1
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1S384 S57 from both sets of ndings were similar, implying that sample selection bias was unlikely to have inuenced study ndings. Discussion: Persistent and incident internalising and externalising prob- lems from mid-childhood into adolescence are associated with later PLEs in the general population, whereas childhood-limited psychopathology (re- mitting problems) are not. Interventions that target the persistence or incidence of internalising or externalising psychopathology from childhood to adolescence may impact on the expression of PLEs. Further research is needed to elucidate whether common or distinct mechanisms inuence the associations of internalising and externalising psychopathology with PLEs. 4:30 PM INFLAMMATORY RESPONSE INFIRST-EPISODE PSYCHOSIS Jaana Suvisaari 1 , Teemu J.S. Mäntylä 1,2 , Tuukka Raij 3 , Tuula Kieseppä 1 , Minna Torniainen 1 , Outi Vaarala 1 1 National Institute for Health and Welfare; 2 National Institute for Health and Welfare, Helsinki, Finland and Brain Research Unit in Aalto University School of Science, Espoo, Finland; 3 Aalto University Background: Cytokines, and chemokines as their subgroup, are a large group of proteins that regulate all aspects of innate and adaptive immu- nity. Several rst-episode psychosis studies have observed elevations in proinammatory cytokines in rst-episode psychosis, while chemokines have received much less attention. Therefore, we set out to investigate changes in cyto- and chemokines in patients with rst-episode psychosis and matched general population controls. Methods: First episode psychosis patients with a median of 27 days of antipsychotic medication and matched controls were recruited from the capital area of Finland. Serum levels of 38 cytokines and chemokines were analyzed using the Milliplex MAP Kit (HCYTMAG-60K-PX38, Millipore Corp., Billerica, MA). In addition, cardiovascular risk markers were measured. The analyses were done at baseline and for patients also 2 months later. Results: The study group consisted of 37 (21 males) rst-episode patients and 19 (10 males) controls, with a mean age of 26.1 and 28.6 years, respectively. At baseline, patients and controls did not differ signicantly in terms of BMI or waist circumference. FEP patients as compared to healthy controls had higher CCL22 and lower TGFα, CXCL1, CCL7, IFNα2, ApoA-I and HDL-C levels. The ndings remained signicant after adjusting for BMI, age and sex. Duration of antipsychotic treatment did not correlate signicantly with cytokine levels. CCL22 level had decreased signicantly at 2 month follow-up, but was still higher than in controls. Discussion: Inammatory response is dynamic, and our ndings reect the situation in a subacute phase of rst-episode psychosis. The observed prole of systemic chemokines in rst-episode psychosis, such as increased CCL22 and decreased CXCL1, CCL7 and IFN-α, could reect up-regulation of STAT6 signaling. The classical proinammatory state characterized by elevated IL-1, IL-6 and TNF-α may be a relatively short-lived phenomenon associated with acute psychosis, and was not observed in this study. The earliest metabolic alteration in rst-episode psychosis was decreased HDL- C and ApoA-I, suggesting a vulnerability to metabolic syndrome from the onset of psychosis. 4:45 PM PREMORBID AND CURRENT COGNITIVE FUNCTION IN SCHIZOPHRENIA ASSOCIATE WITH TREATMENT RESISTANCE AND EGF 61 AA GENOTYPE Vaidy Swaminathan 1,2 , Avril M. Pereira 3 , Cynthia Shannon-Weickert 4 , Thomas Weickert 4 , Suresh Sundram 3 1 University of Melbourne; 2 The Florey Institute of Neuroscience and Mental Health; 3 The Florey Institute; 4 Neuroscience Research Australia Background: Disaggregating clinical clusters within schizophrenia (SCZ) such as cognitive impairment (CI) and treatment resistance will assist in identifying pathological mechanisms and possible biomarkers. Others’ and our data have elucidated involvement of the epidermal growth factor (EGF) system in both these clinical processes in SCZ and other neuropsychiatric disorders. We have proposed that decient EGF signalling is ameliorated by clozapine through EGF receptor transactivation in treatment resistant SCZ (TRS) and low EGF function is associated with cognitive impairment in Parkinson’s disorder, dementias and mouse models of psychosis. A func- tional single nucleotide polymorphism in the EGF gene (61A>G) provides a model where the 61AA homozygote produces less EGF than the AG heterozygote and GG homozygote. We therefore, postulated that cogni- tive impairment is associated with TRS and that the EGF 61A>G SNP is associated with impaired cognitive processes. Methods: Clinical and cognitive data and DNA from participants with a diagnosis of SCZ (n=664) were accessed from the Australian Schizophrenia Research Bank. TRS was dened as current or past treatment with clozapine. Cognitive data were the Wechsler Test of Adult Reading (WTAR) standard score as a measure of premorbid cognitive ability and Letter Number Sequencing (LNS), Controlled Oral Word Association Test (COWAT) and Re- peatable Battery for the Assessment of Neuropsychological Status (RBANS) as measures of current cognitive ability. These scores were z transformed (based on a cohort including healthy controls n=634) and composite scores were computed for the domains of Executive Functioning, Memory and Attention. Genotyping for EGF 61 A>G SNP (rs4444903) was performed using a TaqMan ® assay and allele frequencies for AA, AG and GG genotypes were obtained. The groups were compared using standard statistical tests. Results: TRS patients had signicantly lower premorbid intellectual func- tion when compared to non-TRS patients (WTAR score TRS=−0.55±1.2, non TRS=−0.23±1.1, mean±σ;p=0.004). TRS patients had signicantly lower current performance when compared to non-TRS patients in working memory and executive functioning tests (LNS score TRS=−0.72±0.86, non-TRS=−0.33±0.92; p<0.001; RBANS Memory composite score TRS=−1.11±0.91, non-TRS=−0.43±0.90; p<0.001; RBANS Attention compos- ite score TRS=−0.83±0.80, non-TRS=−0.46±0.87; p<0.001; but not COWAT score; p=0.79, and RBANS Language composite score; p=0.17). The EGF genotypes were in Hardy-Weinberg Equilibrium. Patients with the 61AA genotype had signicantly lower premorbid cognitive ability (WTAR score AA participant s=−0.40±1.12), than non-AA participants (0.21±1.1; p=0.031). AA patients had signicantly lower current cogni- tive abilities characterised by working memory (LNS; AA=−0.55±0.84, non AA=−0.38±0.93; p=0.018), Executive Functioning (COWAT; AA=−0.50±0.91, non AA=−0.31±0.96; p=0.014) and RBANS Attention domain composite score (AA=−0.64±0.82, non AA=−0.49±0.89; p=0.033) but not RBANS Lan- guage composite score (p=0.21) and Memory composite score (p=0.19). Discussion: These data demonstrate in a large cohort that people with TRS have signicantly poorer pre-morbid intellectual function than people with treatment responsive schizophrenia and that impairment persists through the illness. Moreover, cognitive impairment is associated with the 61AA genotype suggesting that lower EGF levels may contribute to this symptom domain. Together these data support a model where a hypofunctioning EGF system may predispose and link to both treatment resistance and cognitive impairment in schizophrenia. This provides genetic and molecular targets to investigate as plausible biomarkers for treatment planning and early intervention in schizophrenia. 5:00 PM REAL-TIME DETECTION OF COGNITIVE DECLINE INCHILDREN AT HIGH GENETICRISK OF SCHIZOPHRENIA AND BIPOLAR DISORDER Michel Maziade 1 , Thomas Paccalet 2 , Elsa Gilbert 2 , Nicolas Berthelot 3 , Chantal Mérette 4 , Nancie Rouleau 4 1 Laval University; 2 Centre de recherche Institut universitaire en santé mentale de Québec; 3 Université de Québec à Trois-Rivières; 4 Université Laval Background: There is an emerging consensus that schizophrenia is a neurodevelopmental disorder characterized by a cognitive deterioration beginning in childhood (1-3). We have already reported severe cognitive impairments in children and adolescents (HR) descending from multi- affected families of Eastern Quebec (4). We now report in a longitudinal study of 40 high-risk offspring aged 6 to 26 that 10 of them presented a global IQ decline of 10 points suggesting that they are going through a developmental transition toward the disease. Methods: We already reported that the phenotypic, endophenotypic and genetic ndings in the children, the non-affected adults and the patients of this familial sample were strongly resembling the ndings reported in general or sporadic samples (5). In this high-risk sample, we used a step by step sampling approach to narrow-down the early disease mech- anisms. Upstream, we started with a 20-year follow-up of 48 densely

4:30 PM INFLAMMATORY RESPONSE IN FIRST-EPISODE PSYCHOSIS

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Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384 S57

from both sets of findings were similar, implying that sample selection bias

was unlikely to have influenced study findings.

Discussion: Persistent and incident internalising and externalising prob-

lems from mid-childhood into adolescence are associated with later PLEs

in the general population, whereas childhood-limited psychopathology (re-

mitting problems) are not. Interventions that target the persistence or

incidence of internalising or externalising psychopathology from childhood

to adolescence may impact on the expression of PLEs. Further research is

needed to elucidate whether common or distinct mechanisms influence the

associations of internalising and externalising psychopathology with PLEs.

4:30 PM

INFLAMMATORY RESPONSE IN FIRST-EPISODE PSYCHOSIS

Jaana Suvisaari1, Teemu J.S. Mäntylä1,2, Tuukka Raij3, Tuula Kieseppä1,

Minna Torniainen1, Outi Vaarala1

1National Institute for Health and Welfare; 2National Institute for Health and

Welfare, Helsinki, Finland and Brain Research Unit in Aalto University School

of Science, Espoo, Finland; 3Aalto University

Background: Cytokines, and chemokines as their subgroup, are a large

group of proteins that regulate all aspects of innate and adaptive immu-

nity. Several first-episode psychosis studies have observed elevations in

proinflammatory cytokines in first-episode psychosis, while chemokines

have received much less attention. Therefore, we set out to investigate

changes in cyto- and chemokines in patients with first-episode psychosis

and matched general population controls.

Methods: First episode psychosis patients with a median of 27 days of

antipsychotic medication and matched controls were recruited from the

capital area of Finland. Serum levels of 38 cytokines and chemokines were

analyzed using the Milliplex MAP Kit (HCYTMAG-60K-PX38, Millipore Corp.,

Billerica, MA). In addition, cardiovascular risk markers were measured. The

analyses were done at baseline and for patients also 2 months later.

Results: The study group consisted of 37 (21 males) first-episode patients

and 19 (10 males) controls, with a mean age of 26.1 and 28.6 years,

respectively. At baseline, patients and controls did not differ significantly in

terms of BMI or waist circumference. FEP patients as compared to healthy

controls had higher CCL22 and lower TGFα, CXCL1, CCL7, IFNα2, ApoA-I and

HDL-C levels. The findings remained significant after adjusting for BMI, age

and sex. Duration of antipsychotic treatment did not correlate significantly

with cytokine levels. CCL22 level had decreased significantly at 2 month

follow-up, but was still higher than in controls.

Discussion: Inflammatory response is dynamic, and our findings reflect

the situation in a subacute phase of first-episode psychosis. The observed

profile of systemic chemokines in first-episode psychosis, such as increased

CCL22 and decreased CXCL1, CCL7 and IFN-α, could reflect up-regulation

of STAT6 signaling. The classical proinflammatory state characterized by

elevated IL-1, IL-6 and TNF-α may be a relatively short-lived phenomenon

associated with acute psychosis, and was not observed in this study. The

earliest metabolic alteration in first-episode psychosis was decreased HDL-

C and ApoA-I, suggesting a vulnerability to metabolic syndrome from the

onset of psychosis.

4:45 PM

PREMORBID AND CURRENT COGNITIVE FUNCTION IN SCHIZOPHRENIA

ASSOCIATE WITH TREATMENT RESISTANCE AND EGF 61 AA GENOTYPE

Vaidy Swaminathan1,2, Avril M. Pereira3, Cynthia Shannon-Weickert4,

Thomas Weickert4, Suresh Sundram3

1University of Melbourne; 2The Florey Institute of Neuroscience and Mental

Health; 3The Florey Institute; 4Neuroscience Research Australia

Background: Disaggregating clinical clusters within schizophrenia (SCZ)

such as cognitive impairment (CI) and treatment resistance will assist in

identifying pathological mechanisms and possible biomarkers. Others’ and

our data have elucidated involvement of the epidermal growth factor (EGF)

system in both these clinical processes in SCZ and other neuropsychiatric

disorders. We have proposed that deficient EGF signalling is ameliorated

by clozapine through EGF receptor transactivation in treatment resistant

SCZ (TRS) and low EGF function is associated with cognitive impairment

in Parkinson’s disorder, dementias and mouse models of psychosis. A func-

tional single nucleotide polymorphism in the EGF gene (61A>G) provides

a model where the 61AA homozygote produces less EGF than the AG

heterozygote and GG homozygote. We therefore, postulated that cogni-

tive impairment is associated with TRS and that the EGF 61A>G SNP is

associated with impaired cognitive processes.

Methods: Clinical and cognitive data and DNA from participants with a

diagnosis of SCZ (n=664) were accessed from the Australian Schizophrenia

Research Bank. TRS was defined as current or past treatment with clozapine.

Cognitive data were the Wechsler Test of Adult Reading (WTAR) standard

score as a measure of premorbid cognitive ability and Letter Number

Sequencing (LNS), Controlled Oral Word Association Test (COWAT) and Re-

peatable Battery for the Assessment of Neuropsychological Status (RBANS)

as measures of current cognitive ability. These scores were z transformed

(based on a cohort including healthy controls n=634) and composite scores

were computed for the domains of Executive Functioning, Memory and

Attention. Genotyping for EGF 61 A>G SNP (rs4444903) was performed

using a TaqMan® assay and allele frequencies for AA, AG and GG genotypes

were obtained. The groups were compared using standard statistical tests.

Results: TRS patients had significantly lower premorbid intellectual func-

tion when compared to non-TRS patients (WTAR score – TRS=−0.55±1.2,

non TRS=−0.23±1.1, mean±σ; p=0.004). TRS patients had significantly lower

current performance when compared to non-TRS patients in working

memory and executive functioning tests (LNS score – TRS=−0.72±0.86,

non-TRS=−0.33±0.92; p<0.001; RBANS Memory composite score –

TRS=−1.11±0.91, non-TRS=−0.43±0.90; p<0.001; RBANS Attention compos-

ite score – TRS=−0.83±0.80, non-TRS=−0.46±0.87; p<0.001; but not COWAT

score; p=0.79, and RBANS Language composite score; p=0.17).

The EGF genotypes were in Hardy-Weinberg Equilibrium. Patients with

the 61AA genotype had significantly lower premorbid cognitive ability

(WTAR score – AA participant s=−0.40±1.12), than non-AA participants

(−0.21±1.1; p=0.031). AA patients had significantly lower current cogni-

tive abilities characterised by working memory (LNS; AA=−0.55±0.84, non

AA=−0.38±0.93; p=0.018), Executive Functioning (COWAT; AA=−0.50±0.91,

non AA=−0.31±0.96; p=0.014) and RBANS Attention domain composite

score (AA=−0.64±0.82, non AA=−0.49±0.89; p=0.033) but not RBANS Lan-

guage composite score (p=0.21) and Memory composite score (p=0.19).

Discussion: These data demonstrate in a large cohort that people with TRS

have significantly poorer pre-morbid intellectual function than people with

treatment responsive schizophrenia and that impairment persists through

the illness. Moreover, cognitive impairment is associated with the 61AA

genotype suggesting that lower EGF levels may contribute to this symptom

domain. Together these data support a model where a hypofunctioning EGF

system may predispose and link to both treatment resistance and cognitive

impairment in schizophrenia. This provides genetic and molecular targets

to investigate as plausible biomarkers for treatment planning and early

intervention in schizophrenia.

5:00 PM

REAL-TIME DETECTION OF COGNITIVE DECLINE IN CHILDREN AT HIGH

GENETIC RISK OF SCHIZOPHRENIA AND BIPOLAR DISORDER

Michel Maziade1, Thomas Paccalet2, Elsa Gilbert2, Nicolas Berthelot3,

Chantal Mérette4, Nancie Rouleau4

1Laval University; 2Centre de recherche Institut universitaire en santé mentale

de Québec; 3Université de Québec à Trois-Rivières; 4Université Laval

Background: There is an emerging consensus that schizophrenia is a

neurodevelopmental disorder characterized by a cognitive deterioration

beginning in childhood (1-3). We have already reported severe cognitive

impairments in children and adolescents (HR) descending from multi-

affected families of Eastern Quebec (4). We now report in a longitudinal

study of 40 high-risk offspring aged 6 to 26 that 10 of them presented

a global IQ decline of 10 points suggesting that they are going through a

developmental transition toward the disease.

Methods: We already reported that the phenotypic, endophenotypic and

genetic findings in the children, the non-affected adults and the patients

of this familial sample were strongly resembling the findings reported

in general or sporadic samples (5). In this high-risk sample, we used a

step by step sampling approach to narrow-down the early disease mech-

anisms. Upstream, we started with a 20-year follow-up of 48 densely