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(Stroke. 1996;27:1211-1214.)
© 1996 American Heart Association, Inc.

Articles

Effects of Fluoxetine and Maprotiline on Functional Recovery in Poststroke Hemiplegic Patients Undergoing Rehabilitation Therapy

M. Dam, MD; P. Tonin, MD; A. De Boni, MD; G. Pizzolato, MD; S. Casson, MD; M. Ermani, MD; U. Freo, MD; L. Piron, MD L. Battistin, MD

the Department of Neurological and Vision Sciences, University of Verona (M.D.); Department of Neurorehabilitation, Hospital San Camillo, Venice (P.T., A. De B., S.C.); and the Department of Neurology and Psychiatry, University of Padua (G.P., M.E., U.F., L.P., L.B.) (Italy).

Correspondence to M. Dam, Department of Neurology and Psychiatry, University of Padua, via Giustiniani 5, 35128 Padua, Italy. E-mail Clneurol@ipdunidx.unipd.it.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose In animals, drugs that increase brain amine concentrations influence the rate and degree of recovery from cortical lesions. It is therefore conceivable that antidepressants may influence outcome after ischemic brain injury in humans. We evaluated the effects of the norepinephrine reuptake blocker maprotiline and the serotonin reuptake blocker fluoxetine on the motor/functional capacities of poststroke patients undergoing physical therapy.

Methods Fifty-two severely disabled hemiplegic subjects were randomly assigned to three treatment groups; during 3 months of physical therapy, patients were treated with placebo, maprotiline (150 mg/d), or fluoxetine (20 mg/d). Before and at the end of the observation period, we assessed activities of daily living by the Barthel Index, degree of neurological deficit by a neurological scale for hemiplegic subjects, and depressive symptomatology by the Hamilton Depression Rating Scale.

Results The diverse treatments ameliorated walking and activities of daily living capacities to different extents. The greatest improvements were observed in the fluoxetine-treated group and the lowest in the maprotiline-treated group. Furthermore, fluoxetine yielded a significantly larger number of patients with good recovery compared with maprotiline or placebo. These effects of the drugs were not related to their efficacy in treating depressive symptoms.

Conclusions Fluoxetine may facilitate or, alternatively, maprotiline may hinder recovery in poststroke patients undergoing rehabilitation. The effects of fluoxetine as an adjunct to physical therapy warrant further investigation, since treatment with fluoxetine may result in a better functional outcome from stroke than physical therapy alone.

Key Words: antidepressive agents • fluoxetine • maprotiline • rehabilitation • stroke outcome

	Introduction

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Depression is a common sequela of stroke, being diagnosed in 20% to more than 60% of patients.^{1 2 3 4 5 6} Because depression is associated with a poor outcome,^{1 7} different antidepressants are currently prescribed to improve quality of life and active participation in rehabilitation programs.^{8 9 10 11}

Since noradrenergic but not serotonergic drugs facilitate recovery in lesioned animals,^{12 13 14 15} the prolonged administration of serotonergic or noradrenergic antidepressants may differently influence the restorative processes that follow stroke in humans.

We therefore investigated motor/functional recovery in three groups of hemiplegic patients after unilateral ischemic stroke in the territory of the middle cerebral artery; the patients were treated with rehabilitation therapy in combination with placebo, the selective 5-HT reuptake inhibitor fluoxetine, or the norepinephrine reuptake inhibitor maprotiline.¹⁶ Fluoxetine and maprotiline were chosen among antidepressants because of their absent or relatively low anticholinergic activity, which may hinder recovery.^{17 18 19}

	Subjects and Methods

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Subjects unable to walk 1 to 6 months after a CT-proven hemispheric ischemic stroke in the territory of the middle cerebral artery were considered eligible for the study. Patients with a history of major affective disorders or alcohol abuse or a history and/or clinical evidence of severe heart, lung, kidney, or liver diseases or mental deterioration were excluded.

Patients were randomly divided into three groups and treated for 3 months with physical therapy associated with placebo, 150 mg/d maprotiline, or 20 mg/d fluoxetine. Drugs were withdrawn in the presence of persistent or severe side effects. Informed consent was obtained from all participants in the study.

The rehabilitation program lasted 3 months and consisted of 1 to 2 hours per day of individual physical therapy, 2 hours of occupational therapy, and 1 hour of speech therapy if needed 5 days per week. The major techniques used were as described by Bobath.²⁰

The degree of neurological impairment was assessed with a graded neurological scale (HSS) as described by Adams et al.²¹ According to this scale, higher scores indicate greater neurological deficits. In this study we considered total score (HSS Total; range, 0 to 100) and subscores for motor function (HSS Motor; range, 0 to 40) and ability to walk (HSS Gait; range, 1 to 6). Gait was considered functionally adequate in subjects with an HSS Gait score of 3 or less. Patients with an HSS Gait score of 3 do not require assistance (other than a simple device) for walking, but distance is limited.

Autonomy in ADL was monitored by the BI score (range, 0 to 100; the higher the score, the greater the independence in ADL).²² Patients with a BI score above 70 were considered independent in ADL.

Depressive symptoms were rated with the HDRS (17 items).^{23 24} Patients with severe brain lesions, as those enrolled in this study, may be unable to report their symptoms because of a left hemispheric stroke or to recognize their emotional status because of a right hemispheric stroke.²⁵ Therefore, the assessment of depression, as previously applied to aphasic patients,²⁶ depended primarily on the observation of the patient's behavior. The HDRS score was mainly inferred from evidence of agitation, anger, weeping, weight loss, appetite and sleep alterations, and degree of participation in the rehabilitation program and social activities.

HSS, HDRS, and BI scores were determined at entry into the study and at the end of 3 months of therapy. The examining neurologists were blinded to the treatment administered to the patients.

The Wilcoxon test was used to determine the statistical significance of the differences in the BI, HSS Motor, HSS Gait, and HDRS mean scores between the two evaluations in each treatment group. The Mann-Whitney U test was used to evaluate the statistical significance of the differences in outcome measures (BI, HSS Total, HSS Motor, HSS Gait, and HDRS mean scores) among the three treatment groups at entry and at the end of the study. We used cluster analysis to separate patients into groups with poor or good outcome using BI and HSS Gait final scores. The ² test was used to evaluate the difference in the number of placebo-, maprotiline-, and fluoxetine-treated patients allocated to the poor or good recovery group.

Statistical significance was considered at P.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Fifty-two patients entered the study. One of the 17 patients allocated to the placebo group did not complete the study because of a second stroke. Of the 17 maprotiline-treated patients, 2 dropped out from the study because they moved to a rehabilitation center closer to their family home, and 1 patient was excluded because of epileptic seizures. Two other patients complained of sedation for several days, but this side effect disappeared later. Among the 18 fluoxetine-treated patients, 2 patients were withdrawn from the study because of epileptic seizures. Two patients reported transient nausea or insomnia.

The characteristics of the 46 patients who completed the study are shown in Table 1. Age, time elapsed between stroke and the beginning of rehabilitation, and duration of antidepressant treatments were similar among groups. There were no statistical differences in the percentages of patients with left-sided stroke or with sphincter continence in the placebo-, maprotiline-, and fluoxetine-treated groups (² test).

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

As shown in Table 2, the degree of neurological impairment (HSS Total and HSS Motor scores) at entry into the study was similar among groups. At the end of the study, significant improvements (ranging from 9% to 11%) from baseline values were observed in all groups, regardless of therapy.

View this table: [in this window] [in a new window]   Table 2. Neurological Recovery in Poststroke Hemiplegic Patients Undergoing Rehabilitation Therapy

The mean scores of the functional indices (BI and HSS Gait scores) at the two evaluation points are shown in Table 3. At the beginning of therapy, patients of the different groups were equally compromised in their walking and ADL capacities. The diverse treatments significantly improved both functional indices but to different extents. The HSS Gait mean scores improved from baseline values by 36%, 16%, or 21% in the fluoxetine-, maprotiline-, and placebo-treated patients, respectively. After the same treatments, the BI mean values improved by 61%, 32%, and 55%, respectively. Both BI and HSS Gait final mean scores were statistically different between the maprotiline- and fluoxetine-treated groups but not between either of these groups and the placebo group.

View this table: [in this window] [in a new window]   Table 3. Functional Recovery in Poststroke Hemiplegic Patients Undergoing Rehabilitation Therapy

The initial HDRS mean score was significantly higher in the maprotiline-treated group compared with the placebo group but not significantly different from the HDRS mean score of the fluoxetine group (Table 4). Fluoxetine and maprotiline significantly decreased HDRS baseline values by 30% and 18%, respectively. Final HDRS mean scores were not significantly different among groups.

View this table: [in this window] [in a new window]   Table 4. HDRS Score of Poststroke Hemiplegic Patients Undergoing Rehabilitation Therapy

Cluster analysis based on both final HSS Gait and BI scores was used to separate patients into two groups, as shown in the Figure. The poor recovery group exhibited persistent compromise in terms of both gait (HSS Gait mean score, 5.3±0.7) and ADL (BI mean score, 39.8±9.1). The good recovery group was characterized by a mean level of functional improvement very close to independence in terms of both gait (HSS Gait mean score, 3.4±0.58) and ADL (BI mean score, 70±10.8). This group comprised 12 of the 16 patients treated with fluoxetine (75%), 5 of the 14 patients treated with maprotiline (36%), and 6 of the 16 patients treated with placebo (38%). The number of fluoxetine-treated patients allocated to the good outcome group was statistically different compared with the remaining treatment groups.

View larger version (30K): [in this window] [in a new window]   Figure 1. Percentage of placebo-treated (), maprotiline-treated (), and fluoxetine-treated () patients classified by cluster analysis in the poor (HSS Gait mean score, 5.4±0.7; BI score, 39.8±9.1) and good (HSS Gait score, 3.4±0.6; BI score, 70±10.8) outcome groups. *Significantly different from placebo-treated and maprotiline-treated groups (P.05).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study evaluated the degree of recovery from a single hemispheric stroke in response to rehabilitation therapy alone or associated with fluoxetine or maprotiline.

Treatment with either antidepressant was associated with some side effects: drowsiness with maprotiline, nausea and insomnia with fluoxetine, and seizures requiring discontinuation of therapy with both drugs. The observed complications were expected,^{27 28} even though seizures are reported as a very rare side effect during fluoxetine treatment in neurologically normal depressed patients.²⁹

At the end of the treatment, rehabilitation by itself or combined with either antidepressant produced significant gains in HSS Gait and BI scores.

However, the greatest improvements were observed in the fluoxetine-treated patients and the lowest in the maprotiline-treated patients. Furthermore, fluoxetine treatment yielded a significantly larger number of patients with good outcome compared with maprotiline therapy or physical therapy alone. Although depression is associated with poorer walking and ADL abilities in poststroke subjects,^{7 30} it is unlikely that the higher efficacy of fluoxetine in terms of functional outcome may depend on differences in depressive symptomatology among groups. In fact, both fluoxetine and maprotiline treatments significantly improved depressive symptoms, so that the final HDRS mean scores were not different among groups.

The theory that fluoxetine stimulates recovery should be viewed with caution. An alternative possibility is that the superior effects of fluoxetine over maprotiline may occur because the latter hinders recovery. In addition, although our groups were well balanced in terms of age, lesion side, stroke rehabilitation interval, degree of neurological and functional deficits, and sphincter continence, it is difficult to take into account all the determinants of recovery.^{31 32} Therefore, group differences that could have influenced the outcome regardless of the therapy administered cannot be definitely ruled out.

By blocking 5-HT reuptake sites and/or by upregulating 5-HT release,³³ long-term fluoxetine treatment increases serotonergic transmission that stimulates motor function and possibly the restorative processes that follow a brain injury. In fact, 5-HT induces new synaptic contacts and long-term facilitation in sensorimotor synapses,³⁴ increases the excitability of spinal motor neurons,³⁵ and modulates and/or improves purposeful motor responses such as fictive swimming in amphibians, fictive walking and swallowing in rats, and treadmill-induced locomotion in spinal cats.^{36 37 38 39} Long-term treatment with fluoxetine may also improve motor function by upregulating 5-HT₂ receptors, the stimulation of which has been reported to promote motor activity.^{40 41} Finally, the contributing effect of an indirect action on the adrenergic system should also be considered, since fluoxetine upregulates ß-adrenergic receptors.⁴²

In animals, short-term (single) injection of noradrenergic drugs enhanced motor recovery from a cortical injury.^{12 13 14} In this study, long-term treatment with maprotiline did not influence the motor/functional outcome of poststroke patients. However, long-term exposure to antidepressants leads to a myriad of long-term neuronal changes that do not occur after short-term administration.⁴³ Therefore, the treatment regimens used in the above studies may differently influence adaptive mechanisms to brain lesions, yielding opposing results. In addition, our findings do not deny the clinical relevance of norepinephrine in facilitating the recovery processes in response to physical therapy, as demonstrated in two previous studies.^{44 45} In fact, the lack of effect of maprotiline may partially depend on its anticholinergic properties, which are relatively low but present.

In conclusion, this study indicates that fluoxetine and maprotiline may differently influence functional outcome after ischemic brain injury. Serotonergic antidepressants should be further investigated because of their possible efficacy in facilitating recovery in stroke survivors undergoing physical therapy.

	Selected Abbreviations and Acronyms

 

ADL = activities of daily living BI = Barthel Index HDRS = Hamilton Depression Rating Scale HSS = Hemispheric Stroke Scale 5-HT = 5-hydroxytryptamine (serotonin)

Received December 21, 1995; revision received February 22, 1996; accepted March 22, 1996.

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