The Role of Inflammation in Treatment-Resistant Depression

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Author: Riya Gupta

Peer Reviewer: Riya Kumar

Professional Reviewer: Divya Kumar

Major Depressive Disorder affects 10% of Americans and is the leading cause of disability worldwide [14]. Many affected people benefit from the use of antidepressants; however, one-third of people with depression do not experience symptomatic relief in response to typical antidepressants [14]. This phenomenon is known as “treatment-resistant depression”. Depression is a complex disorder that involves the malfunction of neurons and may have genetic origins. Research seeks to understand the root cause of depression. Recently, evidence has been found to suggest that inflammation may play a role in the onset of depression, and that anti-inflammatory drugs may be used to treat patients with treatment-resistant depression (TRD).

Depression is often described as a “chemical imbalance of the brain”. However, the causes of depression are thought to be much more complex than simply altered levels of brain chemicals. Depression is thought to have genetic, biological, and psychological origins. The abnormal function of neurons, which may be hereditary in nature, is thought to be a cause of depression [9]. Dysfunction of several different regions of the brain is thought to cause the altered mood commonly seen in depressed people [17]. Like other psychiatric disorders, depression is thought to be caused by the abnormal function of processes that usually aid with survival. For example, inflammatory responses in humans elicit avoidance and alarm, which is helpful in avoiding dangerous situations. Additionally, the immune system uses inflammation to interact with the nervous system to fight infections and heal wounds. However, evidence shows that people with depression have higher levels of the inflammatory cytokines IL-1, IL-6, TNF-?, and CRP, which may suggest that abnormally high inflammation is related to depression [12]. Nevertheless, the reason as to why people with depression are more likely to have signs of inflammation is still unclear. [12]

Gupta, Figure 1
Diagram showing how an inflammatory response may lead to depressive symptoms [14]

Depression is typically treated with drugs that augment the amount of monoamine neurotransmitters in the synapses between nerve cells in the brain. These neurotransmitters include serotonin, dopamine, norepinephrine, epinephrine, and histamine. Monoaminergic drugs prevent the neurotransmitters from being reabsorbed by nerve cells, allowing them to function in the synapses for a longer period of time [7]. As depression is thought to be characterized by abnormal function of these neurotransmitters [8], individuals with major depressive are responsive to monoaminergic drugs, and many people even experience full remission from depression following one or more trials of these antidepressants. It is quite common to increase the dosage of an antidepressant or try different antidepressants to achieve remission. However, as previously mentioned, a large portion of the population does not respond to monoaminergic drugs, despite multiple trials. New research suggests that there is a connection between depression and inflammation in the brain, and that anti-inflammatory drugs may be able to elicit a positive response in people with TRD. 

Inflammatory cytokines, such as LPS and IFN?, induce the expression of enzymes that catabolize (destroy) large neutral amino acids (LNAA) that are precursors for neurotransmitters [2]. Tyrosine is a LNAA for dopamine, a neurotransmitter that influences reward and euphoria. Tryptophan is a LNAA that is a precursor for serotonin, a neurotransmitter that functions in memory processing and mood. Inflammatory cytokines can cause tryptophan to turn into kynurenine, a neurotoxin. They do this by upregulating the expression of the gene that creates indoleamine 2,3 dioxygenase, an enzyme that changes tryptophan into kynurenine. Kynurenine is the precursor for 3-hydroxykynurenine and quinolinic acid, which are neurotoxic [14]. These two substances act as agonists for NMDA receptors in the brain. NMDA receptors control memory and neural plasticity. Severe and sustained hypofunction of these receptors, caused by agonal blockage, has been associated with psychosis and Alzheimer’s Disease [16]. Thus, the neurotoxicity brought on by inflammatory cytokines is also thought to be linked to depression. 

Gupta, Figure 2
Diagram showing the conversion of tryptophan to kynurenine [13]

There is clinical evidence of the depressive effect of inflammatory cytokines. According to several studies, 40% of patients receiving treatment for hepatitis C or melanoma with the inflammatory cytokines interleukin-2 and interferon-alpha experienced a depressive episode [13], [4], [3], [11]. Studies show that the treatment of depression with traditional antidepressants (monoaminergic drugs) is usually less effective in the context of inflammation. Monoaminergic drugs may be ineffective against TRD because they rely on neurotransmitters that are already present in the synapses to function [1]. If less of the neurotransmitter exists because the inflammatory cytokines prevented it from being formed, then the monoaminergic drugs are not as effective, resulting in TRD. Additionally, monoaminergic drugs do not modulate the neurotoxic effects that kynurenine and its metabolites have on NMDA receptors [19], [2], [5], [20]. As previously explained, the neurotoxic effects are augmented in the presence of inflammatory cytokines. Thus, monoaminergic drugs are largely found to be ineffective against TRD. 

Evidence suggests that anti-inflammatory drugs could function as antidepressants. Drugs such as anti-TNF? and indomethacin reverse the effects of inflammatory cytokines. A recent study [18] shows that anti-inflammatory drugs suppress the expression of genes that are affected by an inflammatory challenge. The proinflammatory cytokines LPS and IFN? upregulated genes encoding the tryptophan transporters SLC16A10 and SLC7A5. They also upregulated genes that encode enzymes that convert tryptophan to kynurenine, IDO1, KYNU, and KMO. IDO1 catalyzes the first reaction that converts tryptophan to kynurenine. This shows that the inflammatory cytokines are likely to aggravate depressive symptoms by reducing the availability of tryptophan, and therefore reducing synaptic serotonin. Furthermore, this conversion increases the concentration of neurotoxic metabolites. Anti-TNF? and another anti-inflammatory drug, prednisolone, reduced the expression of genes that were upregulated by proinflammatory cytokines, and increased the expression of genes that were downregulated. Thus, anti-inflammatory drugs may be able to prevent inflammatory stimuli from reducing serotonin availability and increasing neurotoxic kynurenine levels. The study found that the monoaminergic drugs escitalopram and nortriptyline did not modulate the changes in gene expression caused by inflammatory challenge. The study concludes that, as each anti-inflammatory drug had varying effects, combinations would likely be most effective in combating TRD.

Gupta, Figure 3

The connection between inflammation and depression is becoming more and more apparent. Now, many studies have been done regarding the potential to treat TRD with anti-inflammatory drugs. There have been many studies done about the effectiveness of an anti-inflammatory diet for people with MDD, with promising results. For example, several meta-analyses have shown that a supplement of Omega-3 fatty acids benefits clinically depressed patients, as explained in a paper published by the American Journal of Psychiatry [10]. Omega-3 fatty acids have been shown to have anti-inflammatory properties in vivo [10]. There have even been some clinical trials that test the effectiveness of anti-inflammatory drugs as antidepressants for people with TRD. One ongoing study is testing the use of anti-inflammatory drugs along with an antidepressant [6]. Another study tested the effectiveness of using an anti-inflammatory drug alongside an antidepressant to treat Major Depressive Disorder. The anti-inflammatory drug celecoxib, which inhibits cyclooxygenase-2 (COX-2) — a chemical that induces the production of pro-inflammatory cytokines– was tested in a double-blind, randomized experiment along with the antidepressant reboxetine. The study used two groups: one with reboxetine and a placebo, and one with reboxetine and celecoxib. Patients in both groups were diagnosed with Major Depressive Disorder. Plasma blood levels of reboxetine were measured in each patient each week to ensure compliance with the treatment plan. Both groups experienced a significant reduction of depressive symptoms (measured using the Hamilton Depression Scale), but the group with celecoxib experienced significantly greater improvement [15]. The graph of the mean Hamilton Depression score for each group over time shows that the experimental group with celecoxib experienced a greater and more sustained decrease in depressive symptoms [15]. The role of inflammation in the onset and severity of depression is now apparent and may lead to revolutionary treatments for people with TRD. 

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