Neuroimmunology of Anxiety Disorders
There is unequivocal evidence that stress is both causally related and a concomitant of most psychiatric disorders, including anxiety syndromes. For example, the post-traumatic stress disorder typically arises after unusual stress life experiences. Panic disorder is a syndrome with anxiety as the core of the disease and panic attacks possibly representing repeatedly recurring stress episodes. The obsessive–compulsive disorder involves recurrent thoughts (obsessions), that are experienced as intrusive and senseless, and/or repetitive seemingly purposeful behaviours (compulsions); both obsessions and compulsions cause marked distress. In phobic disorders, the phobic fear is a potent stressor.
There is agreement in the literature that stress profoundly affects immune function. Therefore, since patients with anxiety disorders endure considerable stress, it is plausible to expect alterations of immune competence in these subjects. On the other hand, it has been demonstrated that immune elements, namely some cytokines, are able to induce 'ansiogenic-like' and/or 'depressive-like' effects in the animal (Anisman et al., 1998; Dantzer et al., 1998); hence, it is likely that changes in immune parameters following real-life stress may be involved in the aetiopathology of anxiety syndromes and/or symptoms. Conversely, one would expect that if alterations of immunity occur in anxiety disorder patients, treatments aiming to alleviate anxiety symptoms should restore immune parameters.
The purpose of this review is to first consider the effects of stress on immune function; then, the changes in immune system that are associated with different anxiety syndromes will be discussed; finally, the effects of both pharmacological treatments and psychotherapeutic interventions on immune parameters will be analysed.
Early evidence for an association between stress and immune function in humans came from the demonstration that human susceptibility to infections was increased by stress events. Kissen (1958) suggested a link between recent loss of a love object and the morbidity and mortality of pulmonary tuberculosis. Other authors suggested that hypnotically induced stress reactivates herpes simplex infection in susceptible individuals (Ullman, 1947), whereas hypnosis itself was found to be able to reverse both immediatetype and delayed-type hypersensitivity to tuberculin (Black, 1963; Black, Humphrey and Niven, 1963).
There is a large body of literature showing that stress has a significant impact on immune function. Initially, human studies examining the effects of experimental (speech task and mental arithmetic task) and real-life stressors (academic examination stress, bereavement, unemployment, divorce, caring for patients with chronic diseases) suggested that stress is associated with reduced immune responsiveness, and therefore it may compromise immune function (Dantzer and Mormede, 1995). However, there is now agreement in the literature that stress may even enhance immune activity.
In bereaved widows and widowers, a suppression of mitogeninduced lymphocyte proliferation was noted (Schleifer et al., 1983); similarly, divorce, separation and unemployment were reported to decrease lymphocyte mitogen reactivity (Arnetz et al., 1987; Kiecolt-Glaser et al., 1987). A blunted unstimulated proliferation of peripheral blood mononuclear cells (PBMC) was observed in Israeli civilians during the period of Scud missile attacks (Weiss et al., 1996), while recently released prisoners of war in Bosnia showed altered immune functions with reduced number of natural killer (NK) cells (Dekaris et al., 1993).
Subacute or chronic real-life stressors were shown to decrease the number or the percentage of T-helper (CD4+) cells, the Thelper/T-suppressor (CD4+/CD8+) cell ratio, and the number of NK cells in peripheral blood (Glaser et al., 1985; Bachen et al., 1992). To the contrary, acute laboratory and naturalistic stressors were reported to transiently elevate the number of total T and B lymphocytes, CD8+ cells and the NK cells in the peripheral blood of healthy subjects (Fittshen et al., 1990; Brosschot et al., 1992). Moreover, Maes et al., (1999a) reported that students who responded to academic examination stress with a strong psychological reaction showed an increased number of activated T cell leukocyte subset profile. Furthermore, in those students, modifications of immune profile were positively and significantly associated with the stressinduced increase in self-rated severity of perceived stress and negative emotions.
Similarly to what occurs in cell-mediated immunity, increases or decreases in humoral immune parameters were reported after stress experiences. Some authors found increased salivary levels of immunoglobulin (Ig) A, while others reported reduced salivary concentrations of these Igs after exposure to acute or subacute stressors (Jemmott and Magloire, 1988; Bosch et al., 1996). Increased concentrations of serum IgA, IgM and IgG were found by Maes et al., (1997a) in students with high levels of stress perception following academic examination, but not in those with low stress perception. Moreover, academic examination stress significantly increased serum levels of the C3 complement factor as well as those of the acute phase (AP) protein α2-microglobulin, Furthermore, students with high stress perception had a trend toward significant increases in serum levels of the complement C4 factor and AP proteins haptoglobin and α1-acid glycoprotein, whereas students with low stress perception exhibited a reduction of these immune parameters (Maes et al., 1997a).
Several studies assessed the effects of stress on cytokine production in humans. Early reports showed that psychological stress did not affect plasma interleukin-1 (IL-1) or interleukin-6 (IL-6) concentrations (Dugué et al., 1993) or decreased the production of interferon-γ (IFγ) or increased that of IL-1β (Dobbin et al.,