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Keywords:

  • anti-inflammatory;
  • inflammation;
  • neuroplasticity;
  • prodrome;
  • schizophrenia

Abstract

  1. Top of page
  2. Abstract
  3. CYTOKINES INFLUENCE ADULT BRAIN AND NEURODEVELOPMENT
  4. FROM PRECLINICAL TO FULL-BLOWN PSYCHOSIS
  5. SCHIZOPHRENIA IS ASSOCIATED WITH ABNORMALITIES IN INFLAMMATORY MEDIATORS
  6. GENETIC FACTORS CONTRIBUTE TO DYSREGULATION OF INFLAMMATION IN SCHIZOPHRENIA
  7. ENVIRONMENTAL SUSCEPTIBILITY TO INFLAMMATORY IMBALANCES IN SCHIZOPHRENIA
  8. MODULATION OF INFLAMMATION AS A TREATMENT STRATEGY FOR SCHIZOPHRENIA AND UHR INDIVIDUALS
  9. FINAL REMARKS
  10. ACKNOWLEDGMENTS
  11. REFERENCES

Aims:  In this paper, we review the literature on the efficacy of anti-inflammatory agents as neuroprotectors in clinical and preclinical stages of schizophrenia.

Method:  A synthetic and integrative approach was applied to review studies stemming from epidemiology, phenomenology, cognition, genetics and neuroimaging data. We provide conclusions and future directions of research on early-onset schizophrenia.

Results:  Abnormal inflammatory activation has been demonstrated in schizophrenia. Increases or imbalances in cytokines before birth or during childhood may impact neurodevelopment and produce vulnerability to schizophrenia. The specificity of inflammatory abnormalities in psychiatric disorders is controversial. Similar increases in pro-inflammatory cytokines have been described in other disorders, especially mood and anxiety disorders. One of the most important challenges at this point is the understanding of neurobiological correlates of prodromal stages of schizophrenia.

Conclusion:  Although future research should investigate the exact role of different cytokines in pathophysiology of schizophrenia, these mediators emerge as promising molecular targets to its prevention and treatment.

SCHIZOPHRENIA IS A chronic and highly disabling clinical syndrome that comprises a broad range of symptoms, such as hallucinations, delusions, blunted affect, and lack of volition. Its estimated incidence and prevalence rates are 15.2 per 100 000 and 4.6 per 1000, respectively.1,2 Schizophrenia is one of the top ten causes of disability in the 15–44-year-old age group according to the global burden of disease study.3 The onset of schizophrenia usually occurs during young adulthood, and despite advances in treatment, most patients experience persistent or fluctuating symptoms.3

In recent years, there has been growing interest in the study of early and prodromal stages of psychotic disorders. Despite a well-established recognition that a prodromal period of low-grade symptoms and signs may precede the onset of psychosis in schizophrenia, it was not until the past 15 years that attempts have been made to identify and intervene in this early phase.4 Unfortunately, no interventions so far have been effective to prevent schizophrenia in high-risk samples and to date there are insufficient trials to draw definitive conclusions.5

The causes of schizophrenia are still largely unknown, although a consistent body of evidence underscores the importance of imbalances in neuroprotective/neurodegenerative factors.6,7 Among the factors that modulate the delicate balance between neuronal death and cell survival, the role of cytokines8 has been consistently reported in schizophrenia.9–13

This article reviews the evidence linking inflammation imbalances to schizophrenia and discusses the potential role of this mechanism in the pathophysiology of schizophrenia, as well as the possible therapeutic role of anti-inflammatory agents in the clinical and prodromal stages.

CYTOKINES INFLUENCE ADULT BRAIN AND NEURODEVELOPMENT

  1. Top of page
  2. Abstract
  3. CYTOKINES INFLUENCE ADULT BRAIN AND NEURODEVELOPMENT
  4. FROM PRECLINICAL TO FULL-BLOWN PSYCHOSIS
  5. SCHIZOPHRENIA IS ASSOCIATED WITH ABNORMALITIES IN INFLAMMATORY MEDIATORS
  6. GENETIC FACTORS CONTRIBUTE TO DYSREGULATION OF INFLAMMATION IN SCHIZOPHRENIA
  7. ENVIRONMENTAL SUSCEPTIBILITY TO INFLAMMATORY IMBALANCES IN SCHIZOPHRENIA
  8. MODULATION OF INFLAMMATION AS A TREATMENT STRATEGY FOR SCHIZOPHRENIA AND UHR INDIVIDUALS
  9. FINAL REMARKS
  10. ACKNOWLEDGMENTS
  11. REFERENCES

Inflammation, which is part of a complex biological response to harmful stimuli, is produced by immune cells and soluble mediators called cytokines. Cytokines are peptides, proteins, or glycoproteins that are secreted in response to immunological challenges. Many cytokines are found in the central nervous system (CNS), where they play important signaling roles, in addition to their immunological functions.14

Cytokines have several targets in CNS, including immune cells, neurons, astrocytes and oligodendrocytes. Their actions remain not completely known and can involve both neuroprotective and neurotoxic properties. They are, in several ways, dependent on factors such as intensity and duration of stimuli as well as concomitance of presence of other cytokines or even other neuromodulators (neurotransmitters, neurotrophins and hormones).15 The involvement of cytokines in cellular processes in the adult CNS includes regulation of neuronal excitability and synaptic transmission; as well as synaptic plasticity.15 There is evidence, mostly from animal studies, that cytokines modulate behavioral functions, such as sleep,16,17 memory, and neural plasticity.18 Cytokine interleukin-1-β (IL-1-β) has been associated with learning and memory functions.18–20 Interleukin-6 (IL-6) has been associated with age-related memory impairment.21 Regarding TNF-α, studies investigating the role of this cytokine in memory have produced contradictory results. TNF-α knockout mice had normal performance in the water maze paradigm,22,23 whereas 60-day old adult mice with TNF-α overexpression showed impaired spatial memory, even though this finding was not observed in young mice.18

In addition to their effects on the adult brain, cytokines are also known to be important mediators of neural development.24,25 Their role in the developing brain must necessarily be considered in light of the complexity of the CNS. In fact, elaboration of the human CNS depends on cellular interactions that establish positional information, development of cell type specificity, and interconnectivity between different cell populations.26 These processes are orchestrated through the expression of a broad range of cytokines and the subsequent responses of target cells.27 The normal development of the CNS is critically dependent on the timing and site of multiple cellular processes, and even mild abnormalities in brain organization may result in functional impairment.28 Developmental disruption of neural connectivity has been postulated as a relevant pathophysiological event in schizophrenia.29

The human CNS is initially formed during gastrulation from a specialized layer of ectodermal cells, the neural plate.30 As embryogenesis proceeds, the neural plate undergoes invagination to produce a neural tube.31 After this, a differential growth pattern gives origin to three primary vesicles: the forebrain, the midbrain, and the hindbrain.31 Each of these portions has a unique cytoarchitecture and specification of distinct cell types. The regionalization of neural tube depends on signals from the local environment,32 where inflammatory cytokines are found. Signaling agent abnormalities have been suggested as mediators of defects in neurodevelopment that could be associated with neuropsychiatric disorders.33

Recent studies with humans have indicated that neurodevelopmental disorders are associated with changes in inflammatory responses. In autism, elevated levels of various pro-inflammatory cytokines, such as IL-6, TNF-α, and IL-1-β, have been found in the cerebrospinal fluid (CSF)34 and blood35 of affected individuals. Increased levels of pro-inflammatory cytokine IL-8 have also been detected in neonatal blood samples of individuals later diagnosed with Down syndrome.36 In addition, the levels of IL-6, IL-1-β, and TNF-α may also be elevated in the CSF of people with epilepsy.37 Although most of these studies have reported only preliminary findings, they suggest that imbalanced levels of cytokines in the CNS may be, at least in part, responsible for developmental abnormalities associated with neuropsychiatric disorders. The possible role of cytokines in the pathophysiology of schizophrenia will be discussed in detail in the next sections.

FROM PRECLINICAL TO FULL-BLOWN PSYCHOSIS

  1. Top of page
  2. Abstract
  3. CYTOKINES INFLUENCE ADULT BRAIN AND NEURODEVELOPMENT
  4. FROM PRECLINICAL TO FULL-BLOWN PSYCHOSIS
  5. SCHIZOPHRENIA IS ASSOCIATED WITH ABNORMALITIES IN INFLAMMATORY MEDIATORS
  6. GENETIC FACTORS CONTRIBUTE TO DYSREGULATION OF INFLAMMATION IN SCHIZOPHRENIA
  7. ENVIRONMENTAL SUSCEPTIBILITY TO INFLAMMATORY IMBALANCES IN SCHIZOPHRENIA
  8. MODULATION OF INFLAMMATION AS A TREATMENT STRATEGY FOR SCHIZOPHRENIA AND UHR INDIVIDUALS
  9. FINAL REMARKS
  10. ACKNOWLEDGMENTS
  11. REFERENCES

In the last decade, there has been increasing interest in the study of preclinical or prodromal stages of schizophrenia and their evolution to full-blown psychosis.38 This is based on the assumption that interventions in early stages of psychosis could be more beneficial than late treatments,4,39 and also that research on preclinical stages might provide insights into early pathophysiological processes moderating or mediating the progression to schizophrenia.40 For a detailed review on the prodromal phase of schizophrenia, see Larson et al.41

The most adequate term to describe the preclinical stages of psychotic disorders is still under discussion. Because the terms ‘prodrome’ and ‘prodromal’ implicate a retrospective concept, with the determination of this state being asserted only after frank psychosis has emerged, they have been replaced with the concept of ultra high risk (UHR).40,42,43 At present, the UHR model is the most widely employed to identify preclinical stage candidates for inclusion in research protocols. The criteria to detect UHR individuals aged 14–25 years include one or more of the following: attenuated psychotic symptoms (subthreshold or attenuated positive psychotic symptoms during the past year); brief limited intermittent psychotic symptoms (episodes of frank psychotic symptoms for no more than a week and abating spontaneously); or trait and state risk factor (schizotypal personality disorder or having a first-degree relative with a psychotic disorder and a significant decrease in functioning during the previous year).44,45 Based on these or very similar criteria, studies with follow-up times ranging from 1 to 9.6 years report a transition rate to full psychotic syndromes of 9–54%.46–48 A 2-year follow-up study of 292 help-seeking individuals found a transition rate of 16%, which is considerably lower than the rates reported in earlier studies (over 40%).45 More recently, a conversion rate of 19% in 18 months has been reported in subjects identified by a combination of UHR criteria and cognitive disturbances.38

Although UHR has been defined as a set of clinical characteristics, several neurobiological abnormalities were also described in individuals in this group. These include structural findings, such as reductions in grey matter in the prefrontal cortex;49 and functional alterations, such as decreased activation of anterior cingulate gyrus.49,50 There is also evidence of cognitive impairment in UHR individuals, including deficits in working memory,51 processing speed measures (digit symbol coding, Trail Making Test-B, Stroop Color Naming), as well as in verbal working memory measures, verbal memory and learning, and verbal fluency.52 Although the understanding of neurobiology of prodromal stages are quickly increasing, inflammatory mediators as well as other biomarkers involved in neuroplasticity, such as brain-derived neurotrophic factor (BDNF), were not studied in this population.

Interventions to prevent the evolution of UHR or prodromal stages to psychosis have been evaluated in some studies, mostly focused on antipsychotics, and are summarized in Table 1. From a clinical point of view, antipsychotic therapy in subclinical populations is controversial. First, a significant proportion of individuals who meet UHR criteria will not convert to psychosis.47 Second, the exposure of this population to the well-known side-effects of antipsychotics – movement disorders, weight gain, metabolic syndrome, and sexual dysfunction – may be harmful.57–59 In this context, other therapeutic options, especially neuroprotective approaches, may be useful. In fact, one placebo-controlled trial using long chain omega-3 polyunsaturated fatty acids found a beneficial effect in preventing conversion to psychosis in individuals with UHR.56 Even though these findings still need to be confirmed, they have opened a promising avenue of investigation.41 Although neuroprotective interventions could be potentially beneficial, omega-3 supplementation is the only medication tested in this population. Other promising neuroprotective interventions, such as low-dose lithium, anti-inflammatory or anti-oxidant substances, have not been tested yet.

Table 1.  Summary of the results of randomized controlled trials with pharmacological interventions to prevent the evolution of ultra high risk to psychosis
AuthorsYearInterventionMain outcomeResults
  1. CBT, cognitive behavioral therapy.

McGorry et al.2002Risperidone plus CBT vs needs-based interventionRate of conversion to psychosis in 6 monthsLower rate of conversion in risperidone plus CBT (10%) than in control (36%)53
McGlashan et al.2006Olanzapine vs placeboRate of conversion to psychosis in 1 yearNon-significant differences in conversion rates (olanzapine: 16.1% and placebo 37.9%)54
Yung et al.2011Risperidone plus CBT vs CBT plus placebo vs supportive therapy plus placeboRate of conversion to psychosis in 6 monthsNon-significant differences in conversion rates55
Amminger et al.2010Omega-3 supplementation vs placeboRate of conversion to psychosis in 1 yearLower conversion rate in Omega-3 supplementation group (4.9%) than in placebo group (27.5%)56

SCHIZOPHRENIA IS ASSOCIATED WITH ABNORMALITIES IN INFLAMMATORY MEDIATORS

  1. Top of page
  2. Abstract
  3. CYTOKINES INFLUENCE ADULT BRAIN AND NEURODEVELOPMENT
  4. FROM PRECLINICAL TO FULL-BLOWN PSYCHOSIS
  5. SCHIZOPHRENIA IS ASSOCIATED WITH ABNORMALITIES IN INFLAMMATORY MEDIATORS
  6. GENETIC FACTORS CONTRIBUTE TO DYSREGULATION OF INFLAMMATION IN SCHIZOPHRENIA
  7. ENVIRONMENTAL SUSCEPTIBILITY TO INFLAMMATORY IMBALANCES IN SCHIZOPHRENIA
  8. MODULATION OF INFLAMMATION AS A TREATMENT STRATEGY FOR SCHIZOPHRENIA AND UHR INDIVIDUALS
  9. FINAL REMARKS
  10. ACKNOWLEDGMENTS
  11. REFERENCES

Early suggestions that schizophrenia could be understood as a pro-inflammatory state derivate from the intriguingly higher rate of general medical comorbidities in individuals with this disorder as compared with the general population.57 In fact, the most marked impact of general medical comorbidities in mortality are associated with metabolic complications, such as diabetes mellitus, high blood pressure, obesity and dyslipidemia. All of these conditions share a low grade and persistent activation of inflammatory mechanisms that underlie and contribute to the pathophysiology of arteriosclerosis and vascular disorders.56

Several studies show a consistent association between changes in cytokines and schizophrenia.9,10,12,13,60,61 Despite the heterogeneity of the findings, a shift from a type 2 immune response (Th2) to a type 1 (Th1) response in schizophrenia has been reported, indicating a possible deregulation of the balance between cellular and humoral immune responses.62 Increases in Th1 have been found in individuals with schizophrenia,63 together with reduced expression of the interferon (IFN)-γ gene.64 Another important Th1 pro-inflammatory cytokine, IL-2, has a concentration-dependent effect on dopamine, increasing dopamine release at lower concentrations and inhibiting its release at higher concentrations.65 Most in vitro and in vivo studies have confirmed a decrease in IL-2 production by lymphocytes66,67 and IL-2 plasma levels10,68 in the presence of schizophrenia. Notwithstanding, other studies have found no difference in IL-2 expression between patients with schizophrenia and healthy controls64 or increased IL-2 plasma levels in patients with schizophrenia.69 Higher levels of TNF-α, another prototypical Th1 pro-inflammatory cytokine, have been observed in patients with schizophrenia when compared with healthy individuals, with reduction to control levels after treatment.63,70 Evidence from various studies also reveals a decrease in the activity of IL-10 and IL-4, critical anti-inflammatory cytokines. These mediators are both produced by and inhibit Th2 lymphocytes, regulating inflammatory responses. The increased TNF-α/IL4 ratio in acute exacerbations of schizophrenia suggests a Th1/Th2 imbalance in this disorder.71

Cytokines play a complex role in schizophrenia, causing or resulting from other neuropathological processes. In the brain, cytokines seem to be involved in regulating the action of several neurotransmitters, such as serotonin, noradrenalin, dopamine, and glutamate. The interaction of cytokines with dopamine and glutamate seems to be especially relevant to the pathophysiology of schizophrenia. Recent evidence from animal studies suggests that an immune challenge produced by the injection of lipopolysaccharides in the prefrontal cortex increases IL-1 and IL-2 levels and that these cytokines activate dopaminergic neurons in this region.72

Another potential effect of immune activation on inhibitory circuit dysfunction in cases of schizophrenia has been demonstrated by the recent observation that IL-6 mediates the deleterious effects of noncompeting N-methyl-D-aspartate (NMDA) antagonists on cortical interneurons.73 Beyond their effects on neurotransmission, cytokines have a profound impact on the regulation of neuroplasticity, cellular resilience, and apoptosis control. TNF-α seems to inhibit BDNF release, compromising the protective effect of this neurotrophin.74

Interestingly, some abnormalities in cytokines levels are associated with symptomatology in schizophrenia. TNF-α levels are related to Brief Psychiatric Rating Scale and Scale Assessment of Positive Symptoms scores.75 In addition, IL-2 and IL-8 levels in baseline were related to response to haloperidol and risperidone, with the individuals with higher levels presenting a higher probability to present improvment with medications.76 In addition, quetiapine has been suggested as able to increase concentration of sIL-2R, which were correlated with severity of positive symptoms.77 In the same way, increases in IL-2, typically an anti-inflammatory cytokine, are related to lower scores in positive symptoms in the Positive and Negative Syndrome Scale (PANSS).78

GENETIC FACTORS CONTRIBUTE TO DYSREGULATION OF INFLAMMATION IN SCHIZOPHRENIA

  1. Top of page
  2. Abstract
  3. CYTOKINES INFLUENCE ADULT BRAIN AND NEURODEVELOPMENT
  4. FROM PRECLINICAL TO FULL-BLOWN PSYCHOSIS
  5. SCHIZOPHRENIA IS ASSOCIATED WITH ABNORMALITIES IN INFLAMMATORY MEDIATORS
  6. GENETIC FACTORS CONTRIBUTE TO DYSREGULATION OF INFLAMMATION IN SCHIZOPHRENIA
  7. ENVIRONMENTAL SUSCEPTIBILITY TO INFLAMMATORY IMBALANCES IN SCHIZOPHRENIA
  8. MODULATION OF INFLAMMATION AS A TREATMENT STRATEGY FOR SCHIZOPHRENIA AND UHR INDIVIDUALS
  9. FINAL REMARKS
  10. ACKNOWLEDGMENTS
  11. REFERENCES

The exact mechanism causing inflammatory dysregulation in schizophrenia is still unknown, but its bases are probably both genetic and environmental. Several studies have argued that cytokine abnormalities in schizophrenia have a genetic basis, implicating various genes. Polymorphisms in inflammatory mediators have been recently found to take part in the modulation of the vulnerability to schizophrenia. Variances have been observed in polymorphisms of the IL-3 gene79 and the IL-3RA gene.80–82 Sun et al. have also found an increase in the frequency of the IL-6R C allele in patients with schizophrenia when compared with normal controls.83 An increase in GCC homozygotes (the high IL-10-producing haplotype) was observed by Bocchio Chiavetto et al.84 Two polymorphisms (_1082G/A, _592C/A) in the promoter region of the IL-10 gene were associated with higher risk of developing schizophrenia in different ethnic groups.85,86 Ozbey et al. have reported that individuals who are heterozygous for a polymorphism within the IL-12B promoter region might be more susceptible to developing schizophrenia.87 Regarding TNF-α, Boin et al. were the first to describe an association between the -G308A TNF-α gene polymorphism and schizophrenia, which is supported by one study but not by others.88–92 A meta-analysis by Sacchetti et al. reports a weak association between the AA genotype of the TNF-α -G308A polymorphism and schizophrenia, but also demonstrates that the A allele was more specifically related to susceptibility in male subjects, later age of onset, and in the paranoid subtype.93 Paul-Samojedny et al. found an association between the IFN-γ+874T/A polymorphism, specifically the A/A genotype, with paranoid schizophrenia in male subjects.94 The A/A genotype has been linked to a reduction in IFN-γ production. As for the IL-2 gene, the −330 T/T genotype has been significantly associated with schizophrenia95 and functionally linked to diminished IL-2 production, as shown by in vitro data.96

The genetic influence of the IL-4 dysfunction is controversial. In one study,95 schizophrenia was associated with the IL-4 −590 C/C genotype, linked to more pronounced Th1-like activation. In turn, Jun et al. found a trend, however without statistical significance, for a correlation of the C-allele with schizophrenia.97 Finally, no association was observed by Watanabe et al.98 Regarding the IL-10 gene, the presence of the allele G at position −1082 has been correlated with an increasing risk of schizophrenia,84,86,99 although studies in different populations have not confirmed this association.87,100 The presence of the G allele at position −1082 correlates with increase in IL-10 production, while allele A is associated with low IL-10 production.101

ENVIRONMENTAL SUSCEPTIBILITY TO INFLAMMATORY IMBALANCES IN SCHIZOPHRENIA

  1. Top of page
  2. Abstract
  3. CYTOKINES INFLUENCE ADULT BRAIN AND NEURODEVELOPMENT
  4. FROM PRECLINICAL TO FULL-BLOWN PSYCHOSIS
  5. SCHIZOPHRENIA IS ASSOCIATED WITH ABNORMALITIES IN INFLAMMATORY MEDIATORS
  6. GENETIC FACTORS CONTRIBUTE TO DYSREGULATION OF INFLAMMATION IN SCHIZOPHRENIA
  7. ENVIRONMENTAL SUSCEPTIBILITY TO INFLAMMATORY IMBALANCES IN SCHIZOPHRENIA
  8. MODULATION OF INFLAMMATION AS A TREATMENT STRATEGY FOR SCHIZOPHRENIA AND UHR INDIVIDUALS
  9. FINAL REMARKS
  10. ACKNOWLEDGMENTS
  11. REFERENCES

During the prenatal period, environmental factors seem to play an important role in increasing cytokine production. Such an increase has an impact on neural development and consequently on the vulnerability to schizophrenia. Among various environmental factors, maternal infections are presumed to promote the release of cytokines and trigger inflammation. Maternal infections seem to account for the association between birth seasonality and differences in schizophrenia rates. A meta-analysis has confirmed a small but significant risk of schizophrenia in offspring born in winter/spring.102

Brown and Derkits (2010) have recently reviewed the association between prenatal infection and schizophrenia.11 They calculated the attributable proportion for schizophrenia of selected infections. The results were 14% for influenza, 13% for elevated toxoplasmosis immunoglobulin G antibody, and 6% for periconceptional genital or reproductive infection. The hypothesis of a role of maternal infection in the development of schizophrenia is gaining ground. However, because most infections do not appear to cross the placenta, it is likely that the effect of maternal infection results from immune responses. Buka et al. observed elevated TNF-α at the time of birth in mothers of children with psychosis.103 Moreover, fetal exposure to higher levels of IL-8 has been associated with structural neuroanatomical abnormalities related to schizophrenia.13,60 Although the exact mechanism implicated in the impact of infections and the resulting increase in cytokine levels on neural development is largely unclear, some explanations have been suggested.104 One suggests that in the presence of maternal infection, placental cytokines could contribute to altered placental blood flow, with downstream effects on fetal neural development. In addition, several groups have proposed an involvement of oxidative stress in the CNS.104 This hypothesis is supported by observed increases in markers of oxidative stress together with decreases in reduced glutathione levels in the brains of rat fetuses several hours following maternal immune stimulation.105 In addition, a cytokine-induced reduction in nonheme iron, found in all types of infections, has also been considered important. Adequate iron supply to the fetus is essential for the development of mesencephalic dopamine neurons, and disruption of iron supply following maternal infection can affect the offspring's dopamine function.106 Finally, cytokines may disturb maturation of oligodendrocytes, contributing to white matter abnormalities, which have been found in postmortem studies of schizophrenia.107

Another potentially relevant environmental factor is early life stress. Several lines of evidence suggest that maternal stress during pregnancy may be related to increased risk of schizophrenia in offspring. The risk of schizophrenia was increased in the offspring of women in the first and second quarter of pregnancy at the time of the German invasion of the Netherlands during World War II.108 Exposure in the second month of fetal life to the Israeli Six-Day War was associated with increased schizophrenia risk in female offspring.109 Not all studies of maternal stress and offspring risk of schizophrenia have observed significant associations, however.11

Childhood events, such as physical and sexual abuse and neglect, have been associated with schizophrenia. Many studies report high rates of sexual and physical abuse in individuals with psychosis and schizophrenia.110–113 Most of the studies evaluating the association between childhood trauma and schizophrenia114 have a cross-sectional design, which prevents inferences about causality.

Data from studies analyzing the consequences of childhood trauma on the biology of the hypothalamic-pituitary-adrenal (HPA) axis demonstrate a hyperresponsiveness of the HPA axis to different types of stress and trauma115 in both animals116–120 and humans.121–124 The interaction between the neuroendocrine and the immune system is complex. Despite the well-known anti-inflammatory effects of glucocorticoids,125 chronic exposure to hypercortisolemia could lead to desensitization through glucocorticoid receptor resistance, triggering a heightened inflammatory response and an increase in the levels of cytokines, such as IL-6.126 However, at the physiological level, cortisol is a fundamental aspect of normal immune function. This has led to the interpretation of glucocorticoids as immunomodulators, which act specifically by shifting the immune response from a Th1 to a Th2-type pattern.127 High levels of IL-6 as well as a Th2-type response shift have been described in schizophrenia, as detailed above.

The HPA axis is the most important neuroendocrine stress response system, and it is implicated in the adaptation of the organism to environmental changes and demands.128 HPA axis activation is postulated to have a dual effect on the immune system. Stress and the resulting hypercortisolemia act as a negative feedback mechanism to suppress the immune response, a well-documented effect of corticosteroids. Another possible physiological effect of HPA activation is the stimulation of an inflammatory response. In fact, the effect of psychological stress on cytokine secretion has been investigated in several studies,129–136 with results that suggest that immunosuppressive response is not uniform. Even if a definitive pattern has not emerged, several authors favor the hypothesis that stress gives rise to inflammatory responses.131,134,135,137 The association between childhood trauma and activation of the inflammatory response seems to be relevant in autoimmune disorders, ischemic heart disease, cancer, chronic lung disease, skeletal fractures, liver disease, and other adult diseases in which inflammation imbalances are a relevant mechanism.11,138–140

Taken together, the findings of studies evaluating genetic and environmental factors suggest that the activation of inflammation mechanisms might be the final step of pathways involving specific genetic polymorphisms and environmental toxic events in critical periods of neural development.

MODULATION OF INFLAMMATION AS A TREATMENT STRATEGY FOR SCHIZOPHRENIA AND UHR INDIVIDUALS

  1. Top of page
  2. Abstract
  3. CYTOKINES INFLUENCE ADULT BRAIN AND NEURODEVELOPMENT
  4. FROM PRECLINICAL TO FULL-BLOWN PSYCHOSIS
  5. SCHIZOPHRENIA IS ASSOCIATED WITH ABNORMALITIES IN INFLAMMATORY MEDIATORS
  6. GENETIC FACTORS CONTRIBUTE TO DYSREGULATION OF INFLAMMATION IN SCHIZOPHRENIA
  7. ENVIRONMENTAL SUSCEPTIBILITY TO INFLAMMATORY IMBALANCES IN SCHIZOPHRENIA
  8. MODULATION OF INFLAMMATION AS A TREATMENT STRATEGY FOR SCHIZOPHRENIA AND UHR INDIVIDUALS
  9. FINAL REMARKS
  10. ACKNOWLEDGMENTS
  11. REFERENCES

Given the converging evidence in support of the relevance of inflammation in schizophrenia, it seems reasonable to hypothesize that modulating inflammation could prove beneficial for this condition. Even if not conclusive, an increasing body of data from in vivo and in vitro studies suggests that typical and atypical antipsychotic drugs may have immunomodulatory effects. Antipsychotics modulate cytokine networks, and the suppression of IL-2 activity is a common feature of neuroleptic drugs.141 Treatment with chlorpromazine142 and risperidone143 also appears to increase the levels of anti-inflammatory cytokine IL-10 in peripheral blood. In addition, some antipsychotics have been shown to reduce the activation of microglia,144 including several typical antipsychotics and the atypical olanzapine, risperidone, ziprasidone and aripiprazol.145,146

Cytokines also appear to play a role in some adverse effects caused by antipsychotics. In a randomized trial, Kluge et al. found that olanzapine and clozapine-induced weight gain and clozapine-induced fever are closely associated with the effects of cytokines:147 patients with these adverse events had higher IL-6 serum levels, whereas the levels of IL-2 receptors as well as of TNF-α and its receptors sTNFR-1 and sTNFR-2 correlated with body mass index.

Modulation of inflammation has emerged as a possible target for the treatment of schizophrenia.148–153 Nonsteroidal anti-inflammatory drugs (NSAIDs) have been demonstrated to prevent kainic-acid-induced neuronal death, producing a therapeutic effect mediated by modulation of glutamatergic transmission.151 NSAIDs are currently being tested as an adjunctive treatment in schizophrenia, based on their putative ability to restore the balance of the Th1/Th2 immune response. Celecoxib, a cyclooxygenase-2 inhibitor, has been tested as an adjunctive treatment in schizophrenia in some studies. Muller et al. and Akhondzadeh et al. found more improvement in PANSS total scores in the risperidone-plus-celecoxib group than in the risperidone-placebo group.145,151 In the first study, a combination of risperidone and celecoxib was more effective than risperidone plus placebo after 5 weeks in a sample of 50 people with schizophrenia.153 The study of Akhondzadeh et al. was an 8-week, double blind, placebo-controlled trial with 30 patients receiving 6 mg of risperidone plus 400 mg of celecoxib and 30 patients receiving 6 mg of risperidone plus placebo.151 Improvement in positive symptoms, general psychopathological symptoms and PANSS total scores was significantly greater in the celecoxib group during the 8-week trial. No significant differences were observed between the means of the two groups on the negative scores. Other reports did not find similar effects. Bresee et al. and collaborators found that celecoxib did not affect the levels of cytokines in schizophrenia subjects.150 Rapaport et al. failed to show any beneficial effects with the addition of celecoxib to an antipsychotic regimen.149

Another anti-inflammatory alternative tested for schizophrenia was acetylsalicylic acid. Laan et al. conducted a 3-month randomized, double blind, placebo-controlled add-on trial to investigate the efficacy of adjuvant treatment with aspirin (1000 mg) in addition to regular antipsychotic therapy in individuals diagnosed with schizophrenia-spectrum disorders.152 They found that decreases in positive PANSS subscale were more pronounced in the aspirin group than in the placebo group. The study did not find any effect on negative and total PANSS scores. The reduction in psychotic symptoms was greater in patients with relatively high production of inflammatory cytokines. Although data are still limited, these studies offer an opportunity for the future development of new psychopharmacological strategies for the treatment of psychosis.

As discussed before, the study of strategies to prevent the evolution of UHR individuals to psychosis is a topic of great importance. To date, most interventions have combined low doses of atypical antipsychotics and psychosocial interventions.154 However, low conversion rates and the potential deleterious effects of the long-term exposure to anti-psychotic medication have been considered limitations of this type of study. In this context, inflammation emerges as a possible target for the investigation of preventive pharmacological strategies in prodromal stages of psychosis. This is based on the hypothesis that inflammatory dysregulation probably begins very early in life, produced by a combination of specific polymorphisms in cytokine genes and intrauterine events. Childhood stress may also have an impact, producing neurodevelopmental abnormalities and possibly a mild and continuous pro-inflammatory state. Because these changes are presumably produced before the onset of a full-blown psychotic episode, it seems logical to speculate that anti-inflammatory drugs may be beneficial for UHR individuals, although this type of intervention has not been tested yet.

Anti-inflammatory agents are not free from adverse effects, but their acceptability and low cost and the fact that they are sufficiently well-tolerated warrant their use in different stages of schizophrenia, including prodromal stages. In addition, the neuroprotective effect of anti-inflammatory agents potentially might limit the damage produced by the first psychotic episode. If this hypothesis is correct, anti-inflammatory agents might be effective in preventing psychosis, or limiting the duration of psychotic episodes, delaying the onset of illness, or reducing its severity (Fig. 1).

image

Figure 1. Schematic representation of the role of inflammatory cytokines in the cellular processes that could underlie the disease progression from an asymptomatic phase to full-blown psychosis, through a prodromal period. Anti-inflammatory agents can be a possible pharmacological intervention, targeting these pathways and thus preventing illness development. IL, interleukin; TNF, tumor necrosis factor.

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FINAL REMARKS

  1. Top of page
  2. Abstract
  3. CYTOKINES INFLUENCE ADULT BRAIN AND NEURODEVELOPMENT
  4. FROM PRECLINICAL TO FULL-BLOWN PSYCHOSIS
  5. SCHIZOPHRENIA IS ASSOCIATED WITH ABNORMALITIES IN INFLAMMATORY MEDIATORS
  6. GENETIC FACTORS CONTRIBUTE TO DYSREGULATION OF INFLAMMATION IN SCHIZOPHRENIA
  7. ENVIRONMENTAL SUSCEPTIBILITY TO INFLAMMATORY IMBALANCES IN SCHIZOPHRENIA
  8. MODULATION OF INFLAMMATION AS A TREATMENT STRATEGY FOR SCHIZOPHRENIA AND UHR INDIVIDUALS
  9. FINAL REMARKS
  10. ACKNOWLEDGMENTS
  11. REFERENCES

The research about inflammatory modulation in schizophrenia and UHR has some limitations that should be taken into account. Although psychoneuroimmunology is a fast-developing field, the study of immune and inflammatory abnormalities is schizophrenia is only in its infancy. Studies available until now did not incorporate more sophisticated methods of immunological investigation. Most of them use simple measurements in plasma or serum, without considerate interference of several factors that can potentially influence results, such as body mass index (BMI), menstrual cycle and tobacco use. In addition, the extension of correlation between peripheral and central levels remains undetermined.

The specificity of inflammatory abnormalities in psychiatric disorders is controversial. Similar increases in pro-inflammatory cytokines have been described in other disorders, especially mood and anxiety disorders.15,155 Regarding preclinical stages, some investigators argue that attenuated psychotic symptoms might be a predictor of psychopathology in general, and not specifically in schizophrenia.156

Inflammatory abnormalities in schizophrenia are an important topic that still requires much attention. Elucidation of the role of inflammatory imbalances in neural development as well as in regulation of neuroplasticity may open new avenues of investigation about the pathophysiology of schizophrenia since its preclinical stages. One of the most important challenges at this point is to understand the neurobiological correlates of the prodromal stages. The comprehension of these phenomena will serve as the starting point for the design and testing of preventive pharmacological interventions. Future research should investigate the exact role of different cytokines to define more specific molecular targets. Because inflammation is a promising candidate to mediate the pathophysiology of psychosis, the use of anti-inflammatory drugs in clinical and preclinical phases may become a treatment alternative for people with schizophrenia, even though their beneficial effect remains largely speculative.

REFERENCES

  1. Top of page
  2. Abstract
  3. CYTOKINES INFLUENCE ADULT BRAIN AND NEURODEVELOPMENT
  4. FROM PRECLINICAL TO FULL-BLOWN PSYCHOSIS
  5. SCHIZOPHRENIA IS ASSOCIATED WITH ABNORMALITIES IN INFLAMMATORY MEDIATORS
  6. GENETIC FACTORS CONTRIBUTE TO DYSREGULATION OF INFLAMMATION IN SCHIZOPHRENIA
  7. ENVIRONMENTAL SUSCEPTIBILITY TO INFLAMMATORY IMBALANCES IN SCHIZOPHRENIA
  8. MODULATION OF INFLAMMATION AS A TREATMENT STRATEGY FOR SCHIZOPHRENIA AND UHR INDIVIDUALS
  9. FINAL REMARKS
  10. ACKNOWLEDGMENTS
  11. REFERENCES