Cytokines and schizophrenia: Microglia hypothesis of schizophrenia

Akira Monji, MD, PhD,* Takahiro Kato, MD, PhD and Shigenobu Kanba, MD, PhD
Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

The etiology of schizophrenia remains unclear, while there has been a growing amount of evidence for the neuroinammation and immunogenetics, which are characterized by an increased serum concentration of several pro-inammatory cytokines. Despite the fact that microglia comprise only <10% of the total brain cells, microglia respond rapidly to even minor pathological changes in the brain and may contribute directly to the neuronal degeneration by producing various pro-inammatory cytokines and free radicals. In many aspects, the neuropathology of schizophrenia has recently been reported to be closely associatedwith microglial activation. Previous studies have

shown the inhibitory effects of some typical/atypical antipsychotics on the release of inammatory cytokines and free radicals from activated microglia, both of which have recently been known to cause a decrease in neurogenesis as well as white matter abnormalities in the brains of patients with schizophrenia. The microglia hypothesis of schizophrenia may shed new light on the therapeutic strategy for schizophrenia. Key words: antipsychotics, cytokine, inammation, microglia, schizophrenia.

CHIZOPHRENIA IS A chronic and often debilitating illness that affects approximately 1% of the world population. In addition to severely disrupting the life of patients and their families, schizophrenia imposes a great cost on society in terms of productivity loss and treatment-related expenses.1,2 The etiology of schizophrenia remains elusive, while dopaminergic hyperfunction in the limbic system and dopaminergic hypofunction in the frontal cortex as well as glutamatergic hypofunction are known to play important roles in the pathophysiology of schizophrenia.

We herein review the relationship between cytokines and schizophrenia. We also propose the microglia hypothesis of schizophrenia (Fig. 1), and suggest a therapeutic strategy for schizophrenia through the inhibition of microglial activation.

CYTOKINES AND MICROGLIA

Cytokines serve cellular communication. Released for auto- and paracrine signaling, membrane-associated for cellcell interaction, or occasional biological information through body uids, these small proteins regulate cell growth, survival, differentiation, and activities. Several cytokines, including growth factors, and their receptors have been found to be present and functional in the central nervous system (CNS).3 Among them are tumor necrosis factor-a (TNF-a), interferon (IFN), interleukin 1 (IL-1), IL-2,

*Correspondence: Akira Monji, MD, PhD, Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. Email: amonji@hf.rim.or.jp Accepted 27 January 2009.

2009 The Authors Journal compilation 2009 Japanese Society of Psychiatry and Neurology

257

258

A. Monji et al.

Psychiatry and Clinical Neurosciences 2009; 63: 257265

Stressful life events (e.g. birth, trauma, infection etc)

Stimulating agents of microglia (e.g. LPS, IFN- etc) Resting microglia (ramified type)

Activated microglia
Cytokines TNF- IL-1 IL-6 etc Free Radicals Nitric Oxide (NO) Superoxide (O2-) Peroxynitrite (ONOO-) etc

Neuronal cells Progenitor cells Oligodendrocytes

Neuronal degeneration, decreased neurogenesis, white matter abnormalities etc

Pathophysiology of Schizophrenia
Figure 1. Microglia hypothesis of schizophrenia. Immunological/inammatory activators such as interferon (IFN)-g and lipopolysaccharide (LPS), which are induced by varieties of stress events and life events, activate microglia in the central nervous system. Activated microglia release pro-inammatory cytokines and free radicals. These mediators are known to cause neuronal degeneration, white matter abnormalities and decreased neurogenesis. These neuronmicroglia interactions may thus be one of the important factors in the pathophysiology of schizophrenia. IL, interleukin; TNF, tumor necrosis factor.

-3, -4, -6, -10, -12, -15, and -18, transforming growth factor-b (TGF-b), colony-stimulating factors such as macrophage colony-stimulating factor (M-CSF), platelet-derived growth factor (PDG), epidermal growth factor (EGF), broblast growth factor (FGF), insulin-like growth factor (IGF), and neurotrophic factors such as nerve growth factor (NGF), brainderived neurotrophic factor (BDNF), and neurotrophins (NT-3 and NT-4). An increasing body of evidence relates to the evergrowing family of chemokines. Neurodevelopmental roles are postulated for various cytokines. Some also modulate neuronal activities in the mature CNS and participate in

neuro-immuneendocrine communication. Constitutive functions of typical immunoregulators in the day-to-day physiology of the normal immuneprivileged CNS are still unclear, while certain cytokines appear in the affected brain region and the cerebrospinal uid (CSF) when the CNS homeostasis is disturbed as a result of trauma, stroke, ischemia, infection, or degenerative processes. Increased cytokine levels in the CNS may result from bloodbrain barrier (BBB) disruption or synthesis by invading immune cells, both of which originate from extraneuronal sources. Nevertheless, most, if not all, neuropathologies are to various extents associated with the

2009 The Authors Journal compilation 2009 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2009; 63: 257265

Cytokines and schizophrenia

259

activation of microglia and astrocytes. Microglia are the primary reservoirs of pro-inammatory cytokines such as IL-6, TNF-a and IFN-g and act as antigenpresenting cells in the CNS.4 Despite the fact that microglia comprise only <10% of the total brain cells, microglia respond rapidly to even minor pathological changes in the brain and may contribute directly to neuronal degeneration by producing various pro-inammatory cytokines and free radicals.5,6 In contrast, the neuron microglia interaction has been reported to orchestrate the balance between synaptogenesis and neuronal death during the brains development and injuries.7

Microglial activation and schizophrenia

Prolonged microglial hyperactivity may lead to neuronal apoptosis and brain damage, which are commonly seen in neurodegenerative disorders such as Parkinsons disease (PD) and Alzheimers disease (AD).20,21 A neurodegenerative and neurodevelopmental process is indicated in the course of schizophrenia22,23 and may be associated with microglial activation. Hypoglutamatergic states and impaired N-methyl-D-aspartate (NMDA) signaling underlie the pathophysiology of schizophrenia. NMDA antagonists such as phencyclidine (PCP), ketamine, and MK-801 offer an appropriate animal model of schizophrenia. All three NMDA antagonists are known to induce microglial activation in the brains of rodents.24,25 Interestingly, microglial activation or increased microglial cellular density has also been suggested by post-mortem studies, at least in subpopulations of individuals with schizophrenia.2628 Highly elevated microglial cell numbers have been demonstrated in the anterior cingulate cortex and mediodorsal thalamus of patients with schizophrenia who had committed suicide during acute psychosis.29 Using [11C] (R)-PK11195, a specic ligand of the peripheral benzodiazepine-binding sites (PBBS) used for a systematic study of microglial activation in vivo, researchers have recently reported increased microglial activation in the gray matter of patients with schizophrenia, which is similar to patients with neurodegenerative dementia.30,31 That positron emission computed tomography study demonstrated that activated microglia are present in schizophrenia patients within the rst 5 years after the onset of disease.31

NEUROINFLAMATION IN SCHIZOPHRENIA: MICROGLIA HYPOTHESIS OF SCHIZOPHRENIA

There has been more evidence indicating the signicance of neuroinammation and immunogenetics in schizophrenia, characterized by an increased serum concentration of several pro-inammatory cytokines.812 Increased serum concentrations of IL-2, IL-6 and IL-8 have been observed in schizophrenia patients,13,14 and immunomodulatory drugs such as cyclooxygenase-2 (COX-2) inhibitors have recently been reported to have benecial effects on schizophrenia symptoms.15,16 Increased serum and CSF levels of S100B, a suitable marker for the destruction of CNS tissue in the context of different diseases including neurodegenerative disorder, were reported in schizophrenia patients with negative symptoms or a chronic duration.17 Epidemiologic studies demonstrate a signicant environmental impact of maternal viral infection and obstetric complications on the risk of schizophrenia. Elevated inammatory process is known to play an important role in these circumstances.18,19 A recent DNA microarray study has shown the increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia.8 Another recent study using the prefrontal cortex in schizophrenia has shown that the molecular basis for schizophrenia changes from early to chronic stage, providing evidence for a changing nature of schizophrenia with disease progression. Namely, short-term illness was associated with disruption in gene transcription, metal-binding, RNA expression and vesicle-mediated transport, while long-term illness was associated with inammation, stimulusresponse and immune functions.10

Neurogenesis and schizophrenia

The relationship between depression and neurogenesis has been described in general,32 while one recent human post-mortem brain study using Ki-67 immunoreactivity indicated that the phenomenon of neurogenesis is much more related to the pathophysiology of schizophrenia than that of depression.33 Repeated administration of PCP as well as MK-801 has recently been reported to inhibit hippocampal neurogenesis in vivo.34,35 Mice harboring compound disruption in the neuronal PAS domain protein 3 (NPAS3) and related NPAS1 genes manifest behavioral and neuroanatomical abnormalities reminiscent of schizophrenia.36 Basal neural precursor

2009 The Authors Journal compilation 2009 Japanese Society of Psychiatry and Neurology

260

A. Monji et al.

Psychiatry and Clinical Neurosciences 2009; 63: 257265

cell proliferation in the dentate gyrus of NPAS3 gene-decient mice has been found to be reduced signicantly, which indicated impaired neurogenesis involved in schizophrenia.37 Disruptedin-schizophrenia 1 (DISC1) is a well-known schizophrenia susceptibility gene. A recent study has shown that DISC1 regulates integration of newly generated neurons in the adult brain.38 The aforementioned results indicate the close relationship between schizophrenia and neurogenesis. With regard to neurogenesis, atypical antipsychotics, but not typical antipsychotics, induced neurogenesis in the adult brains of rodents.35,39,40 In contrast, CNS inammation is detrimental for adult hippocampal neurogenesis.41,42 The negative effects of inammation on differentiation and survival of the neuronal cells are due, in vitro, to microglia-derived TNF-a and nitric oxide (NO).41,43 Pro-inammatory cytokines such as Il-1b and TNF-a have been reported to inhibit neurogenesis in vivo.44,45 In addition, in vivo, neurogenesis can be restored by anti-inammatory drugs such as minocycline and indomethacin that inhibit microglial activation.41,42

cause elimination without cell death.50,51 Inappropriate activation of apoptosis occurs not only in the neurons, but also in the oligodendrocytes and synapses.50 Pro-inammatory cytokines such as TNF-a have been well characterized as mediators of oxidative stress, and they induced apoptosis in human cortical neuron as well as oligodendrocytes.52,53 In addition, NO has been reported not only to directly induce neuronal apoptosis, but also to be involved in cytokine-mediated neuronal apoptosis.54,55 The interaction between NO and superoxide anion (O2-), which can be generated from activated microglia, forms peroxynitrite (ONOO-). Peroxynitrite is highly toxic and triggers apoptotic cell death. Moreover, high levels of NO and TNF-a may also affect synaptogenesis, synaptic plasticity and connectivity, and the composition of synaptic membranes.56,57 The alteration in the synaptic organization of the brain is one of the key features of schizophrenia.58

Oligodendrocyte dysfunction in schizophrenia

Neuroimaging studies have shown that rst-episode schizophrenia patients had a signicant volume reduction in white matter with abnormal brain connectivity.59,60 The reduced density and compromised morphology of the oligodendrocytes as well as signs of deviant myelination are evident in schizophrenia.61,62 Iwamoto et al. reported a functional single-nucleotide polymorphism in the 2,3-cyclic nucleotide 3-phosphodiesterase gene, which affects the expression of oligodendrocyte-related genes in schizophrenia.63 Combined with the evidence of dysregulation of the myelination-related genes, a disruption of the oligodendrocyte function in schizophrenia is strongly implicated.64 Microglial activation in the CNS has been implicated in the pathogenesis of white matter disorders and it has recently been reported that microglial cytotoxicity of oligodendrocyte is mediated through free radical-related molecules such as NO and peroxynitrite generated by activated microglia,65,66 and inammatory cytokines such as TNF-a and IFN-g.53 In addition, TNF-a has been shown to compromise the growth of oligodendrocytes and the expression of mRNA for myelin basic protein in cultures.67 Furthermore, it inhibited the survival and proliferation of the oligodendrocyte progenitors and their subsequent differentiation into mature myelinating phenotypes.68

Apoptosis and schizophrenia

Structural brain abnormalities have been described extensively and consistently in schizophrenia patients. Longitudinal studies using high-resolution magnetic resonance imaging (MRI) to examine brain structure have found that MRI volume changes were progressive over time and related to the course of illness and treatment outcome in schizophrenia patients.4648 A recent review has shown that continuous progressive brain tissue decreases, and lateral ventricle volume increases in chronically ill patients with schizophrenia, until at least 20 years after the rst symptoms.49 In fact, multiple lines of evidence combine to implicate increased susceptibility to apoptotic death in the pathophysiology of schizophrenia. Reduced neuronal and glial cell numbers, decreased neuropil (especially of the synapse elements), lack of gliosis, and in vivo neuroimaging evidence of progressive gray matter loss early in the disorder, as mentioned earlier, make apoptosis a plausible mechanism to explain the neurodegenerative course of schizophrenia. The activation of apoptotic process can lead to a rapid neuronal death. Emerging data, however, also indicate that sublethal apoptotic activity can lead to a limited form of apoptosis in terminal neuritis and individual synapses to

2009 The Authors Journal compilation 2009 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2009; 63: 257265

Cytokines and schizophrenia

261

ANTIPSYCHOTICS AND MICROGLIAL ACTIVATION

Atypical antipsychotics are becoming standard drugs for the treatment of schizophrenia due to their less adverse effects and greater effectiveness for the negative symptoms of schizophrenia.48,69 Some recent reports have suggested the possibility of specic atypical antipsychotics having pharmacological properties that could produce neurotrophic, neurogenetic, or neuroprotective effects. Namely, specic atypical antipsychotics such as olanzapine and risperidone have been reported to decrease the reduction of MRI volume during the clinical course of schizophrenia.6972 Moreover, recent reports have demonstrated that atypical antipsychotics, such as clozapine and risperidone, decreased serum levels of cytokines such as IL-2, IL-6 and TNF-a,73 the main source of which in the CNS is considered to be activated microglia in schizophrenia patients. A possible antipsychotic effect of minocycline, which is a potent inhibitor of microglial activation, has also been reported in patients with schizophrenia.74,75 Miyaoka et al., using the Positive and Negative Syndrome Scale, demonstrated statistically signicant and robust clinical improvements with minocycline as an adjunctive therapy to antipsychotics for schizophre-

nia.74,75 We thus hypothesize that antipsychotics may have anti-inammatory effects on microglial activation.

Typical and atypical antipsychotics with dopamine D2 receptor antagonism

To the best of our knowledge, there have been only a few previous studies on the effect of antipsychotics on microglial activation in vitro (Table 1). Kowalski et al. demonstrated that upentixol and triuperidol reduced the secretion of TNF-a and NO by activated microglia,76 and upentixol, triuperidol, chlorpromazine and loxapine have been reported to reduce IL-1b and IL-2 release by activated microglia.77,78 Until recently, the pharmacological action of atypical antipsychotics on microglial cells has not been well understood. Hou et al. demonstrated that olanzapine inhibited NO release from the activated microglia, while haloperidol and clozapine did not.79 We recently demonstrated that risperidone signicantly inhibited the IFN-g-activated microgliaderived production of NO and pro-inammatory cytokines such as IL-1b, IL-6, and TNF-a in comparison to haloperidol, a typical antipsychotic.80 We furthermore demonstrated the same inhibitory effects on IFN-g-induced microglial activation by other

Table 1. Effects of antipsychotics on microglial activation

Antipsychotics Flupentixol Triuperidol Chlorpromazine Loxapine Haloperidol Clozapine Olanzapine Haloperidol Risperidone Quetiapine Perospirone Ziprasidone Aripiprazole Spiperone Primary culture Cell line (N9) Microglia Primary culture Activator LPS LPS LPS LPS LPS LPS LPS IFN-g IFN-g IFN-g IFN-g IFN-g IFN-g LPS LPS ATP Pro-inammatory cytokines IL-1b and IL-2, TNF-a: Inhibited IL-1b and IL-2, TNF-a: Inhibited IL-1b and IL-2: Inhibited IL-1b and IL-2: Inhibited IL-1b, IL-6 and TNF-a: Inhibited IL-1b, IL-6 and TNF-a: Inhibited TNF-a: Inhibited TNF-a: Inhibited TNF-a: Activated TNF-a: Inhibited IL-1b, TNF-a: Inhibited (mRNA) Nitric oxide Inhibited Inhibited Not inhibited Not inhibited Inhibited Slightly inhibited Inhibited Inhibited Inhibited Inhibited Inhibited Inhibited Inhibited Inhibited Labuzek et al. (2005)78 Hou et al. (2006)79 Reference Kowalski et al. (2003, 2004)76,77

Cell line (6-3) Cell line (6-3)

Kato et al. (2007)80 Bian et al. (2008)81

Cell line (6-3) Primary culture Cell line (BV-2) Primary culture

Kato et al. (2008)82 Zheng et al. (2008)83

ATP, adenyl triphosphate; IFN-g, interferon-g; IL, interleukin; LPS, lipopolysaccharide; TNF, tumor necrosis factor.

2009 The Authors Journal compilation 2009 Japanese Society of Psychiatry and Neurology

262

A. Monji et al.

Psychiatry and Clinical Neurosciences 2009; 63: 257265

atypical antipsychotics such as perospirone and quetiapine.81 There have been some reports that suggested a relationship between schizophrenia and IFN-g, a major immunoactivator in the CNS. The most important immunological studies in schizophrenia have shown that a shift from T-helper 1 (Th1)-like cellular to Th2-like humoral immune reactivity is the most characteristic common immune nding and these studies have suggested a blunted IFN-g signal in schizophrenia.84 Rothermundt et al., however, have argued that the reduced IFN-g production in vitro may reect an increased production in vivo, because it is found in several autoimmune disorders.85 Furthermore, the serum levels of IL-2 and IFN-g, and the production of these cytokines from the peripheral blood mononuclear cells stimulated by phytohemagglutinin have been reported to be signicantly higher in schizophrenia patients than in controls.86 Furthermore, a recent systematic quantitative review on the inammatory cytokine alterations in schizophrenia did not support the Th2 shift hypothesis of schizophrenia.11 Spiperone, a typical antipsychotic, also inhibited the production of NO and pro-inammatory cytokines such as IL-1b and TNF-a from activated microglia, while spiperone was neuroprotective, because the drug reduced microglia-mediated neuroblastoma cell death in the microglia/neuron co-culture.83

Perspective
All of these studies suggest that some antipsychotics may therefore have a potentially useful therapeutic effect on patients with schizophrenia by reducing microglial inammatory reactions, which may cause the apoptotic process, the inhibition of neurogenesis, and the white matter abnormalities in the brains of patients with schizophrenia. This is consistent with the evidence showing antipsychotics inuence on slowing the progressive reduction in cortical gray matter in schizophrenia.72 In contrast, microglia can secrete neurotrophic factors other than proinammatory cytokines and free radicals such as BDNF. A recent study has shown that a7 nicotinic acetylcholine receptor agonist (a7nAChR) can modify microglial activation into a neuroprotective role by suppressing the inammatory state and strengthening the protective function.89 These results are very interesting because some a7nAChR agonists are known to improve the cognitive dysfunction of schizophrenia.90 The appropriate control of microglial activation may thus be a promising therapeutic target for schizophrenia. Pro-inammatory cytokines are also known to play important roles in the pathophysiology of depression.91 Etanercept, which is a soluble TNF-a receptor that prevents TNF-amediated response, has recently been reported to relieve fatigue and symptoms of depression with psoriasis.92 Immnosuppression or immunomodulatory drugs may thus be benecial at least for the treatment of acute schizophrenia.93

Antipsychotic with dopamine D2 receptor partial agonism

Aripiprazole is a novel atypical antipsychotic, which is a high-afnity dopamine D2 receptor partial agonist. We also demonstrated that aripiprazole signicantly inhibited the generation of NO and TNF-a from IFN-g-activated microglia, while quinpirole, dopamine D2 full agonist did not. Our results demonstrated that not only antipsychotics that have dopamine D2 receptor antagonism but also aripiprazole, a dopamine D2 receptor partial agonist, have anti-inammatory effects via the inhibition of microglial activation.82 Microglia are known to have some kinds of neurotransmitters including dopamine D2 receptors,87 but because second generation drugs have positive effects on neuronal cell growth and survival by unique signaling pathways,88 the pharmacological basis for their neuroprotective effect appears not always to be related directly to the conventional neurotransmitter receptors.

CONCLUSIONS
In many aspects the neuropathology of schizophrenia is closely associated with microglial activation. We and other researchers have shown the inhibitory effects of some typical or atypical antipsychotics on the release of inammatory cytokines and free radicals from activated microglia. Our microglia hypothesis of schizophrenia (Fig. 1) may shed new light on the therapeutic strategy for schizophrenia.

REFERENCES
1 Koyama A, Ito H, Nakanishi M, Sawamura K, Higuchi T. Addition of antipsychotics to medication regimens during schizophrenic inpatient care. Psychiatry Clin. Neurosci. 2008; 62: 5664. 2 Chien IC, Hsu JH, Bih SH et al. Prevalence, correlates, and disease patterns of antipsychotic use in Taiwan. Psychiatry Clin. Neurosci. 2008; 62: 677684.

2009 The Authors Journal compilation 2009 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2009; 63: 257265

Cytokines and schizophrenia

263

3 Ozbey U, Tug E, Kara M, Namli M. The value of interleukin-12B (p40) gene promoter polymorphism in patients with schizophrenia in a region of East Turkey. Psychiatry Clin. Neurosci. 2008; 62: 307312. 4 Bessis A, Bechade C, Bernard D, Roumier A. Microglial control of neuronal death and synaptic properties. Glia 2007; 55: 233238. 5 Ogawa K, Yamada T, Tsujioka Y et al. Localization of a novel type trypsin-like serine protease, neurosin, in brain tissues of Alzheimers disease and Parkinsons disease. Psychiatry Clin. Neurosci. 2000; 54: 419426. 6 Ishizuka K, Kimura T, Igata R, Katsuragi S, Takamatsu J, Miyakawa T. Identication of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimers disease. Psychiatry Clin. Neurosci. 1997; 51: 135138. 7 Hanisch U. Microglia as a source and target of cytokines. Glia 2002; 40: 140155. 8 Arion D, Unger T, Lewis DA, Levitt P, Mirnics K. Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia. Biol. Psychiatry 2007; 62: 711721. 9 Drzyzga L, Obuchowicz E, Marcinowska A, Herman ZS. Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav. Immun. 2006; 20: 532545. 10 Narayan S, Tang B, Head SR et al. Molecular proles of schizophrenia in the CNS at different stages of illness. Brain Res. 2008; 1239: 235248. 11 Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inammatory cytokine alterations in schizophrenia: A systematic quantitative review. Biol. Psychiatry 2008; 63: 801808. 12 Sperner-Unterweger B. Immunological aetiology of major psychiatric disorders: Evidence and therapeutic implications. Drugs 2005; 65: 14931520. 13 Lin A, Kenis G, Bignotti S et al. The inammatory response system in treatment-resistant schizophrenia: Increased serum interleukin-6. Schizophr. Res. 1998; 32: 915. 14 Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC. Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: Relationship to outcome in schizophrenia. J. Clin. Psychiatry 2004; 65: 940947. 15 Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B. Celecoxib as adjunctive therapy in schizophrenia: A double-blind, randomized and placebo-controlled trial. Schizophr. Res. 2007; 90: 179185. 16 Muller N, Riedel M, Schwarz MJ, Engel RR. Clinical effects of COX-2 inhibitors on cognition in schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 2005; 255: 149151. 17 Schmitt A, Bertsch T, Henning U et al. Increased serum S100B in elderly, chronic schizophrenic patients: Negative correlation with decit symptoms. Schizophr. Res. 2005; 80: 305313. 18 Ashdown H, Dumont Y, Ng M, Poole S, Boksa P, Luheshi GN. The role of cytokines in mediating effects of prenatal

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

infection on the fetus: Implications for schizophrenia. Mol. Psychiatry 2006; 11: 4755. Nawa H, Takei N. Recent progress in animal modeling of immune inammatory processes in schizophrenia: Implication of specic cytokines. Neurosci. Res. 2006; 56: 213. Nurun BN, Tanaka T, Kamino K et al. Toll-like receptor 3 mediated hyperphosphorylation of tau in human SH-SY5Y neuroblastoma cells. Psychiatry Clin. Neurosci. 2006; 60: S27S33. Block ML, Hong JS. Microglia and inammation-mediated neurodegeneration: Multiple triggers with a common mechanism. Prog. Neurobiol. 2005; 76: 7798. Lieberman JA. Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biol. Psychiatry 1999; 46: 729739. Perez-Neri I, Ramirez-Bermudez J, Montes S, Rios C. Possible mechanisms of neurodegeneration in schizophrenia. Neurochem. Res. 2006; 31: 12791294. Nakki R, Koistinaho J, Sharp FR, Sagar SM. Cerebellar toxicity of phencyclidine. J. Neurosci. 1995; 15: 2097 2108. Nakki R, Nickolenko J, Chang J, Sagar SM, Sharp FR. Haloperidol prevents ketamine- and phencyclidine-induced HSP70 protein expression but not microglial activation. Exp. Neurol. 1996; 137: 234241. Bayer TA, Buslei R, Havas L, Falkai P. Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci. Lett. 1999; 271: 126128. Radewicz K, Garey LJ, Gentleman SM, Reynolds R. Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. J. Neuropathol. Exp. Neurol. 2000; 59: 137150. Steiner J, Mawrin C, Ziegeler A et al. Distribution of HLADR-positive microglia in schizophrenia reects impaired cerebral lateralization. Acta Neuropathol. 2006; 112: 305 316. Steiner J, Bielau H, Brisch R et al. Immunological aspects in the neurobiology of suicide: Elevated microglial density in schizophrenia and depression is associated with suicide. J. Psychiatr. Res. 2008; 42: 151157. Cagnin A, Kassiou M, Meikle SR, Banati RB. In vivo evidence for microglial activation in neurodegenerative dementia. Acta Neurol. Scand. Suppl. 2006; 185: 107114. Berckel BN, Bossong MG, Boellaard R et al. Microglia activation in recent-onset schizophrenia: A quantitative (R)[11C]PK11195 positron emission tomography study. Biol. Psychiatry 2008; 64: 820822. Warner-Schmidt JL, Duman RS. Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment. Hippocampus 2006; 16: 239249. Reif A, Fritzen S, Finger M et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol. Psychiatry 2006; 11: 514522. Liu J, Suzuki T, Seki T, Namba T, Tanimura A, Arai H. Effects of repeated phencyclidine administration on adult

2009 The Authors Journal compilation 2009 Japanese Society of Psychiatry and Neurology

264

A. Monji et al.

Psychiatry and Clinical Neurosciences 2009; 63: 257265

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

hippocampal neurogenesis in the rat. Synapse 2006; 60: 5668. Maeda K, Sugino H, Hirose T et al. Clozapine prevents a decrease in neurogenesis in mice repeatedly treated with phencyclidine. J. Pharmacol. Sci. 2007; 103: 299308. Pickard BS, Pieper AA, Porteous DJ, Blackwood DH, Muir WJ. The NPAS3 gene: Emerging evidence for a role in psychiatric illness. Ann. Med. 2006; 38: 439448. Pieper AA, Wu X, Han TW et al. The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice. Proc. Natl Acad. Sci. USA 2005; 102: 1405214057. Duan X, Chang JH, Ge S et al. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 2007; 130: 11461158. Wakade CG, Mahadik SP, Waller JL, Chiu FC. Atypical neuroleptics stimulate neurogenesis in adult rat brain. J. Neurosci. Res. 2002; 69: 7279. Kodama M, Fujioka T, Duman RS. Chronic olanzapine or uoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol. Psychiatry 2004; 56: 570580. Monje ML, Toda H, Palmer TD. Inammatory blockade restores adult hippocampal neurogenesis. Science 2003; 302: 17601765. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inammation is detrimental for neurogenesis in adult brain. Proc. Natl Acad. Sci. USA 2003; 100: 1363213637. Cacci E, Claasen JH, Kokaia Z. Microglia-derived tumor necrosis factor-alpha exaggerates death of newborn hippocampal progenitor cells in vitro. J. Neurosci. Res. 2005; 80: 789797. Iosif RE, Ekdahl CT, Ahlenius H et al. Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. J. Neurosci. 2006; 26: 97039712. Kaneko N, Kudo K, Mabuchi T et al. Suppression of cell proliferation by interferon-alpha through interleukin-1 production in adult rat dentate gyrus. Neuropsychopharmacology 2006; 31: 26192626. Davis KL, Stewart DG, Friedman JI et al. White matter changes in schizophrenia: Evidence for myelin-related dysfunction. Arch. Gen. Psychiatry 2003; 60: 443456. Kumra S, Ashtari M, Cervellione KL et al. White matter abnormalities in early-onset schizophrenia: A voxel-based diffusion tensor imaging study. J. Am. Acad. Child Adolesc. Psychiatry 2005; 44: 934941. Salisbury DF, Kuroki N, Kasai K, Shenton ME, McCarley RW. Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia. Arch. Gen. Psychiatry 2007; 64: 521529. Hulshoff Pol HE, Kahn RS. What happens after the rst episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr. Bull. 2008; 34: 354366.

50 Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF. Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr. Res. 2006; 81: 4763. 51 Jarskog LF, Glantz LA, Gilmore JH, Lieberman JA. Apoptotic mechanisms in the pathophysiology of schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2005; 29: 846858. 52 Medina S, Martinez M, Hernanz A. Antioxidants inhibit the human cortical neuron apoptosis induced by hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42. Free Radic. Res. 2002; 36: 11791184. 53 Buntinx M, Moreels M, Vandenabeele F et al. Cytokineinduced cell death in human oligodendroglial cell lines: I. Synergistic effects of IFN-gamma and TNF-alpha on apoptosis. J. Neurosci. Res. 2004; 76: 834845. 54 Palluy O, Rigaud M. Nitric oxide induces cultured cortical neuron apoptosis. Neurosci. Lett. 1996; 208: 14. 55 Hu S, Peterson PK, Chao CC. Cytokine-mediated neuronal apoptosis. Neurochem. Int. 1997; 30: 427431. 56 Sunico CR, Portillo F, Gonzalez-Forero D, Moreno-Lopez B. Nitric-oxide-directed synaptic remodeling in the adult mammal CNS. J. Neurosci. 2005; 25: 14481458. 57 Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature 2006; 440: 10541059. 58 Roberts RC, Roche JK, Conley RR. Synaptic differences in the postmortem striatum of subjects with schizophrenia: A stereological ultrastructural analysis. Synapse 2005; 56: 185197. 59 Price G, Cercignani M, Bagary MS et al. A volumetric MRI and magnetization transfer imaging follow-up study of patients with rst-episode schizophrenia. Schizophr. Res. 2006; 87: 100108. 60 Schlosser RG, Nenadic I, Wagner G et al. White matter abnormalities and brain activation in schizophrenia: A combined DTI and fMRI study. Schizophr. Res. 2007; 89: 111. 61 Uranova NA, Vostrikov VM, Orlovskaya DD, Rachmanova VI. Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: A study from the Stanley Neuropathology Consortium. Schizophr. Res. 2004; 67: 269275. 62 Uranova NA, Vostrikov VM, Vikhreva OV, Zimina IS, Kolomeets NS, Orlovskaya DD. The role of oligodendrocyte pathology in schizophrenia. Int. J. Neuropsychopharmacol. 2007; 10: 537545. 63 Iwamoto K, Ueda J, Bundo M, Nakano Y, Kato T. Effect of a functional single nucleotide polymorphism in the 2,3cyclic nucleotide 3-phosphodiesterase gene on the expression of oligodendrocyte-related genes in schizophrenia. Psychiatry Clin. Neurosci. 2008; 62: 103108. 64 McCullumsmith RE, Gupta D, Beneyto M et al. Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia. Schizophr. Res. 2007; 90: 1527.

2009 The Authors Journal compilation 2009 Japanese Society of Psychiatry and Neurology

Psychiatry and Clinical Neurosciences 2009; 63: 257265

Cytokines and schizophrenia

265

65 Li J, Baud O, Vartanian T, Volpe JJ, Rosenberg PA. Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc. Natl Acad. Sci. USA 2005; 102: 99369941. 66 Merrill JE, Ignarro LJ, Sherman MP, Melinek J, Lane TE. Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J. Immunol. 1993; 151: 21322141. 67 Cammer W, Zhang H. Maturation of oligodendrocytes is more sensitive to TNF alpha than is survival of precursors and immature oligodendrocytes. J. Neuroimmunol. 1999; 97: 3742. 68 Feldhaus B, Dietzel ID, Heumann R, Berger R. Effects of interferon-gamma and tumor necrosis factor-alpha on survival and differentiation of oligodendrocyte progenitors. J. Soc. Gynecol. Invest. 2004; 11: 8996. 69 Lieberman JA, Tollefson GD, Charles C et al. Antipsychotic drug effects on brain morphology in rst-episode psychosis. Arch. Gen. Psychiatry 2005; 62: 361370. 70 Chakos MH, Schobel SA, Gu H et al. Duration of illness and treatment effects on hippocampal volume in male patients with schizophrenia. Br. J. Psychiatry 2005; 186: 2631. 71 Massana G, Salgado-Pineda P, Junque C et al. Volume changes in gray matter in rst-episode neuroleptic-naive schizophrenic patients treated with risperidone. J. Clin. Psychopharmacol. 2005; 25: 111117. 72 Girgis RR, Diwadkar VA, Nutche JJ, Sweeney JA, Keshavan MS, Hardan AY. Risperidone in rst-episode psychosis: A longitudinal, exploratory voxel-based morphometric study. Schizophr. Res. 2006; 82: 8994. 73 Lu LX, Guo SQ, Chen W, Li Q, Cheng J, Guo JH. Effect of clozapine and risperidone on serum cytokine levels in patients with rst-episode paranoid schizophrenia. Academic journal of the rst medical college of PLA. Di Yi Jun Yi Da Xue Xue Bao 2004; 24: 12511254 (in Chinese). 74 Miyaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J. Possible antipsychotic effects of minocycline in patients with schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2007; 31: 304307. 75 Miyaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J. Minocycline as adjunctive therapy for schizophrenia: An open-label study. Clin. Neuropharmacol. 2008; 31: 287292. 76 Kowalski J, Labuzek K, Herman ZS. Flupentixol and triuperidol reduce secretion of tumor necrosis factor-alpha and nitric oxide by rat microglial cells. Neurochem. Int. 2003; 43: 173178. 77 Kowalski J, Labuzek K, Herman ZS. Flupentixol and triuperidol reduce interleukin-1 beta and interleukin-2 release by rat mixed glial and microglial cell cultures. Pol. J. Pharmacol. 2004; 56: 563570. 78 Labuzek K, Kowalski J, Gabryel B, Herman ZS. Chlorpromazine and loxapine reduce interleukin-1beta and interleukin-2 release by rat mixed glial and microglial cell cultures. Eur. Neuropsychopharmacol. 2005; 15: 2330.

79 Hou Y, Wu CF, Yang JY et al. Effects of clozapine, olanzapine and haloperidol on nitric oxide production by lipopolysaccharide-activated N9 cells. Prog. Neuropsychopharmacol. Biol. Psychiatry 2006; 30: 15231528. 80 Kato T, Monji A, Hashioka S, Kanba S. Risperidone signicantly inhibits interferon-gamma-induced microglial activation in vitro. Schizophr. Res. 2007; 92: 108115. 81 Bian Q, Kato T, Monji A et al. The effect of atypical antipsychotics, perospirone, ziprasidone and quetiapine on microglial activation induced by interferon-gamma. Prog. Neuropsychopharmacol. Biol. Psychiatry 2008; 32: 4248. 82 Kato T, Mizoguchi Y, Monji A et al. Inhibitory effects of aripiprazole on interferon-gamma-induced microglial activation via intracellular Ca2+ regulation in vitro. J. Neurochem. 2008; 106: 815825. 83 Zheng LT, Hwang J, Ock J, Lee MG, Lee WH, Suk K. The antipsychotic spiperone attenuates inammatory response in cultured microglia via the reduction of proinammatory cytokine expression and nitric oxide production. J. Neurochem. 2008; 107: 12251235. 84 Schwarz MJ, Muller N, Riedel M, Ackenheil M. The Th2hypothesis of schizophrenia: A strategy to identify a subgroup of schizophrenia caused by immune mechanisms. Med. Hypotheses 2001; 56: 483486. 85 Rothermundt M, Arolt V, Bayer TA. Review of immunological and immunopathological ndings in schizophrenia. Brain Behav. Immun. 2001; 15: 319339. 86 Cazzullo CL, Sacchetti E, Galluzzo A et al. Cytokine proles in drug-naive schizophrenic patients. Schizophr. Res. 2001; 47: 293298. 87 Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007; 30: 527535. 88 Lu XH, Dwyer DS. Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12 cells via PI3K/AKT, ERK, and pertussis toxin-sensitive pathways. J. Mol. Neurosci. 2005; 27: 43 64. 89 Suzuki T, Hide I, Matsubara A et al. Microglial alpha7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role. J. Neurosci. Res. 2006; 83: 14611470. 90 Lieberman JA, Javitch JA, Moore H. Cholinergic agonists as novel treatments for schizophrenia: The promise of rational drug development for psychiatry. Am. J. Psychiatry 2008; 165: 931936. 91 Raison CL, Capuron L, Miller AH. Cytokines sing the blues: Inammation and the pathogenesis of depression. Trends Immunol. 2006; 27: 2431. 92 Tyring S, Gottlieb A, Papp K et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: Doubleblind placebo-controlled randomised phase III trial. Lancet 2006; 367: 2935. 93 Knight JG, Menkes DB, Highton J, Adams DD. Rationale for a trial of immunosuppressive therapy in acute schizophrenia. Mol. Psychiatry 2007; 12: 424431.

2009 The Authors Journal compilation 2009 Japanese Society of Psychiatry and Neurology