How do inflammatory conditions affect suicide risk?

For all the hidden stories and all the hidden hurt you are not seeing – seize this opportunity to learn more, to understand better.  If you have ever lost a loved one to suicide, you will understand the significance, the weight of this topic.  If you do not have a mental health problem and are struggling to understand what someone you love is going through, let me offer this quotation from David Foster Wallace:

The so-called ‘psychotically depressed’ person who tries to kill herself doesn’t do so out of quote ‘hopelessness’ or any abstract conviction that life’s assets and debits do not square. And surely not because death seems suddenly appealing. The person in whom Its invisible agony reaches a certain unendurable level will kill herself the same way a trapped person will eventually jump from the window of a burning high-rise. Make no mistake about people who leap from burning windows. Their terror of falling from a great height is still just as great as it would be for you or me standing speculatively at the same window just checking out the view; i.e. the fear of falling remains a constant. The variable here is the other terror, the fire’s flames: when the flames get close enough, falling to death becomes the slightly less terrible of two terrors. It’s not desiring the fall; it’s terror of the flames. And yet nobody down on the sidewalk, looking up and yelling ‘Don’t!’ and ‘Hang on!’, can understand the jump. Not really. You’d have to have personally been trapped and felt flames to really understand a terror way beyond falling.

A mental disorder is not something that is “all in your head”.  It’s not something you can “snap out of” or fix by “changing your attitude”.  This is a serious medical condition with real biological underpinnings.  We cannot be afraid to speak up, because silence kills.  We should not be any more ashamed of asking for help with our mental well being than we are to ask for help with infections, cuts, burns, cancer...

The biology is real.  New research demonstrates that inflammation and the immune system play a prominent role in mental health disorders and that’s just the tip of the iceberg [2,3,10,12,14].   A point brought up by one team of researchers was that even the perceived “threat” that triggered the suicidal contemplation could activate inflammatory pathways and further increase the risk [4].

Did you know that interferon treatment (read that as increasing inflammation) for certain cancers and multiple sclerosis is linked to depression, suicidal ideation and suicide attempts in otherwise psychiatrically healthy patients [3]?  What about other conditions involving inflammatory immune responses such as allergies (5, 6 to read more about seasonal allergens and increased spring time suicides), asthma, multiple sclerosis, systemic lupus erythematosus, and celiac disease?  Yep, also linked to suicidal ideation and attempt [3,5].  For the sake of perspective, consider studies that have found these rates in people with the following conditions compared to the rates in the general population

"Psychiatric" Disorders Major Depressive Disorder Schizophrenia "Biological" Disorders Celiac disease Diabetes mellitus Heart attacks Multiple sclerosis Systemic lupus erythematosus Traumatic brain injury

20x increased suicide risk [3] 4.9-10% lifetime suicide risk [17] 2x increased suicide risk [3] 13.3-26.4% increased suicide risk [3] 3x increased risk of psychiatric disorder [20] 3x increased suicide risk [18] 2x increased suicide risk [3] 40% develop depression [3] 3x increased suicide risk [3]

 Let’s take a quick look at how this can happen from the perspective of immune and inflammatory pathways.

Your immune system has these wonderful messengers called cytokines and these cytokines can affect neurotransmission in the brain [3].  Analysis of cytokine levels in those who attempt suicide reveals centrally increased cytokine levels in the orbitofrontal cortex (IL-4, IL-13), the anterior prefrontal cortex (IL-1β, TNF-α, and IL-6), and in cerebrospinal fluid (most notably IL-6) [3,4].  

We may also be able to use markers of peripheral inflammation to detect suicide risk [3].  For example, it’s been found that S100B levels also correspond with suicidal ideation intensity, and can lead to inflammation-derived glial dysfunction in patients with schizophrenia [3,7].  CRP might be a more familiar marker of inflammation to you.  Last month a research team in Arkansas published a study concluding that there is a gradient in CRP levels in those who attempted suicide (highest), had suicidal ideation or were an inpatient psychiatric control [12].  

You may well wonder whether the inflammation was caused by the method of attempted suicide or existed aside from that.  Follow up and longitudinal studies have shown the inflammation to be related to depression and suicidal behaviour rather than simply a result of it [3,10,16].

So what happens when we have all this inflammation and how does it affect suicide risk?  This can occur through the kynurenine pathway, designed to break down tryptophan.  Tryptophan is used to make neurotransmitters like serotonin.  However, when there is significant inflammation (such as in the form of cytokines), there is a shift from making serotonin to activating enzymes for tryptophan breakdown instead [11].  This results in increased blood levels of kynurenine, and relates to increased IL-6 in cerebrospinal fluid [3].  This pathway can then produce picolinic acid, quinolinic acid or kynurenic acid.  Kynurenic acid has some neuroprotective function (although you don’t want excessive amounts of it) but quinolinic acid causes neuroinflammation [10,11].  Increased quinolinic acid relative to picolinic acid and kynurenic acid is associated with increased suicide risk [10,11].  

How do genetic factors fit in?  Just last month genetic variation in the SNP rs2121337, responsible for a key enzyme involved in the kynurenine pathway, was found to be associated with neuroinflammation and suicide attempts [10].  This enzyme allows the kynurenine pathway to produce the neuroprotective picolinic acid, and without its proper function the pathway will create more of the neuroinflammatory quinolinic acid [10].

So it’s not a basic matter of your brain being on fire with CNS-derived inflammation.  Pro-inflammatory cytokines from elsewhere in the body can trigger inflammation in the brain, and having this genetic variation can further compound matters, increasing risk for suicide [10,11].  Additionally, neuroinflammation may increase permeability of the blood brain barrier [13].

What about learned helplessness, hopelessness, impulsivity, aggression, thought patterns and all those other psychological concepts we’ve associated with mental health disorders like depression?  Turns out cytokines like IL-6 affect these traits too [3, see 15 for a more in-depth view of the complex IL-6 story].

And inflammation isn’t even the entirety of the different biological processes involved.  It’s just a small sample to demonstrate the relevance of biology rather than just psychology.

In the next post we’ll discuss how mental health problems do not have to be a death sentence - there is hope.

References

1.    https://afsp.org/about-suicide/suicide-statistics/
2.    Brundin L, Bryleva EY, Thirtamara rajamani K. Role of Inflammation in Suicide: From Mechanisms to Treatment. Neuropsychopharmacology. 2016.
3.    Brundin L, Erhardt S, Bryleva EY, Achtyes ED, Postolache TT. The role of inflammation in suicidal behaviour. Acta Psychiatr Scand. 2015;132(3):192-203. 
4.    Courtet P, Giner L, Seneque M, Guillaume S, Olie E, Ducasse D. Neuroinflammation in suicide: Toward a comprehensive model. World J Biol Psychiatry. 2015;:1-23.
5.    Christodoulou C, Douzenis A, Papadopoulos FC, et al. Suicide and seasonality. Acta Psychiatr Scand. 2012;125(2):127-46.
6.    Makris GD, Reutfors J, Ösby U, et al. Suicide seasonality and antidepressants: a register-based study in Sweden. Acta Psychiatr Scand. 2013;127(2):117-25.
7.    Hong W, Zhao M, Li H, et al. Higher Plasma S100B Concentrations in Schizophrenia Patients, and Dependently Associated with Inflammatory Markers. Sci Rep. 2016;6:27584.
8.    Winerman, L. (2005). “Helping men to help themselves”. American Psychological Association. Available at: http://www.apa.org/monitor/jun05/helping.aspx. Accessed September 5, 2016.
9.    Kersting, K. (2005). “Men and depression: battling stigma through public education”. American Psychological Association. Available at: http://www.apa.org/monitor/jun05/stigma.aspx
10.    Brundin L, Sellgren CM, Kim CK, Grit J, Palsson E, Landen M, Samuelsson M, Lundgren K, Brundin P, Fuchs D, Postolache TT, Traskman-Bendz L, Guillemin GJ, & Erhardt S. (2016). An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation. Translational Psychiatry. 2016;6(8):e865.
11.    Richter CB, Linderholm, KR, Lim, CK, Samuelsson M, Traskman-Bendz L, Guillemin GJ, Erhardt S, & Brundin L. (2015). A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. Brain, Behaviour, and Immunity. 2015;43:110-7. 
12.    Gibbs HM, Davis L, Han X, Clothier J, Eads LA, Cáceda R. Association between C-reactive protein and suicidal behavior in an adult inpatient population. J Psychiatr Res. 2016;79:28-33.
13.    Ventorp F, Barzilay R, Erhardt S, et al. The CD44 ligand hyaluronic acid is elevated in the cerebrospinal fluid of suicide attempters and is associated with increased blood-brain barrier permeability. J Affect Disord. 2016;193:349-54.
14.    Priya PK, Rajappa M, Kattimani S, Mohanraj PS, Revathy G. Association of neurotrophins, inflammation and stress with suicide risk in young adults. Clin Chim Acta. 2016;457:41-5.
15.    Isung J, Aeinehband S, Mobarrez F, et al. High interleukin-6 and impulsivity: determining the role of endophenotypes in attempted suicide. Transl Psychiatry. 2014;4:e470.
16.    Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry. 2014;71(10):1121-8.
17.    Hor K, Taylor M. Suicide and schizophrenia: a systematic review of rates and risk factors. J Psychopharmacol (Oxford). 2010;24(4 Suppl):81-90.
18.    Rettner, R. (2010). “Heart attack patients at higher risk for suicide”. Live Science. Available at: http://www.livescience.com/35251-heart-attack-suicide-101210.html. Accessed September 6, 2016.
19.    Sarkar S, Balhara YP. Diabetes mellitus and suicide. Indian J Endocrinol Metab. 2014;18(4):468-74.
20.    Butwicka A, Frisén L, Almqvist C, Zethelius B, Lichtenstein P. Risks of psychiatric disorders and suicide attempts in children and adolescents with type 1 diabetes: a population-based cohort study. Diabetes Care. 2015;38(3):453-9.