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Cytokine-Associated Emotional and Cognitive Disturbances

CITATION:  Reichenberg, A., Yirmlya, R., et al. (2001). Cytokine-Associated Emotional and Cognitive Disturbances.  Arch Gen Psychiatry. 58:445-452


Background: Infectious, autoimmune, and neurodegenerative diseases are associated with profound psychological disturbances. Studies in animals clearly demonstrate that cytokines mediate illness-associated behavioral changes. However, the mechanisms underlying the respective psychological alterations in humans have not been established yet. Therefore, we investigated the effects of low-dose endotoxemia, a well-established and safe model of host-defense activation, on emotional, cognitive, immunological, and endocrine parameters.

Methods: In a double-blind, crossover study, 20 healthy male volunteers completed psychological questionnaires and neuropsychological tests 1, 3, and 9 hours after intravenous injection of Salmonella abortus equi endotoxin (0.8 ng/kg) or saline in 2 experimental sessions. Blood samples were collected hourly, and rectal temperature and heart rate were monitored continuously.

Results: Endotoxin had no effects on physical sickness symptoms, blood pressure, or heart rate. Endotoxin caused a mild increase in rectal temperature (0.5C), and in-creased the circulating levels of tumor necrosis factor a (TNF-a), soluble TNF receptors, interleukin (IL)-6, IL-1 receptor antagonist, and cortisol. After endotoxin ad-ministration, the subjects showed a transient significant increase in the levels of anxiety (effect size [ES] =0.55) and depressed mood (ES=0.66). Verbal and nonverbal memory functions were significantly decreased (ES = 0.55 to 0.64). Significant positive correlations were found between cytokine secretion and endotoxin-induced anxiety (r=0.49 to r=0.60), depressed mood (r=0.40 to r=0.75), and decreases in memory performance (r=0.46 to r=0.68).

Conclusions: In humans, a mild stimulation of the primary host defense has negative effects on emotional and memory functions, which are probably caused by cyto-kine release. Hence, cytokines represent a novel target for neuropsychopharmacological research.


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