Inflammation in Depression

There is growing evidence of a relationship between inflammation and psychiatric illness. Increased inflammation has been observed in a significant subgroup of patients with mood disorders. The inflammatory hypothesis is one of the most prevalent topics concerning depression. To understand the bidirectional relationship between inflammation and depression, which one process can drive the other and ultimately production of more effective depression treatments. We reviewed several studies from the international database Pubmed Central, textbook, review paper, comment, and editorial, to evaluate contemporary concepts concerning inflammation and their relationship to various depressive disorders. Pro-inflammatory cytokines have been found to influence the progression and severity of depressive disorders in different populations. Anti-inflammatory treatment of depression may have adjuvant properties with current depression medications. There is significant evidence that inflammatory processes influence the development and progression of depression. Future studies with larger arrays of cytokine profiles aided by neuroimaging may provide more sensitive and specific diagnostics modes in determining depression aetiology and guide individual therapies.


Introduction
Depression is a severe disease and will burden the world's top health global problems in the next 2030. Depression is estimated to affect nearly 350 million people worldwide.
Based on the Indonesia Basic Health Research in 2018, the prevalence of mental-emotional disorders in Indonesia reached 6.1%. [1,2] Depression often occurs alongside chronic medical diseases related to inflammatory processes such as cancer, diabetes mellitus, stroke, brain tumours, and coronary heart disease. [3] Depression worsens prognosis, decreases life quality, shortens life expectancy, especially in illnesses that cause pain, disability, or social isolation, which leads to fatigue, self-doubt, and hopelessness. [2,4,5] The disorder is chronic progressive, has a high relapse rate and a low remission rate. Therefore, a new approach is needed to treat depression. [6,7] The neurobiological approach concludes that depression is associated with brain neurotransmitter deficiencies, namely serotonin (5-HT), norepinephrine (NE), and dopamine (DA). [6,8,9] Some results show a correlation between inflammatory processes and depression. Specific inflammatory mediators are thought to play a significant role in influencing behaviour, symptoms, and circuit changes in the brain of people with depression. It is actively supported by some findings that stated that the third of people with depression showed an increase in inflammatory mediators even without medical illness. [10,11] People with depression showed higher levels of inflammatory mediators. However, there are limited reviews on how inflammatory mechanisms can cause depression, how depression cause inflammation, or even simultaneously. This review is created to provide an overview of the reciprocal mechanisms between depression and inflammation comprehensively. ] 12 , 2 [

Stress and Inflammation
Psychosocial stress leads to an increase of hypothalamic pituitary adrenal (HPA) axis activity. Its characterized by an increase in corticotropin-releasing hormone (CRH) in cerebrospinal fluid (CSS). CRH increases episodes of adrenocorticotropin hormone secretion (ACTH) hypersecretion, increasing cortisol (hypercortisolemia) release. Cortisol is useful to maintain life to regulate sleep, appetite, kidney function, and immune system. Elevated cortisol levels should stimulate a negative feedback mechanism like the hypothalamus suppresses CRH secretion. It then sends a message to the pituitary to lower ACTH production and is passed back to the adrenals to reduce cortisol production. In chronic stressful conditions, the autoregulation system or negative feedback function does not work. HPA axis hyperactivity causes depression during psychosocial stress and has a greater risk of self-harm, ideas, or suicidal behaviour. [12] The largest expression of glucocorticoid receptors in the brain is in the hippocampus (HC). The prefrontal cortex makes this area highly sensitive to stresstrigger stimuli leading to indirect microglia effects in this region. [16,17] Stressful life experiences in childhood are associated with an increase in pro-inflammatory cytokines associated with a high risk of mental illness in adulthood (two-hit hypothesis). The hypothesis states that early stress in life makes microglial cells priming in the central nervous system (CNS) generates an excessive increase in microglia activity that impact onto adulthood stress. This cause brain changes and become the development basis of mental disorders in the future. Microglia are myeloid cells as the primary form of the immune response in the CNS. These cells modulate neural function during inflammatory responses and brain plasticity in order to quickly respond small changes in the brain. [18,19] In a healthy environment, most microglia morphology have long and thin branches, allowing microglia to look for harmful agents (resting morphology). When a stressor deteced, these cells turn into enlarged soma, fewer branches and processes (amoeboid morphology). [17]

Depression and Inflammation
Some studies suggest a link between pro-inflammatory cytokines and depressive symptoms through the immune-tobrain communication pathway. Pro-inflammatory peripheral cytokines can affect the brain's immune system, HPA axis, and neurotransmitters synthesis, thereby triggering behaviour changes resembling depression. [18] Some data indicate that a person experiencing depression also experiences inflammation characterized by increased C-reactive protein levels (CRP) > 3 mg / L compared to non-inflammatory individuals with CRP levels of < 1 mg / L. This increase is associated with anhedonia and psychomotor retardation. [10,22] Systemic inflammation induced by cytokines can modulate behavioural changes such as sleep disorders, anorexia, weight loss, fatigue, cognitive impairment, and psychomotor deceleration. This syndrome is referred as sickness syndrome with an image that resembles depression-like behaviour.

Mechanism of Neurotransmission
The presence of pro-inflammatory cytokines, including IFNs, IL-1β, TNF, are associated with depression. A research data showed that the activation of cell-mediated inflammation (CMI) and brain pro-inflammatory cytokines such as TNF-α, IL-1β, IL- anti-inflammatory drugs. [27], [28].