Mendelian randomisation study. BMJ 2020;369:m1203.
225. Guloksuz S, van Os J. The slow death of the concept of schizophrenia and the painful birth of the psychosis spectrum. Psychol Med 2018;48:229–44.
226. Cai N, Choi KW, Fried EI. Reviewing the genetics of heterogeneity in depression: operationalizations, manifestations and etiologies. Hum Mol Genet 2020;29(R1):R10–8.
227. Børglum AD, Demontis D, Grove J, et al. Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci. Mol Psychiatry 2014;19:325–33.

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

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