The initial search found 95 potential articles; after removing duplicates and applying inclusion criteria, this was reduced to 20. The included articles involved a total of 1,163 participants aged ≥ 18 years (study population sizes ranged from 12 to 200) and comprised randomized clinical trials (RCTs) (N = 12), non-randomized clinical trials (N = 2), post-hoc follow-up study (N = 1), published treatment protocols or abstracts for studies (N = 5). The articles originated from China (N = 8), Australia (N = 3), New Zealand (N = 2), Sweden (N = 2), United Kingdom (UK; N = 1), the Netherlands (N = 1), and Denmark (N = 1), South Korea (N = 1), Russia (N = 1).

All articles focused on active symptomatic treatment to reduce the impact of clinically diagnosed post-stroke fatigue. The articles reported various therapeutic interventions across these broad categories: conventional pharmacotherapies (N = 9 treatments, Table 1), complementary and alternative medicines (including Traditional Chinese Medicines) (N = 3 treatments, Table 2), non-pharmacological strategies (including, physical therapy, psychotherapy) (N = 4 treatments, Table 3), potential therapies (N = 5, Table 4), combination therapy (N = 3, Table 5).

Table 1 Conventional Pharmacotherapies explored for Post-stroke FatigueTable 2 Complementary and Alternative Medicines (including traditional Chinese medicines, TCMs) explored for Post-stroke FatigueTable 3 Non-Pharmacological Strategies: Physical and Cognitive modalities explored for Post-stroke FatigueTable 4 Potential Therapies being explored for Post-stroke FatigueTable 5 Combination Therapies: Combined therapeutic modalities explored for Post-stroke Fatigue

Most of these included articles reported clinical effectiveness in terms of impact on fatigue as a primary outcome using one of the following validated measurement scales:

Fatigue Assessment Scale (FAS)

Fatigue Severity Scale (FSS)

Checklist Individual Strength—Fatigue subscale (CIS-F)

Multidimensional Fatigue Inventory-20 (MFI-20)

Self-Observation List–Fatigue (SOL-F)

Mental Fatigue Scale (MFS)

Self-Reported Post-Stroke Fatigue Severity (FSS-9 total score)

Visual Analogue Scale-Fatigue (VAS-F)

A small number of studies used simple and subjective measures such as patient self-report and/or qualitative feedback/opinion regarding fatigue symptoms.

Conventional Pharmacotherapy

This review identified eight conventional pharmacotherapies, comprising six pharmacological agents (e.g., selective serotonin reuptake inhibitors, wakefulness promoters) and one vitamin supplement (Table 1). All identified studies evaluating the efficacy of conventional pharmacotherapies for post-stroke fatigue were early-phase, small-scale clinical trials of generally low quality. Two identified studies lacked randomization [33,34], and another three lacked blinding procedures [35,36,37]. There was a wide range of participant numbers in these identified studies, from as few as 12 [38] to a relatively larger sample size of 128 individuals [36]. In addition, the maximum duration of treatment was only three months [33,34], and only two studies provided follow-up observations [34,39].

Overall, conventional pharmacotherapies for post-stroke fatigue have demonstrated relatively good efficacy, primarily by targeting neurotransmitters or hormones (dopamine, serotonin) and/or neuropeptide up-regulation. These agents reportedly reduce the severity of fatigue in between 15 to 81% of stroke survivors.

To date, modafinil (a nootropic agent) appears to be the most robustly tested and the most efficacious conventional pharmacotherapy. Two early-phase studies have investigated modafinil's potential in alleviating post-stroke fatigue [33,40]. The MIDAS trial (single-center randomized, double-blind, placebo-controlled, crossover study) involved 36 patients taking 200 mg of modafinil daily for 12 weeks [40]. Half of the patients had a significant decrease in post-stroke fatigue and an improved quality of life after using modafinil when compared to those receiving a placebo (Table 1). Among the patients who found modafinil effective in improving fatigue and quality of life, the average MFI-20 scale score decreased by 10% (mean difference from placebo: −7.38), the average FSS-9 scale score dropped by 13% (mean difference from placebo: −6.31), and the average SS-QoL score increased by 7.7% (mean difference from placebo: 11.81) [40]. In another small-scale, single-center, non-randomized, double-blind, placebo-controlled trial, 21 stroke patients received 400 mg of modafinil daily for 90 days [33]. In the majority (81%) of patients fatigue was reduced after modafinil treatment, demonstrated by lower FSS scale scores than in the placebo group (P < 0.05). Furthermore, there was a significant decrease in scores on both FSS-7 and FSS-9 scales from baseline to 90 days in the modafinil group compared to placebo (P < 0.05). Specifically, the reductions in median FSS-9 scale scores were 20.9% for modafinil versus 1.9% for placebo (P = 0.019), and the reduction in median FSS-7 scale scores was 41.3% versus 1.3% (P = 0.042), respectively (Table 1) [33]. Additionally, modafinil-treated patients experienced larger improvements in quality of life, as indicated by higher scores on several SS-QoL domains (P < 0.05), including self-reported work and productivity, upper extremity function, and language [33]. A 12-month post hoc follow-up study was conducted to examine the long-term effectiveness of modafinil among a subset of patients from the MIDAS phase 2 trial and reported sustained reductions in fatigue scores and improvements in quality of life among those who continued taking modafinil regularly or occasionally as needed [39]. A separate parallel brain-imaging study observed that modafinil modulates resting-state functional connectivity which may be associated with a reduction in post-stroke fatigue [41]. Modafinil also appears to be well tolerated in stroke survivors [39], with the most commonly reported adverse effects being nausea and dizziness. Using the risk–benefit profile reported by the MIDAS trials, modafinil has also been shown to be potentially highly cost-effective [42]. The MIDAS-2 Phase III, multicentre, prospective, randomized, placebo-controlled, double-blind, parallel group study is currently underway to clarify the longer-term risk–benefit of modafinil use in the treatment of post-stroke fatigue [43].

Less promising pharmacotherapeutic options include antidepressants such as fluoxetine (selective serotonin reuptake inhibitor, SSRI) and the compound (-) OSU6162 (mono-aminergic, dopamine stabiliser which) (Table 1). In a non-randomized, double-blind, placebo-controlled study, 83 stroke patients received 3 months of fluoxetine at a daily dose of 20 mg. Follow-up assessments were conducted over 6 months to evaluate post-treatment outcomes. Fluoxetine did not show any benefit when compared to placebo, with no significant difference in the number of stroke patients experiencing fatigue nor any differences in fatigue-VAS and FSS fatigue scale scores at any follow-up period. At the 3-month follow-up, the reduction in mean VAS-F scale scores was 8.1% (placebo) versus 12.2% (fluoxetine), and in mean FSS scale scores was 7.5% (placebo) versus 8.5% (fluoxetine) (P > 0.05). At the 6-month follow-up, the decrease in mean decrease VAS-F scale scores was 8.1% (placebo) versus 11.9% (fluoxetine), and in mean FSS scale scores were 9.2% (placebo) versus 9.8% (fluoxetine) (P > 0.05) [44]. In a study of 12 patients with either stroke (N = 6) or other traumatic brain injury (N = 6), 58% of patients experienced a reduction in mental fatigue after receiving (-) OSU6162, however, the treatment effects for each condition were not reported separately, so the potential impact on post-stroke fatigue specifically is unclear [38]. Nausea is a commonly reported side-effect for both fluoxetine and (-) OSU6162 [38,44]. A marked reduction in appetite has also been observed with (-) OSU6162 use [38].

Despite there being no evidence of an association between vitamin deficiency and post-stroke fatigue, vitamin supplementation has also been trialled for treating post-stroke fatigue. A small randomized, placebo-controlled, unblinded pilot study (involving a total of 30 participants) investigated the effect of sulbutiamine (synthetic derivative of vitamin B1) at a dose of 200 mg of twice daily for 30 days on fatigue. The sulbutiamine treatment group experienced a significant reduction in fatigue compared to the placebo group (mean MFI-20 fatigue score: 13 versus 15.6, mean difference: −1.07, 95% CI: −1.85 to −0.3) (Table 1) [37]. This study did not report the specific proportion of patients who experienced an improvement in fatigue.

Among all explored treatment strategies for post-stroke fatigue, conventional pharmacotherapies appear to be associated with a higher rate of treatment-related side effects (compared to other treatment modalities). For example, 4 out of 8 studies reported side effects [33,34,38,40], with dizziness being the most frequently observed, followed by dry eye/mouth, and then headache and sleep disturbance. Although short-term clinical outcomes (up to 12 months) have been reported for these agents using different measurement scales, the long-term efficacy (effectiveness and safety) of each pharmacotherapy in stroke survivors has not yet been evaluated. However, most of the agents identified are licenced/registered agents that have been used long-term in other conditions (e.g., fluoxetine has been used by millions of people with depression for decades) with extensive post-marketing surveillance. Their efficacy profiles have been well-established, providing valuable insight into their potential use in other indications. Nevertheless, additional trials are needed to confirm the long-term efficacy and harms of each pharmacotherapy in a large population of stroke participants using appropriate and standardized measurements.

Complementary and Alternative Medicines (CAMs)

Traditional Chinese Medicines (TCM) are the most common type of complementary and alternative therapy explored for post-stroke fatigue (Table 2). This includes oral herbal medicines and non-oral techniques to address a Qi deficiency (pronounced as “chi” and broadly defined as “energy” or “vital life force”) which is regarded to be a feature of fatigue. TCM is also used to promote blood circulation and sensory stimulation in the context of post-stroke fatigue [45,46]. The herbal medicines identified within this review were generally made from raw materials (with the ratio of ingredients in each formula tailored for individual patients), primarily ingested orally, and used alone or combined with other therapies (conventional pharmacotherapies or non-pharmacological strategies) [36,47]. Various TCMs have been patented for use (e.g., Herbal Peiyuanhuan Decoction), however, there is a lack of accessible and detailed published data regarding many of these; only those with published data has been included in this review [48].

Within the published data, the CAMs identified for managing post-stroke fatigue were evaluated through limited small-scale (maximum of 128 patients) and/or short-term (usually no longer than 5 weeks treatment) studies or clinical trials, with none including follow-up observations. Clinical trials often lacked robustness due to the absence of randomisation and/or blinding processes, and/or used comparator treatments that lacked rationale or evidence for their selection.

Among all the identified oral TCM-based therapeutic strategies, the herb Astragalus membranaceus (AM; also known as “Huangqi”) is a commonly used core ingredient of many herbal formulas, intended to relieve post-stroke fatigue by supplementing Qi and modulating the circulation [45,46]. Acupuncture is the most widely used non-oral approach, intended to stimulate the sensory nerves [46,49,50]. To date, both Astragalus membranaceus and acupuncture have been shown to be somewhat effective in a number of small-scale and early-phase studies, with most patients experiencing some reduction in self-reported fatigue symptoms, decrease in measured fatigue levels, and/or an improvement in quality of life [45,46,49,50]. Among the reviewed TCM studies an average reduction of 45% in mean fatigue scores on the Fatigue Severity Scale (FSS) or Brief Fatigue Index (BFI) has been reported (Table 2) [35,46,50].

A randomized, comparative, albeit unblinded, study (involving 128 stroke patients) investigated the combination of electro-acupuncture (acupuncture in which a small electrical current is applied between two needles) with cupping (heated unction cups are applied on the skin to improve the flow of energy) [36] compared to the combination pharmacotherapy comprising sertraline plus vitamin supplementation. No rationale nor evidence was provided to support the selection of the comparator treatment. The authors categorised treatment responses using the following quality of life (SS-QoL) thresholds: 'basically cured' defined by an SS-QoL score ≥ 12; 'markedly effective' defined by SS-QoL score < 12 but with a ≥ 70% increase in score from baseline; and, 'effective' as a SS-QoL score < 12 but with an increase in baseline score of between 40 to 70%. Although a significant improvement in quality of life (increased mean SS-QoL scale scores) was observed in both groups (P < 0.05; the authors did not state the exact SS-QoL scores), a greater improvement in quality of life was observed with combination TCM therapy. Overall, the TCM combination was effective on some level in 96.87% of participants, significantly higher than the proportion of patients using combination pharmacotherapy (84.37%; P < 0.01). The 'basically cured' (SS-QoL ≥ 12) rates were higher for combination TCM compared to combination pharmacotherapy (65.62% versus 35.94%, respectively; P < 0.05), whilst the 'markedly effective' rates were the same (20.31%); the 'effective' rates were higher for combination pharmacotherapy compared to combination TCM (28.12% versus 10.94%; P < 0.05) [36].

Combining TCM with physical rehabilitation has also demonstrated clinical benefits. In a randomized, double-blind trial involving 90 stroke patients, a combination of traditional Chinese medicine (TCM) known as 'Qi Supplementing Dominant Chinese Materia Medica' (QSDCMM) plus physical rehabilitation significantly reduced fatigue, and improved quality of life, to a greater extent than the comparator treatments (physical rehabilitation plus citicoline injection or placebo) [47]. The reductions in mean FSS scale scores (indicating reduced fatigue) were 66%, 20.2%, and 16.0% (P < 0.05) in the TCM combination, placebo, and pharmacotherapy combination groups, respectively. The increases in mean SS-QoL scale scores (indicating improved quality of life) were 35.6%, 18.2%, and 12.9% (P < 0.05) in the TCM combination, placebo, and pharmacotherapy combination groups, respectively [47] (Table 4).

In terms of safety, only one study, which was randomized, double-blind, and placebo-controlled, and involved 64 stroke patients with a treatment period of 28 days, reported adverse effects in the Astragalus membranaceus-treated group [46]. These adverse effects included headache, unilateral hemicrania, dizziness, dry mouth and tongue, runny nose, and urinary urgency. There are also less common but more serious safety concerns, such as an increased risk of colon cancer and recurrent stroke.

Overall, CAMs have shown some potential benefits in reducing fatigue, however, the mechanisms of actions, optimal dosing regimens, and long-term clinical efficacy (especially safety) have not been fully elucidated for most of these options. Furthermore, the rationale behind the choice of combinations and comparators in some of those studies was not explicitly provided. Many of these options are also not well-known in global practice and, therefore, more research involving large sample sizes, standardised regimens, long-term harms and validated measurement scales, is needed.

Non-Pharmacological Strategies: Psycho-Cognitive, Physical, and Educational Modalities

Evidence regarding non-pharmacological strategies comes from a limited number of clinical trials, including four completed randomized trials (Table 3) and three ongoing trials (Table 4) (total of 518 stroke patients). Among the completed trials, two were unblinded, one assessor-blinded, and one single-blinded, with participant numbers ranging from 15 to 83 [51,52,53,54]. The maximum treatment period was 12 weeks [51], and only two reported follow-up data (up to 4 months) regarding the longer term efficacy [52,54]. Aside from these completed trials, the review identified a published protocol (Table 4) for a randomized, single-blind, multi-center, two-arm phase III trial (parallel, superiority design) for education-based therapy; at the time of this review, the trial had not concluded (effectiveness and safety outcomes from this trial are not yet known), therefore, it was not reported further [55].

The majority of trials tested strategies that focused on core psycho-cognitive approaches (e.g., cognitive restructuring, stress reduction) often combined with education (e.g., education about fatigue) and/or physical activity (e.g., enhancement of physical fitness). The basis for most of the reviewed non-pharmacological strategies was cognitive behavioural therapy (CBT), e.g., cognitive behavioural therapy alone or mindfulness-based stress reduction therapy, drawing on the psycho-educational framework, aiming to change the negative feelings associated with post-stroke fatigue [51,52]. These strategies have been shown to have other therapeutic benefits after stroke including the reduction of post-stroke pain and mood disturbances (e.g., depression and anxiety) [51,53].

The identified non-pharmacological strategies have effectively reduced post-stroke fatigue. The use of CBT alone for a duration of 8 to 12 weeks was reported to have a significant therapeutic benefit, reducing self-reported fatigue (using standardized measurements scales for assessment) in 24 to 60% of stroke survivors [51,52], and even greater benefits when combined with other modalities [51,54]. One small-scale, randomized controlled, assessor-blind, multi-center study has shown that the combination of CBT and physical activity (i.e., Graded Activity Training-GRAT) reduced fatigue in significantly more stroke survivors (N = 22, 58% of patients) than CBT alone (N = 11, 24%; P = 0.002) [51]. Participants in the GRAT group had a greater reduction in fatigue scores albeit not statistically significant, with a 20.2% decrease in the mean Checklist Individual Strength–Subscale Fatigue (CIS-F) scale scores and a 16.7% decrease in mean Self-Observation List-Fatigue (SOL-F) scale score. In comparison, the CBT alone group had a 17.3% reduction in CIS-F mean scores and a 8.6% reduction in SOL-F mean score [51]. CBT combined with other approaches, i.e., psycho-educational approaches, shows promise in reducing fatigue, although not shown to be statistically or clinically significant in the limited small studies undertaken to date. In a 6-week, single-blind, randomized controlled pilot study, 16 patients received Educational Fatigue Management (EFM), i.e., CBT plus a targeted psycho-educational approach. Among the EFM-treated patients, 30% (N = 3) experienced a reduction in fatigue to below the FSS scale fatigue-defining threshold (FSS < 3.9), whereas all participants in the control group (receiving stroke education similar to EFM but not targeted at reducing fatigue) remained above this threshold. In both groups, fatigue (FSS scale scores) reduced from baseline to post-treatment. EFM-treated patients experienced a greater, albeit not statistically significant, reduction in mean FSS scores than the control group (20.7% reduction versus 3.7%, P = 0.711) [54].

Overall, none of the reported strategies either prevented (primary prevention) or eliminated (cured) post-stroke fatigue. There is currently insufficient evidence to confirm the effectiveness of education-based therapies within the spectrum of identified non-pharmacological approaches. There is emerging evidence from studies with small sample sizes suggesting possible effectiveness. Furthermore, safety issues/harms have not been reported among identified non-pharmacological strategies.

Discussion and Conclusion

This review has identified the broad spectrum of treatment options investigated for the management of clinically diagnosed post-stroke fatigue, most of which have not yet progressed beyond small-scale pilot studies or single-site phase 2 trials. The overall dearth of high-quality clinical trials is a key finding of this review. Within the limited evidence available, conventional pharmacotherapies have been the most robustly studied to date and specific agents, such as modafinil, show promise in significantly reducing fatigue. Some small studies suggest that complementary and alternative medicines (CAMs) (acupuncture, Astragalus membranaceus herb) and non-pharmacological strategies (cognitive behavioural-based therapies) may also have potential for treating post-stroke fatigue. Further research is required to fully comprehend the risks and benefits associated with their use.

Conventional pharmacotherapies appear to be the most effective for reducing post-stroke fatigue and improving patients' quality of life, targeting specific neurological or biochemical pathways. However, their precise effects on the complex physiological networks implicated in fatigue remain elusive [23]. Unsurprisingly, many of the explored options are commonly used to treat mental health or mood disorders, noting that neurotransmitters (serotonin, dopamine) are involved in regulating both mood and energy levels. Whilst there is currently insufficient evidence to confirm the superiority of any one agent and/or to establish them as first-line options for managing fatigue, their potential is reinforced through years of extensive study and use in clinical practice for other indications, alongside long-term safety data. Further, these treatments are highly accessible, being relatively widely available and easily prescribed by healthcare providers.

Regarding the broad spectrum of options identified in this review, aside from signals of potential benefit, there are broader reasons for considering CAMs and non-pharmacological strategies further. Firstly, compared to conventional pharmacotherapies, CAMs and non-pharmacological strategies tend to be more cost-effective, often being less expensive in their overall development, administration, and implementation [54,55] [56]. A post hoc analysis found that acupuncture plus non-pharmacological strategy for treating post-stroke aphasia (over 12 weeks) was more cost-effective than the latter alone (€4001.72 versus €4323.57) [57]. The potential affordability and accessibility of CAMs and non-pharmacological strategies for both patients and health systems may support their widespread and sustainable use in practice. However, implementing these approaches at scale presents challenges, including maintaining therapist availability and expertise, addressing cost-reimbursement issues, and standardisation of treatment protocol. Real-world cost-effectiveness needs to be confirmed through large-scale clinical trials.

Secondly, the potential strategies identified could cater to the needs of a diverse stroke population, where age, ethnocultural background, socioeconomic status, and treatment preferences may impact therapeutic adherence as highlighted by studies in other chronic conditions. A Malaysian study reported that pa