Examining immune-inflammatory mechanisms of probiotic supplementation in depression: secondary findings from a randomized clinical trial.

We recently indicated that four-week probiotic supplementation significantly reduced depression along with microbial and neural changes in people with depression. Here we further elucidated the biological modes of action underlying the beneficial clinical effects of probiotics by focusing on immune-inflammatory processes. The analysis included a total of N = 43 participants with depression, from which N = 19 received the probiotic supplement and N = 24 received a placebo over four weeks, in addition to treatment as usual. Blood and saliva were collected at baseline, at post-intervention (week 4) and follow-up (week 8) to assess immune-inflammatory markers (IL-1ß, IL-6, CRP, MIF), gut-related hormones (ghrelin, leptin), and a stress marker (cortisol). Furthermore, transcriptomic analyses were conducted to identify differentially expressed genes. Finally, we analyzed the associations between probiotic-induced clinical and immune-inflammatory changes. We observed a significant group x time interaction for the gut hormone ghrelin, indicative of an increase in the probiotics group. Additionally, the increase in ghrelin was correlated with the decrease in depressive symptoms in the probiotics group. Transcriptomic analyses identified 51 up- and 57 down-regulated genes, which were involved in functional pathways related to enhanced immune activity. We identified a probiotic-dependent upregulation of the genes ELANE, DEFA4 and OLFM4 associated to immune activation and ghrelin concentration. These results underscore the potential of probiotic supplementation to produce biological meaningful changes in immune activation in patients with depression. Further large-scale mechanistic trials are warranted to validate and extend our understanding of immune-inflammatory measures as potential biomarkers for stratification and treatment response in depression. Trial Registration: www.clinicaltrials.gov , identifier: NCT02957591.

Modulation of HPA axis response to social stress in schizophrenia by childhood trauma.

HPA axis functioning plays an important role in the etiology of schizophrenia spectrum disorders (SSD). However, only few studies have examined HPA axis responsivity to psychosocial stress in SSD, and results are heterogeneous. Furthermore, childhood trauma is known to influence psychopathology and treatment outcome in SSD, but studies on the influence of childhood trauma on stress related HPA axis activity are missing. The purpose of this study was to investigate cortisol response to a psychosocial stress challenge in SSD patients, and to examine its association with severity of childhood trauma. The present study included 25 subacutely ill patients with a current episode of a chronic SSD and 25 healthy controls. Participants underwent the modified Trier Social Stress Test, and salivary cortisol levels were assessed. The childhood trauma questionnaire was used to assess severity of adverse life events. Overall, cortisol response was blunted in the patient group compared to the control group (p<0.01). Furthermore, we identified two patient subgroups (cortisol responders (n=12) vs. non-responders (n=13) to the modified TSST) that differed in their severity of childhood trauma experience: responders had experienced more emotional abuse in their past (p<0.042). Therefore, childhood trauma might influence stress-related HPA axis activity in SSD. Our data contribute to the hypothesis that severity of childhood trauma may be of pathophysiological relevance in schizophrenia. In addition, it may be an overlooked factor contributing to inconsistent findings regarding HPA axis response to psychosocial stress in SSD.

Experimentally induced psychosocial stress in schizophrenia spectrum disorders: A systematic review.

BACKGROUND: There is evidence that exposure to social stress plays a crucial role in the onset and relapse of schizophrenia; however, the reaction of patients with schizophrenia spectrum disorder (SSD) to experimentally induced social stress is not yet fully understood. METHOD: Original research published between January 1993 and August 2015 was included in this systematic literature research. Social stress paradigms, reporting subjective responses to stress measures, plasma or saliva cortisol, or heart rate (HR) in patients with SSD were included. 1528 articles were screened, 11 papers (390 patients) were included. RESULTS: Three main findings were attained concerning chronically ill patients: (1) overall similar subjective responses to stress ratings between SDD patients and controls, (2) no group differences in cortisol response to psychosocial stress and (3) an increase in HR after the stress exposure was seen in patients and controls. The study examining first-episode patients found higher subjective responses to stress and lower stress-induced cortisol levels. CONCLUSION: The results indicate that first-onset medication free patients may show differences in subjective responses to stress measures and cortisol release while chronically ill patients display no differences in subjective and cortisol response. This may be the correlate of a pathophysiological dysfunction of the hypothalamic-pituitary-adrenal axis prior or at the onset of SSD and a subsequent change in dysregulation during the course of the illness. Given the paucity of studies investigating psychosocial stress in SSD and the pathophysiological relevance of psychosocial stress for the illness, there is need for further research. (PROSPERO registration number: CRD42015026525).