Translational research

Medical Background

Depressions are among the most common mental illnesses. With a lifetime prevalence of 10-15%, they are a major cause of work disability. The World Health Organization (WHO) predicts that by 2020, unipolar depression – along with cardiovascular diseases – will be the world’s leading cause of disease.The disease is characterized by symptoms such as depressed mood, lack of interest or pleasure in usual activities, feelings of guilt and worthlessness, disorders of sleep and appetite, lack of energy, difficulty concentrating and suicidal thoughts. These symptoms can reappear and in the worst case show chronic manifestation, which can substantially impair the ability to cope with everyday life. At worst, depression can be life threatening – if untreated, 10-15% of those affected commit suicide.

Depression is proven to be a risk factor for cardiovascular disease, comparable with elevated blood lipid levels or high blood pressure. In addition, studies show that depression in adult diabetic patients is three to four times more frequent than in persons with a healthy metabolism. An estimated one in four people with diabetes suffers from a mild depressive disorder, about one in ten from severe depression.

About 40-50% of the risk of developing depression is due to a genetic predisposition. Nevertheless, a vulnerability gene has not yet been identified and validated, pointing to a complex reciprocal relationship between genetic components and environmental factors as cause. A relevant environmental factor for the pathogenesis of depression is stress and in this context the capability of the organism to manage stress. During stress the brain activates a number of different centers involved in sensory, motor, autonomous, cognitive and emotional functions in order to adjust adequately to the respective situation. Dysregulation of this physiological stress response in terms of over-reaction or chronic activation can have serious psychological and physiological consequences, even including the development of mental disorders.

Today, depression pharmacotherapy is based almost exclusively on substances which modulate neurotransmission via biogenic monoamines – a pharmacological principle that was accidentally discovered back in the 1950s. Although since that time significant progress has been made with respect to reducing adverse side effects, the efficiency of this substance class is still unsatisfactory, i.e. only about 60% of patients respond to this medication, and even modern antidepressants take several weeks before they develop their full effect.

The development of new drugs is complicated by the fact that – like in many other complex mental and neurological diseases – the underlying mechanisms are generally not well understood. An additional difficulty is that it is hard to gain access to primary human tissue and/or it is practically not available. Hitherto, only very inadequate bona fide animal models exist for these diseases.

Project Aim

The aim of the Clinical Cooperation Group Molecular Neurogenetics is to unravel the causes and mechanisms of mental diseases – especially depression – on the genetic, molecular and cellular level and thus make a significant contribution to a deeper understanding of the etiology and pathophysiology of mental disorders. Genetic mouse models are primarily used for this purpose. Based on insights gained from basic research and from the animal model, new therapy options will be tested in clinical trials.