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Inflammation, Insulin Resistance and the Pathophysiology of Depression: Implications for Novel Antidepressant Developments

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Inflammation, Insulin Resistance and the Pathophysiology of Depression: Implications for Novel Antidepressant Developments REVIEW ARTICLE Psychiatry and Clinical Psychopharmacology 2020;30(1):71-80 DOI: 10.5455/PCP.20200215032026 Inflammation, Insulin Resistance and the Pathophysiology of Depression: Implications for Novel Antidepressant Developments Brian E. Leonarda, Feyza Aricioglub a Department of Pharmacology and Therapeutics,National University of Ireland, Galway, b Department of Pharmacology and Psychopharmacology Research Unit University of Marmara, Istanbul, Turkey Abstract This review summarises the impact of chronic low grade inflammation as a causative factor in the pathophysiology of major depression. Evidence is presented to show that proinflammatory cytokines both directly, and indirectly by increasing hypercortisolaemia, desensitise insulin receptors and thereby ARTICLE HISTORY decrease the transport of glucose into the brain (the diabetic brain). In addition, the proinflammatory Received: May 30, 2019 cytokines activate the tryptophan-kynurenine pathway which results in the synthesis of the NMDA- Accepted: Jan 29, 2020 glutamate receptor agonist quinolinic acid. This acts as a neurotoxin and facilitates neuronal apoptosis. As metabolic changes initiated by low grade inflammation underlie the pathophysiology of depression, drugs which attenuate the inflammatory cascade may present an approach to the KEYWORDS: inflammation, novel development of antidepressants. The review concludes with a summary of drugs which might insulin resistance, depression be considered for their novel therapeutic activity. Key points are; i)Chronic low grade inflammation commonly occurs in major depression and contributes to adverse changes in brain energy metabolism by decreasing insulin receptor function and thereby reducing glucose transport into the brain. ii) Low grade inflammation initiates an increase in the tryptophan-kynurenine pathway which enhances the NMDA-glutamate receptor function and thereby increases neuronal apoptosis, iii) As many of the pathophysiological changes in depression result from dysfunctional brain metabolism caused by chronic low grade inflammation, it is concluded that drugs targeting the inflammatory pathways may offer new possibilities for the development of novel antidepressants. INTRODUCTION In recent years there has been more attention directed disorder and the anxiety disorders [4,5,6]. In addition to towards a more holistic view of depression in which the the proinflammatory cytokines, prostaglandin E2 (PGE2), immune and endocrine systems play a significant role. reactive oxygen species and lipid peroxidation also increase The potential importance of the immune system in in depression in response to stress. Thus proinflammatory the pathology of major depression led Smith, in 1991, cytokines can interact with virtually all pathophysiological to formulate the macrophage theory of depression changes that characterise major depression and thereby [1] in which he summarised the clinical evidence of influence neurotransmitter function, synaptic plasticity inflammation due to the overactivity of peripheral and and ultimately neuronal structure. This could result in central macrophages as an important causal factor. Since increased apopotosis and contribute to dementia in later then, evidence has accumulated to indicate that chronic life (Figure 1). low grade inflammation is an important contributor to 2. The link between inflammation and insulin resistance the pathophysiology of depression [2]. For example, Dowlati and colleagues [3], in a detailed meta-analysis Inflammation has emerged as a major pathophysiological of raised proinflammatory cytokines in major depression, link between major depression and the metabolic syndrome confirmed that interleukin-6 (IL-6) and tumour necrosis [7]. Both conditions, irrespective of the underlying factor-alpha (TNF-alpha) were consistently raised. psychiatric disorder, are characterised by an increase in These proinflammatory cytokines are raised in response proinflammatory cytokines and the development of insulin to stress and have been demonstrated to occur in other and glucocorticoid receptor resistance. While it may appear major psychiatric disorders such as schizophrenia, bipolar to be contradictory that stress induced hypercortisolaemia Corresponding author: Brian E. Leonard, E-Mail: [email protected] To cite this article: Leonard BE, Aricioglu F. Inflammation, Insulin Resistance and the Pathophysiology of Depression: Implications for Novel Antidepressant Developments.Psychiatry and Clinical Psychopharmacology 2020;30(1):71-80, DOI: 10.5455/PCP.20200215032026 Leonard B. & Aricioglu F. co-exists with elevated proinflammatory cytokines, in due to the internalisation for the receptors from the cell depression and in chronic stressful situations the peripheral surfaces, changes which arise from the excessive activation and central glucocorticoid receptors become insensitive of the receptors by the elevated glucocorticoids [8]. Figure 1. The link between inflammation and insulin resistance. Sites of action of putative antidepressants: targets linked to disrupted brain metabolism. PUFA’s=polyunsaturated fatty acids; ROS=rapid oxygen species; NSAID’s=non steroidal antiinflammatory drugs; (+) activation; (-) inhibition. Functional insulin insensitivity arises as a consequence of the 2,3 dioxygenase, located in the brain and many peripheral glucocorticoids decreasing the insulin mediated expression tissues, andby tryptophan dioxygenase which is activated by of the glucose transporter GLUT4. This results in a reduction glucocorticoids and located in the liver. In depression, and in the transport of glucose into both peripheral and, most under stressful situations, these enzymes are activated and importantly, the brain [9]. Further changes in insulin result in the metabolism of tryptophan to kynurenine and receptor signalling arise due to the cortisol induced release kynurenine metabolites [12,13]. Kynurenine is a substrate of fatty acids from cellular lipoproteins while the increased for both kynureninase and kynurenine aminotransferase. proinflammatory cytokines also directly contribute to the In depression the former enzyme is activated leading to the desensitisation of the insulin receptors [10]. formation of quinolinic acid, an agonist at N-methyl-D-aspartate These adverse changes in the insulin receptor signalling are (NMDA) glutamate receptors, and the diabetogenic kynurenine usually offset by the activity of the adipokine, adiponectin, metabolites anthranilic acid and 3-hydroxyanthranilic acid. which can reactivate the desensitised receptor. However, By reducing the activity of insulin, these substrates further the concentration of adiponectin is decreased in depression contribute to the reduction in the availability of glucose for and as a consequence of the metabolic syndrome thereby sustaining brain metabolism [14,15]. This neurodegenerative, compounding the reduction in insulin receptor function diabetogenic pathway is normally balanced under non-stress [11]. Thus the key metabolic changes initiated by conditions by the synthesis of the NMDA glutamate agonist, hypercortisolaemia and chronic low grade inflammation kynurenic acid, which is formed by the action of kynurenine are instrumental in causing insulin receptor dysfunction. As aminotransferase. This neuroprotective pathwayis decreased in a consequence, glucose transport is impeded which would depression while the neurodegenerative arm of the tryptophan- have a significant impact on brain glucose metabolism. kynurenine pathway is increased [13]. However, in depression a chronic decrease in high energy 3. The contribution of the tryptophan-kynurenine substrates resulting from a deficit in glucose and essential pathway to decreased insulin receptor function. cofactors in depression may also be of importance in causing In recent years there has been a renewed interest in the role of the increase in neuronal apoptosis [16]. The situation is the tryptophan-kynurenine pathway in depression. In depression, further complicated by the increase in oxygen free radicals the free plasma tryptophan concentration is decreased caused by xanthenuric acid and 3-hydroxykynurenine which thereby reducing its availability for the synthesis of serotonin. damage the mitochondrial membranes thereby resulting in This effect is linked to the increase in the metabolism of a reduction in the synthesis of adenosine triphosphate and tryptophan by proinflammatory cytokine activated indoleamine other high energy intermediates [17] (Figure 2). 72 Psychiatry and Clinical Psychopharmacology Figure 2. Illustration of the integration of the changes in tryptophan-kynurenine pathway with the changes in the immune and endocrine systems which are relevant to the development of novel psychotropic drugs. 4. Inflammation, insulin insensitivity and reduced brain reasonable to expect such drugs to alleviate the impact of energy metabolism in depression: could the link provide chronic low grade inflammation associated with depression a guide for the development of novel antidepressants? and other psychiatric disorders in which inflammation contributes. The search for novel psychotropic drugs has, with few exceptions, largely depended on the extension of currently Of the NSAID’s available, aspirin is still the most widely available drugs into areas for which they were not used largely on grounds of efficacy and cost. However, initially developed. For example, many second generation the adverse effects of long term use are well known and antipsychotics are now
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