As objective measures that serve as early warning systems for patient health, biomarkers are playing an increasingly important role within the diagnosis and treatment of psychiatric conditions.1

What are Biomarkers?

The word “biomarker” is derived from the terms “biological marker” and “biochemical marker.” According to the Food and Drug Administration and the National Institutes of Health (FDA-NIH) Working Group, biomarkers are defined characteristics that are objectively measured as indicators of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions.2

There are a variety of biomarkers that are currently used in clinical practice, including diagnostic, monitoring, pharmacodynamic/response, predictive, prognostic, and susceptibility/risk biomarkers.


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Two of the most important biomarkers in psychiatry are:

  1. Physiological biomarkers of body processes (e.g. blood pressure and heart rate);3 and,
  2. Peripheral biomarkers of behavioral signs and symptoms (e.g. sleep patterns and changes in physical activity).4

While the use of biomarkers in research, assessment, and diagnosis have been successful in several medical fields, their use in psychiatry has been limited.5 Advances have been made; however, particularly within depression, post-traumatic stress disorder (PTSD), and schizophrenia.

Biomarkers for Depression

As a leading cause of disability worldwide, identifying depression biomarkers could revolutionize psychiatry and result in more personalized interventions that will drive better patient outcomes and prognoses.5

Currently, there are several known biomarkers used in the treatment of depression:

  • Inflammatory biomarkers

Studies have revealed that atypical inflammatory markers generally co-occur with depression and that there is a bidirectional association between inflammation and depression.6 For example, the biomarker High-sensitivity C-Reactive Protein (Hs-CRP) offers predictive validity for outcomes of the chimeric monoclonal antibody infliximab (Remicade) when used to treat treatment-resistant depression. Furthermore, Hs-CRP can also discriminate patients’ differential treatment response to the serotonin reuptake inhibitor escitalopram (Cipralex/Lexapro) versus the tricyclic antidepressant nortriptyline (Pamelor).5

  • Protein biomarkers

Blood tests can help determine Major Depressive Disorder (MDD) via nine biomarkers:

  • α1 antitrypsin;
  • Brain-derived neurotrophic factor (BDNF);
  • Apolipoprotein C3;
  • Epidermal growth factor;
  • Cortisol;
  • Resistin;
  • Prolactin;
  • Myeloperoxidase; and,
  • Soluble tumour-necrosis factor α receptor type II.

Additionally, brain-derived and insulin-derived growth factors, as well as cytokines, also serve as psychiatric biomarkers for diagnosing depression and predicting patient response to treatment. Similarly, the glial marker SB 100, a neurotrophic protein, is elevated in patients with depression and can thus also be considered as a psychiatric biomarker.5

  • Electrophysiological biomarkers

Since depression affects certain regions of the brain, EEG testing has revealed differences in alpha and beta frequency ranges during rest in patients with depression. For example, the following kinds of electrical activity can predict and/or identify depression:5, 7

  • Increased alpha amplitude (the strength of the “slow” frequency pattern of brain signals) in patients predicts depression;
  • Decreased power values (activity in specific frequency bands of the brain signal) in the frontal lobe regions are found in patients with depression; and,
  • Increased beta activity (strength of the “fast” frequency pattern of brain signals) in the frontal lobe regions are also found in patients with depression.
  • Other biomarkers

Studies report that plasma neopterin, malondialdehyde, and urinary isoprostanes are elevated in patients with depression. Altered DNA methylation is also found in these patients. Still, methylation changes generally occur in children, especially those whose mothers suffer from depression, smoked during pregnancy, or have a history of trauma.5, 8 Altered methylation mainly results in changes in serotonin receptors, causing depression in these children.5

Biomarkers for PTSD

There exist several biomarkers with the potential to identify PTSD, and possibly even PTSD subtypes, that align with previously documented neural and cognitive correlates of PTSD:9

  • Entorhinal cortex (EC) volume

Lower EC volume is associated with higher PTSD symptom severity. This is significant, as the EC is essential to neurocognitive functions such as memory; thus, the severity of memory loss and uncontrolled recall of the traumatic event can help determine symptom severity.

  • Rostral Anterior Cingulate Cortex (rACC) volume

The volume of the rACC has been shown to predict patients’ cognitive-behavioral response to treatment. Thus, the use of the rACC biomarker has the potential to guide early mechanism-based interventions.

  • Other volumes

Small hippocampus volume, as well as abnormal volumes of the amygdala, insular cortex, medial prefrontal cortex, and dorsal prefrontal cortex, have also been identified as biomarkers that might predict PTSD. However, results are conflicting, and further research is required.

Biomarkers for Schizophrenia

Significant progress has been made in the identification of schizophrenia biomarkers. The National Institute of Mental Health (NIMH) has proposed a novel system, called the Research Domain Criteria (RDoC), as a new evaluation system to study mental illnesses by excluding categorical diagnoses in favor of adopting a dimensional evaluation based on genetic, neural, and behavioral indicators instead.10,11

Some of the schizophrenia biomarkers included in the RDoC system include:

  • Gene biomarkers such as autophagy and beclin 1 regulator 1 (AMBRA1) and transcription factor 4 (TCF4);
  • Neurometabolite biomarkers such as N-acetylaspartate (NAA) and choline (Cho);
  • Protein biomarkers such as vesicle-associated membrane protein (VAMP) and synaptosomal-associated protein-25 (SNAP-25);
  • Brain morphology and connectivity biomarkers such as changes in the anterior cingulate cortex grey matter and frontotemporal white matter; and, 
  • Neurocognition biomarkers such as slower processing speed and impaired executive functioning.

All of these biomarkers solidify the growing knowledge that schizophrenia is a multi-modal disease and that there are several biological substrates responsible for its clinical manifestations.10

Additionally, biomarker studies are now incorporating sex differences into the research process, with rudimentary results revealing that some schizophrenia biomarkers differ between men and women.12 One study that investigated sleep disturbances and inflammatory biomarkers in men and women with schizophrenia found that not only was worse sleep quality associated with increased levels of pro-inflammatory biomarkers (high-sensitivity C-reactive protein and interleukin-6) in patients with schizophrenia, but that women with schizophrenia had significantly elevated levels of pro-inflammatory biomarkers and worse sleep disturbances compared to men with schizophrenia.12

There is a clear need to use dimensional perspectives via biomarkers to develop new therapeutics for schizophrenia, which may begin to compensate for the limitations of categorical diagnostic classifications.10

Conclusion

Due to the heterogeneity in the clinical presentation of psychiatric illnesses, the identification and use of biomarkers is becoming essential for the correct assessment, diagnosis, and treatment of patients. Indeed, identifying the factors that predict treatment response will reduce undesirable trial-and-error switches between medications and facilitate the discovery of novel, more effective treatments to establish more personalized medicine.

References

  1. NIH. Biomarkers. Health & Education: National Institute of Environmental Health Sciences. https://www.niehs.nih.gov/health/topics/science/biomarkers/index.cfm. September 3, 2020. Accessed October 11, 2020.
  2. García-Gutiérrez MS, Navarrete F, Sala F, Gasparyan A, Austrich-Olivares A, Manzanares J. Biomarkers in psychiatry: Concept, definition, types and relevance to the clinical reality. Front Psychiatry. 2020;11:432.
  3. Haskell R. What is a Biomarker? NursingCenter Blog. Lippincott NursingCenter. https://www.nursingcenter.com/ncblog/november-2019/biomarker. November 13, 2019. Assessed October 11, 2020.
  4. Hidalgo-Mazzei D, Young AH, Vieta E, Colom F. Behavioural biomarkers and mobile mental health: A new paradigm. Int. J. Bipolar Disord. 2018;6(1):1-4.
  5. Venigalla H, Mekala HM, Hassan M, et al. An update on biomarkers in psychiatric disorders – Are we aware, do we use in our clinical practice. Ment Health Fam Med. 2017;13:471-479.
  6. Huang M, Su S, Goldberg J, et al. Longitudinal association of inflammation with depressive symptoms: A 7-year cross-lagged twin difference study. Brain Behav Immun. 2019;75:200-207.
  7. de Aguiar Neto FS, Rosa JLG. Depression biomarkers using non-invasive EEG: A review. Neurosci Biobehav Rev. 2019;105:83-93.
  8. Clark SL, Hattab MW, Chan RF, et al. A methylation study of long-term depression risk. Mol Psychiatry. 2020;25(6):1334-1343. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061076/
  9. Ben-Zion Z, Zeevi Y, Keynan NJ, et al. Multi-domain potential biomarkers for post-traumatic stress disorder (PTSD) severity in recent trauma survivors. Transl Psychiatry. 2020;10(1):1-11.
  10. Yamada Y, Matsumoto M, Iijima K, Sumiyoshi T. Specificity and continuity of schizophrenia and bipolar disorder: Relation to biomarkers. Curr Pharm Des. 2020;26(2):191-200.
  11. McCleery A, Nuechterlein KH. Cognitive impairment in psychotic illness: Prevalence, profile of impairment, developmental course, and treatment considerations. Dialogues Clin. Neurosci. 2019;21(3):239.
  12. Lee EE, Ancoli-Israel S, Eyler LT, et al. Sleep disturbances and inflammatory biomarkers in schizophrenia: Focus on sex differences. Am Journal of Geriatr Psychiatry. 2019;27(1):21-31.