A Narrative Review on the Non-Pharmacologic Interventions in Post-Stroke Depression

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A Narrative Review on the Non-Pharmacologic Interventions in Post-Stroke Depression

Authors Wijeratne T, Sales C, Wijeratne C

Received 30 October 2021

Accepted for publication 10 June 2022

Published 7 July 2022 Volume 2022:15 Pages 1689—1706

DOI https://doi.org/10.2147/PRBM.S310207

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Igor Elman

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Video abstract presented by Tissa Wijeratne.

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Tissa Wijeratne,^{1– 3} Carmela Sales,⁴ Chanith Wijeratne<sup>5

1</sup>School of Psychology and Public Health, La Trobe University, Melbourne, Australia; ²Department of Neurology, Western Health & University Melbourne, AIMSS, Level Three, WHCRE, Sunshine Hospital, St Albans, 3021, Australia; ³Department of Medicine, Faculty of Medicine, University of Rajarata, Saliyapura, Anuradhapura, Sri Lanka; ⁴Department of Medicine and Neurology, AIMSS, Melbourne Medical School, Sunshine Hospital, Western Health, St. Albans, Victoria, Australia; ⁵Monash Medical School, Clayton, Victoria, Australia

Correspondence: Tissa Wijeratne, Email tissa.wijeratne@wh.org.au

Abstract: Stroke is a major cause of death and disability globally. Post-stroke depression (PSD) is a major driver for poor recovery and poor quality of life with extra burden for the patient and the caregiver. We have previously shown the inflammatory basis of PSD with associated bioenergetic failure, disruption of the blood-brain barrier, cell death, and persistent maladapted inflammation, making the PSD a norm rather than the exception, highlighting the unmet need for therapeutic intervention in PSD across the recovery trajectory. In this era, various interventions are focused on pharmacotherapy; however, non-pill-based medication should also be explored as post-stroke patients are likely to suffer from the adverse effects of polypharmacy. This narrated review explores the status of non-pharmacological interventions in managing PSD. We performed a PubMed search using pre-specified keywords looking at various non-pharmacologic approaches for the management of PSD. Worldwide, approaches such as non-invasive brain stimulation, behavioral and psychosocial therapy, as well as exercise, acupuncture, music, literature, and art therapies are available as monotherapy or adjunctive treatment for PSD. While current literature shows convincing results on the benefits of non-pharmacologic interventions, more robust studies are necessary to determine its utility in PSD.

Keywords: stroke, depression, non-pharmacological intervention, disability

Introduction

The Global Burden of Disease Study reported a steady decline in stroke-related mortality over the past three decades.¹ However, cerebrovascular diseases remain to be one of the leading causes of morbidity worldwide with more than 80 million people being affected in 2016 alone.¹ With a steep decline in mortality rates, long-term sequelae are expected among stroke survivors with staggering costs both for patients and their caregivers. While physical disability and cognitive complications significantly impact on patients’ well-being, studies suggest that persistent depression after stroke is predictive of poor quality of life in the long term.²

Post-stroke depression (PSD) is a growing burden worldwide. It is a common yet often unrecognized post-stroke complication. Sufferers feel hopelessness, increased levels of anxiety and general lack of interest, as well as experiencing sleep alteration.³ It affects one-third of patients with a history of stroke and with incidences highest in the first six months post-stroke and a second peak notable at 18 months after.^4–6 In the first three months after a stroke, some of the risk factors identified which increase the risk of PSD include previous mental illness, female gender, age <70, neuroticism, family history, severity of stroke and the level of disability.⁷ On the other hand, longitudinal studies demonstrated that functional dependence and persistent relationship problems due to the antecedent stroke are the strongest predictors of PSD at 18 months.⁶

PSD is attributable to various neurochemical and anatomical alterations to their brain, regardless of the severity of the original stroke, and in association with various psychosocial influences.⁸ Depending on which vascular territory is affected, various cortical and subcortical structures have been noted to manifest mood disorders post-stroke.⁸ The biological hypothesis is thought to result from a cascade of processes activating the hypothalamic-pituitary axis, leading to altered responses of the neurogenic system and altered energy metabolism.⁹ Disruption of the glutaminergic system resulting in excitotoxicity may also contribute to the development of PSD, particularly coupled with the chronic, low grade neuroinflammatory state brought on by the patient’s stroke.^10,11 Psychosocial variables such as baseline social ties and emotional support along with individual characteristics such as helplessness, passive coping, less acceptance, and perceived benefits have also been shown to impact significantly on PSD etiology.¹²

Management of PSD is equally complex, necessitating a multi-pronged approach using both pharmacologic and non-pharmacologic measures. Inadequate interventions have been shown to contribute to poor functional outcomes, increased stroke recurrence and increased mortality rates among PSD patients.⁸ Pharmacologic therapy with antidepressants such as noradrenaline reuptake inhibitors, tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) is undoubtedly a cornerstone of current PSD treatment.¹³ However, post-stroke patients have been observed to be poorly adherent to pharmacotherapy.¹⁴ In a large cohort study involving more than 12,000 patients, nearly half of all PSD patients involved were either poorly adherent to antidepressant regimens or not adherent at all, leading to poor clinical outcomes.¹⁴ Polypharmacy is likely a key factor contributing to this poor adherence,¹⁵ thus non-pharmacologic approaches are well worth exploring as alternatives.

In a recent Cochrane review of interventions for post-stroke depression, it has been determined that there is no strong evidence to suggest that pharmacologic interventions are effective in reducing depressive symptoms post-stroke.¹⁶ These conclusions, however, were drawn based on low-certainty evidence because of various forms of biases and high attrition rates noted in several studies.¹⁶ While more robust data are necessary to assess the efficacy of pharmacologic management, the need to evaluate non-pill-based management is likewise imperative which can be utilized as monotherapy or adjunct to the former. This is particularly useful for stroke patients who are prescribed with several medications and may be at a high risk for interactions with antidepressants.¹⁷ Its utility is further highlighted in special populations such as the elderly who may have a slightly increased risk for falls with anti-depressant therapy.¹⁸ In this narrative review, we discuss various non-pharmacologic approaches for the management of post-stroke depression.

Methodology

A PubMed literature search was performed from September to November 2021. The following topics were included: post-stroke depression; non-invasive brain stimulation; behavioral therapy; psychosocial interventions; acupuncture; exercise therapy; light therapy; music therapy and art therapy. Only literature in English and published in the past 25 years were included in this review. Outcomes of studies included should be various objective measures for the assessment of post-stroke depression. Summary of studies included in this review is outlined in Table 1.

Table 1 Summary of Studies on the Non-Pharmacologic Interventions for PSD

Non-Invasive Brain Stimulation

Non-invasive brain stimulation is an established non-pharmacologic treatment for patients with major depressive disorder. However, its utility in PSD still needs further investigation. Transcranial Direct Current Stimulation (tDCS) is one of the techniques that has been explored in this regard. The earliest reports suggesting tDCS may be potentially beneficial for PSD were published by Bueno et al.¹⁹ They reported a significant improvement in the mood and cognition of a post-stroke patient following 30-minute anodal stimulation of the left dorsal prefrontal cortex (DLFPC) for ten days.¹⁹ However, immediate relapse was noted three weeks after discontinuation, necessitating the need for further maintenance sessions.¹⁹ This regimen was also evaluated among aphasic patients with concomitant depression and bilateral DLFPC stimulation showed more than 50% improvement in their depressive scores.²⁰ Following this, 48 PSD patients were randomised to tDCS and sham treatment over six weeks for a total of 14 sessions.²¹ This RCT proved that the former was significantly more effective in averting PSD with a number needed to treat of three.²¹ However, no long-term follow-up was established in this study, and previous studies on non-stroke patients have noted more than 50% relapse following discontinuation of treatment.²² Clearly, more studies on this intervention still need to be done, ideally performed using a larger population and with a longer follow-up period.

Repetitive Transcranial Magnetic Stimulation (rTMS) is another novel intervention in the field of neurorehabilitation. This involves stimulation or inhibition of various neural structures by application of electromagnetic impulses aimed at optimizing neuroplasticity to maintain residual neural function while also acquiring new skills.²³ Repetitive Transcranial Magnetic Stimulation targeting the left dorsolateral prefrontal cortex has been beneficial in the management of patients with PSD. In a randomized control trial comparing patients who received ten sessions of 10Hz rTMS to those receiving sham controls, significant decreases in depression scale scores were noted in the former.²⁴ In the Novel TMS for Stroke and Depression (NoTSAD) trial, an accelerated TMS protocol for PSD was employed, consisting of five sessions per day for four consecutive days within the subacute stroke period and likewise revealing beneficial results.²⁵ Another RCT done in Australia provided evidence for the efficacy of high-frequency TMS in the reduction of Beck Depression Scores among PSD patients compared to sham controls.²⁶ In this study, the authors also performed EEG to assess neurophysiologic correlation and noted enhanced theta frequency in the treatment group.²⁶ This is suggestive of improved connectivity between the dorsolateral prefrontal cortex and the parietal cortex, areas potentially compromised in PSD.²⁶ However, this remains speculative due to the small population size of this study. While the benefits of rTMS have likewise been replicated in a meta-analysis of 7 RCTs with 351 patients, its effects are likely limited to a short period.²⁷ Furthermore, subgroup analysis suggests that it may be more effective in Asian subjects, although unblinded techniques in the former may be prohibitive of its generalizability.²⁷ More studies involving more heterogenous populations are needed to assess the efficacy and safety of non-invasive brain stimulation among post-stroke patients developing depression.