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Abraham Reichenberg, PhD; Raz Yirmiya, PhD; Andreas Schuld, MD; Thomas Kraus, MD; Monika Haack, MA; Abraham Morag, MD; Thomas Pollmächer, MD

Arch Gen Psychiatry. 2001;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 (0.5°C), and increased the circulating levels of tumor necrosis factor (TNF-), soluble TNF receptors, interleukin (IL)-6, IL-1 receptor antagonist, and cortisol. After endotoxin administration, 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 cytokine release. Hence, cytokines represent a novel target for neuropsychopharmacological research.

From the Department of Psychology, the Hebrew University, Jerusalem, Israel (Drs Reichenberg and Yirmiya); Max Planck Institute of Psychiatry, Munich, Germany (Drs Schuld, Kraus, and Pollmächer and Ms Haack); and the Clinical Virology Unit, Hadassah-Hebrew University Medical Center, Jerusalem (Dr Morag). Dr Morag is deceased.

Corresponding author: Raz Yirmiya, PhD, Department of Psychology, the Hebrew University of Jerusalem, Jerusalem, Israel (e-mail: msrazy{at}mscc.huji.ac.il).