Stroke represents one of the leading causes of permanent disability, and poststroke recovery is influenced by various factors such as stroke type, comorbidities, age, and gender.1 Poststroke depression (PSD) is a common complication that has been linked with negative outcomes following stroke. The estimated prevalence of PSD ranges from 11%-52% across studies.1

PSD is a form of vascular depression that typically emerges soon after stroke, but can also have a late onset of >6 months. Previous findings point to stroke severity as the primary risk factor for PSD, and to left anterior lesions (specifically, in the left dorsolateral prefrontal cortex) as an additional risk factor.1

If left untreated, PSD may lead to reduced quality of life, increased cognitive and social impairment, and increased mortality rates. However, research regarding the efficacy of pharmacological therapies for PSD has produced mixed results. Some studies have demonstrated benefits, while others have shown limited efficacy as well as significant side effects, such as an increased risk for brain hemorrhage with the use of selective serotonin reuptake inhibitors.2

Emerging evidence indicates that alternative treatment strategies, including noninvasive brain stimulation (NIBS), may have a role in PSD management. Techniques such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) may be used to modulate the neuronal activity that follows stroke, thus “creating temporary or long-lasting desirable brain changes that could improve the PSD treatment making it more effective and less expensive in terms of money and time,” according to the authors of a recent systematic review published in the Journal of Affective Disorders.1

They examined evidence pertaining to the use of NIBS for PSD and found 7 studies that met their inclusion criteria, comprised of 157 people with PSD combined. Although the results generally support the efficacy and safety of both tDCS and rTMS, the overall quality of evidence was low. There were few randomized controlled trials (RCTs), as well as “small sample sizes, heterogeneous methodologies, lack of uniform diagnostic criteria, and divergent data,” wrote the authors.

The research findings are briefly summarized below.

  • A 2004 double-blind study of patients with refractory PSD showed significant reduction in depressive symptoms, by 7.3 points on the Hamilton Depression Scale, after 10 sessions of rTMS.3 In addition, 1 patient met criteria for remission,and 3 patients demonstrated a clinical response.
  • A later double-blind study of rTMS (although not in patients refractory to other treatments) also found improvement in PSD symptoms, which was maintained for 4 weeks posttreatment.4
  • In a study published in 2010, rTMS was associated with a 41.3% reduction in Hamilton Depression Scale scores, which persisted for more than 1 month in 60% of patients.5
  • Two cases studies (with 1 and 4 patients, respectively) reported symptom improvement in PSD following tDCS.6,7
  • An RCT published in 2017 demonstrated that only active tDCS was associated with remission (in 20.8% of patients) compared with sham treatment.8
  • In other recent research, Beck Depression Inventory scores changed from 38.8 ± 4.7 before active tDCS to 16.8 ± 4.6 after tDCS.9

Although further investigation is needed, the evidence currently “supports the hypothesis that rTMS and tDCS may constitutean effective treatment for depressive symptoms that bypasses the risks associated with antidepressants exposure,” the authors concluded.1

For additional perspectives on the topic, Psychiatry Advisor interviewed the following experts: Jonathan Howlett, MD, director of the TMS treatment program in the department of psychiatry at the University of California, San Diego; Rajani Sebastian,PhD, CCC-SLP, assistant professor in the department of physical medicine and rehabilitation at Johns Hopkins University School of Medicine; and several researchers from West Virginia University, including Amelia Adcock, MD, assistant professor and associate director of the WVU Stroke Center; Elizabeth Engler-Chiurazzi, PhD, research assistant professor; and Jessica Frey, neurology resident. (The latter group is currently investigating the use of TMS for PSD and provided collective responses to the interview questions.) 

Psychiatry Advisor: What does the evidence suggest thus far regarding the effects of noninvasive brain stimulation on PSD?

Dr Howlett: In general, rTMS is a highly studied noninvasive brain stimulation technique in the treatment of depression. It has been shown to be a safe and effective treatment of treatment-refractory major depressive disorder (MDD) in large, multicenter RCTs and has been FDA approved for this purpose. 

Related Articles

rTMS specifically for PSD has been studied in small, preliminary, randomized studies. An initial study of 20 individuals with PSD who had not responded to 2 trials of antidepressant medications observed a significant improvement in symptoms of depression with active rTMS compared with sham rTMS.A recent meta-analysis of 22 studies including 1764 patients with PSD concluded that rTMS was associated with improved depression symptoms, response rates, stroke severity, and activities of daily living, but not with lower remission rates.10 However, many of these studies did not include a sham rTMS control arm, raising concerns about the validity of the results. Additionally, there was substantial heterogeneity across studies.

Another small randomized study (n=48) investigated the use of tDCS in patients with PSD and found improvement in depression symptoms compared with sham tDCS.8 Overall, larger, controlled studies are needed to fully assess the safety and efficacy of rTMS and other noninvasive brain stimulation techniques in PSD.

Dr Sebastian: PSD is among the most frequent neuropsychiatric consequences of stroke, negatively affecting the patient’s functional recovery and quality of life. Noninvasive brain stimulation techniques such as tDCS and TMS have been used in treating PSD. Studies have mainly targeted the dorsolateral prefrontal cortex, a key region implicated in depression. Evidence from the literature generally shows positive results regarding the effects of NIBS on PSD. However, the true efficacy of NIBS for the treatment of PSD is still unclear due to [study limitations]. 

Enger-Chiurazzi and colleagues: There are some small studies that have looked at TMS for PSD, mainly in the chronic stages (beyond 6 months from the stroke). Preliminary data suggest that TMS is a safe and effective treatment option for patients with PSD. Patient enrollment in our current study is ongoing and will inform the body of literature regarding the utility of TMS as an intervention for this population. However, larger RCTs are needed to further elucidate the population of patients that would benefit the most from this type of intervention as well optimization of treatment protocols.

Psychiatry Advisor: What are the potential treatment recommendations or other implications for clinicians?

Dr Sebastian: There are different treatments for depression after stroke. Antidepressants have been effective in some groups of patients; however, tolerability and treatment adherence are not very good. Therefore, there is a critical need for the development of novel treatments that can significantly diminish the burden of PSD. Targeted treatments using neuromodulation techniques such as tDCS and TMS are interesting options. Several characteristics, such as noninvasiveness, absence of pharmacokinetics interactions, safety, and tolerability, make tDCS and TMS interesting tools to be used in the treatment of PSD.

However, research findings have not been translated yet to common clinical practice. Therefore, their use for PSD remains largely experimental and used mostly in specialized centers. It should be noted that the FDA approved TMS for the treatment of MDD (without stroke) in 2008.  

Enger-Chiurazzi and colleagues: PSD is an often underdiagnosed and unrecognized phenomenon that affects up to 50% of stroke survivors. Current treatment options for PSD are limited. TMS is a noninvasive treatment that may have fewer side effects or drug-drug interactions compared with antidepressants and may be more convenient or better tolerated and more efficacious in certain individuals. Further, as depression is associated with significant treatment compliance challenges that are exacerbated by stroke, TMS could be an ideal method to achieve beneficial therapeutic effects while overcoming this barrier.

In addition, TMS could also be utilized in tandem with traditional pharmacologic as well as behavioral therapies, possibly creating a synergistic effect. These implications may provide significant advantages for the treatment of PSD in certain patient populations in which access to mental healthcare is limited or associated with substantial barriers. Such is the case for rural populations.

Psychiatry Advisor: What should be the focus of future studies regarding these therapies for PSD?

Dr Howlett: There is a need for larger, controlled studies to more firmly establish the efficacy and safety of rTMS as a treatment for PSD. One important question is whether patients are at higher risk for seizure, which is a potential complication of rTMS. Another question is the optimal number of antidepressant trials that should occur prior to initiating rTMS in PSD, and whether the optimal stimulation parameters for rTMS differ in PSD compared with MDD. Finally, much more research is needed to assess the potential of other NIBS techniques, such as tDCS.

Dr Sebastian: Future research should focus on the development of large RCTs to further assess the true efficacy of NIBS as a therapeutic tool for the treatment of PSD. In addition, studies should evaluate the long-term efficacy and optimal dosing of NIBS, alone and in combination with pharmacological treatment.

Enger-Chiurazzi and colleagues: There are many future avenues for research on neuromodulation for PSD, particularly at what time after the stroke is the optimal time for TMS to be applied and whether or not antidepressants have a synergistic effect with TMS for [people with] PSD. Further investigation of factors, such as stimulation paradigm (TMS or tBS [beta]), stimulation site, and schedule and duration of stimulation will inform optimal regimens for PSD end points. In addition, mechanistic studies could shed light on depression networks in general, identifying future therapeutic targets and expanding our knowledge of mood disorders.

References

1. Bucur M, Papagno C. A systematic review of noninvasive brain stimulation for post-stroke depression. J Affect Disord. 2018;238:69-78.

2. Hackam DG, Mrkobrada M. Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis. Neurology. 2012:79(18):1862-1865.

3. Jorge RE, Robinson RG, Tateno A, et al. Repetitive transcranial magnetic stimulation as treatment of poststroke depression: a preliminary study. Biol Psychiatry. 2004;55(4):398-405.

4. Gu SY, Chang MC. The effectsof 10-Hz repetitive transcranial magnetic stimulation on depression in chronic strokepatients. Brain Stimul. 2017;10(2):270-274.

5. El Etribi A, El Nahas N, Nagy N, Nabil H. Repetitive transcranial magnetic stimulation treatment in post stroke depression. Curr Psychiatry. 2010;17(1):9-13.

6. Bueno VF, Brunoni AR, Boggio PS, Bensenor IM, Fregni F. Mood and cognitive effects of transcranial direct current stimulation in post-stroke depression. Neurocase. 2011;17(4):318-322.

7. Valiengo LC, Casati R, Bolognini N, et al. Transcranial direct current stimulation for the treatment of post-stroke depression in aphasic patients: a case series. Neurocase.2016;22(2):225-228.

8. Valiengo LC, Goulart AC, de Oliveira JF, Benseñor IM, Lotufo PA, Brunoni AR. Transcranial direct current stimulation for the treatment of post-stroke depression: results from a randomised, sham-controlled, double-blinded trial. J Neurol NeurosurgPsychiatry. 2017;88(2):170-175.

9. An T-G, Kim S-H, Kim K-U. Effect of transcranial direct current stimulation of stroke patients on depression and qualityof life. J Phys Ther Sci. 2017;29(3):505-507.

10. Shen X, Liu M, Cheng Y, et al. Repetitive transcranial magnetic stimulation for the treatment of post-stroke depression: a systematic review and meta-analysis of randomized controlled clinical trials. J Affect Disord. 2017;211:65-74.