Ohr Barak

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).

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavioral responses to immune challenges, such as lipopolysaccharide (LPS). To explore further the effects of antidepressants on neuroimmune interactions, rats were treated daily with either fluoxetine (Prozac) or saline for 5 weeks, and various behavioral, neuroendocrine, and immune functions were measured following administration of either LPS or saline. Chronic fluoxetine treatment significantly attenuated the anorexia and body weight loss, as well as the depletion of CRH-41 from the median eminence and the elevation in serum corticosterone levels induced by LPS. Chronic treatment with imipramine also attenuated LPS-induced adrenocortical activation. In rats and in mice, which normally display a biphasic body temperature response to LPS (initial hypothermia followed by hyperthermia), chronic treatment with fluoxetine completely abolished the hypothermic response and facilitated and strengthened the hyperthermic response. The effects of antidepressants on the responsiveness to LPS are probably not mediated by their effects on peripheral proinflammatory cytokine production, because LPS-induced expression of TNFα and IL-1β mRNA in the spleen (assessed by semiquantitative in situ hybridization) was not altered following chronic treatment with either fluoxetine or imipramine. The effects of antidepressants on the acute phase response may have important clinical implications for the psychiatric and neuroendocrine disturbances that are commonly associated with various medical conditions.

Comparison of the predictive power of socio-economic variables, severity of injury and age on long-term outcome of traumatic brain injury: sample-specific variables versus factors as predictors.

The primary objective of this study was to measure the predictive power of pre-injury socio-economic status (SES), severity of injury and age variables on the very long-term outcomes of traumatic brain injury (TBI). By applying a within-subjects retroactive follow-up design and a factor analysis, the study also compared the relative power of sample-specific predictors to that of more commonly used variables and conceptually based factors. Seventy-six participants with severe TBI were evaluated at an average of 14 years post-injury with an extensive neuropsychological battery. The results show that pre-injury SES variables predict long-term cognitive, psychiatric, vocational, and social/familial functioning. Measures of severity of injury predict daily functioning, while age at injury fails to predict any of these variables. Sample-specific predictors were more powerful than more commonly used predictors. Implications regarding long-term clinically based and conceptually based prediction, and those regarding comparisons of predictors across samples are further discussed.

Hope, dispositional optimism and severity of depression following traumatic brain injury.

Primary objective: To investigate the extent in which two coping variables—hope and dispositional optimism—are related to depression severity amongst individuals who have sustained traumatic brain injury (TBI). Methods and procedures: Sixty-five participants were administered the Beck Depression Inventory (BDI), the Adult Hope Scale (AHS), the Life Orientation Test-Revised (LOT-R) and a demographic and injury-related data questionnaire. In addition, relevant injury-related data was collected from the medical records. Main outcomes and results: High levels of depression were experienced in the study sample, while hope and dispositional optimism were significantly lower in comparison to the general population. The correlation patterns indicate that both hope and dispositional optimism negatively correlated with participants’ depression levels and that they showed significant positive correlations with each other. In the case of mild depression, the hope-Pathways sub-scale of the AHS was the only variable negatively correlated to it, while in moderate-to-severe depression all coping variables were negatively correlated to it. Regression analysis revealed that the AHS and LOT-R, but not the demographic and injury-related variables, predicted depression severity. Conclusions: Clinical implications in referring persons with TBI with mild vs. severe depression to rehabilitation programmes are discussed.

Unawareness of Cognitive Deficits and Daily Functioning Among Persons With Traumatic Brain Injuries

This study examines levels of unawareness of cognitive deficits and their relationship to functional outcome among persons with traumatic brain injury (TBI). Data from 61 persons with TBI and 34 family members consisting of various measures were used. The results suggest that awareness of cognitive deficits is not differentially distributed along a concrete- continuum of cognitive domains. Awareness in this sample was significantly related to psychiatric symptomatology and partially associated with behavior disturbances and daily functioning, but not with vocational outcomes. Persons with TBI who over-estimated their cognitive abilities were found to function worse on most outcome measures, except vocation, than persons who did not overestimate their abilities.

Involvement of brain cytokines in the neurobehavioral disturbances induced by HIV-1 glycoprotein120.

Intracerebroventricular (i.c.v.) administration of HIV-1 glycoprotein 120 (gp120), the envelope protein used by the virus to gain access into immune cells, induces neurobehavioral alterations in rats. To examine the role of proinflammatory cytokines in mediating these effects, we measured the effects of gp120 on brain proinflammatory cytokine expression and the effects of anti-inflammatory agents, including interleukin-1 receptor antagonist (IL-1ra), pentoxifylline (a TNFalpha synthesis blocker) and IL-10, on gp120-induced sickness behavior. I.c.v. administration of gp120 induced the expression of IL-1beta, but not TNFalpha, mRNA in the hypothalamus, 3 h after the injection. Pretreatment of rats with IL-1ra, but not with pentoxifylline, significantly attenuated gp120-induced anorexia and loss in body weight, whereas both agents had no effect on gp120-induced reduction in locomotor activity in the open field. Pretreatment with either IL-1ra and pentoxifylline simultaneously, or with IL-10, produced effects that were similar to the effects of IL-1ra alone. Together, these findings indicate that IL-1, but not TNFalpha, mediates some of the behavioral effects of acute gp120 administration, suggesting that brain IL-1 may be involved in some of the neurobehavioral abnormalities evident in AIDS patients.

Intracerebral administration of Mycoplasma fermentans produces sickness behavior: role of prostaglandins

Mycoplasmas are small microorganisms, which cause various diseases in animals and in humans, activate the immune system, and induce the release of various cytokines. Some of the effects of mycoplasmas are mediated by the CNS. Moreover, Mycoplasma fermentans (MF) has recently been found in the brain, as well as other tissues of some AIDS patients, who usually display severe neurobehavioral disturbances. The present study was designed to examine the behavioral effects of central administration of MF, and the role of prostaglandins in mediating these effects. In one set of experiments, rats were injected intracerebroventricularly (i.c.v.) with either saline or a dose of MF (5.1-36 microg per rat), and several behavioral parameters were measured. In addition, body temperature and locomotor activity were continuously monitored by a biotelemetric system. MF induced a significant elevation in body temperature and suppression of motor activity levels. MF also significantly reduced the time spent in social exploration, decreased locomotor and exploratory activity in the open field test, suppressed the consumption of food and saccharine solution, and reduced body weight. In a second set of experiments, i.c.v. administration of MF (7.2 microg) was found to produce a significant increase in the production of prostaglandin E2 (PGE2) in hypothalamic, hippocampal, and cortical tissues. This effect was blocked by indomethacin, a prostaglandin synthesis inhibitor. Indomethacin also attenuated the effects of MF on body temperature, motor activity and body weight, suggesting the involvement of prostaglandins in mediating some of the effects of MF. Together, these findings suggest that the presence of MF in the brain may be responsible for some of the neurobehavioral abnormalities in HIV-infected patients.

Intracerebral HIV-1 glycoprotein 120 produces sickness behavior and pituitary-adrenal activation in rats: Role of prostaglandins

HIV infection is associated with profound neurobehavioral and neuroendocrine impairments. Previous studies demonstrated that HIV causes neuropathological alterations indirectly, via shedding of glycoprotein 120 (gp120) within the brain. To extend these findings, we examined the neurobehavioral and neuroendocrine effects of central administration of gp120, as well as the role of brain prostaglandins in mediating these effects. Intracerebroventricular (i.c.v.) injection of gp120 in rats produced a marked sickness behavior syndrome, consisting of reduced exploratory behavior, suppressed consumption of food and saccharin solution, and reduced body weight. Gp120 also induced a significant febrile response and increased serum levels of ACTH and corticosterone. Following i.c.v. gp120 administration, the ex vivo production of PGE2 by the hypothalamus, frontal cortex, and hippocampus was significantly elevated, and indomethacin, a prostaglandin synthesis inhibitor, attenuated this elevation. Pre-treatment with indomethacin reduced the fever and adrenocortical activation induced by gp120 administration, but not its behavioral effects. These findings indicate that gp120 may be responsible for some of the behavioral and endocrine abnormalities seen in HIV-infected patients. Prostaglandins are important mediators of the physiological, but not the behavioral effects of brain gp120.

A novel permissive role for glucocorticoids in induction of febrile and behavioral signs of experimental herpes simplex virus encephalitis

Herpes simplex virus type 1 (HSV-1) encephalitis may present with fever and behavioral changes, to the extent of a psychotic state and psychomotor agitation. We developed a clinically relevant experimental model of HSV-1 encephalitis and investigated host brain responses associated with its clinical signs and whether these responses depend on the presence of circulating glucocorticoids. Intracerebral inoculation of HSV-1 in rats induced fever, motor hyperactivity and aggressive behavior. In adrenalectomized rats HSV-1 failed to induce these signs, although mortality rate was identical to sham-operated rats. Hypophysectomy or blocking glucocorticoid receptors also prevented HSV-1-induced fever. Dexamethasone replacement therapy to adrenalectomized rats restored the HSV-1-induced fever and behavioral abnormalities. HSV-1 inoculation produced hyperproduction of prostaglandin E(2) by brain slices. This effect was abolished in adrenalectomized rats and was restored by dexamethasone treatment. In intact rats HSV-1 induced brain interleukin-1beta (IL-1beta) gene expression. Adrenalectomy alone caused brain IL-1beta expression, which did not increase after HSV-1 infection. Similarly, HSV-1 induced IL-1beta expression in astrocyte cultures. Removal of cortisol from the culture medium caused basal IL-1beta mRNA expression which was not increased by infection. In conclusion, fever, motor hyperactivity and aggressive behavior during experimental HSV-1 encephalitis are dependent on brain responses, including prostaglandin E(2) and IL-1beta synthesis. Circulating glucocorticoids play an essential permissive role in the induction of these host brain responses.