Psychopharmacology of traumatic brain injury

Handbook of Clinical Neurology, Vol. 165 (3rd series) Psychopharmacology of Neurologic Disease V.I. Reus and D. Lindqvist, Editors https://doi.org/10.1016/B978-0-444-64012-3.00015-0 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 15

Psychopharmacology of traumatic brain injury GINGER POLICH, MARY ALEXIS IACCARINO, AND ROSS ZAFONTE* Department of Physical Medicine and Rehabilitation, Harvard Medical School, Spaulding Rehabilitation Hospital, Boston, MA, United States

Abstract The pathophysiology of traumatic brain injury (TBI) can be highly variable, involving functional and/or structural damage to multiple neuroanatomical networks and neurotransmitter systems. This wide-ranging potential for physiologic injury is reflected in the diversity of neurobehavioral and neurocognitive symptoms following TBI. Here, we aim to provide a succinct, clinically relevant, up-to-date review on psychopharmacology for the most common sequelae of TBI in the postacute to chronic period. Specifically, treatment for neurobehavioral symptoms (depression, mania, anxiety, agitation/irritability, psychosis, pseudobulbar affect, and apathy) and neurocognitive symptoms (processing speed, attention, memory, executive dysfunction) will be discussed. Treatment recommendations will reflect general clinical practice patterns and the research literature.

INTRODUCTION The pathophysiology of traumatic brain injury (TBI) can be highly variable, involving functional and/or structural damage to multiple brain regions and neurotransmitter systems. Cortical and subcortical regions, their interconnecting axons, and the brainstem can all be affected, as can dopaminergic, noradrenergic, serotonergic, and cholinergic neurotransmitter networks. This wide-ranging potential for physiologic injury is reflected in the diversity of neurobehavioral and neurocognitive symptoms following TBI. Selecting pharmacologic treatments for TBI-related symptoms can be a challenging task for several reasons. For one, recognizing and disentangling target symptoms is rarely a straightforward process. Posttraumatic symptoms can co-occur or overlap—apathy may manifest as part of a depressive episode or as a standalone symptom, the treatment of which may subtly vary. The bidirectionality of various symptoms further complicate matters— attentional impairment may exacerbate anxiety and anxiety may exacerbate inattention. Also, on occasion and

especially in the cases of more severe injury, patients may not be able to reliably relay their subjective experiences due to altered awareness, memory deficits, or difficulties with abstraction. Further challenging the psychopharmacologic management of TBI is the relative scarcity of literature on the topic. To date, no pharmaceuticals have yet received approval by the Federal Drug Administration (FDA) for specifically treating TBI (Diaz-Arrastia et al., 2014). As such, rather than being research-based or highly formalized, clinical practice patterns in TBI often follow guidelines for treating similar symptoms in other disease entities. For example, treatments for post-TBI attentional or memory impairments often mirror treatments for attention deficit disorder or Alzheimer’s disease, respectively. Though a “treatment-by-analogy” approach is often effective, additional caution is nevertheless advised due to safety and tolerability issues within in the TBI population (Wortzel and Arciniegas, 2012; Quinn and Agha, 2018). Various guiding principles regarding use of psychopharmacologic treatment in TBI reflect further safety concerns. One recommendation advises a “start low

*Correspondence to: Ross Zafonte, Department of Physical Medicine and Rehabilitation, Harvard Medical School, Spaulding Rehabilitation Hospital, Massachusetts General Hospital, Brigham and Women’s Hospital, Boston, MA, United States. Tel: +1-617-952-5243, Fax: +1-617-952-5934, E-mail: [email protected]

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and go slow” approach, given that individuals with a history of TBI can be particularly susceptible to adverse effects from psychotropic medications, especially antipsychotics, anticholinergics, and dopamine agonists (Hurley and Taber, 2002; Arciniegas et al., 2005; Wortzel and Arciniegas, 2012). A second emphasizes the value of “staying the course,” meaning trialing pharmaceuticals for adequate durations and adequate doses prior to deeming a medication ineffective (Hurley and Taber, 2002; Arciniegas et al., 2005; Wortzel and Arciniegas, 2012). To date, numerous reviews on psychopharmacology for TBI have been compiled (Warden et al., 2006; Chew and Zafonte, 2009; Bhatnagar et al., 2016; Plantier and Luaut, 2016). Here we aim to provide a succinct, clinically relevant, and as research-informed as possible, update to this material, focusing on the postacute to chronic period.a This chapter will be divided into two main parts, the first part focusing on psychopharmacology for post-TBI neurobehavioral disorders and the second on psychopharmacology for post-TBI neurocognitive disorders. The motoric sequelae of TBI will not be discussed here.b Numerous symptoms will be covered, and in each case, efforts made to first briefly describe the symptom, possible etiology, and prevalence before reviewing pharmacologic treatment and discussing common side effects. At the end of this review, we will briefly summarize the limited research on natural treatments. Finally, it is necessary to acknowledge that both nonpharmacologic (e.g., psychologic, behavioral, or environmental) and pharmacologic interventions are to be considered when treating post-TBI neurobehavioral and neurocognitive deficits. While this review focuses exclusively on pharmacologic interventions, nonpharmacologic or combination therapy may be the preferred as first-line treatment in many instances.c

post-injury year (Alway et al., 2016a). Depression and anxiety are the most frequent diagnoses (Hibbard et al., 1998; Deb et al., 1999a,b; Whelan-Goodinson et al., 2009). Symptoms in many cases can be longlasting (McMahon et al., 2014). Biologic, psychologic, and social factors can all contribute to an increased relative risk of psychiatric disturbances following TBI. Biologically, direct damage to neural tissue can disrupt functioning in networks implicated in psychiatric disease, such as prefrontal regions involved in self-control and emotional regulation or the amygdala and other limbic regions. Psychologic factors also play a significant role. Head injury is often a highly stressful (if not traumatic) event. The physical and cognitive sequelae of TBI—headache, motor impairments, memory deficits, impaired insight, etc.—can also all function as major stressors in and of themselves. TBI can additionally precipitate substantial social stress by disrupting interpersonal and occupational functioning, leading to isolation or loss of employment. Regarding the contribution of these biopsychosocial factors as they relate to the time course of symptoms, some suggest that psychiatric disorders manifesting shortly after injury more often reflect a biologic etiology (i.e., a consequence of direct neuronal damage). In contrast, a delayed onset of symptoms may more frequently reflect one’s psychologic reaction to the injury or to various psychosocial factors (Jorge et al., 1993a). Several symptom clusters correspond with diagnoses outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), but many exceptions also exist. For example, posttraumatic agitation or irritability do not fit neatly with any existing diagnostic criteria. In the following sections, treatments for mood disorders including depression and mania, anxiety, agitation/irritability, psychosis, pseudobulbar affect, and apathy will be discussed.

NEUROBEHAVIORAL DISORDERS FOLLOWING TBI

DEPRESSION

Neurobehavioral symptoms and disorders following TBI occur across all levels of injury. In one study, 31% of individuals admitted for traumatic injury were diagnosed with a psychiatric illness within the first postinjury year; for 22% of this cohort, the psychiatric diagnosis was novel (Bryant et al., 2010). The rate was more than double in a study involving only those with moderate to severe injuries (Alway et al., 2016a). Most neurobehavioral symptoms following TBI arise within the first

In TBI, most depressive symptoms correspond with DSM-5 criteria (depressed mood, anhedonia, changes in weight, impaired sleep, psychomotor agitation or retardation, decreased energy, poor concentration, feelings of worthlessness, or thoughts of death) though a few particularities have been noted. Most notably, irritability, anger, and aggression are observed more frequently after TBI than sadness and tearfulness (Seel et al., 2010).

a

For a review of pharmacotherapy for TBI in the acute setting, see Diaz-Arrastia et al. (2014). For a discussion of motor impairments following TBI, see Ozolins et al. (2016). c For a review on nonpharmacologic approaches to posttraumatic cognitive impairments, see Wortzel and Arciniegas (2012). b

PSYCHOPHARMACOLOGY OF TRAUMATIC BRAIN INJURY Depression is the most common posttraumatic mood disorder, affecting 25%–50% of individuals within the first year after TBI (Jorge and Arciniegas, 2014), with over 60% receiving the diagnosis over the course of their lifetime (Koponen et al., 2002). Despite its frequency, post-TBI depression remains highly undertreated. One survey of depressed TBI patients found that less than half of the cohort were receiving pharmacologic or psychologic treatment (Whelan-Goodinson et al., 2009). Regarding neuroanatomy, functional neuroimaging studies of depressed patients in the general population have documented abnormal activity in the dorsolateral prefrontal cortex, anterior cingulate, and ventrolateral prefrontal cortex (Drevets, 2000). These regions, involved in self-control and emotional regulation, are frequently injured in TBI. The limited research regarding antidepressant use for post-TBI depression is weakly positive. A recent metaanalysis suggested that overall, pharmacotherapy for depression in TBI appears to be effective (Salter et al., 2016). A separate, large meta-analysis evaluated the efficacy of antidepressants for treating depression across a range of neurologic conditions in addition to TBI, including Parkinson’s disease, stroke, epilepsy, and multiple sclerosis among others. Pooled analyses showed pharmacologic treatment to nearly double the rate of remission at 6–8 weeks compared to placebo (Price et al., 2011). Numerous studies have also assessed the efficacy of individual antidepressants for post-TBI depression. Regarding use of selective serotonin reuptake inhibitors (SSRIs), a small RCT (Lee et al., 2005) and a nonrandomized study (Fann et al., 2000), both supported use of sertraline in treating post-TBI depression. Additional open-label studies have suggested the benefit of fluoxetine (Horsfield et al., 2002), citalopram (Rapoport et al., 2008), and the combined use of citalopram and carbamazepine (Perino et al., 2001). Despite these promising studies however, in the two largest double-blind RCTs on the use of the SSRI sertraline for posttraumatic depression, rates of improvement did not significantly differ between experimental and control groups (Ashman et al., 2009; Fann et al., 2017). It is possible that placebo effects were a major confounder in these studies (Polich et al., 2018). More recent studies have begun to examine whether SSRIs, specifically sertraline, could prevent later onset of depression when administered shortly after the time of injury. Two small RCTs addressing this question has thus far been positive (Novack et al., 2009; Jorge et al., 2016). However, another study evaluating prolonged use of citalopram to prevent relapse in those previously effectively treated by the drug failed to show any preventative benefit (Rapoport et al., 2010).

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SSRIs generally take several weeks to reach peak effect but, on average, tend to be well tolerated. Some recommend use of sertraline, citalopram, and escitalopram over other formulations, as these medications have shorter half-lives and fewer anticholinergic effects (Arciniegas et al., 2005). Additional caution is warranted for fluoxetine and paroxetine due to their increased risk of drug–drug interactions via inhibition of cytochrome P450 enzyme and more so for paroxetine because of greater anticholinergic effects (Jorge and Arciniegas, 2014). With SSRIs, theoretical concerns over the platelet-activating effects of serotonin have been raised, though it appears that the relative risk of increased intracranial bleeding, if even present, is small (Ramasubbu, 2004). A few studies have evaluated the effectiveness of tricyclic antidepressants (TCAs) in post-TBI depression. While one small RCT showed benefit of desipramine for depression in severe TBI (Wroblewski et al., 1996), other studies have suggested that TCAs treat post-TBI depression less effectively than depression in the general population (Dinan and Mobayed, 1992) and that TCAs are less effective than SSRIs in treating post-TBI depression (Fann et al., 2009). TCAs are also generally less well tolerated than SSRIs. Their anticholinergic effects, including dry mouth, changes in bowel habits, and sedation can be prohibitive for some. Cardiac effects are also a concern with TCAs, including orthostatic hypotension and arrhythmias for those with a history of cardiovascular disease. The possibility of lowering the seizure threshold has also been raised with use of TCAs (Wroblewski et al., 1990). Other small studies have suggested that there is benefit in treating depression following TBI with milnacipran, a serotonin–norepinephrine reuptake inhibitor (SNRI) (Kanetani et al., 2003) and moclobemide, a monoamine oxidase-A (MAO-A) inhibitor (Newburn et al., 1999). Some suggest methylphenidate may be useful in treating depression in the early recovery course from TBI, given that the medication may yield both cognitive benefits and augmentative antidepressant effects (Gualtieri and Evans, 1988). Accordingly, in one placebo-controlled study, methylphenidate outperformed placebo on measures of post-TBI depression (Lee et al., 2005).

MANIC, HYPOMANIC, AND MIXED DISORDERS Mania is generally characterized by marked changes in mood (e.g., persistently elevated, expansive, or irritable) lasting days–weeks, decreased sleep requirements, increased psychomotor activity, reckless behavior, and distorted, disorganized thought processes. Compared to mania in the general psychiatric population, manic

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episodes in TBI have been noted to be relatively short and more often involve irritable or mixed vs euphoric mood states (Shukla et al., 1987; Jorge et al., 1993b). Posttraumatic mania or hypomania are far less common than depression or anxiety. Nevertheless, estimates range from 1.7% to 9.0% following TBI (Jorge et al., 1993b; Van Reekum et al., 2000; Jorge and Arciniegas, 2014). Whether these rates are greater than those in the general population remains unclear (Jorge and Arciniegas, 2014). Some have cautioned that it may be easy to overdiagnose mania and hypomania after TBI via misattribution of affect dysregulation, impulsivity, impaired sleep, and/or cognitive disturbances (Jorge and Arciniegas, 2014). Studies have suggested an association between posttraumatic mania and lesions of the temporal lobes, orbitofrontal cortices, as well as right-sided limbic regions more broadly (Starkstein et al., 1987; Jorge et al., 1993b). Outside of this direct neuropathophysiology, the psychosocial stress of injury or adjustment to disability may also play a role (Starkstein et al., 1987). Very little literature has evaluated pharmacotherapy for post-TBI mania. A small number of cases have suggested the benefit of lithium (Hale and Donaldson, 1982; Stewart and Hemsath, 1988), though others have cautioned against use of this medication in TBI due to its potential for adverse cognitive symptoms, motor effects such as tremor and ataxia, lethargy, and lowering of the seizure threshold (Jorge and Arciniegas, 2014). A few reports also suggest a possible benefit of valproate and divalproex (Pope et al., 1988; Yassa and Cvejic, 1994; Kim and Humaran, 2002), though these medications are also associated with adverse cognitive and motor effects, albeit to a lesser degree than lithium. Finally quetiapine has shown some efficacy in a small number of post-TBI mania cases (Oster et al., 2007; Daniels and Felde, 2008). Given such sparse data on the topic, practice patterns often mirror those for treating mania in the more general psychiatric population. In TBI, valproic acid or quetiapine may be a reasonable starting place given high rates of efficacy and slightly more favorable side-effect profile (Jorge and Arciniegas, 2014). With use of valproic acid as well as most mood stabilizers, monitoring is required, including regular testing of liver function tests and complete blood counts. Use of antipsychotics, including atypical agents, is typically cautioned in TBI, as these agents have the potential to affect neurorecovery as well as cognition as will be described further in the following sections.

ANXIETY Anxiety can manifest in many forms following TBI, variably resembling diagnoses of generalized anxiety disorder (GAD), panic disorder, phobias, obsessive– compulsive disorder (OCD), or posttraumatic stress

disorder (PTSD) found in the DSM-V (Hiott and Labbate, 2002; Mallya et al., 2015). Some have hypothesized a role for injury to the mesial temporal lobe, including the amygdala, and compromised top-down PFC functioning in the pathophysiology of posttraumatic anxiety (Hoffman and Harrison, 2009). The rate of GAD after TBI is estimated to be 15%– 24%, substantially higher than that found in the general population (Fann et al., 1995; Diaz et al., 2012). The rates of OCD following TBI range between 1% and 5%, similar to rates in the general population (Hiott and Labbate, 2002). At least one study suggests that panic disorder is common after TBI, occurring in roughly 9%, several times higher than rates in the general population (Deb et al., 1999a,b; Hiott and Labbate, 2002). The rates of PTSD has been found to vary widely, ranging from 12%–30% in mild–moderate TBI to 3%–23% in severe TBI (Zatzick et al., 2010; Tanev et al., 2014; Alway et al., 2016a,b). Discussion of PTSD, TBI, their overlapping symptomatology, and psychopharmacologic management is complex and covered more thoroughly in other reviews (Bahraini et al., 2014; Tanev et al., 2014). Following TBI, anxiety is often most marked shortly after injury, due to the stress of the injurious event itself as well as initial adjustment to any deficits. Thereafter, anxiety is often multifactorial, representing biologic, psychologic, and social insults (Fann and Jakupcak, 2013). Interestingly, some evidence suggests an inverse relationship between injury severity and anxiety disorders, with milder injuries associated with greater likelihood of PTSD, social phobia, panic disorder, and agoraphobia (Van Reekum et al., 2000; Hiott and Labbate, 2002; Bryant et al., 2010). Some caution that anxiety disorders in TBI can often be overlooked when symptoms are not obvious or the symptoms are taken as a “normal response” to the injury (Hiott and Labbate, 2002). As was the case for depression, posttraumatic anxiety disorders are also significantly undertreated, with only half of patients receiving appropriate treatment (Whelan-Goodinson et al., 2009). Regarding pharmacotherapy, to date no controlled trials have been performed. In the general psychiatric population, SSRIs or SNRIs are again often used firstline, given their efficacy and tolerability in the treatment of GAD, OCD, panic, phobias, or PTSD. As frequently practiced in general psychiatry, it may be worthwhile trialing a second SSRI or SNRI agent before another medication class. Buspirone, a drug that acts as a partial 5-HT1A receptor agonist, D2 antagonist, and a2 antagonist, is another viable treatment option, though data here too is lacking. Also notable with buspirone is that some of the common side effects—light-headedness and dizziness—can be problematic for the TBI population.

PSYCHOPHARMACOLOGY OF TRAUMATIC BRAIN INJURY Benzodiazepines, while highly effective in the short term, are generally to be avoided, if possible, among those with TBI. Benzodiazepines are sedating, associated with attentional and memory impairments with both short- and long-term use (Barker et al., 2004a,b), and can cause behavioral disinhibition. Animal models raise additional concern that benzodiazepines may lead to a delayed or truncated recovery (Schallert et al., 1986). These agents furthermore have addictive potential, which may be especially problematic for individuals with TBI, given their high premorbid and postinjury rates of substance use disorders. If benzodiazepines are nevertheless indicated, for example, when used as a bridge until SSRIs or SNRIs become therapeutic, some recommend use of shorteracting agents such as lorazepam, which carry a reduced likelihood of cognitive and sedative side effects. Longacting agents such as clonazepam may be preferable in other cases due to their lower likelihood of addiction or abuse.

AGITATION AND IRRITABILITY Behaviorally, agitation can manifest in a variety of ways, including motor restlessness, heightened emotional reactivity, irritability, aggression, or inappropriate behavior. While most common in the initial postinjury weeks (Brooke et al., 1992), agitation can last for years in up to 25% of cases (Baguley et al., 2006). Irritability has also been examined as a standalone symptom following TBI. Estimates of post-TBI irritability range from 33% to 66%, with higher rates among those with more severe injuries (McKinlay et al., 1981; Deb et al., 1999a,b). Injury to the frontal and temporal lobes, amygdala, and hippocampus have all been implicated in post-TBI agitation and irritability, as have neurochemical imbalances, including an excess of dopamine and deficiency of serotonin (Lombard and Zafonte, 2005). Treatment generally starts with a careful evaluation of environmental factors, followed by efforts at behavioral modification and/or psychotherapy. Pharmacotherapy tends to be used adjunctively. A range of medications have been examined in the treatment of posttraumatic agitation and irritability. The greatest evidence supports use of b-blockers as first-line treatment (Fleminger et al., 2006). These medications are generally well tolerated and do not cause significant sedation, though due to their hypotensive effects, dose escalation may be limited in some cases. A handful of clinical trials, including a small number of controlled trials, support the use of nonselective b blockers in the treatment of post-TBI agitation (Greendyke and Kanter, 1986; Greendyke et al., 1986; Brooke et al., 1992). More recently, a large RCT aimed to evaluate

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whether the combined use of propranolol along with clonidine, an a2 agonist, could acutely decrease sympathetic hyperactivity after severe TBI (Patel et al., 2012), but due to unremarkable findings at the interim analysis, this study was terminated early. Of further relevance regarding use of clonidine in TBI is the small number of preclinical and clinical studies suggesting that by reducing catecholaminergic outflow, this medication may adversely affect motor recovery (Goldstein and Davis, 1990; Goldstein, 1995; Feeney et al., 2004). Antiepileptic agents and mood stabilizers can also be used to treat post-TBI agitation, though the evidence on the use of these agents is limited. Benefit was observed in a case series of valproic acid (Wroblewski et al., 1997), a case series of divalproex (ChathamShowalter and Kimmel, 2000), a case series of carbamazepine (Chatham-Showalter, 1996), and a single case study of lamotrigine (Pachet et al., 2003). Benefit in the use of lithium was also suggested in a small number of cases (Glenn et al., 1989; Bellus et al., 1996). As mentioned earlier, use of many of these agents requires monitoring of blood counts, liver function tests, and, additionally in the case of lithium, serum drug levels. A handful of small studies have evaluated the utility of various antidepressants, with some evidence to suggest possible benefit in the use of sertraline (Kant et al., 1998b) and amitriptyline (Mysiw et al., 1988). Amantadine has also been evaluated as a treatment for posttraumatic irritability. Amantadine is an uncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor, which also indirectly enhances dopaminergic neurotransmission. An initial RCT found amantadine to be an effective treatment for irritability (Hammond et al., 2014). However, in a subsequent, multisite study by the same research group, the medication was found to be no better than placebo on observer ratings; though a small benefit was observed among patient ratings, the difference did not persist after correction for multiple comparisons (Hammond et al., 2015). In a further subgroup analysis involving individuals from this same cohort, use of amantadine was associated with improvements in chronic aggression (Hammond et al., 2017). Precautions with amantadine include theoretical concerns over lowering the seizure threshold and use among those with impaired renal function. Furthermore, as a dopaminergic agent, anxiety, confusion, and even irritability can be a concern, especially at high doses. A handful of studies have evaluated use of typical and atypical antipsychotics in the treatment of post-TBI agitation. A retrospective case study suggested efficacy of methotrimeprazine in the treatment of post-TBI aggression (Maryniak et al., 2001). Another small study showed benefit of intramuscular droperidol and haloperidol (Stanislav and Childs, 2000). A single case report

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demonstrated efficacy of loxapine (Krieger et al., 2003). Regarding the atypical antipsychotics, a pilot study demonstrated the benefit of quetiapine (Kim and Bijlani, 2006), a small case series suggested the benefit of clozapine (Michals et al., 1993) and ziprasidone (No
e et al., 2007), and a single case study suggested the benefit of aripiprazole (Umene-Nakano et al., 2013). Yet antipsychotic use in TBI requires careful consideration. Some antipsychotics, including chlorpromazine and clozapine, are associated with a lowering of the seizure threshold (Hedges et al., 2003). The extrapyramidal symptoms (tremor, dyskinesia, akathisia, dystonia, parkinsonism) associated with antipsychotics also give reason for caution when the drugs are used in the TBI population. This is especially true with typical antipsychotics, which have a greater affinity for D2 receptors, compared to atypical agents, which tend to more broadly affect the D2, D3, D4, as well as 5-HT2 receptors. Antipsychotic use can also compromise cognitive function. Demonstratively in one TBI study, tapering or discontinuing antipsychotics resulted in improved cognition (Stanislav, 1997). A final, important issue regarding antipsychotic use in TBI centers around these agents’ potential for limiting neuro recovery. Numerous studies involving animal models of brain injury (Feeney et al., 1982; Kline et al., 2008; Phelps et al., 2015) suggest that antipsychotics disrupt the process of neuroplasticity (Hoffman et al., 2008). Typical agents may be more deleterious in this regard than atypical agents (Wilson et al., 2003). In humans, two clinical trials have associated antipsychotic use with a prolongation of posttraumatic amnesia; however in these studies, rehabilitation outcomes (i.e., Functional Independence Measurement Scores) were notably not impacted (Rao et al., 1985; Mysiw et al., 2006). Despite the many reasons to avoid these agents, antipsychotics may still be indicated in select cases. Use of atypical vs typical antipsychotics is generally recommended here. For one, atypical agents have reduced dopamine blocking properties, which may be desirable for those with dopaminergic circuits already compromised by TBI. Atypical antipsychotics also offer a relatively more favorable risk profile with regard to extrapyramidal symptoms and possibly, neurorecovery (Arciniegas et al., 2003).

PSYCHOSIS Psychosis can also occur following TBI. Most frequently, posttraumatic psychosis results from a delirium early on after injury or as a feature of a mood disorder, such as depression or mania with psychotic features. Less often, a more persistent psychosis may develop in the later postinjury period. Associations have been made

between frontal and temporal injury and psychotic symptoms in such cases (Fujii and Ahmed, 2002). This more pervasive form of psychosis typically presents as a delusional disorder (e.g., jealously delusion, somatic delusion, and delusional misidentification syndrome) or as a schizophrenia-like illness. In contrast to schizophrenia in the general population, in the schizophrenia-like illness presenting after TBI, auditory hallucinations and paranoid delusions are more common than visual hallucinations or negative symptoms (Fujii and Ahmed, 2014; Stefan and Mathe, 2016). Recent studies estimate the prevalence of post-TBI psychosis at 1%–9% (Fujii and Ahmed, 2014). These rates likely do not appreciably surpass those observed in the general population (Ponsford et al., 2018). Given the overlapping peak age of onset in psychotic illness and peak age of exposure to TBI (late teens–early adulthood), some argue for considering TBI a risk factor for psychosis, increasing the likelihood of illness in those already genetically predisposed (Kim, 2008; Molloy et al., 2011; Stefan and Mathe, 2016). Use of antipsychotics for psychosis is first-line therapy in general psychiatry, but very little data on the use of antipsychotics for posttraumatic psychosis exist. Case studies suggested benefit from the use of olanzapine (Butler, 2000; Viana et al., 2010). Antipsychotic use for psychosis after TBI may also, as mentioned earlier, warrant caution, given the potential for delayed neurorecovery, adverse cognitive effects, sedation, and the potential for lowering the seizure threshold. As such, if psychosis is accompanied by mood or behavioral symptoms, the use of mood stabilizers is alternatively recommended. If not, the benefit of antipsychotic treatment may, nevertheless, outweigh the risks.

PSEUDOBULBAR AFFECT Pseudobular affect (PBA) goes by many other names— pathologic laughing and crying, emotional incontinence, emotional lability. It refers to a condition whereby patients display brief, involuntary episodes of laughing or crying, which may be emotionally congruent or incongruent and are typically provoked by seemingly trivial events (McAllister, 2013). This contrasts with the persistent alteration in baseline emotion occurring because of a mood disorder or cases of individuals who simply have a lifelong lower threshold for expressing emotion (Green et al., 1987; Work et al., 2011; Engelman et al., 2014). In the pathophysiology of PBA, recent studies have implicated disruptions to the cortico-limbic–subcortico-thalamic–ponto-cerebellar network (Rabins and Arciniegas, 2007), regions frequently affected by TBI. One study reported a prevalence of greater than 10% following the first post-TBI year (Tateno et al., 2004).

PSYCHOPHARMACOLOGY OF TRAUMATIC BRAIN INJURY Elsewhere much higher rates have been reported, but these appear to be in large part driven by the choice of assessment tool (Work et al., 2011; Engelman et al., 2014). Treatment for PBA is typically pharmacologic, and literature here is once again sparse. SSRIs are generally used first-line (Wortzel et al., 2008) with a small handful of case studies suggesting benefit of citalopram, fluoxetine, sertraline, and paroxetine (Nahas et al., 1998; M€ uller et al., 1999; Kaschka et al., 2001). From the perspective of minimizing side effects and drug–drug interactions, sertraline, citalopram, and escitalopram once again may be more favorable SSRI choices (Jorge and Arciniegas, 2014). Beyond SSRIs, one case study also suggested benefit in the use of lamotrigine in patients with TBI (Chahine and Chemali, 2006). In other neurologic conditions, PBA has been treated with TCAs, noradrenergic reuptake inhibitors, and dopaminergic agents, though no data for these agents exist for treatment of PBA in TBI (Wortzel et al., 2008). More recently, dextromethorphan/quinidine (DM/Q) has been evaluated as a potential treatment for PBA in TBI (Garcia-Baran et al., 2016). DM is an uncompetitive NMDA receptor antagonist, s1 receptor agonist, and SNRI; Q blocks DM hepatic metabolism to increase DM bioavailability (Pioro, 2014). Treatment of posttraumatic PBA with DM/Q was further supported by a recent open-label multisite trial (Hammond et al., 2016). The overall incidence of PBA and the benefits of pharmacologic treatment remain ill defined. Further treatment and cost effectiveness studies are needed.

APATHY Apathy has been defined as a reduction in goal-directed behavior, which can exist along a continuum from diminished motivation and apathy at the milder end to abulia and akinetic mutism in more severe cases (Marin, 1991; Levy, 2012). Multiple neurologic circuits are implicated in the pathophysiology of apathy, including frontal–subcortical networks, cholinergic connections to the anterior cingulate cortex, and mesolimbic dopaminergic reward pathways (Levy, 2012). Apathy following TBI is common. While it can occur in isolation, apathy more often presents in conjunction with depression (Seel et al., 2011). One study reported a 10% prevalence of pure apathy in a cohort of TBI patients, with an additional 60% exhibiting apathy in conjunction with depression (Kant et al., 1998a). If apathy exists independent of depression, it is often more difficult to treat. To date, very little literature on the treatment of apathy after TBI exists. Generally, behavioral and environmental

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interventions are applied first-line. Regarding pharmacotherapy, small studies suggest possible efficacy of dopaminergic drugs such as methylphenidate (Gualtieri and Evans, 1988), amantadine, or bromocriptine (Van Reekum et al., 1995; Powell et al., 1996), or serotonergic drugs such as fluvoxamine and fluoxetine (HoehnSaric et al., 1990). Outside of TBI, pharmacotherapy approaches are similar and have included catecholaminergic agents (methylphenidate, amantadine, bromocriptine, and bupropion), cholinergic agents (donepezil, galantamine, and rivastigmine), as well as atypical antipsychotics such as olanzapine (Roth et al., 2007).

NEUROCOGNITIVE DISORDERS Neurocognitive deficits following TBI are common. Direct neurobiologic injury is the primary cause of posttraumatic neurocognitive disorders in most instances. The classic neuroanatomic pattern of TBI involves damage to the anterior and orbital prefrontal cortex, anterior and inferior temporal lobes, along with diffuse axonal injury. Reflecting damage to these key anatomic regions, the most common posttraumatic cognitive deficits include impairments in attention, processing speed, episodic memory, and executive function (Wortzel and Arciniegas, 2012). In cases of mild TBI, cognitive deficits typically resolve completely in a matter of weeks (Carroll et al., 2004), though in a significant minority, symptoms can last much longer (Arciniegas et al., 2005). With moderate to severe injury, recovery is far more variable. While a few may experience full symptom resolution, many others are left with significant symptoms persisting for months to years or even indefinitely (Millis et al., 2001). Posttraumatic neurocognitive deficits can also be influenced by additional factors, including medical comorbidities, physical problems such as untreated pain, and psychologic factors. When evaluating cognitive function after TBI, a careful review of current medical prescriptions is also warranted as many medications (e.g., benzodiazepines, opioids, antipsychotics, anticonvulsants, or anticholinergics) can adversely affect cognition. Accordingly, before pursuing pharmacotherapy for posttraumatic cognitive deficits, it may be more appropriate to first evaluate and appropriately treat comorbid conditions and minimize potentially problematic medications. It may be useful to think of domains of cognition in terms of their hierarchical organization. For example, attentional processes underlie higher order functions such as memory and executive function—attention is necessary for memory encoding, and in many cases both

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attention and memory are necessary for tasks requiring executive function. As such, providing pharmacologic support to enhance attentional processes may ultimately improve memory or executive function. As was the case with posttraumatic neurobehavioral disorders, first-line treatment for neurocognitive disorders after TBI is often nonpharmacologic, and may include psychoeducation, appropriate expectation setting, environmental modifications, and cognitive rehabilitation (Wortzel and Arciniegas, 2012). When appropriate, pharmacology for posttraumatic cognitive deficits most often involves augmentation of catecholaminergic or cholinergic function. In the following section, use of such agents for treating posttraumatic deficits in attention, processing speed, memory, and executive function will be reviewed.

PROCESSING SPEED AND ATTENTION Attention is often separated into various domains— simple attention, selective attention, alternating attention, divided attention, executive attention, and sustained attention—which can all be impacted by TBI (McDowell et al., 1997; Schmitter-Edgecombe and Nissley, 2000; Catroppa and Anderson, 2005; Ziino and Ponsford, 2006; Dymowski et al., 2015). Networks of attention are distributed diffusively throughout the brain. They most notably involve frontoparietal cortices and subcortical regions, and are subserved by noradrenergic, dopaminergic, and cholinergic projections. Attention problems are very common after TBI. In moderate–severe TBI, 60% report chronic, long-lasting problems with inattention (Ponsford et al., 2014a,b). One study documented attentional deficits in 40%– 60% of individuals in the first few months following mild TBI (McAllister, 1994), though the rates of chronic inattention in mild TBI are much lower, as symptoms completely resolve in the majority of cases. Interestingly, when looking across various studies on post-TBI attentional deficits, it appears that delays in processing speed may be in large part driving attentional deficits (Whyte et al., 1997, 2004; Kim et al., 2006, 2012; Mathias and Wheaton, 2007; Willmott and Ponsford, 2009), though this may be less the case for executive attention (Dymowski et al., 2015). As such, improvements in processing speed might positively impact attentional functioning. Stimulants remain the most widely studied medication class used to treat posttraumatic attentional impairments. A handful of studies (Kaelin et al., 1996; Plenger et al., 1996; Whyte et al., 1997; Kim et al., 2006), including three RCTs (Whyte et al., 2004; Willmott and Ponsford, 2009; McAllister et al., 2016) have demonstrated efficacy of methylphenidate on various attentional tasks. In an

industry-sponsored study, attentional capacities were also shown to improve following use of lisdexamfetamine (Tramontana et al., 2014). In two smaller studies, however, neither methylphenidate (Speech et al., 1993) nor its extended-release formulation (Dymowski et al., 2016) were found to be beneficial. Use of stimulants after TBI require caution, especially in those with a history of cardiovascular disease, as these agents can increase heart rate and blood pressure. Stimulants can also depress appetite and are known to exacerbate anxiety and irritability, and cause insomnia if administered too late in the day. Regarding alternative agents for augmenting attentional capacities after TBI, a single study of atomoxetine was negative (Ripley et al., 2014). Dopaminergic agents have also been studied. A small case series suggested benefit in the use of amantadine (Kraus and Maki, 1997), as did one small RCT (Meythaler et al., 2002), though a second small RCT was negative (Schneider et al., 1999). A subsequent small RCT evaluating the effectiveness of bromocriptine on attention was also negative (Whyte et al., 2008). Acetylcholinesterase inhibitors have also been evaluated. In a cohort study of chronic TBI patients (Khateb et al., 2005) and a small RCT (Zhang et al., 2004), some evidence of benefit in using donepezil was demonstrated. A controlled study of physostigmine (Levin et al., 1986) and an RCT involving rivastigmine also suggested modest benefit (Tenovuo et al., 2009).

MEMORY Memory impairment is one of the most common and disabling deficits following TBI (Capruso and Levin, 1992). Various domains of memory, including working memory (holding information temporarily online) and declarative memory (memory of facts and events), are both frequently affected in TBI. The hippocampus, prefrontal cortex, and their connecting pathways are the main regions involved in these memory functions. Procedural memory (learning of motor sequences) is less often impacted by TBI. Cognitive rehabilitative interventions such as the teaching of internal and external memory strategies are typically considered first-line treatment. Pharmacologically, some data on the use of stimulants and cholinesterase inhibitors exist. The evidence on methylphenidate is mixed, with some studies suggesting benefit (Gualtieri and Evans, 1988; Kim et al., 2006) and others reporting a lack of effectiveness (Speech et al., 1993; Plenger et al., 1996). If efficacious at all, stimulants may be more likely to improve working memory or declarative memory through augmentation of attention and processing speed.

PSYCHOPHARMACOLOGY OF TRAUMATIC BRAIN INJURY Studies on cholinesterase inhibitors are also available. A handful of case studies (Taverni et al., 1998; Masanic et al., 2001; Khateb et al., 2005; Trovato et al., 2006; Samuel and Ng, 2013), as well as a small trial (Morey et al., 2003), and an RCT (Zhang et al., 2004) have suggested a possible benefit in the use of donepezil. A systematic review of the use of donepezil for cognitive symptoms following TBI “suggests” the “possibility” of its efficacy (Ballesteros et al., 2008). Use of physostigmine for post-TBI memory impairments was found to be effective in one placebo-controlled study (Cardenas et al., 1994), though the combination of physostigmine with lecithin in another study did not show any benefit (Levin et al., 1986). A multicenter RCT on rivastigmine was no better than placebo in treating post-TBI memory impairments (Silver et al., 2006), though in a post hoc analysis involving individuals with the most severe injuries, benefits of rivastigmine over placebo were reported. In a subsequent extension of this study whereby individuals in both the active medication and placebo group were administered rivastigmine for several additional weeks (Silver et al., 2009), 40% showed improvement in memory (Silver et al., 2009). In another small RCT, galantamine was found to be superior to placebo in a delayed memory task (McAllister et al., 2016). Acetylcholinesterase inhibitors are generally well tolerated, with few concerning side effects or drug–drug interactions. Headaches and gastrointestinal symptoms such as nausea, vomiting, and diarrhea are the most common. Citicoline has also been evaluated in the treatment of posttraumatic memory deficits. Citicoline is active in the biosynthesis of neuronal membrane phospholipids and understood to enhance cerebral metabolism as well as dopaminergic, adrenergic, and cholinergic activity. In a small study of mild–moderate TBI, citicoline was found to have a modest benefit for memory function (Levin, 1991). However, in a recent large double-blind RCT, citicoline failed to show any improvement in memory, nor in any other cognitive domain (Zafonte et al., 2012). Finally, while commonly used for treating memory impairments in Alzheimer’s, no studies have yet evaluated whether memantine, an NMDA receptor antagonist, may be of benefit for post-TBI memory impairments.

EXECUTIVE DYSFUNCTION Executive function refers to the capacity to organize, plan, execute, conceptualize, and exhibit mental flexibility. Neuroanatomically, executive dysfunction is typically attributed to injury of the frontal–subcortical regions (McDonald et al., 2002). Disruptions in executive function may have a more adverse impact on

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everyday life functioning compared with other cognitive processes such as attention, processing speed, or memory (Spitz et al., 2012). First-line strategies usually involve various forms of cognitive rehabilitation, such as metacognitive strategy instruction (Ponsford et al., 2014a,b). Once again, the role for pharmacotherapy is limited. A small study combining memory and attention compensation training with the use of methylphenidate demonstrated improvements in domains of executive functioning (McDonald et al., 2016). A study of lisdexamfetamine showed some improvement in executive function measures (Tramontana et al., 2014). One small, placebo-controlled study suggested that low-dose bromocriptine may be helpful in improving performance in a few domains of executive function (McDowell et al., 1998). As mentioned previously, it may be more likely that these interventions support or improve underlying attentional capacity rather than directly treat deficits in executive function.

NATURAL THERAPIES Lastly, in recent years, a small number of natural treatments with neuroprotective properties have been explored for their potential benefit in treating the neurocognitive or neurobehavioral sequelae of TBI. Here we briefly review four natural treatments, vitamin D, zinc, N-acetyl cysteine, and enzogenol, for which preliminary human studies in the postacute or chronic period are available (Scrimgeour and Condlin, 2014; Drake et al., 2017; Quinn and Agha, 2018). Vitamin D has been receiving more attention of late with animal studies suggesting a role for vitamin D as an antiinflammatory and neuroprotective agent (Lawrence and Sharma, 2016). A recent retrospective clinical study showed a high prevalence of vitamin D deficiency after TBI, with 46% meeting criteria for deficiency and 80% for insufficiency/deficiency. In this study, vitamin D deficiency, furthermore, correlated with cognitive impairment and more severe symptoms of depression (Jamall et al., 2016). Zinc, an essential trace element with multiple regulatory functions in the neurologic system, has also been evaluated for its potential neuroprotective effect following TBI (Drake et al., 2017). To date, multiple human studies associating low levels of zinc with depressive symptoms, and zinc supplementation with prevention and improvement of symptoms have been published (Scrimgeour and Condlin, 2014). Given that individuals with a history of TBI often exhibit decreased levels of zinc (McClain et al., 1986), supplementation in those with comorbid depression may deserve further

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evaluation. Of note, caution must be practiced with zinc supplementation, as excess levels of zinc can be neurotoxic. Additional antioxidants with preliminary support for use in TBI include enzogenol, a flavonoid extracted from Pinus radiata bark. In a small pilot study involving individuals with mild TBI, enzogenol use was associated with reduced self-reported cognitive failures (Theadom et al., 2013). N-Acetyl cysteine, another antioxidant, has been evaluated in a cohort of active duty service members with blast exposure. In this placebo-controlled study, treatment with N-acetyl cysteine was associated with decreased overall symptom burden, including performance on various neuropsychologic tests (Hoffer et al., 2013). Further research on such natural interventions is needed.

CONCLUSION Neurobehavioral and neurocognitive impairments following TBI are common and often persistent. In most cases, nonpharmacologic approaches are considered first-line and pharmacologic treatments adjunctive. In this chapter, we have reviewed the literature on psychopharmacology for the most common sequelae of TBI in the postacute to chronic period. For some impairments, especially depression, agitation/irritability, and inattention, a fair amount of literature exists. For others, literature is limited to small case series and uncontrolled studies, and practice guidelines are often modeled after clinical practice patterns devised for treating similar symptoms in different disease entities. In adapting psychopharmacologic treatments for use in the TBI, it is important to practice caution and consider the specific physiologic and psychologic vulnerabilities of this population.

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