Medicines to aid Executive Function post TBI

From: Neuropharmacology In TBI: What We Know & What We Don’t - ppt download  Mount Sinai Hospital

Agents to Support Executive Function:

What We know:

There exits evidence to support use of amantadine.

• Meythaler et al 2002 found amantadine improved neurorecovery in TBI with DAI in Double-Blind randomized crossover 6 week trial
  • 35 patients with TBI, GCS of 10 or less
  • Amantadine 200mg/day/placebo given in first 6 weeks or 2^nd 6 weeks
  • Improved MMSE, DRS, GOS, and FIM cognitive Score in amantadine group in first 6 weeks, and no improvement in next 6 on placebo. No sig effect on GOAT
  • In group on amantadine in weeks 6-12, statistical sig improvment in MMSE, DRS, GOS, an FIM cog after active drug
    • No sig effect on GOAT

• • Conclusion: rapid functional improvement on amantadine when given in first 3 months after injury

There exits evidence to support use of amantadine.

• Kraus et al 2005 found improvements of tests of executive function after treatment with amantadine in patients with chronic TBI
  • N=22, amantadine 200mg BID
  • Outcome measures: neuropsychological testing (pre and post-12 week treatment) and PET scanning on 6 participants
  • Results:
    • Significant improvements on tests of executive function
    • Analysis of PET data demonstrated significant increase in left prefrontal and medial temporal cortex glucose metabolism
      • This correlated with improvement in measures of executive function

• • • Memory and attention did not significantly improve

The evidence to support the use of Atomoxitine is limited and conflicting.

• In animal models with experimental TBI, low dose atomoxetine attenuated cognitive deficits after experimental TBI in a water maze study (Reid and Hamm 2008)
  • Performed worse with higher doses
  • No effect when started 11 days post injury

• However: remember Ripley et al, 2014:
  • In adults with TBI at least 1 year from injury atomoxetine dosed at 20 mg 2 x /day for 2 weeks did not improve scores on measures of attention (Ripley et al, 2014)

Citicoline does not improve cognition and function when used acutely or subacutely.

• Citicoline is an endogenous compound, thought to have neuroprotecticve properties.
• Citicoline is an approved therapy for TBI in 59 countries
• COBRIT: Citicoline Brain Injury Treatment Trial was a large phase 3 double blind, RCT among 1213 patients at 8 US trauma centers to investigate Citicoline vs. placebo in pts. with TBI (mild, mod and severe), Zafonte et al 2012
• 90 days if citicoline 2000mg vs placebo initiated within 24 hours of injury
• At 90 days measured TBI clinical trials network core battery (trails a and b, GOS-E, COWAT, CVLT, PSI, DS and WAISIII, Stroop 1 &2)
• At 90 days there was no sig difference btwn 2 groups on the battery
  • Favorable imrpovement for the GOS-E in the citicholine group
  • COBRIT questions worldwide use of Citicholine

The evidence to support the use of bromocriptine is limited

• McDowell et al 1998 examined low dose bromocriptine on frontal lobe (working memory and executive function)
  • N=24,
  • double blind placebo controlled crossover
  • Gave bromocriptine 2.5 mg with testing 90 minutes later
  • Bromocripine improved tests of executive function and dual task performance, but not working memory or attention

The evidence to support the use of SSRIs is limited.

• Horsfield et al 2002 studied Prozac 20-60 mg/day after TBI
  • N=5, 8 months
  • Cog and Memory tests: at baseline and after 8 months: Trails A, attention motor speed test, part of WAIS II, Some portions of test, but need addtiional research

• Sertraline caused psychomotor slowing in further studies (next slide)

What We Don’t Know:

• Conflicting results in the literature.
  • Large recent meta-analysis “Impact of Phamacolological Treatemtns on Cognitive and Behavioral Outcome in the Postacute States of Adult TBI,” Wheaton et al 2011, found:
    • SSRIs:
      • Citalopram and carbamezepine improve psychosocial function.
      • Serotonin increases post concussive sx and decrease psychomotor speed.
      • Milnacipran (serotonin and Noradren) improvement on cog testing (MMSE).

• • • Dopaminergics:
      • Methyphenidate supported for psychosoical, cognitive, but mixed results on attention.
      • Amantadine improved global outcome on DRS (Maythaler 2002).

• • • Cholinergic:
      • Support of donepazil for attention and memory (Zhang et al 2004), but no improvement with physiostigmine and lecithin.

• • • Peptide Treamtents: Lysine/vasopressin had 1 study supporting improved memory, cerebrolysine improved memory and attention, no studies support desmopressin use.
    • CDP-Choline may improve memory, but impair attention.

Summary and Practice Recommendations:

• Amantadine has most support for improving executive function after TBI, but is not supported in memory or attentional recovery.
• It is unclear how bromocriptine improves executive function.
• Citicoline and atomoxetine do not have literature that supports use in promoting cognitive function after TBI.
• When treating executive function deficits, it is important to treat other impairments (emotional and behavior disturbances and motor dysfunction).
• The literature is limited in medication use to treat executive function deficits.
• SSRI’s have utility in non-depressed patients with stroke, with good functional results.
• FLAME trial showed that in patient with ischemic stroke and moderate to severe motor deficits, the early prescription of fluoxetine with physical therapy led to enhanced motor recovery after three months.
• Patients treated with citalopram for three months post stroke had a better recovery from disability one year after stroke than patients who did not receive antidepressant therapy.
• Citalopram can enhance dexterity in chronic stroke patients.
• Donepezil may improve the FIM motor score in elderly cognitively impaired patients post stroke.
• Reboxetine induced a significant improvement in tapping speed and grip strength in ten patients with chronic stroke.
• Currently there is limited evidence for supporting or refuting the use of levodopa to support post-stroke motor recovery.
• Currently there is limited evidence for supporting or refuting the use of amphetamines to support post-stroke motor recovery.
• The evidence for the efficacy of dopaminergic agents in aphasia therapy is mixed.
• Donepezil has been shown to improve the severity of aphasia and motor aspects of speech in poststroke aphasia.
• Memantine alone or combined with constraint-induced aphasia therapy in chronic poststroke aphasia patients improved aphasia severity. These effects persisted on long-term follow-up.
  • Melatonin has value for sleep disorders following head injury.
  • Trazodone is a multifunctional drug that helps patients with TBI sleep.

• Amantadine is the agent of choice for treating profound hypoarousal following TBI, especially when a patient has a disorder of consciousness.
• Amantadine and/or methylphenidate may improve emergence from coma in hypoxic ischemic encephalopathy resulting from cardiac arrest.
• A very small number of patients with disorders of conscious are responders to zolpidem, and it is not possible to distinguish responders in advance.
• Agitation is fairly common after brain injury, with incidence of 10-30% and in some reports 90%, and poses a danger to the patient and caregivers, interferes with rehabilitation, and affects disposition.
• Clinician must evaluate and treat for treatable of agitation/behavioral problems that include environment, neurologic, metabolic, pain, medication, etc.
• Stable environment is key as well as removing contraindicated medications.
• Amantadine, methylphenidate, propranolol, valproic acid have evidence for treatment of agitation after brain injury.
• Quetiapine can be used in severe cases of severe agitation, however olanzapine has slightly more support when agitation exists with psychosis.
• Check levels, CBC and LFT as well as EKG where indicated.
• Remember rules for any medication use: Start low and go slow, and remove when agents agitation begins to resolve.
• Methylphenidate relatively safe, and recommended to improve attention, processing speed, concentration and vigilance but limited evidence that it improves functional outcome.
• Atomoxetine does not significantly improve performance on measures of attention.
• Cholinesterase inhibitors have preliminary evidence for recovery of attention.
• We need additional studies to support use of medications for memory recovery after traumatic brain injury.
• Escitalopram and Donepezil are supported in the literature for memory recovery in CVA.
• Amantadine has most support for improving executive function after TBI, but is not supported in memory or attentional recovery.
• It is unclear how bromocriptine improves executive function.
• Citicoline and atomoxetine do not have literature that supports use in promoting cognitive function after TBI.
• When treating executive function deficits, it is important to treat other impairments (emotional and behavior disturbances and motor dysfunction).
• The literature is limited in medication use to treat executive function deficits.