Selective serotonin reuptake inhibitors in the treatment of major depressive disorder after brain trauma: Systematic review and meta-analysis

Abstract

BACKGROUND

Traumatic brain injury (TBI) poses a considerable risk to human health. After TBI, individuals are susceptible to a range of psychiatric disorders, with depression being a primary complication. Selective serotonin reuptake inhibitors (SSRIs) are frequently used in the treatment of depression; however, their efficacy in addressing major depressive disorder (MDD) in adults following TBI remains uncertain.

AIM

To investigate the efficacy of SSRIs in the treatment of MDD after TBI.

METHODS

A comprehensive search across multiple databases was conducted following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, encompassing studies published until May 2024. This review focused on studies that examined the efficacy of SSRIs in the treatment of MDD following TBI. Studies were assessed based sample size, treatment duration, treatment methodologies, severity of brain injury, assessment techniques, and drug response. A random-effects model was used to derive the summary effect size.

RESULTS

Eight studies compared the reduction in depression scores in patients with MDD after TBI and SSRI treatment. The eight studies did not exhibit heterogeneity (I² = 38%). The depression score for MDD after TBI in the SSRI group decreased more than that in the control group [odds ratio (OR) 1.68, 95%CI: 1.09-2.58, P = 0.02]. The adverse reactions after treatment included diarrhea, dizziness, dry mouth, nausea, or vomiting. There was no difference in the incidence of adverse reactions after treatment between the two groups (OR 1.16, 95%CI: 0.78-1.73, P = 0.46]. These studies did not show significant heterogeneity (I² = 44%).

CONCLUSION

SSRIs may be effective in treating patients with MDD after TBI. Adequately powered, randomized, controlled trials are required to confirm these findings.

Key Words: Antidepressant; Meta-analysis; Depression; Traumatic brain injury; Selective serotonin reuptake inhibitors

Core Tip: Results of this meta-analysis indicate that selective serotonin reuptake inhibitors have advantages over placebos for the treatment of major depressive disorder after Traumatic brain injury. The incidence of adverse reactions after treatment did not differ substantially between the two groups. However, these studies did not exhibit heterogeneity, although the sample sizes of all studies included in this meta-analysis were relatively small (n < 100). This may have resulted in an overestimation of the treatment effects in small trials. Future prospective studies with larger sample sizes are needed to verify the results of the present study.

INTRODUCTION

Traumatic brain injury (TBI) is a condition that threatens human health. More than 50 million individuals are affected by TBI annually and approximately half of the world's population may experience TBI at least once during their lifetime[1]. The main type of damage caused by TBI is the destruction of the brain tissue structure that occurs immediately after injury; however, persistent pathological changes are more serious after injury. TBI can cause neurological dysfunction and death of nerve and glial cells, leading to serious consequences or even death. The age range of patients exhibits a bimodal distribution, with a higher probability of occurrence between 14 and 25 years of age and after 70 years[2]. There are several causes of TBI; the primary being falls, which are common among the elderly and children, followed by blunt trauma, and motor vehicle accidents. Patients with TBI who experience falls and motor vehicle accidents account for > 50% of all cases[3]. TBI not only threatens human life and health but also imposes an economic burden on society, reducing quality of life and well-being.

Patients are prone to various mental illnesses after TBI, depression being one of the main complications[4]. Depression is characterized by low mood, decreased willpower, and lack of pleasure. Other symptoms include changes in body weight and appetite, insomnia, drowsiness, restlessness, fatigue, and suicidal tendencies[5]. In recent years, with the accelerated pace of life and increased social pressure, the annual incidence of depression has increased. According to the World Health Organization, depression is expected to become the second most harmful disease after heart disease by 2020. Major depressive disorder (MDD) is a common form of depression that affects millions of individuals globally[6].

A study evaluated and followed up patients 2 weeks after TBI and 1, 6, and 12 months later; patients were found to be more likely to experience depression after TBI[7]. Many clinical studies have reported that depression is associated with TBI; however, the actual incidence of depression after TBI reported in different studies remains quite different. For example, the prevalence of depression 1 year after TBI is 15.3%-18.0%, the incidence of depression 1 year after TBI is 53.1%, and as high as 61.0% 8 years after TBI. The probability of a high incidence of depression in patients with TBI varies from 15%-77%[8].

Sertraline, citalopram, and other selective serotonin reuptake inhibitors (SSRIs) have the potential to improve mood and cognition[9-11]. In one study, 16 patients with post-TBI depression were treated with sertraline for 8 weeks, and all subjects exhibited substantial improvements in sleep, mood, social function, and work ability, demonstrating that the drug was effective in treating depression in patients with TBI. Compared to non-TBI depression, tricyclic antidepressants are less effective in relieving post-TBI depressive symptoms and cause more adverse reactions. The effectiveness of norepinephrine-dopamine reuptake inhibitors remains controversial because these drugs can lower the seizure threshold. SSRIs are first-line drugs for treating major depressive symptoms[12]; however, their effectiveness in treating major depression after TBI remains unclear.

To clarify the clinical effects of SSRIs on MDD after TBI, we conducted a systematic review and meta-analysis of studies investigating SSRIs for the treatment of MDD after TBI.

MATERIALS AND METHODS

Search strategy

This meta-analysis evaluated all studies investigating SSRIs in patients with MDD after TBI according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two authors independently reviewed all studies. Published and unpublished studies were considered. A systematic electronic literature search of the PubMed, Embase, Web of Science, EBSCO, and the Cochrane Library databases, from inception up to May 2024, was performed using the following combined MeSH heading and keyword search terms: (traumatic brain injury OR concussion OR closed head injury OR TBI) AND (depression OR depressive disorder). In the case of MeSH headings, the search included the heading term (e.g., “concussion”) and was mapped to include any terms that appeared below it in the corresponding MeSH table (e.g., “post-concussive syndrome”, “intracranial hemorrhage”, “traumatic intracerebral hemorrhage”). The search was limited to clinical trials involving adult participants published in English. The reference list of each full text used for the review, as well as any existing reviews identified, were manually searched to identify additional potentially eligible citations not found in the electronic database search.

Inclusion criteria

The following inclusion criteria were applied to ensure that relevant studies were selected. We included studies that measured depressive symptoms as a secondary outcome to include more studies in an area of research that has been exhausted. Unpublished and ongoing studies were not retrieved and were therefore excluded. These studies were not restricted to specific settings such as secondary care. The inclusion criteria for the current meta-analysis were: Age ≥ 18 years; clinical trials measuring the effects of SSRI treatments on depression after TBI; diagnosis of depression before the start of the study; and the sample included participants with TBI of any severity (mild, moderate, or severe).

Data extraction and evaluation of quality

Using EndnoteX9 (Clarivate, London, United Kingdom) for literature management, irrelevant, duplicate, and nonexperimental (particularly animal-based) studies were excluded. Subsequently, the titles and abstracts were thoroughly reviewed to exclude studies that failed to fulfill the inclusion criteria. The refined literature pool was scrutinized in detail to ensure a comprehensive methodological approach. The full texts of the retrieved studies were read for secondary screening and a third researcher resolved any disagreements through consensus discussion. Two researchers independently evaluated the quality of the studies using the Cochrane bias tool.

Statistical analysis

Review Manager version 5.4 (The Cochrane Collaboration) was used for the meta-analysis. Measurement data were transformed with mean difference into effect size, and count data were transformed with odds ratios (OR). Cochran’s Q statistic was used to test for heterogeneity among the included studies, and the Higgins I² test was used to evaluate the differences among effect sizes. When the I² value exceeded 50%, heterogeneity among studies was considered statistically significant. Parallel subgroup and sensitivity analyses excluded obvious heterogeneity from the meta-analysis. A fixed-effects model was used for meta-analyses when heterogeneity among the studies did not reach statistical significance. Differences with P < 0.05 were considered to be statistically significant.

RESULTS

Study selection

A flow diagram illustrating the study selection process is shown in Figure 1. After the initial title/abstract inspection, 428 duplicates and 635 studies were excluded. After further reading of the full texts, 197 studies that did not meet the screening criteria were excluded; these included 55 studies without a depression outcome, 47 that were not pharmacological interventions, 43 where participants did not have depressive symptoms at baseline, seven with no outcome, five that were not in English, and three that were not randomized, controlled trials. Eight studies were ultimately included in the analysis.

Figure 1 Studies included and excluded from the meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RCT: Randomized clinical trial.

Research characteristics

The characteristics of the studies included in this review are summarized in Table 1[8,11,13-18]. The primary antidepressants used were SSRIs (sertraline and escitalopram). The treatment duration in each study was 4-24 weeks. The outcome measurement tools included Hamilton Depression Rating Scale, nine-item Patient Health Questionnaire Depression Scale, Glasgow Coma Scale, and Montreal Depression Rating Scale. A total of 396 patients were included in the study: 231 in the SSRI group and 165 in the control group.

Table 1 Study characteristics of 8 studies for major depressive disorder after traumatic brain injury.

Ref.	Country	Antidepressant(s)	Weeks treated	n	SSRI (n)	Control (n)	Time since injury	Severity of injury	Outcome measure
Ansari et al[8], 2014	India	Sertraline	24	80	40	40	> 2 weeks	Mild and moderate	PHD-9
Ashman et al[13], 2009	United States	Sertraline	10	41	22	19	17 years	Mild to severe	HAM-D
Fann et al[14], 2000	United States	Sertraline	8	30	15	15	10.6 months	Mild	HAM-D
Fann et al[15], 2017	United States	Sertraline	12	53	24	29	4.6 months	Mild to severe	HAM-D
Jorge et al[11], 2016	Argentina	Sertraline	24	94	48	46	-	Severe	GCS
Lee et al[16], 2005	Korea	Methylphenidate and sertraline	4	30	20	10	32.2 days	Mild to moderate	HAM-D
Rao et al[17], 2016	United States	Escitalopram	12	14	8	6	Not reported	Not reported	MADRS
Rapoport et al[18], 2008	Canada	Citalopram	10	54	54	Self-control	< 1 year	Mild to severe	HAM-D

MDD: Major depressive disorder; TBI: Traumatic brain injury; SSRI: Selective serotonin reuptake inhibitor; PHD-9: 9-item Patient Health Questionnaire Depression Scale; HAM-D: Hamilton Depression Rating Scale; GCS: Glasgow Coma Scale; MADRS: Montreal Depression Rating Scale.

Study methodology

This analysis compared the baseline conditions of patients in eight studies. Figure 2 present tables outlining the "Risk of Bias in Included Studies”. Detailed descriptions of the study characteristics can be found in the section titled "Characteristics of Included Studies”. Several trials have shown a high risk of bias, primarily due to performance bias, allocation concealment, self-reported outcomes, random sequence generation, and inadequate protection against other biases. The challenges posed by unsegregated participants, age, and multiple outcome measures increased the risk of bias in most of the included randomized clinical trials.

Figure 2 Risk of bias in included studies. A: Risk of bias summary: Each bias risk item of all included studies was judged by review authors; B: Risk of bias graph: The review authors quantified each bias risk item of included studies as a percentage. The risk of bias assessment for each included study in accordance with “Cochrane RoB 2”. Low risk (+), unclear (?), and high risk (-).

Mean reduction in depression score post-treatment

Eight studies compared the reduction in depression scores in patients with MDD after SSRI treatment following TBI. The included studies did not exhibit heterogeneity (I² = 38%). The depression score of MDD after TBI in the SSRI group decreased more than that in the control group (OR 1.68, 95%CI: 91.09-2.58, P = 0.02; Figure 3A).

Figure 3 Forest plot of major depressive disorder after selective serotonin reuptake inhibitor treatment of traumatic brain injury. A: Forest plot of the reduction in depression scores of major depressive disorder (MDD) after selective serotonin reuptake inhibitor (SSRI) treatment of traumatic brain injury (TBI); B: Forest plot of the incidence of adverse reactions in SSRI-treated MDD after TBI. Diamond: Pooled estimate; squares: Individual study effects; horizontal lines: Confidence intervals; MDD: Major depressive disorder; SSRI: Selective serotonin reuptake inhibitor.

Adverse reactions

The adverse reactions after treatment included diarrhea, dizziness, dry mouth, nausea, or vomiting. There was no statistical difference between the two groups in the incidence of adverse reactions after treatment (OR 1.16, 95%CI: 0.78-1.73, P = 0.46; Figure 3B). Analysis revealed no significant heterogeneity (I² = 0%).

Publication bias analysis

The publication bias of each result was assessed using funnel plots, which indicated good symmetry and scatter points evenly distributed in the funnel, indicating that publication bias did not significantly affect the results of the meta-analysis (Figure 4). The I² value in each figure was less than 50%, indicating that there was no heterogeneity among the studies.

Figure 4 The funnel plot of this study. A: The reduction in depression scores of major depressive disorder; B: Adverse reactions. OR: Odds ratio.

DISCUSSION

MDD is a common complication after TBI. Although the specific causes of depression after TBI are not fully understood, studies have shown that multiple brain regions, pathways, and neurotransmitters are inextricably linked[19]. The current diagnostic criteria for severe depression after TBI need to be improved, and the treatment methods for severe depression after TBI remain in their infancy. Currently, the treatment of severe depression after TBI is very difficult because of its complex mechanism(s); therefore, it is necessary to identify key targets and therapeutic drugs for severe depression after TBI from multiple sources[20]. SSRIs are the first-line treatment in clinical practice. The therapeutic effects of SSRIs in patients with MDD after TBI has been investigated[21]. The present investigation systematically reviewed and analyzed these findings.

Antidepressants may be associated with reduced depressive symptoms after TBI[15,22]. Our meta-analysis indicated that SSRI treatment for TBI reduced depression scores post-MDD (OR 1.63, 95%CI: 1.12-2.38, P = 0.01), indicating that SSRIs were more effective than the control in treating post-TBI MDD. This finding is consistent with that of previous studies. This was further supported by a randomized, controlled trial in which both the placebo and experimental groups exhibited substantial reductions in depressive symptoms over the course of the study[15]. Further research is needed to determine the SSRIs that yield better results in patients with post-TBI MDD.

Our meta-analysis consistently demonstrated no statistically significant differences in the incidence of diarrhea, dizziness, dry mouth, nausea, or vomiting between the SSRI and control groups. The incidence of adverse reactions after treatment was similar between the two groups (OR 1.16, 95%CI: 0.78-1.73, P = 0.46). Analysis indicated no heterogeneity (I² = 0%). These adverse reactions were mild and did not require drug intervention. Further research is needed to screen for safer SSRIs.

Limitations

The present meta-analysis has some limitations. First, only eight studies were included and the sample sizes were relatively small (n < 100). This may have resulted in an overestimation of treatment effects. Second, although the heterogeneity among the included studies was low, different doses and drug treatments may have affected the summary results, and further subdivision of the treatment effects of different SSRIs should be considered in the future. Finally, early use of SSRIs may have a better effect on TBI, and future studies should explore this possibility.

CONCLUSION

The meta-analysis indicates that SSRIs were slightly superior to the placebo in the treatment of post-TBI MDD. Larger, prospective studies in well-defined populations of patients with TBI are warranted to elucidate treatment effects and the relationship between post-TBI MDD and individual SSRIs.