Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro inflammatory cytokines facilitate metabolism of tryptophan along the kynurenine pathway (KP) putatively resulting in reduced neuroprotective and increased neurotoxic KP metabolites in MDD, in addition to modulating metabolic and immune function. This central nervous system hypothesis has, however, only been tested in the periphery. Here, we measured KP-metabolite levels in both plasma and cerebrospinal fluid (CSF) of depressed patients (n = 63/36 respectively) and healthy controls (n = 48/33). Further, we assessed the relation between KP abnormalities and brain-structure volumes, as well as body mass index (BMI), an index of metabolic disturbance associated with atypical depression. Plasma levels of picolinic acid (PIC), the kynurenic/quinolinic acid ratio (KYNA/QUIN), and PIC/QUIN were lower in MDD, but QUIN levels were increased. In the CSF, we found lower PIC in MDD. Confirming previous work, MDD patients had lower hippocampal, and amygdalar volumes. Hippocampal and amygdalar volumes were correlated positively with plasma KYNA/QUIN ratio in MDD patients. BMI was increased in the MDD group relative to the control group. Moreover, BMI was inversely correlated with plasma and CSF PIC and PIC/QUIN, and positively correlated with plasma QUIN levels in MDD. Our results partially confirm previous peripheral KP findings and extend them to the CSF in MDD. We present the novel finding that abnormalities in KP metabolites are related to metabolic disturbances in depression, but the relation between KP metabolites and depression-associated brain atrophy might not be as direct as previously hypothesized.

Immune cells and cytokines are largely recognized as significant factors in the pathophysiology of neuropsychiatric disorders. The possible role of other blood cells such as leukocytes in events of acute psychosis is in contrast only emerging. To study blood-born markers in acute psychosis we here evaluated plasma proteins in drug-naive first-episode psychosis (FEP) patients and healthy controls using a multiplex proximity extension assay technique. We analyzed a panel of 92 immune markers and plasma samples from 60 FEP patients and 50 controls and evaluated the changes obtained using multivariate statistical methods followed by protein pathway analyses. Data showed that 11 proteins are significantly different between FEP patients and healthy controls We observed increases in pro-inflammatory proteins such as interleukin-6, oncostatin-M, and transforming growth factor-alpha in FEP patients compared with controls. Likewise, the extracellular newly identified RAGE-binding protein (EN-RAGE) that regulates the expression of various cytokines was also elevated in the plasma of FEP patients. The results indicate that neutrophil-derived EN-RAGE could play an important role during the early phase of acute psychosis by stimulating cytokines and the immune response targeting thereby likely also the brain vasculature.

Background

Depersonalization/derealization disorder is a dissociative disorder characterized by feelings of unreality and detachment from the self and surroundings. Depersonalization/derealization disorder is classified as a primary disorder, but depersonalization symptoms are frequently observed in mood and anxiety disorders. In the context of major depressive disorder (MDD), depersonalization symptoms are associated with greater depressive severity as indexed by treatment resistance, inpatient visits, and duration of depressive episodes. In the current investigation, we tested four network-based, neural-functional hypotheses of depersonalization in MDD. These hypotheses were framed in terms of functional relationships between 1) extrastriate body area and default mode network (DMN); 2) hippocampus and DMN; 3) medial prefrontal cortex and ventral striatum; and 4) posterior and anterior insular cortex.

Methods

We conducted functional magnetic resonance imaging during resting state on 28 female patients with MDD and 27 control subjects with no history of a psychiatric disorder. Functional connectivity between seed and target regions as specified by our network-level hypotheses was computed and correlated with scores on the Cambridge Depersonalization Scale. We used a conservative, unbiased bootstrapping procedure to test the significance of neural-behavioral correlations observed under each of the four models tested.

Results

Of the four neural-functional models of depersonalization symptoms tested, only the model proposing that reduced connectivity between the extrastriate body area and DMN predicts higher levels of depersonalization symptoms in MDD was confirmed.

Conclusions

Our results indicate that depersonalization/derealization disorder symptoms in patients with depression are related to reduced functional connectivity between brain regions that are proposed to support processing of body-related (extrastriate body area) and autobiographical (DMN) information.