Mechanisms and personalized treatment of depression-induced alcoholism

• Applicants: Professor Dr. Erich Gulbins; Professor Dr. Johannes Kornhuber; Professor Dr. Christian P. Müller, Ph.D.
• Subject Area: Biological Psychiatry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 523437055

Alcohol addiction is a common psychiatric disorder with severe health consequences for the individual and detrimental effects for social environment and society. A pathway into alcoholism is the depression-induced alcohol addiction. Thereby, adverse life events, stress, or a particular susceptibility leads to a primary depression. In an attempt to reduce stress and counteract primary depression, controlled alcohol consumption can develop into a high frequency compulsive use and, finally, alcohol addiction. In contrast, high alcohol consumption may also induce a secondary depression in non-depressed individuals. At present, there are no specific therapies available to selectively treat the different aetiopathologies of alcohol addiction. In the previous project, we identified the enzymes acid- (ASM) and neutral sphingomyelinase (NSM) and its sphingolipid product ceramide in the brain as major mediators for the alcohol-addiction/ depression co-morbidity. In parallel, we showed an important role of the brain sphingolipid rheostat for cognitive behaviour. In a pilot study, we found that blood plasma ceramide levels are enhanced in alcohol addicts as well as patients with major depression when enrolled for treatment. We characterized potential effects of plasma ceramide (pCer) and found a brain mechanism by which it controls stress-induced depression and depression-related behaviour. The aim of this project is to identify the role of pCer in alcohol addiction/ depression comorbidity and delineate a new treatment target. We will first characterize how an enhanced pCer activity controls alcohol consumption and addiction-related behaviours in two stress models. We will then identify a pathway of how pCer regulates neuronal signalling and neuronal activity in the reward system of the brain. Then we will investigate a technique to remove elevated ceramide from plasma as a potential new treatment strategy for the alcohol addiction/ depression co-morbidity. To translate these findings into humans, we will characterize pCer and sphingolipid enzyme activity in the blood of treatment seeking alcohol addicts as potential biomarker, which might allow distinguishing alcohol dependent patients with comorbid primary vs. secondary depression, and specifically guide a personalized treatment. This project will further help to develop new diagnosis tools and pharmacotherapies for specific subtypes of alcohol addiction that are personalized and tailored to specific aetiology and needs.

• DFG Programme: Research Grants