AIM - To synthesize and interpret existing evidence and present aggregated effect with focus on biomarkers by phase of illness in bipolar disorder

1. Total slides – 46
Presenter
Dr Rachit Sharma
Junior Resident (Psychiatry)
Armed Forces Medical College,
Pune
Moderator
Dr VS Chauhan
Assoc Prof (Psychiatry)
Armed Forces Medical College,
Pune

2. Overview
INTRODUCTION
• Background
• Related studies
ARTICLE
• Aim and Objectives
• Material and Methods
• Statistical Methods
• Results
• Discussion
• Strengths & Limitations
• Critique
2

3. Background
3

4. Background
4
Aiff H, Attman PO, Aurell M, Bendz H, Schön S, Svedlund J.

5. Pathways underlying
neuroprogresssion in BPAD
1. Dopaminergic system
2. Glutaminergic system
3. Inflammation
4. Oxidative stress and mitochondrial
dysfunction
5. Neurotrophins
6. Epigenetic mechanisms
5

6. Cytokine Cascade
6
IL 1β TNF α
NF-κβ
IL-6
Activate
IFN γ IL-8
Activate
Increased levels
Haptoglobulin CRP Compliment factors

7. Pathways underlying
neuroprogresssion in BPAD
7
Berk M et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation,
oxidative stress and neurotrophic factors. Neuroscience & biobehavioral reviews. 2011 Jan 1;35(3):804-17

8. Neuroprotective therapeutic
agents and Target pathways
8
Berk M et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation,
oxidative stress and neurotrophic factors. Neuroscience & biobehavioral reviews. 2011 Jan 1;35(3):804-17

9. Neuroprotective therapeutic
agents and Target pathways
9
Berk M et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation,
oxidative stress and neurotrophic factors. Neuroscience & biobehavioral reviews. 2011 Jan 1;35(3):804-17

10. Cellular loci of action of known
pharmacological agents
10
Berk M et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation,
oxidative stress and neurotrophic factors. Neuroscience & biobehavioral reviews. 2011 Jan 1;35(3):804-17

11. Related Study 1
Aim: To investigate whether neutrophins and
inflammatory marker vary with mood states and are
increased in patients with BPAD I during euthymia as
well as in all affective states as a group, compared to
levels in healthy control subjects
11

12. Related Study 1
Method- Prospective cohort, state specific,
intra-individual alterations in levels of BDNF,
hsCRP, IL-1 β, IL-6, IL-8, IL-18 and TNF- α in
60 patients with BPAD I
Compared with repeated measurements in
healthy control subjects
Results – Higher levels of hsCRP during manic states
compared with depressive states
12

13. Related Study 2
13
Aim: To investigate the executive performance of BD
type I euthymic patients and its relation with the
plasma levels of BDNF, TNF- α and its related soluble
receptors (sTNFR1 and sTNFR2)

14. Related Study 2
Methods – Plasma levels of BDNF, TNF- α, sTNFR1 and
sTNFR2 were measured using ELISA in 25 euthymic BPAD
I patients and 25 healthy controls. Executive functioning
was assessed through the Frontal Assessment Battery
(FAB)
Results- BDNF levels are reduced, sTNFR1 levels were
raised but do not correlate with executive functioning
14

15. Departmental AFMRC Project
• Method - Assessment of three markers of
cellular immunity (NK cells, CD4, CD8 cells)
and three markers of humoral immunity (IL-2,
IL-6 & CRP) was carried out on the depressed
and control groups
• The depressed patients were treated with
antidepressants (SSRIs or TCAs) for 08 weeks
and reassessed
15

16. Results - CRP & IL-2 levels showed significant
decrease while IL-6 levels showed a significant
increase
16

17. Article in focus
Issue - Sep 2018

18. British Journal of Psychiatry
• 1963-
• Impact Factor 2017 – 5.867
• SJR 2017 – 2.864
• Rank - 19/ 525, H Index – 127
• Editor in chief- Dr Kamaldeep Bhui, CBE
Neuropsychiatrist, 67 research works with 440
citations and 2080 reads
18
http://www.scimagojr.com/journalrank.php?category=2738&area=2700&year=2017

19. Lead Author
19
-
Dr. Tobias Rowland, MD
IHR Academic Clinical Fellow in Psychiatry,
Mental Health and Wellbeing,
Warwick Medical School, University of Warwick, UK
Publications –
Areas of interest – Bipolar disorder, Psychiatric
epidemiology

20. Aim
To synthesize and interpret existing evidence and
present aggregated effect with focus
on biomarkers by phase of illness in bipolar
disorder
20

21. Objective
To provide preliminary evidence and inform
research strategies to deliver selective
biomarker signatures for bipolar disorder
21

22. Material and Methods
• Nature of Study
–Systematic review and Meta-analysis
• Nature of Data
–Circulating biomarkers (14) in blood or
serum of patients with bipolar disorder
compared with healthy controls
22

23. Material and Methods
• Data ( up to 01 Feb 2017)
–Embase (1947–)
–Ovid Medline (1946–)
– Web of Science (inception–)
–SciELO (1998– )
– PsycINFO (1806–)
–First 20 pages of Google Scholar
23

24. Inclusion Criteria
1. Primary studies evaluating biomarker levels
in patients with bipolar disorder (in any
mood phase)
2. Bipolar disorder diagnosis confirmed using
structured clinical instruments
3. Patients aged >16 years
4. Matched healthy control group
5. Studies in any language
24

25. Inclusion Criteria
6. Peer-reviewed papers, alongside searchable
conference abstracts and theses
7. Methods for biomarker assay were validated
commercially available assays
25

26. Exclusion criteria
1. Studies focusing purely on genetic
differences between groups (no measured
biomarker)
2. Studies including participants < 16 years of
age either in the patient or control group
26

27. Statistical Analysis
1. Mean and SD for each biomarker was
separated into mood phase
2. Data was processed using RevMan 5.3
3. SMD and 95% CIs between cases and
controls were calculated and displayed in
forest plots (Random effects model)
4. Weight given to each study by Inverse
variance method
5. Publication bias - Assessed by funnel plots
27

28. Fixed Effects Model
28

29. Random effects model
29

30. Results
30

31. PRISMA Diagram
31

32. Data Characteristics
1. 53 studies included in meta-analyses
2. 49 - Case –Control
03 - Prospective cohort studies
01 - Non-randomised control trial
3. Extracted baseline data was treated as for
case–control studies
32

33. Data Characteristics
1. 37 studies investigated patients in a Manic or
Hypomanic phase
2. 40 investigated patients in a Euthymic phase
3. 26 investigated patients in a Depressive phase
33

34. Data Characteristics
• 33 Studies - Included patients of BPAD I
• 07 Studies – Also included BPAD II
• 01 Study - Included Rapid-cycling BPAD,
including both BPAD I & II
34

35. Participants characteristics
Case participants 2467
Controls 2360
Mean age 38.7 years (23 to 65)
35

36. Results : Neurotropins &
Inflammatory mediators
36

37. Differential biomarker effect size
37

38. Results : Oxidative stress markers
38

39. Results
39

40. Discussion
1. A combination of hsCRP/IL-6, BDNF/TNF-α and
sTNFR1 appeared to be differentially altered in each
mood phase
40
BIOMARKER ILLNESS/PHASE
hsCRP/IL-6 Discriminate Biploar depression
sTNFR1 Discriminate Mania
BDNF &TNF α Generalised markers of affective
disturbance in BPAD

41. Discussion
2. Potential discriminatory biomarkers-
– IL-1RA – raised only in manic phase
3. Levels of IL-2, IL-4, IL-10 and IFN-γ - Not
significantly different from healthy controls in
either mania or euthymia
41

42. Strengths (as per author)
1. Results of each biomarker by mood phase
2. First study to combine multiple circulating
blood-derived biomarkers separated by mood
phase in bipolar disorder
3. Use of random-effects models
42

43. Limitations (as per author)
43
1. Quality of the primary studies: Mostly are
observational and at significant risk of bias and
confounding
2. Heterogeneity in the study
– Methodology, Patient characteristics, Duration of illness
– Specific assay used, Plasma/Serum used for assay
– BPAD II or Hypomania
– YMRS and HRSD scores to define mood phases
– Definition of healthy controls

44. Limitations (as per author)
3. Psychotropic drugs affect Biomarker levels
4. Relationship between remission/resolution
and lag time for normalization of biomarkers
5. Linking Mixed episode with biomarker levels
6. Publication Bias
44

45. My comments
1. This study is first study of combination
biomarkers, it would require some
Prospective studies in Indian context
2. Initial mood phase at which the illness
manifested may effect biomarker levels in
subsequent mood phases
3. Correlation between duration of illness and
Biomarker levels needs further evaluation
45

46. Consort Checklist 2010
Criteria Yes
(2)
Partial
(1)
No
(0)
N/A
1 Question/ objective
sufficiently described?
√
2 Study design evident &
appropriate?
√
3 Inclusion & Exclusion
Criteria characteristics
sufficiently described?
√
4 Sample size appropriate? √
46

47. Criteria Yes
(2)
Partial
(1)
No
(0)
N/A
5 Results reported in sufficient
detail?
√
6 Analytic methods
described/justified &
appropriate?
√
7 Conclusions supported by the
results?
√
8 Controlled for confounding? √
9 Outcome measures well-
defined and robust to
measurement/misclassificatio
n bias? Means of assessment
reported
√
47

48. Critique
• Clear message: 3 /5
• Contribution to literature: 2/5
• Potential to change thinking or practice: 2/5
• Quality of manuscript: 3/5

49. 49
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