Soc Psychiatry Psychiatr Epidemiol (2014) 49:841–849 DOI 10.1007/s00127-014-0887-z
INVITED REVIEWS
Inflammatory biomarker profiles of mental disorders and their relation to clinical, social and lifestyle factors David Baumeister • Alice Russell • Carmine M. Pariante Valeria Mondelli
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Received: 1 February 2014 / Accepted: 14 April 2014 / Published online: 1 May 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract In the last few decades, mental health research has increasingly provided evidence supporting the role of inflammation in pathogenesis, course and treatment of mental disorders. With such a steep incline of research, resulting in a wealth of emerged findings, it has become difficult to follow developments within the field. The present review sets out to present the recent developments and to give an overview of the inflammatory profiles of depression, psychosis and bipolar disorder, as well as variations within these disorders. Moreover, mediating factors such as social environment and childhood experience are discussed, both in terms of their potential in elucidating the complex interface between the inflammation and other closely related biological systems, as well as the possibly confounding impact of various lifestyle factors. Whilst many issues in this fascinating area of research remain to be fully understood and elaborated, all current evidence suggests that inflammation plays a key role in mental disorders and may open up novel avenues for clinical treatment. Keywords Inflammation Cytokine Interleukin Bipolar disorder Psychosis Depression
D. Baumeister A. Russell C. M. Pariante V. Mondelli (&) Stress, Psychiatry and Immunology Lab, Department of Psychological Medicine, Institute of Psychiatry, Kings College London, The James Black Centre, 125 Coldharbour Lane, SE5 9NU London, UK e-mail: [email protected]
Introduction Over the last decades, the activation of the immune system has attracted increasing interest in mental health research. Whilst perhaps most prominent in depressive disorders, evidence suggests abnormal levels of inflammatory biomarkers in a broad range of disorders, including other severe mental illnesses. Although it remains somewhat unclear as to which degree inflammatory dysregulation plays a role in the pathogenesis and aetiology of mental illness, and how this may differ between different disorders and syndromes, current evidence suggests more than a correlational effect. Though a range of inflammatory biomarkers have been examined in this context, the most commonly measured are cytokines, a group of signalling molecules. A role of proinflammatory cytokines within the innate immune system is the adaptive induction of sickness behaviour in illness. In the absence of illness however, these signalling patterns may contribute to the symptoms of several disorders [1]. Specifically suggesting causal effects, recombinant preparations of interferon-a (IFN-a), a cytokine used to treat medical conditions such as hepatitis C, can elicit a variety of neuropsychiatric symptoms, with differential effects depending on dose, length of treatment as well as idiosyncratic patient diatheses. As an acute response, IFN-a can induce transient confusional states, generally marked by disorientation, psychomotor retardation, lethargy, psychotic symptoms, parkinsonism and speech impediments, albeit in rare cases. More long-term effects with on-going treatment include fatigue and depressive symptoms prevalent in up to 80 and 60 % of patients, respectively. Furthermore, IFN-a treatment can bring on manic symptoms, irritability and hyper-vigilance in a small proportion of patients [2]. This suggests that the mere up-regulation of
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IFN-a and its downstream effects on related cytokines can significantly contribute to the emergence of a broad spectrum of psychiatric symptoms, notably those usually associated with depression, psychosis and bipolar disorder. With a steep incline of research interest in exploring possible inflammatory characteristics in these psychiatric disorders, it has become increasingly difficult to follow developments within the field. Several reviews, systematic reviews and meta-analyses have been published on the wealth of findings on inflammation and biomarkers in mental disorders, as well as other relevant aspects such as mediating factors and the effects of medication on inflammatory markers. Moreover, evidence from a theoretical perspective points to a host of mechanisms via which inflammation may play a role in the development of psychopathology. This review will offer an overview of specific and non-specific inflammatory characteristics across depression, psychosis and bipolar disorder as well as individual symptoms, relying on meta-analyses and systematic reviews where possible in order to ensure accuracy, reliability and quality of presented findings. Moreover, evidence on mediating or possibly confounding variables, such as early life trauma, psychosocial stress or physical health and lifestyle factors will be discussed.
Impact of inflammation on other biological systems implicated in the onset of psychiatric disorders There is extensive evidence of bidirectional crosstalk between the inflammatory system and other closely related systems implicated in the pathogenesis of mental disorders, such as the neuroendocrine hypothalamic–pituitary–adrenal axis (HPA axis) [3]. As a crucial part of the interface between stress and brain functioning, HPA axis activity regulates neuroplastic processes in brain structures extensively implicated in psychopathology, particularly the hippocampus and amygdala [4]. HPA axis activity has been found to be elevated in patients with major depression, at least partly related to a reduced feedback inhibition by endogenous glucocorticoids. This may be due to decreased functioning of the glucocorticoid receptor (GR), which provides negative feedback within the HPA axis in response to high cortisol levels in healthy individuals [5]. Studies in patients with major depression have shown non-suppression of cortisol secretion following administration of the GR-selective synthetic glucocorticoid dexamethasone; impaired GR function in peripheral blood mononuclear cells in vitro and in vivo; and reduced GR expression in studies of post-mortem human brains (reviewed in [5–7]). The HPA axis has also been shown to be functionally altered in psychosis, with a high degree of similarities: first episode psychosis patients show hyperactivity of the HPA axis, as shown by cortisol non-
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suppression on the dexamethasone suppression test and by elevated diurnal cortisol levels, the latter of which appears to be normalised by antipsychotic medications [8, 9]. Similarly, bipolar disorder is associated with elevated baseline cortisol levels and diminished dexamethasone response both during manic and depressive phases [10]. Noteworthy, cytokines can both activate the HPA axis and suppress functioning of the GR [11]. Elevated proinflammatory signalling can lead to inhibition of the glucocorticoid receptor through activation of the P38 mitogenactivated kinase (P38 MAPK). Vice versa, deficient protein-DNA interaction of the cytosolic GR is associated with enhanced inflammation, susceptibility to septic shock induced by lipopolysaccharide (LPS) as well as depressivelike behaviours [12]. Taken together, such evidence suggests that appropriate GR functioning is crucial for the regulation of inflammatory processes. Signalling cascades of some cytokines also significantly affect monoaminergic systems. Several cytokines including IL-1b and tumour necrosis factor-a (TNF-a) induce upregulation of serotonin transporters, increase uptake of serotonin, and bring on behavioural signs of depression mediated by MAPK activation [13–16]. Moreover, there is evidence for cytokine-induced inhibition of dopaminergic signalling in the basal ganglia; cytokine-induced inhibition of tetrayhydrobiopterin, a crucial enzyme co-factor in the synthesis of dopamine; as well as effects of MAPK-mediated up-regulation of dopamine transporter expression. At the same time, cytokines decrease expression of the vesicular monoamine transporter 2, leading to increased cytosolic dopamine and the potential of dopaminergic autooxidation. Furthermore, LPS-induced inflammation leads to increased firing of the locus coeruleus, the principal site for noradrenaline synthesis and a key modulator of the sympathetic nervous system during stress [17]. Further, modulation of monoaminergic and glutamatergic systems by inflammatory processes can negatively impact adult neurogenesis, and ties in with wider neurodegenerative processes. Cytokine-induced activation of indoleamine 2,3-dioxygenase (IDO) leads to metabolism of the serotonin precursor tryptophan along the competitive kynurenine pathway. This process appears to be associated with excitotoxicity due to downstream production of the Nmethyl-D-aspartate receptor agonist quinolinic acid, as well as decreased bioavailability of tryptophan for serotonin production [18]. Our laboratory has recently demonstrated that the suppressive effects of the pro-inflammatory cytokine interleukin-1b (IL-1b) on neurogenesis in human hippocampal cell lines are indeed mediated by activation of the kynurenine pathway and quinolinic acid [19]. Moreover, recent evidence and hypotheses have pointed to oxidative and nitrosative stress as well as neurotrophic signalling pathways as systems that, in interplay with
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Table 1 Emerged inflammatory profiles of depression, schizophrenia and bipolar disorder Disorder
Meta-analysis
IL1b
Depression
Dowlati et al. [33]
=
IL1RA
IL2
sIL2R
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IL4
IL5
Schizophrenia Bipolar disorder
sIL6R
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=
IL8
IL10
=
=
:
Hiles et al. [36] Howren et al. [35]
IL6
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:
IL12
TNFa
sTNFR1
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IFNc =
=
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Liu et al. [34]
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Miller et al. [42]
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Potvin et al. [41]
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Modabbernia et al. [44]
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Munkholm et al. [43]
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inflammatory activity, appear to be implicated in neurodevelopmental and neurodegenerative processes [20–24]. Pro-inflammatory cytokines can enhance the activity of radical oxygen and nitrogen species (ROS and RNS, respectively) via activation of macrophages and neutrophils [25], and there is evidence that TNF-a may increase oxidative stress via microglia in hippocampal regions [26]. Notably, alterations of ROS and RNS levels as well as impaired cellular and enzymatic anti-oxidant resilience have been found in depression, bipolar disorder as well as schizophrenia and have been hypothesised to lead to neuroprogressive changes observed in these disorders via induction of neuronal apoptosis, inhibition of neurogenesis and alteration of neuroplasticity [20, 22, 23]. Similarly, levels on neurotrophins such as brain-derived neurotrophic factor (BDNF), which are crucial mediators of adult neurogenesis and neuroplasticity, have been found decreased in serum of bipolar disorder, depression and schizophrenia [27–29]. Curiously, recent evidence showed that IL-6 positively predicts BDNF levels in depressed patients but not controls [30] and in vitro stimulation of human monocytes by TNF-a and IL-6 increases BDNF secretion [31]. However, recent evidence obtained by our lab in first episode psychosis patients showed that stress predicted lower BDNF levels, partly mediated by increase of IL-6 levels [32]. Thus, whilst it is not entirely clear what exactly the impact of inflammation is, it is feasible to assert that inflammatory processes can impact on neurotrophic function. In conclusion, effects of cytokine dysregulation may have far reaching consequences in a host of other closely related biological systems implicated in a variety of mental disorders.
Differences in inflammatory profiles across psychiatric disorders Research has consistently reported abnormalities in inflammatory biomarker levels in several psychiatric
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disorders, though with differences across diagnoses as well as a degree of inconsistency within a single disorder (see Table 1). In depression, the present review identified four meta-analyses encompassing nine inflammatory markers [33–36]. The most consistent finding in depression, all four meta-analyses reported elevated levels of IL-6, a proinflammatory cytokine that has the ability to cross the blood–brain barrier [37]. Two of the meta-analyses found evidence for a slight publication bias towards favouring of positive results [35, 36] and one identified comorbid factors such as cardiovascular disease as a confounding variable associated with smaller effect sizes [36]. Furthermore, the same paper found that studies which failed to adequately match controls based on age and sex also obtained smaller effect sizes. Similarly, both Dowlati et al. [33] and Liu et al. [34] reported TNF-a to be significantly elevated in depressed patients. However, they also found some variation in methodology-related outcome depending on whether serum or plasma samples were used. More inconclusive evidence was obtained for IL-1b, which induces interleukin-1 receptor-associated kinase (IRAK)dependent activation of several key inflammatory pathways. Out of the three meta-analyses evaluating its role within depression, one found a significant elevation of IL1b with dose-dependent effects depending on clinical status [35]; another found a significant elevation only in European samples [34]; and the last one came to non-significant results [33]. Notably, some meta-analyses found evidence for publication biases for positive outcomes as well as heterogeneity between study outcomes and method [35], whilst others did not [33, 34]. IL-1 receptor antagonist (IL-1RA), a non-productive ligand on IL-1 receptors which may therefore be considered anti-inflammatory due to its inhibition of IL-1b effects, was also found to be increased by Howren et al. [35], albeit with some evidence of publication bias for positive results. Similarly, Liu et al. reported a significant increase in soluble IL-2 receptor (sIL-2R), which primarily
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acts as a storage reservoir for circulating IL-2 in order to increase longevity of IL-2 signalling but appears not to induce signalling cascades of its own [38]. Conversely, both Dowlati et al. and Liu et al. found no changes in levels of the pro-inflammatory cytokine IL-2, results which somewhat clash with the finding on sIL-2R activity. This apparent discrepancy may be explained by the fact that sIL2R and IL-2 are usually analysed using enzyme-linked immunosorbent assays, which, in case of elevated circulating levels of sIL-2R/IL-2 complexes, may fail to identify the bound IL-2 accurately. Several other cytokines were identified as normal in depressed populations, including IL4, IL-8, IL-10 and IFN-c. Interestingly, a further meta-analysis focussed specifically on longitudinal data from studies measuring the inflammatory marker C-reactive protein (CRP) and IL-6 and subsequent development of depression, whilst all of the meta-analyses discussed above looked at cross-sectional data [39]. Their results showed that elevations of CRP and to a somewhat lesser extent IL-6 preceded the onset of depressive symptoms, supporting the hypothesis that inflammation may indeed play a causal role in the aetiology of depression. However, here again some evidence for publication bias was found, and the analysis relied on a relatively small number of studies, highlighting the need for more prospective long-term research. This is also an issue in the other disorders discussed in the present review. Noteworthy, whilst the present review primarily discusses CRP as a marker of acute inflammation that elevates in response to increased inflammatory signalling, it appears that depending on conformational changes CRP itself can also increase or inhibit inflammation [40]. Therefore, further research would need to clarify the actual role of CRP in modulating inflammatory process. In schizophrenia, two meta-analyses were identified [41, 42], both of which confirmed an elevation of IL-6 that was also found in depression, however, with some variations. Whilst Potvin et al. [41] found a significant elevation of IL6, with greater effect sizes specifically in European or North American samples, Miller et al. [42] found that elevations were significant only in currently symptomatic patients when compared to healthy controls, but not in stably medicated outpatients. Moreover, both papers found significant elevations of sIL-2R, but whilst Miller et al. did not investigate IL-2 levels, Potvin et al. found a significant decrease which was especially pronounced in medicated outpatients. Other findings appeared more inconsistent between the reviews: whilst Potvin et al. found no significant changes in TNF-a or IFN-c, Miller et al. showed elevated levels for both these cytokines which were present both during acute phases and remission. Similarly, Potvin et al. found that IL-1b levels were increased, whereas Miller et al. found no change. Further findings included
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significant elevations of IL-1RA and IL-12, but no changes in IL-4, soluble IL-6 receptor (sIL-6R) and IL-10. Two meta-analyses were also identified for bipolar disorder, however, here with more consistent findings between the two papers. Both Munkholm et al. [43] and Modabbernia et al. [44] reported significantly elevated levels of sIL-2R, IL-4, TNF-a, soluble TNF-a receptor 1 (sTNFR1) as well as sIL-6R, which has a similar affinity to that of the membrane-bound IL-6R and prolongs the half-life of IL-6 [45]. Contrary to findings in both psychosis and depression, both papers found no changes in IL-6, although this may again indicate potential methodological issues in light of findings on sIL-6R up-regulation. Moreover, both papers found no significant changes to levels of IL-2, IL-8 and IFN-c. Findings of the two meta-analyses differed on three inflammatory markers: whilst Modabbernia et al. reported elevations of IL-1b, IL-1RA and IL-10, no such changes were found by Munkholm et al. Furthermore the latter paper also investigated IL-4 and IL-12, but again without significant findings.
Effects of clinical features on inflammatory biomarkers Despite evidence for variation in inflammatory profiles across disorders, it remains problematic to extrapolate the meaning of these findings, particularly so if the association is established with the diagnostic label, rather than a specific symptom or narrow syndrome within this diagnosis. Indeed, given both the broad involvement of several markers such as TNF-a across disorders, as well as the large overlap in activation of downstream signalling pathways by individual cytokines, it appears feasible to suggest that the contribution of inflammatory dysregulation may be non-specific to a significant degree. Furthermore, dysregulation can be induced by individual inflammatory messengers, as demonstrated by the side-effects of IFN-a as well as experimental evidence in animal models [1]. In line with this, symptoms similar to sickness behaviour, i.e. anhedonia, loss of appetite, cognitive difficulties, fatigue, lethargy and fragmented sleep, can all be observed in depression, negative symptoms of schizophrenia or depressive episodes of bipolar disorder [46]. Interestingly however, some biomarkers appear relatively specific to distinct phenotypes, and increasingly evidence suggests inflammatory alterations can also be linked to individual symptoms and symptom clusters within, but not limited to, particular diagnoses. In line with this notion, some inflammatory markers appear to be indicative of a certain symptomatic state, or are associated with specific subtypes of the reviewed disorders. As Howren et al. report in their meta-analysis on depression, IL-1b levels may relate to clinical status in a severity-
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dependent manner, i.e. clinical samples appear to have more exacerbated elevations than community samples. Furthermore, recent evidence suggests that atypical depression appears to be more closely linked to elevation of the inflammatory markers CRP, IL-6 and TNF-a than melancholic depression, which in turn is marked by more pronounced HPA dysregulation [47]. There is evidence that treatment-resistance to current antidepressants may be particularly associated with elevated levels of IL-6 and TNF-a [48, 49]. Similarly, a recent systematic review reported that suicidal behaviour is specifically associated with elevations of IL-2, IL-6, IL-8 and TNF-a, and that the specific inflammatory profile in major depression differs depending on the presence of suicidal behaviour [50]. A further interesting observation is that psychopharmacological treatments impact on inflammatory markers—a meta-analysis by Hiles et al. [51] found that antidepressant treatment is associated with significant decreases of IL-6 and CRP, but not IL-10. In psychosis, levels of several inflammatory markers may vary depending on whether the patient is currently symptomatic or in remission/treatment. Miller et al. performed sub-analyses by grouping results by clinical status, i.e. acute relapse, first episode psychosis and post-treatment, when comparing to healthy controls and found several intriguing results. IL-6 and IL-1b were found elevated in acute phases of psychosis, but significantly decreased as a consequence of treatment, suggesting them to be state markers. Lack of change in TNF-a and IFN-c levels following treatment suggest these cytokines to be stable trait markers, although non-significant tendencies towards attenuation were observed. Conversely, both IL-12 and sIL-2R were elevated in first episode cases, but increased further following treatment. Interestingly, Potvin et al. found a decrease of IL-2 levels in in vitro samples of schizophrenia patients compared to healthy controls, which was augmented in medicated outpatients. Relating inflammatory markers to specific symptoms, evidence suggests CRP is only linked to cognitive impairments but not positive, negative or general psychiatric symptoms in schizophrenia [52]. Similarly, Garcia-Rizo et al. [53] showed in antipsychotic-naı¨ve first episode patients that those with enduring negative symptoms had significantly higher levels of IL-6 and CRP. Similar patterns of inflammatory alterations specific to clinical status have been observed in bipolar disorder. In a recent meta-analysis, Munkholm et al. [54] reported elevated levels of TNF-a, sTNFR1 and sIL-2R in manic patients compared to controls, of which sTNFR1 and TNFa were also elevated compared to euthymic patients, whilst only sTNFR1 was elevated in euthymic patients compared to controls. No significant changes were observed for depressive episodes. Interestingly, individual papers also
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suggest correlations of particular markers with individual symptoms, e.g. sIL-2R decreases correlate with symptomatic improvement of acute mania [55, 56] and elevated CRP is inversely related to cognitive performance in bipolar disorder but associated with manic symptoms [57, 58]. Investigating the association of inflammatory markers with affective symptoms, Hope et al. [59] found negative correlations between depression scores/sad mood and IL1RA and IL-6 levels, whilst sTNFR1 and elevated mood were positively correlated. Furthermore, they reported elevations of inflammatory markers towards higher mood states, with significant differences of sTNFR1 and IL-1RA in depressed patients compared to those with elevated mood, and of IL-6 between depressed patients and those with neutral mood. It should be noted that in making links between inflammatory markers and certain states, distinguishing between remission and medication effects can be problematic. Furthermore individual differences have also been identified as grounds for more longitudinal studies, as a means of strengthening the observed findings comparing cross-sectional samples.
Impact of early life experience, social environment and lifestyle factors Several factors may moderate or mediate the relationship between individual inflammatory markers and mental disorders, which could individually attenuate, augment or partially account for the observed associations. Particularly, the close allosteric relationship with the HPA axis may lead to stress-mediated changes in inflammatory function of clinical populations. Within this context, it has been shown that a history of early life trauma, even in the absence of mental disorder, is associated with clinically significant levels of inflammation in adulthood, as shown by elevated levels of CRP and increased production of IL6 in response to experimental psychosocial stress [60, 61]. A recent systematic review presented evidence that childhood trauma is associated with a wide range of increased baseline levels of inflammatory markers, most notably CRP, TNF-a and IL-6 [62]. Notably, even lower socioeconomic status or early life social class is associated with higher levels of inflammatory signalling [63], which may however, be buffered by protective factors such as maternal warmth [64]. These findings not only point to the importance of developmental factors, but also demonstrate the impact of the social environment on inflammatory function. Theoretically, HPA axis hyperactivity and inflammation may be part of the same pathophysiological process; ineffective action of glucocorticoid hormones on target tissues
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could lead to immune activation; and, equally, inflammation could stimulate HPA axis activity via both a direct action of cytokines on the brain and by inducing glucocorticoid resistance [65]. Indeed, there is evidence that childhood trauma is associated with increased down-regulation of GR expression [66], alterations to awakening cortisol response [67, 68], and blunted response to pharmacological challenge independent from clinical status [69–71]. Therefore, childhood trauma, in the context of dysregulation of the HPA axis, may partially mediate the association between inflammation and mental illness, as childhood trauma itself has been shown to be associated with a variety of adult mental disorder [72–74]. Also noteworthy, a recent meta-analysis showed that acute psychological stress significantly augments levels of IL-6, IL-1b and CRP, but not TNF-a [75]. This raises the issue that vulnerability of the HPA axis may partially contribute to the apparent relationship between these inflammatory markers and psychopathology in the form of increased stress-reactivity to daily life events. Indeed, depressed patients show an increased response to psychosocial stressors [6] and are more likely to report daily events as stressful [76]. Moreover, there is evidence showing that acute psychological stress is associated with an exacerbated inflammatory response in both patients with depression [61, 77] and bipolar disorder [78] as well as healthy individuals with a history of childhood trauma [79]. Similarly, psychosis patients show elevated baseline levels of cortisol and non-suppression to dexamethasone test [8] as well as greater emotional reactivity to daily life stress [80]. Further, factors that are often associated with mental disorders, such as sleep quality, socioeconomic status or metabolic and cardiorespiratory health, may independently impact on inflammatory markers. Moreover, health concerns such as vitamin D deficiency, periodontal disease, atopic disease and altered gut permeability are also associated with increased inflammation, as well as mental disorders such as depression or schizophrenia [81–84]. Given the widespread functions of innate immunity and its responsiveness to medical illness, physical and psychological stressors, pharmacological interventions as well as lifestyle factors, it is difficult to adequately control for such effects in psychiatric research. O’Connor et al. [85] reviewed a list of behavioural variables which may impact on the measurement of inflammatory markers, with several important implications for the evidence presented in the present review. The review reported that factors such as age, gender, socioeconomic status, ethnicity, body-mass index, cardiorespiratory fitness, sleep quality and quantity, caffeine consumption, smoking as well alcohol consumption are associated with increases and/or decreases of individual inflammatory markers. As the authors suggest,
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all of these factors should be controlled for in research and some, such as sleep loss on the night before testing or current alcohol dependence, should lead to subjects’ exclusion. The relevance of this to mental health research was shown in several of the meta-analyses presented in this review—for example in depression, Liu et al. found that age was a significant moderator in heterogeneous results of IL-6 and Hiles et al. showed that studies which matched for age and gender found greater overall effect sizes [34, 36]. Furthermore, Howren et al. found that effect sizes of the association between depression and IL-6 decreased with increased mean age of sample, and that studies which adjusted for BMI found attenuated associations between both CRP and IL-6 and depression [35]. However, as Miller et al. report, most studies included in their metaanalysis did not control for confounding variables, suggesting this may not be adequately practiced in current research [42].
Conclusions and further remarks Research of the last decades has provided robust evidence that inflammatory abnormalities are a consistent feature of many psychiatric disorders. Although it has been demonstrated that these changes can be part of etiological developments, it is currently only partially understood to which extent they contribute to the emergence of psychopathology in natural settings. Further, more extensive research is needed to elaborate the extent to which differences in inflammatory profiles contribute to symptomatology and how this data could be utilised to develop specifically targeted treatment approaches. Also, whilst longitudinal evidence indicates that at least depression may be preceded by inflammation, it is currently not clear whether this is the case for schizophrenia and bipolar disorder too. Several authors have called for more research in this subject matter to elaborate pathogenetic implications of inflammation and potential cumulative effects of ongoing illness [86–88]. Whilst it has become apparent that current psychiatric treatments may impact on inflammatory markers, the reverse, i.e. utilising adjunctive anti-inflammatory agents to alleviate psychiatric symptoms, is in early stages of development. Recent evidence has suggested antidepressant effects of several agents with anti-inflammatory properties, with more mixed evidence for treatment effects in bipolar and psychotic disorders. Whilst the full potential of psychoneuroimmunological research both in terms of understanding of psychopathology as well as clinical strategies remains yet to be fully elaborated, all current evidence supports the notion that inflammation plays a key role in psychiatric disorders.
Soc Psychiatry Psychiatr Epidemiol (2014) 49:841–849 Acknowledgments This work was supported by the Grant ‘‘Persistent Fatigue Induced by Interferon-alpha: A New Immunological Model for Chronic Fatigue Syndrome’’ from the Medical Research Council (UK) MR/J002739/1. Additional support has been offered by the National Institute for Health Research Mental Health Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London; by a Grant from the Psychiatry Research Trust, UK (McGregor 97); by Janssen Parmaceutica NV/Janssen Pharmaceutical Companies of Johnson & Johnson; and by the Institute of Psychiatry at Kings College London.
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INVITED REVIEWS
Inflammatory biomarker profiles of mental disorders and their relation to clinical, social and lifestyle factors David Baumeister • Alice Russell • Carmine M. Pariante Valeria Mondelli
•
Received: 1 February 2014 / Accepted: 14 April 2014 / Published online: 1 May 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract In the last few decades, mental health research has increasingly provided evidence supporting the role of inflammation in pathogenesis, course and treatment of mental disorders. With such a steep incline of research, resulting in a wealth of emerged findings, it has become difficult to follow developments within the field. The present review sets out to present the recent developments and to give an overview of the inflammatory profiles of depression, psychosis and bipolar disorder, as well as variations within these disorders. Moreover, mediating factors such as social environment and childhood experience are discussed, both in terms of their potential in elucidating the complex interface between the inflammation and other closely related biological systems, as well as the possibly confounding impact of various lifestyle factors. Whilst many issues in this fascinating area of research remain to be fully understood and elaborated, all current evidence suggests that inflammation plays a key role in mental disorders and may open up novel avenues for clinical treatment. Keywords Inflammation Cytokine Interleukin Bipolar disorder Psychosis Depression
D. Baumeister A. Russell C. M. Pariante V. Mondelli (&) Stress, Psychiatry and Immunology Lab, Department of Psychological Medicine, Institute of Psychiatry, Kings College London, The James Black Centre, 125 Coldharbour Lane, SE5 9NU London, UK e-mail: [email protected]
Introduction Over the last decades, the activation of the immune system has attracted increasing interest in mental health research. Whilst perhaps most prominent in depressive disorders, evidence suggests abnormal levels of inflammatory biomarkers in a broad range of disorders, including other severe mental illnesses. Although it remains somewhat unclear as to which degree inflammatory dysregulation plays a role in the pathogenesis and aetiology of mental illness, and how this may differ between different disorders and syndromes, current evidence suggests more than a correlational effect. Though a range of inflammatory biomarkers have been examined in this context, the most commonly measured are cytokines, a group of signalling molecules. A role of proinflammatory cytokines within the innate immune system is the adaptive induction of sickness behaviour in illness. In the absence of illness however, these signalling patterns may contribute to the symptoms of several disorders [1]. Specifically suggesting causal effects, recombinant preparations of interferon-a (IFN-a), a cytokine used to treat medical conditions such as hepatitis C, can elicit a variety of neuropsychiatric symptoms, with differential effects depending on dose, length of treatment as well as idiosyncratic patient diatheses. As an acute response, IFN-a can induce transient confusional states, generally marked by disorientation, psychomotor retardation, lethargy, psychotic symptoms, parkinsonism and speech impediments, albeit in rare cases. More long-term effects with on-going treatment include fatigue and depressive symptoms prevalent in up to 80 and 60 % of patients, respectively. Furthermore, IFN-a treatment can bring on manic symptoms, irritability and hyper-vigilance in a small proportion of patients [2]. This suggests that the mere up-regulation of
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IFN-a and its downstream effects on related cytokines can significantly contribute to the emergence of a broad spectrum of psychiatric symptoms, notably those usually associated with depression, psychosis and bipolar disorder. With a steep incline of research interest in exploring possible inflammatory characteristics in these psychiatric disorders, it has become increasingly difficult to follow developments within the field. Several reviews, systematic reviews and meta-analyses have been published on the wealth of findings on inflammation and biomarkers in mental disorders, as well as other relevant aspects such as mediating factors and the effects of medication on inflammatory markers. Moreover, evidence from a theoretical perspective points to a host of mechanisms via which inflammation may play a role in the development of psychopathology. This review will offer an overview of specific and non-specific inflammatory characteristics across depression, psychosis and bipolar disorder as well as individual symptoms, relying on meta-analyses and systematic reviews where possible in order to ensure accuracy, reliability and quality of presented findings. Moreover, evidence on mediating or possibly confounding variables, such as early life trauma, psychosocial stress or physical health and lifestyle factors will be discussed.
Impact of inflammation on other biological systems implicated in the onset of psychiatric disorders There is extensive evidence of bidirectional crosstalk between the inflammatory system and other closely related systems implicated in the pathogenesis of mental disorders, such as the neuroendocrine hypothalamic–pituitary–adrenal axis (HPA axis) [3]. As a crucial part of the interface between stress and brain functioning, HPA axis activity regulates neuroplastic processes in brain structures extensively implicated in psychopathology, particularly the hippocampus and amygdala [4]. HPA axis activity has been found to be elevated in patients with major depression, at least partly related to a reduced feedback inhibition by endogenous glucocorticoids. This may be due to decreased functioning of the glucocorticoid receptor (GR), which provides negative feedback within the HPA axis in response to high cortisol levels in healthy individuals [5]. Studies in patients with major depression have shown non-suppression of cortisol secretion following administration of the GR-selective synthetic glucocorticoid dexamethasone; impaired GR function in peripheral blood mononuclear cells in vitro and in vivo; and reduced GR expression in studies of post-mortem human brains (reviewed in [5–7]). The HPA axis has also been shown to be functionally altered in psychosis, with a high degree of similarities: first episode psychosis patients show hyperactivity of the HPA axis, as shown by cortisol non-
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suppression on the dexamethasone suppression test and by elevated diurnal cortisol levels, the latter of which appears to be normalised by antipsychotic medications [8, 9]. Similarly, bipolar disorder is associated with elevated baseline cortisol levels and diminished dexamethasone response both during manic and depressive phases [10]. Noteworthy, cytokines can both activate the HPA axis and suppress functioning of the GR [11]. Elevated proinflammatory signalling can lead to inhibition of the glucocorticoid receptor through activation of the P38 mitogenactivated kinase (P38 MAPK). Vice versa, deficient protein-DNA interaction of the cytosolic GR is associated with enhanced inflammation, susceptibility to septic shock induced by lipopolysaccharide (LPS) as well as depressivelike behaviours [12]. Taken together, such evidence suggests that appropriate GR functioning is crucial for the regulation of inflammatory processes. Signalling cascades of some cytokines also significantly affect monoaminergic systems. Several cytokines including IL-1b and tumour necrosis factor-a (TNF-a) induce upregulation of serotonin transporters, increase uptake of serotonin, and bring on behavioural signs of depression mediated by MAPK activation [13–16]. Moreover, there is evidence for cytokine-induced inhibition of dopaminergic signalling in the basal ganglia; cytokine-induced inhibition of tetrayhydrobiopterin, a crucial enzyme co-factor in the synthesis of dopamine; as well as effects of MAPK-mediated up-regulation of dopamine transporter expression. At the same time, cytokines decrease expression of the vesicular monoamine transporter 2, leading to increased cytosolic dopamine and the potential of dopaminergic autooxidation. Furthermore, LPS-induced inflammation leads to increased firing of the locus coeruleus, the principal site for noradrenaline synthesis and a key modulator of the sympathetic nervous system during stress [17]. Further, modulation of monoaminergic and glutamatergic systems by inflammatory processes can negatively impact adult neurogenesis, and ties in with wider neurodegenerative processes. Cytokine-induced activation of indoleamine 2,3-dioxygenase (IDO) leads to metabolism of the serotonin precursor tryptophan along the competitive kynurenine pathway. This process appears to be associated with excitotoxicity due to downstream production of the Nmethyl-D-aspartate receptor agonist quinolinic acid, as well as decreased bioavailability of tryptophan for serotonin production [18]. Our laboratory has recently demonstrated that the suppressive effects of the pro-inflammatory cytokine interleukin-1b (IL-1b) on neurogenesis in human hippocampal cell lines are indeed mediated by activation of the kynurenine pathway and quinolinic acid [19]. Moreover, recent evidence and hypotheses have pointed to oxidative and nitrosative stress as well as neurotrophic signalling pathways as systems that, in interplay with
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Table 1 Emerged inflammatory profiles of depression, schizophrenia and bipolar disorder Disorder
Meta-analysis
IL1b
Depression
Dowlati et al. [33]
=
IL1RA
IL2
sIL2R
=
IL4
IL5
Schizophrenia Bipolar disorder
sIL6R
:
=
IL8
IL10
=
=
:
Hiles et al. [36] Howren et al. [35]
IL6
:
:
IL12
TNFa
sTNFR1
:
IFNc =
=
:
Liu et al. [34]
:
Miller et al. [42]
=
Potvin et al. [41]
:
:
;
:
=
:
=
Modabbernia et al. [44]
:
:
=
:
:
=
:
Munkholm et al. [43]
=
=
=
:
:
=
:
=
:
:
=
:
inflammatory activity, appear to be implicated in neurodevelopmental and neurodegenerative processes [20–24]. Pro-inflammatory cytokines can enhance the activity of radical oxygen and nitrogen species (ROS and RNS, respectively) via activation of macrophages and neutrophils [25], and there is evidence that TNF-a may increase oxidative stress via microglia in hippocampal regions [26]. Notably, alterations of ROS and RNS levels as well as impaired cellular and enzymatic anti-oxidant resilience have been found in depression, bipolar disorder as well as schizophrenia and have been hypothesised to lead to neuroprogressive changes observed in these disorders via induction of neuronal apoptosis, inhibition of neurogenesis and alteration of neuroplasticity [20, 22, 23]. Similarly, levels on neurotrophins such as brain-derived neurotrophic factor (BDNF), which are crucial mediators of adult neurogenesis and neuroplasticity, have been found decreased in serum of bipolar disorder, depression and schizophrenia [27–29]. Curiously, recent evidence showed that IL-6 positively predicts BDNF levels in depressed patients but not controls [30] and in vitro stimulation of human monocytes by TNF-a and IL-6 increases BDNF secretion [31]. However, recent evidence obtained by our lab in first episode psychosis patients showed that stress predicted lower BDNF levels, partly mediated by increase of IL-6 levels [32]. Thus, whilst it is not entirely clear what exactly the impact of inflammation is, it is feasible to assert that inflammatory processes can impact on neurotrophic function. In conclusion, effects of cytokine dysregulation may have far reaching consequences in a host of other closely related biological systems implicated in a variety of mental disorders.
Differences in inflammatory profiles across psychiatric disorders Research has consistently reported abnormalities in inflammatory biomarker levels in several psychiatric
:
=
:
:
=
=
=
=
:
:
:
=
=
=
:
:
=
=
=
:
=
:
=
disorders, though with differences across diagnoses as well as a degree of inconsistency within a single disorder (see Table 1). In depression, the present review identified four meta-analyses encompassing nine inflammatory markers [33–36]. The most consistent finding in depression, all four meta-analyses reported elevated levels of IL-6, a proinflammatory cytokine that has the ability to cross the blood–brain barrier [37]. Two of the meta-analyses found evidence for a slight publication bias towards favouring of positive results [35, 36] and one identified comorbid factors such as cardiovascular disease as a confounding variable associated with smaller effect sizes [36]. Furthermore, the same paper found that studies which failed to adequately match controls based on age and sex also obtained smaller effect sizes. Similarly, both Dowlati et al. [33] and Liu et al. [34] reported TNF-a to be significantly elevated in depressed patients. However, they also found some variation in methodology-related outcome depending on whether serum or plasma samples were used. More inconclusive evidence was obtained for IL-1b, which induces interleukin-1 receptor-associated kinase (IRAK)dependent activation of several key inflammatory pathways. Out of the three meta-analyses evaluating its role within depression, one found a significant elevation of IL1b with dose-dependent effects depending on clinical status [35]; another found a significant elevation only in European samples [34]; and the last one came to non-significant results [33]. Notably, some meta-analyses found evidence for publication biases for positive outcomes as well as heterogeneity between study outcomes and method [35], whilst others did not [33, 34]. IL-1 receptor antagonist (IL-1RA), a non-productive ligand on IL-1 receptors which may therefore be considered anti-inflammatory due to its inhibition of IL-1b effects, was also found to be increased by Howren et al. [35], albeit with some evidence of publication bias for positive results. Similarly, Liu et al. reported a significant increase in soluble IL-2 receptor (sIL-2R), which primarily
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acts as a storage reservoir for circulating IL-2 in order to increase longevity of IL-2 signalling but appears not to induce signalling cascades of its own [38]. Conversely, both Dowlati et al. and Liu et al. found no changes in levels of the pro-inflammatory cytokine IL-2, results which somewhat clash with the finding on sIL-2R activity. This apparent discrepancy may be explained by the fact that sIL2R and IL-2 are usually analysed using enzyme-linked immunosorbent assays, which, in case of elevated circulating levels of sIL-2R/IL-2 complexes, may fail to identify the bound IL-2 accurately. Several other cytokines were identified as normal in depressed populations, including IL4, IL-8, IL-10 and IFN-c. Interestingly, a further meta-analysis focussed specifically on longitudinal data from studies measuring the inflammatory marker C-reactive protein (CRP) and IL-6 and subsequent development of depression, whilst all of the meta-analyses discussed above looked at cross-sectional data [39]. Their results showed that elevations of CRP and to a somewhat lesser extent IL-6 preceded the onset of depressive symptoms, supporting the hypothesis that inflammation may indeed play a causal role in the aetiology of depression. However, here again some evidence for publication bias was found, and the analysis relied on a relatively small number of studies, highlighting the need for more prospective long-term research. This is also an issue in the other disorders discussed in the present review. Noteworthy, whilst the present review primarily discusses CRP as a marker of acute inflammation that elevates in response to increased inflammatory signalling, it appears that depending on conformational changes CRP itself can also increase or inhibit inflammation [40]. Therefore, further research would need to clarify the actual role of CRP in modulating inflammatory process. In schizophrenia, two meta-analyses were identified [41, 42], both of which confirmed an elevation of IL-6 that was also found in depression, however, with some variations. Whilst Potvin et al. [41] found a significant elevation of IL6, with greater effect sizes specifically in European or North American samples, Miller et al. [42] found that elevations were significant only in currently symptomatic patients when compared to healthy controls, but not in stably medicated outpatients. Moreover, both papers found significant elevations of sIL-2R, but whilst Miller et al. did not investigate IL-2 levels, Potvin et al. found a significant decrease which was especially pronounced in medicated outpatients. Other findings appeared more inconsistent between the reviews: whilst Potvin et al. found no significant changes in TNF-a or IFN-c, Miller et al. showed elevated levels for both these cytokines which were present both during acute phases and remission. Similarly, Potvin et al. found that IL-1b levels were increased, whereas Miller et al. found no change. Further findings included
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significant elevations of IL-1RA and IL-12, but no changes in IL-4, soluble IL-6 receptor (sIL-6R) and IL-10. Two meta-analyses were also identified for bipolar disorder, however, here with more consistent findings between the two papers. Both Munkholm et al. [43] and Modabbernia et al. [44] reported significantly elevated levels of sIL-2R, IL-4, TNF-a, soluble TNF-a receptor 1 (sTNFR1) as well as sIL-6R, which has a similar affinity to that of the membrane-bound IL-6R and prolongs the half-life of IL-6 [45]. Contrary to findings in both psychosis and depression, both papers found no changes in IL-6, although this may again indicate potential methodological issues in light of findings on sIL-6R up-regulation. Moreover, both papers found no significant changes to levels of IL-2, IL-8 and IFN-c. Findings of the two meta-analyses differed on three inflammatory markers: whilst Modabbernia et al. reported elevations of IL-1b, IL-1RA and IL-10, no such changes were found by Munkholm et al. Furthermore the latter paper also investigated IL-4 and IL-12, but again without significant findings.
Effects of clinical features on inflammatory biomarkers Despite evidence for variation in inflammatory profiles across disorders, it remains problematic to extrapolate the meaning of these findings, particularly so if the association is established with the diagnostic label, rather than a specific symptom or narrow syndrome within this diagnosis. Indeed, given both the broad involvement of several markers such as TNF-a across disorders, as well as the large overlap in activation of downstream signalling pathways by individual cytokines, it appears feasible to suggest that the contribution of inflammatory dysregulation may be non-specific to a significant degree. Furthermore, dysregulation can be induced by individual inflammatory messengers, as demonstrated by the side-effects of IFN-a as well as experimental evidence in animal models [1]. In line with this, symptoms similar to sickness behaviour, i.e. anhedonia, loss of appetite, cognitive difficulties, fatigue, lethargy and fragmented sleep, can all be observed in depression, negative symptoms of schizophrenia or depressive episodes of bipolar disorder [46]. Interestingly however, some biomarkers appear relatively specific to distinct phenotypes, and increasingly evidence suggests inflammatory alterations can also be linked to individual symptoms and symptom clusters within, but not limited to, particular diagnoses. In line with this notion, some inflammatory markers appear to be indicative of a certain symptomatic state, or are associated with specific subtypes of the reviewed disorders. As Howren et al. report in their meta-analysis on depression, IL-1b levels may relate to clinical status in a severity-
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dependent manner, i.e. clinical samples appear to have more exacerbated elevations than community samples. Furthermore, recent evidence suggests that atypical depression appears to be more closely linked to elevation of the inflammatory markers CRP, IL-6 and TNF-a than melancholic depression, which in turn is marked by more pronounced HPA dysregulation [47]. There is evidence that treatment-resistance to current antidepressants may be particularly associated with elevated levels of IL-6 and TNF-a [48, 49]. Similarly, a recent systematic review reported that suicidal behaviour is specifically associated with elevations of IL-2, IL-6, IL-8 and TNF-a, and that the specific inflammatory profile in major depression differs depending on the presence of suicidal behaviour [50]. A further interesting observation is that psychopharmacological treatments impact on inflammatory markers—a meta-analysis by Hiles et al. [51] found that antidepressant treatment is associated with significant decreases of IL-6 and CRP, but not IL-10. In psychosis, levels of several inflammatory markers may vary depending on whether the patient is currently symptomatic or in remission/treatment. Miller et al. performed sub-analyses by grouping results by clinical status, i.e. acute relapse, first episode psychosis and post-treatment, when comparing to healthy controls and found several intriguing results. IL-6 and IL-1b were found elevated in acute phases of psychosis, but significantly decreased as a consequence of treatment, suggesting them to be state markers. Lack of change in TNF-a and IFN-c levels following treatment suggest these cytokines to be stable trait markers, although non-significant tendencies towards attenuation were observed. Conversely, both IL-12 and sIL-2R were elevated in first episode cases, but increased further following treatment. Interestingly, Potvin et al. found a decrease of IL-2 levels in in vitro samples of schizophrenia patients compared to healthy controls, which was augmented in medicated outpatients. Relating inflammatory markers to specific symptoms, evidence suggests CRP is only linked to cognitive impairments but not positive, negative or general psychiatric symptoms in schizophrenia [52]. Similarly, Garcia-Rizo et al. [53] showed in antipsychotic-naı¨ve first episode patients that those with enduring negative symptoms had significantly higher levels of IL-6 and CRP. Similar patterns of inflammatory alterations specific to clinical status have been observed in bipolar disorder. In a recent meta-analysis, Munkholm et al. [54] reported elevated levels of TNF-a, sTNFR1 and sIL-2R in manic patients compared to controls, of which sTNFR1 and TNFa were also elevated compared to euthymic patients, whilst only sTNFR1 was elevated in euthymic patients compared to controls. No significant changes were observed for depressive episodes. Interestingly, individual papers also
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suggest correlations of particular markers with individual symptoms, e.g. sIL-2R decreases correlate with symptomatic improvement of acute mania [55, 56] and elevated CRP is inversely related to cognitive performance in bipolar disorder but associated with manic symptoms [57, 58]. Investigating the association of inflammatory markers with affective symptoms, Hope et al. [59] found negative correlations between depression scores/sad mood and IL1RA and IL-6 levels, whilst sTNFR1 and elevated mood were positively correlated. Furthermore, they reported elevations of inflammatory markers towards higher mood states, with significant differences of sTNFR1 and IL-1RA in depressed patients compared to those with elevated mood, and of IL-6 between depressed patients and those with neutral mood. It should be noted that in making links between inflammatory markers and certain states, distinguishing between remission and medication effects can be problematic. Furthermore individual differences have also been identified as grounds for more longitudinal studies, as a means of strengthening the observed findings comparing cross-sectional samples.
Impact of early life experience, social environment and lifestyle factors Several factors may moderate or mediate the relationship between individual inflammatory markers and mental disorders, which could individually attenuate, augment or partially account for the observed associations. Particularly, the close allosteric relationship with the HPA axis may lead to stress-mediated changes in inflammatory function of clinical populations. Within this context, it has been shown that a history of early life trauma, even in the absence of mental disorder, is associated with clinically significant levels of inflammation in adulthood, as shown by elevated levels of CRP and increased production of IL6 in response to experimental psychosocial stress [60, 61]. A recent systematic review presented evidence that childhood trauma is associated with a wide range of increased baseline levels of inflammatory markers, most notably CRP, TNF-a and IL-6 [62]. Notably, even lower socioeconomic status or early life social class is associated with higher levels of inflammatory signalling [63], which may however, be buffered by protective factors such as maternal warmth [64]. These findings not only point to the importance of developmental factors, but also demonstrate the impact of the social environment on inflammatory function. Theoretically, HPA axis hyperactivity and inflammation may be part of the same pathophysiological process; ineffective action of glucocorticoid hormones on target tissues
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could lead to immune activation; and, equally, inflammation could stimulate HPA axis activity via both a direct action of cytokines on the brain and by inducing glucocorticoid resistance [65]. Indeed, there is evidence that childhood trauma is associated with increased down-regulation of GR expression [66], alterations to awakening cortisol response [67, 68], and blunted response to pharmacological challenge independent from clinical status [69–71]. Therefore, childhood trauma, in the context of dysregulation of the HPA axis, may partially mediate the association between inflammation and mental illness, as childhood trauma itself has been shown to be associated with a variety of adult mental disorder [72–74]. Also noteworthy, a recent meta-analysis showed that acute psychological stress significantly augments levels of IL-6, IL-1b and CRP, but not TNF-a [75]. This raises the issue that vulnerability of the HPA axis may partially contribute to the apparent relationship between these inflammatory markers and psychopathology in the form of increased stress-reactivity to daily life events. Indeed, depressed patients show an increased response to psychosocial stressors [6] and are more likely to report daily events as stressful [76]. Moreover, there is evidence showing that acute psychological stress is associated with an exacerbated inflammatory response in both patients with depression [61, 77] and bipolar disorder [78] as well as healthy individuals with a history of childhood trauma [79]. Similarly, psychosis patients show elevated baseline levels of cortisol and non-suppression to dexamethasone test [8] as well as greater emotional reactivity to daily life stress [80]. Further, factors that are often associated with mental disorders, such as sleep quality, socioeconomic status or metabolic and cardiorespiratory health, may independently impact on inflammatory markers. Moreover, health concerns such as vitamin D deficiency, periodontal disease, atopic disease and altered gut permeability are also associated with increased inflammation, as well as mental disorders such as depression or schizophrenia [81–84]. Given the widespread functions of innate immunity and its responsiveness to medical illness, physical and psychological stressors, pharmacological interventions as well as lifestyle factors, it is difficult to adequately control for such effects in psychiatric research. O’Connor et al. [85] reviewed a list of behavioural variables which may impact on the measurement of inflammatory markers, with several important implications for the evidence presented in the present review. The review reported that factors such as age, gender, socioeconomic status, ethnicity, body-mass index, cardiorespiratory fitness, sleep quality and quantity, caffeine consumption, smoking as well alcohol consumption are associated with increases and/or decreases of individual inflammatory markers. As the authors suggest,
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all of these factors should be controlled for in research and some, such as sleep loss on the night before testing or current alcohol dependence, should lead to subjects’ exclusion. The relevance of this to mental health research was shown in several of the meta-analyses presented in this review—for example in depression, Liu et al. found that age was a significant moderator in heterogeneous results of IL-6 and Hiles et al. showed that studies which matched for age and gender found greater overall effect sizes [34, 36]. Furthermore, Howren et al. found that effect sizes of the association between depression and IL-6 decreased with increased mean age of sample, and that studies which adjusted for BMI found attenuated associations between both CRP and IL-6 and depression [35]. However, as Miller et al. report, most studies included in their metaanalysis did not control for confounding variables, suggesting this may not be adequately practiced in current research [42].
Conclusions and further remarks Research of the last decades has provided robust evidence that inflammatory abnormalities are a consistent feature of many psychiatric disorders. Although it has been demonstrated that these changes can be part of etiological developments, it is currently only partially understood to which extent they contribute to the emergence of psychopathology in natural settings. Further, more extensive research is needed to elaborate the extent to which differences in inflammatory profiles contribute to symptomatology and how this data could be utilised to develop specifically targeted treatment approaches. Also, whilst longitudinal evidence indicates that at least depression may be preceded by inflammation, it is currently not clear whether this is the case for schizophrenia and bipolar disorder too. Several authors have called for more research in this subject matter to elaborate pathogenetic implications of inflammation and potential cumulative effects of ongoing illness [86–88]. Whilst it has become apparent that current psychiatric treatments may impact on inflammatory markers, the reverse, i.e. utilising adjunctive anti-inflammatory agents to alleviate psychiatric symptoms, is in early stages of development. Recent evidence has suggested antidepressant effects of several agents with anti-inflammatory properties, with more mixed evidence for treatment effects in bipolar and psychotic disorders. Whilst the full potential of psychoneuroimmunological research both in terms of understanding of psychopathology as well as clinical strategies remains yet to be fully elaborated, all current evidence supports the notion that inflammation plays a key role in psychiatric disorders.
Soc Psychiatry Psychiatr Epidemiol (2014) 49:841–849 Acknowledgments This work was supported by the Grant ‘‘Persistent Fatigue Induced by Interferon-alpha: A New Immunological Model for Chronic Fatigue Syndrome’’ from the Medical Research Council (UK) MR/J002739/1. Additional support has been offered by the National Institute for Health Research Mental Health Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London; by a Grant from the Psychiatry Research Trust, UK (McGregor 97); by Janssen Parmaceutica NV/Janssen Pharmaceutical Companies of Johnson & Johnson; and by the Institute of Psychiatry at Kings College London.
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