Introduction

Neuropsychiatric consequences of moderate to severe traumatic brain injury (TBI) include various emotional and neurobehavioural problems such as mood swings, impulsivity, apathy, irritability, agitation, aggression, depression, anxiety and psychosis. Using Schedule for Clinical Assessment in Neuropsychiatry (SCAN) interviews, Deb et al. found that at 1 year from a TBI, there were more people with an ICD10 diagnosis of a psychiatric condition as than in the general population.¹ However, rates for psychiatric symptoms that did not fulfil diagnostic criteria for a specific psychiatric condition as per formal diagnostic criteria were much higher. This finding is consistent with the clinical experience with post-TBI cases where neuropsychiatric presentation are often more varied, atypical and may not meet the diagnostic threshold for common psychiatric conditions.

In a 30-year follow-up study, using DSM-IV criteria, a 48.3% prevalence of Axis I disorders and 23.3% for Axis II personality disorders were reported that started after TBI.² The most common psychiatric diagnoses following TBI included major depression (26.7%), alcohol abuse or dependence (11.7%), panic disorder (8.3%), specific phobia (8.3%) and psychotic disorders (6.7%). People with TBI were nearly twice more likely to have psychiatric problems than general population.

A prospective 5-year study reported a 75.2% prevalence of Axis I disorders according to DSM-IV criteria, the large majority of these conditions (77.7%) starting during the first year after the TBI.³ Anxiety, mood and substance-use disorders were the most common diagnostic classes, often presenting co-morbidly. The strongest predictors of post-TBI psychiatric disorders were pre-injury disorder and accident-related limb injury.

Figure 9.1 schematically represents a range of common neuropsychiatric problems seen after moderate to severe TBI. These conditions will be discussed in greater detail in the subsequent sections.

Figure 9.1 Neuropsychiatric problems following traumatic brain injury.

Mood Disorders

Mood disorders are a common consequence of TBI and include depression and other persistent milder mood disorders such as dysthymia. Depression, in particular, is associated with subjective distress, poor outcomes, increased dysfunction and has the potential to affect quality of life significantly.

Fann et al reported depression in up to 60% of patients with TBI in the first year after TBI but prevalence rates range from 17% to 60% depending on screening tools, study populations, study design and diagnostic criteria/threshold used which determines the variability in the prevalence rates.⁴ People who had a pre TBI depression or ongoing depression at the time of TBI are more likely to have more significant and persistent depression post-TBI.⁵

Depression following TBI can be caused by a number of factors including biological, psychological and social factors which often overlap.⁶ Psychological factors comprise reaction to psychological trauma, loss of function, loss of role, diminished tolerance to frustration, low self-esteem and maladaptive coping strategies. Social factors encompass lack of adequate social support, difficulties with relationships, unrealistic expectations and involvement in litigation. Biological factors include brain lesions in the frontal and temporal lobes disrupting neural networks between the prefrontal cortex, amygdala, hippocampus, basal ganglia and thalamus, neurochemical and neuroendocrinal abnormalities, such as serotonergic deficits and hypothalamic–pituitary–adrenal axis function are frequently associated with depression after TBI.⁷ These biological, psychological and social factors commonly co-exist and interact with each other and good clinical assessment should take into account all of these factors.

Major depressive disorder after TBI is often associated with poorer cognitive functioning, aggression and anxiety, greater functional disability, poorer recovery and greater health care costs.⁵ Depression is also an independent predictor of poorer health-related quality of life after TBI. People who sustained a TBI with structural brain lesions have a four times increased risk of suicide as compared to the general population.⁸ A retrospective study on veterans showed that suicide risk is associated with depression, partner relationship problems and family circumstance problems, but not with TBI severity, alcohol dependence or post-traumatic stress disorder (PTSD). However, odds for suicide seem to increase with the number of psychiatric comorbidities with three psychiatric comorbidities being associated with 6.5 times increased risk of suicide, highlighting the importance of identifying and treating psychiatric conditions associated with TBI.⁹

In terms of differential diagnosis, it is important to bear in mind that a number of symptoms of depression could overlap with core features of TBI including tiredness, poor concentration, sleep and appetite changes. This makes the assessment of depression more difficult. Depression should ideally be routinely screened either though use of standardised depression screening instruments followed by full neuropsychiatric assessment. Attempts should be made to rule out conditions that could lead on to symptoms similar to depressive symptoms after TBI. These include conditions such as hypopituitarism and apathy-amotivation.

Affective dysregulation due to frontal lobe damage may also be confused with depression. There may be sudden outbursts of crying or laughter, without any obvious reason that even surprise the patient. This is often called pathological laughter/crying or called pseudobulbar affect. This is different from the emotional lability associated with frontal lobe dysfunction, where there are constant changes in emotions. These cases can be misdiagnosed as depression if the crying spells are frequent, but this should be avoided for diagnostic clarity and prognosis, even though the pharmacological treatment is similar to depression. These cases benefit from use of SSRI medication with evidence being best for citalopram. Psychological approaches such as cognitive behavioural therapy (CBT) are not helpful for this condition.

In terms of treatment, antidepressants are considered to be effective in treating depression in neurological settings.¹⁰ Clinicians should have a low threshold for diagnosing and treating depression post-TBI given the costs for not doing so in terms of outcomes and quality of life. A systematic review looking at treatment for depression after TBI showed that SSRIs and cognitive behavioural interventions appear to have the best preliminary evidence for treating depression following TBI.⁴ Sertraline and citalopram seem to be well tolerated. Clinically, as a routine these are recommended as a first line treatment for post-TBI depression. Tricyclic antidepressants do not have good evidence for efficacy and have a higher risk of side effects and are generally avoided. Monoamine oxidase inhibitors (MAOIs) are not recommended due to a lack of efficacy data and potentially serious side effects, specifically with difficulties in adhering to dietary restrictions due to cognitive difficulties. Psychological treatments such as CBT have comparable efficacy to antidepressants and are first line approach for milder symptoms or combined with pharmacological treatment for moderate to severe depression. Other psychological treatments often used include goal setting, behavioural activation and problem solving therapy in multidisciplinary neurorehabilitation settings.¹¹

Anxiety Disorders

A wide spectrum of anxiety disorders can develop following a TBI, including acute stress reaction, generalised anxiety disorder (GAD), specific phobic anxiety, social phobia, panic disorders, obsessive compulsive disorder (OCD) or post-traumatic stress disorder (PTSD). Some of these anxiety disorders such as acute stress reaction are transient and settle with time. Others such as phobic anxiety can be persistent and distressing and may affect an individual’s functioning quite significantly. While travel-related anxiety is fairly common after road traffic accidents, other specific phobias could relate to stairs after a fall and going out to public places in cases of assaults. These can be highly disabling with a huge impact on functioning and in some cases on finances.

A large prospective cohort study on post-TBI anxiety showed a high proportion of participants suffered from significant levels of anxiety during the first year post-TBI regardless of TBI severity and gender. At 4, 8 and 12 months, respectively, 29.9%, 29.2% and 30.8% of participants presented clinically significant anxiety symptoms.¹² Participants with a positive premorbid history of anxiety disorders had greater anxiety on the Hospital Anxiety and Depression Scale (HADS) compared to those with a negative premorbid anxiety history. Prevalence rates for various anxiety disorder following TBI is reported based on kind of anxiety disorder including panic disorder 8.3%, specific phobia of 8.3% and generalised anxiety disorder of 1.7%.²

Patients with TBI can also experience other physical and psychological symptoms of trauma including fear of death or fear of subsequent treatment.¹³ These traumatic experiences may result in or contribute to the development of PTSD. The diagnosis of PTSD may be difficult following TBI because of overlap with symptoms of TBI particularly with post-concussion syndrome. In addition, various behavioural symptoms following the TBI such as increased alcohol consumption, depression, impulsivity or irritability may also alter PTSD presentation making it harder to diagnose. However, PTSD rates after a TBI are approximately five times higher than those reported in the general population.^{14, 15} Rates of PTSD are higher in mild TBI than severe TBI. Disruption to memory and cognitive function in severe TBI are considered to be a protective factor. However, there have been reports that PTSD can occur after TBI even when there is a significant disturbance of consciousness or disrupted memory for the trauma.¹⁴

PTSD presents with symptoms of intrusive memories such as flashbacks and nightmares, avoidance of reminders of the trauma and hyperarousal. PTSD is commonly associated with co-morbid psychiatric conditions. Most common of these are depression, substance misuse and other anxiety disorders. People suffering from co-morbid PTSD and TBI complain of more severe neurocognitive symptoms and disability. Sleep disturbance is common in PTSD after TBI and may hinder recovery if not treated. PTSD commonly affects behaviour and may exacerbate TBI-associated irritability, agitation and aggression. The relationship between PTSD, TBI and epilepsy is discussed in Chapter 11.

Diagnosis of anxiety disorders following a TBI requires careful consideration of the overlap between anxiety disorders, depression and other neurobehavioral disorders due to TBI. Treatment of anxiety is best managed as part of neurorehabilitation care at a multidisciplinary level with a combination of anxiety management techniques, CBT and pharmacological treatments with SSRI.

Apathy

Apathy or amotivation is not uncommon following TBI and can be misdiagnosed as depression. Apathy has been described using a variety of terms including amotivation and abulia but it is not simply a lack of motivation as it is associated with reduced goal-directed behaviour, impaired initiative, diminished activity and lack of concern. Furthermore, a distinction should be made between apathy as a symptom of mood disorder, altered level of consciousness or cognitive impairment and apathy as a syndrome of acquired changes in mood, behaviour and cognition, not due to mood disorder, altered level of consciousness or cognitive impairment.¹⁶ Symptoms of apathy are commonly divided into three dimensions: behavioural, cognitive and emotional. Assessment consists of a good history and account of symptoms from carers and wider multidisciplinary team, measures such as the Apathy Evaluation Scale can help with diagnosis.¹⁷

Apathy is associated with poor outcomes due to lack of engagement in neurorehabilitation and may impact on family, social and occupational functioning of patients and can cause increased caregiver distress.

Treatment of mild cases can be based on cognitive interventions while more severe cases require a combination of pharmacological and non-pharmacological approaches. Cognitive interventions are the most commonly used strategy but other interventions such as music therapy and cognitive rehabilitation have also been used.¹⁸ Behavioural approaches such as activity scheduling are also used. Pharmacological treatments include dopaminergic drugs such as selegiline, stimulants such as methylphenidate and modafinil, cholinesterase inhibitors such as donepezil and SSRIs.

Psychosis

While some consider post-TBI psychosis controversial, accumulating evidence is pointing towards a higher prevalence (up to 7 times) of psychosis following TBI as compared to general population. Rates of psychosis in TBI are estimated to be up to 10% but ranging between 1.35% and 9.2%.¹⁹ Risk factors include male gender, alcohol and substance use, including cannabis and pre-existing psychiatric conditions like depression. Frontal, temporal or hippocampal lesions, as well as memory dysfunction and impairment of executive functions, seem also to be associated. The development of post-traumatic epilepsy (PTE) or subclinical epileptiform discharges can also be a contributory factor.

Psychosis following TBI most commonly presents as a delusional disorder or a schizophrenia-like psychosis. Delusional disorders may present with specific syndromes such as Capgras’ syndrome, reduplicative paramnesia, delusional jealousy, Cotard’s syndrome or somatic delusions (11%). Schizophrenia-like psychosis commonly presents with auditory hallucinations, persecutory delusions and negative symptoms. The onset of a psychosis after TBI could be delayed by years with a mean latency ranging between 3 and 5 years while delusional disorders tend to develop in the first year after TBI.²⁰

Clinical assessment should focus on establishing the phenomenology of psychotic symptoms and rule out other causes including substance induced psychosis, epilepsy-related psychosis and a primary psychotic disorder. Initial post-TBI presentation with agitation and behavioural problems associated with post-traumatic amnesia can be confused with psychosis. Diagnosis of psychosis should be avoided when the patient is still in post-traumatic amnesia. Treatment of psychosis after TBI is not different from the treatment of any other psychotic disorder but special consideration should be given to interactions with other medication, sensitivity to side effects and impact on neurocognitive functions.

Acute Behavioural Changes and Post-Traumatic Amnesia

Post-traumatic amnesia (PTA) can last from minutes to months depending on the severity of TBI and is commonly associated with agitation, disruptive behaviour, impulsivity and aggression. In the initial aftermath of TBI, there is commonly a transient state of inability to encode new memories, difficulty sustaining attention associated with confusion and disorientation along with lack of insight and awareness.²¹ This state is called PTA. Duration of PTA is commonly used as a reliable measure of severity of TBI along with other indices such as Glasgow Coma Scale (GCS) score and duration of loss of consciousness. It is now widely recognised that PTA is an important predictor of functional outcome after a TBI.

In addition to cognitive and behavioural difficulties including agitation, PTA is commonly associated with disordered language and cognitive communication impairments. Confusion may also manifest in communication impairments such as confabulation, perseveration and disorganised discourse²² as well as autonomic changes associated in form of tachycardia, transient pyrexia and clamminess.²¹ PTA can be associated with focal lesions and decreased cerebral perfusion in the frontal and temporal lobes.²³

However, agitation can be due to a number of other causes including epilepsy, particularly non-convulsive status, depression, frontal lobe and paralimbic pathology as well as withdrawal states. There is no clear association with gender or age. Post-TBI agitation can be associated with higher chances of subsequent neuropsychiatric problems. Worse outcome for agitation are associated with a longer duration of agitation, severity of agitation behaviour and structural abnormalities on brain scan.²⁴

Assessment of PTA include scales such as the Westmead PTA Scale²⁵ but a detailed assessment of agitated patient after TBI will not only involve assessment of PTA but will require a detailed neuropsychiatric assessment to establish past and family history of psychiatric problems including any personality issues, alcohol and substance misuse and doing a detailed mental state examination. This helps establish the cause of agitation and clarify if there are any other co-morbid psychiatric conditions present.

Management of agitated behaviour during the PTA requires careful management of environment with minimisation of excessive stimulation, reorientation and avoidance of restraints while maintain safety. A wide range of pharmacological agents has been used in agitation following TBI but evidence for any pharmacological agent or even drug class is poor. Currently no medication is approved for treatment of agitation after TBI. Nevertheless, various medications, including beta blockers, atypical antipsychotics (e.g. risperidone) and antiepileptic agents (e.g. carbamazepine and valproate), are widely used in the management of patients with acute agitation or aggression. However, a Cochrane review showed that only high doses of beta blockers seem to be effective in controlling agitation following TBI but the two controls trials included in this review involved a small number of patients and this finding has not been replicated.²⁶ This review did not find enough evidence for efficacy of other agents such as valproate or carbamazepine. Use of beta blockers needs to be carefully monitored due to its effect on blood pressure and chances of inducing falls due to postural hypotension. A recent French guideline noted that there are no standards or consensus regarding the use of neuroleptics. Greater sensitivity to their adverse effects post-TBI was noted.²⁷

The antiepileptic agents carbamazepine (CBZ) and valproate (VPA) are commonly used as mood stabilisers to treat agitation after TBI. The North American neurobehavioral guideline working group noted that carbamazepine seems to be effective for some patients experiencing aggression after TBI, though the published literature did not support a recommendation for use of carbamazepine at that time.²⁸ They concluded that there is insufficient evidence to support the development of any standards for the treatment of aggression following TBI. More recently, a French guideline noted that carbamazepine and valproate were effective for treatment of agitation and aggression and are recommended as first line treatment.²⁷ Other antiepileptic agents such as oxcarbazepine, lamotrigine and gabapentin do not have any evidence to support their use. Levetiracetam has no positive effect on aggressiveness post-TBI and can make agitation and aggressiveness worse along with the risks of behavioural and mood disorders, hence should be avoided.

Benzodiazepines can sometimes be used in acute emergency for sedation, but generally their regular use should be avoided as they can have negative effects on neurocognition and can make aggression paradoxically worse. Other pharmacological agents which have been tried for agitation and aggression following TBI include amantadine, buspirone, modafinil and methylphenidate. Out of these agents methylphenidate seems to be most promising though further evidence is required before routine clinical use can be recommended.