This study investigated the association between acute exposure to mood stabilizers and the risk of stroke in patients with bipolar disorder. The study used a case-crossover design and analyzed data from Taiwan's National Health Insurance Research Database. The results found that acute exposure to carbamazepine was associated with an increased risk of ischemic stroke, while valproic acid exposure increased the risk of hemorrhagic stroke. Combining carbamazepine with first-generation antipsychotics also raised the risk of stroke. Lithium and lamotrigine did not significantly impact stroke risk. The study provides new insights into how different mood stabilizers and their combinations may influence stroke risk in bipolar patients.

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
• Annual incidence of stroke in the patients with
bipolar disorder (Taiwan) - 54.8 cases per 10
000 person-years (36–64 years)
• Annual incidence of stroke in general
population (Taiwan)- 21.3 per 10 000 person-
years (36–64 years)
4
Wu HC, Chou FH, Tsai KY, Su CY, Shen SP, Chung TC. The incidence and relative risk of stroke among patients with bipolar
disorder: a seven-year follow-up study. PloS one. 2013 Aug 30;8(8):e73037.

5. Background
• Common comorbidities with bipolar disorder
– Obesity, Hyperlipidemia, Hypertension, Diabetes
mellitus (Increased risk for stroke)
– Use of antipsychotic drugs, linked to increased risk
of insulin resistance, lipid abnormalities and
hypertension – Increased risk of vascular events
such as stroke
5
2. Wu HC, Chou FH, Tsai KY, Su CY, Shen SP, Chung TC. The incidence and relative risk of stroke among patients with bipolar
disorder: a seven-year follow-up study. PloS one. 2013 Aug 30;8(8):e73037.
1. Benjamin J. Sadock , Virginia A. Sadock , Pedro Ruiz MD. Kaplan and Sadock's Comprehensive Textbook of Psychiatry 10th
edition . Wolters Kluver ; 2017.

6. Background
– Associated with psychiatric comorbidities -anxiety,
substance or alcohol use disorder
– Unhealthy lifestyle
6
2. Wu HC, Chou FH, Tsai KY, Su CY, Shen SP, Chung TC. The incidence and relative risk of stroke among patients with bipolar
disorder: a seven-year follow-up study. PloS one. 2013 Aug 30;8(8):e73037.
1. Benjamin J. Sadock , Virginia A. Sadock , Pedro Ruiz MD. Kaplan and Sadock's Comprehensive Textbook of Psychiatry 10th
edition . Wolters Kluver ; 2017.

7. Background : AEDs & Stroke
1. Enzyme inducing anti-epileptics and effects on
lipid profile
• Phenytoin, Phenobarbital, Carbamazepine and
Primidone increases the activity of CYP 450,
involved in synthesis of serum cholesterol
• Lanosterol Cholesterol intermediates, which
inhibits HMG CoA reductase by negative feedback
• Increases in cholesterol persists even after 5 years
of therapy
7
LoPinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of vascular risk. Current treatment
options in neurology. 2010 Jul 1;12(4):300-8.

8. Background: AEDs & Stroke
2. Enzyme inducing anti-epileptics and effects
on other vascular risk markers
Increases levels of -
• Lipoprotein (a)
• CRP
• Homocysteine
8
LoPinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of vascular risk. Current treatment
options in neurology. 2010 Jul 1;12(4):300-8.

9. Background: AEDs & Stroke
3. Valproic acid and its effects on coagulation
profile
• Affect both procoagulation and anticoagulation
factors decreasing the levels of factor VII and VIII,
protein C and fibrinogen, and platelet counts
• Increases risk of hypocoagulation and hemorrhagic
complications (longterm treatment)
• Also associated with elevation in plasma
homocysteine and serum lipoprotein concentrations
9
LoPinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of vascular risk. Current treatment
options in neurology. 2010 Jul 1;12(4):300-8.

10. Background: Lithium & Stroke
4. Neuro-protective effects of Lithium
• Inhibition of GSK-3β, an enzyme linked to
apoptosis induced by various neural insults
• Induction of Brain derived neurotrophic factor
(BDNF), which plays a key role in neuronal
development, plasticity, and survival
• Increased expression of vascular endothelial
growth factor (VEGF), which induces neuronal
proliferation and neurovascular remodeling
10
In animal stroke models, GSK-3β was
found to be upregulated, and its inhibition
by lithium was implicated as an important
neuroprotective mechanism
Lan CC, Liu CC, Lin CH, Lan TY, McInnis MG, Chan CH, Lan TH. A reduced risk of stroke with
lithium exposure in bipolar disorder: a population‐based retrospective cohort study. Bipolar
disorders. 2015 Nov;17(7):705-14.

11. Background: Lithium & Stroke
• Inhibition of NMDA receptor-mediated
calcium influx and downstream apoptotic
pathways, resulting in decreased glutamate
mediated excitotoxicity
• Inhibition of phosphoinositol phosphatase and
regulation of apoptosis, a critical process for
neuronal survival and functioning
11
Lan CC, Liu CC, Lin CH, Lan TY, McInnis MG, Chan CH, Lan TH. A reduced risk of stroke with
lithium exposure in bipolar disorder: a population‐based retrospective cohort study. Bipolar
disorders. 2015 Nov;17(7):705-14.

12. Background: Lithium & Stroke
• Lithium reduces the expression of vascular cell
adhesion molecule VCAM-1 decreased the
infiltration of macrophages into the
atherosclerotic plaque Plaque-stabilizing
effect
• Animal studies :Lithium inhibited vascular
smooth muscle cell proliferation and migration
reduction in abnormal neovascularization in the
atherosclerotic plaque Plaque stabilization
12
Lan CC, Liu CC, Lin CH, Lan TY, McInnis MG, Chan CH, Lan TH. A reduced risk of stroke with
lithium exposure in bipolar disorder: a population‐based retrospective cohort study. Bipolar
disorders. 2015 Nov;17(7):705-14.

13. Related Study 1
Aim: To evaluated the risk of myocardial infarction (MI),
stroke, and death associated with epilepsy and to
examine if risk was modified by treatment with
antiepileptic drugs (AEDs)
13

14. Related Study 1
Method- A cohort consisting of the Danish population
was followed from January 1997 to December 2006
Results –In patients without previous stroke, AED-
treated epilepsy was associated with an increased risk of
stroke, Cardiovascular deaths.
14

15. Related Study 1:Results
15

16. Related Study 1:Results
16

17. Related Study 2
17
Aim: To determine whether lithium is related to the
susceptibility to stroke and its occurrence in patients
with bipolar disorder

18. Related Study 2
Methods –
Population-based retrospective cohort study
Results-
1. Of the 1,885 subjects, 86 (4.6%) experienced stroke,
including 2.8% of the lithium group and 5.4% of the non-
lithium group.
2. Reduced risks of stroke were also associated with the
highest cumulative lithium dose (≥720 DDD), the longest
cumulative exposure period(≥720 days) and the highest
exposure rate(≥2 DDD/day)
18

19. Article in focus
Issue - Oct 2018

20. 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
Professor of Cultural Psychiatry & Epidemiology
Hon Consultant Psychiatrist, University of London
• 67 research works with 440 citations and 2080 reads
20
http://www.scimagojr.com/journalrank.php?category=2738&area=2700&year=2017

21. Lead Author
21
Dr. Pao-Huan Chen, MD
Lecturer
Department of Psychiatry,
Taipei Medical University , Taipei
Publications – 18 Articles, 76 Citations
Areas of interest – Bipolar disorder, Psychiatric
epidemiology

22. Aim
1. To investigate the association between
acute exposure to mood stabilisers and risk of
stroke in patients with bipolar disorder
2. To explore the effects of combination therapy
of mood stabilisers and antipsychotic drugs on
the risk of stroke
22

23. Material and Methods
• Nature of Study
–Retrospective cohort study
–Case-crossover study design
• Nature of Data
–Psychiatric Inpatient Medical Claims (PIMC)
database of Taiwan National Health
Insurance Research Database (NHIRD)
23

24. Case-crossover study design
24
1. This design is a scientific way to ask and
answer “Was the patient doing anything
unusual just before the onset of illness?”
2. To answer this question we need to do the
comparison within the individual
3. Compares exposure to certain agent during
the interval when the event does not occurs
(control period) to exposure during interval
when the event occurs (Hazard period)

25. Case-crossover study design
25
4. It can be viewed as matched case-control
study design, where it involves cases only
and each indl serves as his/her control
5. The data from this design can also resemble
as cohort data, if the units of exposure are in
person-time
6. Analysis for the study can be treated as a
pooled analysis of several cohort studies
each with a sample size of one

26. Case-crossover study design
26

27. Case-crossover study design
• “If there are precipitating events, these events
should occur much more frequently during a
period immediately prior to the onset of
disease than at a similar period which is more
distant from the disease onset”
27

28. Case-crossover study design
The case-crossover study is most suitable for
studying relations with the following
characteristics:
1. Exposure varies within short time intervals
2. Disease has abrupt onset and short latency
for detection
3. Onset of action with in short period of time
28

29. Material & Method
29

30. Material and Methods
• Data
–Bipolar cohort
–Patients whose admitting diagnostic codes
range from ICD-9 codes 296.0 – 296.16,
296.4 – 296.81 or 296.89 (BPAD)
–Admitted between 1 January 1999 and 31
December 2012
30

31. Inclusion Criteria
1. Patients aged 15 - 65 years
2. At least one psychiatric admission for bipolar
disorder between 01 Jan 1999- 31 Dec 2012,
but no psychiatric admission between 01 Jan
1996 – 31 Dec 1998
3. Incidental stroke after first psychiatric
admission
31

32. Exclusion criteria
1. Patients having psychiatric admission
between 1 January 1996 and 31 December
1998
2. Patients who were diagnosed with stroke
before the first psychiatric admission
32

33. Study flow diagram
33

34. Study flow diagram
34

35. Statistical Analysis
1. Case-crossover study design was used in which
potential factors during 14 day “Hazard period”
(1-14) before the stroke was compared with
four individual 14 day “control periods”
2. Adjusted risk ratio was calculated after
adjusting potential confounders
3. Two step multivariate conditioned logistic
regression analysis and subgroup analysis was
done
4. Data was computed by SAS statistical software
35
Every 13 weeks: 92–105 days,
183–196 days, 274–287 and
365–378 days before the
stroke

36. Defined daily dose (DDD)
1. WHO Definition- DDD is the assumed average
maintenance dose per day for a drug used for
its main indications in adults
2. The recommended maintenance dose (long
term therapeutic dose) is usually preferred
when establishing the DDD.
3. The initial dose may differ from the
maintenance dose but this is not reflected in
the DDD.
36
https://www.whocc.no/ddd/definition_and_general_considera/

37. Defined daily dose (DDD)
• DDD for drugs used in this study
37
ATC Code Drug DDD Route of
administration
N03AF01 CARBAMAZEPINE 1 gm Oral
N03AG01 VALPROIC ACID 1.5 gm Oral
N03AX09 LAMOTRIGINE 0.3 gm Oral
N05AN01 LITHIUM 24 mmol Oral

38. Results
38

39. Demographic and clinical profile
39

40. Results
1. Cumulative duration and the cumulative
defined daily dose of each mood stabiliser
and the risk of all-cause stroke and its
subtypes was assessed
2. Combined sets of specific mood stabilisers
and the first- and second-generation
antipsychotics on the risk of stroke was
assessed
40

41. Results
41

42. Results
42

43. Results
43

44. Results
44

45. Result: Sub-group analysis
45

46. Result: Sub-group analysis
46

47. Discussion
47

48. Discussion
1. Acute exposure of mood stabilisers and the
risk of stroke
– Carbamazepine – Ischemic stroke
– Valproate – Hemorrhagic stroke
2. Combination therapy and the risk of stroke
– Interaction of carbamazepine (enzyme inducer)
and FGA increased the risk of stroke
48

49. Strengths (as per author)
1. First nation wide, population based case-
crossover study exploring association between
acute exposure of mood stabilizers and the
risk of stroke in patients with bipolar disorders
2. First study to find association between the risk
of stroke and the combination therapy of
mood stabilisers and antipsychotic drugs in
patients with bipolar disorder
49

50. Limitations (as per author)
1. Unavailability data on severity of bipolar
affective symptoms
2. Unavailability data regarding onset of illness
and/or hospitalization prior to year 1996
3. Selection of mood stabilizer itself could have
acted as a confounding factor (Prescription
bias)
4. Unavailability of data on unhealthy lifestyle
50

51. My comments
1. Information pertaining to change of
medication and Wash-out period was not
provided
2. Data in Person- years was not available
3. Study was based on defined daily dose of
each mood stabilizer rather than actual
dosage
4. No data on how author have decided the
length of Hazard period of 14 days
51
1. The recommended maintenance
dose (long term therapeutic dose)
is usually preferred when
establishing the DDD.
2. The initial dose may differ from
the maintenance dose but this is
not reflected in the DDD.

52. My comments
5. No data on how cumulative duration of use
was calculated
7. Why the case-crossover study design was
used altogether?
52

53. 53
Criteria Yes
(2)
Partial
(1)
No
(0)
NA
1 Question/ Scientific background/
Rationale/ Objective sufficiently
described?
√
2 Study design evident &appropriate? √
3 Inclusion & Exclusion Criteria
characteristics sufficiently
described?
√
4 Sample size appropriate? √

54. 54
Criteria Yes
(2)
Partial
(1)
No
(0)
NA
5 Results reported in sufficient detail
(Participants/descriptive data/outcome
data/main results) ?
√
6 Statistical method described/justified &
appropriate?
√
7 Conclusions supported by the results
(with limitations/ interpretation/
generalisability)?
√
8 Controlled for confounding? √
9 Outcome measures well-defined and
robust to measure bias? Means of
assessment reported
√

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

56. Communication to the author
56

57. Take home message
1. Patients with bipolar disorder are at a
significantly higher risk for stroke
2. Risk of stroke varies among the different
types of mood stabilisers
3. Acute use of carbamazepine appeared to
carry the highest risk of stroke, followed by
valproic acid
4. Lithium and lamotrigine did not increase the
risk of stroke
57

58. Take home message
5. Lithium may be considered for both acute
and maintenance phase of bipolar disorder
particularly in patients who are at high risk
for cerebrovascular diseases
58

59. 59
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