Annalisa Giordano

Cortisol and Inflammatory Biomarkers Predict Poor Treatment Response in First Episode Psychosis

Background: Cortisol and inflammatory markers have been increasingly reported as abnormal at psychosis onset. The main aim of our study was to investigate the ability of these biomarkers to predict treatment response at 12 weeks follow-up in first episode psychosis. Methods: In a longitudinal study, we collected saliva and blood samples in 68 first episode psychosis patients (and 57 controls) at baseline and assessed response to clinician-led antipsychotic treatment after 12 weeks. Moreover, we repeated biological measurements in 39 patients at the same time we assessed the response. Saliva samples were collected at multiple time points during the day to measure diurnal cortisol levels and cortisol awakening response (CAR); interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-α, and interferon-γ (IFN-γ) levels were analyzed from serum samples. Patients were divided into Non-Responders (n = 38) and Responders (n = 30) according to the Remission symptom criteria of the Schizophrenia Working Group Consensus. Results: At first onset, Non-Responders had markedly lower CAR (d = 0.6, P = .03) and higher IL-6 and IFN-γ levels (respectively, d = 1.0, P = .003 and d = 0.9, P = .02) when compared with Responders. After 12 weeks, Non-Responders show persistent lower CAR (P = .01), and higher IL-6 (P = .04) and IFN-γ (P = .05) when compared with Responders. Comparison with controls show that these abnormalities are present in both patients groups, but are more evident in Non-Responders. Conclusions: Cortisol and inflammatory biomarkers at the onset of psychosis should be considered as possible predictors of treatment response, as well as potential targets for the development of novel therapeutic agents.

Globally Efficient Brain Organization and Treatment Response in Psychosis: A Connectomic Study of Gyrification

Background: Converging evidence suggests that patients with first-episode psychosis who show a poor treatment response may have a higher degree of neurodevelopmental abnormalities than good Responders. Characterizing the disturbances in the relationship among brain regions (covariance) can provide more information on neurodevelopmental integrity than searching for localized changes in the brain. Graph-based connectomic approach can measure structural covariance thus providing information on the maturational processes. We quantified the structural covariance of cortical folding using graph theory in first-episode psychosis, to investigate if this systems-level approach would improve our understanding of the biological determinants of outcome in psychosis. Methods: Magnetic Resonance Imaging data were acquired in 80 first-episode psychosis patients and 46 healthy controls. Response to treatment was assessed after 12 weeks of naturalistic follow-up. Gyrification-based connectomes were constructed to study the maturational organization of cortical folding. Results: Nonresponders showed a reduction in the distributed relationship among brain regions (high segregation, poor integration) when compared to Responders and controls, indicating a higher burden of aberrant neurodevelopment. They also showed reduced centrality of key regions (left insula and anterior cingulate cortex) indicating a marked reconfiguration of gyrification. Nonresponders showed a vulnerable pattern of covariance that disintegrated when simulated lesions removed high-degree hubs, indicating an abnormal dependence on highly central hub regions in Nonresponders. Conclusions: These findings suggest that a perturbed maturational relationship among brain regions underlies poor treatment response in first-episode psychosis. The information obtained from gyrification-based connectomes can be harnessed for prospectively predicting treatment response and prognosis in psychosis.

The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial

Summary Background The antibiotic minocycline has neuroprotective and anti-inflammatory properties that could prevent or reverse progressive neuropathic changes implicated in recent-onset schizophrenia. In the BeneMin study, we aimed to replicate the benefit of minocycline on negative symptoms reported in previous pilot studies, and to understand the mechanisms involved. Methods In this randomised, double-blind, placebo-controlled trial, we recruited people with a schizophrenia-spectrum disorder that had begun within the past 5 years with continuing positive symptoms from 12 National Health Service (NHS) trusts. Participants were randomly assigned according to an automated permuted blocks algorithm, stratified by pharmacy, to receive minocycline (200 mg per day for 2 weeks, then 300 mg per day for the remainder of the 12-month study period) or matching placebo, which were added to their continuing treatment. The primary clinical outcome was the negative symptom subscale score of the Positive and Negative Syndrome Scales (PANSS) across follow-ups at months 2, 6, 9, and 12. The primary biomarker outcomes were medial prefrontal grey-matter volume, dorsolateral prefrontal cortex activation during a working memory task, and plasma concentration of interleukin 6. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN49141214, and the EU Clinical Trials register (EudraCT) number is 2010-022463-35I. Findings Between April 16, 2013, and April 30, 2015, we recruited 207 people and randomly assigned them to receive minocycline (n=104) or placebo (n=103). Compared with placebo, the addition of minocycline had no effect on ratings of negative symptoms (treatment effect difference −0·19, 95% CI −1·23 to 0·85; p=0·73). The primary biomarker outcomes did not change over time and were not affected by minocycline. The groups did not differ in the rate of serious adverse events (n=11 in placebo group and n=18 in the minocycline group), which were mostly due to admissions for worsening psychiatric state (n=10 in the placebo group and n=15 in the minocycline group). The most common adverse events were gastrointestinal (n=12 in the placebo group, n=19 in the minocycline group), psychiatric (n=16 in placebo group, n=8 in minocycline group), nervous system (n=8 in the placebo group, n=12 in the minocycline group), and dermatological (n=10 in the placebo group, n=8 in the minocycline group). Interpretation Minocycline does not benefit negative or other symptoms of schizophrenia over and above adherence to routine clinical care in first-episode psychosis. There was no evidence of a persistent progressive neuropathic or inflammatory process underpinning negative symptoms. Further trials of minocycline in early psychosis are not warranted until there is clear evidence of an inflammatory process, such as microgliosis, against which minocycline has known efficacy. Funding National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.

T46. TARGETING THE IMMUNE SYSTEM TO TREAT DEPRESSION AND NEGATIVE SYMPTOMS IN SCHIZOPHRENIA

Abstract Background Negative symptoms consist of impaired quality of life, social isolation, reduced emotional responsiveness, self-neglect and anhedonia, which have been categorised into avolition-apathy and expressive deficits sub-domains. The treatment of negative symptoms remains a challenge. Depression is commonly seen in schizophrenia and previous findings have suggested a relationship between depression and negative symptoms via the avolition-apathy sub-domain, (Barnes et al., 2016). It is possible this is the result of a common aetiology, distinct from expressive deficit or other symptoms of schizophrenia. Immune dysfunction has been implicated in both psychotic and depressive illnesses; increased circulating pro-inflammatory markers (such as IL-6, TNF-α & CRP). This suggests a novel target for treatments. A putative neuroprotective role of minocycline has been suggested via reducing microglial activation, and decrease in the production of cytokines including IL-6. Minocycline has been shown to be effective in the treatment of negative symptoms (Xiang et al., 2017) and depression (Soczynska et al., 2012). Within schizophrenia, we predict that that minocycline will lead to a longitudinal improvement in depression and the avolition-apathy sub-domain of negative symptoms Methods Data from the BeneMin study will be presented. BeneMin recruited 207 patients with a current research diagnosis of schizophrenia within 5 years of onset and randomised to minocycline (300mg/day) or matching placebo for 12 months adjunctive to antipsychotic medication. For this analysis the primary outcome variable is the negative symptom subscale from the Positive and Negative Syndrome Scales (and broken down into avolition-apathy and expressive deficits sub-domains), Calgary Depression Scale in Schizophrenia (CDSS) and circulating IL-6, TNF-α and CRP over 4-time points 2, 6, 9, and 12 months. Results At baseline, 40% were depressed (mean CDSS score = 5). The mean avolition-apathy PANSS score was 9.5 and expressive deficits was 9, and was comparable across placebo and minocycline arms. Preliminary results show that markers of inflammation were low in both treatment arms, compared with previous research (baseline CRP Md = 1.45, IL-6 Md = .57, TNF-α Md = 2.43) and this was comparable across depressed and non-depressed patients. TNF-α was significantly associated with expressive-deficits (B = .75, p = .005). Conversely, no marker of inflammation was associated with avolition-apathy or depression. However, in four linear mixed effect models across the 2, 6, 9 and 12-month follow-up assessments compared with placebo, minocycline had no effect on total negative symptoms, avolition-apathy, expressive deficits or depression. Further analysis stratifying patients by depression scores and markers of inflammation will be presented. Discussion Preliminary results indicate that minocycline does not lead to a reduction in avolition-apathy or depression in early schizophrenia. This may be the result of a medicated, sample recruited within 5 years of illness onset, and low levels of depression. Future studies should target depression in psychosis as a primary aim with samples of individuals with increased inflammatory response to fully investigate minocycline’s potential in targeted intervention.

T14. ASSESSING DIFFERENCES IN INFLAMMATORY MARKERS BETWEEN FIRST EPISODE PSYCHOSIS PATIENTS AND HEALTHY CONTROLS: THE IMPORTANCE OF CONTROLLING FOR CONFOUNDING FACTORS

Abstract Background Although there is a cumulative evidence for increased level of markers of inflammation in psychosis, it has not been conclusively proven yet whether this is due to the disorder in itself or to other factors. One reason for this is the lack of studies that have controlled for major confounding factors such as obesity, smoking, antipsychotic use and stress. The BMI, as an indirect measure of body fat level, and tobacco smoking are known to play a role in modulating the immune system, but little research has been done in this area in patients with psychosis. The aim of this study was to investigate the differences in markers of inflammation and neuroplasticity between FEP patients and HC while controlling for a priori confounding factors, such as BMI and tobacco smoking. Methods Nineteen First Episode Psychosis (FEP) patients and 21 healthy controls (HC) matched for age, gender, ethnicity and marital status were recruited in South London (UK). Blood samples were collected to measure High Sensitivity C-Reactive Protein (hs-CRP), Interleukin (IL)-6, IL-8 and Brain-Derived Neurotrophic Factor (BDNF). Body Mass Index (BMI) was also assessed. Moreover, patients were asked whether they were tobacco smokers. Differences in continuous variables were analysed using independent samples t-tests. Categorical variables were assessed using the chi-square (χ2) test. One-way ANCOVAs were conducted to assess difference between FEP patients and HC in markers of inflammation and BDNF while controlling for the effect of BMI and tobacco smoking. All analyses were conducted using IBM SPSS statistical software version 23. The significance value for all tests was set at α = 0.05. Results FEP patients had higher serum level of hs-CRP compared to controls (N = 19, M = 2.29 mg/L, SD = 2.76; N = 21, M = 0.56 mg/L, SD = 0.41; respectively, t(27.79)=-2.41, p=0.02), suggestive of a hyperactivation of the immune system. There was no significant difference in IL-6, IL-8 and BDNF serum levels between the two groups. BMI was significantly higher in patients than controls (N = 19, M = 27.67, SD = 4.91; N = 21, M = 23.55, SD = 3.31; respectively, t(38)=-3.14, p=0.003) and there was a significantly higher number of smokers in the FEP patient group than in the HC group (smokers= 57.9% of FEP patients; smokers=14.3% of HC; χ2(1)=8.34, p=0.004). The one-way ANCOVAs showed that there was not significant effect of group on hs-CRP, IL-6, IL-8 and BDNF values when controlling for BMI and tobacco smoking. In fact, BMI was significantly related to the hs-CRP level, F(1,36) = 7.20, p = 0.01. Discussion We found that BMI and tobacco smoking may be important confounding factors when investigating disease-related alterations in the levels of hs-CRP, IL-6, IL-8 and BDNF. More studies are needed to assess the role of potential confounding factors on markers of inflammation in psychosis and to understand the role of immune activation in the pathophysiology of these disorders.

Poster #S28 IMMUNE RESPONSE TO STRESS IN POSTPARTUM PSYCHOSIS

pregnancy, NDBS taken at the time of birth, and adult plasma samples taken at the time of enrollment. Methods: The study population for this case-control study was selected from individuals born in northern Sweden between 1975 and 1985, identified with the use of Swedish register data. Non-affective psychoses were defined according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and International Classification of Disease (ICD-9 and -10). Maternal serum samples were available for 138 cases and 394 ageand sex-matched controls. NDBS were available for 100 cases and 196 controls who consented to their collection. 87 cases and 183 controls further consented to have a blood sample taken at the time of enrollment. The concentration of nine different APP were measured in each sample using a magnetic bead-based multiplex panel (Bio-Rad, Hercules, CA, USA): alpha-2 microglobulin (a2m), C-reactive protein (CRP), haptoglobulin, serum amyloid P (SAP), procalcitonin (PCT), ferritin, tissue plasminogen activator (tPA), fibrinogen, and serum amyloid A (SAA). Results: Median values for all APP except ferritin were lower in maternal serum from cases compared to controls. Similarly, median values for a2m, SAP, PCT, and tPA were lower in NDBS from cases compared to controls. However in adult plasma samples, median CRP, tPA, haptoglobin, PCT, and SAA levels were higher in cases compared to controls, while levels of a2m and SAP remained lower in cases compared to controls. Values of APP were not correlated between maternal serum and NDBS, nor were they correlated between NDBS and adult plasma samples. Discussion: To our knowledge, this is the first longitudinal biomarker study in a population diagnosed with non-affective psychoses to include perinatal as well as adult samples. The pattern of lower APP in cases compared to controls in perinatal samples was reversed in samples taken from adults after the time of diagnosis. Findings of lower APP in cases compared to controls in both maternal serum samples as well as NDBS are in contrast to the “Maternal Immune Activation” hypothesis that posits that inflammation during gestation increases risk for schizophrenia and non-affective psychoses later in life. Our study was, however, generally consistent with previous studies in adults, showing that some, but not all, APP were higher in cases compared to controls. Future studies include investigation of cytokines in maternal serum samples, to compare with the APP signature in maternal serum as well as to compare directly to previous studies. Additionally, we plan studies of antibodies to infectious agents and dietary antigens in the longitudinal sample set, in order to study whether exposures during different periods of life are correlated with changes in APP patterns over the life course.