Mood disorders today: a prevalent disease…

A mental disorder is characterized by a clinically significant disturbance in an individual’s cognition, emotional regulation, or behavior.  It is usually associated with distress or impairment in important areas of functioning. 

In 2019, 1 in every 8 people, or 970 million people around the world were living with a mental disorder, with mood disorders the most common. Mood disorders consist of anxiety disorder, major depressive disorder and bipolar disorder, which share common clinical features in the domains of emotion, behavior and cognition. In 2020, the number of people living with anxiety and depressive disorders rose significantly because of the COVID-19 pandemic.  Initial estimates show a 26% and 28% increase respectively for anxiety and major depressive disorders in just one year.

Before the pandemic, in 2019, 301 million people were living with an anxiety disorder including 58 million children and adolescents.  Anxiety disorders are characterized by excessive fear and worry and related behavioral disturbances. Symptoms are severe enough to result in significant distress or significant impairment in functioning.

Also in 2019, 280 million people were living with depression, including 23 million children and adolescents. Depression is different from usual mood fluctuations and short-lived emotional responses to challenges in everyday life.  During a depressive episode, the person experiences depressed mood (feeling sad, irritable, empty) or a loss of pleasure or interest in activities, for most of the day, nearly every day, for at least two weeks. Several other symptoms are also present, which may include poor concentration, feelings of excessive guilt or low self-worth, hopelessness about the future, thoughts about dying or suicide, disrupted sleep, changes in appetite or weight, and feeling especially tired or low in energy. Depression is about 50% more common among women than among men. Worldwide, more than 10% of pregnant women and women who have just given birth experience depression.

Regarding bipolar disorder 40 million people suffer from this disorder.  People with bipolar disorder experience alternating depressive episodes with periods of manic symptoms.  During a depressive episode, the person experiences depressed mood (feeling sad, irritable, empty) or a loss of pleasure or interest in activities, for most of the day, nearly every day.  Manic symptoms may include euphoria or irritability, increased activity or energy, and other symptoms such as increased talkativeness, racing thoughts, increased self-esteem, decreased need for sleep, distractibility, and impulsive reckless behaviour.  

People with severe depression and bipolar disorder are at an increased risk of suicide. More than 700 000 people die due to suicide every year. Suicide is the fourth leading cause of death in 15–29-year-olds.The high prevalence’s make mood disorders the leading cause of disability among people of working age in the world and Europe and therefore constitute a major economic and public health issue.

… Still not cured well. Other approaches are necessary.

Although many patients with mood disorders have access to effective treatments in the EU countries, the overall prognosis of the disease is far from optimal and satisfactory. Some examples speak for themselves: only 50% of patients with major depressive disorder respond in first instance to currently regular antidepressant treatments, at least one third of patients suffer from treatment-resistant depression (TRD). Current therapies and psychotherapies are struggling to provide optimal management for patients with mood disorders. The urgency today is to understand, prevent and treat the mood pathologies. The suffering of patients and their families requires adequate care.

Several difficulties stand in the way of this necessity. Firstly, the pathogenesis of mood disorders remains largely unexplained. As a result, the current classification of mood disorders (DSM, ICD) is based only on clinical symptoms and fails to take into account biological abnormalities. Unfortunately, these clinical categories do not explain and predict response to treatment and can’t help to identify underlying etiological mechanisms. To date, studies have identified several immune pathophysiological mechanisms and potential immune predictors of treatment outcome for mood disorders. The integration of all these data into a clinical-immune biological model that would take into account symptoms, patient suffering and immune abnormalities would make it possible to identify homogeneous subgroups of patients, diagnosed by objective and quantifiable markers, in order to propose more effective prevention and therapy strategies that are more effective because they are based on the correction of the underlying immune biological mechanisms.

An integrative approach that takes into account these domains is necessary: socio-demographic, psychological, clinical, immune, microbial and genetic characteristics are associated with prognosis and could therefore be appropriate predictors.

The promises of Immuno-psychiatry for mood disorders

Indeed, immune abnormalities, central or peripheral, are the most promising leads in psychiatry, and particularly in relation to mood disorders. A large number of recent studies (including our own) suggest a strong association between T cells defect and mood disorders. T cells (also known as T lymphocytes) are a type of white blood cells which play an essential role in the adaptive immune response of our body to infections and stress. The ‘T’ stands for ‘thymus’, the organ in which T cells mature. There are different kinds of T cells, working together in a well-balanced T cell system, which (in cooperation with our hormone system and neurological system) helps us to recover from infections and stress. Imbalances in the T cell system can have a genetic and/or environmental background, such as (chronic) virus infections, such as with COVID-19 (a well-known recent example). T cell imbalances disturb our “defense system”. For example, the T cell system can become “weaker”, when the natural aging of T cells is accelerated (“premature T cell aging”) due to such a chronic viral infection in genetically vulnerable individuals, resulting in a much earlier occurrence of age-related pathologies.

 A healthy T cell system is capable of dampening excessive inflammation, caused by inflammatory stimuli like childhood trauma or infection. When T cells are imbalanced, and the dampening of inflammation is not functioning well enough, this results in so called chronic low-grade inflammation. This has an extra impact on the brain where such low-grade inflammation disturbs white matter functioning.

Chronic low-grade inflammation is known to be associated with mood disorders episodes and to specific characteristics and appears thus a good target to make progress in treatment and support of patient suffering with mood disorders

Research in immunopsychiatry in Europe: MOODSTRATIFICATION and previous projects of the coordinator.

Research in immunopsychiatry has been the subject of investment of funds by Europe in recent years. See the tab “Research”

MOODSTRATIFICATION outcomes

Despite considerable delays, due to the lock downs of the corona pandemic and (administrative) struggles with our ethical review boards, we have successfully ended the MOODSTRATIFICATION project in 2023. We have reached virtually all of our objectives and have delivered important new breakthroughs:

• We discovered abnormal immune states of T cells and of monocytes, macrophages and microglia in major mood disorders
• We found differences in these abnormal immune states between Major Depressive Disorder (MDD) and Bipolar Disorder (BD).

This difference makes an early laboratory diagnosis of MDD and BD possible which facilitates an earlier and better treatment of the disorders.

• We found a new therapy (low dose IL-2) for MDD and BD in two placebo-controlled trials. This therapy increases the numbers of a beneficial subgroup of immune cells (the T regulatory cells) and alleviates the severity of the depression.
• We showed that a new therapy using thymus hormone had beneficial effects in an open label non-placebo-controlled trial of a small group of five depressed patients. The therapy rejuvenated premature aging T cells and alleviated the severity of depression.
• We identified a subgroup of depressed patients characterized by a specific T cell state (a premature aging of a specific subgroup of T cells) , who were in particular reactive to the beneficial effects of spinning therapy. This approach was also cost-effective.
• Overall our data show that antidepressant treatments (be it immune or non-immune) “do not fit all”, but that depressed patients need to be preselected with our developed immune tests to enable personalized immune and non-immune treatment schemes for better results.

MOODSTRATIFICATION: A paradigm change.

Concretely, MOOSTRATIFICATION has introduced a paradigm change and:

• Identified immune cell abnormalities as cause for severe mood disorders
• Identified new immune treatments for severe mood disorders correcting these immune cell abnormalities,
• Identified characteristic immune states responsive to these treatments.

It’s a realistic scenario that in the late 2020’s we will be able to give a personalized treatment of patients with psychiatric disorders like depressions, based on the immune signatures in these patients. Four (fictive) cases of patients illustrate what could be the impact of the current research. We describe what would happen to these patients before and after the development of new diagnostic methods and treatments in the EU-funded project MOODSTRATIFICATION:

A future scenario

The year 2020:

In Rotterdam, the main port of Europe, Samantha, Fatima, Jan and Rose have appointments with Sigmund, a psychiatrist, all of them because of severe fatigue, loss of energy, irritability, sleeping problems and difficulties with concentrating. Samantha never had these complaints before, the other three had a previous mild episode. After a consult, assessing current complaints and symptoms as well as psychiatric and physical illness history, all four are diagnosed with a major depressive disorder in the course of probably a unipolar major depressive disorder. Sigmund starts with pharmacological treatment, i.e. as the first step with the serotonin-re-uptake inhibitor (SSRI) sertraline in all patients.

Four weeks later, Samantha, Fatima, Jan and Rose have a follow-up appointment with Sigmund. In Samantha the depressive symptoms have reduced considerably, in the three others not. Sigmund switches to augmentation with lithium in all three.

Another 4 weeks later only Jan has responded. The other two are now prescribed the tricyclic antidepressant (TCA) amitryptiline.

After another 4 weeks only Fatima has improved, but she also reports considerable side effects.

Sigmund discusses with Rose the possibility of electroconvulsive therapy (ECT). Rose is afraid of this treatment, has lost her motivation after now 4-5 months of depression, and decides to look elsewhere. Her depression is certainly not over and she is not back to work. It is known that the prognosis of Rose is very poor, the vast majority of these patients are so-called treatment resistant and have a very high chance of having to live on welfare benefits for considerable periods of time and will also suffer in their private lives (breaking up marriages, etc.) They are a burden for themselves and society.

The year 2030

In Rotterdam, the main port of Europe, Samantha, Fatima, Jan and Rose have appointments with Sigmund, a psychiatrist, all of them because of severe fatigue, loss of energy, irritability, sleeping problems and difficulties with concentrating. Samantha never had these complaints before, the other three had a previous mild episode. After a consult, assessing current complaints and symptoms as well as psychiatric and physical illness history, all four are diagnosed with a major depressive disorder in the course of probably a unipolar major depressive disorder. Sigmund starts with pharmacological treatment, i.e. as the first step with the serotonin-re-uptake inhibitor (SSRI) sertraline in all patients.

Sigmund also sends Samantha, Fatima, Jan and Rose to Koch, the clinical immunologist, for blood tests. The blood samples are analyzed in the following days, using routine diagnostic tools. After 5 days Sigmund receives the results of the tests. The tests show that:

• Samantha (26 years) does not have any immune abnormalities. The clinical and immune profile predicts that she will respond to the SSRI sertraline;

• Fatima (28 years) has clear signs of an early aging T helper cell system (reduced naïve T helper cells, increased memory T helper cells) and also increased levels of pro-inflammatory compounds in serum. This immune profile predicts that she requires a pharmacological treatment with the SSRI sertraline enforced with an anti-inflammatory therapy (e.g. minocycline) and spinning therapy to get a good anti-depressant response.

• Rose (38 years) has a clear monocyte inflammatory profile, high serum levels of pro-inflammatory cytokines and reduced serum markers of T cell activity (low IL-2 and IL-7). A MOODSTRATIFICATION trial (funded in EU Horizon 2020) and ended in 2023 has shown that in such patients augmentation of the SSRI with a T cell enforcing therapy (e.g. low dose IL-2 therapy) is successful to get a better and more sustained anti-depressant response;

• Jan (32 years) also has a strong monocyte inflammatory profile and high hCRP, reduced CD3+ T cells, yet without signs of a CD4+ T helper cell defect. In contrast he has high numbers of Th2 and Th17 cells, high numbers of T central memory cells and also BDNF is high in serum. On the basis of this profile his depression is probably an early episode within an evolving bipolar disorder, which suggests that adding lithium would be a better option than an SSRI alone. For a further optimal response the lithium needs to be enforced by low dose IL-2 therapy.

The next week, Samantha, Fatima, Jan and Rose visit the clinic of Sigmund again to discuss the lab outcomes. Sigmund explains the diagnosis to the patients and also discusses the reason for the various add-on pharmacological, immune and physical medications he advises. The patients agree and are treated accordingly.

Two months later Samantha, Fatima, Jan and Rose have a follow-up appointment with Sigmund. In Samantha and Jan almost all symptoms have disappeared, while in Fatima and Rose symptoms have reduced considerably. Sigmund suggest to continue medication to all four patients for at least another 6 weeks and they agree. All have been back to work.