Periodic Reporting for period 4 - MOODSTRATIFICATION (Immune Signatures for Therapy Stratification in Major Mood Disorders)
Reporting period: 2022-07-01 to 2023-06-30
The hypothesis of MOODSTRATIFICATION is that a large proportion of severe mood disorders, i.e. of major depressive disorder (MDD) and bipolar disorder (BD), are in part caused by (inborn and acquired) monocyte/macrophage and T cell defects. Monocytes/macrophages and T cells are not only essential for adequate immune reactions, but also for a proper development and function of the brain.
Therefore defects in monocytes/macrophages and T cells in MDD and BD patients
1. will impact the development and function of the brain, in particular of the limbic system,
2. will result in flares of chronic low grade inflammation, further impacting brain function.
Since severe mood disorders are prevalent (5% of the population) and disabling for patients and relatives, improved diagnoses based on laboratory tests and new cures are required based on the novel insight that immune defects underlie a large proportion of the mental disorders. MOODSTRATIFICATION addresses the development of such improved diagnoses and new avenues for treatment.
The first objective of MOODSTRATIFICATION is to refine this novel immune concept for mood disorders by further exploring monocyte/macrophage, T cell and cytokine abnormalities in the earlier collected large datasets of the previous EU funded research projects MOODINFLAME (2008–2012) and PSYCH-AID (2013-2017).
The second objective is to develop simple blood tests to measure the immune abnormalities in clinical practice .
The third objective is to carry out proof-of-principle clinical studies with T cell enforcing therapies to correct the immune defects,
The fourth objective is to develop novel immune correcting therapies in immune-stratified patients using the developed simple blood tests and to study the socio-economic benefits of such novel interventions.
Therefore defects in monocytes/macrophages and T cells in MDD and BD patients
1. will impact the development and function of the brain, in particular of the limbic system,
2. will result in flares of chronic low grade inflammation, further impacting brain function.
Since severe mood disorders are prevalent (5% of the population) and disabling for patients and relatives, improved diagnoses based on laboratory tests and new cures are required based on the novel insight that immune defects underlie a large proportion of the mental disorders. MOODSTRATIFICATION addresses the development of such improved diagnoses and new avenues for treatment.
The first objective of MOODSTRATIFICATION is to refine this novel immune concept for mood disorders by further exploring monocyte/macrophage, T cell and cytokine abnormalities in the earlier collected large datasets of the previous EU funded research projects MOODINFLAME (2008–2012) and PSYCH-AID (2013-2017).
The second objective is to develop simple blood tests to measure the immune abnormalities in clinical practice .
The third objective is to carry out proof-of-principle clinical studies with T cell enforcing therapies to correct the immune defects,
The fourth objective is to develop novel immune correcting therapies in immune-stratified patients using the developed simple blood tests and to study the socio-economic benefits of such novel interventions.
With regard to objective 1 we have found that the immune defects in MDD and BD differ.
1. MDD is characterized by premature senescence of the T helper and monocyte/macrophage compartment leading to mild low grade inflammation, which under circumstances of childhood trauma and obesity will lead to more signs of inflammation (clear monocyte inflammatory activation, higher serum levels of pro-inflammatory cytokines).
2. BD is characterized by a defect in the generation of T effector memory cells and a reduced level of IL-7 (a T cell differentiation factor). T central memory cells, including Th17 cells are increased. During depressive or manic episodes stronger signs of low grade inflammation are evident (monocyte activation, increase in inflammatory cytokines)
With regard to objective 2 we have developed simplified and reliable blood tests. APD (commercial partner, Belgium) has developed a set of reliable and sensitive ELISAs for IL-7, IL-6, hsCRP, BDNF and sCD25, while PRONTO (Israel) has developed a finger prick assay to test for the immune blood cell defects using limited gene expression profiles.
With regard to objective 3 two double blind placebo-controlled trials using low dose IL-2 have been carried out. Outcomes of both trial are a break through showing a novel way for treating depression. A significant increase in T regs was found after 5 days low dose IL-2 treatment , while depression scores improved reaching significance versus placebo at the end of the trials (day 60). Positive significant correlations were found between the improvement of the depression scores and the increase of T regs. Low dose IL-2 treatment hardly had side-effects. Patients with low signs of T cell activity, low numbers of naïve CD4+ and CD8+ T cells, and high signs of low grade inflammation had the highest chance of a favorable response to low dose IL-2.
In another small open label trial 5 depressed immune-deficient patients were treated with thymus hormone (Thymalfasin). Treatment with Thymalfasin was safe, did correct signs of T cell senescence and improved depression scores (particularly anxiety scores) in a similar fashion as treatment as usual with regular antidepressants.
For objective 4 we treated depressed patients with physical training schemes (spinning). Controls were treated as usual (TAU). We wanted to find an immune senescence parameter which predicts favorable outcome of spinning (it is known that physical activity combats immune senescence). Data indeed show that a premature senescence of T helper cells (as measured by a high percentage of T helper memory cells, in particular T helper central memory cells) is a predictor of better outcome of add-on spinning therapy iand preselection of patients via this immune senescence characteristic improved complete remitter percentages after half a year from 10% (TAU group) to 50% (spinning group plus TAU group).
By combining available evidence from the literature (disability weights, relapse rate, and empirical costs of depression) and available data (the remission and immune signature rates from the spinning cohort), we built an economic model of the health benefits of immune signature based approaches versus current practice. Findings (though preliminary) indicate that immune signature stratified add-on spinning therapy renders both a substantial decrease in the disability from depression and a substantial cost reduction in five years compared to the current practice.
1. MDD is characterized by premature senescence of the T helper and monocyte/macrophage compartment leading to mild low grade inflammation, which under circumstances of childhood trauma and obesity will lead to more signs of inflammation (clear monocyte inflammatory activation, higher serum levels of pro-inflammatory cytokines).
2. BD is characterized by a defect in the generation of T effector memory cells and a reduced level of IL-7 (a T cell differentiation factor). T central memory cells, including Th17 cells are increased. During depressive or manic episodes stronger signs of low grade inflammation are evident (monocyte activation, increase in inflammatory cytokines)
With regard to objective 2 we have developed simplified and reliable blood tests. APD (commercial partner, Belgium) has developed a set of reliable and sensitive ELISAs for IL-7, IL-6, hsCRP, BDNF and sCD25, while PRONTO (Israel) has developed a finger prick assay to test for the immune blood cell defects using limited gene expression profiles.
With regard to objective 3 two double blind placebo-controlled trials using low dose IL-2 have been carried out. Outcomes of both trial are a break through showing a novel way for treating depression. A significant increase in T regs was found after 5 days low dose IL-2 treatment , while depression scores improved reaching significance versus placebo at the end of the trials (day 60). Positive significant correlations were found between the improvement of the depression scores and the increase of T regs. Low dose IL-2 treatment hardly had side-effects. Patients with low signs of T cell activity, low numbers of naïve CD4+ and CD8+ T cells, and high signs of low grade inflammation had the highest chance of a favorable response to low dose IL-2.
In another small open label trial 5 depressed immune-deficient patients were treated with thymus hormone (Thymalfasin). Treatment with Thymalfasin was safe, did correct signs of T cell senescence and improved depression scores (particularly anxiety scores) in a similar fashion as treatment as usual with regular antidepressants.
For objective 4 we treated depressed patients with physical training schemes (spinning). Controls were treated as usual (TAU). We wanted to find an immune senescence parameter which predicts favorable outcome of spinning (it is known that physical activity combats immune senescence). Data indeed show that a premature senescence of T helper cells (as measured by a high percentage of T helper memory cells, in particular T helper central memory cells) is a predictor of better outcome of add-on spinning therapy iand preselection of patients via this immune senescence characteristic improved complete remitter percentages after half a year from 10% (TAU group) to 50% (spinning group plus TAU group).
By combining available evidence from the literature (disability weights, relapse rate, and empirical costs of depression) and available data (the remission and immune signature rates from the spinning cohort), we built an economic model of the health benefits of immune signature based approaches versus current practice. Findings (though preliminary) indicate that immune signature stratified add-on spinning therapy renders both a substantial decrease in the disability from depression and a substantial cost reduction in five years compared to the current practice.
We have - after 5 and a half years study - reached all of our objectives formulated above and the project has delivered important and even break through new data for the diagnosis and treatment of severe mood disorders:
1. We have laid the basis for a paradigm shift, namely the change from a conventional DSM-based psychiatric diagnosis (MDD/BD) to a clinical immunological diagnosis in a considerable proportion of mood disorder patients.
The immunologically defined disorders (combinations of premature T cell senescence/defects and low grade inflammation) not only lead to mood disturbances but also to proneness to auto-immunity, infection and vasculopathy.
2. Simple test systems have been developed to aid in the diagnosis of these immunologically defined disorders.
3. The immune diagnoses of MDD and BD differ and differences in T cell profiles between the two disorders exist. This facilitates an early differential diagnosis between the two disorders, making a better treatment possible.
4. Correction of the T cell abnormalities in MDD and BD by low dose IL-2 or thymus hormone treatment is safe and has clear anti-depressant effects beyond those of regular treatment. Particularly TRD patients with outspoken low grade inflammation and low signs of T cell activation seem to benefit from these immune correcting therapies.
5. Another impact of the paradigm shift (psychiatric diagnosis to immune diagnosis) is that we can preselect patients for relatively novel add-on treatments combatting T cell senescence, such as spinning therapy. MOODSTRATIFICATION shows that in particular patients with signs of premature T cell senescence benefit on the long run from spinning therapy. Moreover our data show that this approach of preselecting patients for this therapy has a favorable cost-benefit ratio.
1. We have laid the basis for a paradigm shift, namely the change from a conventional DSM-based psychiatric diagnosis (MDD/BD) to a clinical immunological diagnosis in a considerable proportion of mood disorder patients.
The immunologically defined disorders (combinations of premature T cell senescence/defects and low grade inflammation) not only lead to mood disturbances but also to proneness to auto-immunity, infection and vasculopathy.
2. Simple test systems have been developed to aid in the diagnosis of these immunologically defined disorders.
3. The immune diagnoses of MDD and BD differ and differences in T cell profiles between the two disorders exist. This facilitates an early differential diagnosis between the two disorders, making a better treatment possible.
4. Correction of the T cell abnormalities in MDD and BD by low dose IL-2 or thymus hormone treatment is safe and has clear anti-depressant effects beyond those of regular treatment. Particularly TRD patients with outspoken low grade inflammation and low signs of T cell activation seem to benefit from these immune correcting therapies.
5. Another impact of the paradigm shift (psychiatric diagnosis to immune diagnosis) is that we can preselect patients for relatively novel add-on treatments combatting T cell senescence, such as spinning therapy. MOODSTRATIFICATION shows that in particular patients with signs of premature T cell senescence benefit on the long run from spinning therapy. Moreover our data show that this approach of preselecting patients for this therapy has a favorable cost-benefit ratio.