Periodic Report Summary 1 - PSYCH-AID (Advanced Immuno-neuro-endocrine Diagnostics in Psychiatry)
PUBLISHABLE SUMMARY
The current diagnosis of psychiatric disorders such as schizophrenia (SZ) and mood disorders, is highly subjective, due to the lack of empirical markers or objective tests specific for these diseases. PSYCH-AID searches to fill the gap through the in-parallel study of schizophrenia and mood disorder patients combining, validating and registering sets of biomarker tests already in advanced stages of development via two previous other EU-FP7 projects of partners (MOODINFLAME and SchizDX).
Biomarkers of PSYCH-AID are based on an altered immune response system in conjunction with an abnormal neuro-endocrine set point. The “macrophage-T cell theory of depression and schizophrenia” postulates an aberrant immune state of monocytes/macrophages and T cells in mood disorder and SZ patients and considers this aberrant state of the cells as a driving force contributing to the illnesses, since aberrant levels of inflammatory monocyte/macrophage and T cell cytokines destabilize brain function and the neuro-endocrine system and make the brain and the neuro-endocrine system vulnerable to stress and unknown endogenous factors, thereby leading to psychiatric derailments. To detect these abnormal states, studies have focused mainly on determinations of single molecules in the serum of psychiatric patients. Using this approach outcomes have been inconsistent and not precise and robust enough to consistently detect the abnormal immune-neuro-endocrine state in major disorders and SZ. Apparently further identification of new immune-neuro-endocrine factors (biomarkers) and their combination and integration are required to a reach reliable test system to diagnose psychiatric diseases and to identify patients and individuals responsive to existing and novel treatments targeting the abnormal immune-neuro-endocrine system.
PSYCH-AID aims at the development of clinically applicable blood assays identifying patients/individuals with such altered set points by combining the efforts of academia and industry.
PSYCH-AID unites nine European partners excelling in this field: five academia and five industrial partners.
The strategic objective of PSYCH-AID is to build up a long-lasting, large inter-sectoral, integrative academia-industry consortium in Europe (and the world) for developing empirical immune-neuro-endocrine markers and objective diagnostic and prognostic blood tests for psychiatric disorders through exchanges of researchers.
Indeed in the first 2 years of the project an inter-sectoral, integrative academia-industry consortium as well as various interactive activities, i.e. 3 consortium meetings, 2 work group meetings, numerous telephone and internet meetings and a website (http://www.psychaid.eu/) have been developed as planned. With regard to the exchanges, 13 have been carried out, 2 recruitments have been realized and individual training plans constructed. A serious drawback has been the bankruptcy of one of the partners (CRL, responsible for the patient database), which have delayed the exchange plans. Counteractive measures have been taken immediately to safeguard the project’s progress. The bankrupt SME will be replaced by a similar SME, namely RMS, who safeguarded the database. This change in partners has delayed exchanges considerably, and building up of the database is hampered due to this delay. Nevertheless we have been able to fully continue the selection and collection of patients and materials as well as carrying out tests (see underneath). To fully catch up in order to attain all objectives foreseen, an increase in exchanges has been planned for the 3rd and 4th year.
PSYCH-AID‟s scientific objective is to identify, mutually correlate and validate sets of empirical immune-neuro-endocrine markers for the diagnosis and prognosis of various mood disorders, such as patients with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Postpartum Psychosis (PP), Offspring of a BD parent (KBO study), Twins of BD index cases and Schizophrenia (SZ) patients. The scientific objective can be specified into the following sub-objectives to:
Collect sufficient patients and controls and their material to carry out the analyses (WP4).
Large numbers of patients have been collected and large numbers of assays have been carried out on large panels of serum, plasma and collected immune cells (see Table). In fact after 2 years we have reached the envisaged number of patients and fully reached the objective of this sub-aim (Note that more SZ patients have been collected then is indicated in the table, i.e. over 300).
Table 1 Patient group characteristics and progress sample analysis
Disease Code Sampled Sampled Insufficient quality Monocyte gene expression FACS analysis PBMC Serum analysis
n % % % % %
MDD 812 100 22 22 26 18
BD 413 100 23 47 62 23
C-MDD/BD 607 607 100 18 51 55 28
BD-TWIN; Timepoint 2 68 100 79 79 0
C-TWIN 60 100 93 93 0
KBO Timepoint 4 110 100 93 93 82
C-KBO 52 100 96 96 94
KBO-BD Parent 59 100 100 100 0
KBO-Healthy Parent 59 100 100 100 0
PP 250 100 37 30 35
C-PP 92 100 55 43 68
SZ 60 100 0 0 0
C-SZ 60 100 0 0 0
Refine the macrophage-T cell expression fingerprint (transcriptomics) (WP5),
-Apart from a set of inflammatory and motility/adhesion genes new sets of genes are in the process of being evaluated to be part of biomarker gene signatures specific for sub-groups of patients with different diagnoses and prognoses. These new sets of genes include the glucocorticoid receptor genes, Interferon-induced genes, the KAT enzymes and genes of the fatty acid metabolism and ferritin/transerythrin pathway.
-Studying the expression of these cellular genes in patients a dynamic expression profile over time became apparent, necessitating a study in an animal model (the NOD mouse) with a similar dynamic expression pattern. In this animal model the dynamic inflammation course is due to a partial deficient development of the macrophage and T cell arm, which on its turn appeared due to a lack of sufficient growth factors for these immune cells. This necessitated the development of specific proteomic assays for these growth factors (see below).
Identify further proteomic biomarkers (proteomics) (WP6),
-FACS analysis of the T cells identified a partial T cell deficiency, particularly in PP and children of a BD parent (BD offspring), underlining the lack of sufficient growth factors for these cells.
- ELISA assays set-up for a panel of immune growth factors (IL-2, sCD25, IL-3, IL-7, SCF, GM-CSF, IGF-BP2, EGF) showed in preliminary experiments deficiencies in sub groups of patients (MDD, BD Offspring).
-The already identified signature of 51 analytes has been further refined for the diagnosis of schizophrenia, while further analytes are being identified (via advanced proteomic techniques) for treatment prognosis in both MDD and SZ.
-Some of the these newly identified analytes are being tested at the genomic level in WP5 to add to the genomic signature.
Identify further biochemical biomarkers, in particular tryptophan catabolites (trypcats) (WP7),
-Assays have been standardized via an EQUAS system and a panel of various trypcats have been tested in over 300 MDD patients, 50 PP patients and 40 BD patients
- Key abnormal trypcat pathways are the Tryptophan/Kynurenin ratio, the KynureninA/Kynurenin ratio, the 3HK/Kynurenin ratio and the 5-HIAA pathway.
-Antibodies have been developed against QUIN and KynA and specificities are tested for ELISA usage.
Validate these differential markers and their associations for disease specificity (WP8)
This validation is in progress and most far for MDD and PP patients. Already clear interactions can be seen between immune markers and trypcats and it is envisaged that combined biomarker panels can be developed for specific sub classification of MDD patients, who might benefit from specific interventions.
Further progress in this WP is in particular foreseen in the 3rd and 4th year of the project. From this we will select diagnostic assay panels, another sub-aim of PSYCH-AID.
PSYCH-AID‟s business objective is the commercialisation the various test systems (WP9). As consortium we have been the first to develop a marketable test system to aid in the diagnosis of schizophrenia (via Myriad) (see WP9). We are confident that future developments along the planned lines will precise this test system and will complete it with other test systems (such as a genomic panel and a trypcat panel) and software programs to analyse laboratory data in conjunction with demographic and clinical data of psychiatric patients.
We dare to say that our consortium is one of the leading groups in unravelling the immune-neuro-endocrine underpinnings of psychiatric disease and translating knowledge into clinically applicable approaches and test systems. European industry will benefit from this competitive lead. Since the disorders have a serious impact on the quality of life of the individuals affected, an improved diagnosis and prognosis will substantially contribute to improving their quality of life. Furthermore, PSYCH-AID gives the researchers involved a platform to acquire complementary skills, thus ameliorating their professional career opportunities.
The current diagnosis of psychiatric disorders such as schizophrenia (SZ) and mood disorders, is highly subjective, due to the lack of empirical markers or objective tests specific for these diseases. PSYCH-AID searches to fill the gap through the in-parallel study of schizophrenia and mood disorder patients combining, validating and registering sets of biomarker tests already in advanced stages of development via two previous other EU-FP7 projects of partners (MOODINFLAME and SchizDX).
Biomarkers of PSYCH-AID are based on an altered immune response system in conjunction with an abnormal neuro-endocrine set point. The “macrophage-T cell theory of depression and schizophrenia” postulates an aberrant immune state of monocytes/macrophages and T cells in mood disorder and SZ patients and considers this aberrant state of the cells as a driving force contributing to the illnesses, since aberrant levels of inflammatory monocyte/macrophage and T cell cytokines destabilize brain function and the neuro-endocrine system and make the brain and the neuro-endocrine system vulnerable to stress and unknown endogenous factors, thereby leading to psychiatric derailments. To detect these abnormal states, studies have focused mainly on determinations of single molecules in the serum of psychiatric patients. Using this approach outcomes have been inconsistent and not precise and robust enough to consistently detect the abnormal immune-neuro-endocrine state in major disorders and SZ. Apparently further identification of new immune-neuro-endocrine factors (biomarkers) and their combination and integration are required to a reach reliable test system to diagnose psychiatric diseases and to identify patients and individuals responsive to existing and novel treatments targeting the abnormal immune-neuro-endocrine system.
PSYCH-AID aims at the development of clinically applicable blood assays identifying patients/individuals with such altered set points by combining the efforts of academia and industry.
PSYCH-AID unites nine European partners excelling in this field: five academia and five industrial partners.
The strategic objective of PSYCH-AID is to build up a long-lasting, large inter-sectoral, integrative academia-industry consortium in Europe (and the world) for developing empirical immune-neuro-endocrine markers and objective diagnostic and prognostic blood tests for psychiatric disorders through exchanges of researchers.
Indeed in the first 2 years of the project an inter-sectoral, integrative academia-industry consortium as well as various interactive activities, i.e. 3 consortium meetings, 2 work group meetings, numerous telephone and internet meetings and a website (http://www.psychaid.eu/) have been developed as planned. With regard to the exchanges, 13 have been carried out, 2 recruitments have been realized and individual training plans constructed. A serious drawback has been the bankruptcy of one of the partners (CRL, responsible for the patient database), which have delayed the exchange plans. Counteractive measures have been taken immediately to safeguard the project’s progress. The bankrupt SME will be replaced by a similar SME, namely RMS, who safeguarded the database. This change in partners has delayed exchanges considerably, and building up of the database is hampered due to this delay. Nevertheless we have been able to fully continue the selection and collection of patients and materials as well as carrying out tests (see underneath). To fully catch up in order to attain all objectives foreseen, an increase in exchanges has been planned for the 3rd and 4th year.
PSYCH-AID‟s scientific objective is to identify, mutually correlate and validate sets of empirical immune-neuro-endocrine markers for the diagnosis and prognosis of various mood disorders, such as patients with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Postpartum Psychosis (PP), Offspring of a BD parent (KBO study), Twins of BD index cases and Schizophrenia (SZ) patients. The scientific objective can be specified into the following sub-objectives to:
Collect sufficient patients and controls and their material to carry out the analyses (WP4).
Large numbers of patients have been collected and large numbers of assays have been carried out on large panels of serum, plasma and collected immune cells (see Table). In fact after 2 years we have reached the envisaged number of patients and fully reached the objective of this sub-aim (Note that more SZ patients have been collected then is indicated in the table, i.e. over 300).
Table 1 Patient group characteristics and progress sample analysis
Disease Code Sampled Sampled Insufficient quality Monocyte gene expression FACS analysis PBMC Serum analysis
n % % % % %
MDD 812 100 22 22 26 18
BD 413 100 23 47 62 23
C-MDD/BD 607 607 100 18 51 55 28
BD-TWIN; Timepoint 2 68 100 79 79 0
C-TWIN 60 100 93 93 0
KBO Timepoint 4 110 100 93 93 82
C-KBO 52 100 96 96 94
KBO-BD Parent 59 100 100 100 0
KBO-Healthy Parent 59 100 100 100 0
PP 250 100 37 30 35
C-PP 92 100 55 43 68
SZ 60 100 0 0 0
C-SZ 60 100 0 0 0
Refine the macrophage-T cell expression fingerprint (transcriptomics) (WP5),
-Apart from a set of inflammatory and motility/adhesion genes new sets of genes are in the process of being evaluated to be part of biomarker gene signatures specific for sub-groups of patients with different diagnoses and prognoses. These new sets of genes include the glucocorticoid receptor genes, Interferon-induced genes, the KAT enzymes and genes of the fatty acid metabolism and ferritin/transerythrin pathway.
-Studying the expression of these cellular genes in patients a dynamic expression profile over time became apparent, necessitating a study in an animal model (the NOD mouse) with a similar dynamic expression pattern. In this animal model the dynamic inflammation course is due to a partial deficient development of the macrophage and T cell arm, which on its turn appeared due to a lack of sufficient growth factors for these immune cells. This necessitated the development of specific proteomic assays for these growth factors (see below).
Identify further proteomic biomarkers (proteomics) (WP6),
-FACS analysis of the T cells identified a partial T cell deficiency, particularly in PP and children of a BD parent (BD offspring), underlining the lack of sufficient growth factors for these cells.
- ELISA assays set-up for a panel of immune growth factors (IL-2, sCD25, IL-3, IL-7, SCF, GM-CSF, IGF-BP2, EGF) showed in preliminary experiments deficiencies in sub groups of patients (MDD, BD Offspring).
-The already identified signature of 51 analytes has been further refined for the diagnosis of schizophrenia, while further analytes are being identified (via advanced proteomic techniques) for treatment prognosis in both MDD and SZ.
-Some of the these newly identified analytes are being tested at the genomic level in WP5 to add to the genomic signature.
Identify further biochemical biomarkers, in particular tryptophan catabolites (trypcats) (WP7),
-Assays have been standardized via an EQUAS system and a panel of various trypcats have been tested in over 300 MDD patients, 50 PP patients and 40 BD patients
- Key abnormal trypcat pathways are the Tryptophan/Kynurenin ratio, the KynureninA/Kynurenin ratio, the 3HK/Kynurenin ratio and the 5-HIAA pathway.
-Antibodies have been developed against QUIN and KynA and specificities are tested for ELISA usage.
Validate these differential markers and their associations for disease specificity (WP8)
This validation is in progress and most far for MDD and PP patients. Already clear interactions can be seen between immune markers and trypcats and it is envisaged that combined biomarker panels can be developed for specific sub classification of MDD patients, who might benefit from specific interventions.
Further progress in this WP is in particular foreseen in the 3rd and 4th year of the project. From this we will select diagnostic assay panels, another sub-aim of PSYCH-AID.
PSYCH-AID‟s business objective is the commercialisation the various test systems (WP9). As consortium we have been the first to develop a marketable test system to aid in the diagnosis of schizophrenia (via Myriad) (see WP9). We are confident that future developments along the planned lines will precise this test system and will complete it with other test systems (such as a genomic panel and a trypcat panel) and software programs to analyse laboratory data in conjunction with demographic and clinical data of psychiatric patients.
We dare to say that our consortium is one of the leading groups in unravelling the immune-neuro-endocrine underpinnings of psychiatric disease and translating knowledge into clinically applicable approaches and test systems. European industry will benefit from this competitive lead. Since the disorders have a serious impact on the quality of life of the individuals affected, an improved diagnosis and prognosis will substantially contribute to improving their quality of life. Furthermore, PSYCH-AID gives the researchers involved a platform to acquire complementary skills, thus ameliorating their professional career opportunities.