Recovery-promoting drugs after stroke: a systematic review
Adjuvant physical therapy was inconsistently repor-
ted and insufficient to allow for replication. There was
extreme variation between therapy amount, type (i.e.
Bobath vs Arm Ability training; physiotherapy vs oc-
cupational therapy, etc.) and duration. In 15 studies, no
adjuvant therapy was reported (15, 17, 18, 21, 34, 35,
48, 49, 51, 52, 54, 55, 61, 62, 64), while in another 13
studies dose of adjuvant therapy was not reported (25,
30–32, 40, 42, 44, 45, 50, 53, 56, 57, 63). In 3 studies,
a total of ≤ 60 min of adjuvant therapy was provided
over the duration of the trial (16, 22, 26).
It was deemed impossible to perform data syntheses
(meta-analyses) to compare RPDs regardless of drug
class, due to the large variability in design, duration
and outcome measures.
DISCUSSION
Eighteen of 28 drug interventions identified in this
review demonstrated recovery-promoting poten-
tial without associated increased rates of mortality
or SAEs. Yet, there were high attrition rates and bias,
and variable outcomes used, which prevented meta-
analysis. These issues are not isolated to RPD; the
Stroke Recovery and Rehabilitation Roundtable group
highlighted this as common in stroke rehabilitation
trials (10, 65, 66). Nevertheless, several classes of
RPDs should be discussed in more detail.
Three SSRIs were found to have some evidence
of efficacy and safety: citalopram, escitalopram and
fluoxetine (17, 18, 24, 30, 45, 60). Typically used
as antidepressants, SSRIs inhibit serotonin reuptake
into presynaptic neurones thereby enhancing nerve
transmission. Motor excitability over the unaffected
hemisphere is thought to be decreased, whilst neuro-
protective capacity and hippocampal neurogenesis is
promoted (67). Of all SSRIs reviewed, fluoxetine was
most extensively studied (4/7 SSRI trials with largest
cohorts n = 8–118) (18, 28, 30, 45). It is therefore
unsurprising that fluoxetine is involved in 3 current
international trials (FOCUS, AFFINITY, EFFECTS,
combined n =5,045 at May 2018), the results of which
will provide reliable estimates of effect (68, 69).
Levodopa (as single-drug intervention) was the
subject of 5 studies in this review, 4 of which were
favourable (15, 16, 19, 20, 43). Replenishing deple-
ted striatal dopamine, levodopa stimulates dopamine
pathways to increase motor activity (67). Trials admi-
nistered immediate-release levodopa preparations just
prior to motor retraining, in order to favourably exploit
levodopa’s short duration of action, theoretically pri-
ming the brain and maximizing remodulation of neural
pathways with minimal side-effects or potential dose
tolerance (67). Timing of dose administration relative
to physical rehabilitation is an important consideration.
327
Current trials provide insufficient evidence to guide
these decisions. Nevertheless, further exploration of
levodopa as an RPD appears worthwhile.
Safety measurement was inconsistent. When as-
sessed, mortality and AE were predominantly not
different to placebo. Assessment of safety may have
been overlooked, in part, due to dosages tested being
consistent with dosages used for other indications, with
previously established safety profiles. Implementation
of standardized guidelines for measurement of safety
e.g. International Council for Harmonisation Harmo-
nised Tripartite Guideline S7a – Safety Pharmacology
Studies For Human Pharmaceuticals, would improve
trial rigour and increase potential for meta-analyses
in future (70).
This review demonstrates the challenge of com-
prehensively and easily identifying all RPD studies,
even with a robust systematic approach. While 1,548
articles were identified for screening from the com-
prehensive database search, yielding 29 studies for
inclusion in this review, a further 3,231 citations were
identified from the references and forward citations
of these included studies. This probably highlights
the inconsistent categorization of RPD studies within
research databases, which relies on several variables,
including limitations of current non-specific MeSH
and key terms to adequately tag publications, and the
personal preferences and perspectives of the submitting
authors when ascribing MeSH and key terms to their
submissions (71). If RPD research is to continue to gain
momentum as an important field of study, developing
a dedicated MeSH term, such as “recovery-promoting
drug”, is worth consideration.
Personalization of RPD intervention for stroke sur-
vivors based on individual recovery needs, medical
profile, personal preferences and character traits is an
exciting prospect. With several RPDs demonstrating
potential efficacy, how and for whom they are prescri-
bed requires careful consideration. Coupling a more
detailed understanding of RPD pharmacology and
biological processes responsible for motor recovery
may aid the development of a more ordered classifica-
tion system for RPDs based on their biological targets.
Differing mechanisms of action and varied indica-
tions for use of the drugs in this review offer future
possibilities of combining RPDs to exploit synergistic
effects. Pilot testing of combination therapy would be
necessary to establish safety. Based on this review,
combined daily dosing of an SSRI, i.e. fluoxetine, and
levodopa, administered 60–90 min prior to a clinician-
led rehabilitation regimen of evidence-based adjuvant
physical therapy, has potential to maximize therapeu-
tic value by capitalizing on different mechanisms of
action. The results of the fluoxetine mega-trials are
awaited with interest.
J Rehabil Med 51, 2019