6.4 Pharmacological Measure for Aggressive and Agitated Behaviour

 

Case Study (continued)

The patient has an Agitated Behavioural Scale score of 30.  He has experienced two seizures since coming on the rehabilitation unit.  The nurses are concerned about his aggressive behavior and report he upturned his dinner tray and broke one of his drinking glasses.

 
To treat the patient’s aggressive behavior, what medication would be most appropriate?
 
 
  1. Valproic Acid and Divalproex do not appear to have significant neuropsychological side effects but do appear to stabilize mood and irritability as well as destructive and aggressive behaviours: they are also used to control seizures in patients with epilepsy.
 

Case Study (continued)

 The patient gets very angry at staff and family members. The therapist notes that his rehabilitation is complicated by inattention.

 
To treat the patient’s anger what medication would be most appropriate?
 
  1. Methylphenidate has been shown to reduce anger following brain injury while also assisting with inattention.
 

Case Study (continued)

 The patient is reported to be aggressive and very depressed and anxious.

To treat the patient’s depression and anxiety what medication would be most appropriate?
 
  1. SSRIs may improve depressive syndromes, psychological distress and aggression, but it does into improve arousal. 
     
  2. Valproic Acid and Divalproex do not appear to have significant neuropsychological side effects but do appear to stabilize mood and irritability as well as destructive and aggressive behaviours: they can also control seizures.

Case Study (continued)

The patient is very anxious and restless with numerous episodes of aggressive behavior.

What medication(s) would be most appropriate to treat anxiety, restless and aggressive behavior?

  1. Beta-blockers improve aggressive behaviour following brain injury.
     
  2. Valproic Acid and Divalproex do not appear to have significant neuropsychological side effects but do appear to stabilize mood and irritability as well as destructive and aggressive behaviours: they can also control seizures.
     
  3. SSRIs may improve depressive syndromes, psychological distress and aggression, but it does into improve arousal.

Case Study (continued)

The patient is still considered to be in PTA. He has an Agitated Behaviour Scale score of 30. The patient is exhibiting agitated and aggressive behavior.

What would the typical dose for each of the following medications be?

Medication

Dosage

Amantadine

Start at 100mg/day bid to maximum dose of 300 mg/day

Amitriptyline

Titrated up to 75 mg/day

Buspirone (Bu Spar)

Start at 7.5 mg/day to a maximum of 60 mg/day

Carbamazepine

Start at 200mg/day bid to a maximum of 2400 mg/day

Citalopram

Start at 20 mg/day to a maximum of 60 mg/day

Divalproex

250 to 2000 mg/day

Haloperidol

Start at 1-5 mg/day BID or TID to a maximum dose of 100 mg/day

Lamotrigine

125 to 300 mg/day

Lithium Carbonate

300 to 1200 mg/day

Methotrimeprizine

2-50 mg 2-4 times per day

Olanzapine (Zyprexa)

Start with 2.5-5 mg every 4 hours or BID then increase in increments of 2.5-5 mg up to 20mg/day

Pindolol

6-100100 mg/day

Propanolol

Start at 60 mg/day or 40 mg/day (BID) and increase by 60mg/3 days to a maximum of 640 mg/day

Quetiapine (Seroquel)

25 to 300 mg/day

Risperidine (Risperdal)

Start with 0.5 mg/ghs (or BID) then increase in increments of 0.5-1 mg up to 3gm/day; some will go as high as 4-10gm/day.

Sertraline (Zoloft)

50-200 mg/day

Trazadone (Desyrel)

50 mg/bid – 60mg/d

Valproic Acid (Depakene)

Stare at 250 mg TID and increase to a maximum dose of 4200 mg/day

Discussion

It is important to note that there is little research evaluating the efficacy in using many of these medications in the management of agitation or aggression post ABI 7.

The majority of studies conducted have been case studies, case series or chart audits.  Results from the few RCTs conducted had very poor statistical power as a result of the small sample sizes 9

Deb and Crownshaw 9 noted that although the evidence supporting the use of these medications is limited it does not mean that these medications are ineffective. 

For a more detailed discussion on these medications and their effectiveness post ABI please see ERABI/Mental Health Issues Post ABI.

Abikus Guidelines 10

Pharmacological Measures for Aggressive and Agitated Behaviour

  1. “Thereshould be careful considerations of the sensitivity of people with traumatic brain injury to psychotropic medication before trial use. Psychotropic medications should be used with caution. Where medications are clinically indicated ‘start low and go slow’, keep under direct clinical monitoring to ensure that the drug is tolerated and producing the expected improvement and used with caution where indicated. (pg 18)
  2. Perform a detailed physical exam prior to commencing any trial of medications. People with traumatic brain injury and their caregiver should be asked about any prescribed medications, over the counter remedies, herbs or supplements they are taking to check for potential interactions and adverse effects. (pg 18)
  3.  Appropriateinvestigationsshould be completed prior to medication trials to rule out and minimize metabolic abnormalities including evaluation of: plasma blood sugar, electrolytes, hormones, hemoglobin, oxygenation and infection. (pg 18)
  4. Clinicians should also consider the possibility of brain injury related sleep disorders as a cause of cognitive and other behavioural changes. (pg 18)
  5. Any trial of medication for a person with traumatic brain injury should be preceded by a clear explanation to the person with traumatic brain injury and their caregivers, and a caution that effects of medications are less predictable in people with traumatic brain injury. (pg 18)
  6. Minimize use of benzodiazepines and neuroleptic antipsychotic medicationsas animal studies suggest these medications may slow recovery after brain injury. (pg 18)
  7. Beta Blockersare recommended; a guideline for the treatment of aggression after TBI. Studies reported the efficacy of both Propranolol (maximum dose 420-520 mg/day) and Pindolol (maximum dose 40-100 mg/day) in the treatment of aggression in this population. (pg 19)
  8. Anticonvulsants: Carbamazepine and/or Valproic Acid may be used to decrease the incidence of aggressive behaviours. (pg 19) 
  9. Valproic Acidmay be preferred over Phenytoin post brain injury as it does not have any significant neuropsychological side effects, and is effective for controlling established seizures and stabilizing mood. (pg 19)”       

For the management of agitation and aggression post TBI are the pharmacological approaches different for early post traumatic agitation while in PTA versus later more episodic agitation and aggression while no longer in PTA?

According to the ABIKUS Recommendations 10.

  1. For the patient with early post traumatic agitation and still in PTA, beta blockers (Propanolol and Pindolol) and the anticonvulsants (Valproic acid and Carbamazepine) are the drugs of choice.
     
  2. For the patient with post traumatic agitation but now out of PTA a number of medications are recommended including the beta blockers, Valproic Acid or Divalproex, the SSRIs and the tricyclic antidepressants, and in selected cases Methylphenidate.

ABIKUS Recommendations 10

Medication Management of Early Post Traumatic Agitation and Post Traumatic Amnesia (2007) (pg. 19)

The clinician is advised to consider the effects of medications in selecting medication for treatment of agitation in the acute phase.  There is no medication that has been shown to be effective in all persons with brain injury.

Minimize use of Benzodiazepines and Neuroleptic antipsychotic medications as animal studies suggest these medications may slow recovery after brain injury (ABIKUS C) (G15-pg 19).

Beta Blockersare recommended as a guideline for the treatment aggression after TBI.  Studies report the efficacy of both Propanolol (maximum dose 420-520 mg/day) and Pindolol (maximum dose 40-100 mg/day) in the treatment of aggression in this population. (ABIKUS A, adapted from GPT 1 p. 1482) (G16-pg 19)

Carbamazepine and/or Valproic Acidmay be used to decrease the incidence of aggressive behaviours (ABIKUS B) (G17-pg 19)

Valproic Acid may be preferred over Phenytoin post brain injury as it does not have any significant neuropsychological side effects, and is effective for controlling seizures and stabilizing mood (ABIKUS B) (G18-pg 19)

ABIKUS Recommendations 10

Pharmacological Management of Episodic Behavioural or Emotional Dyscontrol After Emergence from Post Traumatic Amnesia (2007) (p. 20-21)

Valproic Acid and Divalproexmay be used (in usual anticonvulsant dosages) to reduce neurobehavioural symptoms including destructive and aggressive behaviours. This medication may be particularly useful in those people with concurrent seizure disorders. (ABIKUS B) (G27-pg 20)

Treatment with Methylphenidate following brain injury may be considered in persons with brain injury to reduce anger as measured using several anger outcome measures (particularly if they have deficits in attention and concentration).(ABIKUS B) (G28-pg 20)

Selective Serotonin Reuptake Inhibitors (SSRIs) are recommended at the options level for the treatment of aggression following TBI. Specifically, Sertraline (25-200mg/day) and Paroxetine (20 mg/day) have been reported to be effective for the treatment of aggression in the population. (ABIKUS B, adapted from GPT, 1, p.1492) (G29-pg 21)

Beta-blockersare recommended as a guideline for the treatment of aggression after TBI. Studies reported the efficacy of both Propranolol (maximum dose 420-520 mg/day) and Pindolol (maximum dose 40-100 mg/day) in the treatment of aggression in this population. (ABIKUS A, adapted from GPT, 1, p.1482) (G30-pg 21)

The use of tricyclic antidepressants is recommended as an option for the treatment of aggression after TBI if the options above are not affective. Specifically, Amitriptyline and Desipramine (both up to 150 mg/day) have been reported to be effective for the treatment of aggression in this population.(ABIKUS B, adapted from GPT, 1, p.1492) (G31-pg 21)

What evidence is there for pharmacological agents treating aggressive and disruptive behavior?

According to Rees et al.11 there is evidence that agitation can be reduced by the following:

  1. Divalproex – Limited (level 4) evidence it reduces a variety of neurobehavioral symptoms including ABI-induced agitation.
     
  2.  Amantadine – Limited (level 4) evidence for early treatment of post-TBI agitation.
     
  3. Trazadone – Limited (level 4) evidence for early treatment of post-TBI agitation.
     
  4. Methotrimeprazine – Limited (level 4) evidence for reducing agitation.
     
  5. Carbamazepine – Limited (level 4) evidence for reducing agitation.
     
  6. Lithium carbonate – Limited (level 5) evidence for reducing agitation.

General principles of prescribing medications are to aim for the fewest side effects with regular monitoring to titrate effective dose to the minimum 11.

Describe what interactions, precautions, indications and contraindications that might be seen when the following medications are prescribed. 

Interactions

Serious side effects can occur if used with MAOI, there is a risk of increased of QTc interval if used with pimozide and if administered with cimetidine there can be an increase in serum levels of sertraline.

Precautions

If planning to get pregnant or are pregnant.

Those planning on nursing post delivery.

Sexual dysfunction- may affect compliance.

May increase sex drive.

Increased risk of bleeding.

Indications

Used in the treatment of: major depressive disorder; OCD; panic disorder; PTSD; PMDD; social anxiety disorder; to improve alertness and motivation

Contraindications

Contraindicated in patients with an allergy to the drug, those who are lactating, those who are experiencing seizures, are pregnant, have renal disease.

 

Amitriptyline (TCA, tertiary amine – SSRI)

 

Interactions

To be used with extreme caution with the elderly, women who are pregnant, those lactating and children and adolescents. Should not be administered to children under 12 as a treatment for depression. If given with anticholinergics, clonidine, CNS depressants, lithium, MAO inhibitors and sympathominetics monitor patient closely and it may be necessary to lower the dose of other medications.

Precautions

Those with a cardiovascular disease, should be started on a low dose, which may be (with caution) increased slowly over time, and patients should be monitored closely and have EEGs; those receiving higher than usual doses should be monitored closely, have EEGs periodically.

Indications

Is used in the treatment of depressive illness (bipolar), and it has been used in the treatment of fibromyalgia, migraine prophylaxis, rheumatoid arthritis and various neuropathies.

Contraindications

Contraindicated in patients who have shown hypersensitivity to the drug.

 

Carbamazepine (anti-epileptic)

 

Interactions

Serum levels may increase and there is the risk of toxicity when given with erythromycin, troleandomycin, cimetidine and other medications; if given with other barbiturates, there is the risk of decreased serum levels and it effectiveness maybe affected.  May decrease the effectiveness of anticoagulants (warfarin) so these may need to be increased while on carbamazepine.  The absorption rate of carbamazepine may be decreased with administered with primidone and valporic acid; however it effectiveness in controlling seizures will not be affected.  

Precautions

It has been suggested this medication be used in the treatment of seizures only, not to be used as a general analgesic, and this medication is to be given with food.

Indications

Used in the treatment of seizures: partial, tonic-clonic, mixed seizure patterns, pain associated with trigeminal neuralgia, treatment of acute manic and mixed episodes of bipolar disorder, certain psychiatric disorders, neurogenic diabetes insidpidus, along with a few other conditions.

Contraindications

Carbamazepine has not been recommended for those with a hypersensitivity to the medication, history of bone marrow depression, those on MAOIs, women who are pregnant or lactating.  If an individual has a history of adverse hematologic reaction to any drug used with caution.

 

Lamotrigine (anti-epileptic)

 

Interactions

Levels of lamotrigine will decrease (40 to 50%) if medication is given with carbamazepine, phenytoin, phenobarbital and primidone.  If given with valporic acid there is a decrease clearance of lamotrigine, thus a lower dose of lamotrigine is suggested.

Precautions

It is suggested that patients be monitored for rashes, and should a rash occur discontinue medication and monitor patient’s breathing closely.  When administering the medication administer who dispersible or chewable tablets with water.

Indications

Used in the treatment of seizures with adults and children, used to treat bipolar 1 disorder and to delay the occurrences of acute mood episodes.

Contraindications

Medication is not suggested in those with allergies to the medication or those lactating.  Caution is recommended is being given to those who are pregnant, or are under 16 years of age.  Caution is also recommended with impaired hepatic, renal or cardiac function.

 

Valporic Acid/Divalproex (anti-epileptic)

 

Interactions

May increase phenobarbitol, primidone, ethosuximide, diazepam and zidovudine levels. May also increase the levels of salicylates, cimetidine, chlorpromazine, erythromycin, felbamate leading to toxicity.  May interact with phenytoin leading to break through seizures. When mixed with carbamazepine, rifampin, lamotrigine the effects may be decreased.  Mixing this medication with alcohol or other CNS depressants may lead to an increase in sedation.

Precautions

Administering this medication to those who are allergic to valproic acid, divalproex, or to any of the ingredients of the medication; who have been diagnosed with a urea cycle disorder or those who have liver disease or a significant reduction in liver function is not suggested

Indications

Used in the treatment of certain types of seizures, and in the treatment of bi-polar disorder –to treat manic episodes. Valporic acid may also be used in the treatment of migraine headaches. Unlabeled uses include administering the medication to children with ADHD, organic brain syndrome, or in the treatment of schizophrenia.

Contraindications

It is not recommended that this medication be given to those who have demonstrated a hypersensitivity to valporic acid or those who have hepatic disease or significant hepatic impairment.  If administering this medication to children < 2 years of age, caution is suggested.  Caution is also recommended if administering this medication with those who are on multiple antiepileptics.

 

Quetiapine(anti-psychotic)

 

Interactions

The effects of the medication may be impaired by phenytoin, thioridazine, carbmazepine, Phenobarbital, rifampin, gluocorticoids.  Patients on these medications should be monitored closely and adjust drug doses appropriately if these drugs are added or removed while on quetiapine.  There may be an increased effect in antihypertensives and lorazepam while on quetiapine. The effectiveness of  Levodopa and dopamine antigonists may decrease while on quetiapine.  Patients are at risk for heat stroke while on quetiapine, and an increased risk of this medication interacting with drugs that affect temperature regulation.

Precautions

Medication should be used cautiously with those who have cardio vascular disease, hypotension, hepatic impairments, seizures, thyroid disease, may be pregnant, have autonomic instability, or are exposed to extreme heat.

Indications

Used in the treatment of schizophrenia, and in acute manic episodes, either alone or in combination with lithium or divalproex

Contraindications

Quetiapine is contraindicated with coma or severe CNS depression, if the patient has an allergy to it, or is lactating. 

 

Lithium Carbonate (anti-manic)

 

Interactions

There is an increased risk of toxicity with thiazide diuretics due to the decreased renal clearance of lithium. There is an increased risk of CNS toxicity with carbamazepine. When taken with halperidol encephalopathic syndrome with irreversible brain damage may occur.  If taken with urinary alkalinizers there may be a decrease in the medication’s effectiveness due to the increased risk of excretion.  There is an increased risk of an adverse effect if taken with SSRIs. There is an increased risk of plasma lithium levels if taken with indomethacin and other NSAIDs (ibuprofen, piroxicam etc)

Precautions

Use cautiously with individuals who have a history of protracted sweating, diarrhea, suicidal or impulsive tendencies, or may have a fever resulting from infection.

Indications

Used in the treatment of manic episodes of manic depressive (bi-polar disorder) illness and as maintenance therapy to prevent or diminish frequency and intensity of subsequent manic episodes and in the treatment refractory depression.  Unlabeled uses include the treatment of cluster headaches.

Contraindications

For individuals with a have a history of cardiovascular disease, renal disease, severe debilitation or dehydration or sodium depletion, the risk of lithium toxicity is higher.  If a psychiatric condition is life-threatening, lithium treatment may be begun at low doses and under hospital supervision.

 

Ziprasidone (atypical antipsychotic) (new to Canada)

 

Interactions

There is an increased risk of severe cardiac arrhythmias if taken with other drugs that prolong the QTc interval. If given with other antihypertensive medications there is the risk of increased hypotension.

Precautions

For those who have a history of renal or hepatic impairment, CV disease, or who may be pregnant or lactating use with caution.

Indications

Approved in the treatment of acute agitation in patients with schizophrenia, mania and mixed states in those with bi-polar affectiveness disorder.  May be used in the treatment of tic disorders.

Contraindications

Medication is contraindicated with those who have an allergy to ziprasidone, prolonged QTc interval or a history of severe cardiac disease.  Not recommended for elderly patients with dementia related psychosis.

 

Haloperidol (antipsychotic, dopaminergic blocker)

 

Interactions

If given with Lithium there is an increased risk of toxic side effects. The effects of haloperidol with given with carbamazepine may decrease its effectiveness.  There is an additive anticholinergic effect and the possibility of a decrease in the antipsychotic efficacy if given with anticholinergic drugs.

Precautions

To be taken with caution if the patients is lactating, has a respiratory disorder, glaucoma, prostatic hypertrophy, epilepsy, or a history of epilepsy, allergies to aspirin, NMS, breast cancer.  With children, those under 12 who have chicken pox or those who may have a CNS infection give with extreme caution.

Indications

Used in the management of psychotic disorder, controlling of tics, vocalizations in Tourette’s syndrome, behavioural disorders in children resulting in combative, explosive hyper-excitability.  May be given to children to treat hyperactivity with excessive motor activity or mood lability. Unlabeled uses may include: the treatment of intractable hiccoughs, agitation, hyperkinesia, infantile autism, acute psychiatric situations (IV use), controlling nausea and vomiting.

Contraindications

Haloperidol is contraindicated: hypersensitivity to typical antipsychotics, coma or sever CNS depression, bone marrow depression, subcortical brain damage, liver damage, cerebral arteriosclerosis, coronary disease, severe hypotension and hypertension, Parkinson’s disease, circulatory collapse etc.

 

Buspirone (anxiolytic)

 

Interactions

Give with caution to those who may be taking alcohol, or other CNS depressants.  If given with fluoxetine there may be a decreased effect of buspirone. If taken with erythromycin, an increase in serum levels of buspirone may be noted. If combined with haloperidol, haloperidol levels may increase.

Precautions

Use with caution if pregnant, there is a history of mild renal or hepatic impairment.

Indications

Used in the management of anxiety disorders or in the short term relief of symptoms of anxiety.  May be given to relief PMS symptoms.

Contraindications

This medication is contraindicated if the patient is hypersensitive to buspirone, had marked liver or renal impairment or lactating.

 

Methylphenidate (CNS stimulant)

 

Interactions

There can be an increased effect and toxicity of methylphenidate with MAOIs. There is a risk that serum levels of phenytoin, TCAs, oral anticoagulants and SSRIs when given with methylphenidate will increase. 

Precautions

For individuals who have seizure disorders, who are hypertensive, have or had drug dependence issue, a history of alcoholism. Caution should also be taken if this medication is being prescribed to someone who is lactating or pregnant.

Indications

Uses in the treatment of attention deficit disorder, and to alleviate neurobehavioral symptoms following an ABI.  May be given to both adults and children with certain behavioral issues such as: moderate to severe distractibility, short attention span, emotional lability and impulsivity.

Contraindications

It is not recommended for those who are hypersensitive to methylphenidate, who have marked anxiety, tension and agitation, glaucoma, and motor tics.

 

Pindolol (antihypertensive-beta blocker)

 

Interactions

Pindolol effects may be increased if given with verapamil. There may be a decrease in its effectiveness if given with indomethacin, ibuprofen, piroxicam or sulindac. Pindolol may prolong the hypoglycemic effects of insulin. If given with lidocaine look for increased serum levels of toxic effects.

Precautions

Use with caution if administering to those who have been diagnosed with diabetes, thyrotoxicosis and CHF.

Indications

Used in the treatment of hypertension alone or in combination with other medications. May also be use to treat ventricular arrhythmias, antipsychotic-induced akathisia and situational anxiety.

Contraindications

This medication is contraindicated with sinus bradycardia, cardiogenic shock, bronchial asthma, severe chronic obstructive pulmonary disease, pregnancy or lactating

 

Propranolol (anti-anginal, anti-arrhythmic, anti-hypertensive)

 

Interactions

There is an increased effect if given with verapamil and a decreased effect if given with indomethacin, ibuprofen, piroxicam, sulindac, or barbiturates.

Precautions

If prescribing medication to those with diabetes, hypoglycemia, thyrotoxicosis and hepatic impairment use caution.

Indications

Used to treat hypertensions, angina pectoris, cardiac arrhythmias,

May be given to those with schizophrenia, acute panic symptoms, anxiety and CHF.

Contraindications

This medication is contraindicated with lactation, pregnancy, CHF, bronchial asthma, COPD, broncospasm, sinus bradycardia, or allergies to beta-blocking agents, cardio genic shock, and second or third degree hear block.