Serotonergic Modulation of Motor Function in Subacute and Chronic SCI
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Hospital, Orthopedic |
| Therapuetic Areas: | Orthopedics / Podiatry, Other |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 4/21/2016 |
| Start Date: | June 2005 |
| End Date: | July 2016 |
The manifestation of weakness and involuntary reflexes following motor incomplete spinal
cord injury (SCI) may be partly a result of damage to descending pathways to the spinal cord
that release serotonin. In models of SCI, for example, application of agents that simulate
serotonin has been shown to modulate voluntary motor behaviors, including augmentation of
walking recovery. In humans following neurological injury, the effects of 5HT agents are
unclear. Few previous reports indicate improved motor function following administration of
agents which enhance the available serotonin in the brain, although some data suggests that
decreased serotonin may be beneficial. In this application, the investigators propose to
study the effects of clinically used agents that increase or decrease intrinsic serotonin
activity in the brain on strength and walking ability following human motor incomplete SCI.
Using detailed electrophysiological recordings, and biomechanical and behavioral measures,
the investigators will determine the effects of acute or chronic doses of these drugs on
voluntary and involuntary motor behaviors during static and dynamic conditions. The novelty
of this proposed research is the expectation that agents that enhance serotonin activity may
increase abnormal reflexes in SCI, but simultaneously facilitate motor and walking recovery.
Despite potential improvements in voluntary function, the use of pharmacological agents that
may enhance spastic motor behaviors following SCI is in marked contrast to the way in which
drugs are typically used in the clinical setting.
cord injury (SCI) may be partly a result of damage to descending pathways to the spinal cord
that release serotonin. In models of SCI, for example, application of agents that simulate
serotonin has been shown to modulate voluntary motor behaviors, including augmentation of
walking recovery. In humans following neurological injury, the effects of 5HT agents are
unclear. Few previous reports indicate improved motor function following administration of
agents which enhance the available serotonin in the brain, although some data suggests that
decreased serotonin may be beneficial. In this application, the investigators propose to
study the effects of clinically used agents that increase or decrease intrinsic serotonin
activity in the brain on strength and walking ability following human motor incomplete SCI.
Using detailed electrophysiological recordings, and biomechanical and behavioral measures,
the investigators will determine the effects of acute or chronic doses of these drugs on
voluntary and involuntary motor behaviors during static and dynamic conditions. The novelty
of this proposed research is the expectation that agents that enhance serotonin activity may
increase abnormal reflexes in SCI, but simultaneously facilitate motor and walking recovery.
Despite potential improvements in voluntary function, the use of pharmacological agents that
may enhance spastic motor behaviors following SCI is in marked contrast to the way in which
drugs are typically used in the clinical setting.
The proposed study will consist of a double-blinded, randomized controlled trial using a
crossover design to assess the effects of SSRIs (escitalopram oxalate, Lexapro®, Forest
Pharmaceuticals, Inc) and 5HT-antagonists (cyproheptadine [CYPRO], Periactin ®, Merck, Inc)
on volitional and spastic motor behaviors in subjects with motor incomplete SCI following
both acute and chronic medication delivery. Voluntary and reflexive motor behaviors in 120
subjects with SCI will be assessed. These interventions will be applied to individuals with
acute (< 6 months post injury) chronic (> 1 year post injury) motor incomplete SCI to
determine both the rate and extent of changes in volitional motor performance and
involuntary spastic behaviors. For the training portion of the study (referred to as
subproject 2 below), a portion of the acute and chronic subjects will be evaluated every 2
weeks for up to16 weeks and participate in locomotor training, to investigate and better
understand changes in motor function and recovery in individuals with spinal cord injuries.
Following 2-4 weeks of this training, individuals will be given either the study drug, or
placebo and continue evaluation and training. Following an additional 4 weeks, subjects will
be given either the placebo or study drug (whichever they did not receive during the prior 4
weeks). The order will be randomized.
crossover design to assess the effects of SSRIs (escitalopram oxalate, Lexapro®, Forest
Pharmaceuticals, Inc) and 5HT-antagonists (cyproheptadine [CYPRO], Periactin ®, Merck, Inc)
on volitional and spastic motor behaviors in subjects with motor incomplete SCI following
both acute and chronic medication delivery. Voluntary and reflexive motor behaviors in 120
subjects with SCI will be assessed. These interventions will be applied to individuals with
acute (< 6 months post injury) chronic (> 1 year post injury) motor incomplete SCI to
determine both the rate and extent of changes in volitional motor performance and
involuntary spastic behaviors. For the training portion of the study (referred to as
subproject 2 below), a portion of the acute and chronic subjects will be evaluated every 2
weeks for up to16 weeks and participate in locomotor training, to investigate and better
understand changes in motor function and recovery in individuals with spinal cord injuries.
Following 2-4 weeks of this training, individuals will be given either the study drug, or
placebo and continue evaluation and training. Following an additional 4 weeks, subjects will
be given either the placebo or study drug (whichever they did not receive during the prior 4
weeks). The order will be randomized.
Inclusion Criteria:
- age of subjects between 18 and 65 years of age, due to the effects of greater age on
functional recovery of ambulation (Penrod et al. 1990);
- medically stable with medical clearance from the subject's primary internist or
physiatrist to participate;
- level of the lesion between C5-T10 spinal cord level due to non-progressive etiology;
- <6 months or >1 yr since initial injury. Range of motion requirements include: ankle
dorsiflexion ankle to 10 degrees and plantarflexion to 30 degrees, knee flexion from
0 to 120 degrees, hip flexion to 90 degrees, and hip extension to 10 degrees.
Exclusion Criteria:
- presence of concurrent severe medical illness, including unhealed decubiti, existing
infection, cardiovascular disease, significant osteoporosis (as indicated by history
of fractures following injury)
- active heterotrophic ossification in the lower extremities
- known history of peripheral nerve injury in lower legs
- history of known traumatic head injury
- a history of cardiovascular or pulmonary complications, including significant
obstructive and/or restrictive lung diseases
- inability to tolerate 30 minutes of standing without orthostasis (decrease in blood
pressure by 20 mmHg systolic and 10 mmHg diastolic)
- individuals who are undergoing concurrent physical therapy will be excluded to
eliminate confounding effects
- women of childbearing potential will not be excluded, although women who are pregnant
will be excluded due to the lack of proven safety of pharmacological agents in
pregnant women
- cranial stimulation exclusions: history of epilepsy or a seizure event, metal
implants in the head or face, unexplained and recurring headaches, skull
abnormalities or fractures, implanted cardiac pacemaker or suffered a concussion
within the last 6 months
- interactions with other medications or previous sensitivity to SSRIs, 5-HT
antagonists or anti-histamines
- patients prescribed medications for alleviation of spastic motor behaviors,
anti-depressant medications, or other medications with known interactions to SSRIs
will be excluded from participation unless both attending physician and patient agree
to cease all such medications during the evaluation and training period. A 14-day
minimum washout period for all such medications will be utilized
- patients with known liver, renal, or other metabolic disease that may interfere with
drug action and/or clearance will be excluded from the proposed study. The low daily
dosage of the agent to be used (10 mg Lexapro and 16 mg Cypro) has shown very little
side effects with patients with hepatic or renal disease
- patients who are diagnosed or previously diagnosed with depression will be excluded.
A preliminary screening tool (Center for Epidemiological Studies - Depression Scale)
will be administered to all patients. Scores > 16 indicate symptoms of depression.
For those patients, a physician will be required to evaluate the subject to determine
eligibility.
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