Avraham Morag

Illness, Cytokines, and Depression

Abstract: Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double‐blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus‐induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS‐induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS‐induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive‐like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS‐induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF‐α mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness‐associated depression.

Cytokines, “Depression Due to A General Medical Condition,” and Antidepressant Drugs

Activation of the immune system during various medical conditions produces neural, neuroendocrine, and behavioral effects. The psychological and physiological effects of immune activation resemble many characteristics of depression. The essential features of depression are depressed mood and loss of interest or pleasure in all, or almost all activities (anhedonia). Several associated symptoms are also present, including, appetite disturbance, change in body weight, sleep disturbance, psychomotor disturbance, fatigue, loss of energy, and difficulty in thinking or concentrating (DSM-IV, 1994). Depression is also characterized by specific alterations in the functioning of neurochemical and neuroendocrine systems, including monoaminergic systems and the hypothalamic-pituitary-adrenal (HPA) axis (Brown, Steinberg, & van Praag, 1994; Holsboer, 1995). Most of these psychological and neuroendocrine symptoms appear both in humans and animals during diseases that involve immune activation. Based on these findings, and on several additional lines of evidence that will be presented below, we have recently argued that immune activation is involved in the etiology and symptomatology of depression associated with various medical conditions (Yirmiya, 1997).

Mucosal [SIgA] and serum [IgG] immunologic responses in the community after a single intra-nasal immunization with a new inactivated trivalent influenza vaccine

Influenza morbidity affects entire populations, imposing an enormous burden in economic terms from working days lost. Protection afforded by current vaccines is often unsatisfactory and many individuals remain averse to injections. To counter these drawbacks, we tested an inactive intra-nasal trivalent influenza vaccine on 182 vaccinated and 92 placebo subjects in the community. On study completion 73 and 66% of the subjects were immune to the vaccines two A strains, 40% (> or=1:40) and 65% (> or=1:20) to its B strain; 30-40% demonstrated a 4x hemagglutination inhibition (HAI) titer increase; GMT titers increased 2.2-2.5x. About 50% of those initially non-immune became immune. A local antibody response to the three vaccine strains was recorded in 31-44% of vaccinees in which 57, 68 and 54% exhibited a mucosal and/or serum antibody response to the A/Johannesburg, A/Nanchang and B/Harbin strains, respectively. A higher dose (40mg) of A/Johannesburg in the vaccine did not influence response. The new vaccine was safe, without side-effects, and offered reasonable protection after one dose. It could thus play an important role in increasing enrollment into immunization programs.

A double-blind trial of a new inactivated, trivalent, intra-nasal anti-influenza vaccine in general practice: relationship between immunogenicity and respiratory morbidity over the winter of 1997–98

BACKGROUND Influenza is responsible for considerable morbidity not only among older people but in younger age groups as well. However, most large-scale anti-influenza vaccination campaigns are still aimed principally at the elderly using injectable vaccines. Until now there has been much less emphasis on targeting younger populations or using intra-nasal vaccines in mass anti-influenza immunisation programmes. OBJECTIVES To assess the immunogenicity of a new inactivated intra-nasal anti-influenza vaccine and to measure its effect on respiratory morbidity in a volunteer general practice population. STUDY DESIGN A prospective, double-blind, placebo-controlled trial using the new vaccine was carried out over the winter of 1997-98 on 274 healthy patients aged 12-60 from three Israeli general practices, 182 in the vaccine group and 92 in the placebo group. Following vaccination the changes in the antigen levels and episodes of respiratory illness in the vaccine and placebo groups were measured. RESULTS Protective antibody levels occurred after a single dose of vaccine [influenza H1N1, 41% immune pre-vaccination to 73% post-vaccination; influenza H3N2, 35-66%; influenza B, 27-64%]. Between January and March 1998, when influenza activity was at a peak in Israel, the average number of respiratory illness events in the vaccine group [14 events/100 subjects per month] was significantly less than in the placebo group [22 events/100 subjects per month]; similarly, the average number of respiratory illness days in the vaccine group over the same period [69 days/100 subjects per month] was significantly less than in the placebo group [117 days/100 subjects per month]. CONCLUSIONS The new vaccine possessed significant immunogenicity and was associated with a significant reduction in respiratory morbidity among a group of healthy older children and adults. Since intra-nasal vaccines are simpler to administer and more acceptable to the public than injections the vaccines potential for use in routine anti-influenza vaccination campaigns seems promising, especially if its beneficial effects are also reproducible in more medically vulnerable populations.