Enhanced Motor Recovery Using Serotonergic Agents in Stroke
Condition: Patients With Chronic Stroke
MeSH terms: Stroke
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): SSRI; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): SSRI alone or with training; Placebo alone or with training
Other intervention name(s): escitalopram
Intervention MeSH terms: Escitalopram
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: pharmacology; rehabilitation; locomotion