Neuropharmacology

Traumatic Brain Injury Rehabilitation Educational Resources > Traumatic Brain Injury Testing & Treatment > Neuropharmacology

Medications in survivors of traumatic brain injuries (TBI) should be used sparingly with the focus being on ameliorating or decreasing, psychiatric symptoms, behavioral manifestations and maladaptive behaviors that can interfere or impede the rehabilitative process.  Survivors of TBI can present with a myriad of psychiatric symptom manifestations, with the most common ones being depression, explosivity (violent behaviors), which may be situational as well as out of the blue, apathy, lack of interest, anhedonia, particularly in individuals with frontal lobe trauma.  In individuals with dominant hemisphere trauma, symptoms may include psychosis (being out of touch with reality), auditory or visual hallucinations, delusions (having fixed firm beliefs) which may be paranoid or persecutory in nature, symptoms of bipolarity with manic qualities such as pressured speech, racing thoughts, poor concentration, increased energy with alterations in circadian rhythms are common in survivors of TBI with the most common symptoms being insomnia, difficulty falling asleep, maintaining sleep or reversal of sleep-wake cycle.  Survivors of TBI may experience a change in personality either regressive or expansive of underlying pre-morbid personality traits.  It is not unusual for survivors of TBI to develop dis-inhibition and may act out in a sexually inappropriate manner towards self or others.  From a cognitive stand point, survivors of TBI usually experience deficits in recent memory, recall and working memory.  With executive dysfunction, i.e. difficulty with organization, there is an inability to complete tasks in a sequential fashion, attention deficit, poor concentration and difficulty with abstract concepts, frequently found as sequelae to TBI, particularly frontal lobe injuries.  What the family members or support group of a survivor should remember is that symptoms and behaviors change with time from the date of injury.  What is initially seen in terms of symptoms-behaviors will change, improve or fluctuate, as time goes by.  Most individuals reach maximum medical improvement 1 ½ to 2 years from the date of injury.

In an effort to help survivors of TBI and their loved ones understand the advantages and disadvantages of psychiatric medications, Dr. Villalba, M.D. FAA CAP, has compiled a brief synopsis of same, with emphasis on how these medications affect an individual who has had a TBI.  The emphasis, however, is that there is no such thing as “one size fits all” treatment, and what is effective for one individual may not be effective or even contraindicated in another.

Anti-depressants

Generally work by increasing serotonin and or norepinephrine in the connection between neurons (synapse), decrease in these neurotransmitters have been implicated in development of mood disorders.  Low serotonin levels in the central nervous system (CNS) have also been implicated with violent behaviors to self (suicidality) and others.  Anti-depressants are generally classified according to the neurotransmitter they affect such as SSRI for selective serotonin re-uptake inhibitor or SSNERI mixed type.  There are older anti-depressants called tri-cyclic anti-depressants which also have similar pharmacological action depending on whether they are a tertiary or secondary amine such as Amitrypticine (Elavil) and Nortriptyline (Pamelor), respectively.  Elavil is sometimes used for its pain management properties as well as an anti-depressant.

  • SSRI’s:fluoxetine (Prozac), Sertaline (Zoloft), Paroxetine (Paxil), Citalopram (Celexa), escitalopram (Lexapro), duloxetine (Cymbalta), fluvoxamine (Luvox)
    • Uses: depression, irritability, anxiety, obsessive compulsive disorder, trichotillomania, premature ejaculation, social anxiety-phobias, apathy, psychomotor retardation, anhedonia, eating disorders.
    • Advantages: generally work well with therapeutic effects seen in 2-3 weeks, obsessive compulsive disorder may have longer period for therapeutic effect, sertraline (Zoloft) has a low drug to drug interaction. 
    • Disadvantages: may lower seizure threshold, can have activating features, i.e. causing increased aggression or even mania, rebound anxiety upon discontinuation especially true of Paroxetine (Paxil), can affect serum levels of other medications such as anticonvulsants, can cause erectile dysfunction, weight gain, reports of increased suicidal ideation, inappropriate antidiuretic hormone (SIADH), decrease in serum sodium, akathisia, motor restlessness (inability to sit still) especially common in the elderly.
  • S-NERI:Serotonin - Norephinephrine reuptake inhibitor, venlafaxine (effexor) works on the two major neurotransmitters implicated in depression.
    • Uses: depression, anxiety
    • Advantages: may have activating-energizing features, may improve attention and concentration.
    • Disadvantages: may also lower seizure threshold, may cause increase in blood pressure (usually modest), may cause activation-mania, hyponatremia (low serum sodium) due to SIADH, serotonin syndrome, and cardiac arrythmias (rare).
  • Buproprion (Wellbutrin)is a miscellaneous anti-depressant which may work by blocking the re-uptake of dopamine.
    • Uses: depression, smoking cessation, attention deficit disorder short attention span in individuals with Attention Deficit Disorder.
    • Disadvantages: may significantly lower seizure threshold (5%) and is contraindicated in individuals with seizure disorder or eating disorder such as anorexia nervosa or bulimia. Should be used with extreme caution in individuals with head injuries. Can be activating but is generally considered to be the least activating for development of manic symptoms.

Anti-psychotics

Usually classified as typical and atypical:

  • Typical anti-psychotics:generally older medications, are generally less expensive, have been proven to be just as efficacious in the treatment of psychosis (see CATIE trials) but may have more extra pyramidal symptoms pseudo-Parkinsonian symptoms i.e. motor restlessness - or retardation Akathisia-Akinesia, dystonias and tardive dyskinesia (TD), which are irreversible involuntary movements (note: atypical anti-psychotics such as risperidone (Risperdal) have also been known to cause Tardive Dyskinesia (TD).  Typical anti-psychotics may also be less efficacious on negative symptoms such as flattening of affect, social withdrawal and cognitive dulling then some but not all of the atypical anti-psychotics.  They work by blocking the neurotransmitter dopamine at the level of the D2 receptor.
    • Examples of typical anti-psychotics: chlorpromazine (thorazine), fluphenazine (prolixin), haloperidol (Haldol), perphenazine (Trilafon), trifluoperazine (Stelazine), molindone (Moban).
    • Uses: psychosis, agitated states, tics, Gilles de la Tourette Syndrome, all psychiatric disorders associated with psychotic states, Bipolar Disorder.
    • Advantages: work well on hallucinations, delusions, formal thought disorders, agitation, violent patients.
    • Disadvantages: can lower seizure threshold, anti-cholinergic side effects i.e. dry mouth paralytic ileus, Tardive Dyskinesia, pseudo Parkinsonian Symptoms i.e. flat affect, shuffling gait (Thorazine shuffle), neuroleptic malignant syndrome, weight gain (exception Moban), hyperlipidemia and diabetes (may be less pronounced than the atypical anti-psychotics, especially when compared to Olanzapine (Zyprexa)), extrapyramidal symptoms, dystonias, cardiac arrythmias, hyponatremia, leukopenia-neutropenia and decrease in white blood cell count.
  • Atypical anti-psychotics:block the re-uptake of dopamine at level of D2-D4 (Clozapine) but also block the receptor for serotonin 5-HT - which has been linked to hallucinations.  They have less cognitive dulling and pseudo-parkinsonian symptoms then the typical anti-psychotics, and have more therapeutic effect on negative symptoms such as social withdrawal or a flat affect.  Clozapine (Clozaril ) and Olanzapine (zyprexa) have been known to reverse symptoms of TD (tardive dyskinesia).
    • Examples of atypical anti-psychotics: Risperidone (Risperdal), Olanzapine (Zyprexa), Aripiprazole (Abilify), Ziprasidone (Geodon), Quetiapine (Seroquel), Clozapine (Clozaril), Paliperidone (Invega).
    • Advantages: less extra pyramidal symptoms then typical anti-psychotics, less cognitive dulling, have positive effect on negative symptoms.
    • Disadvantages: weight gain, hyperlipidemia diabetes, aripiprazole (Geodon), more weight neutral.

Mood Stabilizers

Anticonvulsants such as valproic acid (Depakote), carbamazepine (Tegretol), lamotrigine (Lamictal), oxcarbazepine (trileptal), lithium carbonate (Eskalith, Lithobid).  These anticonvulsants are useful in the treatment of explosivity, violent behaviors, bipolar symptomatology, manic symptoms such as pressured speech, racing thoughts lability of mood, poor sleep, increased energy.  In addition, valproic acid (Depakote) is useful for treatment of post traumatic headaches, migraines and hyper-arousability associated with post traumatic stress disorder.

  • Advantages: useful for treatment of seizures, bipolar symptomatology, post-traumatic headaches, frontal lobe syndrome, intermittent explosive disorder, post traumatic stress disorder, (lithium) treatment resistant depression.
  • Disadvantages: side effects with anti-convulsants are generally rare and reversible but do occur, frequent blood monitoring is essential.  These may include: bone marrow suppression, decreased white blood cell count, decreased red blood cell count, decreased platelet counts, hepato-toxicity, liver failure (especially in children), pancreatitis, cardiac arrythmias and lethal skin rashes are possible, but rare. Lithium can slightly increase white blood cells (leukocytosis) with no clinical significance , can bind to the thyroid gland causing hypothyroidism treated with thyroid hormone supplementation, can cause polyuria, polydipsia (increased thirst and urination) and increase in serum sodium.  Both anticonvulsants and lithium can cause a mild essential tremor as well as hair loss.

Anti-Parkinsonian agents (anti cholinergics)

Used to prevent and reverse extra pyramidal symptoms associated with medications that decrease dopamine, i.e. anti-psychotics, generally used in combination with an antipsychotic agent.

  • Advantages: work well on dystonias, akathisia, akinesia (EPS).
  • Disadvantages: cause dry mouth, urinary retention, blurry vision, constipation, will not reverse tardive dyskinesia.
  • Examples of anti cholinergics: Benztropine (cogentin), trihexyphenidyl (Artane), diphenhydramine (Benadryl).

Stimulants

Can be useful in treating individuals with attentional difficulties, apathy, psychomotor retardation, stuporous conditions and, of course, attention deficit disorder with and without hyperactivity in children and some adults.

  • Examples of stimulants: methylphenidate (Ritalin), dextroamphetamine (Dexedrine), dextroamphetamine/amphetamine (Adderall), Modafinil (Provigil), armodafinil (Nuvigil), to name a few.
  • Advantages: generally medications such as methylphenidate, dextroamphetamine have a short half life (eliminated quickly from the body), work well on increasing attention and concentration, have a calming affect on hyperactive children, increase alertness, decreased need for sleep.
  • Disadvantages: can lower seizure threshold, can cause motor tics, decrease appetite, cause insomnia, can cause irritability-mood swings, some individuals can have idiosyncratic responses i.e., can prolong being in a coma rather than reversing it.

Beta blockers

Can be useful in the treatment of tremors and headaches, violent behavior.

  • Examples of beta blocker: propanolol (Inderal), pindolol, atenolol (Tenormin).
  • Advantages: works well on essential tremors, vascular headaches may respond to this medication, some violent individuals with episodic dyscontrol may respond to high doses of beta blockers.
  • Disadvantages: may cause bronchial constriction, may mask hypoglycemia, contraindicated in asthmatics and diabetics, may decrease heart rate (bradycardia), lowers blood pressure.  Not always effective, may require doses to achieve therapeutic results in violent behavior that the individual cannot tolerate because of side effects.

Benzodiazepines

Useful in the treatment of anxiety, seizures, insomnia (short term), violent behavior agitation as needed.  Some benzodiazepines such as alprazolam (Xanax) can have antidepressant properties, used for withdrawal states.

  • Advantages: short half life benzodiazepines such as lorazepam (Ativan) are very useful in short term treatment of agitation and aggression.  Long half life benzos, such as Klonopin are useful in the treatment of seizure disorder, Benzodiazepines are not irritants to the central nervous system.
  • Disadvantages: have abuse potential, cause tolerance, can cause memory loss, disinhibition.
  • Example of benzodiazepines: clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium)

Hypnotics

Individuals who have had a TBI are prone to sleep disturbances primary - secondary insomnia, reversal of sleep wake cycle etc.  Hypnotics are useful for short term management of sleep disorders.  Some individuals may require longer treatment due to chronic insomnia.  The main issue is the development of tolerance such as in the use of benzodiazepines with a short half life triazolam (Halcion).  Medications that work on re-establishing circadian rhythms such as rozerem and melatonin may be useful.

  • Advantages: helps re-establish normal sleep patterns, establishes sleep-wake cycle.
  • Disadvantages: can cause tolerance, some individuals have amnesia and will even drive cars or perform other chores while asleep.
  • Examples of Hypnotics: Zolpidem (Ambien), Triazolam (Halcion), Temazepam (Restoril), Trazodone (Desyral) though an antidepressant is often used as a hypnotic. 

Cognitive enhancers

There have been some studies showing mild improvement in cognition (memory) in individuals with TBI who were treated with medications for Alzheimers.  Some of these medications such as donepezil (Aricept) work by decreasing the degradation of acetylcholine the major neurotransmitter implicated in memory storage.

  • Advantages: may help in improving recent memory.
  • Disadvantages: not always effective, may lower seizure threshold, can cause insomnia, depression, anorexia, urinary frequency, headaches, syncope. 
  • Example of cognitive enhancers: donepezil (Aricept), rivastigmine (Exelon), memantine (Namenda)

Antihypertensives (alpha 2 agonists)

Clonidine (Catapres) and guanfacine (Tenex) are used (off label) in children with hyperactivity, poor impulse control.  They work by down regulating the neurotransmitter norepinephrine.  They work synergistically when used with lithium carbonate. 

  • Advantages: have therapeutic effect on motor tics, decrease hyperactivity.
  • Disadvantages: may cause irritability, sedation, lowers blood pressure, reports of cardiac arrythmias, rebound hypertension if abruptly discontinued. 
  • Examples: clonidine (catapres) guanfacine (Tenex).

In conclusion, survivors of TBI should be treated if at all possible with the least amount of medications.  Symptoms and maladaptive behaviors that interfere with the rehabilitative process should be treated.  Initial reasons for treatment will usually change as the survivor undergoes rehabilitation and nears maximum medical improvement (MMI).  Attempts (when possible) to taper or wean off of psychiatric medications as the individuals date of injury progresses should be made.  Polypharmacy and the use of two or more medications of the same class should be avoided.  The clinician and the loved ones of the survivor should be cognizant of the fact that psychiatric manifestations are common in TBI and not always permanent, but may represent a bump in the road in the rehabilitative process.

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