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disability when taking risk of harm into account (7).
The number of patients included in the studies was too
small to be able to draw firm conclusions regarding the
effect of amphetamines on recovery from stroke (7).
Conversely, another Cochrane Review (n = 52 trials,
4,059 patients) provided “tantalizing evidence” that
selective serotonin reuptake inhibitors (SSRIs) appear
to improve dependence, disability, neurological impair-
ment, and anxiety and depression after stroke (8). Both
reviews recommended larger, well-designed trials be
undertaken to clarify efficacy, and to overcome issues
with heterogeneity and methodology seen in studies
across both drug classes.
As both reviews targeted singular drug classes,
neither could provide judgement comparing the outco-
mes of the drugs with each other. To address this gap,
the aim of this systematic review was to investigate
the efficacy and safety of drug interventions trialled to
enhance motor recovery post-stroke (3, 4).
METHODS
Protocol and registration
This systematic review was registered on PROSPERO (refe-
rence number: CRD42016048035). Preferred Reporting Items
for Systematic Reviews and Meta-Analysis (PRISMA) state-
ment provided the framework for the article (9).
Data sources and searches
Six electronic databases (Cochrane CENTRAL, CINAHL,
Embase, MEDLINE, SCOPUS and Web of Science) were
searched from database inception to 2 May 2017. Reference
lists of included studies were entered into the Web of Science
to identify relevant studies from forward citations.
The search term “recovery-promoting drug” was not widely
recognized. Relevant drug studies identified through a scoping
search were mined for terminology describing the concept
of “promoting neurorecovery”. The resulting search strategy
was curated carefully, containing key words and MeSH terms
associated with target pathways, anatomy and processes (e.g.
“efferent pathways”, “motor cortex” and “neurogenesis”), and
molecules involved in neural plasticity and neural repair (e.g.
more broadly: “nerve growth factors”, “psychotropic drugs”;
specifically “biogenic amines” and “dopamine”) with the in-
tention of selecting motor recovery-specific studies from the
broader pool of neurorecovery trials (Figs S1–S7).
Study selection
Study inclusion criteria were: (i) randomized placebo-controlled
trial design; (ii) commencement of 1 or more RPD intervention/s
> 24 h post-stroke (10); and (iii) a measure of motor outcome
of components of the motor system within the domains of body
functions and structures and activity, as defined by the Inter-
http://www.medicaljournals.se/jrm/content/?doi=10.2340/16501977-2536
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www.medicaljournals.se/jrm
national Classification of Functioning, Disability and Health
(ICF) (11). Non-English publications and aphasia trials were
excluded, the latter being a language disorder, not attributable
to motor function.
Titles and abstracts were reviewed and shortlisted by author
NF, and by author JB if inclusion was unclear. Eligibility was
determined through independent assessments of full-text ver-
sions of shortlisted articles by authors NF and KH, while author
JB confirmed eligibility when necessary.
Data extraction and analysis, and risk of bias assessment
Study details (sample size, time post-stroke, age, sex, stroke
severity), experimental design descriptors (drug and control
intervention details, adjuvant physical therapy, treatment/
follow-up endpoints), outcome measures and corresponding
measures of central tendency were extracted by author NF and
corroborated by author KH utilizing standardized pro forma
(12). Authors of included studies were emailed for missing data.
Physical rehabilitation interventions within each trial were
recorded as “adjuvant therapies”. The endpoint was defined as
final assessment of outcome; whether occurring at final dose
of drug intervention or end of follow-up was noted, along with
whether primary outcome measures were designated. The extent
of safety monitoring and adverse events were recorded, and
whether they were pre-specified outcomes or general obser-
vations. Safety assessment was based on mortality and severe
adverse events (SAEs) associated with drug intervention, e.g.
haemorrhage, neurological deterioration. Risk of bias was asses-
sed by NF and KH using the Cochrane risk of bias assessment
tool (13). Between-group endpoint estimates and change scores
were extracted for motor outcomes. When statistically signi-
ficant p-values were noted, effect sizes were calculated (NF)
from raw data using Cohen’s d method, where possible (14).
RESULTS
Database searching yielded 1,548 results, with 29
studies eligible for inclusion. These studies contained
3,231 references, used to identify further studies, which
led to the inclusion of a further 21 studies (Fig. 1).
Therefore, a total of 50 studies (n = 5,643 participants)
were included. Duplicate citation (25%) or not RCT
(40%) were the most common reasons for exclusion.
Included studies were published between 1973 and
2017 (Table SI). Methodologies varied, including cros-
sover trials (n = 10) (15–24) and short-term studies with
outcomes measured ≤ 24 h post-RPD administration
(n = 11) (16–26). Sample sizes ranged from 8 to 1,099
participants (median: 40, IQR: 18.5–83), mean age
spanned 53 (25) to 78 years (27). Participants were
predominantly male (range 32–100%); only 12 (24%)
studies had ≥ 50% females.
Twenty-eight different RPDs were investigated (Ta-
ble I). Four studies compared 2 drug intervention arms
with placebo (28–31). Four studies evaluated MLC
601 (NeuroAid ™ ) and involved the largest proportion
of participants (n = 2,099, 37.2%) (32–36). The most
frequently studied pharmacological interventions were