Background. Although recent evidence has shown a new role of
fluoxetine in motor rehabilitation, results are mixed. We conducted a randomized clinical trial to evaluate whether combining repetitive
transcranial magnetic stimulation (rTMS) with
fluoxetine increases upper limb motor function in
stroke. Methods. Twenty-seven hemiparetic patients within 2 years of
ischemic stroke were randomized into 3 groups: Combined (active rTMS +
fluoxetine),
Fluoxetine (
sham rTMS +
fluoxetine), or Placebo (
sham rTMS + placebo
fluoxetine). Participants received 18 sessions of 1-Hz rTMS in the unaffected primary motor cortex and 90 days of
fluoxetine (20 mg/d). Motor function was assessed using Jebsen-Taylor Hand Function (JTHF) and Fugl-Meyer Assessment (FMA) scales. Corticospinal excitability was assessed with TMS. Results. After adjusting for time since
stroke, there was significantly greater improvement in JTHF in the combined rTMS +
fluoxetine group (mean improvement: -214.33 seconds) than in the placebo (-177.98 seconds, P = 0.005) and
fluoxetine (-50.16 seconds, P < 0.001) groups. The
fluoxetine group had less improvement than placebo on both scales (respectively, JTHF: -50.16 vs -117.98 seconds, P = 0.038; and FMA: 6.72 vs 15.55 points, P = 0.039), suggesting that
fluoxetine possibly had detrimental effects. The unaffected hemisphere showed decreased intracortical inhibition in the combined and
fluoxetine groups, and increased intracortical facilitation in the
fluoxetine group. This facilitation was negatively correlated with motor function improvement (FMA, r2 = -0.398, P = 0.0395). Conclusion. Combined
fluoxetine and rTMS treatment leads to better motor function in
stroke than
fluoxetine alone and placebo. Moreover,
fluoxetine leads to smaller improvements than placebo, and
fluoxetine's effects on intracortical facilitation suggest a potential diffuse mechanism that may hinder beneficial plasticity on motor recovery.