Role of the Treatment of Post-Concussion Syndrome in Preventing Long-Term Sequela Like Depression: A Systematic Review of the Randomized Controlled Trials

Traumatic brain injury of any severity can result in post-concussion syndrome (PCS). Although the post-concussive symptoms are complex, there is an emerging scientific consensus regarding the initiation of the treatment for these symptoms to improve quality of life and prevent long-term effects. The objective of this systematic review is to assess the comprehensive interventions used for the PCS and it aims to appraise if these interventions could prevent the development of depression as a complication. This research has used randomized controlled trials (RCTs) that evaluate the treatment of PCS and its effect on long-term complications like depression. We searched PubMed/MEDLINE, PubMed Central, Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE from January 1, 2016 to May 31, 2021 for our literature search. A quality check was conducted on the identified studies using the Cochrane risk of bias quality assessment tool (modified Cochrane RoB 2). In total, we included 11 RCTs and used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines for the reporting of this systematic review. Most of the studies reinforced early initiation of the treatment by providing education to the patients and conducting their risk assessment. Strong evidence for the multidisciplinary treatment consisting of cognitive-behavioral therapy, psychoeducation, and physiotherapy is emphasized by some studies. More studies with a longer follow-up period are required to assess the effectiveness of intervention more accurately on depression. Regardless, this study will discuss guidelines and provide direction to physicians. It will help in developing future guidelines by addressing the clinical gaps in the implementation of these guidelines.


Introduction And Background
Mild traumatic brain injury (mTBI) is increasingly becoming a common health problem, affecting 600-1,200 per 100,000 people each year [1]. It may be caused by a motor vehicle collision, falls, assaults, strikes by/against an object, and sports and recreational injuries [2]. Although the majority of patients recover in a few weeks or months, a minority (15-25%) develop post-concussion syndrome (PCS) [3]. According to the International Classification of Diseases, Tenth Revision (ICD10), PCS is defined as a syndrome that follows a head injury severe enough to cause loss of consciousness and includes three or more out of eight symptoms such as headache, dizziness, fatigue, irritability, insomnia, impaired concentration, memory difficulties, and intolerance of stress, emotion, or alcohol [4].
Given the misconception that concussion does not need treatment from healthcare professionals, coupled with the perceived stigma of going through mental health care, the mTBI sustained individuals will be susceptible to develop maladaptive coping strategies. The symptoms may go on to become more prolonged [5]. Prolonged post-concussion syndrome (PPCS) is associated with poor outcomes resulting in lower community reintegration, higher healthcare utilization, higher economic cost, greater cognitive burden, and elevated reporting of psychiatric symptoms [6]. Particularly, depressive disorders are very common and seem to be important as their prevalence continues to be high in chronic stages of traumatic brain injury (TBI) [7,8]. A study by Potter et al. has reinforced the importance of preventing depression as the aforementioned poor outcomes are maintained via vicious cycles by the depression [9]. The ongoing debate on PCS is probably due to inconsistent terminology, various definitions [10], different diagnostic criteria [5], heterogeneity in disease outcome, as well as a variety of interventions [10,11]. Nevertheless, healthcare professionals acknowledge the significance of timely assessment, diagnosis, and treatment [12]. Considering this fact, various guidelines for the treatment of PCS are being evolved. But the area of implementation of these guidelines in clinical practice and their effect on the long-term complications are less explored.
The purpose of this review is to evaluate interventions used to treat PCS and find evidence to support that this intervention could prevent the development of depression. We reviewed the effectiveness of the various treatment modalities currently available for the PCS. We tried to understand the effect of these interventions on the development of depression and other neurobehavioral sequelae. The review will help evaluate the inconsistent clinical practice and provides evidence-based guidelines for implementation in clinical practice.

Review Methods
This systematic review was carried out by adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist [13]. ). We used the specific keywords (post-concussion syndrome and depression) in combination to search for the relevant papers in the Cochrane Library and EMBASE.

Screening of Articles
Titles and abstracts were screened independently by the two authors (TD and IG). The third author (AT) was involved in a discussion to resolve the conflicts, concerns, and doubts. The full text of relevant articles was retrieved and checked for eligibility criteria.

Inclusion and Exclusion Criteria
We only chose the randomized control trials (RCTs) published from January 1, 2016 to May 31, 2021. In addition, only studies published in the English language were included. Among the studies chosen, we ensured that all patients included were experiencing any of the symptoms of PCS or were at risk of developing PCS following TBI and were at least 18 years of age. We also included papers relevant to the research question regarding the long-term sequela of PCS, depression. Articles related to animal studies and the pediatric population were excluded.

Assessment of Study Quality
An assessment of the risk of bias was done on the selected studies using the Cochrane risk of bias tool (modified Cochrane RoB 2) and categorized as a high, low, or unclear risk of bias in each of the seven domains.

Data Extraction
Data extraction for the 11 included studies was done by the two authors (TD and IG). We extracted the objective of the study, participant characteristics (sample size, age group, severity of TBI, and time since TBI), characteristics of intervention and control group, follow-up period, outcome assessed in the study, and the result. The data considered to best reflect the relevance of the study were extracted and discussed by the two authors.

Results
A total of 32,720 articles were identified using the search strategy mentioned in the method section. It was shortlisted to 293 RCTs after applying five filters (RCTs, publication date from January 1, 2016 to May 31, 2021, human species, English language, and 18 plus age group), from which duplicates were removed manually. The articles were then screened based on the title and abstract related to the research question. Papers were also filtered based on the eligibility criteria and availability of full text. A total of 11 articles were identified to be eligible for review and quality assessment was done for these articles. A PRISMA flow diagram is given in Figure 1. Table 1 shows the outcome of the Cochrane risk of bias tool and Table 2 Author

Discussion
Post-concussion syndrome is a chronic health condition and is considered problematic [9]. Despite this, the treatment guidelines are not well known and are widely disseminated [3]. This systematic review provides comprehensive evidence of treatment efficacy in PCS, and we aim to help policymakers and researchers address this evidence gap in the future. Consistent with the previous evidence, the prevention of postconcussion symptoms following any traumatic brain injury is an important priority [14].

Prevention of PCS With Early Interventions
Effective management starts at the emergency department (ED) where the challenge of safe discharge of the TBI-sustained patient is encountered. Bosch et al. conducted a study of 31 EDs to evaluate a theoryinformed and targeted implementation intervention called Neurotrauma Evidence Translation (NET) intervention. The study reinforced the effectiveness of multi-faceted, targeted, theory-informed interventions compared to single-component, non-targeted other interventions in increasing the uptake of recommendations. Three clinical practice recommendations deemed important by NET guidelines are (a) assessing post-traumatic amnesia (PTA) in ED using a validated tool; (b) ascertaining the proper use and timing of computed tomography (CT) imaging; and (c) providing verbal patient information as well as patient education handouts consisting of advice and reassurance during discharge from ED [3]. Another study by Mortimer et al., which was conducted alongside the NET trial, evaluated the cost-effectiveness of this targeted theory-based, multi-faceted intervention. It pointed out that even though the management of mTBI in the ED is more efficient with NET intervention, it is unlikely to be cost-effective [15]. Nonetheless, ED places a crucial role in initiating the treatment for mTBI patients, and further research may be needed to study cost-effective evaluation strategies.
Follow-up with a family physician and other primary care practitioners should be arranged as they play a unique role in implementing and promoting early treatment to prevent chronicity in mTBI. A practice guideline was developed for primary care practitioners by incorporating the best available evidence by an interdisciplinary team supported by Ontario Neurotrauma Foundation (ONF). An RCT studying 114 different primary care clinics measured the improved outcome in mTBI patients following the family physician's behavior change. The study included a guideline implementation tool that was sent to the family physician. It had a tailored letter with ONF guidelines specific to the primary symptoms as suggested by the participant's positive screening test. The study documented fewer post-concussion symptoms in the experimental clinics but the treatment of insomnia was higher in the control clinics [1]. Scheenen et al. mentioned in their study that patients at risk of persistent complaints should be targeted for preventive cognitive behavioral therapy (CBT). They used Head Injury Symptom Checklist (HISC), which is similar to the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), to measure the post-traumatic complaints, and it included further questions on sleeping problems and anxiety. The study emphasized that providing education with CBT in the early phase of the injury is more effective [14]. All these studies support the fact that early intervention should include establishing the diagnosis, initial assessment, and treatment targeting symptoms, as well as providing verbal and written education about anticipated recovery. A summary of the studies on early intervention is shown in Table 3.

Bosch et al. (2019) [3]
To increase the uptake of three key recommendations (PTA tool, CT scan rule, information booklet) in ED. The intervention group received all the below while the control group received only the first two steps.

Treatment of Post-Concussion Symptoms and its Role in Preventing Depression
The prolonged duration of symptoms greater than three months following TBI usually warrants treatment that incorporates interdisciplinary interventions. Various trials have shown improvements in the prolonged symptoms using cognitive rehabilitation, cognitive behavioral therapy (CBT), psychoeducation, and physiotherapy.
CBT: The CBT component in the multidisciplinary intervention plays an essential role in the treatment of PCS. The CBT alone could have an impact without other interventions. As shown in the research done by Potter et al., there is an improvement in the quality of life with a program of only 12 hours of therapist counseling, especially in those completing treatment more quickly [9]. Despite the evidence of treatment effect on anxiety and fatigue, there was no evidence noted for effect on depression [9]. As demonstrated by this trial, CBT has a vital role in the treatment of PCS. Further, Bell et al. have supported the effectiveness of problem-solving treatment in service members, which allowed participants to select the problems to work on from the list generated during the initial telehealth sessions. Hence, the entire 12 telehealth sessions were the participant-centered model. The study showed at six months of follow-up that the PST group reported greater improvements in psychological distress and also noted short-term improvement in depression [16]. As we see, telehealth is emerging as a widely accepted model of practice for common diseases, and this particular scenario for the treatment of PCS via telehealth should be further researched and explored. CBT focuses on identifying key symptoms and prioritizing them during treatment. Hence, CBT can positively impact the quality of life of patients with PCS.
Integrative neurocognitive therapies: Cognitive impairment is a common disability of the PCS. Integrative neurocognitive therapies are widely accepted strategies to address these impairments. It helps to improve the cognitive deficits along with guiding strategies to adapt to life post-injury [17]. Researchers constantly develop, test, and identify cognitive training protocols to improve the daily function of individuals with TBI. Examples of such programs include Goal-Oriented Attentional Self-Regulation (GOALS), problem-solving treatment (PST), goal management training (GMT), and Strategic Memory Advanced Reasoning Training (SMART) [17]. Vas et al. have shown the cognitive benefits of SMART in an mTBI population at a chronic stage. Notable among the secondary outcome is psychological health. Psychological health, measured as the self-report of depressive symptoms and stress-related behaviors, showed significant gains on the SMART group [17]. This points out that interventions could prevent psychiatric sequelae of PCS like depression with multidimensional and inter-related strategies. Another study by Jurick et al. has reinforced this evidence and has emphasized the relations between the inadequate engagement of testing in veterans with mTBI and the increased reporting of psychiatric symptoms. They compared two groups (a) cognitive processing therapy (CPT) combined with the components of cognitive training from Cognitive Symptom Management and Rehabilitation Therapy (CogSMART) to (b) the standard CPT [6]. Consistent with their previous RCTs, the first group SMART-CPT demonstrated greater improvements in mental health symptoms (PCS) and quality of life, even though both groups showed improvements following treatment. In addition, the study included a performance validity test (PVT) to measure the engagement of veterans in the neuropsychological test evaluation. Although both PVT pass and PVT fail groups showed clinically significant improvement in mental health after the treatment, the PVT fail group demonstrated better test engagement at follow-up [6]. The study provides empirical support to enroll the PVT fail group in traumafocused treatment as they may benefit from assessment after treatment [6].
Interdisciplinary rehabilitation: A treatment plan that incorporates multiple therapies and is tailored based on the patient's symptoms would be the best approach to follow in PCS management. The recent developments support the provision of active rehabilitation for the prolonged PCS (PPCS). The trial by Rytter et al. has shown the effectiveness of the specialized interdisciplinary rehabilitation (S-REHAB) compared to the standard care for PCS. This 22-week program focused on education and return to work. It included both individual and group sessions [5]. The trial successfully targets cognitive, emotional, and physical domains along with interpersonal skills. The study concluded improvements in social functioning, increased level of activity life satisfaction coupled with a decrease in mental fatigue, which is a valuable finding entailing a need for individually tailored rehabilitation for the sufferers of PCS [5]. A summary of the studies on the treatment of post-concussion syndrome is shown in Table 4.

Followup period
Outcome Potter et al. (2016) [9] CBT: Twelve weekly one-hour sessions focusing on (i) identifying problems and psychoeducational and (ii) problem-solving and relapse prevention. This is compared to the control waiting list group.
At four months Improvement in QOL in patients with prolonged symptoms. Bell et al. (2017) [16] PST by telehealth which includes 12 biweekly telephone calls for subject select problems and 12 educational brochures. This is compared with the EO group, which includes biweekly emails of brochures and 12 educational brochures.

Pharmacological Interventions
Few studies are employing pharmacological intervention for the PCS in the search results. Also, we found pharmacological intervention targeted specific symptoms the patient identified [19]. Jorge et al. studied 96 patients to assess the efficacy of sertraline to prevent depression following TBI and found the number of need to treat to prevent depression is 5.9. Although the small sample size limits the study, it indicated antidepressants appear to be efficacious in delaying the onset of depression [8]. Theadom et al. also used a pilot RCT of 78 patients to evaluate the effects of NeuroAiD, an antioxidant, on cognitive functioning following TBI and reported evidence that NeuroAiD improved cognitive functioning [18].

Limitations
This review has a few limitations. First, this systematic review has included only RCTs. As PCS includes a number of symptoms, we could have missed reviewing few interventions used to treat PCS. Second, the condition is highly heterogeneous, and there are considerable variations in the selection of participants among the studies. However, most studies included mild to moderate TBI patients in their trials. Third, few studies had the risk of bias that could have pooled up.
Even so, bias in blinding participants in the rehabilitation studies, which studies the subjective symptoms, is an expected problem. Finally, the follow-up period for the studies is not too long to study the development of depression and other long-term sequelae. Taken together, future trials with a large population and long follow-up times will be required for supportive evidence.

Conclusions
Annually, there is an increase in the incidence of PCS following TBI, and various causes that inflict the injury in combination with the rising awareness of PCS among the patients could play a role. This paper was conducted to find the clinical gaps in managing PCS and to determine factors in preventing long-term neurobehavioral problems. The review of the studies shows that management of PCS is associated with significant outcomes in improving the quality of life, decreasing the economic burden on the health system, and perhaps reducing the long-term complications, such as depression and anxiety. Treatment should be initiated as early as possible by providing education about the expected trajectory following TBI and identifying at-risk patients for long-term symptoms. As the PCS includes a group of symptoms, the primary symptom should be identified and given individualized treatment. In addition to these, the multidisciplinary team intervention would provide the best outcome. The interdisciplinary treatment, including but is by no means limited to cognitive behavioral therapy, psychoeducation, physiotherapy, should be incorporated in the treatment process. Future research should include a large population and a long follow-up period to synthesize evidence of long-term outcomes.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.