Pharmacotherapy of Posttraumatic Cognitive Impairments

Pharmacotherapy of Posttraumatic Cognitive Impairments David B. Arciniegas, M.D. Medical Director, Brain Injury Rehabilitation Unit HealthONE Spalding Rehabilitation Hospital and Director, Neurobehavioral Disorders Program Associate Professor of Psychiatry and Neurology University of Colorado Health Sciences Center

[email protected]

Goals and Objectives • Review the neuroanatomy and neurochemistry of TBI relevant to posttraumatic cognitive impairments • Identify potential iatrogenic contributions to delayed cognitive recovery following TBI • Review the literature and offer suggestions regarding the pharmacotherapy of posttraumatic cognitive impairment

Methodology • Review was predicated on searches of the medical literature in PubMed and OVID Medline using the following strategy: – Diagnosis: “traumatic brain injury,” “brain injury,” “brain injuries,” “closed head injury,” “head injury(ies),” “craniocerebral trauma,” and “concussion” – Pathophysiology: The review of the neurobiology of posttraumatic cognitive impairments included information derived from both human and animal studies, and was anchored to terms relevant to the neuropathological, neuroanatomic, neurochemical, and cognitive consequences of TBI – Pharmacotherapies: limited to studies undertaken among adults with traumatic brain injuries only, and was anchored to the classes of and also individual pharmacologic agents discussed here

Methodology • Findings from this review published in: – Arciniegas DB, Silver JM: Pharmacotherapy of posttraumatic cognitive impairments. Behavioural Neurology 17(1):25-42, 2006

• Results of this review subsequently compared with: – Warden et al.: Neurobehavioral Guidelines Working Group Members: Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury. Journal of Neurotrauma 23(10): 1468-1501, 2006

• Integrated with clinical experience at our site and through multiple discussions with two senior neuropsychiatrists with expertise in the management of posttraumatic cognitive impairments in order to generate the suggestions offered here

A Heuristic for the Study, Evaluation, and Treatment of Posttraumatic Neurobehavioral Disturbances Pre-Injury Factors

Cognitive Disturbance

Emotional Disturbance

Traumatic Brain Injury

Post-Injury Psychosocial Factors

Behavioral Disturbance

Physical Disturbance (Silver and Arciniegas 2006)

Impaired Attention Memory Disturbance Language Impairment Executive Dysfunction Intellectual Loss Irritability Rage Depression Anxiety Agitation Aggression Disinhibition Apathy Sleep Disturbance Headaches Pain Visual Problems Dizziness/Vertigo Seizures

Pre-Injury Factors • Age, education, and gender • Baseline intellectual function • Psychiatric problems & substance abuse • Sociopathy • “Risk-taking” and “novelty-seeking” behavior • Premorbid behavioral problems • Social circumstances and SES • Neurogenetic (ie, APOE-4, COMT, ?other)

Injury Factors • Biomechanical Injury – – – –

acceleration/deceleration translational/rotational cavitation (“microexplosive”) diffuse axonal injury (DAI)

• Cytotoxic Injury – – – – –

cytoskeletal & axonal injury disturbance of cell metabolism Ca++ and Mg++ dysregulation free radical release neurotransmitter excitotoxicity

• Secondary Injury – – – –

traumatic hematomas cerebral edema hydrocephalus increased intracranial pressure (ICP) – systemic complications • • • •

hypoxia/hypercapnia anemia electrolyte disturbance infection

(Reviewed in: Meythaler et al. 2001; Nuwer 2005; Povlishock and Katz 2005; Bigler 2007)

Injury Factors: Translation, Rotation, & Angular Acceleration Forces

Rotational force vector

Translational force vector Center of mass Figure adapted from Arciniegas and Beresford 2001









Cerebral Neurotransmitter Systems – Glutamate • principal excitatory neurotransmitter in the CNS • facilitates information processing

– GABA • principal inhibitory neurotransmitter in the CNS • reduces information processing

– Dopamine and Norepinephrine • modulatory neurotransmitters • improve the signal-to-noise ratio in neurotransmission and information processing, particularly in limbic and frontal-subcortical systems

Cerebral Neurotransmitter Systems – Serotonin • modulatory neurotransmitter • participates in pacemaking the system as a whole • modulates neurotransmission and information processing in multiple systems, and especially in limbic and frontal-subcortical systems

– Acetylcholine • modulatory neurotransmitter • optimizes neurotransmission performed by other neurotransmitters through development of excitatory post-synaptic potentials (via most muscarinic and nicotinic receptors) at their target sites, especially in hippocampus and frontal-subcortical circuits • lesser role for inhibitory neuromodulation through development of inhibitory post-synaptic potentials at some muscarinic receptors

Reticulothalamocortical Circuits Cortex

Thalamocortical (glutamate)

GABA

Thalamus Reticular Sensory relay Excitatory Inhibitory

Reticulothalamic (cholinergic) Reticulocortical (DA, NE, 5-HT, ACh) (Adapted from Mesulam 2000)

Injury Factors: Neurotransmitter Excitotoxicity • Biomechanical forces strain axons – within the brainstem and ventral forebrain – along septohippocampal pathway (retroforniceal projections) – projecting through anterior and midline cerebral areas to cortical targets

• Mechanical deformation of axons results in stretch-induced action potentials and the release of potentially neurotoxic excesses of cerebral neurotransmitters (Arciniegas and Silver 2006; Julian and Goldman 1962)

(Adapted from Gilman and Newman 1987)

Injury Factors: Neurochemistry • Neurotransmitter “storm” at time of TBI – acute increases in glutamate (1-5), dopamine (6,7), norepinephrine (6,7), serotonin (6-9), and acetylcholine (10) are reported from CSF samples in the acute post-injury period among persons with severe TBI – these acute neurotransmitter excesses are functionally disruptive – among those who survive their injuries, glutamate, dopamine, norepinephrine, and serotonin levels appear to normalize in the days to weeks following TBI (6; 11-13) (1. Wagner et al. 2005; 2. Kerr et al. 2003; 3. Yamamoto et al. 1999; 4. Alessandri et al. 1999; 5. Koura et al. 1998; 6. Markianos et al. 1996; 7. Markianos et al. 1992; 8. Porta et al. 1975; 10. Grossman et al. 1975; 11. Obrenovitch and Urenjak 1997; 12. Matsushita et al. 2000; 13. Goodman et al. 1996; )

Injury Factors: Neurochemistry • Persistent damage in and dysfunction of areas with dense glutamate and acetylcholine inputs • Chronic primary cortical cholinergic dysfunction – damage to cerebral cholinergic nuclei (1-3) – loss of cholinergic afferents (3,4) – dysfunction of cholinergically-dependent information processing circuits (5-8)

• Possible chronic primary or secondary dysfunction in serotonin-, dopamine-, norepinephrine-dependent neuropsychiatric functions (9) (1. Dewar and Graham 1996; 2. Murdoch et al. 2002; 3. Salmond et al. 2005; 4. Murdoch et al. 1998; 5. Arciniegas et al. 1999; 6. Arciniegas et al. 2000; 7. Arciniegas et al. 2001; 8. Arciniegas et al. 2004. 9. In: Arciniegas and Silver 2006)

Brain-Behavior Relationships and Regional Vulnerability to TBI Dorsolateral prefrontal cortex (executive function, including sustained and complex attention, memory retrieval, abstraction, judgement, insight, problem solving)

Orbitofrontal cortex (emotional and social responding)

Anterior temporal cortex (memory retrieval, sensory-limbic integration)

Amygdala (emotional learning and conditioning, including fear/anxiety)

Ventral brainstem (arousal, ascending activation of diencephalic, subcortical, and cortical structures)

Hippocampal-Entorhinal Complex (declarative memory) Viewed on coronal MRI

(Figure adapted from Arciniegas and Beresford 2001)









Anatomy of Injury and Posttraumatic Cognitive Impairments • Focal cortical contusions and SAH – results in a relatively severe loss of neurobehavioral function served by the injured area

• Focal white matter lesions – interferes with information processing between cortical areas ordinarily connected by the injured white matter fibers – may damage neurotransmitter projections needed to sustain normal cognition

• Diffuse (multifocal) axonal injury – results in slowed and inefficient information processing – damages neurotransmitter projections needed to sustain normal cognition

Post-injury Factors • Untoward medical complications • Failure to receive timely medical, neurological, psychiatric, or other needed rehabilitative services • Lack of education regarding the course of recovery and interpretation of symptoms

Post-injury Factors • Lack of family, friends, or resources to support recovery • Premature return to work/school with ensuing failure to perform at expected levels • Poor adjustment to or coping with disability by injured person or family • Litigation or other legal entanglements

Neuropsychiatric Sequelae of TBI Pre-Injury Factors

Cognitive Disturbance

Emotional Disturbance

Traumatic Brain Injury

Post-Injury Psychosocial Factors

Behavioral Disturbance

Physical Disturbance

(Silver and Arciniegas 2006)

Impaired Attention Memory Disturbance Language Impairment Executive Dysfunction Intellectual Loss Irritability Rage Depression Anxiety Agitation Aggression Disinhibition Apathy Sleep Disturbance Headaches Pain Visual Problems Dizziness/Vertigo Seizures

Posttraumatic Cognitive Impairments • In the acute and late periods following TBI, the domains of cognition most commonly affected by TBI include: – arousal – attention (sustained, divided) – processing speed/reaction time – working memory – memory (new learning [encoding] and/or retrieval) – functional communication – executive function (Reviewed in: Bigler 2007; Arciniegas and Silver 2006; Nuwer 2005; Meythaler et al. 2001)

Pre-Treatment Assessment • First and foremost, other causes of and/or contributors to impaired cognition should be addressed – pre-injury neurological or psychiatric disorders – delirium (due to any cause) – depression – mania – affective lability – apathy – anxiety – psychosis – substance use disorders

– sleep disturbance – pain – headaches – fatigue – dizziness – seizures – environmental over-stimulation – symptom elaboration – medications

Pre-Treatment Assessment • Reevaluate current treatment • Is the diagnosis correct? • Are treatments properly applied?

• Key issues • What are the indications for agents prescribed? • If the target symptom has improved, are the current treatments still necessary? • Is cognitive impairment a potential side effect of current medications?

Pre-Treatment Assessment • Eliminate (or at least attempt to reduce doses of) non-essential medications and/or agents that may impair cognition – neuroleptics/typical antipsychotics – benzodiazepines – strongly anticholinergic medications • including some tricyclic antidepressants and paroxetine

– phenytoin and carbamazepine – α2 agonists (e.g., clonidine) – high-dose opiates – alcohol and other substances of abuse

Dopamine and Norepinephrine Antagonism • In animal models, dopamine and norepinephrine antagonists delay neuronal recovery and neural plasticity1,2 • Among humans, typical antipsychotics exacerbate cognitive impairments among persons with TBI2,3 • Haloperidol increases duration of posttraumatic amnesia following severe TBI4 1. Goldstein 1999; 2. Goldstein 2003; 3. Stanislav 1997; 4. Rao et al. 1985

Benzodiazepines • In animal models, administration of benzodiazepines suppresses induction of LTP (neural mechanism for new learning) and increases motor and sensory impairments1,2,3 • Among humans, benzodiazepines worsen motor and memory function among healthy individuals4 and persons with TBI5 1. Riches and Brown 1986; 2. Brailowsky et al. 1986; 3. Schallert 1986; 4. Buffett-Jerrot and Stewart 2002; 5. Bleigberg et al. 1993

Anticholinergic Agents • In animal models of TBI, administration of scopolamine impairs memory function, even in animals with apparently recovered function1,2,3 • Among humans with TBI, anticholinergic agents (including antidepressants with potent anticholinergic properties) impair memory and other cholinergicallydependent neurobehavioral functions4 1. Dixon et al. 1994; 2. Dixon et al. 1995; 3. Saija et al. 1988; 4. Reviewed in Arciniegas and Silver 2006

Anticonvulsants • Double-blind, placebo-controlled trials of phenytoin1,2,3,carbamazepine2, and valproate3, among persons with TBI demonstrate: – impaired cognition – impaired motor function – no benefit on the prevention of late seizures (i.e., seizures occurring after the first week post-injury)1-5 – if an anticonvulsant must be used, valproate appears to preferable to phenytoin or carbamazepine with respect to its effects on cognition 1. Smith et al. 1994; 2. Dikmen 1991; 3. Dikmen et al. 2000; 4. Schierhout and Roberts 2001; 4. Marion et al. 2006

Pre-Treatment Assessment • Objective evaluation of cognition before and during treatment is essential – assessments emphasizing attention, processing speed/reaction time, new learning and cued recall, and executive function should be included – in the late period after TBI, formal neuropsychological testing remains the gold standard for pre-treatment assessment, and should be obtained whenever possible

Pre-Treatment Assessment • Neuroimaging evaluation may be very helpful and is strongly recommended – severe focal cortical and white matter damage bodes poorly for response to treatments attempting to remediate cognitive deficits served by the damaged area(s) – diffuse axonal injury is a better prognostic finding with respect to the potential benefits of treatment – although "normal" conventional neuroimaging studies do not indicate that the brain is in fact uninjured, they do suggest that underlying injury may be of a sufficiently mild severity to bode well for treatment response

Nonpharmacological Treatment • Environmental management – reduce overstimulation – facilitate adaptive engagement with the environment – support existing strengths and psychosocial resources

• Educational interventions for person with TBI and their families • Symptom-targeted physical therapy, occupational therapy, speech therapy, and neuropsychological treatments (cognitive rehabilitation)1,2 (1. Cicerone et al. 2000; 2. Cicerone et al. 2005)

Principles of TBI Pharmacotherapy • Clearly define target symptoms • Therapeutic trial of all medications – since spontaneous recovery from TBI may continue during symptomatic treatment, taper medications at some point after remission of symptoms

• Start low, go slow – titration to standard therapeutic doses may be needed nonetheless

• Monitor for side effects and drug-drug interactions

Principles of TBI Pharmacotherapy • Ease of use is important – dosing frequency – simplicity of dose titration – where possible, use agents with benefits on multiple target symptoms

• Augment partial treatment responses using agents with complementary pharmacologic properties

Selecting agents for Cognition • At present, no medication has received FDA approval for the treatment of impaired cognition following TBI – accordingly, all such treatments are "off-label"

• At present, there are no widely available clinical tests to facilitate identification of specific neurotransmitter deficits following TBI • Treatments have, for the most part, been based on those commonly prescribed for persons with similar symptoms due to other neurological problems – a more appropriate approach is to derive treatments from the known neurobiology & neurochemistry of TBI and cognition

Catecholaminergic Augmentation

Dopamine, Norepinephrine, and Cognition • The effects of dopamine and norepinephrine on cognition are complex – It appears likely that both systems facilitate cognitive processes by increasing the signal-to-noise ratio with respect to processing sensory and/or cognitively relevant information • when present in adequate amounts, information processing may be directed towards cognitively or behaviorally relevant targets • when present in excess, receptor densitization may occur, thereby increasing the relative amount of cognitive “noise” within information-processing circuits • when present in relatively deficient amounts, the signal-to-noise ratio is low making cognitive processing relatively difficult

Catecholamine Augmentation • Increasing cerebral catecholaminergic activity would be expected to improve many domains of cognitive function • In practice, the effects of catecholaminergically active agents appear to be most robust in the domains of – arousal – speed of processing – sustained attention/vigilance – possibly executive aspects of attention

Dopamine Augmentation: Bromocriptine • At low doses, bromocriptine acts as a pre-synaptic D2 agonist, and thereby reduces dopaminergic release and function in dopaminergically mediated systems • Its net effect at mid-range doses appears to augment the function of cerebral dopaminergic systems • At higher doses, bromocriptine appears to act directly on postsynaptic dopamine type 2 (D2) receptors

Bromocriptine • Passler et al. (2001) – bromocriptine treatment-related improvements in arousal (i.e. transition from persistent vegetative state to minimally conscious state) among 5 subjects with TBI

• Eames (1989) and Powell et al. (1996) – bromocriptine may be useful in treating “cognitive initiation” problems (i.e. apathy) in the late postinjury period

Bromocriptine • McDowell et al. (1998) – counterbalanced, double-blind, placebo-controlled, crossover design in 24 subjects with TBI – observed improved performance on executive function during treatment with bromocriptine but no improvement on other posttraumatic cognitive impairments

Bromocriptine • These studies suggest a possible benefit on posttraumatic impairments of arousal and frontallymediated neurobehavioral functions (e.g. motivation, executive function) • Warden et al. (2006): Bromocriptine in a dose of 2.5 mg is recommendation for use in enhancing aspects of executive functioning (e.g., divided attention/ central executive functions) in patients with severe TBI

Dopamine Augmentation: Carbidopa/L-dopa • L-dopa (levodopa) is a dopamine precursor • Usually co-administered with carbidopa, which serves to decrease the extent of its metabolism in the periphery • This combination is marketed as Sinemet

Carbidopa/L-dopa • Lal et al. (1988) – 12 persons with brain injury (including several patients with hypoxic-ischemic brain injuries) treated with carbidopa/L-dopa 10/100 to 25/250 four times daily – observed improvements in alertness and concentration, decreased fatigue, hypomania, and sialorrhea, as well as improved memory, mobility, posture, and speech

Carbidopa/L-dopa • Treatment-related side effects are common – at low doses (i.e., Sinemet 10/100), nausea is a particular problem – at high doses, psychosis may develop

• Additional and larger studies evaluating the efficacy and safety of this agent should be conducted before recommending its routine use in this population

Catecholamine Augmentation: Mixed Dopaminergic and Noradrenergic Agents • Methylphenidate, dextroamphetamine, mixed amphetamine salts: – increase the release of both dopamine and norepinephrine – at higher doses, block the reuptake of dopamine and norepinephrine – modestly inhibit monoamine oxidase – collectively, these agents increase the effectiveness of dopaminergic and noradrenergic neurotransmission

Methylphenidate • Whyte et al. (1997, 2004): – two double-blind, placebo controlled studies of persons with TBI treated during acute rehabilitation – improvements in arousal and speed of information processing during treatment with methylphenidate (0.3 mg/kg BID) – no other significant effects were observed on other aspects of attention (ie, distractibility or vigilance), memory or motor performance

Methylphenidate • Other studies: – limited evidence for improved arousal – relatively consistent observations of improvements in processing speed – mixed findings on attentional functions – largely negative findings with regard to memory improvements (Worzniak et al. 1997; Evans et al. 1987; Gualtieri and Evans 1988; Speech et al. 1993; Plenger et al. 1996; Kaelin et al. 1996; Tiberti et al. 1998)

Methylphenidate • Warden et al. (2006) – The evidence is strongest for an effect on speed of cognitive processing and sustained attention/vigilance • methylphenidate (0.25–0.30 mg/kg bid) is also recommended to enhance the speed of cognitive processing, although only one study provides evidence to support a change in speed in a naturalistic task • methylphenidate (0.25–0.30 mg/kg bid) is recommended to enhance attentional function • methylphenidate in a dose of 0.30 mg/kg bid may be considered as an option to enhance learning and memory

Methylphenidate • Mood (especially depressive symptoms) may also respond to methylphenidate • cognitive improvements occurring in the context of improved mood may be attributable to this latter improvement alone

• It is not clear whether or for how long cognitive or other treatment-related benefits are sustained by methylphenidate

Methylphenidate • Concerns regarding facilitation of seizures with methylphenidate are often voiced by clinicians unfamiliar with this literature • However, methylphenidate does not appear to significantly increase seizure frequency among persons with TBI, including those with active seizure disorders (Wroblewski et al. 1992)

Dextroamphetamine • Dextroamphetamine (Dexedrine) may used for the same posttraumatic target symptoms as methylphenidate (i.e., arousal, speed of processing, possibly attention) - given its similarity to methylphenidate, it may also have beneficial effects on cognition, depression, anergia, and impaired motivation following TBI

• There is at present very little evidence to support its use in this population (Evans et al. 1987; Hornstein et al. 1996)

Indirect Catecholamine Augmentation: Amantadine and Memantine • Amantadine and memantine are moderate-affinity uncompetitive NMDA receptor antagonists • These agents are of theoretical interest – prevention of traumatically-induced glutamate excitotoxicity – remediation of posttraumatic cognitive impairments

• However, the therapeutic relevance of their effects on glutamatergic signaling is uncertain

Amantadine and Memantine • Amantadine and memantine also: – indirectly increase dopamine release – decrease presynaptic dopamine reuptake – stimulate dopamine receptors – enhance postsynaptic dopamine receptor sensitivity

• The therapeutic effects of these agents among persons with TBI are in all likelihood best attributed to their indirect dopaminergic facilitation properties

Amantadine and Memantine • There are, at present, no published studies describing the use of memantine for the treatment of posttraumatic cognitive impairments • Several studies describe benefits afforded by amantadine on posttraumatic cognitive impairments and frontally-mediated behavioral disturbances (Gualtieri T et al. 1989; Kraus MF and Maki PM 1997; Van Reekum R et al. 1995; Nickels JL et al. 1994)

Amantadine • With regard to cognitive performance, amantadine may: – improve arousal – improve speed of information processing – enhance vigilance – reduce perseverative mistakes

• Amantadine may also have benefits on agitation, aggression, and affective lability, and may improve motivation (Gualtieri T et al. 1989; Kraus 1997a; Kraus 1997b; Van Reekum R et al. 1995; Nickels JL et al. 1994)

Amantadine • Meythaler et al. (2002) – Double-blind, placebo-controlled, crossover design study of amantadine 200 mg daily among 35 subjects with severe TBI treated during the subacute post-injury period – Observed treatment-related improvements in MMSE, DRS, GOS, and in cognitive-FIM scores

• Schneider et al. (1999) – Double-blind, placebo-controlled crossover design study of amantadine 100-300 mg daily in 10 subjects with moderate to severe TBI – no effect on attention/concentration

Amantadine • Warden et al. (2006) – amantadine is an option for the treatment of impairments in ‘general cognitive functioning’ and attention/concentration among persons with moderate to severe TBI

Amantadine • Amantadine potentiates the effects of agents with anticholinergic properties • Amantadine may lower seizure threshold – however, studies of amantadine in persons with refractory epilepsy offer only modest support for this suggestion

• Adverse reactions to amantadine appear to occur more often in elderly patients than in younger patients

Indirect Catecholamine Augmentation: Modafinil • The exact mechanisms of action of modafinil are not understood fully, but may include: – activation of hypocretin (orexin) neurons in the lateral hypothalamus – indirect dose-dependent reductions in gammaaminobutyric acid (GABA) release in the cerebral cortex, medial preoptic area, and posterior hypothalamus – dose-dependent increases in glutamate release in the ventrolateral and the ventromedial thalamus – and/or increases in dopamine in the nucleus accumbens

Modafinil • Elovic (2000) – suggests (anecdotally) that modafinil may be beneficial for posttraumatic impairments in arousal

• Teitelman (2001) – observed improvements in arousal and attention in an open-label study of 10 persons with TBI treated with this agent in an outpatient setting

Modafinil • Modafinil may have a role in the treatment of posttraumatic cognitive impairments • However, further studies of this agent for this purpose are needed before offering any recommendations regarding its use among persons with TBI

Other Stimulant-Like Agents: Protriptyline • Protriptyline, a secondary amine tricyclic antidepressant, may be an exception to the aforementioned caution regarding use of this class of medication among persons with TBI • This agent has been suggested to have sufficient stimulant properties to permit its use for anergia and diminished motivation in TBI patients • However, this agent does not appear to confer any benefit on cognition beyond that afforded by improved arousal and motivation alone • This agent is probably best considered as an alternative treatment option only when other standard psychostimulants have not proven effective Wroblewski 1993

Other Stimulant-Like Agents: Lamotrigine • Lamotrigine is an anticonvulsant agent that may have activating effects – the mechanism by which lamotrigine confers such benefits is unclear

• Showalter and Kimmel (2000) – improvements in arousal among 9 of 13 persons with severe TBI (Rancho Los Amigos Scale I-III) treated during the postacute recovery period – hypothesized that lamotrigine’s ability to block sodium channels and inhibit glutamate release may either prevent excitotoxic injury and/or facilitate recovery from injury

Other Stimulant-Like Agents: Lamotrigine • Pachet et al. (2003) – observed improvements in arousal in a single-case study of lamotrigine used in the late post-injury period following severe TBI • Additional studies are needed to determine whether there is a role for lamotrigine in the treatment of posttraumatic cognitive impairments

Cholinergic Augmentation

Acetylcholine and Cognition Anatomy

Function

• reticular formation

• arousal and attention

• entorhinal-hippocampal formation

• sensory gating • attention • declarative memory

• frontal-subcortical circuits

• executive function • comportment, or social intelligence • motivation

(Mesulam 2000a, 200b; Selden et al. 1998; Blokland 1995; Aigner 1995; Sarter and Bruno 1997; Sarter and Turchi 2002)

Cholinergic Augmentation: Acetylcholinesterase Inhibitors • This class of medications includes: – physostigmine – tacrine – donepezil – rivastigmine – galantamine

• All of these agents principally exert their clinical effects via inhibition of synaptic acetylcholinesterase

Acetylcholinesterase Inhibitors • These agents differ in their: – selectivity for central (i.e., cerebral) vs. peripheral (i.e., neuromuscular, gastrointestinal, cardiac) cholinesterases – additional mechanisms of action of uncertain clinical significance • butyrylcholinesterase inhibition • allosteric modulation (protection from desensitization) of α7 and α4β2 nicotinic receptors

Physostigmine • Physostigmine (Antilirium) is an IV or oral agent that inhibits the enzyme that metabolizes acetylcholine in the CNS and elsewhere – allosterically modulates the α7 and α4β2 nicotinic receptors (clinical relevance uncertain)

• Physostigmine improves sustained attention and memory in the acute and late post-injury periods • Evidence: single case (1) w/double-blind (1), openlabel case series (1), single-site double-blind placebo-controlled (2) (Bogdanovitch et al. 1975; Eames and Sutton 1995; Goldberg et al. 1982; Levin et al. 1986; Cardenas et al. 1994)

Physostigmine • Warden et al. (2006): – Physostigmine may be considered for use in enhancing aspects of attentional function in patients with moderate-to-severe TBI in the subacute to chronic phase of recovery

Donepezil • Donepezil HCl is an oral agent that is a relatively selective inhibitor of central AChE • Donepezil HCl improves attention, memory, and executive function in the subacute and late postinjury periods • Evidence: single-case report (1), open-label case series (8), single-site double-blind placebocontrolled (2), two-site double-blind placebocontrolled (1) (Taverni et al. 1998; Whelan et al. 2000; Masanic et al. 2001; Bourgeois et al. 2002; Morey et al. 2003; Kaye et al. 2003; Walker et al. 2004; Zhang et al. 2004; Khateb et al. 2005; Tenovuo 2005; Trovato et al. 2006; Foster and Spiegel 2008)

Donepezil • Zhang et al. (2004): – 24-week, randomized, placebo-controlled, crossoverdesign study – administered donepezil 5 mg per day x 2 weeks followed by donepezil 10 mg per day for eight weeks, followed by washout and 10 weeks of placebo, or vice versa with respect to placebo followed by donepezil – treatment with donepezil was associated with significant improvements in attention (PASAT) as well as memory (Auditory Immediate Index and Visual Immediate Index)

Donepezil • Warden et al. (2006): – Donepezil (5–10 mg/day) is recommended to enhance aspects of attention for patients with moderate to severe TBI in subacute and chronic periods of recovery – Donepezil (5–10 mg/day) is recommended to enhance aspects of memory function for patients with moderate to severe TBI in subacute and chronic periods of recovery (Taverni et al. 1998; Whelan et al. 2000; Masanic et al. 2001; Bourgeois et al. 2002; Morey et al. 2003; Kaye et al. 2003; Walker et al. 2004; Zhang et al. 2004; Khateb et al. 2005; Tenovuo 2005; Trovato et al. 2006; Foster and Spiegel 2008)

Rivastigmine • Rivastigmine is an oral or transdermal agent that is a relatively selective inhibitor of central AChE – also inhibits BuChE (clinical relevance uncertain)

• Rivastigmine improves posttraumatic memory impairments in the late post-injury period • Evidence: open-label case series (1), multicenter double-blind placebo-controlled RCT (1) (Tenovuo 2006; Silver et al. 2006)

Rivastigmine • Silver et al. (2006) – randomized, double-blind, placebo-controlled trial of rivastigmine for persistent posttraumatic cognitive impairment (attention, memory, or both) • 157 subjects, all > 12 months post-TBI, in 19 centers • age 18-50 years • impaired for age and education on either CANTAB RVIP A´ or HVLT (total Trials 1-3)

– treated with rivastigmine 3-6 mg or placebo x 12 weeks • improvement defined as 1 SD or greater gain on above measures

– in the overall study group, there was no effect of treatment – in the memory impaired subgroup (n=81), rivastigmine improved memory and speed of processing significantly better than placebo

Galantamine • Galantamine is an oral agent that is a relatively selective inhibitor of central AChE – like physostigmine, galantamine allosterically modulates α7 and α4β2 nicotinic receptors

• Galantamine affords subjective improvements in posttraumatic cognitive impairments in the late postinjury period • Evidence: open-label case series (1) (Tenovuo 2005)

Other Agents

Cytidine 5'-Diphosphocholine (CDP-Choline) • Cytidine 5'-diphosphocholine (CDP-choline or citicoline), is an essential intermediate in the biosynthetic pathway of phospholipids incorporated into cell membranes • CDP-choline appears to activate the biosynthesis of structural phospholipids in neuronal membranes, increase cerebral metabolism, and enhance activity of dopamine, norepinephrine, and acetylcholine • As such, it has been suggested that CDP-choline may improve neuropsychological performance among cognitively impaired TBI survivors

Cytidine 5'-Diphosphocholine (CDP-Choline) • Calatayud et al. (1991) – single-blind randomized study conducted in 216 patients with severe or moderate TBI – demonstrated improved global cognitive, motor, and psychiatric outcome of patients – CDP-choline group also had a decreased length of stay in the hospital

Cytidine 5'-Diphosphocholine (CDP-Choline) • Levin (1991) – double blind placebo-controlled study of 14 patients to evaluate the efficacy of CDP-choline for treating postconcussional symptoms in the first month after mild to moderate TBI – CDP-choline reduced the severity of postconcussional symptoms and improved recognition memory for designs

Cytidine 5'-Diphosphocholine (CDP-Choline) • Warden et al. (2006): – CDP choline (1 gram total daily dose) may be considered for use in enhancing aspects of memory function in patients with mild to moderate TBI in the subacute phase of recovery

Cytidine 5'-Diphosphocholine (CDP-Choline) • A metanalysis of studies using CDP-choline in elderly patients suggests that it is associated with fewer adverse effects than placebo • There are no reports of serious adverse events in the TBI population • At present, the limited scope of the relevant literature and the lack of rigorous FDA scrutiny of the safety, tolerability, and efficacy of suggest the need for caution when using CDP-choline in any clinical population (Fioravanti M and Yanagi M 2001)

Summary • TBI is a common problem • The majority of TBI are mild • The majority of persons with mild and moderate TBI will recover fully without specific treatment • Among those persons developing persistent posttraumatic symptoms, cognitive impairments are among the most common

Summary • The neuroanatomy and neurochemistry of TBI lead to understandable and predictable types of cognitive impairments • Although pharmacologic treatments for posttraumatic cognitive impairments are often prescribed by analogy to other neuropsychiatric disorders (i.e., ADHD, Alzheimer’s disease), a more useful approach is predicated on the neuroanatomy and neurochemistry of TBI specifically

Summary • There is sufficient evidence regarding the neurobiological bases and also pharmacotherapy of posttraumatic cognitive impairments to develop neurobiologically rational approaches to treatments specific for this population • Two major pharmacologic approaches – catecholaminergic augmentation – cholinergic augmentation

Summary • Catecholaminergic augmentation – most appropriate target symptoms for this class of agent appear to be arousal, speed of processing, and sustained attention/vigilance – emerging evidence (McAllister et al., Dartmouth Medical School) of differential effects of noradrenergic vs. dopaminergic augmentation on posttraumatic working memory impairments

Summary • Cholinergic augmentation – most appropriate target symptoms for this class of medication are memory (encoding, retrieval, or both) and sustained attention – among patients with posttraumatic memory impairments who respond to cholinesterase inhibitor treatment, attention and executive function may also improve

Summary • Combination approaches – polypharmacy should be avoided whenever possible – however, some patients may require treatment with both catecholaminergic and cholinergic agents – some patients will not respond to any of the available pharmacotherapies

Summary • The development of treatment approaches for posttraumatic cognitive impairments predicated on robust a priori hypotheses, derived from the known neuropathology of TBI, need further development • The development of widely-available markers of cortical neurotransmitter function are needed to facilitate the identification of persons whose posttraumatic cognitive impairments are related to identifiable cerebral neurotransmitter deficits

Future Directions • Ideally, combined in vivo neurotransmitter imaging and neuropsychological testing will be used to facilitate treatment selection • Rigorously performed, multicenter, randomized, double-blind, placebo-controlled studies guided by such in vivo neurotransmitter imaging studies are needed to better define the role of catecholaminergic and/or cholinergic augmentation in the treatment of persons with posttraumatic cognitive impairments

Acknowledgements • Thomas W. McAllister, MD • Jonathan M. Silver, MD • C. Alan Anderson, MD • Kimberly Frey, MS, CCC-SLP • HealthONE Spalding Rehabilitation Hospital