The underlying pathophysiology of stroke is acute neurological injury that is

caused by either ischemia (from events like thrombosis or embolism in the brain
arteries) or hemorrhage (where the intracranial pressure rapidly increases due
to accumulation of blood) leading to damage to the neurons.
When we talk about the consequence of stroke we think about two important
aspects, the first of which is Mortality. Stroke is the 2nd leading cause of death
worldwide in 2010 and 4th leading cause of mortality in Singapore in 2015.
However, stroke mortality has been decreasing. At the same time the second
issue, which is disability due to stroke is becoming an increasing problem.
-Disability associated with stroke refers to the long-term consequences of the
disease due to the development of impairments such as motor dysfunction (for
example the loss of ability to control movements properly), cognitive decline
and a low mood (sometimes even becoming post-stroke depression). These
impairments cause the patients to have increased difficulty in carrying out their
normal activities of daily living and sometimes increases their dependence on
caregivers to do these activities for them. In singapore, stroke is the 2 nd highest
cause of disease burden in elderly above 65 y/o, showing that the burden
related to stroke needs to be addressed.
-Current guidelines in the management of stroke focus heavily on two main
areas: addressing the underlying pathophysiology of acute stroke (through
either dissolving the thrombus in the case of ischemic stroke and stopping the
bleeding for hemorrhagic strokes) and preventing a second stroke event
through a wide range of agents from anti-hypertensives to statins.
While the current treatment is adequate in addressing the issue of stroke, it
fails to address the complications and disabilities related to stroke.
-The road to finding how to ameliorate the disabilities related to stroke is led by
the concept of neuroplasticity. The word neuroplasticity comes from neuro
or brain and plastic which refers to the ability to adapt and change its

organization or structure, just like how plastic can be molded into different
shapes and serve different purposes .
Hence, together, neuroplasticity refers to the ability of the brain to reorganize
its neurons that allows the neuronal circuits to bypass damaged areas and still
be able to serve its original functions via the formation of new connections. This
adaptation can viewed as a structual, functional and chemical adaptation of the
CNS to injury.
-Pre-clinical research points to the connection between different
neurotransmitter systems in the brain and neuroplasticity, though detailed
mechanisms are still not yet elucidated. Anti-depressants act on the nervous
system through regulation of mainly serotonin and norepinephrine at usual
doses. It is used mainly in the treatment of depression, but there has been RCTs
of anti-depressants showing the ability to enhance motor recovery after stroke.
Anti-Alzheimers drugs also act on neurotransmitters in the nervous system, but
mainly through its interaction with acetylcholine and glutamate receptor
systems. While it is usually used for its ability to enhance cognition, there has
also been cases of enhanced sensorimotor functions in post-stroke patients
after treatment with donepezil. Hence, we hypothesize that these two groups
of drugs can potentially enhance stroke recovery.
-Therefore, the objective of this systematic review and meta-analysis is to
evaluate the effective of anti-depressants and anti-Alzheimers drugs in
improving functional outcomes during stroke recovery.
-A comprehensive literature search was conducted using three databases:
pubmed, embase and cochrane library, using generic and class names of antidepressants or anti-Alzheimers drugs in combination with terms that represent
different types of strokes. The search was restricted to only English or Chinese
articles and titles and abstracts were screened for relevance before full text
retrieval. The reference lists of relevant articles were also hand-searched for
additional relevant articles

-Inclusion/exclusion criteria
-The two main outcomes that we are looking at in this analysis are disability and
dependency. Disability refers to how difficult it is for patients to carry out their
activities of daily living and the scales used to quantify disability looks at
different components of a patients life such as feeding, bowel continence and
grooming and the ease with which patients can carry out these activities.
Dependency on the other hand refers to the extent of independence of patients
in carrying out these activities, and is measured by scales that try to quantify the
level of independence of the patients.
-Briefly talk about this
So these were the information that were extracted from each study, and these
information help us to not only conduct the analysis but also to judge different
parameters of the study and how they can be relevant or similar to our own
practices
-To account for baseline imbalances between treatment and control groups, the
change in outcomes scores from baseline was calculated and used for the
analysis. This formula was used to calculate the mean change in score and the
SD of the change score, and r in the above formula refers to the correlation
coefficient that should describe how the baseline and final score should change
together. As there is no available study that report how the different the
different outcome measures change, a value of 0.5 was chosen for the main
analysis as it is the most common value to use. A study reported that the
median correlation for change from baseline amongst trials included in
systematic reviews was 0.59 with an IQR of 0.4-0.81. Hence, sensitivity analysis
was conducted with r = 0 to 0.8 to investigate the robustness of this method.
--

In order to ensure that the scores were comparable for analysis, there were
other statistical issues that needed to be adjusted.
- One study was conducted using the Functional Independence Measure, which
is a disability scale with two components the motor and cognitive component.
-Allocation concealment which is judging how effective the randomization
would be by considering if there was any means of concealing the randomized
sequence
Incomplete outcome data which judges if the results may possibly be biased
due to the drop-outs in the study
Selective report which judges if the paper might be biased by assessing if any
data that were measured but not reported hence indicating possibly an
intention to hide these data
-For dependency outcomes, risk ratio was calculated because the scale used to
measure dependency was of an ordinal nature, and the proportions of patients
who were dependent or not (based on the scoring) was reported.
So now, I will move on to the results and discussion.
-Remember the animations
-These trials covered a range of agents of different classes, but in particular there
were no studies that was related to the use of atypical anti-depressants,
monoamine oxidase inhibitors or NMDA receptor antagonists
-Explain briefly the color coding
This should also be taken into account when interpreting the data.

-For anti-Alzheimer's drug studies, potential publication bias was not assessed as
only 3 studies were included.
-This is the forest plot of standardized mean difference in the change in disability
scores from baseline between treatment and control groups using a randomeffects model for (A) studies on anti-depressants studies, stratified by different
drug classes and using a fixed-effects model for (B) studies on anti-Alzheimer's
drugs (specifically cholinesterase inhibitors). Amongst the evaluated antidepressant drug classes, only patients treated with SSRIs showed significant
improvement in disability score. Anti-Alzheimers drugs failed to show
effectiveness in improving disability.
-Read
-Post-stroke depression occurs in up to 61% of stroke survivors. What does this
mean for the patient? What are the impacts of post-stroke depression and its
impact on how patients should be treated post-stroke? For one, patients with
post-stroke depression were found to be more likely to have functional
limitations. Hence, it may suggest that depression may be related to disability
just as the alleviation of depression may be alleviate disabilities. It was also
found in the previous SSRI meta-analysis that the SMD was higher in depressed
patients, showing that depressed patients obtain a higher benefit from
treatment with SSRIs than non-depressed patients, further signifying that the
enhancement of mood may be a key mechanism in ameliorating disability but
not just limited to the patients with depression only. Some authors suggest that
an enhanced mood may improve outcomes by causing patients to be more
motivated and engaged in their physicial rehabilitation. However, if that is the
case, then all anti-depressants should be able to enhance functional outcomes
since they possess the ability to enhance mood, but our results clearly do not
show as such. The next subgroup analysis was then taken to explore what could

be some causes to why not all evaluated anti-depressants showed an

improvement in disability.
-Anti-cholinergic effects interact with post-stroke disabilities in different
mechanisms. Though it is usually taken to be an undesirable side effect of antidepressant therapy, theoretically, it can have both positive and negative
impacts on stroke recovery. For example bladder and fecal incontinence are
few of the most common disabilities associated with stroke occurring up to 79%
and 40% respectively. Some studies have also found urinary incontinence to be
a major predictor of complications post-stroke. These aspects also form major
components of disability scales, such as of the Barthel Index, where 20% of the
total scoring is attributed to bladder and fecal continence, so it appears that
drugs with some anti-cholinergic effects may prove beneficial to stroke recovery.
However, these effects have also been linked to confusion and development of
dementia post-stroke which may on the other hand, hinder recovery. So initially,
in light of these points, our hypothesis was that anti-depressant with a low level
that is not negligible or too high would be the most beneficial for stroke
recovery, which is the second sub-group (with one plus).
-However, our results showed that this could be due to reasons like
-The next subgroup analysis undertaken was by the different time-points
measured. As only SSRIs showed the ability to significantly improve disability
scores, this was performed only for all time-points reported across the SSRI
studies to evaluate the impact of treatment duration on recovery of disabilities.
There was no significant difference in recovery of disability at 2 weeks, but the
improvement in disability in the treatment group became significantly higher
than the control group with at least 4 weeks of treatment. As treatment
duration increased at 12 weeks there was no significant different and this may
be attributed to the natural recovery of stroke over time since most of the
patients studied had mild or moderate stroke
--

Coincidental trend
-Sensitivity analysis
-There was only one anti-depressant study with fluoxetine that measured
dependency. No anti-Alzheimers drug studies measured dependency. In this
study, the scale called modified Rankin Scale was used to measure
dependency. A score of 3-5 on this scale was considered dependent and this
study compared the proportion of dependent patients after 90 days of
treatment with either fluoxetine or placebo.
-Firstly, the possibility of chance findings due to the small number of studies, for
both anti-Alzheimer's drug studies and subgroups used, and small sample sizes
of the included studies cannot be ruled out. Thus, the current results should be
cautiously interpreted and large-scale studies would be required. Secondly, few
studies were carried out with the primary objective of examining how disability
and dependency could be affected in patients receiving anti-depressants or antiAlzheimer's drugs. Hence, some of the data were not clearly documented and
hence may limit the amount and quality of the published data available for
evaluation. Lastly, as most of the patients in the included studies had mild to
moderate stroke, the results of this meta-analysis may not be generalizable to
patients with severe stroke, since stroke pathophysiology may change with
stroke severity.
-Conclusion
-Thank you