Patients With Chronic Stroke Clinical Trial
Official title:
Enhanced Motor Recovery Using Serotonergic Agents in Stroke
The information derived from this study will be critical to establishing appropriate
rehabilitative interventions post-stroke. In particular, traditional use of pharmacological
agents to alter motor function post-stroke is directed primarily at reducing the "positive"
signs following upper motor neuron lesion, in particular spasticity, or enhanced,
velocity-dependent stretch reflex responses to imposed stretch. While pharmacological
management of spasticity certainly suppresses clinical and quantitative measures of
hypertonia, there is little improvement in functional performance. In contrast, preliminary
data on the administration of 5HT agents following neurological injury indicates an increase
in motor performance (Pariente 2001) and recovery (Dam 1996), despite an increase in spastic
motor activity (Stolp-Smith 1999; see Preliminary Data below). Understanding methods to
maximize function following stroke despite potential, short-term increases in spastic motor
activity may improve therapeutic intervention strategies. The general objective of this
study is therefore to:
1. quantify the effects of short-term SSRI administration on voluntary and spastic motor
behaviors in individuals with chronic spastic hemiparesis,
2. identify the changes in impairments and functional recovery of walking ability during
BWSTT with the presence or absence of SSRIs.
Walking ability post-stroke is characterized primarily by reduced walking speed and
endurance and impaired postural stability which limits functional and societal
reintegration. Decreased over ground walking speed is a result of decreased cadence,
decreased stride length and increased non-paretic single limb stance duration. Mechanisms
underlying reduced velocity are thought to include weakness in the paretic limb, particular
hip flexor and plantarflexor strength, but may also be linked spastic motor behaviors and
loss of inter- and intra-limb coordination. Rehabilitation efforts to improve strength and
muscle coordination patterns during hemiparetic gait may improve gait quality and velocity
and therefore improve performance of activities of daily living.
To improve gait performance and functional outcomes following neurological injury,
rehabilitation efforts have focused on re-establishing normal walking patterns . Towards
this end, the use of body-weight supported treadmill training (BWSTT) has demonstrated
significant improvement in walking capability in individuals post-stroke and spinal cord
injury . By supporting a portion of a subject's body weight over a treadmill and providing
manual facilitation from therapists, previous research has demonstrated improvements in
temporal-spatial gait patterns, including gait velocity , endurance (Macko 2005), balance ,
and symmetry. Importantly, the changes in impairments and functional limitations observed
with intensive BWSTT are often greater than that achieved during conventional or lower
intensity physical therapy. Given these benefits, particularly in those who require
substantial walking assistance following stroke various robotic locomotor retraining devices
have been developed to facilitate practice of "kinematically correct" stepping patterns to
improve the consistency and duration of treadmill training.
While the changes observed following BWSTT are statistically and functionally significant,
it remains unclear is the benefits of such intensive training paradigms are optimized.
Specifically, across many larger studies in subjects with chronic stroke (i.e., those > 6
mo. post-injury), mean increases in walking speed range between 0.09 m/s to 0.15 m/s
following 1-6 mos. of training. Even in current trials investigating changes in over ground
walking speed in robotic- vs. therapist-assisted BWSTT, mean improvements over at least 18
subjects in each group vary from 0.07 to 0.13 m/s, respectively (please see Preliminary
work: Pilot Study 1). While again statistically significant, such changes represent an
approximate 10% improvement in gait speed as compared to healthy adults (Perry 1992).
To enhance the benefits of intensive BWSTT, many investigators continue to search for
combined interventions to augment recovery. One potential adjunct that has received
attention is the use of pharmacological agents. For example, anti-spastic medications (e.g.,
benzodiazepine, baclofen, tizanidine) have been used for decades (to reduce the presence or
severity of involuntary, spastic reflexes in patients with stroke. Spasticity has
traditionally been thought to be a primary limitation to functional mobility post-stroke,
although this premise has been questioned recently . Indeed, many pharmacological agents are
effective in reducing spastic motor behaviors although evidence for improvements in function
following use of these agents post-stroke is limited. In addition, some evidence suggests
that these agents reduce maximal voluntary strength and can impair learning of motor tasks.
New evidence has emerged of a potentially powerful role of excitatory or facilitative
modulatory agents in the treatment of motor impairments post-stroke. Based primarily on
evidence from experimentally induced lesions in mammals, the application of monoaminergic
(i.e., serotonin [5HT] and norepinephrine [NE]) agents excite vs. depress spinal or cortical
excitability have gained momentum. In individuals post-stroke, for example, the use of
amphetamines (directed primarily through NE pathways) had generated substantial interest as
an adjunct to physical therapy interventions, although recent data may suggest no benefit
from this agent. Further, the use of amphetamines may enhance the risk of cerebral or
coronary vascular disease, which is already compromised in this patient population, and
therefore limit the use of these agents in clinical practice.
In contrast, 5HT agents have also been shown to enhance spinal and/or cortical excitability,
and may accelerate locomotor recovery following neurological injury when appropriate
physical interventions are provided . In humans post-stroke, one study has demonstrated
enhanced motor performance and cortical activity following a single dose of SSRIs. In
another study of sub-acute stroke, SSRIs and not selective NE reuptake inhibitors improved
function during inpatient rehabilitation. Interestingly, a small case report indicates a
strong increase in spasticity following use of 5HTergic anti-depressive agents, indicating
that both spinal and cortical excitability may contribute to altered motor function. Such
findings have been replicated here (please see Preliminary work: Pilot Study I, although
certainly require further assessment.
While the above findings are preliminary, two important questions arise. First, if both
spastic and voluntary lower extremity activity are simultaneously altered following
administration of commonly used anti-depressive medications, how does the relation between
these variable alter motor function? Echoing tothers, how important is the prevalence of
spasticity to impaired motor function post-stroke? Secondly, can the increased excitability
of both spinal and cortical systems following SSRI accelerate motor recovery and the
effectiveness of intensive physical rehabilitation strategies, as shown in reduced
preparations? Such data are important for health care professionals treating individuals
with neurological injury to: A) understand the previously unknown modulation in reflex or
voluntary function following a seemingly innocuous agent; and, to B) provide the optimal
neural excitability to accelerate motor performance and recovery post-injury.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment