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Cytokines & Schizophrenia

Cytokines & Schizophrenia. Dr. Yaron Gilat. Numerous immunological findings in schizophrenia. Lymphocyte populations. Antibodies; - nonspecific (i.e. ANA) - specific (i.e. anti-brain) Complement. HLA associations. Cytokine imbalances.

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Cytokines & Schizophrenia

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  1. Cytokines & Schizophrenia Dr. Yaron Gilat

  2. Numerous immunological findings in schizophrenia • Lymphocyte populations. • Antibodies; - nonspecific (i.e. ANA) - specific (i.e. anti-brain) • Complement. • HLA associations. • Cytokine imbalances.

  3. The cytokine network

  4. CNS & Cytokines • Cells of the CNS produce cytokines, such as IL-1, IL-2, IL-6, TNF a and IFN g. • TNF a is produced by neurons innervating the regulatory centers of the hypothalamus where it may function both as an inflammatory cytokine and a neurotransmitter. Naudin et al, 1997. Schizophr Res.

  5. CNS & Cytokines • TNF a promotes nerve cell growth differentiation and survival, and is also cytotoxic to oligodendrocytes. • IL-2 stimulates dopamine release from rats striatal and mesencephalic cells. • Cancer patients treated with high recombinant IL-2 doses exhibited hallucinations and delusions that responded to haloperidol treatment. Monteleone et al, 1997. Psychiatry Res

  6. CNS & Cytokines • IL-6 belongs to the “neurotrophic cytokines” that probably promote recovery after injury or infection and may play a role in both development and functioning of neurons. Naudin et al, 1997. Schizophr Res.

  7. CNS & Cytokines • TNF a and IL-1 poses somnogenic activity. • TNF a, IL-1b and IL-8 may suppress appetite. • IL-1, IL-2 and IL-6 treated mice displayed significant differences in exploration. Erbagci et al, 2001. Mediators Inflamm

  8. CNS & Cytokines • Acute TNF a release stimulates the catecholaminergic system, while chronic TNF a release inhibits catecholamines secretion. Soliven B et al, 1992. J Neurochem.

  9. CNS & Cytokines In mice: • IL-1enhances NE turnover in the hypothalamus and hippocampus, 5-HT turnover in the hippocampus and prefrontal cortex and enhances DA utilization in the prefrontal cortex. • IL-6 increases 5-HT and DA activity in the hippocampus and prefrontal cortex. • IL-2 increases hypothalamic NE turnover and enhances DA turnover in the prefrontal cortex. Zalcman S et al, 1994. Brain Res. DA: Dopamine, NE: Norepinephrine, 5-HT: 5-Hydroxytriptamine

  10. CNS & Cytokines • Astrocytes and microglia poses receptors for IL-1b, TNF a and IL-6. • IL-1b and TNF a are actively transported across the blood-brain barrier by a saturable transport mechanism. • Activation of microglia by IL-1b and TNF a may stimulate IL-2 release, thus increasing dopaminergic activity. Kowalski et al, 2001. Schizophr Res

  11. Explored cytokines in schizophrenia • Interleukin – 1 a, b (& Soluble Il - 1 receptor). • Interleukin – 2 (& Soluble Il - 2 receptor). • Interleukin – 3. • Interleukin – 4. • Interleukin – 6 (& Soluble Il - 6 receptor). • Interleukin – 8. • Interleukin – 10. • Interleukin – 18. • Interferon (IFN)a, g. • Tumor necrosis factor (TNF) a(& TNFreceptor). • Most explored.

  12. Interleukin- 2 • Higher levels in schizophrenics sera(Zhang, 2005. Neuropsychpharmacology; Zhang, 2004. J Clin Psychiatry; Zhang, 2002. Schizophr Res; Ebrinc, 2002. J Int Med Res; Kim, 2000. Schizophr Res; Rothermundt, 1998. Neuropsychobiology) • Higher levels in schizophrenics CSF(McAllister, 1995. Am J Psychiatry; Licinio, 1993. Am J Psychiatry) • Higher in-vitro production(Cazzullo, 2001. Schizophr Res; O’Donnell, 1996. Psychiatry Res)

  13. Interleukin - 2 • Lower levels in schizophrenics sera(Mahendran, 2004. Ann Acad Med Singapore; Thodoropoulou, 2001. Schizophr Res; Arolt, 2000. Mol Psychiatry) • Lower levels in schizophrenics CSF(el-Mallakh, 1993. Prog Neuropsychopharmacol Biol Psychiatry) • Lower in-vitro production(Kowalski, 2000. World J Biol Psychiatry; Bessler, 1995. Biol Psychiatry; Ganguli, 1995. Arch Gen Psychiatry; Hornberg, 1995. Schizophr Res; Villemain, 1989. Am J Psychiatry)

  14. Interleukin - 2; Clinical correlations • Negative correlation between high serum levels and PANSS positive subscore(Zhang, 2005. Neuropsychpharmacology; Zhang, 2002. Schizophr Res). • Negative correlation between increased in-vitro production and bizarre behavior and formal thought disorder(O’Donnell, 1996. Psychiatry Res). • Positive correlation between high serum levels and positive symptoms(Kim, 2000. Schizophr Res). • Higher CSF levels in relapse-prone patients(McAllister, 1995. Am J Psychiatry).

  15. Interleukin - 2; Clinical correlations • Lower in-vitro production in patients with a predominance of positive symptoms(Kowalski, 2000. World J Biol Psychiatry). • Lower in-vitro production in paranoid patients(Wilke, 1996. Eur Arch Psychiatry Clin Neurosci). • Positive correlation between in-vitro production and age of onset, negative correlation between in-vitro production and negative symptoms(Ganguli, 1995. Arch Gen Psychiatry).

  16. Soluble Il - 2 receptor • Higher levels in schizophrenics sera (Gaughran, 1998. Schizophr Res; Barak, 1995. J Basic Clin Physiol Pharmacol; Maes, 1995. Eur Arch Psychiatry Clin Neurosci; Rapaport, 1994. Acta Psychiatr Scand; Rapaport, 1994. Biol Psychiatry; Rapaport, 1993. Eur Arch Psychiatry Clin Neurosci; Rapaport, 1989. Arch Gen Psychiatry; Ganguli, 1989. Arch Gen Psychiatry; Akiyama, 1999. Schizophr Res; Wilke, 1996. Eur Arch Psychiatry Clin Neurosci) • Lower levels in schizophrenics CSF(Barak, 1995. J Basic Clin Physiol Pharmacol; • Higher in-vitro production (Hornberg, 1995. Schizophr Res) • Lower in-vitro production (Kowalski, 2000. World J Biol Psychiatry).

  17. sIl-2 receptor; clinical correlations • Increased serum levels in 1st degree relatives of schizophrenic patients(Gaughran, 2002. Schizophr Res). • Increased serum levels in schizophrenic concordant and discordant monozygotic twins(Rapaport, 1993. Eur Arch Psychiatry Clin Neurosci). • Increased serum levels in tardive dyskinesia(Rapaport, 1994. Acta Psychiatr Scand)

  18. sIl-2 receptor; clinical correlations • Significantly increased levels in younger (< 35 y) patients(Maes, 1994. Acta Psychiatr Scand). • Lower in-vitro production in patients with a predominance of positive symptoms(Kowalski, 2000. World J Biol Psychiatry). • Higher in-vitro production associated with poor prognosis assesment(Kowalski, 2000. World J Biol Psychiatry).

  19. Interleukin - 6 • Higher levels in schizophrenics sera(Zhang, 2005. Neuropsychpharmacology; Zhang, 2004. J Clin Psychiatry; Zhang, 2002. Schizophr Res; van Kammen, 1999. Psychiatry Res; Akiyama, 1999. Schizophr Res; Lin, 1998. Schizophr Res; Frommberger, 1997. Eur Arch Psychiatry Clin Neurosci; Naudin, 1996, 1997. Schizophr Res; Maes, 1995. J psychiatr Res; Ganguli, 1994. Psychiatry Res; Shintani, 1991. Life Sci; Maes, 1994. Acta Psychiatr Scand) • Higher levels in schizophrenics CSF (Graver, 2003. Neuropsychopharmacology)

  20. Interleukin - 6 • Similarplasma concentration as in healthy controls (Erbagci, 2001. Mediators Inflamm; Haack, 1999. J Psychiatr Res;Kim, 1998. Biol Psychiatry; Monteleone, 1997. Psychiatry Res; Baker, 1996. Schizophr Res; Barak, 1995. J Basic Clin Physiol Pharmacol; Katila, 1994. Schizophr Res) • SimilarCSF concentration as in healthy controls (Katila, 1994. Neuropsychobiology; Barak, 1995. J Basic Clin Physiol Pharmacol)

  21. Interleukin - 6; Clinical correlations • Significantly higher CSF levels in delayed responders* vs poor responders or controls(Graver, 2003. Neuropsychopharmacology). • Significantly higher serum levels in treatment resistant patients(Lin, 1998. Schizophr Res). • Higher serum levels in acute exacerbation vs remission(Naudin, 1996. Schizophr Res; Frommberger, 1997. Eur Arch Psychiatry Clin Neurosci(. • Delayed responder: 60% or more improvement in positive symptoms scale from • drug-free baseline, following >1 year of neuroleptic treatment. Poor responder: < 60%.

  22. Interleukin - 6; Clinical correlations • Positive correlation between high serum levels and negative symptoms(Kim, 2000. Schizophr Res). • Positive correlation between high serum levels and duration of illness(Akiyama, 1999. Schizophr Res; Naudin, 1997. Schizophr Res; Ganguli, 1994. Psychiatry Res; Monteleone, 1997. Psychiatry Res) • Higher serum levels in neuroleptic malignant syndrome (case report)(Kaminska, 2003. Med Sci Monit).

  23. Tumor necrosis factor (TNF) • Higher TNFa levels in schizophrenics sera(Thodoropoulou, 2001. Schizophr Res; Naudin, 1997. Schizophr Res; Monteleone, 1997. Psychiatry Res; Monteleone, 1997. Psychiatry Res) • Higher in-vitro production of TNFa (Kowalski, 2001. Schizophr Res)

  24. Tumor necrosis factor (TNF) • SimilarTNFaplasma concentration as in healthy controls (Erbagci, 2001. Mediators Inflamm; Haack, 1999. J Psychiatr Res; Baker, 1996. Schizophr Res; Naudin, 1996. Schizophr Res; Barak, 1995. J Basic Clin Physiol Pharmacol) • SimilarTNFaCSF concentration as in healthy controls (Barak, 1995. J Basic Clin Physiol Pharmacol)

  25. TNFa; Clinical correlations • Positive correlation between serum levels and positive symptoms(Erbagci, 2001. Mediators Inflamm) • Higher serum levels in neuroleptic malignant syndrome (case report)(Kaminska, 2003. Med Sci Monit). • No correlation between positive and negative symptoms and TNFa serum levels(Naudin, 1997. Schizophr Res; Monteleone, 1997. Psychiatry Res; Baker, 1996. Schizophr Res)

  26. Conflicting results may originate from • Small sample sizes. • Variability in assays sensitivity. • Cytokine stability & freezing periods. • Clinical status (exacerbation vs remission). • Medication status (receiving/ not receiving anti-psychotics, known to affect cytokine levels). • The assumption that schizophrenia is a homogenous disorder. Graver, 2003. Neuropsychopharmacology; Baker, 1996. Schizophr Res.

  27. Conflicting results may also originate from • “…cytokines and soluble cytokine receptors are very sensitive to a number of confounding factors such as age, gender, smoking habits…”. • “…other medical conditions coexisting with psychiatric disorders, e.g. infectious or inflammatory diseases, obesity, pulmonary, cardiac and endocrine diseases are accompanied by altered cytokine levels or production and, therefore, may have confounding effects”. Haack, 1999. J Psychiatr Res.

  28. Immunomo-inhibitory treatment trials

  29. COX-2 inhibition as a treatment approach in schizophrenia: Immunological considerations and clinical effects of celecoxib add-on therapy • 50 schizophrenic patients; 25 (11 f, 14m) randomly assigned to a 35 days risperidone & celecoxibtreatment group, and 25 (14 f, 11m) to a 35 days risperidone & placebo group. • All were hospitalized inpatients due to an acute exacerbation of their psychoses. • Therapy with 400 mg celecoxib was well tolerated,and no clinically important side effects were observed. Muller et al. Eur Arch Psychiatry Clin Neurosci (2004) 254 : 14–22

  30. COX-2 inhibition as a treatment approach in schizophrenia: Immunological considerations and clinical effects of celecoxib add-on therapy The celecoxib add-on therapy had a significant effect on the mean improvement in total PANSS score and resulted in an earlier improvement in all subscales. Muller et al. Eur Arch Psychiatry Clin Neurosci (2004) 254 : 14–22

  31. COX-2 inhibition as a treatment approach in schizophrenia: Immunological considerations and clinical effects of celecoxib add-on therapy • The responders to celecoxib had significantly lower sTNF-receptor levels before the start of the therapy. Muller et al. Eur Arch Psychiatry Clin Neurosci (2004) 254 : 14–22

  32. COX-2 inhibition as a treatment approach in schizophrenia: Immunological considerations and clinical effects of celecoxib add-on therapy • The celecoxib group had a significant relationship between the decrease of CD19+ B lymphocytes and the decrease of the PANSS negative-scale. Muller et al. Eur Arch Psychiatry Clin Neurosci (2004) 254 : 14–22

  33. Treatment of Schizophrenia With an Immunosuppressant. • 52 y old paranoid schizophrenia patient. • Also diagnosed with SLE and hypothyroid. • Non-responsive to lithium and neuroleptics. • Received 3 months Azathioprine Tx. • Substantive improvement in psych. condition followed reduction in anti-platelet Ab’s level. • Not related to lupus status nor to the anti-lupus effect of azathioprine. Levine et al, 1994. The Lancet

  34. Treatment of Schizophrenia With an Immunosuppressant. Levine et al, 1994. The Lancet

  35. Side Effect Profile of Azathioprine Treatment of Chronic Schizophrenic Patient. • 11 chronic non-responsive schiz. pt. • High levels of anti-platelet Ab’s. • 7/14 weeks of Azathioprine Tx. • Reduction in anti-platelet Ab’s level observed in 7 pt. • Improvement in psych. condition in 2 pt. • Leukopenia in 2 pt. J Levine,1997.Neuropsychobiology

  36. Improvement in Negative Symptoms of Schizophrenia With Antibodies to Tumor Necrosis Factor-alpha and to Interferon gamma: A Case Report • 56 y old residual schizophrenia patient. • Mainly negative symptoms. • Tx. with anti-TNF a and anti-IFN g. • Notable decrease in negative symptoms by 1st week. • Strong correlation to TNF a levels. Skurkovich et al, 2003. J Clin psychiatry

  37. Improvement in Negative Symptoms of Schizophrenia With Antibodies to Tumor Necrosis Factor-alpha and to Interferon gamma: A Case Report Skurkovich et al, 2003. J Clin psychiatry

  38. Thank you.

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