BRAIN INJURY, 1988, VOL. 2, NO. 4, 309-311

Case studies

Amantadine for the agitated head-injury patient

M A R K C . C H A N D L E R , M . D . , J A R R E T T L . B A R N H I L L , M . D . and C . T H O M A S G U A L T I E R I , M . D .

Rebound, Inc., and the Neuropsychiatry Research Program, Biological Sciences Research Center, Department of Psychiatry, University of North Carolina, USA

Traumatic brain injury may be associated with agitated aggressive behaviour and the potential for injury to the patient and staff. We report two cases ofrecovering brain injury patients with dificult-to- treat destructive behaviour, whose agitation and aggression responded to amantadine. Direct-acting dopamine agonists such as amantadme may be the preferred treatment for patients with behaviour problems in the acute stages of recovery from coma.

There are not many treatment alternatives for the agitated, assaultive, disorganized head- injury patient who is recovering from coma. More precisely, there are a number of medications to choose among-carbamazepine, lithium, benzodiazepines, antihistaminics, beta-blockers-but therapeutic effect is not always predictable. All too often, physicians are compelled to prescribe neuroleptics [ 11. Neuroleptics are reliable tranquillizers in such circumstances, at least over the short term; but they may result in serious side-effects (extrapyramidal reactions, cognitive blunting, temperature disregulation); and there is preclinical evidence to suggest that dopamine antagonists may retard the course of cortical recovery 121.

We have observed that the direct-acting dopamine agonist, amantadine, may sometimes be useful for the acute management of such patients. The fact that dopamine agonists may actually enhance the course of cortical recovery [2] suggests that amantadine may be a rational treatment for the recovering brain-injured patient [l].

Case one, J.

A 30-year-old white male was comatose for 3 weeks following a motor vehicle accident on 14 April 1986. He sustained a right frontal skull fracture, a left frontal haemorrhagic contusion, a slight midline shift of the left hemisphere with partial effacement of the left lateral ventricle as well as several small areas of injury to the right temporal lobe. He required ventriculostomy for drainage of a left frontal hygroma. When admitted to our rehabilitation service on 13 May 1986 he was making purposeful movements with his upper extremities and he could sit up, but could not follow verbal commands. Over the next 7 months he recovered nicely, he could walk, dress with assistance and make appropriate one- word responses. But he was given to episodic agitation, with violent behaviour outbursts lasting as long as 1 hour. A trial of carbamazepine (to serum levels of 10mg/ml) was ineffective. Treatment with amantadine was begun on 5 August 1987 with gradually

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310 M. C. Chandler et al.

increasing doses to 400mg/d. The agitated behaviour resolved almost as soon as the medication reached that dose, and the patient's recovery proceeded at an entirely satisfactory pace. On 1 September 1987 he was discharged to a transitional living facility, where he has continued to progress, with only two subsequent episodes of aggressive behaviour, when his amantadine dose was lowered to 200 mg/d. He had one seizure on a trip home after drinking alcohol.

Case two, S.

A 43-year-old white male who was in coma for 2 months following a motor vehicle accident on 17 July 1987. He sustained a right temporal haematoma which required craniotomy. There was a right frontal fluid collection, and left frontal and bitemporal contusions. He was admitted to our rehabilitation service on 27 October 1987. Although his physical recovery was uneventful, and he could walk briskly and spoke clearly, though hesitantly, his behaviour was extremely difficult, with agitation, violent assaults on staff, destructiveness, non-compliance, emotional lability and wandering. Several psychotropic drugs were administered, serially, in attempts to control this behaviour: neuroleptics, Valium, lithium and carbamazepine.'None was to any avail, however, except for lithium, which was extremely effective; but then he developed severe polydypsia and the medication had to be discontinued. The violent behaviours promptly returned. With amantadine, 400 mg/d, the agitation and violent behaviour cleared rapidly, he became co-operative with therapists and even helpful with other patients who were more physically impaired than he.

Conclusions

Amantadine seemed to exercise dramatic, positive effects on agitated and assaultive behaviour in two patients recovering from closed-head injury. Neither had responded to previous treatment with conventional treatments. If this finding is affirmed in subsequent investigations it will be useful, clinically, and interesting, theoretically. Although there have been previous reports of dopamine agonist treatment in schizophrenic [3] and manic patients [4], this may be the first report of successful treatment with amantadine for agitation following recovery from coma and closed-head injury.

Amantadine is a tricyclic water-soluble amine salt which affects the synthesis, accumulation, release and re-uptake of catecholamines in the central nervous system. It is usually prescribed as an antiparkinsonian agent, as a treatment for neuroleptic-induced extrapyramidal symptoms, and as an antiviral agent. It is rapidly absorbed, but it is not metabolized and is almost completely excreted by the kidney. In animals it is known to have a slight anticonvulsant effect, and it may enhance seizure control in humans [5]. In this regard it resembles other dopamine agonist drugs [6].

Since two case reports are by no means compelling evidence for clinical efficacy, it may be premature to speculate on the mechanism of drug action in cases such as this. Nevertheless, it is reasonable to propose that postsynaptic dopamine receptor stimulation is central to the putative psychotropic effects of amantadine. Indirect-acting dopamine agonists like methylphenidate are known to improve behavioural symptoms in head-injury patients whose recovery is further advanced than the two cases described here [7]. In patients in the acute stage of recovery from coma, or whose recovery suggests brain stem or midbrain dysfunction, a postsynaptic dopamine agonist may be the preferred treatment [8]. Such drugs are known, for example, to reduce septa1 rage in animal models [9]. Amantadine has a favourable toxicity profile, compared to the usual pharmacological alternatives, and it deserves further investigation as a potential treatment for brain-injury patients.

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Amantadine and aggressive behaviour 31 1

References

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2. FEENY, D. M., GONZALEZ, A. and LAW, W. A.: Amphetamine, haloperidol and experience interact to affect rate of recovery after motor cortex injury. Science, 217: 855-857, 1982.

3. JANOWSKY, D. S. and DAVIS, J. M.: Dopamine, psychomotor stimulants and schizophrenia: effects of methylphenidate and the stereoisomers of amphetamine in schizophrenics. In Usdin, E. (ed.), Neuropsychopharmacology of Monoamines and their- Regulatory Enzymes, Raven Press, New York, VD. 317-323. 1974.

4. KULCSAII, 1:s.: Amphetamine sulfate in mania. Lancet, 1: 1164, 1966. 5. SHIELDS, W. D., LAKE, J. L. and CHUGANI, H. T.: Amantadine in the treatment of refractory

6. LIVINGSTON, S.. KAJDI, L. and BRIDGE, E.: The use of benzerine and dexedrine sulfate in the

7. EVANS, R. W. and GUALTIERI, C. T.: Stimulant treatment for the neurobehavioural sequelae of

8. Ross, E. D. and STEWART, R. M.: Akinetic mutism from hypothalamic damage: successful

9. MAROITA, €2. F., POTEGAL, M., GLUSMAN, M. et al.: Dopamine agonists induce recovery from

epilepsy in childhood: an open trial in 10 patients. Neurology, 35: 579-581, 1985.

treatment of epilepsy. journal of Pediatrics, 32: 490-494, 1948.

traumatic brain injury. Brain Injury, 2 273-290, 1988.

treatment with dopamine agonists. Neurology, 31: 1435-1439, 1981.

surgically-induced septa1 rage. Nature, 269 (6): 513-515, 1977.

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