MEDICATION TRIALS - SPECIFIC AGENTS
 Drugs which improve AAI can be classified into major groups, including noradrenergics, dopaminergics, serotoninergics.  Some medication classes with variable neurotransmitter agonism and antagonism include tricyclic antidepressants (TCA's), amphetamines, antiParkinsonian agents, selective serotonin reuptake inhibitor antidepressants (SSRI's), and monamine oxidase inhibitors (MAOI's).  Paradoxical sedation may occur with any agent, but inopportune onset is rarest with noradrenergics, occasional with dopaminergics, and not uncommon with serotonergics, especially in the elderly.

MEDICATIONS - NORADRENERGICS
 Noradrenergic agents such as amphetamine facilitate AAI via enhancing presynaptic release(15) of endogenous stores and decreasing presynaptic reuptake(34) of dopamine and norepinephrine catecholamines.  Dextroamphetamine, methylphenidate, desipramine, protriptyline, and pemoline are therapeutic options.
 Noradrenergics not uncommonly cause tachycardia and other potentially more malignant dysrhythmias.  The clinician should not be reluctant to co-prescribe a lipophobic/hydrophilic beta blocker such as nadolol or atenolol to attenuate cardiac responsiveness and facilitate rhythm stabilization.  This may allow escalation in dosing with informed consent beyond manufacturer recommendations.
 If insomnia occurs, the clinician should consider iatrogenic etiologies, and perform a trial taper of the noontime dose while monitoring for diminished AAI coincident with the intervention. 
 Advantages of desipramine and protriptyline over dextroamphetamine and methylphenidate include a longer duration of action as well as lower probabilities of anorexia, insomnia, on-off sudden inefficacy, abuse, or dependency.(7)  In addition, serum levels can be monitored for protriptyline and other antidepressants.  This is valuable in that patients with impaired hepatorenal function may accumulate drug with toxic effects if dosing is not adjusted in accord with serum levels.  Similarly, many medications speed hepatic drug clearance via biodegradative enzyme systems such as cytochrome P-450, and so doses which may otherwise be therapeutic will exhibit unexpected inefficacy if dosing is not increased in correlation with plasma levels.

 Dextroamphetamine (Dexedrine) is felt to directly enhance endogenous presynaptic release of dopamine(46,148) and norepinephrine,(109) decrease presynaptic catecholamine reuptake,(109) and reduce catecholamine biodegradation.(52)  Dextroamphetamine is a weak monamine oxidase (MAO) inhibitor.(109)  It is a potent psychostimulant.(65,79,119)  Amphetamine promotes recovery of motor function after cortical, internal capsule, and brainstem CVA,(3,38,72,134) and also has been used to enhance language function.(30)  
 Amphetamines have anticonvulsant properties.(46) 
 Dexedrine has more dependency, risk of withdrawal craving, and psychostimulant potency(44) relative to  Ritalin.  As such, it is not the optimal agent in patients with premorbid histories of substance abuse.  It may cause paranoid psychosis.(46)  As an alpha agonist(42) Dexedrine may promote internal sphincter contraction and urinary retention as well as arrhythmias, hypertension, and secondary bradycardia.  Post-void residuals, blood pressure, and heart rate and rhythm should be monitored after starting Dexedrine.  Anorexia and insomnia are additional potential side-effects(52) which should be monitored.
 Concomitant dosing of amphetamine with tricyclic antidepressants may block amphetamine induced release of dopamine,(148) a considerable potential concern in the optimal treatment of akinetic mutism. 
 Initial dosing is 5 mg po q7AM, advanced every 3-5 days to 5 mg po q7AM, 5 mg po q12PM.  Time to peak effect is 2-4 hours, and half-life is 7-10 hours.  Dose range is 10-60 mg qd.(61)  Tabs are available in 5 and 10 mg sizes. 
 Time released once a day spansules are available in 10 and 15 mg formulations, but continuous delivery and potential secondary receptor downregulation and clinical inefficacy remains suboptimally investigated to fully endorse long acting preparations as psychostimulants. 
 Additional amphetamine products include Adderall.
 Benzphetamine (Didrex) is a sympathomimetic amine available in 50 mg tabs with maximal dosing of 150 mg qd.

 Methylphenidate (Concerta, Metadate, Methylin, Ritalin), has a similar monoamine liberating mechanism as Dexedrine, except that Ritalin has also been reported to increase catacholamine degredation.(52)  Other sources report that methylphenidate weakly inhibits MAO.(109)  Ritalin is a nonselective monoamine reuptake inhibitor,(46) and acts at both the reticular activating system as well as in the cerebral cortex.(35)  It potentiates both noradrenergic as well as dopaminergic neurotransmitter activity.(133)  Ritalin induces the presynaptic release and inhibits presynaptic reuptake of catecholamines, particularly dopamine.(149)  Ill-defined serotonergic neurotransmission modulation is affected by methylphenidate.(91) 
 Delivery within 4 days(35) to several months after TBI effects enhanced rate of improved attention relative to the rate identified with natural recovery.(35)  Ritalin is well documented as a potent psychostimulant.(35,113,123,149,164)  It improves arousal and significantly speeds the rate of thought processing, but may be less helpful to improve sustained attention, resistance to distractions, and motor speed.(133)  Others, however, have found marked improvement in attention as well as motor performance.(123)  It has been successfully used in the treatment of coma secondary to TBI,(149) unevacuated subdual hematoma,(149) encephalopathy, and glutethimide intoxication.(164)
 Ritalin also has been described as enhancing memory(85), improving language, and selectively extinguishing aggressive disinhibition.(137)  It also exhibits analgesic properties(91) and capacity to rapidly ameliorate mood depression.(133) 
 As with Dexedrine, methylphenidate may cause hypertension, tachycardia, anorexia, insomnia, hyperarousal, and psychosis, and patients should be monitored for these sequelae during the initial days and weeks of treatment.  Despite the hemodynamic and increased cardiac oxygen consumption, patients with atherosclerosis tolerate methylphenidate well without evidence of ischemia, pulmonary edema, or arrhythmia.(149)  Methylphenidate has been described as being proconvulsant,(46) but other authors suggest that it may have anticonvulsant properties or neither protect nor prevent seizures.(17,43)  Excessively abrupt taper can increase agitation.  Side effects of Ritalin may include motor restlessness.(31)  Tachycardia(35) may result from use of this agent, suggesting that alternative psychostimulants may be more preferable first choices in patients with significant coronary atherosclerosis.
 Food enhances absorption.(42)  Onset of effect is usually within 15-60 minutes, with maximum effect in 2-4 hours and full elimination in most patients in 6-8 hours.  A delay in onset may range from 24 hours(149) to several days, occurring only after an appreciable dose is delivered.  The rapid onset of effect is one of the reasons why this agent is frequently chosen amongst the earliest agents delivered in trials to enhance AAI.  Time to peak effect is 1-2 hours, and half-life is 2-4 hours.(52)  Initial dose 2.5 to 10(149) mg po q8AM and q12PM.  Afternoon dosing may impair sleep.  The dose can be advanced by 2.5mg qd(35) daily or every two(149) to three days to a maximum dose of 45 mg q8AM, 45 mg po q12PM.(61)  One clinician, however, identified no side effects with dosing of 50 mg IM every half hour with 500 mg over one day and 1550 mg over seven days(164) in his successful efforts to awaken a 45 year old patient from coma.  Approximately 95% of the drug is eliminated within 72 hours.(123)  Tabs are available as 5, 10, 20 mg sizes.  A sustained release 20 mg formulation is available for q8AM delivery to maintain arousal once awakening or vegetative reversal has been successfully effected. 
 If ineffective to enhance AAI, the drug should be tapered.  
 Dexmethylphenidate (Metadate) is available as 10mg, 20 mg, and 30 mg tabs with a maximum suggested dose of 60 mg/day. It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.
 
 Desipramine (Norpramin), a secondary amine tricyclic antidepressant, which inhibits presynaptic noradrenergic presynaptic reuptake and decreases noradrenergic biodegredation.(7)  It enhances motor recovery in hemiparesis,(30) improves memory,(7) and is also efficacious as a psychostimulant.(15,58)   Delivery of 75 mg improved ability to verbalize within four days of ingestion in a patient nineteen  months post-TBI.(15) 
 As with other tricyclic antidepressants, these agents have been reported to block amphetamine induced release of DA,(148) a considerable potential concern in the optimal management of akinetic mutism and other states of impaired AAI. 
 Desipramine has significant theoretical benefits over protriptyline, including mildly more noradrenergic activity than protriptyline, 800% less anticholinergic properties, and 700% less antihistamine properties.  However, desipramine has mildly less dopaminergic and serotonergic properties than protriptyline. 
 Initial dose is 10 mg qd and is increased every 1-5 days to 50 mg after one week.(15) 

 Protriptyline (Vivactil), a secondary amine tricyclic antidepressant, has exhibited efficacy to enhance arousal in narcolepsy,(95) and also exhibits significant potency in TBI,(114) anoxic brain injury,(114) and stroke.  It may be effective when methylphenidate, levodopa, amantadine, bromocriptine, nortriptyline, and fluoxetine are incompletely effective psychostimulants.(114) 
 Protriptyline is slightly less noradrenergic than desipramine with considerably more anticholinergic and antihistaminergic activity.  However, it does have a mildly greater dopaminergic and serotonergic effect than desipramine. 
 The significant anticholinergic properties of protriptyline warrants monitoring for urinary retention and tachycardia via vagal inhibition.  As with all tricyclics, the seizure threshold may be lowered.  This does not warrant prescription of anticonvulsants unless new tonic-clonic or petit mal seizure activity is identified clinically or by EEG.  Alternatively, the clinician may wish to reduce dosing if seizure activity occurs as seizures are expected to occur as a dose related effect.  Concomitant prescription of psychostimulants with anticonvulsant properties may be considered. 
 Protriptyline may block dopamine postsynaptic receptors.(     ) Given this fact in addition to its proconvulsant properties, this agent may not be the optimal first adrenergic agent chosen to enhance AAI.
 It may take 6-14 days(114) for psychostimulant efficacy to develop.
 Initial dose is 10 mg po qhs, and dose is increased every 3-5 days to a maximum of 30 mg qhs.  Doses higher than 40 mg have been reported as increasing motor restlessness and irritability.(114)  At higher doses stimulant efficacy is not enhanced, and side effects and antidepressant properties manifest within 3-4 weeks.(114)   Protriptyline levels should be assessed, as co-delivered drugs which enhance biometabolism of protriptyline will decrease serum levels with accompanying decreased delivery to the brain and suboptimal psychostimulant efficacy. 

 Atomoxetine (Strattera) is a fairly newly released selective norepinephrine reuptake inhibitor available in 10 mg, 18 mg, 25 mg, 40 mg, and 60 mg tabs with a maximum recommended dosage of 100 mg qd.  It may demonstrate itself to have considerable efficacy for coma awakening and reversal of the vegetative state. 

 Ephedrine is a noradrenergic agonist which acts as a direct and indirect sympathomimetic.(165)  
Ephedrine started at 25 mg TID and increased over 5 days to 50 mg q4 hours with concomitant dosing with bromocriptine 100 mg/day resulted in ascension of a patient from akinetic mutism secondary to hydrocephalus.(165)  The clinician safely increased the dose to 525 mg/day to take advantage of arousing projections from the brainstem which ascend adjacent to the third ventricle.(165) 

 Phentermine (Adipex, Ionamin) is a sympathomimetic amine available in 37.5 mg scored tabs, but primary pulmonary hypertension and valvular heart disease may occur with its use such that it is clearly a tertiary option.  It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state. 

 Phendimetrazine (Bontril) is a sympathomimetic amine available in 35 mg scored tabs with maximum recommended daily dosing of 210 mg a day. It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

 Sibutramine (Meridia) is a dopamine, norepinephrine, and serotonin reuptake inhibitor available in 5 mg, 10 mg, and 15 mg tabs with maximum recommended dose of 15 mg qd.  It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

 Diethylpropion (Tenuate) is a sympathomimetic amine available in 25 mg tabs with maximum recommended dosing of 75 mg qd.  It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

 Cylert (Pemoline) is felt to enhance the release of dopamine and reduce catecholamine turnover.(52)  It is associated with life threatening hepatic failure and is a final option in terms of medication trials.
 Time to peak onset is two to three weeks.(34)  Half life is twelve hours.(52) 
 It is a less potent psychostimulant and sympathomimetic than Dexedrine or Ritalin,(34) and so it does not have the same heart rate and blood pressure risks, a benefit in patients with coronary artery disease or hypertension.  Cylert has potential hepatotoxicity, and is relatively contra-indicated in patients with histories or baseline liver testing suggestive of liver pathology.  Serial liver testing should be followed.  Nutritional intake should also be monitored, as anorexia may also follow its use.
 Cylert is available in 18.75, 37.5, and 75 mg tabs.  Starting dose is 18.75 mg tab po q8AM.  Dose should be changed at a rate of one 18.75 mg tab q3-7 days.  Maximum dose is 112.5 mg po q8AM,(114) but doses greater than 200 mg a day have been used in the treatment of narcolepsy.(160) 


MEDICATIONS - DOPAMINERGICS
 Dopaminergics enhance AAI by stimulating dopamine (DA) dependent pathways via several different mechanisms.  Dopamine synthesis may be enhanced, dopamine presynaptic release and degradation may be modulated, and different dopamine receptors can be stimulated.  Additionally, DA is converted by noradrenergic neurons to norepinephrine,(15) so delivery of exogenous DA may mediate psychostimulation via enhanced noradrenergic bioactivity.  
 Regions of the brain that are rich in DA receptors include the basal ganglia nucleus accumbens, olfactory tubercle, ventral tegmental area, retina, hypothalamus, central nucleus of the amygdala, median eminence, and the neocortical and prefrontal cortices.(96)  It is felt that the long projections between the substantia nigra and the ventral tegmental area to the striatum (nigrostriatal), limbic (mesolimbic), and frontal cortex (mesocortical) structures mediates at least a component of anhedonia(96) as well as impaired attention and initiation.(29)  Additional central tracts include the mesopiriform, tuberoinfundibular, and tuberohypophyseal paths.(29)
 At least five unique dopamine receptors have thus far been identified, and subtypes also exist.(162) Pharmaceuticals exhibit variable selectivity for different sites.  DA-1, DA-3, and DA-4 have been identified in the mesolimbic and mesocortical systems, and DA-2 has been found in the nigrostriatal and tuberoinfundibular tracts.(96)  DA-1 receptors have been identified in the internal globus pallidus and substantia nigra whereas DA-2 receptors are located in the external globus pallidus.(162)  DA-1 and DA-5 are mediated by activation of adenylate cyclase, and DA-2, DA-3, and DA-4 inhibit this enzyme.(96)  It may have been premature to classify DA receptors relative to adenylate cyclase activity as a DA-1 receptor subtype might be linked to another transduction mechanism.(162)  Efficacy and side effects of different medications are linked to receptor site agonism and antagonism. 
 DA-2 and DA-3 agonists may induce psychosis,(162) and so selectivity of agents is to be valued.
 Ritalin and Dexedrine are indirect dopamine agonists, as they enhance endogenous stored DA release, a function dependent on the presynaptic neuron to synthesize DA.  Direct receptor agonists have the advantage that they stimulate the postsynaptic membrane, even if the presynaptic neuron exhibits anatomic disruption or biochemical subcellular dysfunctional enzymatic conversion of L-dopa to DA.  Conditions such as large strokes or extensive traumatic injury, therefore, may more readily respond to receptor agonists.(64)  However, receptor agonists, in contrast to L-dopa of Sinemet, do not increase DA levels, so they do not undergo bioconversion to norepinephrine to concomitantly facilitate function of the noradrenergic system.  While nigrostriatal DA-2 agonism has been identified as a principal receptor mediating symptomatic improvement in Parkinson's Disease,(96) the most potent dopaminergic receptor mediator of psychostimulation remains undefined.  An additional consideration as alluded to above is that different medications stimulate different DA receptors and so postsynaptic agonists may not optimally address the spectrum of receptor deficits.
 DA agonism has been found to improve memory(114) and speech, while DA antagonism at DA-2 (e.g. haloperidol) and DA-4 (e.g. clozapine) have been means by which psychosis is extinguished.  Antagonistic potency at DA-2, however, is also associated with likelihood of development of extrapyramidal side effects.(96)  In addition DA antagonists may retard motor recovery after stroke or brain injury.
 Dopaminergics must be prescribed with caution in patients with premorbid history of schizophrenia or other psychotic thought processing disorders.(86)  First generation neuroleptics such as haloperidol and thioridazine are felt to exhibit efficacy via DA-2 receptor antagonism whereas D-4 blockade may mediate clozapine's antipsychotic potency.  It may be wisest to deliver dopaminergics in such patients only to awaken such patients from coma and states of akinetic mutism, and then taper the drug once consciousness has been obtained with subsequent monitoring for psychosis. 
 Dopaminergics commonly induce nausea during the initial days of delivery.  The clinician may consider prophylaxis with several days of Tigan, Anzemet, Zofran, or Kitrel, but not Reglan or Compazine or other dopaminergic antagonist. 
 Abrupt withdrawal of dopaminergics has been described as potentially precipitating neuroleptic malignant syndrome, a potentially fatal condition characterized by hyperthermia, rigidity, and delirium.  As such, a gradual taper of all dopaminergic agents should be performed if agents do not exhibit efficacy to treat coma awakening and reversal of the vegetative state.  
 Dopaminergic agents which can be prescribed to enhance AAI include amantadine, carbidopa/levodopa, bromocriptine, selegiline, and Mirapex. 

 Bromocriptine (Parlodel), 2-bromo-alpha-ergocryptine methanesulfonate, is a direct receptor agonist at DA-2,3,4, and 5 receptors and mild antagonist at DA-1.(162)  Bromocriptine also exhibits some agonism at alpha adrenergic, and serotonin receptors.(141)  It has demonstrated considerable psychostimulant efficacy,(33,70,90,102,112,129,144) particularly in akinetic mutism(33,102,112) with abrupt onset of effect usually within 1-7 days after a dose of 25 mg BID or higher is achieved.  Hemispatial neglect may also improve.(33,120,129)  Bromocriptine is also efficacious in post-traumatic parkinsonism,(33) akathisia,(139) and aphasia.   It has not yet been the subject of substantial investigation in terms of potential for motor restoration of hemiplegia.
 Presynaptic damage to the anterior medial forebrain bundles after separation of the nigrostriatal tract may suggest that biosynthetic capacity is compromised, and direct dopamine postsynaptic agonists may be more efficacious than Sinemet or methylphenidate presynaptic agonists.(102)  Conversely, it has been suggested that damage to the anterior cingulate gyri may indicate lessened efficacy of bromocriptine.(102)  The parietal cortex is felt to be devoid of dopaminergic receptors.(141) 
  The mesolimbic and nigrostriatal regions possess presynaptic autoreceptors which function to reduce presynaptic DA release.(151)  At doses greater than 7.5-10 mg/day, postsynaptic DA agonist effects outweigh presynaptic autoreceptor effects,(151) suggesting potential greater psychostimulant efficacy at higher doses and alerting the clinician to the importance of not documenting a failed trial if the patient does not exhibit improved AAI in terms of coma awakening and reversal of the vegetative state at lower bromocriptine doses.
 Bromocriptine has strong(46) anticonvulsant(18,117) properties.  This may be attributable to DA-2 postsynaptic receptor stimulation(46) or to the absence of DA-1 agonism.(46)  Bromocriptine was efficacious in the treatment of akinetic mutism in a patient in whom Sinemet 25/250 QID and methylphenidate 40 mg qd was without significant effect.(102)  With ephedrine, bromocriptine promoted ascension from akinetic mutism in a patient with hydrocephalus.(165)  Bromocriptine also has antidepressant properties(151) and is safe in pregnancy.
 Unlike pramipexole, bromocriptine lacks cytoprotective antioxidant properties.(141) 
 Potential dose dependant side effects requiring monitoring include hallucinations, delusions, headache, dizziness, nausea, dyskinesias, paradoxical sedation, and gastric stasis(33) with increased risks for reflux and aspiration.  Side effects are greater in the elderly, at initial dosing, and with doses greater than 20 mg/day.(151)  Orthostatic hypotension may also occur, and patient blood pressure must be monitored, as cerebral perfusion autoregulation is often dyshomeostatic after CVA and TBI.  Side effects may be less prominent when bromocriptine is ingested with food.(151)  Presyncope and hepatitis may also occur.(33)  It has been suggested that bromocriptine may paradoxically lower the seizure threshold.(50)  Bromocriptine is an ergot derivative and so chronic use may cause pulmonary infiltrates, pleural effusion, or pleural thickening, findings of which may remit towards normal with drug discontinuation.(33)  The percentage of patients who develop these complications is unknown, and a patient receiving bromocriptine for at least 2.5 years has been reported to be free of complications or tolerance.(102)  Dysesthesias(33) and pericardial effusion has also been reported.  Although dystonia has been reported,(33)  bromocriptine may also be used to reverse dystonia.
 Metabolism is hepatic, and so dosing may be decreased in hepatic failure and potentially increased more quickly in patients who are receiving medications which speed hepatic metabolism.
 Half-life of bromocriptine is 7 hours.(33)  Dosing is 2.5 mg po q8AM, q12 PM and increased q3-5 days to a maximum dose of  110 mg BID.(151)  One clinician reported increasing bromocriptine safely over 7 days to 27.5 mg q6 hours.(165)  A triphasic response has been identified with maximal dopamine agonism only at the mid-range doses.(33)  Tablets are available in 2.5 and 5 mg sizes.
 Concomitant dosing of anti-emetics and gastropropulsive agents may diminish symptoms, allowing patients to appreciated the enormous benefits of psychostimulation. 

 Pergolide (Permax) is a DA-2 postsynaptic receptor agonist.(52)  It exhibits some agonism at DA-3, DA-4, alpha adrenergic, and serotonin receptors.(141)  Pergolide is distinct from Bromocriptine in that it exhibits considerable DA-1 agonism.(162)  In Parkinson's disease, this agonism is appreciating more recognition to improve bradykinesia.(162)  In addition, repeated administration of pergolide markedly attenuates dyskinesias.(162)  Pergolide, like bromocriptine, is an ergot derivative, and has risks for iatrogenic causation of pericardial, pleural, and retroperitoneal fibrosis.  Pergolide has less DA-3 agonism than bromocriptine, potentially suggesting a lesser risk of iatrogenic psychosis with pergolide.(162) 
 Pergolide acts on presynaptic autoreceptors to reduce DA release and lower oxidative stress formed as a result of DA metabolism via MAO-B to form hydrogen peroxide.(162) 
 Pergolide strongly protects against seizures,(46) theoretically allowing patients to be tapered from their cognitively offensive anticonvulsants in favor of a cognitively beneficial psychostimulant. 
 Unlike pramipexole, pergolide lacks cytoprotective antioxidant properties.(141) 
 It is available in 0.05, 0.25, and 1 mg tabs.  Initial dosing is 0.05 mg qd or BID with increase in dose by 0.1 mg-0.25 mg q3 days to a maximum dosing 4mg(52) to 6.5 mg qd, usually in 3 divided doses.
 One patient treated by Dr. Geller (yet to be published) was unresponsive to numerous psychostimulants over six months and remained vegetative.  Her Permax dose was increased and after six months of not moving, speaking, or interacting with her husband she abruptly began to speak, smile, and throw a ball two feet back and forth to her husband within two days of a dose escalation of Permax.

 Pramipexole (Mirapex) is a newer non-ergot dopaminergic which exhibits DA3>DA2>DA4  receptor agonism with negligible DA-1 activity.(73)  It exhibits 700% greater DA3 binding affinity relative to its considerable DA2 and DA-4 agonism.(141)  The extent of pramipexole's DA-2 and DA-3 agonism is greater than at both receptor sites relative to bromocriptine.(    )  Mirapex also has alpha-2 and 5HT-1A affinity.(141) 
 Mirapex has very potent antioxidant properties and can even reduce tocopherol.(141)  Investigation for cytoprotective efficacy to ameliorate the cascade of events contributing to secondary injury after CVA and TBI must be defined.  An important concern is the role of DA-3 agonism with respect to treatment of diminished AAI in terms of coma awakening and reversal of the vegetative state. 
 Common potential side effects include orthostatic hypotension, nausea, and constipation.
 It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

 Ropinirole (Requip) is a newer non-ergot dopaminergic. It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

 Selegiline (Eldepryl) is a selective MAO type B inhibitor.  It has exhibited psychostimulant efficacy in Alzheimer's disease.(52)  As with other dopaminergics, selegiline may result in manic behavior.(146)  Initial dosing is 5 mg q7AM or 5 mg q7AM and q12 PM.  At doses of 5 mg po BID it may improve alertness over a 3-6 month period.(1)  It is free of the beer, wine, and cheese potential hypertensive crisis effects of nonselective MAO-A inhibitors.

 Amantadine (Symmetrel) is a 1-aminoadamantane derivative tricyclic amine.(46)  It directly stimulates presynaptic dopamine release(25) and synthesis(82) as well as directly stimulates postsynaptic dopamine receptors.(52)  Others believe that amantadine may alter DA receptor morphology to high affinity states.(29)  If this is so, then the distinct mechanism of action would suggest potential synergism between amantadine and other DA receptor agonists.  Additionally, amantadine reduces presynaptic dopamine reuptake,(29) allowing dopamine to remain liberated in the synapse for a longer time.  It has been suggested that amantadine may also increase the number of dopamine receptors.(25)  The dual pre- and postsynaptic agonism of amantadine suggests that it is a potent agent.  Ability to rapidly titrate dosing makes amantadine an attractive option to enhance AAI.  Antiseizure efficacy has been described at low doses of 100 mg BID, whereas proconvulsant properties may dominate at higher doses.(64)
 It has exhibited efficacy as a psychostimulant(25,28,64,82,84,92,107,122) with additional capacity to enhance arousal,(64) attention,(64) and memory,(25,28) attenuate mutism,(64) and selectively extinguish disinhibited behavior.(64,87)  Amantadine may also improve appetite,(92) posttraumatic tremor,(29) and rigidity and bradykinesia.(25)  Benefit has been reported in patients with TBI(28,107,122) stroke,(122) and Alzheimer's dementia.(82,122)
   Side effects include dose dependent agitation, anxiety, delusions, hallucinations, hypomania, dysarthria, mood depression, paradoxical lethargy,(64) dependent edema, and irritability.(64)  Amantadine may cause livedo reticularis as peripheral DA is released.(29)  Some clinicians report that amantadine is desirably unique amongst the pre- and post-synaptic dopaminergic psychostimulants in that it does not have the potential for paradoxical sedation.(    )  Though anticonvulsant properties have been described(66,82) in up to 3% of patients,(75) seizures on 200 mg po BID may resolve with decreased dosing at 100 mg po BID.(25)  Proconvulsant(29,43,64,66) side effects of amantadine have also been described, and the clinician may harbor some reluctance to deliver trials in patients who are receiving neither prophylactic anticonvulsants nor monitoring in the inpatient setting, especially in individuals with penetrating brain injury or other significant risk factors for seizures.  As an influenza antiviral used in hundreds of thousands of people, amantadine has been proven to be a very safe agent.
 Clearance of this agent is mediated by the kidney, and 90% of the drug is excreted unchanged in the urine.(32)  Drug half-life is 9.7(32)-16(29) hours, but 8 days in patients receiving hemodialysis.(32)  Amantadine induced coma,(32) psychosis,(101) and torsade de pointes ventricular arrhythmia(124)  may occur if the clinician does not increase the dosing interval in patients with severe renal failure. 
 Amantadine is available as 100 mg capsules, and can be given as 50 mg po q7AM and q12PM.  Peak plasma levels are achieved within 1-4 hours of ingestion,(64) and steady state is achieved within 48-72 hours,(82) so dose can be advanced q4 days to a maximum of 200 mg po q7AM and q12PM.  Onset of therapeutic action is within 4-7 days of each dose increase, and the drug should be discontinued if no distinct benefit is identified within 6 weeks of drug initiation.(64)  Onset of effect to enhance AAI is usually within 1-7 days,(28) but peak beneficial effect may be realized only after 10 days,(82) presumably reflected responsive subcellular anatomic receptor changes.  The potential for rapid upward titration of dose relative to other dopaminergics is another distinct benefit of amantadine. 

 Rimantadine (Flumadine) is available in 100 mg tabs described as having a superior side effect profile relative to the first generation drug amantadine.  It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

 Apomorphine is a direct dopamine agonist(102) which merits further investigation as a psychostimulant.

 Bupropion (Wellbutrin) is a aminoketone antidepressant that improves attention that is relatively free of anticholinergic effects.  Less orthostatic hypotension and tachycardia may accompany its use relative to tricyclic antidepressants.  It is hypothesized that it may exert its psychostimulant effect via enhancement of dopaminergic transmission.(52)  Seizure risk is a very low 0.4%(71), but at doses greater than 450 mg qd it has proconvulsant properties.(4)  Dosing is 75-150 mg po BID. It remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.

 Carbidopa/levodopa (Sinemet).  Carbidopa is a peripheral DA decarboxylase inhibitor which diminishes peripheral levodopa conversion to bioactive DA.  Levodopa subsequently enters the brain and is metabolized within the neuron to DA.  L-dopa stimulates DA-1 and DA-2 receptors indirectly by releasing endogenous dopamine.(46)  L-dopa has been described as a blunt pharmacologic tool, as it enhances dopamine activity at all sites in addition to being biotransformed to DA and then to noradrenaline.(46)  If the brain is unable to synthesize its own DA then providing exogenous substrate may compensate for diminished post-insult biosynthetic capacity.  This is undesirable in light of its lack of selectivity towards minimization of side effects, but potentially welcome in terms of its global activity at all DA receptors which may enhance AAI to treat coma awakening and reversal of the vegetative state. 
 If intracellular enzymatic biosynthetic machinery is intact, then the additional enormous potential benefit of  biotransformation of DA substrate to noradrenaline is also invaluable.  Presynaptic damage to the anterior medial forebrain bundles after separation of the nigrostriatal tract may suggest that biosynthetic capacity is compromised, and direct DA postsynaptic agonists may be more efficacious.(102)  This assertion may be as premature, however, as is the ridiculous contention that MRI or CT scan may predict candidacy for psychostimulant trials.  Presynaptic neuronal down-regulation in response to Sinemet with consequent inefficacy has also been suggested.(98)  If this is experimentally proven to occur, then it may suggest superiority of postsynaptic receptor agonists.  It has also been suggested that Sinemet may functionally activate dormant cells, resulting in new neural pathways.(69)  It remains to be proven if Sinemet exhibits greater efficacy with more extensive intracranial lesions in which dopaminergic activity is diffusely compromised.
 Sinemet has exhibited efficacy as a psychostimulant in TBI.(69,76,166)  It has improved alertness,(98) initiation for movement, disinhibited violence and emotional lability, sialorrhea, hypertension, comprehension, and conversation in patients within 18 months of head injury.(69)  Within 3 days of initiation of treatment with Sinemet, a patient who had been in a vegetative state for 6 months ascended to a higher level of consciousness.  A few days later he stated his mother's name, and months later he was independent in basic activities of daily living with independent wheelchair propulsion and subsequent discharge to home with his family.(22)  Akinetic mutism has also been reported by others to respond to Sinemet.(166)  It has been suggested that individuals treated closer in time to their head injury may respond to a greater extent.(69)  L-dopa may also have antidepressant properties.(151) 
 Delivery to patients on dialysis may require vitamin B6 supplementation to avoid Sinemet induced B6 deficiency induced secondary epilepsy.(62)  The risk of Sinemet induced seizures is low, but may occur 6 weeks to 2.5 years after drug initiation.(63)  Although L-dopa has been reported as protective against seizures,(97) it has also been suggested that DA-1 agonism enhances seizure predisposition,(46) and the nonselective effects of L-dopa may potentiate seizures in high risk patients, especially if they are not on anticonvulsants.  Similarly, DA-2 receptor antagonists are used to treat psychosis,(46) so L-dopa stimulation of all DA receptor sites in the absence of agents which may selectively block DA-2 receptors may be a concern in patients with premorbid histories of schizophrenia or other psychiatric conditions with psychosis. 
 Sinemet may cause nausea, hypotension, dyskinesias, sedation, and delirium.  The pro-oxidant properties of Sinemet(162) must also be further investigated with respect to potentiating the deleterious cascade following TBI and stroke.  
  Initial dose is one 10/100 tab po q7AM, q12 AM.  Patients may respond as early as 48 hours after initiation of treatment.  The dose can be increased every 4-7 days to a maximum of Sinemet 25/250 eight tabs a day in four divided doses. 
 Sinemet CR is a controlled release formulation of carbidopa/levodopa, and has been explored favorably in Parkinson's disease to increase motor "on time" without dyskinesias.(147)  However, it also exhibited a disappointing slower response to initial morning dosing, reflecting peak blood levels two hours after morning ingestion as opposed to one hour for the normal release formulation.(147)  The extended release formulation remains to be investigated as a psychostimulant. 

 COMT - inhibitors include tolcapone (Tasmar) and entacapone (Comtan).  Levodopa can be metabolized centrally to DA or it can be metabolized peripherally, decreasing bioavailability by preventing levodopa from access to centrally depleted sites to serve as a psychostimulant for coma awakening and reversal of the vegetative state.  Peripheral bioconversion via dopa decarboxylase may be prevented with carbidopa, and conversion via catechol-o-methyl-transferase can be blocked by (COMT) inhibitors.  Addition of COMT inhibitors to Sinemet may enhance delivery of DA to the brain and decrease peripheral side effects.  Stalevo is a single pill combination of carbidopa, levodopa, and entacapone.

 Modafinil (Provigil) is FDA approved to treat narcolepsy.  It is not an amphetamine, and is an exciting potential new dopaminergic agent which remains to be investigated to facilitate coma awakening and reversal of the vegetative state.  Modafinil's novel pharmacology is exciting as its mechanism is distinct from previously available agents, acting not via altering the release of dopamine or norepinephrine.(160)  An intact alpha adrenergic system, however, is necessary for modafinil to exert its wake promoting activity.(160)  The absence of sympathomimetic properties makes this agent particularly desirable in the elderly and in individuals with cardiac dysrhymthmias or coronary artery disease.  It is available in 100 mg tabs to be delivered as 100-200 mg po BID at q 7AM, q12 PM.  Considerably higher doses have proven safe in non-FDA approved uses, and high doses may be required to address coma awakening and reversal of the vegetative state. 
DA is present in most parts of the CNS in four dopaminergic pathways: nigrostriatal system, mesolimbic system, mesocortical system and tuberoinfundibular system.

 Carbamazepine (Tegretol) is most commonly characterized as being mildly sedating, but it may have some limited efficacy to enhance AAI.(41)  Tegretol may exercise its clinical effect via its ability to facilitate dopamine agonists, reduce dopamine turnover, and enhance presynaptic dopamine release.(46) 
 Tegretol has an incidence of bone marrow suppression is 1:40,000 - 1:125,000.(61)  "It is not at all clear that carbamazepine is likelier than valproate... to cause agranulocytosis or thrombocytopenia."(4)  Risk of severe blood dyscrasias is similar for phenytoin and carbamazepine,(132) amd so a CBC with differential needs to be followed.  Because of these potentially lethal side effects, carbamazepine should be prescribed for its anticonvulsant, analgesic, anti-bipolar disorder properties, but not for the indication of enhancing AAI.  A “safer, newer carbamazepine” has been released in the form of oxcarbazepine (Trileptal).

MEDICATIONS – Tricyclic Antidepressants (TCA's)
 TCA's enhance AAI by inhibiting presynaptic terminal norepinephrine reuptake from the synaptic cleft, thereby increasing the exposure of the postsynaptic membrane to the stimulating effects of the neurotransmitter.  Norepinephrine is felt to be the critical neurotransmitter promoting recovery after brain damage,(15) but studies still must be designed to identify if TCA's share the beneficial properties of amphetamines(38) in potentiating recovery. 
 A baseline ECG may be obtained prior to starting TCA's, as torsade de pointes ventricular dysrhythmia has been reported with heterocyclic antidepressants.(40) 
 Side effects of strongly noradrenergic TCA's to monitor include anticholinergic induced urinary retention secondary to increased smooth muscle alpha noradrenergic mediated tone, and confusion.  TCA's with potent anticholinergic properties may cause confusion and impair memory as well as relax detrusor contractility and predispose to urinary retention.  Similarly, anticholinergic mediated vagal blockade may cause tachycardia in excess of coronary perfusion capacity in patients with coronary artery disease, causing myocardial ischemia.  Though not a TCA, the antidepressant trazodone may impair motor recovery or temporarily reinstate paralysis in patients with acquired brain injuries, and this is felt to be alpha mediated.(    )  Proconvulsant properties of TCA's are dose dependant and felt to occur with an incidence of less than 1%.(78)  Other sources report a proconvulsant range of 0.1-1%.(71)  Maprotiline is a semi-tetracyclic antidepressant with a high incidence of seizures at doses greater than 225 mg/day.(78)  Amoxapine is associated with adverse extrapyramidal side effects as well as a high incidence of seizures relative to TCA's.(78)  The risk for seizures is 2.2% for tricyclic antidepressants in general, and .7% for imipramine.(81)
 TCA's which are more selective towards noradrenergic agonism with minimal anticholinergic, alpha antagonistic, and antihistamine properties are most desirable as psychostimulants.

  Amitriptyline (Elavil), within several days, 50 mg po qd improved motor and speech initiation after several months of plateau.(15)  This may suggest a fundamental role of serotonergic deficiency in responsive patients, as amitriptyline, relative to protriptyline, has approximately 4% of the noradrenergic stimulant properties, similar stimulating dopaminergic activity, 265 times as much sedating antihistamine activity, but 400% of the seratonergic agonism.(   )  This is speculative, and the etiology of amitriptyline's psychostimulant efficacy remains indeterminate.  If the etiology of a patient's suboptimal AAI is that of serotonergic system dysfunction, then amitriptyline may be a efficacious agent. 
 Amitriptyline has potent antihistaminergic properties which are often sedating and anticholinergic properties which predispose to urinary retention via detrusor relaxation.  It also has alpha antagonist properties which may predispose to urinary retention via internal urethral sphincter stimulation and to delayed neurologic healing in brain pathology.(   )   As with other tricyclic antidepressants, Elavil has potential proconvulsant properties.

 Imipramine (  ) can be given up to 300 mg qd.(57)   Imipramine is a nonselective monoamine reuptake inhibitor.(46) 

MEDICATIONS - SEROTONERGICS
 SSRI's improve AAI by interfering with presynaptic neural reuptake of serotonin.  The effect is within 1-3 days, in contradistinction with antidepressant efficacy and receptor protein synthesis alteration which takes 1-2 weeks.  However, serotonin has inconsistent effects on arousal.(52)  Many patients are aroused, but more are paradoxically sedated relative to noradrenergics or dopaminergics.  This most likely reflects the nonselectivity of currently available agents in terms of serotonin receptor subtype agonism and antagonism.  Over eleven distinct serotonin receptors have thus far been identified.(      ) 
 The risk for SSRI induced seizures is low, but secondary cytochrome P450 inhibition may enhance the levels of concomitantly delivered tricyclic antidepressants, increasing the risk for seizures.(78)  It is a safe drug in patients with cardiovascular disease, a benefit in the elderly in whom the clinician may have reservations regarding prescription of noradrenergics such as dextroamphetamine or the tricyclic antidepressants.  Anorexia is not uncommon after SSRI's are delivered.  It remains to be investigated whether Megace and other appetite stimulants are efficacious to afford continued SSRI delivery when psychostimulation is achieved.
 SSRI's may rarely induce extrapyramidal side effects,(4) including tardive dyskinesia,(    ) akathisia,(     ) and bradykinesia.(    )

 Fluoxetine (Prozac) dose is 10 mg po qAM.  Max. dose is 80 mg po qd.(55)  Effects may be seen very quickly, within 3-14 days.(5,8) 


MEDICATIONS - MONOAMINE OXIDASE (MAO) INHIBITORS
 Nonselective MAO inhibitors strongly impair MAO-A and B from oxidatively inactivating norepinephrine, dopamine, and serotonin neurotransmitters after presynaptic reuptake.(96)  Efficacy to enhance attention and memory(109,114) has been appreciated.  The immediacy of effect, in contrast to the delayed antidepressant properties, argues against a role for receptor alteration.(109) 
 A benefit of using MAO inhibitors is their anticonvulsant properties.(78)  Patients who have exhibited idiosyncratic allergy to dextroamphetamine and other classic psychostimulants may be optimal candidates for trials with MAO inhibitors.  These agents may also be beneficial in the patient with baseline hypotension who may not tolerate dopaminergic agonists.  The nonselective diffuse increase in multiple biogenic amines suggests that these agents may be viable options in patients who demonstrate unresponsiveness to traditional psychostimulants. 
 The undesirable aspect of utilizing MAO inhibitors is the potential for hypertensive crisis if beer, wine, cheese, or other tyramine containing substances are ingested.  These medications should be used with great caution if sympathomimetics are also being delivered.  This suggests that delivery of MAO inhibitors may need to be reserved for use in the inpatient setting if compliance with strict dietary restrictions is not a realistic expectation.
 Tranylcypromine (Parnate) and phenelzine (Nardil) are MAO options.  Tolerance to psychostimulation is rare, but may occur.(109) 


MEDICATIONS - CHOLINERGIC AGONISTS
 Physostigmine, an anticholinesterase inhibitor, has been used to reverse intrathecal baclofen overdose induced coma.(67) 
 Donepezil (Aricept) is a piperidine derivative reversible acetylcholinesterase inhibitor.
 Rivastigmine (Exelon) is a carbamate derivative reversible acetylcholinesterase inhibitor.
 Galantamine (Reminyl) is a benzazepine derivative reversible acetylcholinesterase inhibitor.
 Though cholinergic agonists clearly enhance memory after TBI or stroke, this class of medications  remains to be fully investigated for utility for coma awakening and reversal of the vegetative state.  As each medication is derived from a different parent compound and has a different molecular structure, each has different efficacy based on each patient’s individual receptor profile and morphology, reflecting genetic diversity.

MEDICATIONS - ATYPICAL AGENTS

 Valproic acid(4) is an anticonvulsant which usually have mild sedating properties but occasionally has paradoxical potential to enhance AAI.

 Flumazenil has treated hepatic encephalopathy and benzodiazepine intoxication.(80)  It may or may not have efficacy for coma awakening and reversal of the vegetative state. 



EVERY PATIENT DESERVES A CHANCE!!!