Everything in its right place

Abstract

This thesis aimed at exploring immunological aspects of mainly obsessive compulsive disorder (OCD) as well as generalized social anxiety disorder (GSAD), major depressive disorder (MDD) and psychosis. First we reviewed nearly 100 clinical studies on immunological disturbancesin anxiety disorders.In particular, OCD and post-traumatic stress disorder (PTSD) have been associated with mostly inconsistent alterations in the immune system. However, some findings,such as TNF-α disturbances in OCD appear to be reliable and reproducible across different studies. This is supported by our findings of significant lowerlipopolysaccharide (LPS) stimulated TNF-αlevels and decreased NK activity in OCD patients relative to controls. To examine the specificity of the observed immune alterations in OCD, we compared OCD patients, GSAD patients and healthy controls. OCD patients differed from healthy controls with respect to LPS stimulated levels of IL-6, while no statistically significant differences were found between GSAD patients and healthy controls. Direct comparison between OCD and GSAD patients yielded a trend towards lower IL-6 levels in OCD patients. These results underline the diversity of immune alterations in anxiety disorders. To study whether the observed immune alterations in OCD were state dependent we explored, in a small study, the immune function during a standardized provocation paradigm. We found thatLPS stimulated production of TNF-αand IL-6 by peripheralleucocytes decreased during exposure to disgust-relatedobjects in OCD patients but not in healthycontrols, indicating that specific immune factors are affected by the state an OCD patient is in. We hypothesized a role of the noradrenergic system during exposure to explain the observed changes in TNF-αand IL-6 levels. To explore the impact of treatment on the immune status of OCD patients, we studied the effect of antidepressants in a randomized controlled design. The results show that immune parameters were not significantly affected by a 12-week trial with either paroxetine or venlafaxine neither in responders nor in non-responders to treatment. In addition we studied, in an explorative design, the immune and neuroendocrine response on electroconvulsive therapy (ECT) in 12 MDD patients. We found that ECT had an immediate, but transient, effect on several immune and neuroendocrine parameters while consecutive session of ECT showed no additional effect, indicating that this treatment has no lasting effect on immune or neuroendocrine functions. This could suggest that the acute biological changes in response to ECT, as observed in our study, are not involved in its therapeutic effects. Finally we studied neuroendocrine and immune parameters in medication-naïve male patients suffering from a first episode of psychosis, and 15 healthy controls, during a public speaking task. While previous studies suggested that schizophrenia is associated with a blunted stress response, we found that this blunting is already present in medication-naive patients with a first episode of psychosis. This implies that impairments in stress processing are either related to the psychosis or already present before the onset of the first psychotic episode and may be considered an endophenotype or vulnerability factor.