Immune-tryptophan Pathway Interaction – Possible Pathophysiological Role in Major Depressive Disorder

Aye-Mu Myint, Markus J Schwarz, Norbert Mueller, Brian E Leonard
European Psychiatric Review, 2011;4(1):35-40
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Abstract

Major depressive disorder (MDD) is associated with a mild pro-inflammatory state. Both physiological and psychological stress can induce increased production of pro-inflammatory mediators, reactive oxygen species (ROS) and hypothalamic–pituitary–adrenal (HPA) axis disturbances. While both pro-inflammatory mediators and ROS could activate the tryptophan breakdown and kynurenine pathway with a shift toward the neurotoxic arm, chronic hypercortisolism could also enhance tryptophan breakdown and neurodegenerative changes. The imbalanced metabolism in terms of neuroprotective and neurotoxic effects were demonstrated in depressive disorders such as unipolar and bipolar depression, and in drug-induced neuropsychiatric side effects, such as in interferon-treated depression. The changes in the periphery are shown to be associated with central changes. While some of the currently available antidepressants could reverse the pro-inflammatory state of the depressed patients, these medications could not efficiently improve those neurochemical changes within the period that could induce clinical improvement. Pathophysiological and therapeutic roles of kynurenines in depression have been studied in animal models. In this review the role of interaction between the immune system and the tryptophan metabolism, which induces this imbalanced kynurenine metabolism in association with the interactions with other neurochemicals, are discussed as a major contributing pathophysiological mechanism in MDD. The biomarker role of kynurenine metabolites and future therapeutic opportunities are also discussed in this review.
Keywords
Major depression, inflammation, hypothalamic–pituitary–adrenal axis, tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, quinolinic acid, astrocytes
Disclosure The work of the authors is partly funded by European Collaborative Research Project MOODINFLAME and partly funded by Advanced Practical Diagnostics nv, Belgium. Aye-Mu Myint is an advisor at Advanced Practical Diagnostics nv, Belgium.
Received: February 10, 2011 Accepted March 25, 2011
Correspondence: Aye-Mu Myint, Psychiatric Hospital, Ludwig-Maximilians University, Nussbaumstrasse 7, D-80336, Munich, Germany. E: ayemu.myint@med.uni-muenchen.de

Major depressive disorders (MDD) are the most common psychiatric disorders. In Europe, MDD accounts for approximately 13% lifetime incidence with 4% being diagnosed with major depression within the previous 12 months.1 Depression has a major detrimental impact on the quality of life of patients regardless of geographical, educational, socioeconomic and racial backgrounds. According to the 1990 Global Burden of Disease of the World Health Organization (WHO), depression has a greater negative impact on the quality of life than cardiovascular disease and has been projected to be the second most important cause of disability, in disability-adjusted years, by 2030.2 The pattern of occurrence, increasing severity and the frequent resistance to treatment are some of the reasons for the high burden of depression.

There are different hypotheses upon which antidepressants have been developed. However, the currently available antidepressants are not adequately effective to treat the disease; this may be because major depression is a heterogeneous disorder where gene– environment interaction affects several systems in the body, resulting in neurochemical and mood changes that cannot be easily treated by manipulating one molecule or one neurotransmitter system.

During the second half of the 20th century, the role of tryptophan as a precursor of serotonin also became of interest, especially in the pathophysiology of depression. The depletion in tryptophan, which is the precursor of serotonin, has been widely discussed in the pathophysiology of MDD. The enhanced degradation of tryptophan to kynurenine, the pathway that brings the tryptophan away from serotonin, was proposed as a kynurenine shunt.3,4 At the same time, the body and brain crosstalk through the immune system became of interest in the pathophysiology of MDD. In the early 1990s ‘sickness behaviour’ was proposed as peripheral immune activation induced depressive behaviour.5 While sickness behaviour is, unlike MDD, a short-term syndrome, the symptoms of sickness behaviour such as lack of interest, inability to concentrate, loss of appetite, disturbance of sleep and social anhedonia have similar symptoms to depression. Thus, immune activation in the periphery was considered part of the pathophysiological mechanism of MDD.

Regarding immune activation, the first theory proposed was the ‘macrophage theory of depression’6 in which the association between cytokine secreted from macrophage and hypothalamus activity were proposed as the pathophysiological mechanism of MDD. Following this theory, there are several accounts reporting the immune system activation in MDD from the aspect of the impaired natural immune system7 and the activation of the adaptive immune system.8,9 The brain was no longer considered as the immune-privilege organ, and several pathways were proposed as the connection between the peripheral immune system and the central neurochemical and cellular changes such as vagus nerves10,11 or the transport of cytokines across the blood–brain barrier (BBB).12–15

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