In 2011, Chollet et al. published, “Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): A randomised placebo-controlled trial” in The Lancet Neurology that changed the way we think about motor recovery in ischemic stroke. Prior to this, several small clinical trials showed encouraging results on the use of selective serotonin reuptake inhibitors (SSRIs) after ischemic stroke using motor recovery as the primary outcome. The FLAME trial sought to address the following question: Does early administration of fluoxetine, in addition to conventional physical therapy, improve motor recovery following ischemic strokes?
A 2014 systematic review and meta-analysis by McCann et al. proposed that the mechanism for improvement in motor recovery following the use of SSRIs pertains to a serotonin-mediated suppression of post-stroke hyperexcitability, with concomitant improvement in neuroplasticity. While SSRIs did not affect infarct volume, and existing trials suffered from potential publication bias when reporting on neurobehavioral outcomes, SSRIs nonetheless appeared to improve neurobehavioral outcomes by an average of 51.8% and increased neurogenesis by 2.2 SD. Accordingly, we have taken the potential use of SSRIs in motor recovery following ischemic stroke very seriously.
The FLAME Trial
The 2011 FLAME trial followed 113 patients recruited from nine stroke centers in France 5–10 days after acute ischemic stroke with hemiplegia/paresis, and randomized them to either 20mg of daily fluoxetine, or placebo. Patients, caregivers and physicians were blinded. The fluoxetine group was found to have higher Fugl-Meyer Motor Scale (FMMS) scores compared to their placebo counterparts at 90 days (34.0 vs. 24.3; P=0.003). The FMMS, the primary outcome measure in FLAME, benefits from excellent intra-rater and inter-rater reliability and validity. Given that fluoxetine was well tolerated, this was an impressive change when combined with usual physical therapy. Despite sufficient power and good design, the generalizability to clinical practice may be limited by a narrow inclusion criteria and the relatively short-term follow-up period of three months.
The FOCUS Trial
In 2018, the FOCUS Trial Collaboration published new data in Lancet. FOCUS, which stands for “Effects of fluoxetine on functional outcomes after acute stroke,” was a pragmatic, multicenter, double-blind, randomized controlled-trial. The large socioeconomic burden of stroke-related disability, combined with the success of the smaller FLAME trial in 2011 meant that new efforts to study the full potential of fluoxetine in stroke management have been prioritized. In 2012, a Cochrane review found that SSRIs appeared to improve dependence, disability, neurological impairment, anxiety and depression after stroke. The Cochrane review highlighted heterogeneity between trials and methodological limitations, calling for large, well-designed trials to determine whether SSRIs should be given routinely to patients with stroke.
Recruiting from 103 hospitals in the United Kingdom, 3,127 patients with a clinical diagnosis of stroke that included neurological deficit and confirmation of stroke via brain imaging (ischemic or hemorrhagic, but not subarachnoid) were randomly assigned between days 2–15. The two groups again consisted of 20mg of fluoxetine daily or placebo. The primary outcome in FOCUS was an ordinal analysis of the modified Rankin Scale (mRS), which measures degree of disability after a stroke.
FOCUS ultimately found that the use of 20mg of fluoxetine daily for six months after acute stroke did not improve patients’ functional outcomes as measured by the mRS, nor did it improve survival at 6 or 12 months. There was a benefit of decreased depression at six months, but an observation of increased bone fractures as well.
The Future of Fluoxetine in Stroke Rehabilitation
Importantly, the FLAME trial’s legacy continues to inspire important work. There are several ongoing trials building on the study of SSRIs in stroke recovery, such as the AFFINITY trial (which includes a more diverse patient population from Australia, New Zealand and Vietnam) that is looking at the potential value of fluoxetine in cognition, fatigue, mood and function. Additionally, the Swedish EFFECTS trial is underway. There is also a plan for a pooled analysis of FOCUS, AFFINITY and EFFECTS once results are in.
In an editorial in Lancet, Bart van der Worp outlines some of the essential considerations when we compare FLAME and FOCUS. First, while FLAME only enrolled patients with ischemic stroke and FOCUS included hemorrhagic stroke, FOCUS employed predefined subgroup analyses to show that fluoxetine was not effective in ischemic stroke populations. There is also an issue of the timings of outcome assessments; FLAME evaluated patients only at three months whereas FOCUS went to six months. Another potentially important difference is the approach to stroke rehabilitation in the UK, which may not have been as intense based on the way rehabilitation protocols were organized. It is possible that the use of FMMS in FLAME may be better able to detect motor changes than the mRS that FOCUS utilized.
Emphasizing specific limitations in the kind of information gathered between FLAME and FOCUS, we are left at this moment with some uncertainty about the use of fluoxetine that must be considered in the interim while more data comes in. While clinical practice over the past several years has moved to employ fluoxetine specifically and SSRIs in general in ischemic stroke recovery because of the FLAME trial, FOCUS is a legitimate challenge to ongoing arguments that SSRIs should be the standard of care in ischemic stroke motor recovery.
This article was inspired by a joint journal club that took place in April between the University of Pittsburgh Departments of Neurology and Physical Medicine and Rehabilitation. It was led by PM&R Resident Dr. Patrick Polsunas and Neurology Resident Dr. Howell Jarrard.
Jim Eubanks is a rising PGY2 in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh.
Patrick Polsunas is a rising PGY3 in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh.
Howell Jarrard is a rising PGY3 in the Department of Neurology at the University of Pittsburgh.
- Chollet F, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. The Lancet Neurology. 2011. 10(2):123–130.
- McCann SK et al. Efficacy of antidepressants in animal models of ischemic stroke: a systematic review and meta-analysis. Stroke. 2015 Oct;45(10):3055–63.
- FOCUS Trial Collaboration. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, multicenter, double-blind, randomized controlled trial. Lancet. 2018;393:265–74.
- Mead GE et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst Rev. 2012; 11.
- van der Worp B. Fluoxetine and recovery after stroke. Lancet. 2019;393:206–07.
Tips for Success in the Fellowship Match: An Interview with Stephanie Tow, MD
by Allison Schroeder, MD
Stephanie Tow, MD, completed her residency in Physical Medicine and Rehabilitation at the University of Texas Southwestern in 2017 where she served as chief resident. She then completed a fellowship in Pediatric Rehabilitation at the University of Colorado in 2019. In July 2019, she will start a fellowship in Pediatric Sports Medicine at Children’s Mercy in Kansas City. She is one of only four people to pursue both a Pediatric Rehabilitation and Sports Medicine fellowship following residency in Physical Medicine and Rehabilitation. She has been successful in two fellowship matches and was willing to share some of the things she learned throughout the application and interview process.
Q: How did you choose a fellowship program that was the best fit for you?
A: I found that it was important to identify mentors that I could trust for advice. I could ask them what the good programs were. I would not just ask one person, but would ask as many people as possible. They gave me advice on which programs I should apply to and which programs would be the best fit for me. My mentors also knew my personality, and, for example, they were able to point me towards programs that had a lot of autonomy, good adaptive sports opportunities, and would allow me to continue my national work.
Applying broadly and interviewing at a good number of programs also allowed me to learn more about many programs, and helped me get a better sense of which ones were the best fit for what I was seeking. Depending on what your interests and needs are, you definitely want to know if the fellowship program will support you. For example, my Pediatric Rehabilitation Program supported my interest in Sports Medicine and allowed me to rotate with the Sports Medicine department. You will also want to look at how many faculty are doing what you want to be doing.
Q: Is there anything that you wish you had known prior to starting the fellowship application process?
A: I really wish that I had known when programs were going to interview. However, this changes every year and is outside the residents’ control. In terms of things that residents can control, if you are applying to pediatric sports medicine or another “niche” sub-specialty, include a description of how PM&R prepares you to be successful in that specialty. When filling in ERAS, also try to condense information and group information so that you do not look like you are trying to pad your CV, but also make sure to highlight and include everything that you have done. Also, if you do not hear back from a program (but are really interested), send them a specific email about why you are interested; this is especially important for competitive fellowships.
Q: Do you have any tips on how to balance travel for interviews with clinical and residency responsibilities?
A: I would advise residents to meet with your program director, coordinator, and chief resident who are in charge of the schedule and also set expectations with your program on the number of interviews you plan to attend and the number of days you will be away (consider getting this in writing). Look at the match statistics and come up with a plan for interview season and interview timing based on your individual competitiveness for a specialty. Consider saying something like: “I also want to prioritize my responsibilities in residency.” Be careful not to come off as entitled — take a humble approach. Also keep in mind that some programs will interview on Saturdays. For sports medicine, some programs also have you shadow sports coverage the night before or on weekends, so you will need to make travel plans accordingly.
Q: What did you learn from your Pediatric Rehabilitation fellowship application process and from your Pediatric Rehabilitation fellowship that helped you be successful in the Sports Medicine fellowship match?
A: The processes were actually very different. The pediatric rehabilitation process was “easier” because I heard back quickly and was told far in advance for interviews, which was not the case in the sports match (which has more programs involved but is also more competitive). I learned that it was very important to talk to mentors so I would know which programs I should be seriously considering given my specific goals. I also found it helpful to contact programs ahead of time to see which programs fit my needs. This allowed me to determine which programs were more or less responsive.
Q: What aspects of a fellowship should applicants carefully consider when making their rank order list?
A: It seems that the most common reasons that people choose a specific fellowship program are culture, well-roundedness, and good clinical and procedural experience. Diversity of attendings you work with is also important. It is nice to see faculty who are not all inbred from one program, because you know that you will get a diversity of perspectives and experiences. The number of faculty also was important to me. Additionally, I was looking for a program that had more trainees, because those are people who will be your colleagues and who you will work with for the rest of your life. Geography is important for some people but was less important for me. Having autonomy was really important for me, but may be less so for others. I also wanted to make sure I could do the things I cared about — for me that was adaptive sports and continuing my involvement in leadership on a national level. You will not know if a program is the right match until you actually go there and experience it via an interview or away rotation.
Q: Do you have any advice on if you should do an away rotation?
A: It is very program-dependent on whether a specific fellowship prefers residents who do away rotations. Basically, it can be helpful, but it is not completely necessary. Many residencies do not allow for away rotations. However, if you have a specific program that you are interested in and if your current residency program will support you, you should definitely do it — but make sure you “wow” them. Just because you do a rotation at another program does not mean you will be at the top of their rank list. Also, if you are an internal candidate at a program, do not assume that you have “dibs” on their spot.
Q: Do you have any additional advice for fellowship applicants or those early in residency who are planning to pursue a fellowship?
A: Get involved with any clinical experience that interests you!! Be proactive and show you have interest in a certain sub-specialty. Contact your chief residents and coordinator to see if you can have certain experiences earlier in your training. Going to conferences is also helpful to keep up-to-date on current national discussions and for networking. Be present and always be professional. Just show them that you have a good reason to want to stay in the sub-specialty and that you have plenty of experience to be able to apply it. Doing an early rotation is also helpful to get letters of recommendation. For example, for pediatrics, I got involved in camps, and for sports I sought out sports coverage opportunities and tried to volunteer in as many as I could. I think it would also be helpful to have a separate CV from the start of residency that includes descriptions of what you have done, as you will need this for the ERAS fellowship application. In terms of applying, make sure you submit your ERAS application by the time ERAS will start sending applications to programs.
Allison Schroeder is a rising PGY4 and current Administrative Chief Resident in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh Medical Center (UPMC). She is also the AAP RFC Education and Well-Being Representative. Follow her on Twitter @A_SchroederMD