The role of immune activation in major depression comorbid with alcohol use disorders

Major depression (MD) is a common disorder in patients with alcohol use disorders (AUD). This relationship is bidirectional. There are many indications that MD in patients with AUD may be triggered by an alcohol-related activation of the immune system. This activation can be accurately measured by looking at concentrations of certain neuroactive trace elements in blood tests. An example of such is the immunological signaling substance cytokines. In earlier studies in AUD patients in Nepal and Norway we have shown that MD in AUD patients may be linked to differences in cytokines and that the extent of the differences is related to the severity of the AUD. These findings in our previous studies and in other international studies stem from cross-sectional studies and no one has previously investigated this in longitudinal surveys. The main purpose of the present study was to study how changes in cytokines are linked to the incidence and development of MD over time in patients in treatment for AUD. We intended to investigate whether the changes in in cytokines were related to treatment outcomes and how other environmental and genetic factors affect this relationship. The study included both a Nepalese and a Norwegian study group to increase the validity of the findings. The aim of the project was to generate basic knowledge about the relationship between MD and AUD and immunology, but also to provide insight into possible risk factors for MD in AUD patients. At the end of the project, several findings have been made, but in relation to the main objective to investigate the role of immunological factors in relation to the development of MD in people with AUD, the project has not been able to deliver positive findings yet. As the data are now under analysis. However, we suggest that patients with AUD are highly immune activated for other various reasons (somatic disease, medication, and drug use) and the small differences that we can expect between non-MD and MD AUD patients "drown" in this context. In other words, we are investigating a group of patients where the impact of cytokines on MD is very difficult to trace. These findings will be published in detail, but then most likely as negative findings. Several other findings have been made in the project. Patients with antisocial personality disorder are frequent among those treated for AUD and that they have special challenges in treatment. Prolactin, a hormone that reflects cravings for alcohol, has different predictors in men and women. Smoking is an additional problem in patients in treatment and this presents surprisingly many challenges. That there are many people with ADHD among patients in treatment for alcohol use disorder and that these more easily get a PTSD diagnosis. Lastly, we identify a close relationship between insomnia and poor treatment outcomes.

I denne studien av pasienter i behandling for alkoholbrukslidelser så vi på biologiske forklaringer av depresjon, spesielt på årsakssammenhengen mellom immunaktivering og depresjon. Svært mange av pasienter var deprimerte og mange faktorer var relatert til det; kjønn, nedsatt fysisk aktivitet, røyking, tyngre rusmiddelbruk, familiebelastning med depresjon, annen psykisk lidelse, traumer og dårlig søvn. Det var imidlertid ikke mulig å demonstrere at alkoholbrukspasienter med depresjon var mer immunaktiverte enn pasienter uten depresjon. Pasientene som var til behandling, var sterkt immuaktiverte sammenlignet med en kontrollgruppe. Dette skyldte somatisk sykdom, rusmiddelbruk og andre forhold. Denne kunnskapen er av verdi for å vurdere andre undersøkelser av sammenhengen mellom alkoholbruk og depresjon. Den klarte imidlertid ikke å peke på spesifikke immunologiske forklaringsvariabler og heller ikke mulige immunologiske intervensjoner for å forebygge depresjon hos disse pasientene.

Major depression (MD) is often co-morbid with and follows alcohol use disorders (AUD). MD is also often correlated to elevations in circulating pro-inflammatory cytokines, believed to reflect changes in immune function and involvement in the pathophysiology of MD. We have earlier performed cross-sectional studies on the relationship between MD and AUD revealing roles of neuroimmune factors (cytokines, tryptophan metabolism parameters and brain-derived neurotrophic serum Levels (BDNF)) in the alcohol-depression interaction. Particularly, cytokine elevation in depression was attenuated in severe AUD cases. We also found large inter personal differences in these neuroimmune factors. Findings point to the necessity for longitudinal studies on these relationships. The current proposal is for two studies that will investigate MD and AUD both with diagnostic and dimensional instruments, in addition to major life events/trauma, socio-demographic variables and several biological measures (pro-inflammatory cytokines like IL-6, IL-1, TNF, IFN; anti-inflammatory cytokines like IL-10; factors like BDNF, tryptophan, kynurenine and TLR4 activity; SNPs like serotonin transporter, mu-opioid receptor, BDNF, dopamine receptor D2 and microbiota analysis. These measures' ability to predict treatment success and long term relapse will also be investigated. These innovative studies will generate important basic scientific knowledge on the relationship between MD, AUD and immunology in clinical settings, but may also provide insights into possible predictors of MD in AUD patients and thus targets for intervention. The two studies will be performed in Norway and Nepal and will involve both national and international collaborations. An ongoing study from our group on MD patients in treatment (with recording of alcohol use level) will be used as control for these groups. The grant application is for 1 full-time PhD position and 1 full-time post-doc position.