Yet, in some ways, this apparent lack of interaction between drugs that target some of the key effector molecules in the immune system and the various mood disorders is somewhat surprising. Burgeoning neurobiology literature implicates a critical role for the immune system in the pathogenesis of various mood disorders, autism, depression and suicide. Thus, one might have expected our experience with biologics to mimic the occasionally messy circumstances that confound corticosteroid use: The patient’s condition improves, but their ensuing personality change becomes intolerable. They become moody, agitated, anxious and difficult to live with. Or, as I once bore witness to, they plunge into the darkest depths of despair and take their own life. Completed suicide.
Our Immune Systems & Our Psyche
The relationship between mental health and inflammation was first noted in 1887 by Julius Wagner-Jauregg, MD, of the University of Vienna, Austria, who won the Nobel Prize in Medicine in 1927, making him the only psychiatrist to ever win this award. Over the ensuing decades, the elegant elucidation of the maze of neuroendocrine pathways coursing through our bodies and our brains has highlighted the intricate role that glucocorticoids play in maintaining both physiologic and psychological homeostasis during periods of serenity and stress, in serving as a bulwark against the evil forces of autoimmunity and, not surprisingly, in modulating fear, anxiety and trepidation. Glucocorticoid receptors (GRs) have been identified in the hypothalamus and hippocampus, and more recently, they have been detected in the amygdala, the almond-shaped structure buried deep inside our brains that encodes both fear and anxiety. A recent study of post-mortem brain tissue found that GR protein levels, as well as the percentage of GR-containing astrocytes, were significantly higher in the amygdala of patients who suffered from major depression than in control subjects or those with less severe forms of bipolar depression.4
GRs are far from being the only molecular link between mood and immunity. Animal models suggest that systemic inflammatory cytokines, such as interleukin 6 (IL-6), can influence mood. Injection of IL-6 in healthy human volunteers induces low mood, anxiety and reduced cognitive performance. Given its significant role in mediating systemic inflammation, this behavioral link makes perfect sense from an evolutionary viewpoint.
The mood–immune link might be best summarized by the theory of sickness behavior, which consists of a set of behavioral changes, including lethargy, social withdrawal, loss of appetite and anhedonia, that overlap with depression.5 They are thought to provide evolutionary advantages that ensure an organism’s survival during periods of illness. Under normal circumstances, the immune system clears the source of inflammation and sickness behavior resolves because this adaptive behavioral response is no longer advantageous. However, when it lingers, it transforms to a maladaptive sickness—depression.
