Combining Fluoxetine and rTMS in Poststroke Motor Recovery: A Placebo-Controlled Double-Blind Randomized Phase 2 Clinical Trial

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02208466.

Keywords: cortical excitability; fluoxetine; motor recovery; recovery of function; stroke; transcranial magnetic stimulation.

Figure 1

Study visits outline: V1: Screening; V2: Baseline assessments (Day 0), study medication given; V3 (2 weeks after V2): daily rTMS sessions begin; V13: Day 30 assessments; V14– 21: 8 weekly rTMS sessions; V22: Day 90 assessments. HDRS = Hamilton Depression Rating Scale; FMA = Fugl-Meyer Assessment; JTHF = Jebsen-Taylor Hand Function; BDI = Beck’s Depression Inventory; MAS = Modified Ashworth Scale; TMS = Transcranial Magnetic Stimulation; rTMS = repetitive TMS; MMSE = Mini-Mental State Examination.

Figure 2

Study flowchart