Mood disorders secondary to traumatic brain injury (TBI) are a relatively common phenomenon. Having a strong understanding of the risk factors, diagnostic procedures, and currently available treatments strengthens clinicians’ ability to improve quality of life in patients with TBI and alleviate the extra burden imposed by emotional disturbance. We review the characteristics of depressive, manic, and mixed mood disorders following TBI, with a discussion of the current literature on risk factors, DSM-5 ( Diagnostic and Statistical Manual of Mental Disorders ) diagnostic criteria, differential diagnosis, and treatments for individuals experiencing such disorders. Depression is more common than manic and mixed episodes in patients with brain trauma; therefore, the available literature on the former is richer. Treatments using psychotherapy, pharmacotherapy, and electroconvulsive and brain-stimulation techniques are described before discussing possible future directions.
KeywordsBipolar disorder, Depressive disorders, Hypomania, Mania, Manic disorders, Mood disorders, Pharmacotherapy, Psychotherapy, Risk factors, Traumatic brain injury
Mood disorders are a common development in cases of traumatic brain injury (TBI). A number of factors contribute to the outcome of this phenomenon. For instance, factors preceding the trauma (eg, personal medical history, genetic vulnerability), characteristics of the head injury (eg, severity, mechanism and location of brain damage), and external factors (eg, type of treatment, motivations for recovery) may influence the outcome of the mood disorders and the appearance of other comorbid disorders. Such factors may also vary in their degree of importance, depending on the period of postinjury recovery.
Considering the prevalence of mood disorders following TBI, it is necessary and urgent that clinicians and other caregiving personnel understand their etiology, potential treatments, and even their possible prevention. From the perspective of patients suffering from TBI, they may be living their everyday lives, while experiencing deficits in their cognitions or emotions that, sometimes, they themselves do not notice. These individuals with TBI may perceive that their interpersonal relationships have somehow shifted, or that they are experiencing functional difficulties in daily life that they do not recall experiencing previously, but they may not understand why. These skewed perceptions, coupled with physiological alterations resulting from brain injury, increase the likelihood that such patients will experience an affective episode. Thus, when caregivers of patients with TBI can better understand what the patients may be experiencing, and hone their ability to recognize psychiatric issues that might be developing, they can help patients arrive at diagnosis and undergo treatment sooner.
Epidemiology of Depressive Disorders
The frequency with which depressive disorders manifest in patients with TBI varies, depending on the source. The current literature proposes frequencies ranging from 6 to 77% ( ). Probable explanations for the large disparity in frequencies include differences in the measures and cutoff points used to diagnose depression, as well as differences inherent to the samples studied. Our own study of depressive disorders in the first year following TBI indicated that 33% of the patients developed major depression ( ). Diagnoses were made via semi-structured interview, based on the criteria set forth by the DSM-IV-TR (an edition of the Diagnostic and Statistical Manual of Mental Disorders , published by the American Psychiatric Association). In this study, we found a significant association between the presence of anxiety disorders in individuals with TBI and the eventual development of major depression. In fact, almost 75% of our sample was diagnosed with comorbid depression and anxiety. A study using similar methods replicated this finding ( ). In general, the likelihood of developing depression appears to be the highest during the first year postinjury. Nevertheless, in individuals with TBI, the risk of developing depression is greater than that of individuals without TBI, even many years after the injury ( ).
Risk Factors of Depressive Disorders
Though the data on risk factors for depression secondary to TBI have been ambiguous, especially regarding age and gender variables ( ), it is accepted that a myriad of factors play a role in the manifestation of depression.
In particular, we still stand at the frontier of research on genetic factors that may predict neuropsychiatric disorders following TBI. Below is a selection of developments drawn from our current understanding of these factors. The apolipoprotein E-4 (APOE-4) genotype has not been associated with the rate of depressive disorders following mild ( ) and moderate-to-severe ( ) TBI, though it is otherwise linked to cognitive outcomes. Polymorphisms in genes involved in the regulation of ascending neurotransmitter systems have also been researched. A recent study did not support a link between polymorphisms of the serotonin transporter (5HTT) and the incidence or severity of depression after TBI ( ). However, it is possible that genetic variants of the 5HTT could modify a patient’s response to antidepressant treatment. For instance, in the TBI population, an individual’s genotype affects his or her response to citalopram ( ). The same study uncovered more frequent adverse treatment effects in individuals with certain 5HTT polymorphisms, including rs25531. In contrast, the C-(677)T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the val66met polymorphism of the brain-derived neurotrophic factor (BDNF) gene were linked to favorable treatment responses. Additional research on these topics is necessary to determine if there are true preinjury risk factors for the development and treatment of depressive disorders in patients with TBI.
Psychosocial factors, such as a history of childhood adversity, life stressors, and lack of social support, contribute to psychiatric problems in the general population. Although such factors have not yet been clarified in patients with TBI, we found associations between the development of post-TBI depression and patients’ previous history of mood and anxiety disorders and poor social functioning ( ).
Other behavioral conditions, such as alcohol misuse, also contribute to the risk of TBI and mood disorders. We followed a group of patients ( N = 158) for a year post-TBI and found that, of the 55 patients with a history of alcohol misuse, 60% developed a mood disorder, compared with 36.9% of the other patients ( N = 103), who did not have a history of alcohol problems ( ). Approximately 75% of those who abused alcohol during the first year postinjury also had a comorbid mood disorder.
Diagnosis of Depressive Disorders
The persistent and all-consuming nature of depressive disorders permeates the perceptions of those who are afflicted—to such an extent that their thoughts, emotions, and ability to interpret the world are warped. This biased mindset may alter individuals’ personal and professional relationships, their ability to function in daily life contexts, and ultimately their quality of life. In establishing modern DSM-5 ( Diagnostic and Statistical Manual of Mental Disorders ) classification frameworks, the pervasive mood alteration and recurrent nature of major depression are the keys to differentiating it from state-based disturbances of emotional regulation (eg, emotional lability, pseudobulbar affect) that also occur in patients with TBI. In the DSM-5 , depressive disorders linked to TBI are categorized as “Mood Disorder Due to Another Medical Condition (TBI),” with the choice of the following subtypes: (1) with major depressive-like episode (if all criteria for major depression are met), (2) with depressive features (when prominent depressed mood is present, but not all criteria for major depression are met), and (3) with mixed features (when patient exhibits both depressed mood and manic symptoms).
To diagnose depressive disorders, structured or semi-structured psychiatric interviews with a clinician form a solid foundation ( ). Validated scales, such as the Beck Depression Inventory (BDI), Hamilton Depression Scale (HAM-D), Neurobehavioral Functioning Inventory Depression Scale, and the Center for Epidemiologic Scales for Depression, are recommended for further clarification of symptom severity. In patients with TBI, clinician-administered scales are considered particularly useful and may be more advantageous than relying solely on patients’ self-report of their experiences.
suggest that the process of differential diagnosis for depressive disorders following TBI involves the consideration of substance-induced mood disturbances, posttraumatic stress disorder (PTSD), and other syndromes, such as posttraumatic apathy and pathologic laughter and crying. Please note that the above suggestions do not constitute a comprehensive list. A patient behaving out of the norm may also be exhibiting a personality change due to TBI or may have a lifetime depressive disorder not secondary to TBI. The latter are quite common in individuals with TBI and should be taken into account during differential diagnosis of post-TBI depression ( ). Besides the length of remission of depressive symptoms that might have occurred before the TBI, an important criterion for determining the role of TBI, in the current manifestation of depressive symptoms, is whether the clinical presentation differs from what occurred in previous depressive episodes and whether those changes might result from the emotional deregulation associated with brain damage (eg, irritability and aggression).
PTSD is frequently comorbid with post-TBI depression and should be treated differently from how depression without comorbid PTSD is treated, so proper diagnosis is vital. Hypervigilance, flashbacks, nightmares, and a general avoidance of reminders related to the traumatic event are characteristic of PTSD sufferers.
Posttraumatic apathy is common in individuals with TBI and, in contrast with the pervasive sadness and ruminations associated with depression, is characterized by the lack of normal emotional concomitants of goal-directed behavior. Individuals displaying this form of apathy may appear unmotivated or uninterested in typical daily activities and life events ( ). Pathologic laughter and crying (ie, pseudobulbar affect) is characterized by the presence of repetitive, stereotyped affective outbursts that occur independently of, or disproportionately to, usual emotional stimuli and may be incongruent with the underlying mood. The condition lacks the long-lasting alteration of mood that is characteristic of a depressive episode.
Treatment of Depressive Disorders
One common method for treating mood disorders is psychotherapy, which exists in many forms. Clinicians may first strive to educate the patient, the patient’s family, and close others about what they can (and cannot) expect out of therapy. Part of the process also involves bolstering their sense of hope and stressing the need for strong support networks. One of the most common forms of psychotherapy, cognitive behavioral therapy (CBT), works to reduce psychiatric symptoms in the patient, while teaching positive coping skills and strategies for improved psychosocial functioning.
Depending on the patient’s unique situation, psychotherapy groups geared toward specific issues, such as addiction, abuse, or relationship skills may prove beneficial to the patient and his or her family and friends. Such groups, or such therapeutic methods, have been shown to be efficacious even when conducted via telephone ( ) and Web-based ( ) sessions with counselors. In addition, peer-support groups are helpful venues for patients with TBI and their families to learn more about what to expect from their diagnoses, share the issues they are struggling with, and gain social support from others who are in similar situations. It is important for the healthcare provider to recognize the negative effect that a patient’s diagnosis may have on family members and caregivers as these individuals adjust to possible changes in the patient’s functional ability, relational skills, and daily habits. In this manner, the healthcare provider can recommend caregiver support as needed and without delay. Past research shows an association between postinjury depression and family dysfunction ( ). Caregivers of patients with TBI are at a greater risk for experiencing depression themselves ( ). Thus, it is vital that not only the patients are involved in the treatment and recovery process but also the people who spend a lot of time with the patient may require support as well.
Just as in non-TBI cases of depression, patients may benefit from pharmacotherapy or a combination of psychotherapy and pharmacotherapy. Overall, past research has indicated that selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are effective in reducing depression after TBI ( ). Generally, SSRIs are the preferred pharmacotherapy for depression following TBI, whereas TCAs are considered a second, if lesser, option for the treatment of depression after TBI, due to a history of problems with their effectiveness and tolerability. There is evidence that SSRIs also alleviate comorbid irritability and aggression ( ) and the number and severity of other symptoms. Of the SSRIs that have been used in this population, citalopram and sertraline are the most highly recommended, partly due to their limited side effects and obvious benefits. Other SSRIs, such as paroxetine and fluoxetine, are less recommended for patients with TBI for several reasons. Paroxetine, with its anticholinergic effects, may trigger additional cognitive deficits in the patient and has done so even in healthy adults ( ). Fluoxetine, in comparison, inhibits cytochrome enzymes and has resulted in unwanted drug–drug interactions ( ). Methylphenidate and similar stimulants are recommended for inpatient settings and may be used in conjunction with SSRI therapy.
Currently, the effectiveness of antidepressants such as serotonin–norepinephrine reuptake inhibitors (SNRIs), bupropion, and monoamine oxidase inhibitors (MAOIs) in patients with TBI remains unknown. Although such drugs are commonly used in the treatment of non-TBI patients suffering from depression, they may have unwanted effects within the TBI population. The use of MAOIs, in particular, is not recommended in patients with cognitive impairments, particularly if the patients are likely to experience trouble adhering to dietary restrictions. Additionally, bupropion, especially immediate-release bupropion, is not recommended for patients with TBI, as one of its side effects is lowering the seizure threshold ( ). Use of sustained-release bupropion is possible, but proper precautions and careful monitoring are recommended ( ).
Finally, electroconvulsive therapy (ECT) and brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), are possible avenues of treatment for depressive disorders, when the aforementioned therapies are unsuccessful ( ). With regard to ECT, recommend using the lowest possible energy levels that will generate a seizure of 20 s or more, and it may be most beneficial to separate treatments by 2–5 days, while also administering no more than four to six treatments per course. In cases of significant cognitive impairment due to TBI, we recommend nondominant unilateral ECT. The efficacy of rTMS and tDCS in individuals with TBI remains relatively unknown. However, tDCS and low-frequency rTMS may constitute more appropriate treatment options, as those who with a history of TBI already have a greater risk of experiencing seizures because of their brain injury. The effects of other known methods of brain stimulation are currently not well-elucidated in individuals with post-TBI depression.
Prevention of Depressive Disorders
Evidence suggests that depressive disorders comorbid with TBI are relatively prevalent. Thus, the first year following TBI may be an ideal time to target the prevention of depression. We performed a randomized, placebo-controlled clinical trial examining the efficacy of sertraline in preventing the development of depression ( ). Nondepressed subjects ( N = 94) with TBIs of differing severities were recruited from the Department of Neurosurgery at the University of Iowa. They were randomized to receive either a placebo or 100 mg of sertraline daily, over a period of 6 months. At the conclusion of the trial, our intention-to-treat analysis showed that subjects who received the placebo were about four times more likely to develop depression than those who received sertraline [HR = 3.6, 95% CI = 1.1, 16.2]. These results support the notion that selective pharmacological prevention may help reduce or alleviate depression in similar patients.