Scientists try to find molecules that can be used as biochemical markers of depression – to predict who is at risk of developing depression.
Major depressive disorder or clinical depression is a mood disorder that can be difficult to diagnose and treat. Depression is characterised by depressed mood, inability to feel pleasure, and altered cognitive function. There is a diverse array of different symptoms and not everyone experiences the same set of symptoms. Diagnosis of clinical depression is made by using relatively subjective assessments (such as the Diagnostic and Statistical Manual of Mental Disorders). Our understanding of the underlying causes of depression, although growing, are also somewhat limited.
What causes depression?
Depression was initially thought to be caused by a lack of monoamine neurotransmitters such as dopamine and serotonin. It has since been shown that there are many pathways that are dysregulated, all of which may contribute to different aspects of depression. Growth factors, hormones, and dysregulated metabolism have all been shown to contribute to depression. Many of the symptoms of depression and sickness behaviours are similar such as weakness, fatigue, and the inability to concentrate. This prompted scientists to investigate the role inflammation has on depression. The kynurenine pathway links peripheral inflammation and the central nervous system. When this pathway is activated it converts tryptophan into kynurenine. This reduces the amount of tryptophan available for serotonin generation. Once activated the kynurenine pathway will produce oxygen free radicals and highly potent neurotoxins both of which are likely to contribute to depression. This metabolic pathway produces many molecules that have the potential to be used as biomarkers. Biomarkers are molecules whose presence or absence can be used to diagnose a disease or help monitor if treatments are working.
Can we use biomarkers to predict who will develop depression?
In a recent study published in Scientific Reports, researchers in Japan wanted to know if molecules produced by the kynurenine pathway could be used to predict which patients are at risk of developing depression. To answer this question the scientists looked at 120 samples from the Resource Center for Health Science database in Kyoto, Japan. They compared 61 patients who were determined to be a high-risk subject of major depressive disorder (HRMDD) to 59 age-matched healthy control samples. They compared the concentrations of various molecules in the kynurenine pathway for both groups. The team found that the concentration of anthranilic acid was significantly higher in HRMDD group. They also found that the concentration of tryptophan in women in the HRMDD group was lower than that of the healthy control group.
Anthranilic acid may be a good biomarker for depression
The scientists then went on to look specifically at the patients who went on to develop depression. They were able to analyse samples from when they were healthy and compare them to when they had depression. The researchers compared 33 HRMDD subjects and 66 age-matched healthy controls in this analysis. They included two patients who were taking anti-depressants and three patients taking tranquilisers in their analysis. The scientists looked at the molecules in the kynurenine pathway and developed ratios for each metabolite. The ratios were the concentrations for the metabolite when the patient was healthy compared to the concentrations when they were diagnosed as depressed. The only molecule to have a ratio that correlated with the change in the depression status (determined by a change in the Centre for Epidemiological Studies Depression scale) was anthranilic acid. This suggests that anthranilic acid may be a good biomarker for high-risk subjects of major depressive disorder.
The researchers then went on to examine what role these molecules may play in chronic pain disorders. Chronic pain can cause depression and both pain and depression are closely linked with inflammation. The scientists compared people who had both a chronic pain disorder and depression to people with a chronic pain disorder and no depression. They found no significant difference in the kynurenine pathway molecules in people with and without depression.
Does anthranilic acid change in mice?
The team were interested to know if they could detect a change in the concentration of anthranilic acid in mice after they experienced depression. The team used chronic unpredictable mild stress to create depression-like symptoms in mice and subsequently measured the concentration of anthranilic acid. They found that there was an increase in the concentration of anthranilic acid in the mice with depression-like symptoms when compared to a control group.
Single biomarkers are not likely to be used in diagnostic tools
Although the research presented by this team on anthranilic acid is promising it is unlikely that a single biomarker will be used as a predictive diagnostic. This is simply because a single biomarker does not have the specificity or sensitivity required for diagnosis. It is important to note that similar shifts in anthranilic acid and other metabolites from the kynurenine pathway have also been implicated in bipolar disorder and schizophrenia. It is a prevalent belief held in the field that panels of multiple biomarkers will be required to provide a complete assessment of a patient. Large panels of biomarkers will have to be used to identify a spectrum of factors that characterise a particular disease state. More research will be needed before anthranilic acid can be used as a biomarker of depression.
Written by Tarryn Bourhill MSc, PhD Candidate.
References:
- Réus, G. Z. et al. Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies. Journal of psychiatric research 68, 316-328 (2015).
- Strawbridge, R., Young, A. H. & Cleare, A. J. Biomarkers for depression: recent insights, current challenges and future prospects. Neuropsychiatric disease and treatment (2017).
- Müller, N., Myint, A.-M. & Schwarz, M. J. Inflammatory biomarkers and depression. Neurotoxicity research 19, 308-318 (2011).
- Schmidt, H. D., Shelton, R. C. & Duman, R. S. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 36, 2375-2394 (2011).
- Sakurai, M. et al. Serum Metabolic Profiles of the Tryptophan-Kynurenine Pathway in the high risk subjects of major depressive disorder. Scientific Reports 10, 1961, doi:10.1038/s41598-020-58806-w (2020)
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