The term antidepressant has been depicted, more than once, as a misnomer, given the wide spectrum of activity evinced by these pharmacological agents. Adding to this activity spectrum are findings that antidepressants have clear immunomodulatory effects in animals and humans. In general, antidepressants have been found to decrease immune responsiveness (Kenis and Maes 2002). Because of this, these agents may be of benefit for a wide range of symptoms that arise in the context of immune activation. Of special interest, given the ability of inflammatory cytokines to induce sickness behavior and/or major depression, a number of antidepressants have been reported to attenuate proinflammatory cytokine production, not just from peripheral immune cells (Maes 1999) but also from within the CNS, where desipramine has been reported to diminish TNF-k release within the locus coeruleus (Ignatowski and Spengler 1994). Interestingly in this regard, the antidepressant efficacy of desipramine during the forced-swim test has been shown to be dependent on reductions in neuronal production of TNF-a and can be reversed by exogenous TNF-a coadministered with the antidepressant (Reynolds et al. 2004). Desipramine has also been shown to lower peripheral TNF-a production in response to lipopolysaccharide (LPS) administration—an effect that was associated with abrogation of the depressive-like behavioral effects of LPS (Shen et al. 1999). The heterocyclic antidepressant bupropion has been similarly noted to markedly diminish TNF-a production following LPS administration in animals (Brustolim et al. 2006). Of note, concomitant with attenuating proinflammatory cytokine production, antidepressants enhance production of the anti-inflammatory cytokine IL-10 (Maes et al. 1999d).
In addition to potential direct effects on cytokine production, antidepressants impact neuroendocrine and neurotransmitter systems in ways known to diminish inflammatory activity. For example, all antidepressants appear to downregulate the overproduction of CRH and cortisol that frequently occurs in the context of major depression. Much evidence suggests that this downregulation results from the ability of antidepressants to enhance glucocorticoid signaling via increased glucocorticoid receptor functioning, which, in turn, leads to a restoration of glucocorticoid-mediated inhibitory control on the HPA axis (Pariante and Miller 2001). Because CRH has been shown to directly stimulate proinflammatory cytokine production, antidepressants may modulate inflammatory activity in part by diminishing CRH production. Glucocorticoid receptors, in addition to inhibiting CRH release in the hypothalamus, also mediate the well-characterized anti-inflammatory properties of glucocorticoids. It is likely that antidepressants decrease inflammatory activity in part via their ability to potentiate glucocorticoid receptor functioning (Pariante and Miller 2001). Antidepressants also normalize the hyperactivity of the locus coeruleus and SNS frequently seen in major depression (Ressler and Nemeroff 1999). Because catecholamines have been shown to enhance proinflammatory activity, the ability of antidepressants to normalize catecholaminergic functioning would be expected to diminish inflammatory activity. Finally, antidepressants are known to enhance functioning in intracellular second-messenger systems (such as the cyclic adenosine monophosphate [cAMP] cascade) known to suppress the activation of genes that encode for the production of proinflammatory cytokines (Duman et al. 2001).
Whatever the mechanism, it is clear from studies in animals and humans that antidepressants effectively diminish many physical, emotional, cognitive, and behavioral symptoms that arise in the context of immune system activation (Capuron et al. 2002a). In animals, pretreatment with a number of antidepressants has been shown to prevent or diminish the development of sickness syndrome in response to either pathogen or cytokine exposure (Yirmiya et al. 2001). In humans, pretreatment with an antidepressant has been shown in a double-blind, placebo-controlled trial to significantly reduce the development of major depression in patients receiving high doses of the proinflammatory cytokine IFN-a for the treatment of malignant melanoma (Musselman et al. 2001a). In this study, 45% of patients receiving placebo had developed major depression within 3 months of starting IFN-a, compared with only 11% receiving the selective serotonin reuptake inhibitor paroxetine. Of interest, however, paroxetine was not equally efficacious for all the symptoms associated with sickness syndrome. Specifically, the antidepressant significantly reduced the symptoms of depressed mood, anxiety, and poor cognitive functioning but was no more effective than placebo in the treatment of somatic or neurovegetative symptoms, such as fatigue and anorexia, suggesting that these symptom domains may have nonoverlapping etiologies (Capuron et al. 2002a). Consistent with this finding, neurovegetative symptoms tended to develop early (and to persist) in the course of IFN-a treatment in a majority of patients, whereas symptoms of depressed mood, anxiety, and cognitive disturbance tended to develop insidiously over weeks or months of treatment in a smaller percentage of patients (Trask et al. 2000). The success of pretreatment strategies in preventing the development of neuropsychiatric disorders in medically ill patients at high risk for mood disorders is intriguing and suggests that prophylactic antidepressants may be considered in other medical contexts, such as for patients about to undergo treatment with radiation and/or chemotherapy, as well as for patients about to undergo major surgery.
There are also data to suggest that antipsychotics, although not as well studied as antidepressants, may have immunological effects relevant to their mechanism of action. Intriguing in this regard is a study demonstrating increased antipsychotic efficacy in patients with schizophrenia treated with the combination of the cyclo-oxygenase-2 inhibitor celecoxib, an anti-inflammatory drug, and risperidone versus risperidone plus placebo (Müller et al. 2002).
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