<p class="frontmatter-fieldnotes disclaimernew" style="margin-bottom:15px;">This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s <a href="/pages/termsofuse.aspx" target="_blank">Terms & Conditions</a>.</p> <div id="_idContainer000"> 
  <p class="ltrs-br-ltr-br-title"><span class="bold"><a id="_idTextAnchor000"></a>Disequilibrium of Cytokine Serum Levels in Veterans With Chronic Schizophrenia Medicated With Antipsychotics: Association With Measures of Excitement and Hostility</span></p>
  <p class="ltrs-br-ltr-br-body-text"><span class="semibold">To the Editor:</span> In 2013, we published a study<span class="htm-cite"><a href="#ref1">1</a></span> of the levels of serum cytokines from 47 patients with schizophrenia and 20 healthy controls. We found significantly increased levels of GRO, MCP-1, MDC, and sCD40 L and significantly decreased levels of IFN-γ, IL-2, IL-12p70, and IL-17 in schizophrenia patients compared to controls. We also identified a potential role for the IL-17 pathway in worsening of schizophrenia symptoms.<span class="htm-cite"><a href="#ref1">1</a></span> We now have expanded this study by enrolling an additional 24 patients. Further, we obtained sequential samples and psychometric measures from 35 patients at a second visit, and 18 patients at a third visit. We hypothesized that cytokines within the Th17 pathway and their ratios to each other would be linked to distinct symptoms of psychopathology as measured by Positive and Negative Syndrome Scale (PANSS)<span class="htm-cite"><a href="#ref2">2</a></span> scores. We utilized the total PANSS scores, general psychopathology scores, negative scale scores, and positive scale scores and the individual positive subscale symptoms: delusions, hallucinatory behavior, suspiciousness/persecution, conceptual disorganization, excitement, grandiosity, and hostility.</p>
  <p class="ltrs-br-ltr-br-body-text">&nbsp;</p>
  <p class="ltrs-br-ltr-br-body-text"><span class="semibold-ital">Method.</span> In patients, symptom severity was evaluated using the PANSS. Cytokine/chemokine levels were tested with Millipore bead–based flow immunoassays in a Luminex 100 system (Luminex Corporation, Austin, Texas). The levels of 38 cytokines at each visit were correlated with PANSS scores. All statistical analyses were performed using SAS version 9.3 (SAS Institute Inc, Cary, North Carolina). A <span class="italic">P</span> value &lt;<span class="thinspace"> </span>.05 was considered to be statistically different for all comparisons.</p>
  <p class="ltrs-br-ltr-br-body-text"><span class="semibold-ital">Results.</span> Subject demographics included 34.3% Hispanic, 44.3% white, 17.1% black, and 4.3% Asian. The mean<span class="thinspace"> </span>±<span class="thinspace"> </span>SD patient age was 53.7<span class="thinspace"> </span>±<span class="thinspace"> </span>10.4 years and control age was 41<span class="thinspace"> </span>±<span class="thinspace"> </span>11.6 years. Gender distribution was 84% male and 16% female. No statistically significant differences in gender, ethnicity, body mass index, or weight were found between groups. All patients had a long-standing diagnosis of chronic paranoid schizophrenia and were undergoing treatment with antipsychotic medications. Of the patients, 35 (49.29%) were also treated with antidepressants. The mean<span class="thinspace"> </span>±<span class="thinspace"> </span>SD PANSS scores in patients were 21.5<span class="thinspace"> </span>+<span class="thinspace"> </span>8.5 for positive symptoms, 21.9<span class="thinspace"> </span>±<span class="thinspace"> </span>7 for negative symptoms, 40.8<span class="thinspace"> </span>±<span class="thinspace"> </span>11 for general psychopathology symptoms, and 83.7<span class="thinspace"> </span>±<span class="thinspace"> </span>24.2 for total scores. Clinical factors of illness (currently hospitalized or not, in-patient or out-patient), treatment with antidepressants, history of posttraumatic stress disorder, or substance abuse did not associate with psychopathology.</p>
  <p class="ltrs-br-ltr-br-body-text">By performing the Hochberg method for multiple testing, 4 molecules were found to be increased in patients across all 3 visits: GRO, MCP-1, MDC, and sCD40 L. Levels of IFN-γ were decreased in patients compared to controls across all 3 time points. IL-17 levels were reduced only at visit 1, while levels of IL-4 were significantly decreased only at visit 3 (<span class="callout"><a href="#" onclick="createFigure('t1'); return false;">Table 1</a></span>).</p>
  <div id="figure-2"> <a href="#" onclick="createFigure('t1'); return false;"><img src="15l01812T1.gif" alt="Table 1" id="t1" border="0" /></a>
    <p class="click-to-enlarge">Click figure to enlarge</p>
  </div>
  <p class="ltrs-br-ltr-br-body-text">We established a significant correlation between IL-4 and hostility at visit 1 and visit 2 with adjusted <span class="italic">P</span> values of .0028 and .0152 using the Hochberg method. There was also a significant correlation between IL-1β and excitement at visit 1 with an adjusted <span class="italic">P</span> value of .0228 using the Hochberg method (<span class="callout"><a href="#" onclick="createFigure('t2'); return false;">Table 2</a></span>).</p>
  <div id="figure"class="right"> <a href="#" onclick="createFigure('t2'); return false;"><img src="15l01812T2.gif" alt="Table 2" id="t2" border="0" /></a>
    <p class="click-to-enlarge">Click figure to enlarge</p>
  </div>
  <p class="ltrs-br-ltr-br-body-text">The ratios of IL-2:IL-17, IL-4:IL-17, and IL-1β:IL-17 were associated with hostility in veterans with schizophrenia compared to control subjects. The ratio of IL-4:IL-17 was also associated with excitement. The adjusted <span class="italic">P</span> values of the above ratios using the Hochberg method were significant (<span class="callout"><a href="#" onclick="createFigure('t2'); return false;">Table 2</a></span>).</p>
  <p class="ltrs-br-ltr-br-body-text">&nbsp;</p>
  <p class="ltrs-br-ltr-br-body-text">Limitations of this study include the relatively small sample size. Also, we were unable to control for the effects of antipsychotic medications, which may modulate cytokine levels. Importantly, a higher proportion of Th17 cells and elevated plasma levels of IL-17 were described in drug-naive patients with a first episode of schizophrenia.<span class="htm-cite"><a href="#ref3">3</a>,<a href="#ref4">4</a></span> However, after 4 weeks of risperidone treatment, there was a trend toward decreased plasma levels of IL-17.<span class="htm-cite"><a href="#ref3">3</a></span></p>
  <p class="ltrs-br-ltr-br-body-text">Our findings of decreased levels of IL-4, IL-17, and IL12p70 are in agreement with previous studies.<span class="htm-cite"><a href="#ref5">5</a>,<a href="#ref6">6</a></span> When the levels of IFN-γ and IL-2 are low, the production of IL-17 is suppressed.<span class="htm-cite"><a href="#ref6">6</a></span> Further, differentiation of naive T cells (To) to Th17 is mediated by IL-12 and IFN-γ.<span class="htm-cite"><a href="#ref6">6</a></span> The low levels of IL-17 we observed could be influenced by the low levels of IL12p70, IL-2, or IFN-γ.<span class="htm-cite"><a href="#ref7">7</a></span> Also, it is possible that the observed dysregulation of cytokines in veterans with chronic schizophrenia could be due to treatment with antipsychotics.</p>
  <p class="ltrs-br-ltr-br-body-text">Importantly, levels of GRO, MCP-1, MDC, and sCD40 L were significantly elevated across all 3 visits. MCP-1 mediates the transendothelial migration of inflammatory cells across the blood-brain barrier and modulates local inflammatory response by inducing production of IL-4.<span class="htm-cite"><a href="#ref8">8</a></span> Increased levels of IL-4 may reduce the production of IL-17.<span class="htm-cite"><a href="#ref7">7</a></span></p>
  <p class="ltrs-br-ltr-br-body-text">In conclusion, our results indicate that there is a link between imbalance of cytokine levels and psychopathology in veterans with chronic schizophrenia treated with antipsychotics. When the psychopathology was analyzed by the separate items of the positive subscale of the PANSS, we found that serum levels of IL-4 may correlate with hostility and IL-1β may correlate with excitement. We suggest that such an approach should be explored further.</p>
<p class="references_references-heading">REFERENCES</p>
  <p class="references-references-text-1-9"><a name="ref1"></a><span class="htm-ref"> 1.&#9;</span>Dimitrov DH, Lee S, Yantis J, et al. Differential correlations between inflammatory cytokines and psychopathology in veterans with schizophrenia: potential role for IL-17 pathway. <span class="italic">Schizophr Res</span>. 2013;151(1-3):29–35. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=24210870&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a> <a href="http://dx.doi.org/10.1016/j.schres.2013.10.019"><span class="pubmed-crossref">doi:10.1016/j.schres.2013.10.019</span></a></p>
  <p class="references-references-text-1-9"><a name="ref2"></a><span class="htm-ref"> 2.&#9;</span>Kay S, Opler LA, Fizbein A, et al. <span class="italic">Positive and Negative Syndrome Scale (PANSS) Technical Manual</span>. Toronto, Ontario, Canada: Multi-Health Systems Inc; 2006.</p>
  <p class="references-references-text-1-9"><a name="ref3"></a><span class="htm-ref"> 3.&#9;</span>Ding M, Song X, Zhao J, et al. Activation of Th17 cells in drug naive, first-episode schizophrenia. <span class="italic">Prog Neuropsychopharmacol Biol Psychiatry</span>. 2014;51:78–82. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=24447943&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a> <a href="http://dx.doi.org/10.1016/j.pnpbp.2014.01.001"><span class="pubmed-crossref">doi:10.1016/j.pnpbp.2014.01.001</span></a></p>
  <p class="references-references-text-1-9"><a name="ref4"></a><span class="htm-ref"> 4.&#9;</span>El Kissi Y, Samoud S, Mtiraoui A, et al. Increased interleukin-17 and decreased BAFF serum levels in drug-free acute schizophrenia. <span class="italic">Psychiatry Res</span>. 2015;225(1–2):58–63. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=25453636&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a> <a href="http://dx.doi.org/10.1016/j.psychres.2014.10.007"><span class="pubmed-crossref">doi:10.1016/j.psychres.2014.10.007</span></a></p>
  <p class="references-references-text-1-9"><a name="ref5"></a><span class="htm-ref"> 5.&#9;</span>Borovcanin M, Jovanovic I, Radosavljevic G, et al. Elevated serum level of type-2 cytokine and low IL-17 in first-episode psychosis and schizophrenia in relapse. <span class="italic">J&#160;Psychiatr Res</span>. 2012;46(11):1421–1426. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=22974591&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a> <a href="http://dx.doi.org/10.1016/j.jpsychires.2012.08.016"><span class="pubmed-crossref">doi:10.1016/j.jpsychires.2012.08.016</span></a></p>
  <p class="references-references-text-1-9"><a name="ref6"></a><span class="htm-ref"> 6.&#9;</span>Weaver CT, Hatton RD, Mangan PR, et al. IL-17 family cytokines and the expanding diversity of effector T cell lineages. <span class="italic">Annu Rev Immunol</span>. 2007;25(1):821–852. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=17201677&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a> <a href="http://dx.doi.org/10.1146/annurev.immunol.25.022106.141557"><span class="pubmed-crossref">doi:10.1146/annurev.immunol.25.022106.141557</span></a></p>
  <p class="references-references-text-1-9"><a name="ref7"></a><span class="htm-ref"> 7.&#9;</span>Sarkar S, Tesmer LA, Hindnavis V, et al. Interleukin-17 as a molecular target in immune-mediated arthritis: immunoregulatory properties of genetically modified murine dendritic cells that secrete interleukin-4. <span class="italic">Arthritis Rheum</span>. 2007;56(1):89–100. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=17195211&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a> <a href="http://dx.doi.org/10.1002/art.22311"><span class="pubmed-crossref">doi:10.1002/art.22311</span></a></p>
  <p class="references-references-text-1-9"><a name="ref8"></a><span class="htm-ref"> 8.&#9;</span>Reale M, Patruno A, De Lutiis MA, et al. Dysregulation of chemo-cytokine production in schizophrenic patients versus healthy controls. <span class="italic">BMC Neurosci</span>. 2011;12(1):13–22. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=21266029&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a> <a href="http://dx.doi.org/10.1186/1471-2202-12-13"><span class="pubmed-crossref">doi:10.1186/1471-2202-12-13</span></a></p>
  <p class="ltrs-br-ltr-br-author"><span class="bold">Dimitre H. Dimitrov, MD</span></p>
  <p class="ltrs-br-ltr-br-author"><a href="mailto:dimitre.dimitrov@va.gov">dimitre.dimitrov@va.gov</a></p>
  <p class="ltrs-br-ltr-br-author"><span class="bold">Shuko Lee, MS</span></p>
  <p class="ltrs-br-ltr-br-author"><span class="bold">Jesse Yantis, RN</span></p>
  <p class="ltrs-br-ltr-br-author"><span class="bold">Craig Honaker, RN</span></p>
  <p class="ltrs-br-ltr-br-author"><span class="bold">Roberta Coelho, PhD</span></p>
  <p class="ltrs-br-ltr-br-author"><span class="bold">Nicole Braida, MD</span></p>
  <p class="ltrs-br-ltr-br-author"><span class="bold">Consuelo Walss-Bass, PhD</span></p>
  <p class="end-matter"><span class="bold-italic">Author affiliations:</span> South Texas Veterans Health Care System, San Antonio (Drs Dimitrov and Braida, Ms Lee, and Messrs Yantis and Honaker); Department of Psychiatry, University of Texas Health Science Center at San Antonio (Drs Dimitrov, Coelho, Braida, and Walss-Bass); Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston (Dr Walss-Bass); and Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil (Dr Coelho).</p>
  <p class="end-matter"><span class="bold-italic">Potential conflicts of interest:</span> None reported.</p>
  <p class="end-matter"><span class="bold-italic">Funding/support:</span> The research was supported by a New Investigator Award grant to Dr Dimitrov from the VISN 17 of the Department of Veterans Affairs.</p>
  <p class="end-matter"><span class="bold-italic">Role o</span><span class="bold-italic">f t</span><span class="bold-italic">he sponsor: </span>The funding organization had no role in the design or conduct of the study.</p>
  <p class="end-matter"><span class="bold-italic">Published online:</span> November 5, 2015.</p>
  <p class="end-matter"><span class="italic">Prim Care Companion CNS Disord 2015;17(6):</span><span class="doi italic">doi:10.4088/PCC.15l01812</span></p>
  <p class="end-matter"><span class="italic">© Copyright 2015 Physicians Postgraduate Press, Inc.</span></p>
</div>