Interferon therapy and its association with depressive disorders - A review

Abstract

Interferons (IFNs) are important in controlling the innate immune response to viral infections. Besides that, studies have found that IFNs also have antimicrobial, antiproliferative/antitumor and immunomodulatory effects. IFNs are divided into Type I, II and III. Type I IFNs, in particular IFN-α, is an approved treatment for hepatitis C. However, patients developed neuropsychological disorders during treatment. IFN-α induces proinflammatory cytokines, indoleamine 2,3-dioxygenase (IDO), oxidative and nitrative stress that intensifies the body's inflammatory response in the treatment of chronic inflammatory disease. The severity of the immune response is related to behavioral changes in both animal models and humans. Reactive oxygen species (ROS) is important for synaptic plasticity and long-term potentiation (LTP) in the hippocampus. However, excess ROS will generate highly reactive free radicals which may lead to neuronal damage and neurodegeneration. The limbic system regulates memory and emotional response, damage of neurons in this region is correlated with mood disorders. Due to the drawbacks of the treatment, often patients will not complete the treatment sessions, and this affects their recovery process. However, with proper management, this could be avoided. This review briefly describes the different types of IFNs and its pharmacological and clinical usages and a focus on IFN-α and its implications on depression.

Keywords: HPA axis; adverse (side) effects; depression; hippocampus; interferons; neuroinflamamation.

Figure 1

The roles of neurotransmitters in IFN-induced mood dysregulation. IFN-α stimulates IDO1 activity, stimulating the conversion of tryptophan to kynurenine and affects the synthesis of serotonin. Through several pathway metabolisms, kynurenine will be converted to quinolinic acid and picolinic acid. Quinolinic acid decreases the level of IL-10 which has anti-inflammatory effects. The negative effects of quinolinic acid include increasing the levels of IFN-γ which causes inflammation. This inflammatory response result in the production of ROS and iNOS which decreases BH₄. This eventually reduces dopamine secretion. Quinolinic acid is an NMDA agonist and can cause neurotoxicity as seen in patients with Alzheimer’s disease, ALS and depression. Quinolinic acid could cause cellular apoptosis too through the increase in lipid peroxidation. *IDO1: Indoleamine 2,3-dioxygenase 1; IDO2: Indoleamine 2,3-dioxygenase 2; TDO2: tryptophan 2,3-dioxygenase; KYN: Kynurenine; NAD: Nicotinamide adenine dinucleotide; NMDA: N-methyl-D-aspartate; IL-10: Interleukin-10; IFN-γ: Interferon-gamma; IFN-α: Interferon-alpha; ROS: Reactive oxygen species; iNOS: Inducible nitric oxide synthase; GCH1: GTP cyclohydrolase I; BH₄: Tetrahydrobiopterin; KAT: Kynurenine aminotransferase.

Figure 2

The effects of IFN-α therapy. IFN-α disrupts IDO1, SERT and possibly GCH1 systems and HPA axis leading to neurological changes and depression. Lower 5-HT production which is linked to depression is caused by the disruption on the SERT and IDO1 systems. IFN- also causes apoptosis, hippocampal atrophy and neurodegeneration via the KYN pathway as a result of increased IDO1 by (i) inhibiting the conversion of L-TRP, precursor of 5-HT (ii) production of QUIN which increases the stimulation of hippocampal NMDA (iii) production of 3-OH-KYN leading to increased ROS production causing intranucleosomal DNA damages and (iv) production of peripheral KYN which affects the CNS and subsequently neurodegeneration due to the release of neurotoxic metabolites. IFN- therapy also increases the production of pro-inflammatory cytokines which activate the HPA axis and causes depression. Another possible target of IFN-α is on GCH1 which reduces BH4 production, reducing 5-HT and leads to depression. IFN-α, Interferon-alpha; IL-1β, Interleukin-1beta; IFN-γ, Interferon-gamma; TNF-α, TNF-alpha; 5-HT, Serotonin; SERT, Serotonin transporter; IDO1, Indoleamine 2,3 dioxygenase; KYN, Kynurenine; 3-OH-KYN, 3-hydroxy-kynurenine; QUIN, Quinolinic acid; NMDA, N-methyl-D-aspartate; CNS, Central nervous system; ROS, Reactive oxygen species; BH₄, Tetrahydrobiopterin; CRH, Corticotropin-releasing hormone; HPA, Hypothalamic-pituitary-adrenal; GCH1, GTP cyclohydrolase I.

Figure 3

Regulation of HPA axis by IFN-α. When stimulated by stress, cortisol is being released by the HPA axis. Cortisol has short term benefit whereby it could reduce inflammation. However, long term exposure could lead to irreversible change to the neuronal system and function which causes mood dysregulation. Constant stimulation of the HPA axis also could lead to depression because of increased stimulation on the amygdala, hippocampus and frontal cortex. CRH, Corticotropin-releasing hormone; ACTH, Adrenocorticotropic hormone.