Risk of Misdiagnosing Chronic Traumatic Encephalopathy in Men With Depression

In the 20th century, chronic traumatic encephalopathy (CTE), also known as dementia pugilistica, was considered a neurological syndrome affecting some active and retired, long-career, high-exposure boxers (1, 2). Cumulative and chronic brain damage (3) was believed to be the underlying neuropathology (4), and varying degrees of slurred or dysarthric speech, abnormalities in gait and coordination, parkinsonism, cognitive deficits, and dementia were emphasized in the literature (1–3). The neurological problems were often described as pyramidal (e.g., abnormal reflexes) and extrapyramidal (tremors and parkinsonian gait disturbance), and both were often first noticed at a young age, in some active boxers, who were in their 20s and 30s (2, 4–11). It was understood that some boxers with chronic brain damage exhibited diverse psychiatric and neurological problems that co-occurred with the above-described characteristic features (2, 5, 10, 12). For example, some authors described euphoria (6, 13); a childlike demeanor (4) or “fatuous cheerfulness” (6); and aggression, volatility, and anger dyscontrol (4–6, 8, 10, 12) as behavioral characteristics, often representing a complex neuropsychiatric presentation. It was unclear whether this neurological syndrome was static or progressive or whether its course represented two distinct conditions (1, 2, 7, 10, 13–18), and it was common for researchers to emphasize that chronic brain damage in boxers manifested in variable ways or as different syndromes (6, 7, 10, 13, 16).

Prior to 2005, depression and suicidality were not considered to be core or defining clinical features of CTE. In the past few years, however, there has been a much greater emphasis on mental health problems, such as depression, anxiety, and suicidality (19–22), as being a possible core clinical feature. Without question, some former amateur and professional contact and collision sport athletes experience mental health problems, such as depression (23–26), and tragically some former professional athletes die by suicide (27–31). There is a risk, however, that former contact and collision sport athletes with primary depression will be misdiagnosed as having CTE. This is problematic because some authors assert that CTE is a distinct (20, 32–35) and unique (32) neurodegenerative disease (20, 32, 34, 36, 37), in the family of tauopathies (21)—and, therefore, assuming that depression is a phenotypic expression of CTE has dire implications for morbidity and mortality.

As of the beginning of 2019, there are no agreed upon clinical diagnostic criteria for CTE, although several sets of criteria have been proposed in the past few years (15, 22, 38, 39). Preliminary proposed research criteria for traumatic encephalopathy syndrome (TES) (22) include three core features of CTE—cognitive, behavioral (i.e., anger dyscontrol), and mood (i.e., depression or hopelessness). These core features are used to define diagnostic subtypes or variants, according to the research criteria. Two supportive features must also be present (i.e., impulsivity, anxiety, apathy, paranoia, suicidality, headache, motor signs, a progressive clinical course, or a delayed onset of symptoms [for example, after retirement from sport]). The TES criteria are being used in several studies as part of a $15.8 million multicenter grant entitled “Diagnostics, Imaging, And Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy” (DIAGNOSE CTE) (National Institute of Neurological Disorders and Stroke grant U01NS093334). In April 2019, the DIAGNOSE CTE research team hosted the First National Institutes of Health Consensus Workshop to Define the Diagnostic Criteria for Traumatic Encephalopathy Syndrome (TES). A major gap in the literature is that there are no published studies related to the specificity of the proposed research criteria for TES/CTE.

The study reported here is the first to examine the research criteria for the clinical diagnosis of TES (22) in men with depression from the general population. We chose to study men with depression because depression has been proposed as a core clinical feature, or subtype, of TES. We hypothesized that a substantial percentage of these men from the general population would meet the proposed research criteria for CTE.

Methods

Participants

Data from the National Comorbidity Survey Replication (NCS-R), conducted between February 2001 and April 2003 (40, 41), were used for this study. The NCS-R examined the prevalence and correlates of mental disorders in the United States (42–44). The survey was conducted in person in the homes of a nationally representative sample of adult respondents (N=9,282, including 4,139 men and 5,143 women) (41). The sample of interest was obtained by applying a filter to the publicly available NCS-R database selecting all male participants meeting criteria for a DSM-IV major depressive episode in the past 30 days (i.e., NCS-R variable name D_MDE30). This filter resulted in the inclusion of 101 men; an incidence rate of 2.4% of all men in the database.

The 101 men had a mean age of 39.4 years (SD=12.9, range=18–71). Race-ethnicity was reported as follows: white, 72.3%, N=73; African American, 10.9%, N=11; Mexican, 5.9%, N=6; Asian, 1.0%, N=1; and all other races, 9.9%, N=10. Their level of education was as follows: 0–11 years, 25.7%, N=26; 12 years, 31.7%, N=32; 13–15 years, 27.7%, N=28; and ≥16 years, 14.9%, N=15. Approximately half the sample was employed (52.5%, N=53), 43.5% (N=44) were not in the labor force, and 4% (N=4) were unemployed. Relationship status was described as follows: married, 43.6%, N=44; never married, 32.7%, N=33; and divorced, separate, or widowed, 23.8%, N=24.

The NCS-R Protocol

The survey was conducted using laptop computer-assisted personal interviews by researchers from the Survey Research Center of the Institute for Social Research at the University of Michigan. The core diagnostic assessment of all respondents (N=9,282) included the following modules: household listing, screening, depression, mania, irritable depression, panic disorder, specific phobia, social phobia, agoraphobia, generalized anxiety disorder, intermittent explosive disorder, suicidality, services, and pharmacoepidemiology. The NCS-R diagnoses are based on the World Mental Health Survey Initiative version of the World Health Organization Composite International Diagnostic Interview, a fully structured lay-administered diagnostic interview that generates both ICD-10-CM (45) and DSM-IV (46) diagnoses. The NCS-R database is publicly available (http://www.icpsr.umich.edu/icpsrweb/ICPSR/studies/20240).

Research Criteria for TES

Research criteria for TES (22) include three proposed core features of CTE—cognitive, behavioral (i.e., anger dyscontrol), and mood (i.e., depression or hopelessness). The core feature, or subtype, referred to as mood is defined as follows: “Feeling overly sad, depressed, and/or hopeless, as reported by self or informant, by history of treatment, or by clinician’s report. A formal diagnosis of major depressive disorder or persistent depressive disorder would meet this criterion but is not necessary” (22). We selected a sample of men who definitively would meet this core criterion in that they were diagnosed as having a major depressive episode in the past 30 days. This was done to simulate applying the criteria to a man who might present to a clinic for evaluation or treatment. In addition to meeting criteria for TES, the person must have two or more supportive features (i.e., impulsivity, anxiety, apathy, paranoia, suicidality, headache, motor signs, documented decline in functioning or a progression of symptoms, or a delayed onset—such as having problems at least 2 years after the end of a career in contact sports). For the purposes of this study, we selected five of the nine supportive features, available in the NCS-R database, for the primary analyses (i.e., impulsivity, anxiety, apathy, suicidality, and headache) because paranoia, motor signs, decline in functioning, and delayed onset of symptoms were deemed to be less reliable or missing variables in the NCS-R database.

We present the rates of positive screens for TES in two ways. First, the rate at which the men met two of the five supportive criteria is presented. Second, the rate at which the men met one of the five supportive criteria is presented, because this simulates the assumption that the delayed-onset criterion or the decline in functioning criterion would be met. The delayed-onset criterion requires “delayed onset of clinical features after significant head impact exposure, usually at least 2 years and in many cases several years after the period of maximal exposure,” and the “documented decline” criterion requires a “progressive decline in function and/or a progression in symptoms” (22).

Results

Lifetime experiences with major mental disorders, suicidal ideation and behavior, substance abuse, and headaches for the 101 men with depression are presented in Tables 1 and 2. A substantial minority of the sample reported a lifetime history of alcohol dependence (26.7%), drug abuse (36.6%), and drug dependence (20.8%), and 8%−14% reported experiencing these problems in the past 12 months. A lifetime history of generalized anxiety disorder was reported by 30.7%, 25.7% had the disorder in the past 12 months, and 16.8% met criteria for the disorder in the past 30 days. Serious anger control problems were common in that 34.7% had a lifetime history of DSM-IV intermittent explosive disorder (Table 1), and 23.8% met criteria for the disorder in the past 12 months. More than half (52.5%) reported feeling mad or angry during the past month (Table 2). Suicidal ideation and behavior were also common (Table 2). Approximately 43% had contemplated suicide during their lifetime, and 18.8% had attempted suicide. One in five (20.8%) had seriously considered suicide in the past 12 months. One in four (23.8%) reported a current problem with severe headaches (Table 2).

The percentages of men meeting supportive criteria for TES are presented in Table 3. Impulsivity, as reflected by a diagnosis of alcohol or drug abuse in the past year, was present in 20.8%. Problems with anxiety were present in 73.3%, and suicidality was present in 20.8%. Apathy was reported by 36.6%. A significant problem with headaches was reported by 23.8%. Overall, 52.5% met criteria for two or more supportive features for TES; when their two-criteria status was combined with their diagnosis of depression, these men would meet the clinical criteria for TES. We could not apply the criteria related to delayed onset (e.g., mental health problems in a middle-aged man who played collegiate football or hockey) or to progressive worsening of symptoms (i.e., over at least a 1-year duration). Assuming that one of those criteria were met, then only one additional criterion from Table 3 would be necessary to meet research criteria for the syndrome. The proportion of the sample who met one or more of the criteria was 83.2%.

Discussion

This is the first study to examine a proposed set of research criteria for the clinical diagnosis of CTE (22) in a sample of men from the general population who suffer from depression. Depression has emerged in recent years as a proposed core feature and clinical subtype of CTE (19–22). The mean age of the sample used in this study was 39.4 years, and most were between the ages of 26 and 52, with an age range of 18–71. For comparison, the mean age is similar to the age reported as the age at onset of the mood and behavioral symptoms associated with CTE (i.e., mean=34.5 years, SD=11.6, range=19–59 years) (47).

The results were striking in that 52.5% of these men met the proposed research criteria for CTE (i.e., TES). We were unable to study two important secondary criteria, delayed onset and progressive course. If we assume that one of those criteria would be met (i.e., the person developed depression years after playing a sport or years after military service or the person had a worsening of symptoms over the past year), then it would be necessary to meet only one of the five criteria in the present study to screen positive for TES. Under those assumptions, then 83.2% of this sample would meet the research criteria for a clinical diagnosis of CTE.

The clinical problems attributed to CTE (22), such as depression, suicidality, anxiety, anger control problems, and headaches, co-occurred in this sample of men with depression from the general population—illustrating that they are not specific or unique to CTE. These results have important implications. At least 50% of men from the general population, who have depression and are presenting for health care, will appear to have a full complement of symptoms and problems that have been asserted to be characteristic of CTE. For former athletes and military veterans who present many years after retirement and who experienced a documented decline in their mental health, the large majority (i.e., eight out of ten) will meet these research criteria.

We did not examine the exposure criterion (22) in the research definition for TES because a history of participation in contact or collision sports was not included in the NCS-R database. At minimum, the exposure criterion simply requires that the person played sports (e.g., boxing, American football, ice hockey, lacrosse, rugby, wrestling, or soccer) for a minimum of 6 years (with 2 years at the college level [or equivalent] or higher) that resulted in “multiple impacts to the head” that can be concussions or “subconcussive trauma” (i.e., with no clinical symptoms) (22). Military service or police training involving exposure to blasts, explosives, combat, or breaching also is listed as a source of exposure sufficient to meet criteria. Therefore, if the presenting male patient was a former athlete or military veteran, there might be an assumption by the health care provider that he meets the exposure threshold for repetitive mild neurotrauma and that his depressive disorder (with supportive features) is a clinical manifestation of a presumed neurodegenerative disease versus being caused or amplified by a diverse range of other biopsychosocial factors. This has critical implications for the doctor-patient relationship, information provided to the patient and family, prognosis, and recommended course of treatment.

According to the research criteria for TES (22), all former professional soccer players, hockey players, boxers, and American or Canadian football players meet the exposure criteria for repetitive neurotrauma. Careful examination of the criteria reveal that an extraordinarily broad range of psychiatric and neurological presentations from these former athletes could meet the clinical criteria for the syndrome, including the following ten examples: depression, suicidality, and headaches; depression, anxiety, and headaches; depression, anxiety, and substance abuse; depression, posttraumatic stress disorder, and headaches; anger control problems, depression, and anxiety; anger control problems, substance abuse, and suicidality; mild cognitive impairment, anxiety, and substance abuse; Parkinson’s disease or parkinsonism, mild cognitive impairment, and apathy; Alzheimer’s disease, apathy, and paranoia; and frontotemporal dementia, impulsivity, and paranoia. Each of the ten examples includes three clinical problems—a core feature and two supportive features. However, only one supportive feature is required if the person meets the delayed-onset supportive criterion. For example, if a person was healthy in his or her 20s and developed depression and headaches during his or her 30s or 40s, that person would meet the core and supportive criteria for TES. This is clearly problematic in that people presenting with an extraordinarily broad range of psychiatric and neurological problems could be diagnosed, and misdiagnosed, as having TES/CTE.

Our study has three important limitations. First, it is possible, in fact likely, that some of the men in our case series experienced one or more concussions during the course of their lives. Concussions are very common in men in the general population. Second, it is likely that some of them played contact sports, at least briefly, during their lives. No information related to lifetime history of sports participation was available in the database. Third, we were not able to map the results of the NCS-R interviews precisely on to the research criteria for CTE. If we had more variables that aligned with the criteria, the rate of presumed misdiagnosis of the syndrome would have been greater. The obvious strength of the study is that the men were selected from a nationally representative sample of men from the U.S. general population who underwent a thorough in-person psychiatric interview yielding DSM-IV diagnoses, and this database has been used for many studies that have advanced knowledge regarding mental health problems in the U.S. population (42–44).

Conclusions

We conclude with four important points. First, CTE is a postmortem neuropathological diagnosis (21, 48), with the preliminary proposed defining pathological feature being the accumulation of hyperphosphorylated tau (p-tau), in a patchy distribution at the depths of the cortical sulci around small vessels (21, 48). In normal aging and in neurodegenerative diseases, p-tau accumulates in the brain (49–52), but it is not believed to accumulate in a patchy distribution in the depths of sulci in association with aging or other diseases (21, 48). The pathology has been identified after death in the brains of young athletes (30, 35), military veterans (53), active NFL players (30, 35), former collegiate athletes from multiple sports (35), retired boxers (35), retired professional hockey players (35), and retired NFL players (21, 30, 35). However, the neuropathology described as unique to CTE may not be completely unique because it has also been identified in some individuals with no known exposure to repetitive neurotrauma, in association with substance abuse, temporal lobe epilepsy, amyotrophic lateral sclerosis, multiple system atrophy, and other neurodegenerative diseases (54–60).

Second, the extent to which the neuropathology is associated with, or causes, specific clinical symptoms and problems is unclear (48, 61). Third, it has not been established that depression arises from the neuropathology of CTE, and depression was not considered to be a core clinical feature of CTE prior to 2005. Depression was reported in some historical cases (5, 8, 10, 12, 62), but it was usually reported in the context of boxers having more characteristic and obvious neurological problems (as opposed to a primary presentation of depression). It is well established in the literature that people who sustain a single traumatic brain injury, of any severity, are at increased risk of developing depression (63–65), and it is possible that cumulative very mild neurotrauma, acquired over the course of many years of exposure, could increase a person’s risk of developing depression—but this has not been established in the literature. Depression in adults is linked to genetics (66), adverse events in childhood (67, 68), and, of course, current life stressors (69). Moreover, numerous health conditions are associated with increased risk of depression, such as chronic pain (70), headaches and migraines (71, 72), chronic insomnia (73), and sleep apnea (74). Later-in-life neurological diseases also are associated with depression, including mild cognitive impairment (75), Parkinson’s disease (76), and Alzheimer’s disease (77).

Fourth, it is essential to appreciate that many of the mental health, physical, and psychosocial problems that have been attributed to CTE in the recent literature are fairly common in men in the general population (78), they are very common in men with depression, and they tend to co-occur both in the general population and in men with depression. As noted in the DSM-5, individuals with depression often have considerable problems with irritability (e.g., persistent anger, a tendency to respond to events with angry outbursts or blaming others, and an exaggerated sense of frustration over minor matters), and family members often notice social withdrawal. Men with depression have higher rates of anger attacks and aggression, substance abuse, and risk taking (79).

Researchers have not established a clinicopathological correlation between depression and the region-specific accumulation of hyperphosphorylated tau believed to characterize CTE (48), and thus researchers and clinicians should not assume, uncritically, that depression in a former athlete or military veteran is caused or amplified by CTE neuropathology. More research is needed to determine whether depression is, in fact, a clinical subtype of CTE.