This document discusses biomarkers in psychiatry. It defines biomarkers and describes different types including diagnostic, monitoring, pharmacodynamic, predictive, prognostic, safety, susceptibility, and state vs. trait markers. Specific biomarkers are discussed for schizophrenia (inflammatory markers, neurotransmitters, brain imaging, genetic, BDNF), mood disorders (CRP, TNF-α, leptin, ghrelin, growth factors, HPA axis, CYP2D6, acetyl-L-carnitine), bipolar disorder (genetic markers, oxidative stress), anxiety disorders (cortisol, IgA, serotonin), and substance use (carbohydrate deficient transferrin). Samples and techniques used include blood, CSF, urine and various

1. Biomarkers in psychiatry
Dr.Nivethika
MD Psychiatry
Final year

2. SYNOPSIS
• Introduction
• Definition
• Types of biomarkers
• Samples & techniques
• Specific biomarkers for the following psychiatric disorders
1. Schizophrenia
2. Mood disorders
3. Anxiety disorders
4. Substance use disorders
5. Dementia & alzheimer’s disease in elderly population
6. ADHD & ASD among children
• Summary

3. Introduction
• Suffering a serious mental illness reduces life expectancy in 13 to 32
years.
• Mental disorders are leading cause of disability responsible for 30 to
40% of chronic sick leave.
• Simultaneous presence of two or more psychiatric diseases are a/w
greater severity worse response to pharmacological treatment.

4. • Identification of biomarkers has become a new tool for guiding
diagnosis, predicting clinical outcome & improving the understanding
of pathophysiology of mental disorders.
• Term biochemical marker used in 1949.
• Biological marker 1957.
• Term biomarker was used for the 1st time in 1973 to indicate presence
or absence of biological material.

5. DEFINITION
• FDA + National institute of health defined biomarker as a “defined
characteristic that is measured as an indicator of normal biological
processes, pathogenic processes or responses to an exposure or
intervention”.
• Biomarker can be identified at any event
• Occurring since the pathogenesis
• The onset of 1st clinical manifestation
• Diagnosis
• Treatment outcome
• recovery

6. State & trait marker
• Markers that are dependent on the disease episode—appearing just
before, during, or after an illness episode, or present during an
acute exacerbation but not during remission— are state markers.
• Trait markers are independent of variation in clinical state.

7. Types
Pharmacodynamic
or response
biomarker
Predictive
biomarker
Safety
biomarker
Susceptibility or
risk biomarker
Diagnostic
biomarker
Monitoring
biomarker

8. Diagnostic biomarker
• Used to detect or confirm the presence of a disease or medical
condition.
• Plays role in predicting treatment outcome.
• Eg: concentration of AB42 & total tau(t-tau) in CSF of pts with
dementia is a diagnostic biomarker for alzheimer,’s disease.
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. Frontiers
in psychiatry. 2020 May 15;11:432.

9. Monitoring biomarker
• Biomarkers that are analysed at different time points to monitor the
status of a disease or medical condition & as a marker of response to
an intervention including exposure to a medical product or an
environment.
• Quantification of creatine & potassium serum levels.

10. Pharmacodynamic or response biomarkers
• To evaluate the response to a medical condition or clinical
intervention.
• Ex: levels of macrophage migration inhibitory factor in schizophrenia.

11. Predictive biomarkers
• To predict the probability to develop any effect as consequence of a
clinical intervention.
• Ex: specific SNP’s in schizophrenic pts as predictor of better
olanzapine treatment response.

12. Prognostic biomarker
• To identify the probability to develop clinical event in pt with a
disease or a clinical condition.
• Ex: Number of trinucleotide CAG repetition in pts with Huntingtons
disease.

13. Safety biomarkers
• To evaluate the probability of developing signs of toxicity as an
adverse event of the intervention.
• Ex: Number of active CYP2D6 genes that modify risperidone
metabolization including the side effects.

14. Susceptibility or risk
• To measure the risk of an individual to develop a disease or medical
condition.
• Ex: IL-6 & CRP levels as an indicator of schizophrenia risk.

15. OMICS biomarkers & neuropsychiatry
• Genomics
• Proteomics
• Transcriptomics
• Metabolomics
• Epigenetics
1. Assessing risk
2. Diagnosis
3. Monitoring progression
4. Prediction of treatment response

16. Genomic biomarkers
• Measurable DNA & RNA characteristic that is an indicator of normal
biologic processes, pathogenic processes or response to therapeutic or
other intervention.
• These measurable features include expression, function, & regulation
of a particular gene.
• In DNA these features can be characterized by
Single nucleotide polymorphism
Variability of short sequence repeats
Deletions or insertions of a single nucleotide
Cytogenetic rearrangements(translocations, duplications, deletions or
inversions)

17. Techniques
• Comparative genomic hybridization (CGH)
• Microarray
• Exome sequencing
• Whole genome sequence

18. Transcriptomic biomarkers
• Defined as complete set of all RNA molecules in one cell or a
population of cells at a specific developmental stage or physiological
condition.
• Thus transcriptome is dynamic & reflects cellular state.
• 2 key contemporary techniques:
1. Microarrays which quantify a set of predetermined sequences.
2. RNA sequencing which uses high throughput sequencing to capture all RNA
sequences.

19. Proteomic biomarkers
• Proteomic approaches using blood, plasma or serum constitutes a
highly desired method for biomarker profiling of psychiatric disorders.
• Due to the fact that these biological samples are used for routine
diagnostic analyses in clinical practice making easier to obtain
samples.
• CSF potential proteomic biomarker due to its proximity to the brain.
• Gel based or gel free techniques & mass spectrometry are widely used
methods.

20. • Neurofilament light chain is a potential biomarker for neuronal
damage in psychiatric illness.
• In anorexia nervosa levels of NF-L were elevated a/w neuronal
damage that partially normalize with weight recovery.
• Blood plasma, serum & PM Brain of schizophrenic patients identified
alteration in proteins that play a significant role in
1. Neuronal transmission & synaptic function
2. Calcium hemostasis
3. Signalling & energy metabolism
4. Oxidative stress
5. Cytoskeleton
6. Immune system & inflammation

21. Metabolomic biomarker
• This method focus on presence of small molecule metabolites in CSF,
blood, urine, saliva & other human fluids.
• It’s a direct functional measure of cellular activity & physiological
status.
• Changes in metabolome are consequence of interaction b/w lifestyle,
environmental, developmental & pathological factors.
• Analytical platforms:
• GAS chromatography mass spectrometry
• Liquid chromatography mass spectrometry
• Nuclear magnetic resonance

22. • Urinary metabolomics have been proposed to be the useful tool for
identification of pathways that may be involved in mechanism of
action of specific treatments.
• Ex: 77 urinary metabolites were identified in children with autism
spectrum disorder treated with sulforaphane, a supplement that
significantly improved the social responsiveness.
• These metabolites also plays role in regulation of neurotransmitters,
harmones, oxidative stress amino acids or gut microbiome &
sphingomyelin metabolism.

23. Epigenetic biomarker
• Variations in structure of chromatin, which do not change the sequence
of DNA itself but modified the expression of genes have implication in
developmental of psychiatric illness.
• Epigenetics may provide functional interface between genotype,
environmental exposure & phenotype.
• Defined as ‘any epigenetic mark or altered epigenetic mechanism that
can be measured in body fluids or tissues defining a disease, predicts
the outcome of disease, responds to therapy, monitors response to
therapy & predicts the risk of future disease development’.

24. • DNA methylation assays & DNA methylation sequencing are the most
employed techniques.
• Ex: hypermethylation of BDNF gene is identified in brain &
peripheral blood samples of MDD, schizophrenia & BD pts.
• Hypermethylation of FKBP5 gene which is an important modulator of
stress response is detected in peripheral blood samples of PTSD.

25. Samples & techniques used
• Urine
• Saliva
• Tear fluid
• Sweat
• Amniotic
• CSF
• Peripheral fluids
• Cervicovaginal secretion
1.Easily accessable samples
2.Affordable techniques to ensure its
inclusion in routine clinical practice

26. Blood Lymphocytes
• Close bidirectional interaction between CNS & Immune system esp
lymphocytes.
• This is due to fact that receptor properties & transduction processes of
lymphocytes are similar to CNS.
• Can be easily isolated from blood samples & studied on regular basis
to monitor the course of disease.
• Evidence suggest that alterations in neurotransmitters & HPA axis in
CNS are concomitant with alterations in functions & metabolism of
lymphocytes.

27. Genes analysed in lymphocytes
• C fos
• Interleukins( IL-2,4,6,10)
• Nerve growth factor
• Brain derived neurotropic factor
• Cannabinoid receptors
• Acetylcholine
• GABA-A receptors
• B-2 adrenergic/glucocorticoid & mineralocorticoid receptors
• D3 dopamine receptors & serotonin receptors.

28. BIOMARKERS IN
SCHIZOPHRENIA

29. Inflammatory biomarker
• CRP is an acute phase marker of inflammation elevated in pts.
• Has corelation with increased risk of metabolic syndrome.
• Increased concentration of interleukin IL-1B,IL-16,12, TNF-a.
• Transforming growth factor(TGF-B);IL-6 are state markers as they are
elevated in 1st episode & the relapse of disease but decrease after
treatment with antipsychotic.
• IL-1B, IFN-γ ,TNF a are trait markers that do not normalize after
treatment.
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. Frontiers
in psychiatry. 2020 May 15;11:432

30. NEUROTRANSMITTERS
• DA uptake by platelets was shown to correlate with delusional state.
• Tyrosine hydrolase enzyme involved in synthesis of DA is increased in
lymphocytes of schizophrenic patients.
• Elevated levels of DAT in the lymphocytes in schizophrenia &
reduced in psychosis.
• Lower a-7 nicotinic receptor binding in hippocampus & thalamic
nuclei & down regulation of muscarinic receptors are implicated in
cognitive impairment.

31. NEUROTRANSMITTERS
• Elevated norepinephrine signalling is involved in pathophysiology of
schizophrenia.
• Increased concentration of 3-methoxy-4-hydroxyphenylglycol,the
metabolite of norepinephrine in plasma of subjects with schizophrenia.
• Lower levels of GABA in plasma of pts with schizophrenia.
• Lower plasma D-serine & d/l serine ratio were found in treatment
resistant schizophrenia & increased following clozapine treatment.
• Decreased m-RNA levels for a-7 acetylcholine receptors are found in
lymphocytes of subjects with schizophrenia.

32. Brain Imaging Procedures
Computed Tomography (CT)
• lateral and third ventricular enlargement and reduction in cortical
volume in schizophrenic patients
• Cerebral asymmetry, cerebellar volume reduction, and brain density
changes

33. • Thickness differences have been reported between schizophrenic
and control populations (Andreasen 1989)
• Size and symmetry of gray and white matter (Suddath et al. 1989;
Rossi et al. 1990) and hippocampal hypoplasia have been observed
(Suddath et al. 1990).
• Magnetic resonance studies have shown a significant volumetric
reduction of the amygdalo-hippocampal system and the thalamus.

34. Positron Emission Tomography
(PET).
• Reduced glucose utilization activity in the frontal lobe
• Decreased glucose consumption in the basal ganglia that can be
normalized with neuroleptic treatment (Buchsbaum and Haier 1987)

35. Genetic
• Post-mortem analysis has revealed reduced levels of the protein
dysbindin in the brain of those suffering from schizophrenia
• The most consistent genetic marker finding, is an association between
HLAA9 and paranoid schizophrenia.

36. BDNF
• According to neurodevelopmental hypothesis, schizophrenia is a result
of pathologic processes that began during pre & post natal
development of CNS.
• BDNF has an important role in CNS development & maintenance in
neurodevelopmental hypothesis.
• Reduced expression of BDNF gene has decreased BDNF protein
concentration in hippocampus of pts.
• The sources of peripheral BDNF are platelets & vascular endothelial
cells.

37. Biomarkers in mood disorders
• CRP & TNF-a is elevated in depressed pts &BD.
• Leptin & ghrelin appears lower in depression & increases after
remission.
• Growth factors elevated in depressed pts.
1. Vascular endothelial growth factor (VEGF)
2. Fibroblast growth factor
3. Insulin like growth factor

38. HPAAxis
• Hyperactivity associated with major depressive disorders.
• It was proposed that patients had persistently increased cortisol
concentrations, irrespective of stress, so hypercortisolemia may fulfill
the endophenotype criterion of state-independence.

39. Dexamethasone suppression test
• Potent synthetic corticosteroid (dexamethasone 0.75mg=prednisolone
5mg=methylprednisolone 4mg=hydrocortisone 20mg).
• Steroid of choice for evaluation of HPA axis.
• Has high affinity for glucocorticoid receptors & long duration of
action.
• Half life is 36 to 54 hrs.
• It possess minimal mineralocorticoid activity & unlike other
glucocorticoids it does not interfere with cortisol measurement in
plasma, urine or saliva.
Arana GW, Baldessarini RJ, Ornsteen M. The dexamethasone
suppression test for diagnosis and prognosis in psychiatry:
commentary and review. Archives of general psychiatry. 1985

40. • Cytochrome P450 (CYP) enzymes are responsible for oxidative
reactions of many drugs and endogenous substances.
• CYP2D6 accounts for less than 5% of the total CYP content in the
liver, but it is involved in the metabolism of several drugs

41. CYP2D6
• Antidepressants such as fluoxetine, paroxetine, fluvoxamine,
citalopram, escitalopram, venlafaxine, duloxetine, and mirtazapine are
metabolized by CYP2D6.
• Antipsychotics such as chlorpromazine, Thioridazine, haloperidol,
risperidone, and aripiprazole metabolized by CYP2D6.
• Good responders to medications.

42. Acetyl-L carnitine
• Biomarker in MDD
• Has important role in behavioural features.
• Decrease in its concentration was a/w abnormal hippocampal
glutamatergic function & plasticity.
• Such alterations suggest that degree of acetyl-l-carnitine deficiency
was directly proportional to severity & age of onset of MDD &
clinical history of TRD.

43. Genetic biomarkers in BD
• CACNA1C & ANK3 polymorphism cause disturbance to
hippocampus, ACC, DLPFC functioning.
• DTNA
• ITPR2
• GNG2
• FOXP1
• LSAMP
• NCOA2
• NTRK3

44. • Oxidative stress & mitochondrial dysfunction may be influencing the
pathophysiology of BD.
• The dysfunction of mitochondrial electron transport chain is a/w
increased levels of reactive oxygen species (ROS) production.
• This increase in ROS production causes oxidative stress & damages
macromolecules like proteins, lipids, DNA etc.

45. • Lipid peroxidation
• DNA/RNA damage
• Nitric oxide
• Increased in all phases of BD
• Mood stabilizers may produce the treatment effect through their action
on oxidative stress pathway.

46. Biomarkers in anxiety disorders
• Cortisol in saliva is decreased in the morning sample in acute stress.
• IgA occurs in oral mucosa & the psychological factors alters the
concentration of IgA in saliva.
• A positive mood causes increased level & stressful stimuli result in
decrease level.
• Measurement of peripheral serotonin, platelet related to 5-HT such as
whole blood serotonin, platelet serotonin transporters & platelets
inositol 1,4,5-trisphosphate have been identified as predictors of OCD.
Łoś K, Waszkiewicz N. Biological markers in anxiety disorders.
Journal of Clinical Medicine. 2021 Apr 17;10(8):1744.

47. CSF biomarkers
• Neuropeptides plays role in modulating stress & anxiety related
behavious.
• There are 3 neuropeptide biomarkers
1. CCK
2. Oxytocin
3. Ghrelin
• Pts with PD had lower CCK-8 in CSF.
• Pts with GAD & SAD had lower oxytocin in CSF.
• Ghrelin increased during stressful condition.

48. Biomarker in substance use
• Carbohydrate deficient transferrin is a biomarker for chronic alcohol
intake of more than 60g ethanol/d.
• It is superior to markers like glutamyl transferase(GGT) & mean
corpuscular volume.
• % of CDT values were changed even in light alcohol drinking whereas
GGT levels were not changed.
• CDT is indicated in
License reapplication after driving under alcohol influence
Differentiating pt with enzyme inducing medication from those with alcohol
abuse.
Kwako LE, Bickel WK, Goldman D. Addiction biomarkers:
dimensional approaches to understanding addiction. Trends in
molecular medicine. 2018 Feb 1;24(2):121-8

49. Ethyl glucuronide test in urine
• Detects heavy Vs light drinking over 5 days in alcohol dependant pts.
• 100 ng/ml detects heavy drinking upto 5 days.
• 500 ng/ml detects heavy drinking the previous day.

50. Biomarkers in dementia
• CSF ab-42 & tau species are biomarkers for AD.
• AB-42 concentration decreases whereas total (T-tau) is increased
Decreased in pts with AD dementia.
• Characteristic of prodrome AD.
• F-2 isoprostanes are increased in early stages and are suppressed by
antioxidant vitamin supplements.
• CSF neurofilament protein is increased in vascular dementia with
white matter abnormalities.
Sonnen JA, Montine KS, Quinn JF, Kaye JA, Breitner JC, Montine
TJ. Biomarkers for cognitive impairment and dementia in
elderly people. The Lancet Neurology. 2008 Aug 1;7(8):704-14.

51. • Plasma concentration of ab-42 is increased in late onset AD.
• Accumulation of lewy bodies in neocortical regions is a strong
correlate of dementia.
• Presence of CSF tau p-181 is the most useful biomarker for DLB
which yields 80% of accuracy.
• PET scan shows C-PiB retention in multiple cerebral regions including
frontal lobes which caused marked decline in cognitive functions in
pts with FTD.
Sonnen JA, Montine KS, Quinn JF, Kaye JA, Breitner JC, Montine
TJ. Biomarkers for cognitive impairment and dementia in
elderly people. The Lancet Neurology. 2008 Aug 1;7(8):704-14.

52. Biomarker in autism
• Deletions at neurexin 1 (NRXN1) locus.
• Duplication at 7q11.23 & 15q11-13.
• Contactin 4(CNTN4) a/w social & intellectual disability.
• CNTNAP2 – a/w language delay, functional connectivity
abnormalities, selective mutism & anxiety.
• Methylene tetrahydrofolate reductase (MTHFR) polymorphism is one
of the most widely genetic corelation with autism.
Goldani AA, Downs SR, Widjaja F, Lawton B, Hendren RL.
Biomarkers in autism. Frontiers in psychiatry. 2014 Aug
12;5:100.

53. Biomarkers in ADHD
• DAT 1 & DRD4 genes are the candidate marker for ADHD.
• Maternal acetaminophen use during pregnancy increased the risk of
ADHD which is proved by cord blood samples in exposed mothers.
• CSF lower levels of 5HIAA, HVA & methoxy-4-
hydroxyphenylglycol(MHPH) correlated significantly with
behavioural measures of aggression, & impulsivity.
• 5HT transporter gene can influence impulsivity hence has role in the
etiology of ADHD.
Wang LJ, Yu YH, Fu ML, Yeh WT, Hsu JL, Yang YH, Chen WJ,
Chiang BL, Pan WH. Attention deficit–hyperactivity disorder is
associated with allergic symptoms and low levels of
hemoglobin and serotonin. Scientific reports. 2018 Jul 6;8(1):1-

54. ADHD
• MTTL1 mutation Decreases the metabolic stability of tRNA.
• Responsible for deficits in executive functioning, attention & these
cognitive change causes disturbance in everyday life.
Wang LJ, Yu YH, Fu ML, Yeh WT, Hsu JL, Yang YH, Chen WJ,
Chiang BL, Pan WH. Attention deficit–hyperactivity disorder is
associated with allergic symptoms and low levels of
hemoglobin and serotonin. Scientific reports. 2018 Jul 6;8(1):1-