Table 1 Application of Extracellular Genomic Materials in Psychiatric Diseases.

Schizophrenia spectrum disorder

cfDNA

Blood

58 male SZ

11 male schizophreniform

14 male Alcohol-induced PD

30 male HCs

cfDNA index

Fluorescence

İmmunoassay

• Increased level of 8-oxodG- cfDNA in SZ

• No difference in cfDNA index between study groups

[49]

Plasma

100 SZ

60 HCs

Fluorometric quantification

Flow cytometry

• Higher cfDNA in SZ

• Increased 8-oxodG, NOX-4 and BCL-2 levels in SZ

[50]

Plasma

65 SZ

29 mood disorders

62 HCs

Fluorometric quantification

Spectroscopy

qPCR

• Twofold higher and shorter cfDNA levels in SZ

• No difference in cfDNA level in mood disorders

[51]

Serum

164 SZ

48 MDD

29 Alcohol-induced PD

Rt-PCR

ELISA

• Alu repeat sequence increase in SZ

• Alu repeat associated with IL-1β and IL-8 levels

[53, 54]

Serum

174 SZ

100 HCs

qRT-PCR

• A significant increase in cfDNA levels in SZ

• A progressive decrease in cfDNA levels with antipsychotic treatment in a subgroup of 57 newly diagnosed patients

[54]

Plasma

29 FEP

31 HCs

Multiplex PCR

NGS

• Higher total, neuron, astrocyte, oligodendrocyte, and whole brain-derived cfDNA levels in patients

[55]

Cf-rDNA

Blood

100 male SZ

96 male HCs

Nonradioactive Quantitative Hybridization

Increased level of cfDNA and cf-rDNA in SZ

[52]

Cf- mtDNA

Plasma

34 first-episode SZ

28 HCs

Rt-PCR

No difference in Cf-mtDNA level between groups

[56]

Nucleosome

Serum

30 SZ

30 HCs

ELISA

Increased level of nucleosome in SZ

[88]

EV (circular RNA)

Plasma

11 SZ

11 HCs

qRT- PCR

38 upregulated and 6 downregulated circRNAs in SZ that have potential roles in the pathogenesis of disease

[98]

EVs

miRNA

Blood

49 first-episode SZ

46 HCs

qRT- PCR

• Increased level of hsa-miR-206, which regulates BDNF expression, in SZ

[91]

Plasma

138 FEP

134 HCs

qPCR

Increased exosomal miR-137 and decreased COX6A2 levels in FEP which were associated with worse positive and negative symptoms, cognitive impairment and functioning.

[94]

Blood

14 drug-naïve FEP

10 HCs

Nanosight technology

Electron microscopy

qRT-PCR

• Increased miR-203a-3p levels and decreased DJ-1 mRNA and protein in FEP

• Olanzapine returned DJ-1 and miR-203a-3p levels to the levels seen in HCs

[131]

Plasma

9 treatment-resistant SZ

9 HCs

Replication set:

50 non-treatment-resistant SZ

50 HCs

Microarray

qPCR

• Upregulated miR-675-3p in treatment-resistant SZ compared to HCs

• A decreased level of miR-675-3p in non-treatment-resistant schizophrenia cohort compared to HCs

[132]

EVs long noncoding RNA (lncRNA)

Blood

104 SZ (56 drug free, 48 under risperidone treatment)

96 HCs

qRT- PCR

Increased expression of MIAT and PVT1 in serum exosomes of SZ

[99]

Bipolar disorder

cfDNA

Serum

20 drug-free BD

20 HCs

Singleplex real-time PCR

Higher level of cf-nuclear DNA and lower levels of cf-mtDNA in BD

[57]

Cf-mtDNA

Serum

64 BD (adolescant)

41 HCs

qRT- PCR

No difference between groups for cf-mtDNA

[59]

Plasma

10 BD (during both depression and remission phase of the same patients)

10 HCs

Multiplex immunoassay

qRT- PCR

No significant difference in cf-mtDNA copy number between groups

No correlation between plasma cf-mtDNA levels and plasma IL-6 levels

[60]

EVs (miRNA)

Plasma

69 BD (15 depressed, 27 manic, 27 euthymic)

41 HCs

qPCR

• Increased levels of miR-484, -652-3p, -142-3p and decreased level of miR-185-5p in BD

• Findings did not differ according to the disease stage

[101]

Plasma

20 BD-1

21 HCs

Microarray

33 nominally significant microRNAs altered in BD patients

[102]

Major depression disorders

cf-mtDNA

Plasma

55 MDD

50 HCs

qRT-PCR

Increased level of cf-mtDNA levels in MDD

[62]

Plasma

32 late-life depression

21 HCs

qRT-PCR

• Higher cf-mtDNA levels in patients

• A significant correlation between ccf-mtDNA levels and the severity of depression

[63]

Plasma

281 MDD

49 HCs

qRT-PCR

• Lower cf-mtDNA in both patients with current and remitted depression compared to controls.

• No significant difference in ccf-mtDNA between current and remitted depression

• treatment with mood stabilizers lamotrigine, valproic acid or lithium was associated with lower cf-mtDNA

[58]

Plasma

109 MDD

28 BD

17 SCZ

29 HCs

qRT-PCR

Multiplex immunoassay

• Lower plasma mtDNA copy number in MDD compared to other groups

• A correlation between mtdNA copy number and IL-4 levels in MDD

[65]

Serum

21 female MDD

27 HCs

real-time-PCR

• No difference between groups in terms of cf-mtDNA levels

• No correlation between cf-mtDNA levels and severity of depression

[66]

EVs (miRNA)

Plasma

4 treatment-resistant depression

4 HCs

NGS

Upregulated hsa-miR-335-5p an downregulated hsa-miR-1292-3p in patients

[106]

Blood

33 drug-naïve MDD

46 HCs

qRT-PCR

Increased hsa-miR-139-5p expression level in patients

[103]

Serum

52 MDD

31 HCs

qRT-PCR

Higher expression levels of miR-146a in MDD compared to HCs

• let-7e, miR-145, and miR-146a showed acceptable discrimination between the remission and non-remission groups

[105]

Serum

30 MDD

30 HCs

qRT-PCR

Increased exosomal miR-139-5p levels in MDD patients compared to controls

[104]

Serum

Discovery set:

9 drug-free MDD (adolescants)

8 HCs

Validation set:

34 drug-free MDD (adolescants)

38 HCs

RT-PCR

Increased miR-450a-2-3p, miR-556-3p, and miR-2115-3p levels in patients

[108]

Serum

6 MDD

3 HCs

RT-PCR

Increased expression of expression of miR-9-5p in patients

[107]

EVs (NDEVs)

Plasma

40 MDD (20 treatment-responder, 20 nonresponder)

20 HCs

miRNA sequencing

Western blot

qpCR

NDEVs from depressed patients were smaller than controls and NDEV size increased with treatment response.

Changes in miR-21-5p, miR-30d-5p and miR-486-5p in NDEV were associated with treatment response

[109]

Autism spectrum disorders

cfDNA

Plasma

96 ASD

34 HCs

Flourimetric Analysis

Flow cytometry

Higher plasma cfDNA levels in autism patients

• cfDNA of especially severe ASD patients contained a high amount of oxidative modification

[133]

Serum

20 ASD

12 HCs

qRT-PCR

• amount of mtDNA significantly higher for mt-CytB and for mt-7S in ASD

[68]

EVs

Serum

20 ASD

8 HCs

Transmission electron microscopy (TEM)

ELISA

• Extracellular vesicles of ASD do not differ in size or shape

• Amount of total EV-related protein is higher in ASD

[110]

EVs (lncRNA)

Plasma

14 ASD

14 HCs

qRT-PCR

Nanoparticle tracking analysis (NTA)

Transmission electron microscopy (TEM)

• SVAT-lncRNAs of SLC18A2, SYT9, STX8, and SYT15 were measured to be upregulated

• SVAT-lncRNAs of SV2C and SYP were minimally expressed

[111]

EVs (lncRNA)

Serum

100 children with ASD

60 HCs

L1 (L1CAM)-captured EVs (LCEVs)

lncRNA microarray

RNA-sequencing

A total of 1418 mRNAs, 1745 lncRNAs, and 11 miRNAs were differentially expressed, and most of them were downregulated in ASD.

• The levels of EDNRA, SLC17A6, HTR3A, OSTC, TMEM165, PC-5p-139289_26, and hsa-miR-193a-5p were validated in at least 15 ASD and 15 TD individual serum samples

[112]

Other psychiatric disorders

EVs (miRNA)

Plasma

10 MDP

10 HDP

10 HCs

qRT-PCR

Nanoparticle tracking analysis (NTA)

Transmission electron microscopy (TEM)

• no differences in both exosome size distribution and numbers between controls and patients

• 34 differentially expressed miRNAs between HCs and MDPs (7 upregulated, 27 downregulated)

• 19 differentially expressed miRNAs between HCs and HDPs (7 upregulated, 12 downregulated)

• No difference in miRNAs expression between MDPs and HDPs

[113]

Plasma

12 PTSD

12 HCs

Validation cohort

10 PTSD

10 HCs

NGS

qRT-PCR

• EV and EVD fractions were different between groups

• Expression of 11 miRNAs and 6 piRNAs were different in PTSD

[114]

Serum

48 PTSD

47 HCs

qRT-PCR

• PTSD group displayed higher expression of composite marker 1 (miR-200b-3p, miR-433-3p, miR-10a-5p, miR-10b-5p, miR-199a-3p, miR-224-5p, miR-146a-5p, and miR-143-3p) and composite marker 2 (miR-1247-5p, miR-363-5p, miR-346-5p, and miR-486-5p) as compared with control group

[115]

Cf-mtDNA

Plasma

46 SAD

42 HCs

qRT-PCR

• SAD patients had significantly lower cf-mtDNA

• Ni significant change in cf-mtDNA levels after CBT

[69]