Inflammation and depression by J.E
Depression is variable between different people and despite many years of research, the pathology of major depressive disorder (MDD) remains unclear.. It has been suggested that there is a bidirectional relationship existing between depression and inflammation (Kiecolt-Glaser, Derry et al. 2015). During the last 2-3 decades inflammation has emerged as an important factor contributing to MDD (Medina-Rodriguez, Lowell et al. 2018). Depression facilitates inflammatory responses. Inflammation promotes depression (Dowlati, Herrmann et al. 2010, Valkanova, Ebmeier et al. 2013). Inflammation may contribute to depression in a subpopulation (Lotrich 2015). Not all patients with increased levels of inflammatory cytokines develop depression and not all depressed patients exhibit elevated levels of inflammatory cytokines.
Inflammation is part of a complex biological response of the body tissues to harmful stimuli eg pathogens, damaged cells or irritants. It is a protective response involving immune cells, blood vessels and molecular mediators. Inflammatory markers (cytokines) are higher in a third of depressed patients compared to non-depressed subjects (Kiecolt-Glaser, Derry et al. 2015). 33-47% of depressed patients demonstrate elevated peripheral markers of inflammation (Raison and Miller 2011). They are raised in MDD in a subset of patients, even without the presence of systemic disease. Inflammation is not necessary to induce or sustain depression; but it may play a vital role in a subpopulation. It is not the sole cause of depression and it is not possible to claim that depression is an inflammatory disease (Lotrich 2015).
The inflammatory hypothesis
- Inflammatory diseases are associated with an increased risk of depression. These include autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and allergies. Inflammatory cytokine associated depression could however be due to lifestyle changes and chronic pain rather than an increase in inflammation.
- A subgroup of patients with MDD have an increase in pro-inflammatory markers.
- Pro-inflammatory agents can induce MDD. Psychiatrically healthy subjects treated with exogenous cytokines develop depressive symptoms very quickly, which disappear after termination of treatment. Chronic treatment with interferon alpha leads to MDD in 50% of patients (Raison, Capuron et al. 2006). Cytokine therapies used to treat cancer and chronic viral infections provoke an onset of MDD in 45% of patients (Udina, Castellvi et al. 2012).
- Positron emission tomography scans (PET) show neuro-inflammation in MDD (Kopschina Feltes, Doorduin et al. 2017).
What are cytokines?
Cytokines are proteins that are produced by a number of cell types notably white blood cells, in response to inflammation. Types of cytokines include:
Interleukins secreted by leukocytes
Interferons- these activate natural killer cells and macrophages
Tumour necrosis factors which are involved in cell death
Meta-analysis of the literature concludes interleukin 1 beta, interleukin 6, tumour necrosis factor and C- reactive protein (CRP) are the most reliable biomarkers of inflammation in patients with MDD (Miller and Raison 2016). Immune activation increases pro-inflammatory cytokines- Interferon (IFN), IL1, IL6, TNF and CRP (Maes, Bosmans et al. 1997, Levine, Barak et al. 1999, Miller, Maletic et al. 2009).
The search for biomarkers is hindered by the variability of MDD. Patients with depression may show elevated levels of IL1beta, IL6, TNF- alpha in both serum and plasma (Dowlati, Herrmann et al. 2010). Not all patients with depression show prominent immune activation and inflammatory markers are only seen in a subset of patients (Rosenblat, McIntyre et al. 2015). C- reactive protein levels are elevated in depression- its levels are associated with the severity of depressive symptoms.
What do cytokines do?
Cytokines affect the periphery and communicate with the brain. They:
- Increase central nervous system (CNS) inflammation- activate glial cells.
- Alter the production, metabolism and transport of neurotransmitters eg serotonin, dopamine and noradrenaline.
- Alter the metabolism of tryptophan. They induce the enzyme Indolamine 2, 3 -dioxygenase (IDO), diverting tryptophan metabolism from serotonin to kynurenine (Dantzer, O'Connor et al. 2008).
- Cause oxidative stress.
- Dysregulate glutamate, resulting in a reduction of BDNF (brain derived neurotrophic factor) and an impairment of neurogenesis.
- Dysregulate the Hypothalamic Pituitary Adrenal (HPA) axis- this is seen in 75% of patients with MDD (Dinan 1994, Galecki and Talarowska 2018). Approximately 73% of depressed patients have cortisol levels greater than the median cortisol level of non-depressed patients (Stetler and Miller 2011).
Acutely administered cytokines induce “sickness behaviour” which mimic some symptoms of MDD. This include inability to feel pleasure (anhedonia), anorexia, fever, sleep changes and reduced social interaction. Chronic exposure to cytokines increase the risk of MDD. Chronic stress can lead to MDD. A chronic activation of the HPA axis can lead to hypercortisolaemia, leading to dysregulation of the HPA axis- it no longer responds to cortisol as a negative feedback regulator (Yirmiya, Weidenfeld et al. 1999, Yirmiya, Pollak et al. 2000).
Some people are protected from inflammation based depression. There are a number of vulnerability and resilience factors (Kendler, Thornton et al. 2001, Caspi, Sugden et al. 2003, Raison, Capuron et al. 2006, Lotrich 2011).
Image from Shutterstock-1450886714
If vulnerable, low levels of inflammation can lead to MDD and prevent recovery in those predisposed individuals (Patel 2013). Patients can be vulnerable if:
- Prior depressive episodes- this sensitises the immune system enhancing inflammatory MDD.
- Chronic inflammatory exposure.
- Low grade chronic stress, repeated stresses- the likelihood of MDD increases 5-6 fold in the 6 months following a stressful event (Willner 1990). A patient’s ability or lack of ability to cope with stress may predispose to psychiatric illness.
- Early life adversities such as childhood abuse (Felitti, Anda et al. 1998, Kendler, Thornton et al. 2001, Caspi, Sugden et al. 2003, Lotrich 2011, Gouin, Glaser et al. 2012).
Diagram modified from Frontiers of neuroscience 2014-cytokines and mood disorders
Diagram modified from Frontiers of Neuroscience 2014-cytokines and mood disorders
Rethorts (Rethorst, Bernstein et al. 2014) states that 47% of patients with MDD have CRP levels greater or equal to 3mg/L and 29% have CRP levels greater or equal to 5mg/L. The levels of CRP and IL6 have been shown to predict the subsequent development of depression in a 12 year follow up study (Gimeno, Marmot et al. 2008). The severity of depression correlates with high IL6 and also elevated CRP (Felger, Haroon et al. 2018). It is uncertain if IL6 and CRP represent an association, a mediating risk factor, or a causal factor for depression.
Lanquillon (Lanquillon, Krieg et al. 2000) performed a randomised control trial assessing 24 patients with MDD, looking at IL6 and TNF- alpha levels before and after 6 weeks of treatment with amitriptyline. Patients responding to the antidepressant had significantly lower IL6 levels and there was an elevated IL6 in non- responders. IL6 levels dichotomised patients into responders/non-responders. Patients with inflammatory activity prior to treatment are less responsive to antidepressants (Maes, Bosmans et al. 1997, Sluzewska, Sobieska et al. 1997, Lanquillon, Krieg et al. 2000, Benedetti, Lucca et al. 2002). IL6 and CRP are elevated more in patients with treatment resistant depression than those responding to antidepressants (Sluzewska, Sobieska et al. 1997). Baseline concentrations of IL6 and CRP may identify subjects that will fail to respond to conventional antidepressants and may be used to determine novel treatment strategies. Inflammation may provide a new target for therapeutic intervention.
The role of cytokines in promoting depression remains unclear. We need to better characterise the immune response- or the attenuation of cytokine production in patients with MDD may remain a challenge. The discovery of biomarkers will help identify a personalised treatment strategy for individual patients. However, the heterogeneous pathology driving depression makes discovery of biomarkers particularly challenging. Valkanonova (Valkanova, Ebmeier et al. 2013) showed raised inflammatory markers preceded the development of depressive symptoms.
To be used routinely, clinical biomarkers need to provide accurate and reproducible data with well validated norms. IL6 and CRP are not ideal biomarkers for MDD, as they have a short half- life which makes them difficult to detect. Better markers may be neopterin, SCD8 or tryptophan- which all measure the cell mediated immune response (Maes, Galecki et al. 2011). It has been suggested that rather than a blood test, a sweat test could measure biomarkers (Marques-Deak, Cizza et al. 2006). This would be unobtrusive and have less stress associated with it than a blood test. Identification of biomarkers that would predict therapy response, as well as develop a more profound understanding of the pathology of MDD, are key issues for improvement of treatment efficacy and patients prognosis. Despite many years of research, the pathogenesis of MDD remains unclear (Wiedlocha, Marcinowicz et al. 2018).
Pharmacological Treatment of depression
The current antidepressant treatment is effective in a subset of patients and is minimally effective in a large proportion of patients with MDD. Current first line treatments are only effective for approximately one third of patients with MDD (Rosenblat, McIntyre et al. 2015).Due to adverse side effects, there is a 43-61% rate of discontinuation of antidepressant treatment. Conventional antidepressants can take 4-6 weeks to work. Patients may have to try many different antidepressants before they find a balance between treatment effect and minimum side effects. Current method of practice of antidepressant medication prescription is a trial and error process. Over a third of patients fail to respond to 2 or more antidepressant treatments. Conventional antidepressants target monoamine neurotransmission and there is no valid clinical marker to personalise these mediators (Jha and Trivedi 2018). There is thus a need for novel treatments to be investigated.
It has been suggested that an association exists between treatment resistance to monoaminergic antidepressant drugs and elevated CRP levels, but more data is needed. Antidepressant treatment resistance is associated with activation of the immune system. Patients displaying inflammation prior to treatment are less responsive to antidepressants (Sluzewska, Sobieska et al. 1997, Mikova, Yakimova et al. 2001). Some studies report normalisation of cytokine levels after treatment with antidepressants- although this pattern is not consistent in the literature (Marques, Cizza et al. 2007).
High levels of IL17A or high CRP predict a better response to buproprion and SSRI combination therapy (Jha, Minhajuddin et al. 2017). Low levels of CRP < 1mg/L predict a better response to SSRI monotherapy with escitalopram than nortriptyline, whilst high levels of CRP > 1mg/L predict a better response to nortriptyline than escitalopram (Uher, Tansey et al. 2014). How an antidepressant affects cytokine levels is dependent on the class of antidepressant. There is a reduction in inflammatory cytokines seen in SSRI, SNRI and TCA (Piletz, Halaris et al. 2009, Hannestad, DellaGioia et al. 2011).
Studies suggest that patients with elevated CRP levels may be responsive to 2nd line treatment with anti-inflammatory drugs (Chamberlain, Cavanagh et al. 2018). Inflammation could be considered as a pharmacological target to develop new antidepressants in addition to combination treatments with anti-inflammatories and antidepressants. In theory, anti-inflammatories may be of use but it has been hard to demonstrate this in randomised control trials. Many studies have been carried out using anti-inflammatory drugs to treat depression. The results to date have been inconsistent and disappointing.
Non-steroidal anti-inflammatories (NSAIDs)
NSAIDs inhibit COX -1 and/or COX -2, which are enzymes involved in prostaglandin synthesis. Meta-analysis of randomised controlled trials of NSAIDs show monotherapy or combination therapy, may be more effective than placebo in treating MDD (Muller, Schwarz et al. 2006, Kohler, Benros et al. 2014). Celecoxib is a COX -2 inhibitor and has been shown to have a positive effect on antidepressant treatment outcome (Kohler, Benros et al. 2014). NSAIDs have been shown to reduce MDD in patients with osteoarthritis- however this treatment also reduced pain and improved patient function, which could impact on MDD, confounding these results. To complicate the evidence for the efficacy of NSAIDs for the treatment of depression, common anti-inflammatory drugs can attenuate the antidepressant effects of SSRIs (Warner-Schmidt, Vanover et al. 2011). Acetylsalicylic acid (aspirin) is a COX- 1 and COX- 2 inhibitor. An open label study by Mendlewicz (Mendlewicz, Kriwin et al. 2006) showed that when acetylsalicylic acid was added to fluoxetine, the remission rate improved. Patients who didn’t respond to fluoxetine alone showed an improvement when fluoxetine was combined with the acetylsalicylic acid.
Celecoxib given to medically healthy depressed patients in combination with reboxetine showed greater symptomatic improvement compared to reboxetine with a placebo (Muller, Schwarz et al. 2006). A double blind randomised placebo controlled international multicentre study of the selective COX-2 inhibitor cimicoxib as an add-on to sertraline in patients with MDD showed interesting results. There was no benefit of add-on cimicoxib over sertraline alone or placebo in the whole group of depressed patients. The combined treatment showed a statistically significant better outcome in the subgroup of severely depressed patients (Muller in press). Addition of both celecoxib and acetylsalicylic acid augmented treatment responses to fluoxetine (Mendlewicz, Kriwin et al. 2006) and to citalopram. Monotherapy may not exert antidepressant effects; but add on treatment can accelerate the action of the antidepressant, leading to therapeutic benefit and amelioration of depressive symptoms.
If there are no inflammatory comorbidities NSAIDs are of no benefit. If there is chronically elevated inflammatory biomarkers then NSAIDs may be of benefit. Efficacy of NSAIDs has not been demonstrated in long term treatment maintenance therapy or in the prevention of depression. There is a risk of side effects including gastrointestinal bleeding and ulcers, increased risk of cardiovascular (heart) events and renal (kidney) problems. Currently data pertaining to the efficacy of NSAIDs for the treatment of inflammatory associated depression are not robust enough to implement their widespread use. There is a lack of placebo controlled randomised trials in un-medicated and otherwise healthy patients with MDD. Future studies with larger sample size and longer study duration are needed to confirm the efficacy and tolerability of NSAIDs for depression. The more patients with an inflammatory pathology who are involved in clinical trials of the anti-inflammatory compounds, the higher the probability is to see an effect of antidepressant treatment. So far, unfortunately, no valid, reliable marker is available to identify- on a biological or psychopathological basis- the subgroup of patients to whom inflammation is involved in the pathological process.
Monoclonal cytokine antibodies
Monoclonal cytokine antibodies prevent cytokines from interacting with their receptors thereby inhibiting their inflammatory effects.
Ixekizumab is a monoclonal antibody against IL17. In patients with depression and an autoimmune disease, ixekizumab reduced depressive symptoms to a greater degree than a placebo (Griffiths, Fava et al. 2017).
Anti TNF- alpha antibodies adalimumab, etanercept and infliximab have been most commonly studied. They showed a statistically significant improvement in depression symptoms. Etanercept reduced depressive symptoms in psoriasis patients (Tyring, Gottlieb et al. 2006). Etanercept monotherapy in treatment resistant depression partly improved depression severity (Schmidt, Kirkby et al. 2014). Infliximab was successful in a placebo controlled trial in improving depressive symptoms in patients moderately resistant to antidepressant treatment; but only in those patients exhibiting high baseline inflammatory markers. Patients with a higher baseline CRP had a better response rate to infliximab (62%) compared with a placebo (33%) (Raison, Rutherford et al. 2013). The baseline concentrations of TNF- alpha were higher in the infliximab responders. Infliximab responders exhibited a higher decrease in CRP than non- responders (Raison and Miller 2011, Raison, Rutherford et al. 2013). CRP level might be a possible biological marker for the outcome of treatment with anti TNF- alpha antibodies. In patients with lower levels of inflammation, infliximab impaired the placebo response, suggesting that anti-inflammatories to treat depression in patients without inflammation, may be detrimental.
Sirukumab is a monoclonal antibody against IL6. Patients with treatment resistant depression who had CRP levels > 3mg/L responded to Sirukumab with improvement in their depressive symptoms (Zhou, Lee et al. 2017). Valid and reliable data on anti IL6 therapy in patients with MDD is still missing. The right target for anti IL6 therapy remains a matter of discussion. As IL6 levels are higher in the cerebrospinal fluid (CSF) than the periphery and patients with MDD have higher IL6 CSF than controls- CSF IL6 has been postulated to be the most promising therapeutic target.
Monoclonal antibodies have been shown to have antidepressant properties; but there is a lack of randomised controlled trials. Limitations of some studies to date include: patients exhibited concomitant symptoms of anxiety and depression, along with a primary diagnosis of inflammatory disease eg rheumatoid arthritis, Crohn’s, psoriasis. The symptoms of depression were mild to modest and depression was not formally diagnosed.
Cytokine inhibitors reduce the ability to fight infection and so are not suitable for patients with immunosuppressive conditions.
Minocycline has anti-inflammatory properties. The use of minocycline to treat MDD remains unclear. Several clinical trials are under way. A recent study showed that minocycline may be effective as an adjunctive treatment for Difficult-to-Treat Depression (DTD) however, a larger trial is needed to confirm this (Husain et al. 2020). A 6 week study of 150mg minocycline a day plus a conventional antidepressant reduced depressive symptoms in patients with unipolar psychotic depression (Miyaoka, Wake et al. 2012).
Antiepileptic and narcolepsy drug – Modafanil
Modafanil has anti-inflammatory properties. Augmentation treatment targets fatigue and sleepiness in patients with MDD. There are side effects and it must be used with caution.
Statins may be of benefit is a subgroup of patients. Their true antidepressant effect is undetermined.
Omega-3 Fatty Acids
Fatty acids may be of benefit to some patients with MDD. Further research is needed.
The need for novel targets acting outside of the monoamine system is of great importance- as rates of treatment resistant depression (TRD) are high whilst using monoamine modulators alone. The inflammatory pathway may yield a novel target for TRD. The ineffective treatment of depression necessitates biomarker discovery. The heterogeneous pathology driving depression makes biomarker discovery particularly challenging. Technological advances combined with increasing identification of biomarkers will help tailor depression treatment to individual patients, ultimately leading to faster and more efficacious treatment.
Bidirectional links between depression, inflammation and disease make research complex. Although evidence linking inflammation and MDD is increasing- the role of immune response dysfunctions in the pathogenesis of this disorder is still not totally clear. Normalisation of activated inflammatory pathways may be one novel mechanism of antidepressant action. Changes in inflammation are critical in only a subset of patients. Anti-inflammatory drugs such as aspirin, celecoxib and etanercept have been shown to have some antidepressant effects, though more research is needed before these treatments are used routinely in clinical practice. The long term outcomes of anti-inflammatory therapeutics for the treatment of depression are still to be conducted, and their implementation at different stages of depression must be investigated to fully uncover their therapeutic potential.
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