Chronic Neuropsychiatric Sequelae I: Mood Disorders

Hazem Shahin and Ricardo E. Jorge

GENERAL PRINCIPLES

Background

Mood disorders occur in the context of profound changes in cognitive and emotional processing following traumatic brain injury (TBI). Recent studies have described the detrimental effect of traumatic prefrontal injury on patients’ performance in social cognition as well as in the identification and modulation of emotions [1]. These changes may result in poorly integrated self-representations and dysfunctional interpersonal relationships, increasing patients’ vulnerability to develop affective disorders.

Epidemiology

Neuropsychiatric illness is a highly prevalent complication of TBI, with a published incidence of 49% following moderate-to-severe TBI and 34% following mild TBI (MTBI) [2]. Approximately half of TBI patients will develop depression during the first year after a TBI [3–5], with a lifetime prevalence of 26% to 64%. Up to 9% of TBI patients may develop mood disorders within the bipolar spectrum [6]. However, the lifetime risk of bipolar disorder is similar to general population [7].

Classification

Following the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic nomenclature, mood disorders associated with TBI are categorized as mood disorder due to Another Medical Condition with subtypes of (a) with major depressive-like episode (if the full criteria for a major depressive episode are met) or (b) with depressive features (prominent depressed mood but full criteria for a major depressive episode are not met); and (c) with mixed features (e.g., significant irritability, pressured speech, and formal thought disorder). Bipolar and related disorders due to TBI are subdivided in: (a) with manic or hypomanic-like episode; (b) with manic features; and (c) with mixed features.

Pathophysiology

The changes in neuronal circuitry seen in TBI may constitute the neurological substrate of cognitive and behavioral deficits that are frequently seen following injury. Mood disorders may result from deactivation of lateral and dorsal frontal cortex and increased activation in ventral limbic and paralimbic structures including the prelimbic cortex and the amygdala [8,9]. High levels of amygdala activation may be associated with an increased prevalence of anxiety symptoms and negative affect. Moreover, faulty prefrontal modulation of medial limbic structures could explain the impulsive and aggressive behavior frequently observed in these patients [10]. Overall, injury severity, type, or mechanism of injury do not predict the likelihood of development of mood disorders in the aftermath of TBI [11].

ASSESSMENT

Risk Factors

• Genetic polymorphisms modulating central dopaminergic pathways can affect prefrontal function following TBI [12,13]. However, a recent study failed to demonstrate an association between 5-HTT serotonin transport receptor gene polymorphisms and depression following TBI [14].

• Personal history of mood and anxiety disorders, and previous poor social functioning are associated with the occurrence of major depression in the aftermath of TBI [3,15].

• A history of alcohol misuse increases the risk of developing a mood disorder during the first year post-TBI. It is plausible that alcohol toxicity and TBI interact to produce more severe structural brain damage and more profound changes in the ascending aminergic pathways that modulate reward, mood, and executive function [16].

Clinical Presentation and Symptoms

Mood disorders due to TBI are frequently associated with other behavioral disorders. For instance, anxiety disorders coexist with depressive disorders in up to two thirds of the cases [10]. In addition, clinically significant aggression and alcohol misuse coexist in approximately half of the patients who develop a mood disorder following TBI [16,17].

Differential Diagnosis

• The differential diagnosis of post-TBI major depression includes adjustment disorder with depressed and/or anxious mood, posttraumatic stress disorder (PTSD), apathy, and emotional lability or pathological laughter and crying (PLC).

Patients with adjustment disorders develop short lived and relatively mild emotional disturbances within 3 months of a stressful life event. Although they may present with depressive symptoms, they do not meet DSM-5 criteria for major depression.

PLC is characterized by the presence of sudden and uncontrollable affective outbursts (e.g., crying or laughing), which may be congruent or incongruent with the patient’s mood. These emotional displays are recognized by the patient as being excessive to the underlying mood and can occur spontaneously or may be triggered by minor stimuli. This condition lacks the pervasive alteration of mood, as well as the specific vegetative symptoms associated with a major depressive episode.

PTSD is characterized by symptoms of re-experiencing the trauma ranging from transient flashbacks to severe dissociative states, as well as avoidant behavior, hypervigilance, emotional blunting, and social withdrawal [11]. There is a significant degree of overlap between PTSD and mood disorders. For instance, the majority of Veterans from the recent military operations in Iraq and Afghanistan who developed combat related PTSD had a coexistent mood disorder [18] (see also Chapter 18).

• Apathetic syndromes—A recent study of TBI patients referred to a neuropsychiatric clinic because of behavioral disturbance showed that 71% were apathetic. 85% of these apathetic patients were also depressed [19]. Apathy is frequently associated with psychomotor retardation and emotional blunting.

A diagnosis of mood disorder with manic or mixed features should not be made if the mood disturbance occurs only during the course of agitation or delirium. The latter is characterized by sudden onset, fluctuating level of consciousness, disorientation, and prominent attention deficits. The differential diagnosis of bipolar spectrum related disorders includes the following:

• Substance-induced mood disorder—This may occur as a result of intoxication or withdrawal from drugs. It is usually identified by a careful clinical interview and/or toxicological screening.

• Psychosis associated with epilepsy—This may be observed in patients with epileptic foci located in limbic or paralimbic cortices. Psychotic episodes may be temporally linked to seizures or may have a more prolonged interictal course. In the latter case, the clinical picture is characterized by the presence of partial and/or complex-partial seizures, and of a schizoaffective syndrome. EEG and functional neuroimaging studies (e.g., SPECT and PET) will usually define ictal and interictal disturbances.

• Personality change due to TBI—This may include mood instability, disinhibited behavior, and hypersexuality. These patients lack, however, the pervasive alteration of mood that characterizes secondary manic syndromes.

TREATMENT

Guiding Principles

Patients with brain injury are more sensitive to the side effects of medications, especially psychotropic drugs. Doses of psychotropic drugs must be prudently increased, minimizing side effects (i.e., start low, go slow). However, the patient must receive an adequate therapeutic trial with regard to dosage and duration of treatment. Brain-injured patients must be frequently reassessed to determine changes in treatment schedules. Special care must be taken in monitoring drug interactions. Finally, if there is evidence of a partial response to a specific medication, augmentation therapy may be warranted, depending upon the augmenting drug’s mechanism of action and potential side effects [20].

Treatment of mood disorders occurring after TBI involves different pharmacological and nonpharmacological strategies. Unfortunately, there is a lack of evidence-based scientific foundation to provide a solid basis for neuropsychiatric treatment. Selection among competing antidepressants is usually guided by their side-effect profiles. Mild anticholinergic activity, minimal lowering of seizure threshold, and low sedative effects are the most important factors to be considered in the choice of an antidepressant drug in this population.

Specific Pharmacological Recommendations for Treating Depression

• Tricyclic antidepressants:

Desipramine may be effective for treating depression in patients with severe TBI [21].

Tricyclic antidepressants (TCAs) with significant anticholinergic effects (e.g., amitriptyline) should be avoided.

• Selective serotonin reuptake inhibitors:

Sertraline—A small study in patients with MTBI showed statistically significant improvement in psychological distress, anger, and aggression as well as in the severity of postconcussive symptoms [22]. Sertraline may also lead to a beneficial effect on cognitive functioning via improvement in mood state [23].

Citalopram—A recent study suggested that citalopram may be effective in treating major depression occurring in the setting of TBI [24].

Specific Pharmacological Recommendations for Treating Manic Syndromes

There have been no systematic studies of the treatment of manic syndromes. Lithium, carbamazepine, and valproate therapies have been reported to be efficacious in individual cases [20]. It has been proposed that both lithium and valproate have neuroprotective properties, which would certainly constitute an important therapeutic effect among brain-injured populations [25]. However, data from the only controlled trial of valproate in TBI fail to identify a beneficial effect on cognitive and functional outcomes [26]. The role of other anticonvulsants such as lamotrigine or topiramate as mood stabilizers has not been tested in TBI populations. A recent case report, however, reported adequate control of problematic behaviors with lamotrigine treatment [27]. In addition, there have been recent brief reports that suggest a beneficial effect of quetiapine on aggression and mania following TBI [28,29].

Nonpharmacological Interventions

• There is consensus that psychosocial support, reassurance, counseling, and TBI education for patients and their caregivers should be part of the treatment plan, even if delivered through the telephone or internet [6,11,30]. Cognitive behavioral therapy (CBT) and supportive psychotherapy (SPT) are the most commonly used modalities for tackling anxiety, depression, agitation, and other problematic behavior, and they have a long lasting treatment effect [31].

• Electroconvulsive therapy (ECT) can be used with certain precautions in patients refractory to pharmacological treatment in both depressive and manic patients [6].

• Experimentally, noninvasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have shown promising results but larger controlled trials are needed to establish safety [6,11,30]. These modalities are not currently recommended outside of an experimental setting.

Prevention Strategies

Given the prevalence of depressive disorders during the first year after TBI, depression is an ideal target for selective prevention efforts. Initial data are promising; however, further research in this area is required. A recent randomized clinical trial looked at the efficacy of sertraline as a preventive treatment. A total of 94 subjects with TBI of varying severity and who were initially nondepressed were randomized to receive a daily dose of 100 mg of sertraline or placebo during a 6-month period. Intention to treat analysis demonstrated that, at completion of the protocol, subjects receiving placebo were almost four times more likely to develop depression than subjects treated with sertraline [HR = 3.6, 95% CI = 1.1, 16.2]. The pharmacological intervention was well tolerated and there were no clinically relevant differences in the frequency of adverse events between the groups of subjects receiving sertraline or placebo. However, subjects receiving sertraline were more likely to experience diarrhea or dry mouth than subjects who received placebo. This suggests that selective pharmacological prevention is a viable alternative to reduce the burden of depression among this group of patients [32].

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