Major depressive disorder (MDD) is a disease of high prevalence worldwide. Investigators have attempted to unravel the pathophysiology of depression for decades but, in spite of significant breakthroughs, definitive elucidation of the complex mechanisms underlying this disorder (or disorders) still eludes us. The monoaminergic theory of depression, spurned in part by the discovery of the first antidepressant agents and serendipitous observations of pharmacologic agents used to treat other disease entities, guided research for several decades. Enhancing neurotransmitter availability via neurotransmitter reuptake inhibition thus remained the cornerstone of antidepressant drug development. More recently, however, the role of the immune system and interactions between the endocrine, neurotransmitter, and immune systems have opened up new avenues to pursue. Based in part on observations that administration of pro-inflammatory cytokines, therapeutically or experimentally, induces a syndrome, commonly referred to as sickness behavior, in many ways akin to the human depressive syndrome, a new era of biomedical research was ushered in. The Macrophage Theory of Depression was postulated by Smith (1991) and paved the way for a proliferation of studies aimed at elucidating the connection between inflammation and depression. Exploration of a potential causal relationship between inflammation and depression lent support to the contention that there probably is a bidirectional relationship at play. Exogenously administered cytokines can induce a syndrome mimicking many symptoms of the spontaneously occurring syndrome of depression. The majority of clinical studies of depression, in which pro-inflammatory biomarkers were measured, confirmed that a chronic inflammatory status is present, as measured mostly in blood but also in cerebrospinal fluid and postmortem brain of suicide victims with a history of depression. So, if immune system activation and inflammatory responses can lead to depression, and, if depression is accompanied by chronic inflammation, what should be expected to happen when the depressed patient recovers—emotionally, cognitively, and behaviorally—from an episode of depression as a result of successful pharmacologic intervention, or, for that matter, non-somatic interventions? In other words, once a euthymic state is achieved, should inflammation be expected to return to control levels concomitantly? And, if this should be the case, what instigates or mediates normalization of the prior inflammatory status? A direct anti-inflammatory effect of the antidepressant agent used is a theoretical possibility. However, other factors could be involved singly or interactively, notably restoration of homeostatic balance in the autonomic nervous system, normalization of the hypothalamo–pituitary–adrenal (HPA) axis, gradual down-regulation of up-regulated enzymatic activity in critical metabolic pathways, such as the tryptophan/kynurenine pathway, receptors and second messenger systems, or some other hitherto unknown mechanism.

In seeking answers to these questions, the available literature is controversial. Some studies claim that inflammation returns to normal levels as the patient responds to antidepressant therapy and becomes euthymic. However, a larger number of studies do not support this claim. It appears there may also be a difference amongst the measured cytokines with some authors reporting a return to normalcy of one cytokine but not another. No doubt methodological and design differences amongst reported studies play a key role in explaining the discrepancies. The heterogeneity of depressive illness unquestionably plays a key role and renders comparisons across studies often impossible. However, there is substantially greater agreement amongst studies with respect to baseline measurements of inflammation indices than there is about post-treatment effects. This raises the issue whether the length of exposure to the antidepressant agent might not be a crucial variable indicating that the time frame within which euthymia is achieved may not have to be paralleled by immune and endocrine system responses and normalization. In this chapter I will attempt to shed some light on these issues. This review article cannot be an exhaustive review of the literature due to space limitations. Rather I have selected representative articles to support my interpretation of the relevant literature.